The socio-demographic determinants of the outcome of type 1 cartilage tympanoplasty in children: Results from a tertiary-care teaching institute in India.

OBJECTIVE: To explore whether and how the established socio-demographic parameters pertaining to a lower-middle income nation influence the outcome of cartilage tympanoplasty in children with chronic otitis media (COM), inactive mucosal variety. METHODS: In this prospective cohort study, children aged 5-12 years with COM (dry, large/subtotal perforation) were considered for type 1 cartilage tympanoplasty following definite selection criteria. Relevant socio-demographic parameters were noted for each child. These included parents' education (literate/illiterate), living area (slum/village/others), mothers' occupation (laborer/business/housewife or home-maker), family type (nuclear/joint), and monthly family income. Outcome at 6 months follow-up was interpreted as "success" (favorable; anatomically intact and well-epithelialized neograft and dry ear) and "failure" (unfavorable; residual or recurrent perforation and/or discharging ear). The role of individual socio-demographic factor in determining the outcomes was analyzed with relevant statistical methods. RESULTS: The average age of the 74 children included in the study was 9.30 ± 2.13 years. At six months, 86.5% had a successful outcome, with a statistically significant hearing gain (closure of the air-bone gap) of 17.02 ± 8.96 dB (p = .003). Mothers' education had a significant influence on the success rate (Chi: 4.13; significant at p < .05); children of ∼97% of the literate mothers had a successful outcome. Living area was significantly associated with success (Chi: 13.94; significant at p < .01); ∼90% of children living in the slum areas had success, compared to 50% of those residing in villages. The family type also significantly influenced the surgical outcome (Chi: 3.81; significant at p < .05); ∼97% of the children belonging to the joint families encountered success, compared to ∼81% of those brought up in the nuclear families. The success also depended on the mothers' occupation (Chi: 6.47; significant at p < .05); ∼97% of the housewife mothers had children who were successful, against ∼77% of mothers engaged as laborers. Another factor significantly associated with success was the monthly household income. Nearly 97% of the children belonging to families with a monthly household income of >₹3000 (cut-off limit set by the median value) experienced success, in contrast to 79% of those having a monthly family income of <₹3000 (Chi: 4.83; significant at p < .05). CONCLUSION: Socio-demographic parameters are valuable determinants of the outcome of surgical management of COM in children. For type 1 cartilage tympanoplasty, mothers' education and occupation, family type, living area, and monthly family income significantly influenced the surgical outcome.

Phase IV postmarketing surveillance study shows continued efficacy and safety of Stempeucel in patients with critical limb ischemia due to Buerger's disease.

Buerger's disease or thromboangiitis obliterans is a type of obstructive vascular diseases categorized as vasculitis and usually present in 95% of young smoker men. The main pathogenetic mechanism is interplay between immune system and inflammation. Earlier our phase II study has shown that Stempeucel is safe when injected at 2 million cells/kg body weight by virtue of its anti-inflammatory, immunomodulatory, and angiogenetic properties. The present study was conducted to further assess the safety and efficacy of Stempeucel in critical limb ischemia due to Buerger's disease after obtaining approval from Indian FDA based on the data generated in the phase II study. This is an open label, multicenteric phase IV PMS study conducted across India with experienced vascular surgeons. Fifty patients of critical limb ischemia due to Buerger's disease with Rutherford III-5 or III-6 were included in the study and each individual received a dose of 2 million cells/kg body weight of Stempeucel in the calf muscles and around the ulcer. These patients were evaluated over 12 months from drug administration. The present study showed the continued long term efficacy over a period of 12 months follow up in these patients corroborating the result obtained in the previous phase II studies. There was significant improvement in rest pain, ankle systolic pressure, and ankle brachial pressure index with accelerated ulcer healing. In conclusion, the present study shows that the intramuscular administration of Stempeucel continues to be safe, tolerable, and effective alternative treatment in patients with Buerger's disease.

Population Pharmacokinetic Analysis of BMS-986166, a Novel Selective Sphingosine-1-Phosphate-1 Receptor Modulator, and Exposure-Response Assessment of Lymphocyte Counts and Heart Rate in Healthy Participants.

