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juniperpublishers-crdoj · 11 months

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Low Grade Chronic Inflammatory Response in Pathogenicity of Diabetes Mellitus

Authored by Shamim Shaikh Mohiuddin

Abstract

Acute phase reaction which is mainly cytokine-mediated is observed to be closely involved in the pathogenesis of type 2 diabetes. Since maximum world populations are at elevated risk of developing diabetes, we tested this hypothesis by estimating circulating acute phase proteins in type 1(T-1), type 2 (T-2) diabetic patients and type 2 diabetic patients under oral hypoglycemic drugs for duration of at least 5 years.

The acute phase proteins, α1- antitrypsin, α1- acid glycoprotein, ceruloplasmin and fibrinogen were estimated in the plasma in newly diagnosed 12 T-1 cases, newly diagnosed 25 T-2 cases and 25 T-2cases under oral hypoglycemic agent for at least 5 years Thirty normal controls to match the age and sex of the test groups were also studied. The levels of these proteins were correlated with their BMI and random plasma glucose values.

In comparison with the controls, the values of all the four proteins studied were significantly elevated in T-1 patients and T-2 patients (p<.00001) and reduced significantly except α1- acid glycoprotein and ceruloplasmin. Interestingly, no correlation was found with BMI or the degree of hyperglycemia in either of the types. A low grade inflammatory process is definitely implicated in the pathogenesis of type 2 diabetes and even type 1 diabetic patients. This line of pathological basis should be further explored for diagnosis, management and follow up.

Keywords: Chronic inflammation; Diabetes mellitus; Acute phase reaction

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Introduction

Diabetes Mellitus is a syndrome with disordered metabolism and inappropriate hyperglycemia due to either deficiency of insulin secretion or to a combination of insulin resistance and inadequate insulin secretion to compensate [1]. Although hyperglycemia is the main characteristic of all form of diabetes mellitus, the pathogenic mechanism by which hyperglycemia arises differs widely. Some forms of Diabetes mellitus are characterized by an absolute insulin deficiency or a genetic defect leading to defective insulin secretion; where as other forms share insulin resistance as their underlying etiology [1]. Recently, there in increasing evidence that an ongoing cytokine induced acute phase response which is sometimes called low grade inflammation, but part of a widespread activation of the innate immune system, is closely involved in the pathogenesis of type 2 diabetes mellitus and associated complications such as dyslipidemia and atherosclerosis. Elevated circulatory inflammatory markers such as C-reactive protein and interleukin-6 predict the development of type 2 Diabetes mellitus and several drugs with anti-inflammatory properties both lower both acute phase reactants and glycemia and possibly decrease the risk of developing type 2 diabetes mellitus. Age, inactivity, certain dietary components, smoking, psychological stress and low birth weight are among the risk factors for type 2 diabetes mellitus, which are also known to be associated with activated innate immunity. Activated immunity may be the common antecedent of developing type 2 diabetes mellitus [2].

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Material and Methods

Study design

Following four groups of subjects were selected for present study:

A. 12 newly diagnosed untreated type 1 diabetes mellitus patients

B. 25 newly diagnosed untreated type 2 diabetes mellitus patients within the age limit of 30-60 years

C. 25 type 2 diabetes mellitus patients who are under treatment of oral hypoglycemic drugs for at least 5 yrs between the age limit of 30-60 yrs.

D. 30 nondiabetic healthy controls.

Height and weight of all subjects were recorded, and body mass index was calculated. None of the ninety-two volunteers were alcoholics or smokers. The participants did not suffer from chronic inflammatory diseases like asthma, chronic bronchitis, and rheumatoid arthritis as was ascertained by clinical history. Informed consent was taken from the individual subjects prior to blood collection. The study was approved by institutional ethical committee.

The following methods were followed for determination of each of the parameters.

Blood glucose estimation

Blood glucose was estimated with Agappe manual diagnostic kit by GOD-POD methodology. The enzymatic procedure of Trinder P was followed [6]. Glucose is oxidized by glucose oxidase to gluconic acid and H2O2. Hydrogen peroxide in presence of phenol and 4-amino antipyrine is acted upon by peroxidase to form red quinine. The absorbance of colored compound was measured at 532nm.

Fibrinogen assay

Fibrinogen assay in plasma was carried out by Biuret method [7]. Fibrinogen present in the plasma is converted to fibrin in presence of calcium chloride. The fibrin clot formed is collected and then digested with NaOH. Protein content of the clot is determined using a red filter. 0.5ml of plasma was mixed with 14 ml of distilled water and 0.5ml of 2.5% calcium chloride solution in a small beaker and incubated at 37ºC until a clot was formed. Then a glass rod was rotated to collect the clot on to it. The rod was pressed against the side of the beaker to squeeze out any solution and to compress the clot. Care was taken to pick up any small piece of clot on the rod, which may have become detached and was dried by pressing carefully against a filter paper. Then it was transferred into a test tube into which the digestion was to be carried out.

After that, the clot was digested with 0.5ml of 0.1N NaOH in a boiling water bath. After cooling, 3.5ml of working Biuret reagent was added to the tube. The OD of the blue color developed was read at 555nm after standing the tube in a water bath at 37 °C for 5minutes. 0.5ml of standard protein solution (800mg/dl) and 0.5 ml of distilled water as blank were treated similarly.

Estimation of serum ceruloplasmin

Ceruloplasmin assay in serum was carried out by the method of Sunderman et al. [8]. At pH 5.4, ceruloplasmin catalyzes the oxidation of PPD to yield a coloured product which is believed to correspond either to Bandrowski’s base or to Weurster’s red. The rate of formation of colored oxidized product is proportional to the concentration of ceruloplasmin, if, a correction is made for the nonenzymatic oxidation of PPD. Therefore, simultaneous assay were carried out with and without sodium azide, which inhibited the enzymatic oxidation of PPD. The difference between the results of the two assays is proportional to ceruloplasmin concentration.

Estimation of α1-antitripsin

α-1 antitrypsin assay in serum was carried out by the modified method described by Sundaresh et al. [9]. The Proteolytic enzyme trypsin hydrolyses casein, with the formation of smaller peptides. The enzyme reaction after suitable interval of time is arrested by the addition of TCA which precipitated the protein, but the peptides are soluble in the acid. The TCA soluble fragments are a measure of Proteolytic activity of the enzyme. When the inhibitor is added to the preincubated mixture, it prevents the release of peptides by the Proteolytic enzymes. Thus, the estimation of TCA soluble components in the presence and absence of inhibitor is a measure of inhibitory activity against Proteolytic enzymes. The TCA soluble fragments are analyzed by the method of Lowry. The final color formed is a result of Biuret reaction of the peptides with copper ions in alkali and reduction of the phosphomolybdic acid reagent by the presence of tyrosine and tryptophan which are present in the treated peptides.

Determination of serum α-1 acid glycoprotein

α-1 acid glycoprotein assay in serum was carried out by the method of Winzler RJ et al. [10]. After removing heat coagulable proteins with perchloric acid, the orosomucoid which remains in the solution is precipitated by phosphotungstic acid and estimated by determining it carbohydrate content by reaction with an orcinol-sulphuric acid reagent, or its nitrogen by Kjeldahl nesslerization or its tyrosine content using FolinCiocalteau reagent.

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Result

The anthropometric data of the subjects participated in the study are presented in Table 1.

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Discussion

The aim of this study was to examine inflammation as a pathogenetic causeof type 2 diabetes mellitus. Twenty-five type 2 newly diagnosed patients showed increased levels of α1- antitrypsin, α1-acid glycoprotein, ceruloplasmin and fibrinogen. The findings were in agreement with most of the authors who worked with acute phase proteins in type 2 diabetes [11-13]. The role of chronic low-grade inflammation in the pathogenesis of type 2 diabetes seems possible beyond doubt. The course of the disease and resulting complications are similar in both type 1 and type 2 diabetes. The most dreaded complication being that of development of atherosclerosis resulting in cardiovascular diseases. Fibrinogen is identified as an independent risk factor in the development of ischemic heart diseases [14]. Irrespective of the patients being type 1 or type 2, the risk of developing atherosclerosis remains the same. Hence there must be some mechanism which links the pathogenecity of type 1 and type 2 diabetes. Barrazzani et al. [15] infused insulin to non-diabetics, type 1 and type 2 diabetics and studied its role in fibrinogen production. Insulin replacement activity suppressed fibrinogen production in non-diabetics and type 1 diabetic individuals.Fibrinogen production and its plasma concentration increased in insulin resistant type 2 diabetics when euglycemia and euaminoaciduria were maintained. They postulated that an altered response to insulin causes hyperfibrinogenemia in type 2 diabetic patients. If this hypothesis holds well, it doesn’t explain hyperfibrinogenemia in type 1 diabetics where the basic pathology is insulin deficiency. Hence there must be some other factors which stimulate increased fibrinogen synthesis in type 1 patients contributing to cardiovascular disease risk. An insulin resistance syndrome score [16] was developed based on clinical risk factor in patient with type 1 diabetes and validated using euglycemic-hyperinsulinemic clamp studies. Fibrinogen levels were significantly associated with this insulin resistance syndrome score. This may explain high fibrinogen level in type 1 diabetes. But it still does not answer the above findings since the type subjects in this study were newly diagnosed. Hence the mechanism of increased fibrinogen synthesis needs to be proved further.

Group I: Type 1 diabetes mellitus patient (newly diagnosed)

Group II: Type 2 diabetes mellitus patient (newly diagnosed)

Group III: Type 2 diabetes mellitus patient (under treatment for at least 5 years)

Group IV: Control

n =Number of Subjects; SD: Standard Deviation; BMI: Body Mass Index

Ceruloplasmin is known to have antioxidant action [17]. It is also an acute phase protein with a response of intermediate magnitude. Ceruloplasmin is known to stimulate cell proliferation and angiogenesis [18]. The higher levels of ceruloplasmin in both in type 1 and type 2 as compared to controls may be due to an oxidative stress that is prevalent in both types of diabetes [19,20]. Ehrenwald [21] showed a very interesting feature of ceruloplasmin. The intact human ceruloplasmin which is 132 KD molecules caused increased oxidation of LDL in vitro. Starkebaum & Harlan et al. [22] also showed that increased serum ceruloplasmin could generate excess oxidized LDL, and cause vascular injury by generating free radicals such as hydrogen peroxide [22]. These findings defined the earlier notions of the antioxidant activity of ceruloplasmin. By further investigations Ehrenwald et al. [21] found that the holoceruloplasmin, which is seen in serum as a 132KD molecule, has a prooxidant effect and the action was attributed to the copper ions present in ceruloplasmin. The commercially available ceruloplasmin is a degraded product containing either 115KD fragment or 19KD fragment or both. These had an antioxidant effect. The works done to show that ceruloplasmin as an antioxidant used these degraded products. The antioxidant action of a commercial ceruloplasmin was observed even in the system where holoceruloplasmin oxidized LDL [23]. Hence considering ceruloplasmin as an antioxidant in vivo is debatable. The LDL oxidizing action of ceruloplasmin could probably explain at least in part of the increased risk of IHD in both type 1 and type 2 diabetes. Also, it could not be wrong to count ceruloplasmin as an acute phase reactant whose levels are increased in both the types of diabetes.

The values of various parameters when compared between the untreated type 1 patients and type 2 patients reveals a significant increase in type 2 patients. Even the ceruloplasmin values, although not statistically significant, were slightly higher in the type 2 patients. The mean random blood sugar (RBS) values in group 1 (Type 1 diabetes) patients was 338.25±50.97mg/ dl and that of group II (Type 2 newly diagnosed diabetics) was 193.26±35.30mg/dl. Despite this huge difference, the inflammatory markers levels were higher in the type 2 patients which go to prove that the glycemic status doesn’t influence the inflammatory markers. This is in accordance with previous findings [24,25]. Evidence is available to say that inflammatory markers are elevated well before the clinical manifestation of hyperglycemia [26-29]. This also gives credence to the thought that activation of innate immunity is not related to hyperglycemia. But research has shown that decreasing plasma glucose levels decrease the concentration of acute phase reactants [30]. Also 2 hrs post load glucose values showed positive correlation with the inflammatory markers in few studies. α1-acid glycoprotein levels remained within normal limits in the type 1 patients whereas significant high levels were seen in the type 2 patients ( p<0.0001). Although both type 1 and type 2 patients showed significant high α1-antitrypsin levels, the comparison between two groups also reached statistical significance (p =0.003) with higher values in type 2 patients. The above findings can be best explained as insulin mediated increased synthesis of the hepatic proteins.

The underlying mechanism for the augmented acute phase response is not well understood and the stimulus for the response is unknown. Many hypotheses have been put forward and these include insulin resistance, obesity, atherosclerosis, other diabetic complications and maladaptation of the normal innate immune response to environmental threats [31-33]. The most widely studied is the association of obesity, insulin resistance, type 2 diabetes and acute phase reactants. It has been shown that adipocytes secret many proinflammatory cytokines in the postprandial state [34-36]. The term ‘diabecity’ has received attention [37] of late for obese diabetics. The ‘common soil’ theory proposed, evaluates the involvement of inflammation in the pathogenesis of diabetes and atherosclerosis. Hyperglycemia and insulin resistance could promote inflammation and inflammation may be a factor linking diabetes mellitus to the development of atherosclerosis. Elevated glucose levels promote inflammation by increasing oxidative stress [38], by the formation of AGEs and increased TNF (kappa B) [39]. In this study, the mean BMI was found to be 19.5±1.23 in type 1 patient and 24.03±1.46 in type 2 patients. No correlation was found between BMI and acute phase reactants. Hence it can be summarized that there could be multiple pathways involved in the activation of the innate immunity system and much work needed to be done to establish either a casual role in the development of mainly type 2 diabetes and could be type 1 diabetes also.

Having demonstrated that there is an inflammatory process going on in type 2 diabetes, we next thought of estimating inflammatory markers in patients on treatment (for at least 5 years) with oral hypoglycemic drugs. Many of the drugs have been shown to have anti-inflammatory effects. Statin drugs inhibits HMG-CoA reductase and prevent atherosclerosis and inhibit the acute phase response by diminishing the deposition of LDL particles rich in cholesterol and phospholipids in macrophages and smooth muscle cells [40]. Statins were found to reduce CRP levels and did not correlate with the reduction of the lipid levels suggesting that the in addition to their ability to reduce LDL, statins may also inhibit the acute phase response [41]. Freeman et al. [40] showed that statin therapy also prevents diabetes mellitus. Pravastatin therapy in the West of Scotland Coronary Prevention Study resulted in a 30% reduction of risk of developing type 2 diabetes. Salicylates in high doses have been known to lower glycosuria in diabetic patients. Although earlier studies were contradictory, these studies have used lower aspirin doses (<3gm/day) and therapeutic duration was only for a few days. Hundal [42] reported that high doses of aspirin (7gm/day) for 2 wks caused 25% reduction in fasting plasma glucose, 50% reduction in triglyceride and 15% reduction of CRP concentration independently of the changes in the plasma insulin concentration. The recently introduced oral hypoglycemic agents thiazolidinedions (Glitazone) are peroxizome proliferators activated receptor γ (PRAR γ) agonist that have been regarded as insulin sensitizes through mechanisms such as altered transcription of insulin sensitive genes controlling lipogenesis, adipocytes differentiation, fatty acid uptake and GLUT 4 ( Glucose Transporter 4) expression. They also have an anti-inflammatory action inhibiting cytokine production, macrophage activation and reducing CRP as well as WBC count in type 2 diabetic subjects [43-46].

n =Number of Subjects; SD: Standard Deviation; RBS: Random Blood Sugar

Angiotensin Converting Enzyme Inhibitors (ACE inhibitors) are also known to decrease insulin resistance in either type 1 or type 2 diabetic patients with concomitant hypertension [47]. Torlone et al. [48] demonstrated improved glycemic control in patients with arterial hypertension and type 2 diabetes using ACE inhibitors [48]. Insulin has a potent anti-inflammatory activity [32]. Insulin was found to be a rapid nonspecific and dose dependent inhibitors of the cytokine and glucocorticoids stimulation of acute phase protein, gene expression and exerted effect at the transcriptional levels. Insulin inhibition applied to all cell cytokines tested but to various degrees depending upon the particular acute phase gene [49].

