An Observational Study of Dermoscopic and Histopathological Correlation in Spongiotic Disorders - A Hospital Based Cross Sectional Study.

Introduction: Spongiosis is defined as intercellular edema and vesicles in the epidermis. Histopathology is the gold standard for the diagnosis of spongiotic disorders. Clinical diagnosis of eczema is sometimes unclear and confused with other dermatoses; histopathology often shows spongiotic tissue reaction patterns; such conditions are called spongiotic disorders. It is challenging for a dermatologist to make the correct diagnosis noninvasively with a dermoscope and thus we have taken up the study to correlate the dermoscopic and histopathological findings in spongiotic disorders to set dermoscopic criteria for the diagnosis. Objective: To study the dermoscopic features of spongiotic disorders and correlate clinical, dermoscopic, and histopathological findings. Materials and Methods: Two hundred fifty two patients, with history and clinical presentation suggesting eczema were enrolled. They were classified as Acute (<6 weeks), Subacute (6 weeks to 3 months), and Chronic (>3 months) eczemas based on duration. Dermoscopy and skin biopsy were performed on representative lesions. Data were compiled and statistically analyzed using frequency distribution and Chi-square test. Results: We correlated the diagnosis based on acute, subacute, and chronic with three modalities, clinical examination, dermoscopy, and histopathology. On clinical examination, acute (27.4%), subacute (42.9%), and chronic (29.7%) dermatitis. On dermoscopy, acute (28.5%), subacute (40.4%), and chronic (31.1%) dermatitis. On histopathology, acute (29.5%), subacute (44.2%), and chronic (26.3%) spongiosis. A positive correlation of 99%, 96.2%, and 95% was observed on dermoscopy and histopathology, in acute, subacute, and chronic eczemas, respectively. Dermoscopy of acute eczemas showed linear vessels (100%) and red background (100%). White-Clods (98.9%) and excoriation marks (70.1%). Dermoscopy of subacute eczemas showed white scales (99.1%), irregular pigment network (98.3%), vascular changes with irregular dots (97.4%), a brown-white background (93.1%), and black/brown/grey dots (91.4%). Dermoscopy of chronic eczema showed brown-white background (100%), irregular pigment network (100%), and black/brown/grey blotches (100%). Conclusion: Definitive dermoscopic patterns are observed consistently with spongiotic diseases and these can be used additionally to set dermoscopic criteria and confirm the diagnosis. Also, dermoscopic findings are well correlated with the already established histopathological features.

Monotherapy of Biofiller for Atrophic Acne Scars: A Prospective Nonrandomized Study.

Background: Atrophic acne scarring is an unpleasant and often permanent complication and a therapeutic challenge for dermatologists. Platelet-poor plasma (PPP) gel injections are derived from the patient's own blood and used as a "biofiller" for skin rejuvenation. Objectives: The objective was to study the efficacy and safety profile of PPP gel in atrophic acne scars. Materials and Methods: Thirty patients with atrophic acne scars were included in the study. Topical anesthesia was applied on the area of interest 45 min prior to the procedure. 20 mL of blood was collected in eight sodium citrate bulbs and centrifuged to get PPP that is coagulated with heat to form gel. This gel (biofiller) was injected in the scarred areas monthly for 6 months. Patients were evaluated using Goodman and Baron Scar (GBS) scale (quantitative and qualitative), Physician Global Assessment, and Visual Analogue Scale (VAS) at each visit. The final visit was after 3 months of the last procedure. Results: The mean value of GBS at the first visit was 28, which reduced to 8.2 at the final visit. The analysis of variance test was applied to the quantitative scale from the baseline visit to the final visit. The F value was 462.55 with a P value < 0.0001. The paired t-test was applied for the GBS quantitative scale, which showed a value of 22.86 with a P value of <0.001. Transient local side effects were noted. Conclusion: Biofiller is efficacious in improving atrophic acne scars. It is a simple, minimally invasive, cost-effective procedure with no risk of immunogenic reaction.

Outcomes of symptomatic coronavirus disease 19 in maintenance hemodialysis patient in India.

