Small molecular exogenous modulators of active forms of MMPs.

Matrix metalloproteinases (MMPs) are endopeptidases, and their activity depends on calcium and zinc metal ions. These enzymes are expressed originally in zymogenic form, where the active site of proteins is closed by a prodomain which is removed during activation. A homeostatic balance of their activity is primarily regulated by a 'cysteine switch' located on a consensus sequence of the prodomain and natural endogenous inhibitors, called tissue inhibitors of metalloproteinases (TIMPs). Breakage of this homeostasis may lead to various pathological conditions, which may require further activation and/or inhibition of these enzymes to regenerate that balance. Here, we report four modulators, more specifically, three inhibitors (I1, I2 and I3), and one exogenous activator (L) of the active form of human collagenase MMP-1 (without prodomain). The results were confirmed by binding studies using fluorescence-based enzyme assays.

Explaining the Unexplained: Examining the Predictive Value of Semen Parameters, Sperm DNA Fragmentation and Metal Levels in Unexplained Infertility.

Background: There is ongoing research to find an optimum modality to predict male fertility potential. Aims: To compare the semen parameters, sperm DNA damage and seminal metal levels of Zinc, Lead and Aluminium among the male partners of couples with unexplained infertility and men with proven fertility. Settings and Design: Prospective case-control study at a tertiary level teaching hospital. Materials and Methods: One hundred male partners of couples with unexplained subfertility and 50 men with proven fertility were included in the study. Male partners of unexplained infertility couples and fertile men were compared for their semen parameters, sperm DNA Fragmentation Index (DFI) and seminal metal levels in semen. Statistical Analysis Used: Chi-square test, Student's t-test, sensitivity and specificity analysis, binomial logistic regression analysis. Results: Fertile men had statistically significantly higher mean progressive sperm motility than male partners of unexplained infertility (53.12 ± 9.89% vs. 44.81 ± 19.47%, P = 0.005). Semen volume and sperm concentration were comparable among the cases and control population. The mean sperm DFI was significantly lower among fertile men (10.83 ± 6.28 vs. 21.38 ± 10.28, P < 0.0001). Plotting the receiver-operating characteristic curve the threshold for discrimination was calculated to be 18% DFI. The sensitivity specificity and overall accuracy were 43%, 84% and 56.67%, respectively when the DFI cut-off was set at 18%. Zinc concentration in the semen had a strong positive correlation (Point Biserial correlation coefficient = 0.831) with fertility, whereas lead and aluminium had a moderate negative correlation. Conclusion: Conventional semen analysis had limited differentiating ability for unexplained infertility. The sperm DFI may be employed for explanatory purposes among couples with unexplained subfertility. A lower discriminatory threshold of DFI (18%) has better overall accuracy as opposed to a 30% cutpoint for unexplained subfertility. Among metals, Zinc was strongly correlated with fertility status.

Patterns of Neck Nodal Metastasis from Oral Cavity Carcinoma.

Nitin KhuntetaObjectives The aim is to study the patterns of lymph node metastasis from various sites in oral cavity cancer and determine the risk factors for metastasis. Materials and Methods It is a prospective observational study. The inclusion criteria were-245 patients of carcinoma buccal mucosa, anterior two-thirds of tongue, hard palate, oral surface of soft palate, floor of mouth, vestibule, and alveolus. The exclusion criteria were-patients who had received preoperative chemotherapy or radiotherapy and patients with recurrent disease. Statistical Methods All data were analyzed using SPSS 18.0 and Graphpad prism 7 software for statistical analysis. Count data have been expressed as percentages (%). The χ 2 test was used for univariate analysis of the risk factors of cervical lymph node metastasis. The odds ratio value (with 95% confidence interval) was used to express the risk of cervical lymph node metastasis. p -Value of <0.05 was considered as the difference with statistical significance. Results The most common site involved was buccal mucosa. Patterned lymph node metastasis was seen in 93.5% cases. Skip metastasis was seen in 4.31% cases. Level I b was the most common site of nodal involvement for all primary subsites of oral cavity cancer. The incidence of positive nodes on histopathological analysis was highest in cases of lower alveolus (63.15%), followed by tongue. Conclusion In our study, patterns of lymph node metastasis for oral cavity cancer were comparable to other studies with large number of subjects. The incidence of skip metastasis or aberrant status was low. On multivariate analysis, depth of invasion of tumor, pathologic grade, pathologic T stage, and morphologic type of growth were found to be independent predictors of risk for metastasis.

