Grade 3/4 Adverse Event Costs of Immuno-oncology Combination Therapies for Previously Untreated Advanced Renal Cell Carcinoma.

BACKGROUND: Despite 4 approved combination regimens in the first-line setting for advanced renal cell carcinoma (aRCC), adverse event (AE) costs data are lacking. MATERIALS AND METHODS: A descriptive analysis on 2 AE cost comparisons was conducted using patient-level data for the nivolumab-based therapies and published data for the pembrolizumab-based therapies. First, grade 3/4 AE costs were compared between nivolumab + ipilimumab vs. nivolumab + cabozantinib vs. pembrolizumab + axitinib using data from the CheckMate 214 (median follow-up [mFU]: 13.1 months), CheckMate 9ER (mFU: 12.8 months), and KEYNOTE-426 (mFU: 12.8 months) trials, respectively. Second, grade 3/4 AE costs were compared between nivolumab + ipilimumab vs. nivolumab + cabozantinib vs. pembrolizumab + lenvatinib using data from the CheckMate 214 (mFU: 26.7 months), CheckMate 9ER (mFU: 23.5 months), and KEYNOTE-581 (mFU: 26.6 months) trials, respectively. Per-patient costs for all-cause and treatment-related grade 3/4 AEs with corresponding any-grade AE rates ≥ 20% were calculated based on the Healthcare Cost and Utilization Project database and inflated to 2020 US dollars. RESULTS: Per-patient all-cause grade 3/4 AE costs for nivolumab + ipilimumab vs. nivolumab + cabozantinib vs. pembrolizumab + axitinib were $2703 vs. $4508 vs. $5772, and treatment-related grade 3/4 AE costs were $741 vs. $2722 vs. $4440 over ~12.8 months of FU. For nivolumab + ipilimumab vs. nivolumab + cabozantinib vs. pembrolizumab + lenvatinib, per-patient all-cause grade 3/4 AE costs were $3120 vs. $5800 vs. $9285, while treatment-related grade 3/4 AE costs were $863 vs. $3162 vs. $5030 over ~26.6 months of FU. CONCLUSION: Patients with aRCC treated with first-line nivolumab-based therapies had lower grade 3/4 all-cause and treatment-related AE costs than pembrolizumab-based therapies, suggesting a more favorable cost-benefit profile.

Temporal trends of adverse events and costs of nivolumab plus ipilimumab versus sunitinib in advanced renal cell carcinoma.

Aims: To assess grade 3/4 adverse events (AEs) and costs of first-line nivolumab plus ipilimumab versus sunitinib in advanced or metastatic renal cell carcinoma. Methods: Individual patient data from the all treated population in the CheckMate 214 trial (nivolumab plus ipilimumab, n = 547; sunitinib, n = 535) were used to calculate the number of AEs. AE unit costs were obtained from US 2017 Healthcare Cost and Utilization Project and inflated to 2020 values. Results: The proportion of patients experiencing grade 3/4 AEs decreased over time. Patients who received nivolumab plus ipilimumab had lower average per-patient all-cause grade 3/4 AE costs versus sunitinib (12-month: US$15,170 vs US$20,342; 42-month: US$19,096 vs US$27,473). Conclusion: Treatment with nivolumab plus ipilimumab was associated with lower grade 3/4 AE costs than sunitinib.

Immunotherapy combinations are now accepted as safe and effective first-line treatment options for advanced or metastatic renal cell carcinoma. This study used patient data from the CheckMate 214 clinical trial to evaluate the temporal trends and costs related to grade 3/4 adverse events (AEs) among patients treated with nivolumab plus ipilimumab versus sunitinib. We found that the proportion of patients experiencing grade 3/4 AEs decreased over time and that patients treated with nivolumab plus ipilimumab had lower AE costs compared with those treated with sunitinib (at 42 months: US$19,096 vs US$27,473 per patient). As such, nivolumab plus ipilimumab may represent a treatment option that may reduce both the clinical and economic burden among patients with advanced or metastatic renal cell carcinoma.

Urine levels of luteinizing hormone as predictor of the period of ovulation for advantage of timed-artificial insemination in murrah buffalo (Bubalus bubalis).

Assessment of urine levels of luteinizing hormone (LH) for predicting the reproductive status of animals is in practice. The aim of this study was to predict the period of ovulation based on the urine levels of LH for timed-artificial insemination to increase the conception rate in buffaloes, which are naturally silent-oestrous animals. Level of LH in urine was assessed using ELISA, and a cut-off LH concentration for prediction of ovulation period was obtained using receiver operating characteristic analysis. Artificial insemination was performed before- and after -positive prediction of ovulation period adopting this method, and the rates of conception were assessed. Urine LH level of 105 mIU/ml (n = 14) was derived as a cut-off concentration which predicts the ovulation period. The buffaloes in the positively predicted group (day 1 or 2) inseminated via intracervical route had an increase in the conception rate (83.33%); however, the insemination in the before-positive-prediction group resulted in poor conception rates (day 0; 16.66%) compared to that of the naturally inseminated group (day 0; 75.0%). In conclusion, the urinary LH would possibly be a fairly reliable predictor of the ovulation period. The day when cut-off LH concentration is obtained may be taken as the most favourable time for artificial insemination, so as to attain a much better rate of conception in the buffalo.