In this study, of the 25 type 2 diabetic patients on treatment for at least 5 years, 8 patients were in sulfonylurea-metformin combination, 7 were on glitazone, 6 were on sulfonylurea alone, 2 were on glitazone-metformin combination and 2 were on metformin alone. When compared with newly diagnosed untreated group (Group II) the levels of α1-antitrypsin, α1- acid glycoprotein and ceruloplasmin were statistically lower. No significant difference was found in the fibrinogen levels. The values of α1-acid glycoprotein and ceruloplasmin were comparable to those of the control group. The RBS values were like those of untreated group (193.62±33.65 and 193.26±35.30). It is interesting to note that α1-acid glycoprotein levels were almost the same in type 1 diabetes type 2 untreated patients and control (Table 2). Probably α1-acid glycoprotein is the most amenable acute phase protein to treatment modalities. Comparable ceruloplasmin levels in type 2 patients on treatment and controls again raise the question as to the ‘prooxidant’ or ‘antioxidant’ action of ceruloplasmin. No change in fibrinogen values suggest multiple pathway involvement that are poorly understood.

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juniperpublisherscasestudies · 2 years

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A Randomized, Double-Blind, Placebo- Controlled Study Trial to Evaluate the Potential Effects of Naticol®, Fish Collagen Peptides on Symptoms of Sarcopenia in the Elderly

Abstract

Background: Previous research has shown the potential effects of different doses of specific fish collagen peptides (Naticol®) on muscle mass and muscle function. In addition to these benefits, clinical studies have suggested that ingestion of specific fish collagen peptides (Naticol®) might also have beneficial effects on joint health such as osteoarthritis. Joint health, loss of muscle mass, and loss of muscle function are all symptoms experienced by elderly adults, and especially elderly adults suffering from sarcopenia, suggesting a possible role for Naticol® to help to reduce these symptoms in this vulnerable population.

Aim: The aim of this study was to determine the effect of 24 weeks’ supplementation of Naticol® on symptoms of sarcopenia in an elderly population.

Methods: In a randomized, double blind, placebo-controlled, clinical trial 28 elderly adults consumed one 15g sachet of either Naticol® or the Placebo product (maltodextrin) mixed into 20cl of cold water daily before breakfast, for 24 weeks. Symptoms of sarcopenia were assessed using dual x-ray absorptiometry (DXA) to measure lean body mass, the Short Physical Performance Battery to assess physical performance, the handgrip strength assessment to assess upper body muscle function, and the chair stand test to assess lower body muscle function.

Results: This study showed that 24 weeks of supplementation with Naticol® significantly improved symptoms of sarcopenia compared to placebo, by increasing lean muscle mass and increasing muscular function in the handgrip strength assessment, Short Physical Performance Battery, and Chair Stand Test.

Conclusion: The results of this study demonstrated that daily supplementation of Naticol® (containing fish collagen peptides) in elderly adults can improve symptoms of Sarcopenia, increasing lean muscle mass and increasing both upper and lower body muscle function.

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juniperpublishers-dentistry · 2 years

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Emulating Natural Morphology in Anterior Crown Fractures: Two Years Follow-up Report - Juniper

Authored by Bora korkut

Abstract

Patients may suffer from undesirable aesthetic problems due to color, shape and structural or position abnormalities of anterior teeth. Crown fractures are one the most common reasons of these aesthetic complaints especially in young patients. Creating a conservative as well as powerful restoration against destructive occlusal forces while emulating similar outlook to natural dental tissues is the main objective of treatment of such cases. Direct composite resin restorations are one of the best possible treatment options for the anterior crown fractures. As the dental materials and techniques develop, the clinicians start to learn the physical and optical properties of these materials and use them with proper techniques to create more natural alike as well as long lasting restorations. These restorations are no longer named as 'day savior fillings' today but are called minimally invasive, functional and long lasting 'direct aesthetic restorations' that perfectly emulate natural dental tissues even in anterior area. This article illustrates how to perform a minimally invasive, long lasting, functional and natural alike direct aesthetic restorations in a single visit..

Keywords: Crown fracture; Direct aesthetic restorations; Emulating natural tissues

Objective

Performing a minimally invasive, long lasting, functional and natural alike direct composite resin restorations in a single visit.

Introduction

Aesthetic restoration of lost dental tissues of anterior teeth is a crucial challenge in restorative dentistry. Patients may suffer from undesirable esthetic problems due to color, shape, structural and position abnormalities of anterior teeth. Creating more conservative as well as more powerful restorations against occlusal, lateral and protrusive forces and emulating similar outlook to natural dental tissues is the main objective of up-to- date, contemporary dentistry [1]. An increasing number of dentists prefer minimal invasive and less time-consuming treatment options; as direct resin restorations compared to indirect ceramic restorations for the anterior dental aesthetics [2]. In order to create more natural-looking restorations, clinicians must learn and understand the physical properties of the dental tissues and restorative materials that they use and also interactions of these tissues and materials with light [3]. Various dental materials and techniques have been coming on the scene to improve both functional and aesthetic quality of the restorations. However a few of the esthetic resin materials on the market meet the expectant. The ones having such properties such as simplicity, structural stability, surface polish ability, masking discolorations, surface texturing and simulating natural dental color parameters such as hue, value and chrome are one step ahead [4,5].

Clinical considerations

In this report complex crown fractures due to dental trauma on maxillary right central and lateral incisors were corrected with minimally invasive direct composite resin restorations by using layering technique in a single appointment. The composite resin material used in this case study is a recently developed resin based restorative material, Estelite Asteria (Tokuyama, Japan) designed for emulating natural dental tissues.

Case Report

17 years old female patient applied to the clinic with aesthetic complaints due to dental trauma. He had direct trauma to the maxillary incisors a year ago and had no pain or any other symptoms. According to the intraoral examination complex crown fractures on maxillary right central and lateral incisors were determined (Figure 1,2).

According to the radiographic and vital metric analysis the injured teeth were considered as vital. The periodontal tissues were healthy and oral hygiene was in good condition. The patient' s age and the examinations were both taken into consideration and a conservative approach, minimal invasive direct aesthetic resin restorations were considered as the treatment plan.

Shades selected by using macro dental photography and composite shade samples which are also known as the 'Button Technique. Most appropriate body and translucent shade samples of Estelite Asteria (Tokuyama, Japan) were selected and located on the crown of left central incisor. The body shades were located on the mid-third and the translucent shades were located on the incisal-third of the crown. Then a macro photograph was taken from the labial view by using a professional camera set designed especially for dental photography. The set consist of a body (D700), a macro lens (Macro 100mml), a macro twin flash (MT- 24EX Macro Twin Late Flash), two-sided reflectors and a dual flash bracket mount (Novo Flex Unset). The picture taken was processed in a computer software program called Adobe Photoshop CC (Photoshop CC, Adobe Systems Software). A processed black and white form of the photograph was used to decide the translucent shade. Another processed copy on which contrast was increased and brightness was decreased, was used to decide the body shade (Figure 3). A1B and NE shades (Estelite Asteria, Tokuyama, Japan) were selected. Temporary restorations were prepared for the cracked teeth on a cast model and silicone impression was taken to create a palatal silicone index (Figure 4). Rubber dam was applied on maxillary incisors and canines for maximum isolation (Figure 5). 45 degree deep beveling were done on both incisors to cover the crack lines as minimally invasive preparations (Figure 6. One bottle universal adhesive agent (Bond Force II, Tokuyama, Japan) was used with selective etching. The translucent shade composite resin, NE shade, was used to create the palatal enamel wall. The resin was placed on incisallt on the silicone index and refined by using a composite brushed wetting resin. Then the resin and the silicone index were placed intraoral on the palatal surface of the teeth and polymerized. The index removed and palatal enamel wall was created (Figure 7).

The same resin was used to create marginal enamel walls of the restorations by using kidney-shaped metal matrix bandstand wedges (Figure 8). Body shade composite resin, A1B shade, was used to emulate dentin tissue (Figure 9). Labial surface was restored by using the translucent shade resin (NE) to create the surface enamel layer (Figure 10). In order to avoid overcontouring, composite brush was used with the wetting resin for layering. The surface structure was also created in final surface layering step. The resin used for emulating the enamel surface layer was applied in 3 steps; medial third, distal third and middle third, so that creating the surface grooves, ridges and also incisal notches while layering. The irregular scratches on the surface were emulated by using the composite brush gently without wetting resin (Figure 11).

After polymerization of the last layer, glycerin (Air Barrier, GC, Japan) was applied to whole the restoration surfaces and polymerized for 40 seconds to eliminate the oxygen inhibition layer. The surface cleaned with water spray and dried with air spray. Marginal adaptations and removal of excessive resins were done by a #12 lancet, a fine-grained composite polishing disk (Soflex, 3M, Japan) and interface sandpapers (Epitex, GC, Japan). The labial surface was polished by using only a fine-grained spiral rubber disc (Twist-Dia, light blue) in low speed and in dry condition (Figure 12,13).

The patient was informed about the oral hygiene and informed for recalls for every 6 months (Figure 14).

At 2years recall no sensitivities, fractures, secondary caries lesions were detected on both the teeth and the restorations. Also no discolorations or demarcation lines were detected (Figure 15,16).

On the other hand the micro surface morphology on the central incisor, created with brush touches while layering, was barely may observed. The patient reported that the restorations were fully functional during the time and he was also very satisfied with the aesthetic result. Oral hygiene and periodontal health were also in good condition (Figure 17).

Considering all, in 2 years follow-up the structural integrity, the color stability as well as the aesthetic outlook of the restorations was considered as satisfactory. The patient was called for further follow-ups.

Discussion

Ever increasing aesthetic demands of the patients require better dental materials and application techniques and also more clinical experience and knowledge. Natural-looking as well as functional and stable dental restorations may only be created only with the combination of these headlines. Natural dental tissues demonstrate translucency, opalescence, and fluorescence that must be imitated by the chosen restorative material in order to emulate the natural [6,7]. Especially translucency is recently accepted to have a key role in shade match of the restorative materials with natural dental tissues. Translucency is defined as the amount of light that passes through the dental tissues and may vary according to one of the parameters of color, value [8]. If the value of a tooth or dental material is high, lighter reflect from the surface, resulting in low translucency [9]. Taken this into consideration, some dental manufacturers have developed some new generation of aesthetic composite resins to emulate the natural dental tissues better than ever.

In the case presented a recently produced Estelite Asteria (Tokuyama, Japan) was used as the composite resin material which has supra-nano inorganic spherical fillers. Although this resin has an advantage for using as two-step layering, in this case conventional three-step layering was used to mimic the natural dental tissue layers. The composite brush manipulation was very easy and effective while layering as the consistency of the resin was soft enough. It is a fact that the composite layering procedures under reflector light takes much longer time that might be a problem. But the working time of the shades of this resin was also long enough. The polymerizing time for the shades used in this study was 10 seconds that is an advantage for the clinician. The natural surface morphology was emulated with gentle brush touches while surface layering. As the method used for layering depends on not creating over-contouring, the polishing procedures for restoration surfaces only done by a fine grained spiral polishing disc (Twist Dia, light blue). The surface texture created by composite brush hits could only be protected by using this polishing procedure [10]. This polishing material also creates a very shiny surface that is also very resistant to discolorations. Smooth adaptation between resin and dental tissues and having no micro-leakage due to the enhanced physical properties of the resin such as low polymerization shrinkage may describe having no sensitivities or secondary caries at 2 years recall [11]. As the correct indication of the case is an indispensable condition for direct anterior resin restorations, the stability of the restorations depends on having no devastating occlusal forces. The restorations were fully functional during the 2 years time and had no fractures as a result of that [12]. The enhanced fracture resistance of the composite resin might also positively affect the strength of the restorations. Also the glycerin (Air Barrier, GC, Japan) used for enhancing the physical properties of the surface layer made a positive effect on creating a more resistant surface layer to potential fractures and discolorations [13]. The loss in micro surface morphology on the central incisor that was created with brush touches may be related to the erosive or abrasive pattern of patient's diet and brushing style. It may be due to the surface roughness of the restoration which is related to the physical properties of the resin used. However that loss was insignificant for the aesthetic outlook in speaking distance. The patient was very satisfied with the durability, aesthetic outlook and especially the color harmony and gloss of the restorations. The specific spherical fillers and enhanced optical properties of the resin [14], the button technique used for selection of the shades [15], overcontour less layering technique [8,16] and detailed polishing procedures [17] are possibly played the key roles in this aesthetic outcome.

For years the anterior direct resin restorations compared to the indirect veneers and accepted as a loser in general. They were blamed as weak especially about durability and color resistance. However before criticizing, everyone must self-criticize him/ herself and ask the question: if these direct restorations were done correctly or not? Like all dental procedures, direct composite resin restorations have some indications and contra-indications. These can be aliened as; proper occlusal relations [18], correct shade selection [19], good isolation [20], good adhesion [21], detailed polishing [22], frequent recalls [18,21] quality materials [18] and also clinical experience. These are like rings of a circle and if one of them breaks, then the whole restoration fails. If the direct composite resin restorations were performed by taking these into consideration, the success rate of these restorations would definitely increase.

Conclusion

As a conclusion although 2 years times still a short term to evaluate, with correct indication, quality material and proper technique the direct resin restorations were seemed to be highly long lasting, color resistant and aesthetic under the conditions of this follow-up case study If direct restorations with composite resins are done by the rules, they are obviously one of the best treatment options for today's dentistry.

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juniperpublishersmaterialscience · 10 months

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A Spin Coating of Thymol Blue Indicator on F-SnO2 Glass to fabricate a Novel Sensor Electrode in Potentiometric Acid-Base Titration

Authored by: Nasser M Abu Ghalwa

Abstract

This study deals with the investigation for preparation of conductive glass / thymol blue TB sensor electrode by spin coating of the thymol blue (TB) indicator on conductive glass formed from F-SnO2, and it’s using as indicator electrode in potentiometric acid-base titration in aqueous solution at 298K. The change of the open circuit potential with pH (E-pH) curve is linear with slope of 0.052V/dec at 298K. The standard potential of the above electrode E0, was determined with respect to the SCE as reference electrode. The recovery percentage for potentiometric acid-base titration using G/TB as indicator electrode was calculated.

Keywords: Potentiometry; Thymol blue; Sensor; Conducting glass; Titration; Indicator electrode

Introduction

Chemical sensors are devices that convert the concentration of target compounds into an analytical signal. The term analytical implies the concept of measurability. Then a chemical sensor converts the information about the presence of target compounds into a measurable quantity [1]. Chemical sensors play a big role in checking the environment we live in, contributing information on industrial production processes, quality management of food stuffs and beverages, detection and analysis of some ions and many other applications [2]. Transparent conducting oxides possess a unique combination of optical transparency and metallic conductivity in a single material. Their properties are widely exploited in a host of energy, optical, and electrical applications [3-5]. SnO2 is a wide band-gap semiconductor with a band gap of 3.6eV and was the first transparent conducting oxides to receive significant commercialization. It exhibits good transparency and can be easily n-type doped. Degenerate carrier densities can be achieved by doping with fluorine [6,7]. Potentiometric titrations are the basic chemistry laboratory technique for the quantitative analysis of substances with unknown concentrations using standard solutions of known concentration. The substance with unknown concentration and the standard solution are termed analyte and titrant respectively [8]. This method widely used in different fields such as the food industry, scientific research, and chemical, clinical and pharmaceutical laboratories. Titrimetric procedures based on a detection of the endpoint, i.e., the point at which volumetric titration is completed, are successfully employed over a wide range of concentrations and are popular because of their simplicity, speed, accuracy and good reproducibility [9]. Recently, many studies developed some types of electrodes in potentiometric acid base titration [10-13]. Thymol blue (thymolsulphonephthalein) is used as a pH indicator. A solution of thymol blue exhibits three form (red color), Neutral form (yellow color) and basic form (blue color) show Figure 1 [14].hone radiation can lead to adverse effects [10-16]. Thus, the public concern is that increasing the frequency of the radiation will also increase the effects of the radiation [14-16].

The aim of this study for preparing a spin coating of thymol blue indicator TB on conducting glass formed from F-SnO2 to prepare a new modified electrode sensor (glass / indicator electrode), for used in potentiometric acid base titration.

Experimental

Chemicals

The chemicals used in potentiometric titrations and preparation the electrode was tetraethyl orthosilicate (TEOS), Thymol blue (TB), hydrochloric acid, ammonia, Acetic acid, phosphoric acid, sodium hydroxide, sulfuric acid, citric acid and disodium phosphate. The chemicals are of analytical pure grade (Merck) Where the F-SnO2 glass from (Sigma Aldrich).