Changing pattern of admissions for acute myocardial infarction in India during the COVID-19 pandemic.

AIM: Studies on the changes in the presentation and management of acute myocardial infarction (AMI) during the COVID-19 pandemic from low- and middle-income countries are limited. We sought to determine the changes in the number of admissions, management practices, and outcomes of AMI during the pandemic period in India. METHODS & RESULTS: In this two-timepoint cross-sectional study involving 187 hospitals across India, patients admitted with AMI between 15th March to 15th June in 2020 were compared with those admitted during the corresponding period of 2019. We included 41,832 consecutive adults with AMI. Admissions during the pandemic period (n = 16414) decreased by 35·4% as compared to the corresponding period in 2019 (n = 25418). We observed significant heterogeneity in this decline across India. The weekly average decrease in AMI admissions in 2020 correlated negatively with the number of COVID cases (r = -0·48; r2 = 0·2), but strongly correlated with the stringency of lockdown index (r = 0·95; r2 = 0·90). On a multi-level logistic regression, admissions were lower in 2020 with older age categories, tier 1 cities, and centers with high patient volume. Adjusted utilization rate of coronary angiography, and percutaneous coronary intervention decreased by 11·3%, and 5·9% respectively. CONCLUSIONS: The magnitude of reduction in AMI admissions across India was not uniform. The nature, time course, and the patient demographics were different compared to reports from other countries, suggesting a significant impact due to the lockdown. These findings have important implications in managing AMI during the pandemic.

Prevalence and follow-up of subclinical rheumatic heart disease among asymptomatic school children in a north-western district of India based on the World Heart Federation echocardiographic criteria.

BACKGROUND: The present study is based on the World Heart Federation (WHF) echocardiographic criteria to assess the prevalence of subclinical rheumatic heart disease (RHD) and elucidate evolution of the disease when the cases were placed on appropriate antibiotic prophylaxis and regular follow-up. The prevalence of subclinical RHD reported by previous active surveillance studies among asymptomatic school children is not comparable to our study because of major differences in screening methods. METHODS: A random inclusion strategy was adopted to recruit urban and rural school children of Bikaner district in the state of Rajasthan, India. The diagnosis of RHD was based on the echocardiographic criteria proposed by the WHF. All studies were reported on-site by a single experienced cardiologist and the digitally preserved studies were reported by a second cardiologist off-site. The final diagnosis was made by consensus. The second echocardiogram was performed for cases diagnosed with RHD after two years from start of study to document early evolution of the disease with ongoing antibiotic prophylaxis. RESULTS: A high prevalence of subclinical RHD was observed in the study population. Pathological mitral and/or aortic valve regurgitation was the commonest lesion, and a significant proportion of cases improved while on regular antibiotic prophylaxis. No case showed fixity of leaflets/ stenosis. CONCLUSION: The prevalence of subclinical RHD is high in the study population, and the disease seems to regress over time in the presence of appropriate antibiotic prophylaxis.

Incidental Gallbladder Carcinoma in Gallbladder Polyps: Challenges of Gallbladder Malignancy for an Endemic Population.

BACKGROUND: Gallbladder polyps are considered pre-malignant lesions of gallbladder carcinoma. This study aims to highlight the role of early cholecystectomy in the management of gallbladder polyps in an endemic population. METHODS: A retrospective analysis of 2,076 lap cholecystectomy procedures performed at the Department of Surgical Gastroenterology at a tertiary referral centre in Northern India was conducted and incidental malignancy in gallbladder polyps analysed. The 8th edition of the American Joint Committee on Cancer for tumour-node-metastasis (TNM) staging of gallbladder carcinoma was used. RESULTS: Of 54 patients with gallbladder polyps, 53 had benign histology and one had malignant cells in the lamina propria suggestive of T1a adenocarcinoma. The patient with the malignant polyp was older (57 years old) than the patients in the non-cancer group, which had a mean age of 45 (P = 0.039). The size of the malignant polyp was approximately 4 mm, significantly smaller than the average 7.9 mm size of the benign polys (P = 0.031). CONCLUSION: Cholecystectomy needs to be considered early in the management of small-sized gallbladder polyps, particularly in areas endemic for gallbladder carcinoma.