BACKGROUND: Maintenance hemodialysis (MHD) patients face disadvantages with higher risk of acquiring SARS-CoV-2 infection, atypical manifestations, and associated multiple comorbidities. We describe patients' outcomes with symptomatic COVID-19 on MHD in a large cohort of patients from India. METHODS: Data were collected prospectively from hemodialysis units in 11 public and private hospitals between March 15, 2020, and July 31, 2020. The survival determinants were analyzed using stepwise backward elimination cox-regression analysis. RESULTS: Of the 263 total patients (mean age 51.76 ± 13.63 years and males 173) on MHD with symptomatic COVID-19, 35 (13.3%) died. Those who died were older (p = 0.01), had higher frequency of diabetic kidney disease (p = 0.001), comorbidities (p = 0.04), and severe COVID-19 (p = 0.001). Mortality was higher among patients on twice-weekly MHD than thrice-weekly (p = 0.001) and dialysis through central venous catheter (CVC) as compared to arteriovenous fistula (p = 0.001). On multivariate analysis, CVC use (HR 2.53, 95% CI 1.26-5.07, p = 0.009), disease severity (HR = 3.54, 95% CI 1.52-8.26, p = 0.003), and noninvasive ventilatory support (HR 0.59, 95% CI 0.25-0.99, p = 0.049) had significant effect on mortality. CONCLUSION: The adjusted mortality risk of COVID-19 in MHD patients is high in patients associated with severe COVID-19 and patients having CVC as vascular access.

Sex Proportionality in Pre-clinical and Clinical Trials: An Evaluation of 22 Marketing Authorization Application Dossiers Submitted to the European Medicines Agency.

This study assessed to what extent women were included in all phases of drug development; whether the clinical studies in the marketing authorization application dossiers include information per sex; and explored whether there are differences between women and men in the drugs' efficacy and safety. Data were extracted from dossiers submitted to the European Medicines Agency. Twenty-two dossiers of drugs approved between 2011 and 2015 for the treatment of various diseases were included. Female animals were included in only 9% of the pharmacodynamics studies, but female and male animals were included in all toxicology studies. Although fewer women than men were included in the clinical studies used to evaluate pharmacokinetics (PK) (29 to 40% women), all dossiers contained sex-specific PK parameter estimations. In the phase III trials, inclusion of women was proportional to disease prevalence for depression, epilepsy, thrombosis, and diabetes [participation to prevalence ratio (PPR) range: 0.91-1.04], but women were considered underrepresented for schizophrenia, hepatitis C, hypercholesterolemia, HIV, and heart failure (PPR range: 0.49-0.74). All dossiers contained sex-specific subgroup analyses of efficacy and safety. There seemed to be higher efficacy for women in one dossier and a trend toward lower efficacy in another dossier. More women had adverse events in both treatment (73.0 vs. 70.6%, p < 0.001) and placebo groups (69.5 vs. 65.5%, p < 0.001). In conclusion, women were included throughout all phases of clinical drug research, and sex-specific information was available in the evaluated dossiers. The included number of women was, however, not always proportional to disease prevalence rates.

The Adverse Effect of COVID Pandemic on the Care of Patients With Kidney Diseases in India.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic has affected the care of patients with noncommunicable diseases, including those suffering from kidney-related ailments. Many parts of the world, including India, adopted lockdown to curb community transmission of disease. The lockdown affected transportation, access to health care facilities, and availability of medicines and consumables as well as outpatient and inpatient services. We aimed to analyze the effect of lockdown imposed due to the COVID-19 pandemic on the care of patients with kidney diseases in India. METHODS: We surveyed 19 major hospitals (8 in the public and 11 in the private sector) to determine the effect of lockdown on the care of patients with kidney disease, including those on dialysis after the first 3 weeks of lockdown. RESULTS: The total number of dialysis patients in these centers came down from 2517 to 2404. Approximately 710 (28.2%) patients missed 1 or more dialysis sessions, 69 (2.74%) required emergency dialysis sessions, 104 (4.13%) stopped reporting for dialysis, and 9 (0.36%) were confirmed to have died. Outpatient attendance in the surveyed hospital came down by 92.3%, and inpatient service reduced by 61%. Tele-consultation was started but was accessed by only a small number of patients. CONCLUSION: Lack of preparedness before lockdown resulted in an interruption in health care services and posed an immediate adverse effect on the outcome of dialysis patients and patients with kidney disease in India. The long-term impact on the health of patients with less severe forms of kidney disease remains unknown.