Sphingosine-1-phosphate (S1P) binding to the S1P-1 receptor (S1P1R) controls the egress of lymphocytes from lymphoid organs and targets modulation of immune responses in autoimmune diseases. Pharmacologic modulation of S1P receptors has been linked to heart rate reduction. BMS-986166, a prodrug of the active phosphorylated metabolite BMS-986166-P, presents an improved cardiac safety profile in preclinical studies compared to other S1P1R modulators. The pharmacokinetics, safety, and pharmacodynamics of BMS-986166 versus placebo after single (0.75-5.0 mg) and repeated (0.25-1.5 mg/day) oral administration were assessed in healthy participants after a 1-day lead-in placebo period. A population model was developed to jointly describe BMS-986166 and BMS-986166-P pharmacokinetics and predict individual exposures. Inhibitory sigmoid models described the relationships between average daily BMS-986166-P concentrations and nadir of time-matched (day -1) placebo-corrected heart rate on day 1 (nDDHR, where DD represents ∆∆) and nadir of absolute lymphocyte count (nALC). Predicted decreases in nDDHR and nALC were 9 bpm and 20% following placebo, with maximum decreases of 10 bpm in nDDHR due to drug effect, and approximately 80% in nALC due to drug and placebo. A 0.5-mg/day dose regimen achieves the target 65% reduction in nALC associated with a 2-bpm decrease in nDDHR over placebo.

The safety and pharmacokinetics of a novel, selective S1P1R modulator in healthy participants.

Background: Safety, pharmacokinetics and pharmacodynamics of BMS-986166, a novel sphingosine-1-phosphate receptor 1 modulator, were assessed.Research design and methods: Two double-blind, placebo-controlled, randomized Phase l studies were conducted in healthy participants. In the single ascending dose study (N = 70), BMS-986166 was administered as a single dose, upwardly titrated daily doses or a single dose in participants who were fed, fasted or administered famotidine. In the multiple ascending dose study (N = 32), BMS-986166 was administered daily for 28 days. Safety, pharmacokinetics and pharmacodynamics (absolute lymphocyte count [ALC]) were assessed.Results: BMS-986166 was generally well tolerated; treatment-related adverse events were mild. Dose-related, clinically insignificant reductions in time-matched heart rate were recorded versus placebo. Pharmacokinetics were linear and stationary with approximately dose-related increases in blood exposure of BMS-986166. Decreases in ALC percent change from baseline with multiple doses of BMS-986166 versus placebo were dose-related. Between Day 0 and 35, median nadir lymphocyte reductions were 53.7%, 75.9% and 81.9% with 0.25-, 0.75- and 1.5-mg BMS-986166 doses. ALC recovery began 14, 14-21 and 7 days after last dose of 0.25, 0.75 and 1.5 mg.Conclusions: BMS-986166 was generally well tolerated in this population and warrants further investigation.Trial registration: ClinicalTrials.gov: NCT02790125, NCT03038711.

Congenital Heart Disease in the Pediatric Population in Eastern India: A Descriptive Study.

This cross-sectional study assessed distribution and pattern of echocardiography confirmed congenital heart disease, among 593 pediatric patients in outpatient departments of a tertiary care hospital in eastern India. Commonest defects were ventricular septal defect (43, 40.7%), atrial septal defect (241, 31.7%), and tetralogy of Fallot (125, 21%).

Administration of Adult Human Bone Marrow-Derived, Cultured, Pooled, Allogeneic Mesenchymal Stromal Cells in Critical Limb Ischemia Due to Buerger's Disease: Phase II Study Report Suggests Clinical Efficacy.

Critical limb ischemia (CLI) due to Buerger's disease is a major unmet medical need with a high incidence of morbidity. This phase II, prospective, nonrandomized, open-label, multicentric, dose-ranging study was conducted to assess the efficacy and safety of i.m. injection of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells (BMMSC) in CLI due to Buerger's disease. Patients were allocated to three groups: 1 and 2 million cells/kg body weight (36 patients each) and standard of care (SOC) (18 patients). BMMSCs were administered as 40-60 injections in the calf muscle and locally, around the ulcer. Most patients were young (age range, 38-42 years) and ex-smokers, and all patients had at least one ulcer. Both the primary endpoints-reduction in rest pain (0.3 units per month [SE, 0.13]) and healing of ulcers (11% decrease in size per month [SE, 0.05])-were significantly better in the group receiving 2 million cells/kg body weight than in the SOC arm. Improvement in secondary endpoints, such as ankle brachial pressure index (0.03 [SE, 0.01] unit increase per month) and total walking distance (1.03 [SE, 0.02] times higher per month), were also significant in the group receiving 2 million cells/kg as compared with the SOC arm. Adverse events reported were remotely related or unrelated to BMMSCs. In conclusion, i.m. administration of BMMSC at a dose of 2 million cells/kg showed clinical benefit and may be the best regimen in patients with CLI due to Buerger's disease. However, further randomized controlled trials are required to confirm the most appropriate dose. Stem Cells Translational Medicine 2017;6:689-699.

