Učinak vrućice uzrokovane endotoksinom bakterije E. coli na farmakokinetiku i doziranje ceftriaksona u ovaca (Ovis aries).

The effect of fever was studied on the pharmacokinetics of ceftriaxone (CTRX) following intravenous administration at the rate of 50 mg/kg b.m. in Chhotanagpuri sheep. Fever was induced by intravenous administration of E. coli serovar O126:B8 lipopolysaccharide, and plasma CTRX concentration was estimated by HPLC. The plasma drug concentration versus time curve best fitted a two compartment open model. The maximum plasma drug concentration was 16.33 per cent lower in febrile sheep (FS) in comparison to normal sheep (NS). In FS, t1/2α was lower, while t1/2β was higher than in NS. Vdarea and P: C ratio was higher in FS, but ClB and AUC did not differ significantly between the two groups. The results of the present study indicate that CTRX has greater distribution in the peripheral compartment during pyrexia. High values of K12/K /K21 ratio also indicated rapid drug distribution in various body fluids and compartments. The suitable dosage regimen of CTRX in FS by the intravenous route was calculated to be 15 mg/kg b.m. at a 5 h interval.Istraživan je učinak vrućice na farmakokinetiku ceftriaksona (CTRX) nakon njegove intravenske primjene u dozi od 50 mg/kg tjelesne mase u ovaca pasmine Chhotanagpuri. Vrućica je bila uzrokovana intravenskom primjenom lipopolisaharida serovara O126:B8 bakterije E. coli. Koncentracija cefriaksona u plazmi bila je određivana visokotlačnom tekućinskom kromatografijom. Koncentracija lijeka u plazmi u odnosu na vremensku krivulju bila je najsličnija modelu dvaju odjeljaka. Najveća koncentracija lijeka bila je 16,33% manja u febrilnih ovaca u odnosu na nefebrilne. U febrilnih je ovaca t1/2α bio manji, a t1/2β veći nego u nefebrilnih. Prividni volumen raspodjele (Vdarea) i omjer P:C bili su veći u febrilnih ovaca dok se ClB (ukupni klirens lijeka iz organizma) i AUC (površina ispod koncentracijske krivulje lijeka u plazmi) nisu značajno razlikovali između dviju skupina. Rezultati ovog istraživanja naznačuju da ceftriakson ima bolju raspodjelu u perifernom odjeljku za vrijeme vrućice. Velike vrijednosti odnosa K12/K21 također upućuju na brzu raspodjelu lijeka u različitim tjelesnim tekućinama i odjeljcima. Izračunato je da je ceftriakson u febrilnih ovaca najbolje davati intravenski u dozi od 15 mg/kg tjelesne mase u razmaku od pet sati

DAS181 treatment of severe lower respiratory tract parainfluenza virus infection in immunocompromised patients: A phase 2 randomized, placebo-controlled study

BACKGROUND: There are no antiviral therapies for parainfluenza virus (PIV) infections. DAS181, a sialidase fusion protein, has demonstrated activity in in vitro and in animal models of PIV. METHODS: Adult immunocompromised patients diagnosed with PIV lower respiratory tract infection (LRTI) who required oxygen supplementation were randomized 2:1 to nebulized DAS181 (4.5 mg/day) or matching placebo for up to 10 days. Randomization was stratified by need for mechanical ventilation (MV) or supplemental oxygen (SO). The primary endpoint was the proportion of patients reaching clinical stability survival (CSS) defined as returning to room air (RTRA), normalization of vital signs for at least 24 hours, and survival up to day 45 from enrollment. RESULTS: A total of 111 patients were randomized to DAS181 (n = 74) or placebo (n = 37). CSS was achieved by 45.0% DAS181-treated patients in the SO stratum compared with 31.0% for placebo (P = .15), whereas patients on MV had no benefit from DAS181. The proportion of patients achieving RTRA was numerically higher for SO stratum DAS181 patients (51.7%) compared with placebo (34.5%) at day 28 (P = .17). In a post hoc analysis of solid organ transplant, hematopoietic cell transplantation within 1 year, or chemotherapy within 1 year, more SO stratum patients achieved RTRA on DAS181 (51.8%) compared with placebo (15.8%) by day 28 (P = .012). CONCLUSIONS: The primary endpoint was not met, but post hoc analysis of the RTRA component suggests DAS181 may have clinical activity in improving oxygenation in select severely immunocompromised patients with PIV LRTI who are not on mechanical ventilation. Clinical Trials Registration. NCT01644877

Epidemiology, baseline characteristics and risk of progression in the first South-Asian prospective longitudinal observational IgA nephropathy cohort