Influence of IL-1ß, STAT3 & 5 and TLR-5 gene polymorphisms on rheumatic heart disease susceptibility in north Indian population.

BACKGROUND: Rheumatic heart disease (RHD) is the most serious complication of heart that comprises inflammatory reactions in heart valves. Many studies have demonstrated the contribution of host genetic factors in susceptibility to RHD and many cytokine gene variants have been linked with susceptibility to RHD. We sought to determine the role of genetic variants in IL-1ß, STAT3, STAT5B and TLR5 genes in conferring risk of RHD in two cohorts of RHD patients. METHODS: The study included 400 echocardiography confirmed RHD patients and 300 controls from North Indian Population. We categorized RHD patients into two sub-groups based on involvement of heart valves, mitral valve lesion alone (MVL), and combined valve lesions including mitral valve (CVL). Genotyping for all the polymorphisms was done using TaqMan /PCR-RFLP methods. RESULTS: Our results showed that the genotypic frequencies of IL-1ß, STAT3, STAT5B andTLR5 genes polymorphisms were significantly associated with RHD risk. To validate our results, we performed a replication study in additional 200 cases with similar clinical characteristics and results again confirmed consistent findings with RHD risk. In subgroup analysis, STAT3 polymorphism remained significant with MVL in RHD patients. CONCLUSION: IL-1ß, STAT3, STAT5B and TLR5 genes polymorphism may be useful markers for the identification of individuals with high risk of RHD in the susceptible population.

Proteasome-targeted nanobodies alleviate pathology and functional decline in an α-synuclein-based Parkinson's disease model.

Therapeutics designed to target α-synuclein (α-syn) aggregation may be critical in halting the progression of pathology in Parkinson's disease (PD) patients. Nanobodies are single-domain antibody fragments that bind with antibody specificity, but allow readier genetic engineering and delivery. When expressed intracellularly as intrabodies, anti-α-syn nanobodies fused to a proteasome-targeting proline, aspartate or glutamate, serine, and threonine (PEST) motif can modulate monomeric concentrations of target proteins. Here we aimed to validate and compare the in vivo therapeutic potential of gene therapy delivery of two proteasome-directed nanobodies selectively targeting α-syn in a synuclein overexpression-based PD model: VH14*PEST (non-amyloid component region) and NbSyn87*PEST (C-terminal region). Stereotaxic injections of adeno-associated viral 5-α-syn (AAV5-α-syn) into the substantia nigra (SN) were performed in Sprague-Dawley rats that were sorted into three cohorts based on pre-operative behavioral testing. Rats were treated with unilateral SN injections of vectors for VH14*PEST, NbSyn87*PEST, or injected with saline 3 weeks post lesion. Post-mortem assessments of the SN showed that both nanobodies markedly reduced the level of phosphorylated Serine-129 α-syn labeling relative to saline-treated animals. VH14*PEST showed considerable maintenance of striatal dopaminergic tone in comparison to saline-treated and NbSyn87*PEST-treated animals as measured by tyrosine hydroxylase immunoreactivity (optical density), DAT immunoreactivity (optical density), and dopamine concentration (high-performance liquid chromatography). Microglial accumulation and inflammatory response, assessed by stereological counts of Iba-1-labeled cells, was modestly increased in NbSyn87*PEST-injected rats but not in VH14*PEST-treated or saline-treated animals. Modest behavioral rescue was also observed, although there was pronounced variability among individual animals. These data validate in vivo therapeutic efficacy of vector-delivered intracellular nanobodies targeting α-syn misfolding and aggregation in synucleinopathies such as PD.

Influence of cytokine gene polymorphism on the risk of rheumatic heart disease - A meta-analysis.