Epistaxis Due to Leech Infestation in Nose: A Report of Six Cases and Review of Literature.

The aim of this study is to report unusual cause of epistaxis due to leech infestation in nose in hilly area and its management. The study was carried out for a period of 4 years (2008-2012) in a secondary level hospital in hilly area of Darjeeling, West Bengal, India with data collected from the OPD and Emergency register of the patients. This retrospective case series consisted of six cases. All the cases presented with unilateral recurrent epistaxis and foreign body nose. Anterior rhinoscopy revealed fleshy greenish brown mobile mass inside the nasal cavity which was removed by forceps. The animate foreign body was identified as leech in all the cases. To conclude, in hilly areas leech infestation can present as animate foreign body in nose and it should be considered as important cause of epistaxis.

Surgical treatment of pulmonary aspergillosis: A single center experience.

BACKGROUND: Aspergillus fumigatus is a saprophytic fungus which colonizes in the cavitary lesions in the lungs. In our part of the world, where tuberculosis is endemic, the healed tubercular cavities form a good nidus for this fungus. The fungus forms a fungal ball or aspergilloma within the cavity, which erodes the walls of the cavity and causes hemoptysis by erosion of the bronchial vessels. Hemoptysis is the main symptom. Antifungal agents are not useful against the fungal ball. Surgery in the form of lobectomy is the primary treatment. Surgery for aspergilloma is known to be risky because of intra-pleural adhesions, obliteration of the interlobar fissures, massive hemorrhage during dissection and poor pulmonary reserve of the patient due to the underlying disease. MATERIALS AND METHODS: Clinical presentation, radiological investigations, operative techniques, postoperative outcome, and follow-up of 24 cases of pulmonary aspergilloma treated surgically were studied prospectively between August 2010 and July 2013 at IPGMER and SSKM Hospital, Kolkata. RESULTS: There were 15 male (62.5%) and 9 female (37.5%) patients. Mean age of the study population was 34.54 years. All the patients had complex aspergilloma. Tuberculosis was the underlying disease in 22 patients (91%). Hemoptysis was the main symptom in 79.16% cases. Chest X-ray was the first investigation, which gave a clue to the diagnosis. Computed tomography scan was diagnostic in all cases. Lobectomy was done in 16 patients (66.67%). There was one mortality and the overall complication was 33.33%. The average follow-up period was 21.65 months, during which there was no mortality and no recurrence of hemoptysis in these patients. CONCLUSIONS: Though surgery for aspergilloma is considered to be risky, excision of the cavity along with the involved lobe can be done with acceptable morbidity and mortality to provide the patient complete cure and symptom-free survival.

Evaluation of the effects of the weak CYP3A inhibitors atorvastatin and ethinyl estradiol/norgestimate on lomitapide pharmacokinetics in healthy subjects.