Introduction: Glomerular Research And Clinical Experiments-IgA Nephropathy in Indians (GRACE-IgANI) is the first prospective South Asian IgAN cohort with protocolized follow-up and extensive biosample collection. Here we report the baseline clinical, biochemical, and histopathologic characteristics of GRACE IgANI and calculate baseline risk of progression for the cohort. Methods: 201 incident adults with kidney biopsy-proven primary IgAN were recruited into GRACE-IgANI between March 2015 and September 2017. As of April 30, 2020, the cohort had completed a median followup of 30 months (interquartile range [IQR] 16-39). Results: The commonest clinical presentation in GRACE IgANI was hypertension, with or without proteinuria, and nephrotic-range proteinuria was present in 34%, despite Conclusions: The predicted risk of progression in this cohort was considerable. Over the next 5 years, we will dissect the pathogenic pathways that underlie this severe South Asian IgAN phenotype

Three-Year Clinical Outcomes of the First South Asian Prospective Longitudinal Observational IgA Nephropathy Cohort

INTRODUCTION: Glomerular Research And Clinical Experiments—IgA Nephropathy in Indians (GRACE-IgANI) is the first prospective South Asian IgA nephropathy (IgAN) cohort with prespecified objectives, protocolized longitudinal follow-up, and extensive biosample collection. The baseline risk scores predicted high risk of kidney disease progression. METHODS: A total of 195 of 201 patients (97%) completed 3-year follow-up in September 2020. All patients received optimized supportive care, and those at high risk of progression were offered systemic corticosteroids. RESULTS: A total of 76 patients (76 of 193, 39.4%) had rapid progression in 3 years (≥5 ml/min per 1.73 m(2) decline in estimated glomerular filtration rate [eGFR] per year). A total of 72 patients (72 of 195, 36.9%) experienced the composite outcome (CO), defined as ≥50% fall in eGFR, eGFR < 15 ml/min per 1.73 m(2), commenced kidney replacement therapy or death, in 3 years. At each scheduled follow-up, achievement of proteinuria level < 1 g/d significantly delayed the time to the CO. The receiver operating characteristic curve of average annual decline in eGFR ≥ 5 ml/min per 1.73 m(2) had 86% sensitivity and 89% specificity for CO in 3 years and had good discrimination from 1 year onwards (area under the curve 0.8, SE 0.04, 95% CI 0.7–0.9, P < 0.0001). The significant predictors of CO by Cox proportional-hazards model were as follows: baseline MEST-T2 score (hazard ratio [HR] 3.3, 95% CI 1.7–6.5, P < 0.001), along with 24-hour urine protein level ≥ 1 g/d (HR 2.1, 95% CI 1.1–3.9, P = 0.02), eGFR < 60 ml/min per 1.73 m(2) (HR 2.9, 95% CI 1.1–7.6, P = 0.03), and rate of eGFR decline ≥ 5 ml/min per 1.73 m(2)/yr (HR 2.7, 95% CI 1.6–4.8, P < 0.001) all measured at 6 months. Mortality was 11 of 195 (5.6%). CONCLUSION: We identified longitudinal clinical variables measured at 6 months and ≥5 ml/min per 1.73 m(2) annual fall in eGFR after kidney biopsy as important predictors for composite outcome in addition to baseline histology

BHPR research: qualitative1. Complex reasoning determines patients' perception of outcome following foot surgery in rheumatoid arhtritis

Background: Foot surgery is common in patients with RA but research into surgical outcomes is limited and conceptually flawed as current outcome measures lack face validity: to date no one has asked patients what is important to them. This study aimed to determine which factors are important to patients when evaluating the success of foot surgery in RA Methods: Semi structured interviews of RA patients who had undergone foot surgery were conducted and transcribed verbatim. Thematic analysis of interviews was conducted to explore issues that were important to patients. Results: 11 RA patients (9 ♂, mean age 59, dis dur = 22yrs, mean of 3 yrs post op) with mixed experiences of foot surgery were interviewed. Patients interpreted outcome in respect to a multitude of factors, frequently positive change in one aspect contrasted with negative opinions about another. Overall, four major themes emerged. Function: Functional ability & participation in valued activities were very important to patients. Walking ability was a key concern but patients interpreted levels of activity in light of other aspects of their disease, reflecting on change in functional ability more than overall level. Positive feelings of improved mobility were often moderated by negative self perception ("I mean, I still walk like a waddling duck”). Appearance: Appearance was important to almost all patients but perhaps the most complex theme of all. Physical appearance, foot shape, and footwear were closely interlinked, yet patients saw these as distinct separate concepts. Patients need to legitimize these feelings was clear and they frequently entered into a defensive repertoire ("it's not cosmetic surgery; it's something that's more important than that, you know?”). Clinician opinion: Surgeons' post operative evaluation of the procedure was very influential. The impact of this appraisal continued to affect patients' lasting impression irrespective of how the outcome compared to their initial goals ("when he'd done it ... he said that hasn't worked as good as he'd wanted to ... but the pain has gone”). Pain: Whilst pain was important to almost all patients, it appeared to be less important than the other themes. Pain was predominately raised when it influenced other themes, such as function; many still felt the need to legitimize their foot pain in order for health professionals to take it seriously ("in the end I went to my GP because it had happened a few times and I went to an orthopaedic surgeon who was quite dismissive of it, it was like what are you complaining about”). Conclusions: Patients interpret the outcome of foot surgery using a multitude of interrelated factors, particularly functional ability, appearance and surgeons' appraisal of the procedure. While pain was often noted, this appeared less important than other factors in the overall outcome of the surgery. Future research into foot surgery should incorporate the complexity of how patients determine their outcome Disclosure statement: All authors have declared no conflicts of interes