Synthesis of Materials

Preparation of Hydrolyzed TEOS

A mixture of 2. ml of absolute ethanol, 0.86ml of 0.1M of HCl were added to 2.5ml of TEOS under stirring. The obtained solution was kept under stirring at room temperature until a homogeneous clear solution was obtained. The solution was aged at least for 24 hours before used in the coating process. The hydrolyzed TEOS solution was used as a host matrix for the indicators.

Preparation of Indicators

Indicators solution (1×10-2M) thymol blue indicator (TB) were prepared using absolute ethanol as solvent.

Stock solution of indicators

The sample solution was prepared by mixing 1ml of blank hydrolyzed TEOS solution and 1ml for each indicator.

Preparation of Silica-immobilized Thin Films

Substrate Cleaning

Glasses were activated by concentrated H2SO4 for 24 hours, then washed with distilled water and ethanol. The surface was finally rubbed with cleaning paper.

Preparation of glass/TB electrodes using Spin coating method

All thin films layers prepared in this work were made by spinning three drops of the solutions onto a clean glass slide. The coating process was performed using the spin coater machine at 900rpm spinning speed for 1 min. period time. To obtain multilayers of thin films a subsequent spin coating method was performed after gradually drying of the previous layer at room temperature for 24 hours, then dried at 80oC for another 48 hours. And repeat the spin coating two or three time. Where the conducting substrate is usually conducting glass, consisting of glass coated with a thin layer of F-doped SnO2.

Sensor design of potentiometric cell

The potential of the indicator electrode relative to that of the reference electrode was measured on a digital multimeter model YDM 302C (China). Potentials were measured to ±5mv. The potential of Thymol blue, sensor indicators electrodes was measured vs. a saturated calomel electrode (SCE). The error in the measurement of the potential due to liquid- junction potentials in these electrolytes is estimated to be about 0.001V.

The solution in a beaker is stirred by means of a magnetic stirrer. The electrodes (indicator and reference) were dipped slowly into aqueous solution (acid or reductant). After the steady state potential was attained, the titration of the acid was carried out by addition of 1ml of the base to the acidic solution, waiting until the steady potential is established and then measured. The potential variation depends on the type of the base, the progress of neutralization process and on the initial concentration of the acid to be titrated. The results were reproducible to satisfactory value of ±5 mV for potential measurements. The process of addition of the titrant was repeated until the equivalence point was reached.

The E-pH relation of Thymol blue electrode:

The E-pH relation of Thymol blue electrode

According to Figure 2 the change of the open circuit potential (E) of the G/ TB indicator electrode with pH . The E-pH plot of the G/TB indicator electrode fits straight line with slope of 53.11mV at 298K. This value is close to the magnitude of the term 2.303RT/F at the corresponding temperature (59.1mV at 298 K). This value is close to the magnitude of the term 2.303RT/F (where: R gas constant, T absolute temperature and F Faraday constant) at the corresponding temperature (59.1mV at 288K). From Figure 2 the E0 value of the sensor electrode, i.e., the potential at [H+] = 1, is computed as 279.1mV relative to the saturated calomel electrode and can determination by:

This equation is applicable for the reversible behavior of working electrode. From the developed Nernst equation, we indicate that working electrodes can be used as pH-indicator. At high or low pH, the electrode indicates pH less than true value as pH glass electrode, it may be due to damage in electrode or existence of alkali metal ions in solution too.

The response time of the sensor

In general, the response time was defined as the time of sensor’s output reach to 90% of the equilibration after the measurement was started, especially to electrochemical sensors [15-17]. Figures 3a-3e show the response time of the G/TB sensor at different concentration of phosphoric acid, acetic acid, Hydrochloric acid, ammonia and NaOH respectively. Response time, in the range of (100-450) seconds was achieved, which rendered the sensor highly practical.

Effect of temperature on the response characteristics:

The importance of temperature measurement when performing pH measurements has already been mentioned in reference to slope correction. Temperature also has an effect of both pH buffers and solutions, as the hydrogen ion activity will increase with increasing pH [18].

The Thymol blue sensor response was evaluated at different temperatures, Figure 4. At lower temperatures, like 288K, the slope of the sensor was about 33.54mV/decade and the sensor would be used for pH measurements in the range from (2-11). However, when the temperature of the test solutions was adjusted to 298K, the slope significantly increased to 53.11mV/decade. By raising the temperature to 313K and 323 K the slope increased to 54.11mV/ decade and 59.75mV/decade respectively. Figure 4 shows the square of the correlation coefficient (r2) for pH measurements using the solid-state sensor, at different temperatures, as compared to pH values obtained by a conventional pH electrode (Hanna Instruments HI 1131 pH combination electrode) was found to change as the temperature increases where as r2 values for measurements at 283K, 298K, 308K, and 318K were 0.9655, 0.9386, 0.9482, 0.9876, respectively. This indicates that better results could be obtained at 298K due to easy and settable to use without heating.

The relation between conventional glass PH electrode and G/ TB indicator electrode

All potential values were converted with respect to the standard hydrogen electrode (SHE). During experiments, pH was also monitored with a commercial glass electrode that was calibrated daily using commercial standard buffer solutions (2-9) [19]. Figure 5 represents the correlation between the conventional glass PH electrode and G/Thymol blue indicator electrode, it can be easily recognized that excellent correlation between the results obtained by the solid-state pH sensor and the conventional glass pH electrode could be achieved. The slope of this relation was 0.947 and the r2 was 0.947. This indicate that G/TB indicator electrode potential values are closed to the values of conventional glass pH electrode.

Potentiometric of weak acids against NaOH

Figures 6a & 6b represent the potentiometric titration of 0.1M NaOH with different concentrations of acetic acids and phosphoric acid. The variation of G/TB electrode potential at 298K with the different volumes of standard 0.1M NaOH followed typical potentiometric titration curves. These curves show slight decrease in potential (to more negative values) with the addition of the titrant. Where Figure 6c show the potentiometric titration between the volume of 0.1M standard HCl against ammonia. The variation of the TB electrode potential at 298K with the different volumes of standard HCl followed typical potentiometric titration curves. These curves show slight increase in potential (to more positive values) with the addition of the titrant.

Location of endpoints

Figure 7a represent ΔE/ΔV against V plot for the potentiometric titrations of CH3COOH and H3PO4 with 0.1 M standard NaOH. From the plots the values of end points were determined. The obtained results and calculated values of (R%) are listed in Tables 1 & 2 for acetic acid and phosphoric acid respectively. The values of pKa for different concentration of acetic acid and phosphoric acid were calculated using the method of half neutralization as shown in Table 3. There are two jumps in the titration of phosphoric acid with NaOH using G/TB sensor. i.e two end points appear by using this electrode. The obtained values of pKa for the investigated bases are close to the previously reported values. Where Figure 7b represent ΔE/ΔV against V for the potentiometric titrations of ammonia and 0.1M standard HCl respectively. From the plots the values of end points are determined.

Finally, the values of pKb for different concentration of ammonia can be determined using the method of half neutralization. They are listed in Table 3 for the tested bases. The obtained values of pKb for the investigated bases are close to the previously reported values.

Conclusion

This study investigated the preparation of the modified electrodes of type glass/ thymol blue G/TB and their use as sensor indicator electrodes in the potentiometric acid-base titrations in aqueous solution at 298K. E-pH curve is linear with slope of 0.053.1V/decade for the G/BTB electrode at 298K. This value is close to the theoretical value 2.303RT/F (0.059V at 298K) and the recovery percentage for potentiometric acid-base titration using G/TB as indicator electrode was calculated.

i. On other hand the standard potential of the tested electrode, E0, is computed as 279mV with respect to SCE as reference electrode. Acetic acid, phosphoric acid, hydrochloric acid and ammonia were successfully potentiometric titration with NaOH as titrant in aqueous medium at 298K. Finally, this study is applied in different temperatures like 283K, 298K, 308K, and 318K were the correlation coefficient (r2) 0.9655, 0.9383, 0.9482, 0.9876, respectively.

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Is US Patent Policy Strong Enough to Withstand the Winds of Change: A Study of the Need to Change United States Patent Policy

Author by Kent R Acheson

Abstract

The purpose of this case study was to learn how US patent policy requirements differ for the Software and Pharmaceutical Industries, specifically if United States Patent Policy adequately protects intellectual property rights [1] for two divergent industries while still encouraging research and development (R & D) investment sufficient to increase profits and innovation. Data for this study consisted of 38 witness testimonies delivered to US Congress between the years 2005 and 2010 by experts representing the two industries of interest: pharmaceutical and software. Key findings from the data analysis of these 38 testimonies revealed both within industry differences and between industry differences in patent law protection. Within industry differences showed variance based on size of the company and the degree to which they relied on their own R & D. Between industry differences reflected divergent ‘products’ with Pharmaceutical Industries needing long-term protection to recover R & D expenditures that include expenses for human trials research to proceed from patent application to market. Software industry, on the other hand, uses follow-on innovation of others to continue technological advancement by constantly improving upon existing software. The data show that these two industries use patent policy protection in different ways for different reasons. This information will enable Policymakers to develop another form of product protection in lieu of the current patent law to better meet the needs of these two industries rather than try to modify the existing law.

Introduction

Patent law was developed in parts, building on one another with a single purpose in mind of protecting all innovations in a society and this created the basis for patent laws imposed on the current and future generations. Bessen [2,3] stressed that patents may not be valuable in protecting innovation [4-6] but are used solely to diffuse new ideas in the public. Bessen and Maskin [7] had previously highlighted that little research and development (R&D) in the Software Industry is used to gain patent protections and the enforcement issue with patents is difficult, as many patents are issued for products that are not new. Levin [8] and others found much earlier that patents were rated weak at protecting the returns on innovation, far behind the protection gained through lead time and learning curve advantages.

Patent’s role in different industries

The purpose of this qualitative case study was to explore the different requirements for patent policy for the Software and Pharmaceutical Industries. All transcripts from testimonies from the spokespersons representing the two industries introduced to either House between the years 2005 to 2010 concerning the U.S. Patent Reform Bills were collected and analyzed to answer the research question in this case study. The findings could be useful in further adjusting patent policy to encourage innovation for diverse industries, or suggest the creation of another form of idea protection.

A similar problem may be in the type of intellectual property protection that a company chooses to obtain to avoid the constraints of getting a patent and extend the time frame for protection, such as copyright protection that extends protection from the 20 years for a patent to 120 years. Apple Inc. obtained a copyright protection for their popular iPhone [9], which recently lost in a suit against the Federal Government. The landmark decision helps to control copyright creep. Initially when buying an iPhone, Apple Inc. limited the service provider to AT&T and applications had to be bought from the Official Apple Store. Now, however, through a hack on the iPhone, users can choose a different service provider and load other, unofficial, applications not supported by Apple Inc., and hackers are not in violation of Copyright Law.

Policy Makers can use the findings of this study to explore new directions for the United States Patent Policy to optimize advancement of technology in the Software and Pharmaceutical Industries. Historically in the United States, there has been one patent policy. Scholars, academicians, and the United States Government still do not know the ideal amount of IPRs mainly because the objective has been to uphold one uniform policy. This study clarified if further changes were needed for patent policy through a Patent Reform Act, which enables Policy Makers to understand the needs of the Software Industry, or design another form of protection designed specifically for the Software Industry.

Crowe [10] and others stated that a case study design is most appropriate when little is known of a phenomenon in its natural context. A case study is “used to generate an in-depth, multifaceted understanding of a complex issue in its real-life context” (p. 1). The Pharmaceutical Industry has a profitable track record using the existing Patent Law to protect their R&D investments. The Software Industry is comparatively new and therefore their issues are only just now becoming obvious. Case law is outside the boundaries of this study.

The multiple dimensions of the phenomenon of the nature of protecting intellectual property rights in the Software Industry property and the Pharmaceutical Industry are worthy of study to allow all voices to be heard, including large corporations from both software and pharmaceutical companies, generic drug companies, and smaller software startups. After carefully examining all relevant transcripts, these diverse opinions can be given venue to state their needs.

Methodology and main results

The research question addressed in this study was: How do the patent policy requirements differ for the Software and Pharmaceutical Industries? From the Software and Pharmaceutical Industries’ objectives and needs for the United States Patent Policy to address, the questions spotlighted the sufficiency and effectiveness of the United States Patent Policy.

The focus of this study has two parts, they are:

1. What is the evidence United States Patent Policy adequately protects Intellectual Property Rights (IPRs) for both the Software and Pharmaceutical Industries?

2. How does the United States Patent System encourage companies to make R&D investment in the Software and the Pharmaceutical Industry?

The first research question dealt with the effectiveness of the United States Patent Policy in protecting IPRs in two industries: software and pharmaceutical. The second research question related to how companies invest in R&D with support of the United States Patent Policy. The study explored the ability of the United States Patent Policy to foster innovation with satisfactory IPR protection to encourage R&D spending focusing on two specific industries. The Software Industry experiences a sequential and complementary nature of innovations, building on previous discoveries; and may not use the patent policy in effect in the United States. If patent policy does not consider the different requirements within the Pharmaceutical Industry and is too lax then enough R&D spending will not be invested and technological advancements, including new medications, may come to the market slower or not at all.

The scope of the study is to understand how the Software and Pharmaceutical Industries use the patent system and how better to adjust the patent system to optimize technological advancement. As discussed in assumptions, because of the nature of the source of data and the possible bias that was not fully known, the assumptions may or may not have had a credible or dependable basis and may therefore have biased the findings. Qualitative designs such as the case study have inherent limitations that may threaten validity, they may lack rigor and they may not be generalizable. These limitations may be mitigated with transparency in data analysis and reporting. Crowe 5 and others explains on page 8 “seeking potential, alternative explanations, and being explicit about how interpretations and conclusions were reached, helped readers to judge the trustworthiness of the case study report.

Evidence from various sources highlight the United States Patent system does not work as intended and needs a solution to continue or increase innovative activity. The principal problem deals with innovative activity that is sequential in nature and innovative activity that involves much R&D investment to bring a product to market. Sequential inventions build on previous breakthroughs and do not require much R&D investment. Secrecy would hinder follow-on discoveries of sequential innovative products.

This study used a content analysis of witness [11] testimonies to Congress on the Software and Pharmaceutical Industries from the years 2005 to 2010, and the possibility to develop more than one patent policy to accommodate different sectors of the economy. The study concentrated on software and pharmaceutical companies, as these two industries are most at odds with each other, and have prevented the passage of the Patent Reform Act of 2005 through 2010. The Patent Reform Act of 2010 [12,13] is the result of non-passage of the 2009 Act, as was each successive year from 2005. The stance of the Software and Pharmaceutical Industries remained relatively unchanged in their requirements, but the patent reform acts changed to incorporate the majority opinion of industry. The most important recommendations of the Federal Trade Commission (FTC 11) and National Academies of Sciences (NAS) studies that were first introduced in 2005 by Senator [14] Lamar Smith were considered.

The purpose of this descriptive analysis was to examine the current United States Patent Policy and the proposed changes to United States Patent Policy, and answer the research question – How do the patent policy requirements differ for the Software and Pharmaceutical Industries? This study will help decide if the Software and Pharmaceutical Industries effectively use the U.S. Patent Policy through protecting Intellectual Property Rights (IPRs) and encouraged investment research and development (R&D). The qualitative case study was the most suitable approach to study the issues and answer the research questions because it explored real-life experiences of industries looking to patent Intellectual Property (IP).

Data and Sample Statistics

Data were collected and analysis began using the Content Analysis Guide developed for this study. The testimonies of the BSA representatives, other computer software witnesses, Computing Technology Industry Association, PhRMA representatives, other generic pharmaceutical representatives, and the Generic Pharmaceutical Association, Biotechnology Industry Association (BIO), Intellectual Property Owners Association (IPO) [15-18], and venture capital organizations were included in this study. The IPO was included because IPO members represent 30% of patent applications at the USPTO and include members from the Software and Pharmaceutical Industries, among others. The study included Venture capitalists because some members of BSA [19] and other smaller software companies began with venture capital dollars. Each data point was examined for inclusion of any reference to R&D, including duration and support for R&D, the need for patent protections [20,21], and future needs for patent policy.