Lomitapide is a microsomal triglyceride transfer protein inhibitor approved as an adjunctive treatment for adult patients with homozygous familial hypercholesterolemia. Lomitapide is extensively metabolized via cytochrome P450 3A (CYP3A) and is a weak CYP3A inhibitor. Two phase 1 open-label, randomized (1:1), 2-arm drug interaction studies in healthy subjects assessed the effects of atorvastatin and ethinyl estradiol (EE)/norgestimate, both weak CYP3A inhibitors, on lomitapide pharmacokinetics with staggered (separated by 12 hours) or simultaneous administration. All subjects received a single dose of lomitapide (20 mg) in the evening on day 1. Atorvastatin (80 mg once daily, n = 32) or EE/norgestimate (0.035/0.25 mg once daily, n = 32) dosing was initiated on days 11 or 8, respectively, with evening (arm 1) or morning (arm 2) dosing; at steady state (days 15 or 22), a single lomitapide dose was administered; CYP3A inhibitor dosing continued for 6 days. Blood samples for pharmacokinetic analysis were taken until 168 hours postdose. With atorvastatin, lomitapide exposure was increased by approximately 2-fold and 1.3-fold, respectively, with simultaneous and staggered administration, respectively. Simultaneous and staggered EE/norgestimate and lomitapide administration resulted in an approximately 1.3-fold increase in lomitapide exposure. Reductions in lomitapide dose may be required for some patients when administered concomitantly with a weak CYP3A inhibitor.

Activation of coagulation and fibrinolysis during coronary artery bypass grafting: a comparison between on-pump and off-pump techniques.

Coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB) is associated with intense activation of hemostatic mechanisms. But the precise knowledge of the effects of eliminating CPB in patients undergoing off-pump coronary artery bypass grafting (CABG) are not well established. The present study was carried out to compare and document the changes in selected coagulation and fibrinolysis variables in patients undergoing on-pump and off-pump CABG (OPCAB). A total of 42 patients of on-pump and 31 patients of off-pump CABG were selected for the study. Platelet count, prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), Fibrinogen and D-dimer levels were measured immediately, 24 h and 7 days after operation and compared with the baseline preoperative values. Statistical analysis was done by mixed ANOVA for repeated measures and Post-hoc tests using the Bonferroni correction, Chi square and unpaired t test. All the parameters were significantly changed (P < 0.05) with the time. Platelet counts, fibrinogen and D-dimer levels were significantly different between on-pump and off-pump CABG patients on immediate and 24 h postoperative period and attained almost same level after 7 days of operation. Fibrinogen level and platelet counts were increased after a sharp fall in the immediate post-operative period whereas D-dimer levels were persistently increased with a sharp peak of rise in the immediate post-operative period in on-pump group. On-pump surgery was associated with excessive fibrinolytic activity immediately after operation. The off-pump group demonstrated less activation of coagulation and fibrinolysis and delayed postoperative response that became almost equal to the on-pump group in the later postoperative period.

Proteomic analysis of human plasma in chronic rheumatic mitral stenosis reveals proteins involved in the complement and coagulation cascade.

BACKGROUND: Rheumatic fever in childhood is the most common cause of Mitral Stenosis in developing countries. The disease is characterized by damaged and deformed mitral valves predisposing them to scarring and narrowing (stenosis) that results in left atrial hypertrophy followed by heart failure. Presently, echocardiography is the main imaging technique used to diagnose Mitral Stenosis. Despite the high prevalence and increased morbidity, no biochemical indicators are available for prediction, diagnosis and management of the disease. Adopting a proteomic approach to study Rheumatic Mitral Stenosis may therefore throw some light in this direction. In our study, we undertook plasma proteomics of human subjects suffering from Rheumatic Mitral Stenosis (n = 6) and Control subjects (n = 6). Six plasma samples, three each from the control and patient groups were pooled and subjected to low abundance protein enrichment. Pooled plasma samples (crude and equalized) were then subjected to in-solution trypsin digestion separately. Digests were analyzed using nano LC-MS(E). Data was acquired with the Protein Lynx Global Server v2.5.2 software and searches made against reviewed Homo sapiens database (UniProtKB) for protein identification. Label-free protein quantification was performed in crude plasma only. RESULTS: A total of 130 proteins spanning 9-192 kDa were identified. Of these 83 proteins were common to both groups and 34 were differentially regulated. Functional annotation of overlapping and differential proteins revealed that more than 50% proteins are involved in inflammation and immune response. This was corroborated by findings from pathway analysis and histopathological studies on excised tissue sections of stenotic mitral valves. Verification of selected protein candidates by immunotechniques in crude plasma corroborated our findings from label-free protein quantification. CONCLUSIONS: We propose that this protein profile of blood plasma, or any of the individual proteins, could serve as a focal point for future mechanistic studies on Mitral Stenosis. In addition, some of the proteins associated with this disorder may be candidate biomarkers for disease diagnosis and prognosis. Our findings might help to enrich existing knowledge on the molecular mechanisms involved in Mitral Stenosis and improve the current diagnostic tools in the long run.