Management of cardiovascular emergencies during the COVID-19 pandemic.

BACKGROUND: It has been reported that patients attending the emergency department with other pathologies may not have received optimal medical care due to the lockdown measures in the early phase of the COVID-19 pandemic. METHODS: This was a retrospective study of patients presenting with cardiovascular emergencies to four tertiary regional emergency departments in western India during the government implementation of complete lockdown. RESULTS: 25.0% of patients during the lockdown period and 17.4% of patients during the pre-lockdown period presented outside the window period (presentation after 12 hours of symptom onset) compared with only 6% during the pre-COVID period. In the pre-COVID period, 46.9% of patients with ST elevation myocardial infarction underwent emergent catheterisation, while in the pre-lockdown and lockdown periods, these values were 26.1% and 18.8%, respectively. The proportion of patients treated with intravenous thrombolytic therapy increased from 18.4% in the pre-COVID period to 32.3% in the post-lockdown period. Inhospital mortality for acute coronary syndrome (ACS) increased from 2.69% in the pre-COVID period to 7.27% in the post-lockdown period. There was also a significant decline in emergency admissions for non-ACS conditions, such as acute decompensated heart failure and high degree or complete atrioventricular block. CONCLUSION: The COVID-19 pandemic has led to delays in patients seeking care for cardiac problems and also affected the use of optimum therapy in our institutions.

Enzyme nanovehicles: Histaminase and catalase delivered in nanoparticulate chitosan.

Widespread skin allergies are of high societal concern. This pathology usually includes "histamine intolerance" and inflammatory processes affecting the skin. Oxidative stress, due to both intrinsic and environmental factors, leads to skin disorders, disease, and aging. Since the stratum corneum (SC) allows only small, lipophilic molecules to be absorbed through the skin, proteins, which are large amphoteric macromolecules, display limited bioavailability. The present study investigates the potential of chitosan nanoparticles as vehicle for two enzymes (catalytic proteins): catalase (CAT) and diamine oxidase (histaminase, DAO). Chitosan is an inexpensive, biocompatible, biodegradable, mucoadhesive, antibacterial, and antifungal biopolymer. Chitosan nanoparticles (CNP) have a high surface to volume ratio, hence high surface charge density and stronger biological activity than chitosan itself. CNP encapsulating DAO/CAT were prepared by using chitosans from different sources (shrimp and fungal). Nanoparticles were prepared by ionic complexation with sodium tripolyphosphate (TPP). Two different protein concentrations (0.5 mg/mL and 1.0 mg/mL) were investigated in the preparation of the nanoparticles. The resulting CNP were characterized by size (from 200 to 300 nm) and zeta potential (up to 9 mV) measurements, encapsulation efficiency (EE, up to 48%), loading capacity (LC, up to 42%), ratio of residual amino groups (RRAG, up to 14%), Fourier-transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and residual enzymatic activity. The antioxidant activity of the CNP encapsulating CAT was evaluated as well. The kinetics of protein release from the nanocomposites was monitored spectrophotometrically (for 160 h). Here we report that CAT was encapsulated with higher EE and residual enzymatic activity, while encapsulated DAO displayed better release profiles. Following encapsulation and release from CNP, both enzymes retained activity. The activities of DAO/CAT remained constant after five months in storage at -20 °C. These findings show that tailored nanosized chitosan affords enhancement to enzymes with low activity (like DAO) and shows promise as a carrier for therapeutic enzymes. Further investigations into its capability to increase their bioavailability are warranted.

Radial left ventricular dyssynchrony by speckle tracking in apical versus non apical right ventricular pacing- evidence of dyssynchrony on medium term follow up.