The 38 documents submitted to the congressional hearings were analyzed. Documents relating to software and pharmaceutical companies reviewed were not ambiguous but very clear and straight forward following a consistent format, so that anyone conducting another study would reach the same conclusions. They all stated who authored the document, who the document represented, who presented opinion to Congress, their position on the patent reform act, and agreements and disagreements with specific points of the patent reform act. No ambiguity existed and no information required subjective judgments to interpret the information reported. The nature of the data supported the reliability of the findings.

Cisco, Hewlett-Packard, and other big high-tech companies began pushing for reform legislation to limit the number of patent infringement lawsuits and therefore the amounts paid in damages. The United States Patent and Trademark Office’s (USPTO) proceedings’ transcript from the public hearings showed the patent policy needs for BSA’s principle member and founder Microsoft. The public hearing titled Use of the Patent System to Protect Software Related Inventions took place in 1994 at the San Jose Convention Center, California, and at the Crystal Forum in Arlington, Virginia. A brief summary of Microsoft’s speech follows. Microsoft (BSA) recommended that patent protection allow an accused infringer to identify readily the activity forbidden under the claim. The success of a particular claim in meeting these objectives may depend less on the form and more on claim substance and the supporting details.

BSA represents a large base of computer software and hardware companies in the United States. Phelps (2005) from Microsoft Corporation stated that BSA does not want the patent holder to have automatically injunctive relief. Injunctive relief occurs when the courts rule an infringement occurred and automatically issue a ruling to stop the infringer from continuing operations. From the congressional hearing in 2005 on harmonization and other matters, Phelps for BSA supports publication in 18 months. Phelps [39] expressed support for establishing a post grant opposition procedure and supported third-party opportunity to alert USPTO to questionable patents during review. Phelps also supported allowing third parties the opportunity to suggest relevant prior art to examiner during review, supported a limit on damages for willful infringement to include only egregious behavior, and supported limiting damages to only the contributing, patented piece of the invention and not the market value of the whole product, as it is now.

In a congressional hearing in 2005, Simon [40] from Intel , a BSA representative, stated the patent system is difficult to maneuver because of many pieces that comprise computers and software contain “potentially hundreds of patents [that] may be relevant to a particular computer or software technology” [40]. The primary way to challenge a patent under current law is through costly litigation. Intel suggests Congress create a balanced post grant opposition enabling third parties to challenge issued patents that includes a post grant opposition of 2 years from patent grant or 1 year from receiving notice of patent infringement. Simon also encouraged Congress to create a second window to make the post grant review meaningful. Simon suggested a limit on patent application continuations and for the court not to issue a continuation on any claim broader than the broadest claim previously published or issued. BSA suggested a stay on the lower court’s decision in interlocutory appeals before final determination by the Federal Circuit Court of Appeals. Micron Technology, Inc., a non-BSA member, suggested the same patent law reforms as BSA.

In a congressional hearing in 2006, Chandler [41] of Cisco (BSA) suggested a second window triggered by receipt of an infringement complaint. During the first window, the patent issues with thousands or millions of parts making the effectiveness of the patent examination questionable. Chandler (2006) encouraged Congress to make changes to remove venue shopping, and prevent suits from worldwide damages in United States Courts like the Microsoft and AT&T case. The only patent policy need described on the BSA website dated 1994 had no updates, which is understandable because United States Patent Policy has not changed significantly for more than 50 years and the proposed changes have not made it into law. The agreement with the Patent Reform Act was from the most influential voice for the Software Industry; nevertheless, there were disagreements within the Software Industry mainly arising from smaller companies and individual inventors. Software companies wanted patent reform by Congress but differences remained among large software companies and smaller organizations. An overhaul of the patent system and other measures to promote tech development efforts are top priorities of the Business Software Alliance, Cisco, Hewlett-Packard, and other big high-tech companies . BSA members began pushing for reform legislation to limit the number of patent infringement lawsuits, and therefore, the amounts paid in damages.

In an article in PC World dated March 9, 2008, patent reform leads a list of five legislative priorities expressed by BSA in 2008. The opinion article stated that BSA members want Congress to approve the Patent Reform Act but the legislation stalled in the United States Senate because of objections from inventors, pharmaceutical companies and some small tech (computer software) firms. In addition the article proclaimed, more than 170 California businesses and organizations oppose the Patent Reform Act in its current form. They mention that research to stay competitive is both expensive and risky, but strong protections from patent policy attract the necessary investments to commercialize a new product. This is especially the case for the hundreds of smaller, venture capital-backed firms in the state, of which many spun from California’s world-class research universities and private research institutes. According to GlaxoSmithKline, California Wireless and Mi5 Networks in paragraph eight on page one of Gross [42] (2008), the Patent Reform Act “would increase costs to obtain and maintain patents, undermine patent certainty, incentivize infringement, and weaken the enforceability of patent rights and intellectual property protections.”

Dr. Myhrovold [43-45] started Dynamical Systems, a software company, in 1984 that Microsoft bought in 1986. He worked with Microsoft from 1986 to 2000 (14 years). Myhrovold retired from Microsoft in 2000 to start another company, Intellectual Ventures, which files more than 300 patents a year making it the 25th largest inventing organization in America. Dr. Myhrovold stated “[Software is] a complex topic…and it’s all about company culture and how companies use patents” (Perspectives on Patents [46,47]. Continuing Dr. Myhrovold stated “…for most tech companies patents have never been important; they have never been a way to make money” (p. 76, para. 2), and “…patents are, at best, a distraction and most tech companies have made a deliberate decision to ignore the patent system” (p. 76, para. 5). Many other non-BSA members agreed with Myhrovold.

Defensive patenting by software companies explains if a company holds enough patents then this company can steal another product company’s ideas with impunity, but the problem enters when the other entity does not create a product to attack (Myhrovold, 2006, p. 77, para 3). These are the battle lines in the patent reform debate with universities, small inventors and pharmaceutical companies whose lifeblood is the patent system on one side, and companies who decide to infringe or at least do not care about infringing on the other side. Dr. Myhrovold is a witness from the vantage point of a Microsoft senior executive in the 1990s who discussed this role with other firms in the earlier rounds of patent reform debate.

Technology companies exaggerate the problem when over the last 20 years patents have remained in last place of lawsuits for the three forms of idea protection: trademark, copyright, and patents. A study of four high-tech companies that are active in the patent reform debate paid out $3.7 billion in patent lawsuit settlement from 1993 to 2005, but those same four companies earned $1.4 trillion in revenue over the same period making the sums for infringement only 0.26% of revenues on average. The company with the highest number of lawsuits experienced sums for infringement at only 0.51% of revenues. “Patent trolls” are companies that do not market a product but only the idea for a product. Companies that do not produce a product comprise only 2% of the patent infringement lawsuits. Software companies like to blame an innocuous group of patent troll companies when they themselves perform the same litigious practices blamed on trolls. Myhrovold stated the need to embrace the trend to make the alternate resolutions more like a court trial by creating a separate Patent Court, much like the Tax Court, Bankruptcy Court, or Divorce Court to try only specific cases.

Inter Digital is a technology and software company that disagrees with BSA’s proposed changes to patent law. Inter Digital’s Bernstein summarized the differences in the Software industry on page 220 last paragraph at the 2007 congressional hearings: “…the IT industry is absolutely not united in its support for mandatory apportionment, post grant opposition, expansive USPTO rulemaking authority, and interlocutory appeals fall outside the realm of patent ‘reform’.” Bernstein continues by expressing how such an action would degrade patent rights and increase litigation for smaller innovators. The weakening of legitimate patents would protect a few corporate giants and increase the number of lawsuits Bernstein (2007), [48,49].

An article by Mc Dougall [50] and Chabrow (2006), [51,52] in InformationWeek explains the problems as they perceive them with the Patent Reform Act from other software and computer companies. Hans Hxu, founder of online gift registry Felicite.com, says the industry’s large players want the appearance of IP openness but do not practice it. “IBM patents almost everything they do, and then they sit on it, which does not encourage innovation” (Microsoft Agenda, para. 3) says Hxu, a McKinsey consultant although other critics suggest the sellers’ moves cement their advantages when they face rising [53] competition from startups. In an August 2005 essay, Harvard Law School professor and tech entrepreneur James Moore argued the collaborative patent review proposed by IBM, Microsoft, and others would result in fewer patents issued because it would give examiners more ammunition to shoot down patent applications. “If fewer patents are issued, but existing patents are not revoked, IBM and Microsoft win because they already possess vast existing portfolios,” Moore writes (Microsoft Agenda, para. 4). Some Web 2.0 companies dismiss IBM’s argument that business-method patents protect obvious ideas. “Everything is obvious after someone has done it,” says a spokesperson for online movie renter Netflix (Microsoft Agenda, para. 5), which has patents on its queue-ordering system--and is suing Blockbuster for allegedly copying the system.

Small tech companies are taking matters into their own hands, forming patent cooperatives through which they share IPRs. Search company Wink shares in Creative Commons, a group that encourages sharing of copyrights and open source licenses, but there is a line between sharing and protecting intellectual property that creates competitive advantage, says Wink’s Chief Executive Officer (CEO) Michael [54,55] Tanne. “When companies have invested in the development of technologies, they really ought to be able to protect it,” Tanne says (Microsoft Agenda, para. 6). Resolving these issues will influence developing and commercializing tech innovations. Too many lengthy and expensive legal battles will persuade IT departments to stick with familiar technology, and this is something tech vendors should consider as they take one another to court.

The largest and best known pharmaceutical companies in the Pharmaceutical Industry represented by Pharmaceuticals Researchers and Manufacturers of America (PhRMA), Biotechnology Industry Organization (BIO), and the Professional Inventors Alliance disagree with the weakening of patent protection and the long, time frame proposed for patent reexamination. High R&D characterizes these industries and the Pharmaceutical Industry realizes a shortened patent protection because patent protection begins before FDA approval. This shortens patent protection to commercialize the product to the remaining years.

On September 17, 2007, The Professional Inventors Alliance expressed through a letter to President Bush the flaws in the Patent Reform Act of 2007. The Patent Reform Act of 2007 did not pass the United States Senate because of the opposition from PhRMA, small inventors, and small tech firms . The letter from the Professional Inventors Alliance expressed that if the Patent Reform Act of 2007 passed into law it would harm the United States’ innovative character because of the inability to enforce patents and would reduce the royalties associated with a patented technology. In 1980, PHRMA’s members invested $2 billion in R&D for new medicines; although, nearly 30 years later (in 2009), PHRMA’s members invested $50.3 billion in R&D out of the $65.2 billion industry-wide total. Pharmaceutical companies rely on government-granted patents to protect their substantial investments in researching and developing new drugs. It takes 10-15 years and costs $800 million on average to bring a new medicine to market. The Pharmaceutical Research and Manufacturers of America (PhRMA) represents the country’s leading pharmaceutical research and biotechnology companies.

Without patents to protect all the inventions necessary to develop a drug for a limited time, others could simply copy the drugs immediately, offering their versions at a reduced price because they did not incur the high costs to develop the drug. This would seriously affect the pharmaceutical companies’ ability to recoup their costs and reinvest in other research projects. PhRMA stated in 2010 that “a strong patent system is crucial to our economic [56,57] competitiveness, especially in these economically trying times” (PhRMA’s website, 2001, p. 1). The companies in favor and against the Patent Reform Act of 2010 divided into the companies that have favored and opposed the previous patent reform acts, that is, computer software favoring patent reform and pharmaceutical companies and biotechnology companies opposing patent reform. Those opposing and in favor of the patent reform acts through the six years in this study have not changed their needs but, instead, Congress changed trying to create a patent policy agreeable to most patent users.

The large pharmaceutical companies also known as the name brand pharmaceutical companies and the smaller, generic pharmaceutical companies were in general agreement on most issues. Both wanted strong patent protection and both sides were against the Patent Reform Bill [58] of 2005 and 2006 as stated in the congressional hearings on patent reform. The firstinventor- to-file patent system while harmonizing with the large United States trading partners also poses some difficulties and disagreements with United States patentees. The problems lay in the grace period of 1-year and the best mode requirement in the patent application. Harmonizing with other countries’ patent systems as currently written, such as Japan and Europe, would remove the United States grace period of 1 year to file a patent application and would remove the best mode requirement when filing a patent application. The best mode requirement is the descriptive part of the patent application the inventor has to include the inventor’s idea of how best to use or combine the chemicals for complete effectiveness.

The differences between the brand name and generic pharmaceutical companies lay in eliminating the best mode factor of the patent application and the inequitable conduct defense. Brand name pharmaceutical companies say the best mode provision of the patent law is subjective, and therefore should be removed. The generic pharmaceutical companies believe the best mode provision should remain because they cannot copy the patented medication without the recipe or the “best mode” of making the drug. By removing the inequitable conduct defense, brand name pharmaceutical companies will misuse the patent system to the harm of the public and generic pharmaceutical companies. Differences exist between the brand name pharmaceuticals and the generic pharmaceuticals. One example is the issue of patent quality: Best mode. Generic pharmaceuticals want to keep the “best mode” in the patent law language because it lowers cost of medications by allowing generic companies to copy name brand drugs more easily. Ely Lilly [59,60] and PhRMA want to remove the best mode language . The Generic Pharmaceutical Association also has qualms with weakening the inequitable conduct saying that weakening this provision gives brand-name pharmaceutical companies incentive to misrepresent their inventions.

Together the Case Lawre presented the most comprehensive line of court-led patent reforms, which makes patent reform substantially different in 2010 than 2005. Patent lawyers and the law association, AIPLA [63,64], believe that legislation is not necessary and the court system will eventually find a solution for compromise for the different users of the patent system and will define patent law through successive Case Law. Larger, more market capitalized firms make more noise and are heard more clearly than smaller, less capitalized companies or individual inventors, including companies that specialize in innovation but do not concurrently produce a product, also known as patent trolls. More innovation comes from smaller firms and individual inventors than large entities. The larger software enterprises that often infringe on patents held by companies that do not produce a product (patent trolls) behave similarly to the patent trolls. IBM and Microsoft sit on patents without an accompanying product, when another company discovers something similar the patent surprises the unsuspecting company, and a licensing or royalty agreement can avoid costly litigation. IBM earned over a billion dollars in 2005 solely from license agreements and royalties. Licensing and royalty agreements are another possible direction that companies take to avoid patent infringement suits; however, their use threatens other companies to ransom licensing or royalty agreements but is cheaper and the outcome more certain than litigation.

The Pharmaceutical Industry appreciates the current patent policy and is leery of any changes that would disrupt the current manner in which they use the patent system to optimize patent protection; also the Pharmaceutical Industry like the Software Industry makes the best of the current patent policy . Although pharmaceutical firms have to wait until after drug trials and resulting FDA approval to market the medication, which includes the 20-year patent term and drug approval sometimes lasts as much as 10 years, they too have found ways to evade current patent law to extend the patent length. The Pharmaceutical Industry commonly increases the shortened patent length by adding a known chemical to the patent protected drug therapy, and adds another patent protection term of 20 years by increasing the number of patents on a drug. One specific drug therapy created by a name-brand pharmaceutical firm that a generic company was exploring to copy had patent protection by more than 200 patents spanning 40 years.

Discussion and Conclusions

The specific research questions that framed this qualitative case study were 1. What is the evidence United States Patent Policy adequately protects Intellectual Property Rights [65] (IPRs) for both the Software and Pharmaceutical Industries? 2. How does the United States Patent Policy encourage companies to make research and development (R&D) investment in both the Software Industry and in the Pharmaceutical Industry? Based on the differences on how patent policy should read, issues of effectiveness of the United States Patent Policy to both protect and encourage IPRs and R&D investment should be considered. Patent policy in the United States has remained unchanged for the last 55 years, and has been effective in protecting IPRs and encouraging R&D investment. Pharmaceutical firms have been around many years and have flourished in the current patent policy environment. Only with the creation of the personal computer have software companies entered the scene and have expressed concern for the patent policy changes to reduce the software company’s purposeful infringement. In a few words, the large software companies want to weaken patent protections and reduce their costs to defend against patent infringement lawsuits because big software companies do not care about patents or patent infringement.

Three important findings from this study are

1. The Pharmaceutical and Software Industries use patent policy differently

2. BSA explicitly states they want a strong patent policy, but, in effect, want to weaken the current patent policy, and

3. Differences exist within each industry. Congress has attempted to improve patent law 6 years without success because there is not agreement pleasing all industries, but the principle differences embodied the Software and Pharmaceutical Industries.