Immunohistochemical Glomerular Expression of Phospholipase A2 Receptor in Primary and Secondary Membranous Nephropathy: A Retrospective Study in an Indian Cohort with Clinicopathological Correlations

Background: Limited published literature exists on the utility and standardization of anti-phospholipase A2 receptor (anti-PLA2R) immunohistochemistry (IHC) for the diagnosis of primary membranous nephropathy (MN). The study aimed to validate anti-PLA2R IHC for the diagnosis of primary MN and clinicopathological correlations in an Indian cohort. Methods: Subjects included patients with primary and secondary MN diagnosed between January 2012 and August 2014 with an adequate renal biopsy and at least 1 year of clinical follow-up. Anti-PLA2R IHC was performed in all cases with miscellaneous renal lesions as controls. Electron microscopy was performed in selected cases. Sensitivity and specificity of anti-PLA2R IHC to identify primary MN was evaluated. Histopathological analyses of primary and secondary MN were done with clinicopathological correlations including serum creatinine, eGFR, chronic kidney disease stage, 24-h urine protein, serum cholesterol, serum albumin, and hypertension at presentation and follow-up, using the Kruskal-Wallis test and Spearman rank correlation. A p value of ≤0.05 was considered statistically significant. Results: In 153 MN patients (99 primary, 54 secondary) and 37 miscellaneous controls, anti-PLA2R IHC differentiated primary from secondary MN with a sensitivity of 70.2% and a specificity of 96.6%. Secondary MN had increased mesangial matrix expansion compared to primary MN (p = 0.001). Severe nephrotic syndrome, impaired renal function, and hypertension were all more common in primary than in secondary MN. Conclusion: Anti-PLA2R IHC is a specific marker to distinguish primary MN from secondary MN

Novel resistance source and differentials to chilli anthracnose

Not AvailablePre- and post-harvest anthracnose fruit rot is a main disease of chilli (Capsicum spp.). Among Colletotrichum species causing anthracnose, C. capsici is the most common in India. A total of 41 Capsicum genotypes were screened for anthracnose resistance under field conditions. Bhut Jolokia, PBC-380 and IC-383072 were found symptomless and some marginally cultivated lines and other crosses were observed to be resistant. In vitro inoculation of the selected set of genotypes with C. capsici revealed that 9 days after inoculation was appropriate to record observations on disease resistance. Screening the 41 genotypes for resistance to anthracnose under in vitro conditions revealed four symptomless and 11 highly resistant lines. Comparing field and in vitro evaluations, nine lines (BS-35, BS-20, BS- 28, Punjab Lal, Bhut Jolokia, Taiwan-2, IC-383072, Pant C- 1 and Lankamura Collection) showed consistent resistance in field as well as in vitro to the disease. The study on differential reactions on fruits of 16 genotypes inoculated by the two C. capsici isolates (Ccf-Varanasi and Ccc2- Raichur) clearly showed that these isolates are two different pathotypes. A detailed analysis on prevalent strains in the target region would be needed to initiate resistance breeding. Nevertheless, newly identified resistant sources offer better choices for the ongoing anthracnose resistance breeding program.Not Availabl

Clinicopathological Features of Primary Renal Mesenchymal Neoplasms in Adults: A Cross-sectional Study