RHD is an inflammatory disease resulting from interactive immune, genetic, and environmental factors. Various, epidemiological studies have shown the association of genetic variants of cytokine genes with a predisposition to RHD. However, the results from different populations are inconsistent. Therefore, we carried out a meta- analysis of twenty-three published case-control studies and the results indicated that TGF-ß1 +869 T/C (T vs. C: OR = 7.68, 95% CI = 1.62-36.50; TT + CT vs. CC OR = 1.83, 95%CI = 1.39-2.41), TGF-ß1-509 (T vs. C: OR = 2.76, 95% CI = 1.33-5.75), TNF-α(AA vs. GG: OR = 4.93,95% CI = 2.83-8.58; A vs. G: OR = 2.15, 95% CI = 1.13-4.12) and IL-1ß -511C/T (CC + CT vs. TT: OR = 1.35, 95%CI = 1.02-1.78; C vs. T: OR = 2.36, 95% CI = 1.66-3.37) were significantly associated with increased risk of RHD. On the other hand, IL-10(-1082)G/A polymorphism (GA vs. AA: OR = 0.91, 95% CI = 0.36-2.33; G vs. A: OR = 1.90, 95% CI = 0.58-6.22) and IL-6-174 G/C (CC + GC vs. GG: OR = 0.68, 95%CI = 0.32-1, C vs. G: OR = 1.14, 95% CI = 0.82-1.60) were not associated with modified RHD risk. The meta-analysis results were similar in Asians and non-Asians. Therefore, cytokine gene polymorphisms play important role in the genetic susceptibility of RHD in rheumatic fever patients.

Role of common sarcomeric gene polymorphisms in genetic susceptibility to left ventricular dysfunction.

Mutations in sarcomeric genes are common genetic cause of cardiomyopathies. An intronic 25-bp deletion in cardiac myosin binding protein C (MYBPC3) at 3' region is associated with dilated and hypertrophic cardiomyopathies in Southeast Asia. However, the frequency of sarcomeric gene polymorphisms and associated clinical presentation have not been established with left ventricular dysfunction (LVD). Therefore, the aim of the present study was to explore the association of MYBPC3 25-bp deletion, titin (TTN) 18 bp I/D, troponin T type 2 (TNNT2) 5 bp I/D and myospryn K2906N polymorphisms with LVD. This study includes 988 consecutive patients with angiographically confirmed coronary artery disease (CAD) and 300 healthy controls. Among the 988 CAD patients, 253 with reduced left ventricle ejection fraction (LVEF≤45%) were categorized as LVD. MYBPC3 25-bp deletion, TTN 18 bp I/D and TNNT2 5 bp I/D polymorphisms were determined by direct polymerase chain reaction method, while myospryn K2906N polymorphism by TaqMan assay. Our results showed that MYBPC3 25-bp deletion polymorphism was significantly associated with elevated risk of LVD (LVEF <45) (healthy controls versus LVD: OR=3.85, P <0.001; and nonLVD versus LVD: OR=1.65, P = 0.035), while TTN 18 bp I/D, TNNT2 5 bp I/D and myospryn K2906N polymorphisms did not show any significant association with LVD. The results also showed that MYBPC3 25-bp deletion polymorphism was significantly associated with other parameters of LV remodelling, i.e. LV dimensions (LV end diastole dimension, LVEDD: P = 0.037 and LV end systolic dimension, LVESD: P = 0.032). Our data suggests that MYBPC3 25-bp deletion may play significant role in conferring LVD as well as CAD risk in north Indian population.

Can intrabodies serve as neuroprotective therapies for Parkinson's disease? Beginning thoughts.

Misfolded proteins and subsequent protein aggregation appears to underlie a significant fraction of neurodegenerative diseases including Parkinson's disease. One of the neuropathological hallmarks of Parkinson's disease is the presence of α-syn containing intracellular inclusions known as Lewy bodies and Lewy neurites. Intrabodies are antibody fragments that have been engineered to be expressed intracellularly. They can be directed towards specific target antigens present in various subcellular locations, and have shown promise in cancer, HIV, autoimmune diseases, and Huntington's disease. More recently they have been shown to modulate abnormalities caused by aggregated α-syn in cell culture. This mini-review mainly focuses on summarizing structural and cellular effects of intrabodies shown to have affinity for different forms of α-synuclein (monomeric, oligomeric and fibrillar), as well as those exhibiting affinity for particular residues of α-synuclein (e.g., the NAC region, C terminal region).