Firstly, pharmacy and software use patent policy differently: Pharmacy to protect R&D and Software for defensive purposes. Software Industry (BSA) does not use the patent policy as designed to protect R&D, but to defend against the threat of patent infringement lawsuits. The testimonies to Congress provided evidence to answer my research question of how the patent policy requirements differ between the Software and Pharmaceutical Industries. The testimonies to Congress were clear and straightforward. I did not have to infer the meaning or needs of the witnesses. They clearly stated their position and what they wanted in patent policy. Many people in the Pharmaceutical Industry and smaller software companies specifically stated that larger software and computer companies began calling for patent reform to limit the many patent infringement suits against them. Myhrovold shared his experience working for Microsoft in the late 90s stating that large software companies are not concerned with infringing on another’s patents and the only reason they care at all about patents is to defend against patent infringement lawsuits.

Secondly, the data from congressional testimonies clearly showed that the Software Industry (BSA) verbalized they want a strong patent policy but, instead, they want to weaken the rights of patent holders. This weakening is from: An unlimited post patent review period, placing the burden of proof for infringement on the patent holder (instead of the offender), and limiting the damage awards for infringement to only the infringing part of an innovation. The testimonies clearly stated their position and what they wanted. The previous list clearly communicated to Congress what the Software Industry (BSA) wanted in a patent policy, and refuted by other expert testimonies in the Software Industry.

All BSA representatives stated they wanted strong patent protection, and continued with the above reasons, which amount to weakening a patent holders’ legal rights to their Intellectual Property Rights (IPRs). Many testimonies contrary to BSA stated specifically the reasons BSA wants to limit a patent holders’ IPRs is to stave off patent infringement lawsuits. Myhrovold (2006) shared that patent policy did not enter into Microsoft’s and other BSA members’ culture. Patents are not how software companies protect innovation, but, rather, secrecy, and lead time or economies of scale are more effective to protect innovation in a short product lifecycle industry. Thirdly, the entire Software Industry is not united with BSA, and the entire Pharmaceutical Industry is not united with PhRMA. Differences exist between the two industries and differences exist within each industry, such as difference between larger companies and smaller companies in Software Industry and brand name pharmaceutical versus generic pharmaceutical. Each expert clearly stated what they wanted, why they wanted it, and differences within their respective industries. The witnesses to the congressional hearings succinctly stated that the BSA or PhRMA did not represent the entire industry, and the industry was not united in its desires for patent policy. Siwik [66] said in the exact words that the Pharmaceutical Industry is not united, and based on the non-BSA members’ testimonies with them vehemently disagreeing with BSA’s stance, anyone would reach the same conclusions that BSA is far from united too.

The evidence suggests the two industries use patent policy in different ways. For instance, The Software Industry does not use the patent system to protect intellectual property but rather use the patent system for defensive purposes not so much to protect innovation but to defend against infringement lawsuits. Pharmaceutical industry relies heavily on a patent protection to recover large R&D spending. The evidence was found in examples of how each industry effectively uses the patent system. Based on research of the patent system and the evidence of how each industry uses the patent system, the data would suggest agreement with many of the pharmaceutical, biotechnology, and other industries that use the patent system effectively to protect research and development dollars that the system does not need major change. Research shows the answer to the question of how the United States Patent System encourages R&D and promotes innovation; the patent system performs well according to its design. It protects ideas. The current patent policy is effective in protecting innovation and encouraging research and development spending.

For more Open Access Journals please visit our site: Juniper Publishers For more articles, please click on Journal of Organic Medicinal Chemistry

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danuellebennet-blog · 2 years

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Application of (bio) chemical engineering principles and lumping analysis in modelling the living systems

Abstract

The ”whole-cell” simulation of cell metabolic processes under considering a variable-volume modelling framework has been reviewed to prove their advantages when building-up modular model structures of simplified form that can reproduce complex protein syntheses inside cells. The more realistic “whole-cell-variable-volume” (VVWC) approach is reviewed when developing modular kinetic representations of the homeostatic gene expression regulatory modules (GERM) that control the protein synthesis and homeostasis of metabolic processes. The paper review the general concepts of the VVWC modelling, while the cited literature includes past and current experience with GERM linking rules in order to point-out how optimized globally efficient kinetic models for the genetic regulatory circuits (GRC) can be obtained to reproduce experimental observations. Based on quantitative regulatory indices evaluated vs. simulated dynamic and stationary environmental perturbations, the reviewed literature exemplifies with GERM -s from E. coil, at a generic level, how this methodology can be extended:

i) To characterize the module efficiency, species connectivity, and system stability;

ii) To build-up modular regulatory chains of various complexity;

iii) To prove feasibility of the cooperative vs. concurrent construction that ensures an efficient gene expression, system homeostasis, proteic functions, and a balanced cell growth during the cell cycle;

iv) To prove the effect of the whole-cell content ballast in smoothing the effect of internal/external perturbations on the system homeostasis.

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juniperpublishers-rr · 2 years

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Breeding Cowpea Vignaunguiculata l. Walp for Quality Traits

Abstract

Primary hyperparathyroidism (PHPT) is the most common cause of hypercalcemia in outpatient settings, with an incidence in women of reproductive age of 4.7-6.2 cases per 100,000 persons. When untreated in pregnant women, PHPT can lead to maternal and fetal complications. The authors present a case of a patient with a pre-pregnancy hyperparathyroidism diagnosis: she had worsening symptoms during pregnancy, so was referred for surgery due to failure of clinical treatment to keep the disease under control. Clinical issues, laboratory findings, and relevant therapeutic approaches are discussed.

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#Juniper Publishers Google scholar #Annals of Reviews & Research #research & reviews journal of life sciences

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juniperpublishersjojdc · 2 years

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A Novel Methodology for Correction of Cosmetic Problems via Secondary Eyebrow Transplantation - Juniper Publishers

Authored by Yi Jung Lin

Abstract

Eyebrows create a very imperative and noticeable feature of the face. With increasing information, eyebrow transplant has become a prevalent technique. Though it is a small area still requires a lot of precision, knowledge and aesthetic skill regarding anatomy, designing of brows, extraction and implantation technique. In this paper, we performed many cases of eyebrow reconstuction including revision by our own implanter. The cases analyzed in this paper were corrected only by transplantation of occipical donor hair without laser hair removal nor tattoos. This article gives a comprehensive view regarding how to correct previously unsatisfactory eyebrow transplant with special emphasis on several points as hair follicle density, eyebrow shape, entire or partially reconstruction, which has become the most skillful technique.

Keywords: Eyebrow Transplantation; Implanter; Hair Follicle Density; Hypothyroidism

Introduction

Eyebrows are the most communicative feature and form a masterline of the face. It is the orientation fact concerning which all other perspectives and outlines of the face are established. Repairing eyebrows have become a reworthing procedure of hair transplant because of the increasing information and exceptional results. However, eyebrow transplant requires a high degree of skill and experience, not to mention the reconstruction transplant under the condition of previously unsatisfactory eyebrow transplant. With the extensive experience of the author in the field of follicular unit extraction (FUE) and follicular unit transplant (FUT)/strip, especially in aesthetic facial hair restoration, it is feasible to perform high-quality surgical techniques creating satisfactory results and a happy outcomes to patients after previously eyebrow transplant under comprehensive communication.

Procedure evaluation before the transplant

Cosmetic is the most common signs of eyebrow transplant such as inherited absence or insufficient coverage, of a normal appearing eyebrow requiring darker colour or an uneven eyebrow with lack of lateral third or medial portion. The other uncommon indications are trichotillomania, scar due to trauma, burn or tumours, stable alopecia areata, madarosis due to hypothyroidism, leprosy, etc. [1]. Although a correct candidate is one who has accurate expectations, understands limits in density achieved, has a pronounced defect than purely cosmetic purposes and stable or treated disease, the patient still expects a near-perfect surgical result. Even well awaring the difficulties of the reconstruction of eyebrow transplant, after seeing the patients undergoing previous surgery, showing an extremely depressed and anxious state, the authors had to try to deal with the cosmetic problem secondary to previous eyebrow transplant.

Methods

The outline of the eyebrows comes from the arrangement and display of each hair follicle. The qulity and survival rate of the follicles implanted decide the appearance of the eyebrow. FUT/ strip with long hair has long been used using single or small hair grafts for brow transplant [2,3]. Persuing grafts of high quality, Graft quality index (GQI) of grade 1, can present the shape of the eyebrow more accurately. We prefer FUT with long hair to control the qulity of grafts, especially a grade 1 of GQI [4], and only a high surviral rate of hair follicle could show a beautiful outline of eyebrows. We use DIMIS-T 100A of high solution of digital Microscope and Samsung LED monitor for follicle dividing. Despite preparing graft using a dissecting microscope gives the dividing a little slower, however, it is worth the effort and much more perfect.

Case Analysis

Entire reconstruction

The patient received eyebrow transplantation by body hair (leg hair) one year before visiting the clinic. Occasionally, the implanted body hair was too thin and too sparse to connect the original eyebrow hair to present an intact curve. This time, we used the occipital donor hair to make an entire reconstruction. And the result gets more complete than the body hair (Figures 1 & 2).

Partially modified

The patient received eyebrow tattoo before eyebrow transplantion resulting in eyebrow hair lost and fibrosis under eyebrow area noted afterwards. She requested eyebrow implantation and liked it to go unnoticed. After the first implantation, partial eyebrow tail didn’t grow well. We checked the direction and quality of the eyebrow head and made a consecutive curve of the eyebrow. The result of integral contour presented after secondary remodification (Figures 3 & 4).

Shape adjustment

Some patients intend to change their eyebrow shape after transplantation. The stretching points of the eyebrow contour are mostly affected by the spots of brow’s peak. If the peaks’ position beyond the lateral canthus, the patient will appear angry and old look. Trying to enhance both brow heads and closer to the middle nose, it will lower down the arch of the eyebrow’s contour. After adjustment and strengthening the heads of the eyebrows, it would make the face appearing kinder, gentler, and more pleasant (Figures 5 & 6).

Density problem

The contour and shape of the eyebrow are built by several hundred hairs. To implant several hundred hairs onto this limited area is really an arduous and skillful technique. However, the patients often desire the evenly displayed eyebrow hairs without any interspace for the better homogeneous presentation. We used single hair and small 2- hair grafts interspersing in the original hairs, making it look more pleasing and homogeneous (Figures 7 & 8).

Curl direction

Generally, most common problems are related to direction and curl, colour and texture mismatch or lack of regrowth [5]. Despite of the shape design and point location, the curl direction is an important factor to make up the image of the eyebrow. Reverse or crooked direction would damage the smooth curve of the eyebrow. To remedy the interference of the bad curl, we implant more and thicker hairs inside and beside them to ease off the visual effects of the undesired curl directions as much as possible (Figures 9 & 10).

Shaft diameter

Compatible hair qualities are necessary in eyebrow revision, even though it is unreasonable in some case. Selection of shaft diameter is related to the eyebrow even face image before surgery. Thus, selecting compatible shaft diameter is important factor in eyebrow revision. It is more important to check the eyebrow shaft of previous implant by trichoscopy before eyebrow transplant, it could find a better reference for revision [6] (Figures 11 & 12).

Low survival rate

FUE is popular in recent years. Howeveer, unskilled physicians may have undesirable consequences. The patient received FUE eyebrow transplant one year before coming to our clinic. Unfortunately, the implanted follicles from FUE presented extremely low survival rate. And owing to the short shaft of follicle is difficult to orient the hair flow, the hairs growed in odd directions. Because of poor survival rate and different hair flow, it will not present a smooth curve of the eyebrow at all. The affected area is too large for the patient to distinguish between old and new hairs. So, the author has to implant the eyebrows with very high density to facilitate the patient trimming (Figures 13 & 14).

Post-operativecare

The patients are instructed not to wash the face and doing make-up on the periorbital area from the next post-operative day until all crusts have fallen off, about ten days after. After ten days, the implanted hair will start to fall off and nearly all brow transplanted hair fall due to anagen effluvium [7] until two months. Hair regrowth begins at 3-5 months. In next 6-8 months, number increases with more density.

Conclusion

The revision of eyebrow restoration is even more challenging than the virgin eyebrow implantation. The details include low follicle density, peculiar hair curl directions, unnatural looks, unsatisfied shapes, hair qulity and so on after implantation. Inspite of the above, sometimes it still varies regarding the personalities of the patients. To keep careful and conservative communication with the anxious patients is a main determinant before making decision. Overall, with the use of highest standards of techniques and with increasing experience, we provide excellent and beautiful results with patient’s accurate anticipations.

To Know More About JOJ Dermatology & Cosmetics Please click on: https://juniperpublishers.com/jojdc/index.php

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#Juniper publishers #Open access Journals #Peer review journal #Juniper publisher reviews #Juniper publisher journals

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moirtre · 16 days

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‎ ‎ ⋆⠀⠀&.⠀⠀٬⠀⠀(⠀⠀ARSENIC.⠀⠀)⠀...⠀is the first full album (lp) by south korean girl group, letalis. the album was released in both digital and physical form by south korean entertainment company, apricus culture on october 29, 2014.

the album was supported by performances of the title track, "POISON" and two additional promotional singles, "FOR THE THRILL" and "CHECK IT". as the group's first full-length album, ARSENIC received mixed reviews despite its overwhelming commercial success. the group promoted the album for a total of five weeks through music show performances, two seoul concerts, five fanmeetings, and several variety show appearances. the album's title track, "POISON" received a total of 8 music show wins while "CHECK IT" amassed 2 towards the later end of promotions.

despite the album's popularity, critics published mostly lukewarm reviews of the album. most prominently, a common critique was the "repetitive" sentiment shared by critics in both korea and abroad. despite critical favorites "REBOUND", "CHECK IT", "LOVE/OR", and "BAD GIRL" receiving praise for the involvement of contributing members naryun, jiseo, and melanie, other songs were heavily criticized for their recurring themes, genres, and structure. regardless, the group's fanbase would propel the album and its promotional singles onto the gaon and billboard global charts, solidifying the "bread and butter" of letalis' musical character.

⠀*⠀SECTION ONE⠀:⠀the tracklist.

ʬ.ʬ.⠀001:⠀ ⠀٬⠀⠀ REBOUND

ʬ.ʬ.⠀002:⠀⠀٬⠀⠀ FOR THE THRILL⠀

ʬ.ʬ.⠀003:⠀⠀٬⠀⠀ POISON* (title)⠀

ʬ.ʬ.⠀004:⠀⠀٬⠀⠀ GINGER TRUFFLE

ʬ.ʬ.⠀005:⠀⠀٬⠀⠀ DRIP⠀

ʬ.ʬ.⠀006:⠀⠀٬⠀⠀ LIGHT ME UP⠀

ʬ.ʬ.⠀007:⠀⠀٬⠀⠀ CHECK IT

ʬ.ʬ.⠀008:⠀⠀٬⠀⠀ LOVE/OR

ʬ.ʬ.⠀009:⠀⠀٬⠀⠀ MISS.ME

ʬ.ʬ.⠀010:⠀ ⠀٬⠀⠀ GUN

ʬ.ʬ.⠀011: ⠀ ⠀٬⠀⠀ BAD GIRL⠀

ʬ.ʬ.⠀012:⠀ ⠀٬⠀⠀ MINDURZ

ʬ.ʬ.⠀013:⠀ ⠀٬⠀⠀ GLASSSY

⠀*⠀SECTION TWO⠀:⠀the physical album.

‎ ‎ ⋆⠀⠀&.⠀⠀٬⠀⠀two versions of arsenic were available for purchase upon initial release. the group would go on to record the entire album in japanese for a limited edition special release in 2015 as part of their debut anniversary celebration.

ʬ.ʬ.⠀STANDARD VERSION: contains one disc, one photobook (featuring 100 photos), one of four unit posters, one of seven member-written letters, one of seven random photocards, one group poster, and one of three random stickers.

ʬ.ʬ.⠀TONEDEAF VERSION: contains one disc, one photobook (featuring 111 photos), one of four unit posters, one of seven member-written letters, two of seven random photocards, one of seven individual mini-poster, one of two random group posters, three stickers, and one fandom charm.

ㅤ*ㅤSECTION THREEㅤ:ㅤthe styling.

sticking to the general idea of their previous era, the members each had a personal hand in their own looks. each stage built off the individual tastes of each member while holding on to their cohesiveness. easily one of their most identifiable eras solely off the styling.