Introduction: Renal mesenchymal tumours are a subset of primary renal tumours arising from the mesenchymal tissue in the kidney. They are a heterogeneous group of mostly benign tumours that exhibit varied behaviours and molecular characteristics. Aim: To analyse the wide spectrum of histological subtypes, their unique clinical presentation, and pathological features of primary renal mesenchymal neoplasms. Materials and Methods: This was a retrospective cross- sectional observational clinicopathological study conducted in Department of General Pathology, Christian Medical College, tertiary care hospital, Vellore, Tamil Nadu, India, looking at data of adult Primary Renal Mesenchymal Tumours (PRMT) for a 15-year period between January 2006 and March 2021. Clinical details such as age, presenting symptoms, and tumour size were obtained from the hospital information system. Histopathology and immunohistochemical slides were reviewed for all the cases. Additional Immunohistochemistry (IHC) and molecular studies were performed for the undifferentiated sarcomas. The tumours were categorised into three groups as recommended by the World Health Organisation (WHO) 2020 classification of soft-tissue tumours based on biological behaviour: benign, intermediate, and malignant. Continuous variables are expressed as mean and Standard Deviation (SD). Comparison of categorical variables between groups was performed using the Chi-squared test. Continuous variables between groups were compared using the Student’s t-test for significance. A p-value of less than 0.05 was considered statistically significant. Results: Of the 2164 nephrectomies performed for neoplastic conditions, 97 (4.5%) were diagnosed as renal mesenchymal tumours. There were 59 (60.8%) benign, 10 (10.3%) with intermediate biologic behaviour and 28 (28.9%) malignant tumours. The mean ages at presentation were 40.5 years for benign, 43.4 years for intermediate, and 41 years for malignant tumours, respectively. Haematuria was seen in 11 of 38 (29%) intermediate grade and malignant tumours and in only 6 of 59 (10%) benign tumours, a difference that was statistically significant (p-value=0.017). Malignant tumours 24 of 28 (86%) were more likely to be larger (>7 cm) when compared to benign tumours 28 of 59 (47%) at the time of presentation (p-value=0.027). Classical angiomyolipomas constituted 53/59 (90%) of the benign tumours. Of the 10 intermediate grade tumours, epithelioid angiomyolipomas and solitary fibrous tumours were the most common, accounting for 50% and 30% of the intermediate group, respectively. Undifferentiated small round cell sarcoma was the most common malignant neoplasm, making up 12/28 (43%) of the malignant tumours. Conclusion: The present study found that renal mesenchymal tumours constitute a small but unique group of renal tumours. They are predominantly benign, but up to a quarter are malignant. Malignant tumours tend to be larger and more often present with haematuria. The present study highlights the importance of IHC in the diagnosis of intermediate and malignant mesenchymal tumours and the requirement of exhaustive molecular studies individually tailored to the immuno-profile of malignant tumours

Patterns of Renal Dysfunction and Profile of Kidney Biopsies in Hematopoietic Stem Cell Transplant Recipients

Introduction: Post hematopoietic stem cell transplant (HSCT), kidney can be subjected to injury by various causes. Of these, graft versus host disease (GvHD) affecting the kidney is an under-recognized entity with no clear guidelines on its diagnosis, clinicopathological manifestations, and outcomes. Material and Methods: Out of 2,930 patients who underwent HSCT at our center between 2005 and 2020, kidney biopsy was performed in 19 allogenic and 5 autologous recipients. Results: The mean age of the cohort at transplant was 33.2 ± 7 years, and 15 (62%) were males. Median time to kidney biopsy from HSCT was 14 (IQR, 9–30) months. Aplastic anemia was the most common underlying hematological disease (54.2%). All 19 allogenic recipients were classified based on clinicopathological manifestations into either thrombotic microangiopathy (TMA, 12/19 [63%]) or nephrotic syndrome (NS, 7/19 [37%]) pattern. Glomerular tuft “mesangiolysis” was the dominant pattern of injury noted in 9/12 cases of TMA pattern. There was a predominance of acute microangiopathic changes restricted primarily to the glomerular compartment. Of the 7 patients with NS pattern, membranous nephropathy was seen in 4 (57%) and minimal change disease in 3 (43%) patients. Thirty-nine percent (7/18) stained positive for C4d which was predominantly glomerular. Allogenic recipients who did not receive immunosuppression (IS) for renal disease had a lower eGFR at biopsy, a longer latency between withdrawal of GvHD prophylaxis and biopsy, and were significantly at a higher risk of kidney failure (IS: 2/11, 18.1% vs. no IS: 2/6, 33.3%, p = 0.04). “Associated extra-renal GvHD” occurred in 11/19 (57.9%) allogenic recipients. Patients with “associated extra-renal GvHD” had significantly more deaths (6/11, 60% vs. 0, p = 0.02) but comparable renal outcomes. Conclusion: Renal GvHD can present with or without “associated extra-renal GvHD” after a prolonged period of withdrawal of GvHD prophylaxis, requiring careful diagnostic vigilance and consideration of IS