Managing reduced methotrexate clearance in a patient with a heterozygous methylenetetrahydrofolate reductase gene polymorphism.

High dose methotrexate has become one of the treatments of choice for patients with primary CNS lymphomas due to its ability to penetrate the blood-brain barrier. A potentially serious complication of this therapy is methotrexate-related nephrotoxicity. We report the case of a patient with a common genetic polymorphism that may have predisposed this patient experience clinically significant toxicity from systemic folate depletion. After the first cycle of chemotherapy that included high dose methotrexate, the patient's serum creatinine rose and the patient's methotrexate level remained above the toxic range for six days. On cycle two, the patient was treated with a 25% dose reduction in methotrexate and more aggressive hydration and alkalization. With this alteration in the regimen, the patient was able to receive six more cycles and had a complete radiographic tumor response in the brain and a disappearance of tumor cells in the CSF without any further renal complications. This case report illustrates the feasibility of administering high dose methotrexate with modifications as a treatment of choice in individuals with methylenetetrahydrofolate reductase gene mutations.

Intrathecal topotecan in adult patients with neoplastic meningitis.

PURPOSE: The efficacy and safety of intrathecal topotecan were assessed in patients with neoplastic meningitis (NM) by retrospective chart review. SUMMARY: Fourteen patients (median age, 57 years) with NM were treated with the standard of care (i.e., regional or systemic chemotherapy or irradiation or both) plus intrathecal topotecan between January 2004 and September 2005. Three patients developed NM in the setting of systemic cancer; 11 patients had primary central nervous system (CNS) malignancies. All patients received 0.4 mg of topotecan intrathecally two times per week. The efficacy of intrathecal topotecan was assessed on the basis of the number of doses to cerebrospinal fluid (CSF) cytologic clearing--defined as the disappearance of malignant cells from a previously positive CSF cytology. Safety was evaluated by chart documentation of adverse events that might have been associated with topotecan given intrathecally. Of the 11 patients with primary CNS tumors, 6 patients achieved CSF clearing after the first dose of intrathecal topotecan, 2 patients after the second dose, and 1 patient after the fifth dose. For the 3 patients with secondary CSF tumors, 1 patient achieved CSF clearing after the third dose and 2 patients did not reach the primary endpoint. Overall, 6 of the 14 patients achieved CSF clearing after the first dose of intrathecal topotecan; in 10 of the 14 patients, CSF clearing of malignant cells was observed at some point during treatment. Toxicity was modest. The most common adverse effect reported was fatigue. CONCLUSION: Intrathecal topotecan appeared to be effective and safe in adult patients with NM.

Reduced-dose rasburicase in the treatment of adults with hyperuricemia associated with malignancy.

Tumor lysis syndrome is a life-threatening complication of chemotherapy for patients with leukemia and large tumors with a high proliferative index, such as Burkitt's lymphoma. The syndrome is characterized by hyperkalemia, hyperphosphatemia, hypocalcemia, and hyperuricemia. The standard of care for hyperuricemia consists of hydration with or without alkalinization and administration of allopurinol. When treated in this manner, patients often experience persistent hyperuricemia that lasts several days after the start of antineoplastic therapy; sometimes they develop uric acid nephropathy as a consequence. Rasburicase, a recombinant urate oxidase enzyme, quickly removes large amounts of uric acid from plasma. The drug is approved by the United States Food and Drug Administration for management of elevated plasma uric acid levels in pediatric patients with leukemia, lymphoma, or solid tumor malignancies who are receiving chemotherapy. We undertook a retrospective review of adult patients treated with a single dose of rasburicase 6 mg for hyperuricemia associated with malignancy. Ten patients received one 6-mg dose of rasburicase, and one patient received two 6-mg doses as an adjuvant therapy to normalize uric acid levels. In most of the patients, a single 6-mg dose of rasburicase was effective in correcting uric acid levels in the typical time between diagnosis and start of antineoplastic therapy.