ㅤ*ㅤSECTION FOURㅤ:ㅤthe notes.

a fan favorite era

one of their more iconic albums, def a top three vitalis staple album

people either loved or hated this era (including the girls themselves). there were a lot of mixed reviews among critics and it wasn't secret to the girls.

weird animosity between emmy and juniper starts here. no one really knows why but they were regularly exchanging not-so nice words about each other to anyone who cared enough to listen.

one of their encore stages went viral after they used voice changing microphones with shuffled effects (entirely emmy's idea). still one of the highest viewed encores of all time, a letalis fandom staple video as well. several members were in tears from laughter (emmy, jiseo, naryun) while others were completely stoic (naira, juniper). ironically, this video pretty much sums up their public dymanic pretty well.

lots of controversy surrounding the tracks on the album. towards the end of the promotional period, the girls were visibly tired of performing "for the thrill" which was unanimously voted in a fan poll posted to melanie's fancafe as being the fans' least favorite b-side off the album.

despite how well the title track, "poison" did, some of the girls voiced their varying opinions on what they would chosen instead. snowballed into a weird scandal where they were accused of suffering from "celebrity disease". never ended up being addressed but apricus did tighten the reigns on what the girls were allowed to say/bring up during the rest of the promotions.

the true beginning of the core writers and producers that usually appear on letalis albums. also the beginning of the naryun and trenton rumors (that would eventually be entirely true). it wasn't lost on the public that letalis was gonna stick to what works so these same writers and producers in different arrangement are a staple to their discography.

miss. me randomly went viral in 2020 around the time challenges became a regular occurrence. so in between the challenges for the album they were promoting at the time, they were suffering through doing cute little hand choreo for the song.

naryun, melanie, and emmy gained their first credits on this album!

announced their first asian tour after the end of promotions. cute little 15-show tour, mostly in large theaters and arenas, nothing crazy but a precious memory for all the girls.

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just-antithings · 10 months

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I'm not saying adults insisting they only need to read YA books and watch children's cartoons is leading to this culture wide phobia of sex which in turn is becoming a useful vector for the increasing spread of fascism except that is exactly what I'm saying.

Im not that anon but want to expand on their thought, if they're saying what I think they are.

I thought of this more when seeing an old post of someone saying their English teacher should have let them write a report on Divergent instead making them read 1984. Someone commented supporting the OP, saying that they never read Divergent, but 1984 is problematic. Iirc, the commenter referred to Winston (I think that's the protag in 1984; sorry I haven't reread it in years) as a creep. I can't remember is this specific commenter called Winston a misogynist, but that's a common complaint I hear when people say they don't like 1984.

The screenshot of that post also had other screenshots, including the twt posts of YA authors saying that the classics were problematic. It's a sentiment I keep seeing around book twt before I deactivated my account but still on booktube as well, and it's always booktubers who also read and rant about Colleen Hoover, because they know her name gets clicks. Or booktubers that do those videos titled "I read [old/popular/controversial] series so you don't have to".

Sorry, sliding off topic a bit. Going back to what anon said, YA books tend to be more sanitized. They're supposed to be written for a 15-19 audience, so sex and gore aren't supposed to be explicit. There are YA books with sex scenes. 2 I read recently have sex scenes, but they aren't explicit. One uses mostly poetic language and infers to what's happening, and the other essentially fades to black after they get into bed, as they're touching and then picks up the next morning. (One of these YA books had a big controversy on booktube a few years ago for being problematic, though. Gee, wonder why /s)

But for the most part, often for people who enjoy urban fantasy or romances but not steamy scenes, they may go for YA, since it's usually more "PG". Unfortunately, some people get it in their head that this makes YA inherently "better", that adult books that are being more explicit are only doing it to get more sales, when YA tbh has a tighter hold on it marketing-wise.

Okay, I'm not published (yet), but I've been studying it when I need to take a break from writing to see what course is best for me and what I want to write. YA is becoming oversaturated in the market, so it's not as big a "money making genre" for debut authors as it might have been once (and I'd argue that even in the past when YA was smaller, you still had to be lucky, known, or connected to get that 6-figure check for a debut YA novel). YA is more likely to get scrutinized, considering its supposed to he for a younger audience, so a YA author wanting to push boundaries is going to receive more push-back than an adult lit author.

Now pushback happens in adult lit, too, like Ava Reid saying her editor or publisher (I forget who) told her that Juniper&Thorn might be too dark. (I've read it. Yes, it's dark, but bad reviews I saw for the book blew it way out of proportion. If you (gen) like lyrical/poetic narration and gothic horror, I highly suggest it).

But it feels like there's more of a push to keep YA books "clean". You can find some outliers, but like the YA I mentioned above, those outliers in YA that push boundaries can get wrapped in controversy and called problematic.

And for whatever reason, some people on booktube say this is a good thing and say "think of the children!"

They will say censorship is bad but then advocate for sanitized YA to be read instead of classics, because the classics are "bad" and "teach bad things" and "should be left in the past". They advocate for censorship without realizing they are advocating for censorship. It's exhausting, and as someone who wants to be published and does enjoy a lot of YA, it makes me feel discouraged. I don't think I'm "pushing boundaries" at all in my writing or saying anything new, but I'm very sure it's not sanitized enough for most publishers, especially if I wanted to try for one of the beg houses in the US.

Tl;dr One of the major problems in this anti-intellectualism is capitalism.

#mod erin #ask #posted without comment #fascism mention

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juniperpublishers-crdoj · 10 months

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Omega-3 Polyunsaturated Fatty Acids, Metabolic Syndrome and Diabetes Mellitus

Authored by Victoria Serhiyenko

Abstract

Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) are increasingly being used to prevent cardiovascular diseases (CVD), and cardiac societies recommend the intake of 1g/day of the two ω-3 PUFAs eicosapentaenoic and docosahexaenoic acid for primary and secondary prevention of CVD. Clinical trials clearly suggest beneficial effects of ω-PUFAs consumption on lipid metabolism profile, their anti-inflammatory actions; on endothelial activation, which are likely to improve vascular function; antithrombotic and antiatherosclerotic properties. Experimental studies demonstrate direct antiarrhythmic effects, which have been challenging to document in humans. By targeting arterial stiffness and endothelial dysfunction administration of ω-3 PUFAs may prevent atherosclerosis and CVD development. A synergistic interplay showed by ω-3 PUFAs prescription suggest the potential to beneficially impact on fundamental steps involved in the development of preclinical atherosclerosis. We reviewed available evidence of the benefits of ω-PUFAs administration, especially to patients with CVD, metabolic syndrome and type 2 diabetes mellitus, including their effects on potential molecular pathways, effects on glucose and lipids metabolism parameters, thrombocyte aggregation parameters and haemostasis, endothelial function, antioxidant/anti-inflammation and antiarrhythmic properties.

Keywords: Omega-3 polyunsaturated fatty acids; Coronary heart disease, atherosclerosis; Diabetes mellitus; Glucose, lipids; Inflammation; Platelets; Haemostasis; Endothelium; Heart rate variability; Arrhythmias; Arterial stiffness

Abbrevations: ω-3 and ω-6 PUFAs: Ω-3 and ω-6 Polyunsaturated Fatty Acids; MetS: Metabolic Syndrome; T2DM: Type 2 Diabetes Mellitus; CVD: Cardiovascular Diseases; DLP: Dyslipoproteinemia; OS: Oxidative Stress

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Introduction

Numerous studies report salutary effects of ω-3 polyunsaturated fatty acids (ω-PUFAs), i.e. eicosapentaenoic (EPA) and docosahexaenoic acid (DHA) on cardiovascular diseases (CVD) risk factors. These effects include lowering of serum triglyceride (TG) by reducing of hepatic TG production; lowering of blood pressure (BP) by improving of endothelial cell functution; decreasing of platelet aggregation by reducing of prothrombotic prostanoids; decreasing inflammation via reduction in 4-series leukotrienes (LT) production; protection from arrhythmias by modulation of electrophysiological properties of cardiac myocytes. Systematic meta analysis suggests that high doses of ω-3 PUFAs (~3g/day) produce a small, but significant decrease in systolic blood pressure (SBP) in older and hypertensive subjects [1,2]. The aim of this study was to review the latest evidence about the ω-PUFAs, metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM).

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Discussion

Ω-3 and ω-6 PUFAs are essential fatty acids, as they cannot be synthesized de novo in humans. There are limited data available regarding the exact amount of dietary ω-3 PUFAs consumed by the general population. It is reported that the total daily intake of dietary ω-3 PUFAs in the US is approximately 1.6g. Of this α-linolenic acid (α-LLA) accounts for approximately 1.4g/q.d, and only 0.1–0.2g/q.d. comes from EPA and DHA. The conversion rate from α-LLA to EPA and DHA is variable (0.2-15%). Therefore, in general, the total amount of EPA and DHA available to the body from current dietary patterns is well below the recommended amounts. EPA and DHA didn’t show a significant negative effect on glucose metabolism [3].

Several experimental studies have shown that long-chain ω-PUFAs inhibit the absorption of cholesterol in the intestine and its synthesis in the liver, lead to increased clearance of lipoproteins in the blood, prevent the development of insulin resistance (IR) in experimental diabetes, increase the level of glucose transporter 4 in skeletal muscles, have a positive effect on age related decrease of blood flow in the brain and improve glucose utilization under stress; there isn’t any influence on the development of hypertension (HT) and MetS. Ω-3 PUFAs decrease level of BP, dose-dependent prevent the development of T2DM, IR, contribute to positive changes of blood coagulation parameters; enhance endothelial cell migration and inhibits the proliferation of smooth muscle cells [4]. A meta-analysis of 18 studies found a significant effect of fish oil to lower TG concentrations and increase high-density lipoprotein cholesterol (HDL-C) in the blood; while there were no statistically significant changes in preprandial glucose, glycated hemoglobin A1c, total cholesterol, low density-lipoprotein cholesterol levels. Ω-3 PUFAs may affect the IR and glucose homeostasis by inhibition of IR in the muscle tissue >adipose tissue >>liver, inhibition of insulin secretion, which defer the development of T2DM; and on the state of lipid metabolism (in particular, reduce the concentration of TG, very low density-lipoprotein cholesterol (VLDL-C), increase of HDL-C, improve lipid profile by mixed hyperlipidaemia (HLP), slightly decrease BP, improve endothelial function, have an positive impact on the antioxidant status and inflammatory reactions [5]. Ω-3 PUFAs decrease VLDL assembly and secretion, resulting in diminished TG production, through a decreased sterol receptor element binding protein-1c activity [6,5].

The highly concentrated pharmaceutical preparation Omacor™ (Pronova Biocare, Lysaker, Norway), known as Lovaza™ (Glaxo Smith Kline, St Petersberg, FL, US) in North America is approved by the FDA as an adjunct to diet to reduce very high TG levels (≥500 mg•dL-1) in adults. Each 1-g capsule of ω-3-acid ethyl esters contains ethyl esters of EPA (0.465 g) and DHA (0.375g). Patients take a q.d. dose of 4-g or two 2-g doses (two capsules b.i.d.) [7]. Clinical trials have shown that administration of 4 g•day-1 of Lovaza™ results in a decrease in TG levels of 30-50%; does not affect the efficacy of statins [8,5]. In patients with combined HLP, co-administration of Lovaza™ with statins was a safe and effective means of lowering serum TG, despite the persistent high TG levels when the patients received statins alone [9,5].

The anti-inflammatory actions of marine ω-3 PUFAs are [10]: reduced leucocyte chemotaxis (via decreased production of some chemoattractants (e.g. leukotriene B4 down-regulated expression of receptors for chemoatttactants); reduced adhesion molecule expression and decreased leucocyte-endothelium interaction (via down-regulated expression of adhesion molecule genes [via the nuclear factor kappa B (NF-kB) (i.e. peroxisome proliferator-activated receptor-ɣ (PPAR-ɣ) etc.); decreased production of eicosanoids from arachidonic acid (AA) (via lowered membrane content of AA; inhibition of AA metabolism); decreased production of AA containing endocannabinoids (via lowered membrane content of AA); increased production of ‘weak’ eicosanoids from EPA (via increased membrane content of EPA); increased production of anti-inflammatory EPA and DHA containing endocannabinoids (via increased membrane content of EPA and DHA); increased production of pro-resolution resolvins and protectins (via increased membrane content of EPA and DHA); decreased production of inflammatory cytokines (via down-regulated expression of inflammatory cytokine genes (via NF-kB, i.e. PPAR-ɣ etc.); decreased T cell reactivity (via disruption of membrane rafts (via increased content of EPA and DHA in specific membrane regions).

Ω-3 PUFAs may decrease the risk of atherothrombosis by affecting platelet aggregation and haemostasis. The antithrombotic properties of EPA and DHA have been attributed to the incorporation into platelet phospholipids at the expense of the ω-6 PUFAs, such as AA. An important set of pathways clearly influenced by changes in the ω-3/ω-6 ratio are those for synthesis of eicosanoids. These include the cyclooxygenase (COX), lipoxygenase and cytochrome P450 epoxygenase pathways, for which EPA and DHA compete with AA as a substrate, inhibiting the production of the proaggregatory thromboxane A2 (TXA2) originating from AA. Indeed, the production of TXA2 from platelets stimulated by a variety of agonists decreased by between 60% and 80% after fatty acid supplementation both in vitro and in vivo [11,5]. The mechanism by which ω-3 PUFAs influence endothelial function is mediated by their incorporation into biological membrane phospholipids; this allows modulation of membrane composition and fluidity. The reason lies in the fact that endothelial cell membrane houses caveolae and lipid rafts where several receptors and signaling molecules crucial for cell function are concentrated [12]. Caveolae-associated receptormediated cellular signal transduction includes important pathways such as the, the nitric oxide (NO)/cyclic guanosine monophosphate signaling pathway, the nicotinamide adenine dinucleotide phosphate oxidase and tumor necrosis factor-α/ NF-kB induced COX-2 and prostaglandin E2 activation pathway. By modulating the composition of caveolae, as described for other classes of lipids ω-3 PUFAs may exert their beneficial effects, which include increased NO production and reduced production of proinflammatory mediators [13,12]. In addition to increasing NO production, ω-3 PUFAs decrease oxidative stress.

The incorporation of ω-3 PUFAs in synaptic membranes could potentially influence the autonomic control of the heart. Both nervous tissue and heart tissue have a high content of ω-3 PUFAs (especially DHA) and this may be consistent with the finding that this marine ω-3 PUFAs may modulate cardiac autonomic function as assessed by heart rate variability (HRV) [14]. Thus, ω-3 PUFAs may modulate HRV both at the level of the autonomic nervous system and the heart. Most of the data support that ω-3 PUFAs beneficially modulates cardiac autonomic control thereby possibly reducing the risk of arrhythmias. Accumulating evidence from in vivo and in vitro experiments has demonstrated that ω-3 PUFAs exert antiarrhythmic effects through modulation of myocyte electrophysiology. Ω-3 PUFAs reduce the activity of membrane Na+ channels in cardiomyocytes, thus increasing the threshold for membrane potential depolarization. EPA and DHA also modulate the activity of L-type Ca2+ channels, leading to a reduction in free cytosolic Ca2+ ion, which stabilizes myocyte electrical excitability to prevent fatal arrhythmia. EPA blocks the Na+/Ca2+ channel; however, a single amino-acid point mutation in this channel attenuated the inhibitory effect of EPA. These findings suggested that the cardioprotective effect of ω-3 PUFAs is mediated by direct interaction with membrane ion channels [15].

Ω-3 PUFAs intake has shown to reduce BP especially in HT by interacting with several mechanisms of BP regulation: reduction of stroke volume and heart rate; improvement of left ventricular (LV) diastolic filling; reduction of peripheral vascular resistances; improvement of endothelial-dependent and endothelial-independent vasodilation (stimulation of NO production; reduction of the asymmetric di-methyl-arginine; reduction of endothelin-1; relaxation of vascular smooth muscle cells; metabolic effects on perivascular adipocytes; endothelial regeneration. Mechanisms of HT-related organ damage protection: anti-inflammatory, antioxidant, and antithrombotic effects; reduction of arterial stiffness; experimental effects on LV hypertrophy and abnormal gene expression; effects on atherosclerotic plaque progression and stability [7]. Ω-3 PUFAs offer a scientifically supported means of reducing arterial stiffness and this may account for some of the purported cardioprotective effects of ω-3 PUFAs [16,17].