INTRODUCTION: To study effects of various sites of right ventricular pacing lead implantation on left ventricular function by 2-dimensional (2D) speckle tracking for radial strain and LV dyssynchrony. METHODS: This was retrospective prospective study. Fifteen patients each with right ventricular (RV) apical (RV apex and apical septum) and non-apical (mid septal and low right ventricular outflow tract [RVOT]) were programmed to obtain 100% ventricular pacing for evaluation by echo. Location and orientation of lead tip was noted and archived by fluoroscopy. Electrocardiography (ECG) was archived and 2D echo radial dyssynchrony was calculated. RESULTS: The baseline data was similar between two groups. Intraventricular dyssynchrony was significantly more in apical location as compared to non-apical location (radial dyssynchrony: 108.2 ± 50.2 vs. 50.5 ± 24, P < 0.001; septal to posterior wall delay [SLWD] 63.5 ± 27.5 vs. 34 ± 10.7, P < 0.001, SPWD 112.5 ± 58.1 vs. 62.7 ± 12.1, P = 0.003). The left ventricular ejection fraction was decreased more in apical location than non apical location. Interventricular dyssynchrony was more in apical group but was not statistically significant. The QRS duration, QTc and lead thresholds were higher in apical group but not statistically significant. CONCLUSION: Pacing in non apical location (RV mid septum or low RVOT) is associated with less dyssynchrony by specific measures like 2D radial strain and correlates with better ventricular function in long term.

Percutaneous Coronary Intervention in Single Coronary Artery from Right Sinus: Radial Route is Right.

We present percutaneous coronary intervention (PCI) using radial approach in a rare case of single coronary artery originating from the right sinus. Although these anomalies and stenosis of anomalous vessels have been described previously, treatment of atherosclerotic lesions by PCI has rarely been reported. There is a definite procedural risk during PCI in patients with a single ostium because dissection with the guiding catheter would result in a catastrophic event. Additionally, technical difficulties may occur due to the ostial configuration and course of the branch to be stented. The patient suffered an acute coronary syndrome-inferior wall STEMI, and was thrombolysed elsewhere within a window period of 4 h. He had post myocardial infarction (MI) angina and was referred to our center after 3 days of thrombolysis. We present this technically challenging and rare case in which PCI of right coronary artery was performed through the radial route.

A case of 'Masquerading' bundle branch block: a forgotten concept.

'Masquerading' bundle branch block (right bundle branch block in the precordial leads with left bundle branch block in frontal leads and left axis deviation) is seen most commonly with coronary artery disease and hypertension. No definite explanation is available so far for these changes. We are presenting a case of rare congenital intranuclear inclusion myopathy with congestive heart failure and 'Masquerading' bundle branch block in ECG.

Cardiac rhabdomyoma in familial tuberous sclerosis.

Cardiac rhabdomyomas are often associated with tuberous sclerosis in infants. We report a 5 month old child presented with a tumor in the right ventricle and echocardiography features of rhabdomyoma. Both the child and her father had cutaneous features of tuberous sclerosis. In the absence of features of congestive heart failure, surgery is rarely required.

Cor triatiratum dexter: a rare cause of isolated right atrial enlargement.

Cor triatriatum sinistrum (division of the left atrium) is a recognized clinical and surgical entity. Division of the right atrium, also known as cor triatriatum dexter, is an extremely rare congenital abnormality in which persistence of the right valve of the embryonic systemic sinus venosus divides the right atrium into two chambers. Typically, the right atrial partition is due to exaggerated fetal eustachian and thebesian valves, which together form an incomplete septum across the lower part of the atrium. This septum may range from a reticulum to a substantial sheet of tissue. Cor triatriatum dexter can be diagnosed at any age, especially if it is incidentally discovered. Usually, this anomaly is recorded at necropsy. This report describes the case of a divided right atrium evaluated for nonspecific symptoms and unexplained cardiomegaly with right atrial enlargement.

Two pacing spikes on the QRS complex in a single-chamber pacemaker.

AutoCapture algorithm helps the pacemakers to automatically adjust output close to the pacing threshold. This algorithm monitors the evoked response signal of myocardial depolarization, and delivers a high output back-up pulse if there is a loss of capture. This case, with two pacemaker spikes on the QRS complexes in a patient with VVI pacemaker, simulating a sensing failure, demands clear understanding of AutoCapture function before labeling the pacemaker malfunction.