Clinical significance of markers of collagen metabolism in rheumatic mitral valve disease.

BACKGROUND: Rheumatic Heart Disease (RHD), a chronic acquired heart disorder results from Acute Rheumatic Fever. It is a major public health concern in developing countries. In RHD, mostly the valves get affected. The present study investigated whether extracellular matrix remodelling in rheumatic valve leads to altered levels of collagen metabolism markers and if such markers can be clinically used to diagnose or monitor disease progression. METHODOLOGY: This is a case control study comprising 118 subjects. It included 77 cases and 41 healthy controls. Cases were classified into two groups- Mitral Stenosis (MS) and Mitral Regurgitation (MR). Carboxy-terminal propeptide of type I procollagen (PICP), amino-terminal propeptide of type III procollagen (PIIINP), total Matrix Metalloproteinase-1(MMP-1) and Tissue Inhibitor of Metalloproteinase-1 (TIMP-1) were assessed. Histopathology studies were performed on excised mitral valve leaflets. A p value <0.05 was considered statistically significant. RESULTS: Plasma PICP and PIIINP concentrations increased significantly (p<0.01) in MS and MR subjects compared to controls but decreased gradually over a one year period post mitral valve replacement (p<0.05). In MS, PICP level and MMP-1/TIMP-1 ratio strongly correlated with mitral valve area (r = -0.40; r = 0.49 respectively) and pulmonary artery systolic pressure (r = 0.49; r = -0.49 respectively); while in MR they correlated with left ventricular internal diastolic (r = 0.68; r = -0.48 respectively) and systolic diameters (r = 0.65; r = -0.55 respectively). Receiver operating characteristic curve analysis established PICP as a better marker (AUC = 0.95; 95% CI = 0.91-0.99; p<0.0001). A cut-off >459 ng/mL for PICP provided 91% sensitivity, 90% specificity and a likelihood ratio of 9 in diagnosing RHD. Histopathology analysis revealed inflammation, scarring, neovascularisation and extensive leaflet fibrosis in diseased mitral valve. CONCLUSIONS: Levels of collagen metabolism markers correlated with echocardiographic parameters for RHD diagnosis.

Protective effect of aqueous Curry leaf (Murraya koenigii) extract against cadmium-induced oxidative stress in rat heart.

Treatment of rats with a low dose of cadmium chloride caused a significant damage in the rat cardiac tissue indicated by the increase in the level of serum glutamate oxaloacetate transaminase and lactate dehydrogenase1 activities. Histological studies confirmed the damage due to cadmium. That cadmium-induced tissue damage was caused due to oxidative stress was evident from the changes observed in the levels of lipid peroxidation and reduced glutathione, the protein carbonyl content, and the alterations in the activities of cardiac antioxidant and pro-oxidant enzymes. Treatment of rats with cadmium also caused alterations in the activities of mitochondrial Kreb's cycle as well as respiratory chain enzymes. All these changes were ameliorated when the rats were pre-treated with an aqueous extract of Curry leaf (Murraya koenigii). The studies indicated that the aqueous extract of Curry leaf protects the rat cardiac tissue against cadmium-induced oxidative stress possibly through its antioxidant activity. As curry leaf is consumed by people as part of their diet in India and South-East Asian and some European countries as well, and, as it has no reported side-effects, the results seem to have relevance at places where humans are exposed to cadmium environmentally or occupationally.

Evaluation of CNS activities of ethanol extract of roots and rhizomes of Cyperus rotundus in mice.

The ethanol extract of Cyperus rotundus (EECR) was tested for possible pharmacological effects on experimental animals. EECR significantly potentiated the sleeping time of mice induced by standard hypnotics, viz. pentobarbitone sodium, diazepam, and meprobamate in a dose dependent manner. EECR showed significant analgesic properties as evidenced by the significant reduction in the number of writhes and stretches induced in mice by 1.2% acetic acid solution. It also potentiated analgesia induced by morphine and pethidine in mice. Pretreatment with EECR caused significant protection against strychnine and leptazol-induced convulsions. The behavioral studies on mice indicate CNS depressant activity of the ethanol extract of C. rotundus.