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Conclusion

The antiarrhythmic effects of ω-3 PUFAs, which occur by blocking various ion channels, are encouraging. So, cardiovascular benefits of ω-3 PUFAs [7,18] are: antidysrhythmic effects (reduced sudden death; possible prevention of atrial fibrillation; possible protection against pathologic ventricular arrhythmias; improvement in HRV; antiatherogenic effects (reduction in non- HDL-C levels; reduction in TG and VLDL-C levels; reduction in chylomicrons; reduction in VLDL and chylomicron remnants; increase in HDL-C levels; plaque stabilization; antithrombotic effects (decreased platelet aggregation; improved blood rheologic flow); anti-inflammatory and endothelial protective effects (reduced endothelial adhesion molecules and decreased leukocyte adhesion receptor expression; reduction in proinflammatory eicosanoids and LT’s; vasodilation); decreased SBP and diastolic BP. Thus, further research to understand the mechanism of action and confirm the beneficially effect of ω-3 PUFAs on BP profile, artery stiffness and HRV parameters in patiens with MetS, T2DM is needed.

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juniperpublisherscasestudies · 2 years

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Relationship Between Early Menopause, Estrogens Receptor A Polymorphism, Vitamin D3 Receptor Polymorphisms and Osteoporosis in a Mediterranean Population

Abstract

In order to clarify the role of candidate genes for the osteoporosis related phenotypes, we have investigated among polymorphism of the ESR1 gene and polymorphism of VDR3 gene in the relation to BMD and bone loss in a population of women of the southern Italy who underwent early (35-45 years old) menopause. The bone mineral density of all subjects was measured by Dual energy x-ray absorptiometry (DEXA). Molecular analyses were performed on ERa and VDR3 genes exons using both sequencing and RFLP technology. All women showed an average DEXA value less than -2,5. We have identified polymorphisms in the coding region of ESR1 gene that is well correlated with the bone status of the affected subjects. Vitamin D3 receptor also presents polymorphisms and is evident only in the affected subjects. The identified polymorphism of ESR1 is present only in osteoporotic patients and absent in normal subjects, such as the vitamin D receptor. Furthermore all the subjects that show such polymorphisms have DEXA values lesser than -2.5 showing a relationship between the above polymorphisms and bone loss. This let us to hypothesize that identification of polymorphism of ESR1 and vitamin D3 receptor could be a tool for early diagnosis of osteoporosis in early menopause woman.

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slowdesire · 8 months

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omg actually keen to hear ur yellowface thoughts once uve synthesised them... im a chronic rf kuang hater but i also do read her books every time so i would love to know what u thoughtttt

hello omg thank you for asking about this, i would love to know your thoughts too actually!

so it's been a day, i was able to sleep on it... this won't be the most serious review ever but i'll freely share both what i've been mulling over and my thoughts as i type. i think the book is good enough for what i personally thought it would be, which is a silly off-kilter story with a very compelling premise. the bare minimum i initially knew, which is that some white girl stole her dead asian-american friend's work, was enough to intrigue me. what i didn't understand was the hype around how "insane" it is on tiktok (which i will readily admit is where i found out about the book's existence) and i had my hesitations to hold it to that standard. turns out i was right to be hesitant. there was room for so much more. like i understand the pov and insights are deliberately limited and unreliable bc of the main character herself, but here's one example: when juniper made a remark on athena not knowing what it's like to be poor, i expected those thoughts to play a larger role in the story or go a bit deeper, but they were left as few among the many bits and pieces of surface level commentary and somewhat valid criticism against athena and it kind of got lost in the mix. this is such a shame especially because it's clear juniper is big on her own family's dynamics and financial situation, so it could've been such a great comparison point (?) for her to really dig into when it came to her resentment against athena.

i feel like that was the biggest missed opportunity in my eyes because when i read the author bio at the end of the book, i was surprised to find that rf kuang herself is from yale. i didn't know who she was before reading the book, this is my introduction to her and i went in completely blind. knowing a bit of her background now honestly leaves a sour taste in my mouth because this time the story feels too self-referential the way some taylor swift songs can be (and i enjoy tswift btw lol). but i don't know for sure since i still haven't looked into her that much. this is why i would LOVE to know why you're a hater bc i feel we'd have similar reasons

also the buildup to the ending and the ending itself were both so underwhelming that it dampened some of the fun i had in earlier parts of the story. like i was enjoying this white woman going kind of crazy but kuang's stab at the uncanny fell so flat i literally could not stop just thinking about perfect blue 1997 and how i did not pick up the same suspense here. not that they have to be the same at all, i just live like this. also in line with this so much of the book feels chronically online. at first i appreciated how online spaces were so heavily embedded in the story but by the halfway point i was like, um.... i thought this was a satire on the publishing industry, not glimpses of publishing interspersed between losing ur mind over twitter and goodreads LOL.

for now this is all i have to say. fun book! i can tell rf kuang is skilled in her own right. i enjoyed the pacing and the writing style, it was such an easy read and there's nothing wrong with that. nothing i want to take too seriously or sink my teeth too deeply into. people on booktok praise yellowface way too highly that's 10000% for sure

#ans #hope its ok i answer ur ask publicly! let me know if i should take this down lol #but i REALLY want to know why youre a hater bc i truly dont know anything about this author at the moment

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juniperpublishersmaterialscience · 10 months

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Liquid Chromatography-Mass Spectrometry Based Isotopic Abundance Ratio Analysis of the Consciousness Energy Healing Treated L-Cysteine

Authored by: Snehasis Jana

Abstract

L-cysteine is a semi-essential sulfur-containing amino acid found in nails, skin, hair, etc. in the body. This study was performed to investigate the impact of the Trivedi Effect® on the structural properties and the isotopic abundance ratio of L-cysteine using LC-MS analytical techniques. L-cysteine sample was divided into control and treated parts. The treated part only received the Trivedi Effect®-Consciousness Energy Healing Treatment remotely by a renowned Biofield Energy Healer, Dahryn Trivedi. The LC-MS spectra of both the control and treated samples at retention time (Rt) 1.96 minutes exhibited the mass of the molecular ion peak adduct with hydrogen ion at 122 along with low molecular fragmented mass peaks at m/z 105, 102, 87, 76, and 59 for C3H5O2S+, C3H2O2S•+, C3H5NO22+ or C3H5NS•+, C2H6NO2+, and C2H3O2+, respectively were also observed. The peak area of the treated sample (1960679.58) was significantly increased by 8.02% compared to the control sample (1815060.18). The isotopic abundance ratios of PM+1/PM (2H/1H or 13C/12C or 15N/14N or 17O/16O or 33S/32S) and PM+2/PM (34S/32S) in the treated L-cysteine was significantly increased by 41.86% and 32.39%, respectively compared with the control sample. Hence, the 13C, 2H, 15N, 17O, 33S, and 34S contributions from C3H8NO2S+ to m/z 123 and 124 in the treated L-cysteine were significantly increased compared to the control sample. The changes in peak area and isotopic abundance ratios might be the cause of changes in nuclei, possibly through the interference of neutrino particles via the Trivedi Effect®-Consciousness Energy Healing Treatment. The increased isotopic abundance ratio of the treated L-cysteine may increase the intra-atomic bond strength, increase its stability, and shelf-life. The novel Biofield Energy Treated L-cysteine might have increased the stability, solubility, bioavailability, and shelf-life compared to the control sample. The new form of treated L-cysteine would be a better and more stable precursor in the food, cosmetics, pharmaceuticals, personal-care products, additives to cigarettes (act as an expectorant), preventative or antidote for some of the negative effects of alcohol, acetaminophen overdose, clinically used ranging from baldness to psoriasis, excellent for the treatment of asthmatics by enabling them to stop theophylline and other medications, enhances the effect of topically applied silver, tin and zinc salts for preventing dental cavities. In the near future, this Biofield Energy Treated L-cysteine may play a better role in the treatment of diabetes, psychosis, cancer, and seizures.

Keywords: Biofield Energy; Consciousness Energy Healing Treatment; L-cysteine; The Trivedi Effect®; LC-MS

Introduction

Cysteine is a semi-essential sulfur-containing amino acid found in nails, skin, hair, etc. in the body. It contains a thiol group and available as a chiral molecule with dextrorotation (D) and levorotation (L) forms [1]. Cysteine is a non-essential amino acid but may be essential for new-borns, the elderly, and individuals with specific metabolic disease or malabsorption syndromes. The cysteine plenty available in egg, meat, milk, garlic, onions, red peppers, oats, broccoli, wheat germ, brussels sprout, sprouted lentils, etc. Industrially it is also prepared from animal feathers, hair, and even from chemical synthesis [1-3].

Due to its high reactivity of the sulfhydryl group of cysteine (nucleophilic in nature) has numerous biological functions, i.e., it acts, as a precursor to the antioxidant glutathione and iron-sulfur clusters, metal cofactors in enzymes, detoxification, metabolic functions, protein synthesis, collagen production, translation of messenger RNA molecules to produce polypeptides, etc. [1-6]. It is also a precursor in the food, cosmetics, pharmaceuticals, personal-care industries, additives to cigarettes (as an expectorant), preventative or antidote for some of the harmful effects of alcohol (i.e., liver damage and hangover), acetaminophen overdose, production of more wool from sheep, clinically used ranging from baldness to psoriasis, used for the treatment of asthma, enhances the effect of topically applied silver, tin and zinc salts for preventing dental cavities [1,6-9]. Many research work claiming that, in the near future, cysteine may play an important role in the treatment of diabetes, psychosis, cancer, and seizures [10]. The stability of L-cysteine is an issue in the neutral or slightly alkaline aqueous solutions, which is oxidized to cystine by air, and on decomposition, it emits very toxic fumes of sulphur oxides and nitrogen oxides [6].

The physicochemical properties of L-cysteine pay a very important role in the food, cosmetic, pharmaceutical, nutraceutical, and other industries. The Trivedi Effect®- Consciousness Energy Healing Treatment has the astonishing abilities to transform the characteristic properties of both living and non-living object(s) [11-15]. The Trivedi Effect® is a natural and only scientifically proven phenomenon in which an expert can harness this inherently intelligent energy from the “Universal Energy Field” and transmit it anywhere on the planet via the possible mediation of neutrinos [16]. An energy field generated around the body due to the continuous movement of the charged particles in the body known as “Biofield”. The object(s) received the “Energy Therapy” respond to a useful way is known as the Biofield Energy Healing Treatment. There are several Biofield based Energy Therapies that are used nowadays against various disease conditions [17-19]. Biofield Energy Healing therapy has been recognized worldwide as a Complementary and Alternative Medicine (CAM) health care approach by the National Center of Complementary and Integrative Health (NCCIH) with other therapies, medicines and practices such as Ayurvedic medicine, yoga, meditation, homeopathy, traditional Chinese herbs and medicines, naturopathy, chiropractic/osteopathic manipulation, Qi Gong, Tai Chi, aromatherapy, acupressure, acupuncture, healing touch, hypnotherapy, Reiki, cranial-sacral therapy, etc. [20]. These CAM therapies have been adopted by most of the U.S.A. population with several advantages [21]. Similarly, the Trivedi Effect®- Consciousness Energy Healing Treatment also been reported with significant impact on the properties of polymers, ceramics, metals, organic compounds, cancer cell line, microbes, improved skin health, bone health, improved agricultural crop yield, productivity, and quality, and altered the isotopic abundance ratio, improved bioavailability of pharmaceutical/ nutraceutical compounds [22- 37].

The analysis of the natural stable isotope has the importance of many applications to understand the isotope effects resulting from the alterations of the isotopic composition [38-40]. Gas chromatography–mass spectrometry (GC-MS) and liquid chromatography–mass spectrometry (LC-MS) analytical techniques are the widely used analytical techniques for the analysis of isotope ratio with sufficient precision [39]. The Trivedi Effect®-Consciousness Energy Healing Treatment could be an economical approach to alter the isotopic abundance of L-cysteine with improved physicochemical properties for the food, cosmetic, pharmaceutical/ nutraceutical, and other industries. Thus, this study was designed and evaluated the LC-MS based structural characterization and the isotopic abundance ratios in the Trivedi Effect® - Consciousness Energy Healing Treated L-cysteine compared to the control sample.

Materials and Methods

Chemicals and Reagents

The test sample L-cysteine (>98%, titration method) was purchased from Alfa Aesar, India. Other chemicals like methanol, acetonitrile, and ammonium acetate were purchased from Merck, India.

Consciousness Energy Healing Treatment Strategies

The test sample L-cysteine powder was divided into two parts. One part of the L-cysteine powder sample did not receive the Biofield Energy Treatment called the control sample. However, the other part of L-cysteine was received the Trivedi Effect®- Consciousness Energy Healing Treatment remotely under standard laboratory conditions for 3 minutes by the renowned Biofield Energy Healer, Dahryn Trivedi, USA, known as the Biofield Energy Treated L-cysteine. Further, the control sample was treated with a “sham” healer, who did not have any knowledge about the Biofield Energy Treatment. After that, both the Biofield Energy Treated and untreated L-cysteine samples were kept in sealed conditions and characterized using LC-MS analytical techniques.

Characterization

Liquid Chromatography-Mass Spectrometry (LC-MS) Analysis and Calculation of Isotopic Abundance Ratio

The liquid chromatography-mass spectrometric analysis of the L-cysteine was carried out with the help of LC-MS ThermoFisher Scientific, USA, equipped with an ion trap detector connected with a triple-stage quadrupole mass spectrometer. The column used here was a reversed phase Thermo Scientific Synchronis C18 (250mm × 4.6mm × 5micron), maintained at 25˚C. The diluent used for the sample preparation was methanol. The L-cysteine solution injection volume was 20μL and the analyte was eluted using acetonitrile (92%) + 0.1% ammonium acetate (8%) pumped at a constant flow rate of 0.8mL/min. Chromatographic separation was achieved using gradient condition and the total run time was 10 min. Peaks were monitored at 210 nm using the PDA detector. Mass spectrometric analysis was performed under ESI +ve ion mode. The total ion chromatogram, peak area% and mass spectrum of the individual peak which was appeared in LC along with the full scan were recorded.

The natural abundance of each isotope (C, H, N, O, and S) can be predicted from the comparison of the height of the isotope peak with respect to the base peak. The values of the natural isotopic abundance of the common elements are obtained from the literature [40-43]. The LC-MS based isotopic abundance ratios (PM+1/PM and PM+2/PM) for the control and Biofield Energy Treated L-cysteine (C3H8NO2S+) were calculated.

Percentage (%) change in isotopic abundance ratio = [(IARTreated–IARControl)/ IARControl)] × 100

Where IARTreated = isotopic abundance ratio in the treated sample and IARControl = isotopic abundance ratio in the control sample.

Results and Discussion

Liquid Chromatography-Mass Spectrometry (LC-MS)

The LC-SM of the L-cysteine showed a single major peak at retention time (Rt) of 1.96 minutes in both the chromatograms (Figure 1). The peak area of the Biofield Energy Treated sample (1960679.58) was significantly increased by 8.02% compared to the control sample (1815060.18). This indicated that the solubility of the Biofield Energy Treated L-cysteine might have increased compared to the control sample. The finding was supported by the published literature data [12].

The mass spectra of both the samples of the L-cysteine are shown in Figure 2. The mass spectra of both the samples at Rt of 1.96 minutes exhibited the presence of the molecular ion of L-cysteine (Figure 2) at m/z 122 (calcd for C3H8NO2S+, 122.03). Along with the molecular ion peak, low molecular fragmented mass peaks at m/z 105, 102, 87, 76, and 59 for C3H5O2S+, C3H2O2S•+, C3H5NO22+ or C3H5NS•+, C2H6NO2+, and C2H3O2+ were observed in case of both the samples (Figures 2 & 3). The experimental data were well supported by the published literature [44].

Isotopic Abundance Ratio Analysis

The L-cysteine samples showed the mass of a molecular ion at m/z 122 (calcd for C3H8NO2S+, 122.03) with 100% relative abundance in the spectra. The theoretical calculation of isotopic peak PM+1 for the protonated L-cysteine presented as below:

P (13C) = [(3 x 1.1%) × 100% (the actual size of the M+ peak)] / 100% = 3.3%

P (2H) = [(8 x 0.015%) × 100%] / 100%= 0.12%

P (15N) = [(1 x 0.4%) × 100%] / 100% = 0.4%

P (17O) = [(2 x 0.04%) × 100%] / 100% = 0.08%

P (33S) = [(1 x 0.08%) × 100%] / 100% = 0.08%

PM+1 i.e. 13C, 2H, 15N, 17O, and 33S contributions from C3H8NO2S+ to m/z 123 = 3.98%

Similarly, the theoretical calculation of PM+2 for L-cysteine was presented as below:

P (34S) = [(1 × 4.21%) × 100%] / 100% = 4.21%

PM+2, i.e. 34S contributions from C3H8NO2S+ to m/z 124 = 4.21%

The calculated isotopic abundance of PM+1 (3.98%) and PM+2 (4.21%) values was very close to the experimental values 4.3% and 4.6% (Table 1). From the above calculation, it has been found that 13C, 15N, and 34S have the major contribution to m/z 123 and 124.

The isotopic abundance ratio analysis PM, PM+1, and PM+2 for L-cysteine near m/z 122, 123, and 124, respectively of both the samples were obtained from the observed relative peak intensities of [M+], [(M+1)+], and [(M+2)+] peaks, respectively in the mass spectra (Table 1). The isotopic abundance ratio of PM+1/PM (2H/1H or 13C/12C or 15N/14N or 17O/16O or 33S/32S) and PM+2/PM (34S/32S) in Consciousness Energy Healing Treated L-cysteine was significantly increased by 41.86% and 32.39% compared to the control sample (Table 1). Thus, the 13C, 2H, 15N, 17O, 33S, and 34S contributions from C3H8NO2S+ to m/z 123 and 124 in the Biofield Energy Treated sample was significantly increased compared to the control sample.

The isotopic abundance ratios of PM+1/PM (2H/1H or 13C/12C or 15N/14N or 17O/16O or 33S/32S) and PM+2/PM (34S/32S) in the Biofield Energy Treated L-cysteine were significantly increased compared to the control sample. The changes in isotopic abundance could be due to the possible interference of neutrino particles via the Trivedi Effect®-Consciousness Energy Healing Treatment [16]. The altered isotopic composition in the molecular level of the treated L-cysteine might have altered the neutron to proton ratio in the nucleus. A neutrino is an elementary particle that interacts through the weak subatomic force and gravity. The neutrinos have the ability to interact with protons and neutrons in the nucleus, which indicated a close relationship between neutrino and the isotope formation [39,40]. The isotopic abundance ratios 2H/1H or 13C/12C or 15N/14N or 17O/16O or 33S/32S or 34S/32S would influence the atomic bond vibration of treated L-cysteine [45]. The increased isotopic abundance ratio of the treated L-cysteine may increase the intra-atomic bond strength, increase its stability, and shelf-life. The novel Biofield Energy Treated L-cysteine might have increased the stability, solubility, bioavailability, and shelf-life compared to the control sample. The novel Biofield Energy Treated L-cysteine would be more important to the food, cosmetic, pharmaceutical/ nutraceutical, and other industries compared to the control sample.

Conclusion

The Trivedi Effect®-Consciousness Energy Healing Treatment showed a significant impact on the chromatographic peak area and isotopic abundance ratio of L-cysteine. The LC-MS spectra of both the control and Biofield Energy Treated samples at Rt 1.96 minutes exhibited the mass of the molecular ion peak adduct with hydrogen ion at 122 along with low molecular fragmented mass peaks were also observed. The peak area of the Biofield Energy Treated sample was significantly increased by 8.02% compared to the control sample. The isotopic abundance ratios of PM+1/PM (2H/1H or 13C/12C or 15N/14N or 17O/16O or 33S/32S) and PM+2/PM (34S/32S) in the Biofield Energy Treated L-cysteine was significantly increased by 41.86% and 32.39%, respectively compared with the control sample. Hence, the 13C, 2H, 15N, 17O, 33S, and 34S contributions from C3H8NO2S+ to m/z 123 and 124 in the Biofield Energy Treated L-cysteine was significantly increased compared to the control sample. The changes in peak area and isotopic abundance ratios might be the cause of changes in nuclei possibly through the interference of neutrino particles via the Trivedi Effect®-Consciousness Energy Healing Treatment. The increased isotopic abundance ratio of the Biofield Energy Treated L-cysteine may increase the intra-atomic bond strength, increase its stability, and shelf-life. The novel Biofield Energy Treated L-cysteine might have increased the stability, solubility, bioavailability, and shelf-life compared to the control sample. The new form of Biofield Energy Treated L-cysteine would be a better and more stable precursor in the food, cosmetics, pharmaceuticals, personal-care products, additives to cigarettes (act as an expectorant), preventative or antidote for some of the negative effects of alcohol, acetaminophen overdose, clinically used ranging from baldness to psoriasis, excellent for the treatment of asthmatics by enabling them to stop theophylline and other medications, enhances the effect of topically applied silver, tin and zinc salts for preventing dental cavities. In the near future, this Biofield Energy Treated L-cysteine may play a better role in the treatment of diabetes, psychosis, cancer, and seizures.

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lunacornfan2k24 · 4 months

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I’ve seen other fanfic writers do an AO3 wrap up and tbh I’ve been kind of embarrassed to do one myself because I was only a productive writer from May to October which isn’t even half of the year (thanks to Jedi: survivor, bg3, and everything in my authors notes) but it was also my most productive year for writing fanfic that I wanted to do something so…

Ao3 statistics don’t easily separate by year for a multi chapter fic that I started back in 2021, but I can do a rough estimate of 2023 stats and then reflect on every fic that I’ve written this year. (Edit: by the time I finish writing this we will be a week into 2024 at least)

Almyrah’s AO3 2023 Year In Review:

New fics posted: The Spy and The Actor, Phoenix the Vampire Hunter

Fics updated: The Spy and The Liar: The Movie (6x)

Word count: ~50k

Comment threads: 48

Kudos: 81+

Best comment: @agent-calivide (in Exes and Ohs, chapter 7 of The Spy and The Liar: The Movie)

I have had so much support for my writing this year thanks to the amazing I Expect You To Die fandom and the IEYTD fandom discord in particular. To be honest, you guys really make it hard to be humble with how much love is showered over my fics and I am so grateful for every kudos, comment, and bookmark I’ve received since I started the Celebrity Crush series way back in 2021 when a certain actor lived in my head rent free.

Like I said before the statistics are rough estimates and I think that the best way to celebrate all I’ve done this past year is with words more than numbers and statistics.

The Spy and The Liar: The Movie

This is probably the best fic I’ve ever written! I am so proud of how it has grown beyond ten bullet points to be the 66k story it currently is with more to come. I’ve loved weaving foreshadowing and subtext into the story that I think most people have missed.

It’s also really hard to stay humble as this is the most love I’ve ever gotten on a fic and it has somehow seemingly become the Agent Phoenix/John Juniper fic on ao3. I’ve literally dropped all my other wips for other and bigger fandoms because of how much love and support it’s gotten. Especially because of the people in the fandom discord. Maybe it’s the instant appreciation but I had never been more motivated to write than when y’all shared your love for this fic and the Celebrity Crush series in general.

The Celebrity Crush series and ieytd was the first thing that got me back into writing after going through the most traumatic and violent loss and experience of my entire life back in 2020 (wasn’t even covid related lol). Literally an entire year had passed before I could write again. To know that this story has meant as much to you guys as he has to me has been the greatest gift that could ever been given to me.

Thank you.

The Spy and The Actor

This story wasn’t really supposed to be anything. The first (and only) chapter was written on a whim in one sitting based on a conversation in the fandom discord. Just the third time I’d be rewriting the ieytd 2 with an Agent Phoenix/John Juniper twist…

But then came the comments.

For those that don’t know, the point of the fic was that it was written and published by John Juniper but to come off as a fan thirsting for John instead of John thirsting for Phoenix. At its core it was me roleplaying as John Juniper. And the discord decided to roleplay in the comments as various characters from the games and of course I had to respond in character as John Juniper!

Even when I was a teen I thought roleplay was kinda cringe. But now? I get it, like I get it! I had so much fun roleplaying as John Juniper!!! I’m usually really nice so being able to just let go and be an absolute bitch. I’m so excited to work on the next chapter but I know it’ll have to be when I’ll have time to sit down and roleplay with everyone again.

Phoenix the Vampire Hunter

This was written for Calivide for beta reading a chapter in The Spy and The Liar: The Movie. This is the first fully alternate universe fic I’ve ever written and I absolutely adore the world I’ve created. It’s a sandbox that I’d love to play in more and I’d love for others to play in the sandbox too if they ever feel like it and write their own stories of the world. The ending I have planned leaves the world open for so many possible stories for myself or anyone to explore.

And I promise that I wrote vampire!Juniper before I ever played Baldur’s Gate III and fell in love with Astarion

God this got long but these fics mean so much more to me than simple statistics can tell and I hope people can see why I chose to elaborate on everything.

With 2024 signaling the 10th year of me writing and publishing fanfiction and with last year being so productive, I’m hoping to bring all of last years productivity into the new year as long as the video game industry stops releasing so many good games (I haven’t even gotten to spider-man 2 yet lol)

#Almyrah #ao3 writer #2023 ao3 wrapped #fanfic writing #ieytd #i expect you to die #ieytd fandom #ieytd2 #john juniper

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bookwhimses · 1 year

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People who still leave comments on Cheer Up Buttercup, I love you all and your reviews always seem to come in when I’m having a bad week. I honestly can’t begin to describe how much it means to me that people reread and still love that fic. It makes me feel so proud of it.

I have something around or possibly over twenty-eight DGHDA wips. I haven’t been able to write for a long time, and I went through a period where DGHDA in particular was weirdly triggering to engage in for ptsd reasons (don’t worry, there's no fandom drama or anything, I just had a traumatic event happen irl and my confused brain put the trauma in DGHDA). The fic I want to finish most though is a Farah introspec fic I wrote for a Big Bang partnered with Juniper, who was extremely understanding about me having a mental breakdown* and not finishing it. Every time I try to go back to it I feel paralysed by my own promise that it would be the first fic I published once I felt able to write again.

I’ve come to the conclusion that this is dumb. In June I was diagnosed with ADHD. Prior to that, if someone with ADHD told me, “Oh, I have this thing I feel stuck on, pathologically unable to finish; for a long time I was unable to look at it, and now I feel crushed by the weight of my own lack of action and the responsibility and the imagined failure I have projected onto myself, but I told myself I’m not going to do anything easy before I finish this incredibly difficult task,”

I would have said to them, “I’m sorry, but sounds insane. You have ADHD. I’m not a doctor, but from what I understand you don’t naturally produce enough dopamine to ram your head repeatedly into a wall of things that sound like the opposite of dopamine. You’ve set up a system wherein you have one very challenging objective, and you cannot engage in any of the behaviours that would make that objective easier for you until you finish that objective. This is not intelligent game design, and frankly it shows a total lack of kindness towards yourself. It is clearly not working. Try something else.”

It is very difficult to accept that what I would say to someone else is also what I deserve to hear and what is true for me. But every other month I still get comments from people from somewhere across the globe who read something I wrote and felt moved by it. And I think it's worth noting – it's vital for me to note to myself – that having the kind of brain I have does come with other skills.

When I wrote Cheer Up Buttercup I didn’t go into it with a grand plan, let alone conceptualise it as anything more moving or deep than “AU where everything is the same but Dirk works at Lush lol”. I wrote that first chapter fully expecting it to border on crackfic. I think to anyone reading it's obvious that it starts off matching the beats of a standard low-stakes shippy fluff fic. I got a lot of reviews that said things to the effect of "I thought this was going to be a dumb bath bomb store AU, then it got serious, what the fuck" and, honestly, that happened to me too as its writer. I followed that vein of joy of was something fluffy and silly and camp until I unexpectedly struck something more introspective that touched on heavier subject material.

And I have to stress, I don't mean that as "it started as cheap and stupid and then became a more worthwhile and meaningful fic", because the thing I love most about Cheer Up Buttercup is how it is both stupid and meaningful. It's fluffy and silly and camp, traits which are not easy or meaningless things to write, and it draws on very personal experiences, which can be exhausting to read. I still treasure reviews which say that the fluff made the serious less confronting and more accessible, that they didn't expect a Ted talk on mental health and cognitive behaviour patterns in the middle of their gay slowburn bath store AU but it had made them want to change the way they lived their life every day.

Since being diagnosed with ADHD I have suddenly had something to blame for traits I have that have been difficult to bear or highly inconvenient my whole life. I have had many days where I've broken down crying and said that I wished I didn't have ADHD and I could just Do Stuff Normally, With Planning And No Time Blindess. But Cheer Up Buttercup wasn't planned. It was entirely organic. I only sketched out the barest of plot outlines, which quickly spiralled into something completely different while I was writing the chapter where Todd decides to turn his life around. And I don't think I could have written it if I didn't have ADHD.

(I've also had multiple reviewers tell me that they love the way I write Dirk, particularly the neurodiverse aspects of his character. I write Dirk's neurodivergent expression partially based on my own feelings and experiences, and I always knew I had autism while writing Dirk, so I tagged "autistic Dirk" often. Being told that my Dirk seemed very ADHD was one of the first things that made me go, huh?? hmmm. uh-oh. nahhhh.)

I realise that I may sound here like I have a hugely inflated sense of self-importance and like I think my bath bomb store AU is a culturally relevant text soon to be studied in high schools across the nation. I promise I have no such illusions, it's one fic for a relatively small fandom, posted when the fandom was already losing traction and when hope of any further content was very slim. But I can't talk about that fic self-deprecatingly, I refuse to talk about it with anything other than affection and sincerity because it means a lot to me for many reasons, and chief among them is how much it means to other people.

I've had so many people leave comments or message me telling me that reading that fic made them want to change their life, or that they've reread it more than once and each time it motivates them to care for themselves. To me it doesn't matter if they're as successful as Todd is, or if the change is permanent, or even particularly long – and I definitely don't take credit for work that, ultimately, they and/or their loved ones do. I also know that I'm far from the only fic writer who's gotten reviews like that. But even then and either way, the value conferred onto that 100k ship fic by even one person telling me it has made them care about themself, even for just a moment, feels so immense to me that I can't picture the scope of it in my mind's eye.

By extension I feel a value has been conferred onto me, and my efforts, and my thoughts and feelings. And my brain, and the way it works. Because all of those things were put whole-heartedly into that fic. Again, I don't mean this in the sense of ego or importance but in the sense that it feels like being given a gift which in itself is the awareness of having a gift. Having it in the sense of being given it by others, having it in the sense of being born with it, having it in the sense that I want to give it to another person. It expands endlessly onto itself, precious and beautiful and startling. And a gift is something to be grateful for.

So, yes, alright, I may have not planned this post out either at all, as I very clearly start off saying that I can't describe how the reviews make me feel, then go on to try to describe how the reviews make me feel. And yes, this post may in fact have just been prompted by someone commenting on Cheer Up Buttercup and reminding me that I've written something worth rereading, and I likely would not have written this post this way if I knew how to Do Stuff Normal With Planning And No Time Blindness. But, thankfully, I have ADHD, so I just spent some uncertain amount of time realising that it's dumb that I'm imposing Do Stuff Normal People Rules on me, when I'm a Do Stuff At Total Random With Zero Planning But Golly Gosh, So Much Heart kind of person. And instead of waiting another two years for my brain to suddenly not have ADHD so I can finish my Farah fic and then, I don't know, become a bank clerk or something, I should just find a fic, any happy little fic, and write that. And trust that wherever it takes me will be more interesting than this.

And I miss the DGHDA universe. It is practically custom tailored for Do Stuff At Total Random With Zero Planning But Golly Gosh, So Much Heart kind of people. I miss finding a way to put a horse in a bathroom in every fic. I'll stop doing it once it stops being funny to me personally.

*As in I literally had a mental breakdown, that’s why I disappeared from the fandom. Not that I was a prominent person in any way I just mean that I used to interact with mutuals and friends a lot on Discord and Tumblr and then I just sort of disappeared.

#i know like three people will see this most likely but pls dont reblog #i can't honestly imagine anyoen would i just put that tag on to anything i don't want reblogged #shout out to ao3 user aindia for the comments ily <3 #cheer up buttercup #this is not me giving up on my farah fic btw i will never truly give up on her #i've done a todd introspec fic and i've thought extensively about dirk introspec enough to have basically written one #farah deserves more content bc here's the thing you're honour she's a nightmare #MY nightmare

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