Burden of Herpes Zoster Among Patients with Psoriatic Arthritis in the United States.

Purpose: Patients with psoriasis (PsO) and psoriatic arthritis (PsA) are at increased risk of herpes zoster (HZ), but healthcare resource use (HRU) and costs relating to HZ in adults with PsA are unknown. We aimed to estimate the incidence of HZ among adults with PsA vs without psoriatic disease and the additional HRU and costs among patients with PsA with vs without HZ. Patients and Methods: This retrospective, longitudinal, cohort study estimated HZ incidence in PsA+ vs PsO-/PsA- cohorts and HRU and medical/pharmacy costs among PsA+/HZ+ vs PsA+/HZ- cohorts comprised of adults from Optum's de-identified Clinformatics Data Mart Database during 2015-2020. For the HRU/cost analyses, index was the date of first HZ diagnosis (PsA+/HZ+ cohort) or was randomly assigned (PsA+/HZ- cohort). Generalized linear models were used for adjusted comparisons between cohorts. Results: HZ incidence was higher in the PsA+ (n = 57,126) vs PsO-/PsA- (n = 23,837,237) cohort (14.85 vs 7.67 per 1000 person-years; adjusted incidence rate ratio [aIRR]: 1.23; 95% confidence interval [CI]: 1.16-1.30). Numbers of outpatient visits, emergency department visits, and inpatient admissions were significantly higher in the PsA+/HZ+ (n = 1045) vs PsA+/HZ- (n = 36,091) cohorts during the first month after HZ diagnosis (outpatient: aIRR: 1.74; 95% CI: 1.63-1.86; emergency department: 3.14; 95% CI: 2.46-4.02; inpatient: aIRR: 2.61; 95% CI: 1.89-3.61). Mean all-cause per-patient costs were significantly higher in the PsA+/HZ+ vs PsA+/HZ- cohorts during the first month after index ($6493 vs $4521; adjusted cost difference: $2012; 95% CI: $1204-$3007). HRU and costs were numerically higher in the PsA+/HZ+ cohort during the first 3 and 12 months. Conclusion: These findings, which provide evidence on the increased incidence and HRU and economic burden associated with HZ among adults with PsA, could be used to inform clinical practice and decision-making.

Why was the study done? Psoriatic arthritis affects the joints of around 20% of patients with the skin condition, psoriasis.Patients with psoriatic arthritis are at increased risk of shingles, which can cause a painful skin rash and complications.This study aimed to provide information on how many patients with psoriatic arthritis get shingles and the healthcare use and costs of caring for patients with psoriatic arthritis and shingles. What did the researchers do and find? Using data from a large US health plan database, we estimated that for every 1000 patients with psoriatic arthritis observed for 1 year, 15 will develop shingles.Patients with psoriatic arthritis were 23% more likely to develop shingles than people without psoriatic disease.Patients with psoriatic arthritis and shingles had 2­3 times as many healthcare visits in the month after a shingles diagnosis as patients with psoriatic arthritis but no shingles.This resulted in an average additional cost of approximately $2000 per patient. What do these results mean? Psoriatic arthritis increases the risk of shingles.The costs associated with shingles in patients with psoriatic arthritis are substantial.Measures to prevent shingles in this population could be beneficial.

Effect of silicon carbide on kerf convergence and irregularity of the surface during abrasive water jet machining of fiber-metal hybrid composites.

The traditional way to machine hybrid composites is hard because they tend to break, have a high retraction, have a high service temperature, and have an uneven surface irregularity. For high-strength fiber/metal composite constructions, alternative machining methods have drawn interest as a solution to these problems. Current research focuses on enhancing the Abrasive Water Jet Machining process by optimizing its variables using a composite material of epoxy reinforced with silicon carbide, stainless steel wire mesh, and Kevlar. The variables assessed are the Nozzle-to-substrate gap (S), the Abrasive discharge molding and different percentages of silicon carbide (SiC) filler (0%, 3%, and 6% by weight), three different types of hybrid laminates (H1, H2, and H3) were produced. The response surface method (RSM) was utilized in this learning, specifically on a central composite design, to calculate and optimize machining variables based on the Kerf convergence ratio (Kt) and Surface irregularity (Ra) as responses. According to the results, the traverse feed velocity, Abrasive discharge proportion, and Nozzle-to-substrate gap are the critical factors in determining Surface irregularity and Kerf convergence width (H1 laminate) for a fiber/metal laminate with 0%, 3% and 6% weight fraction. In the case of a 3% weight fraction H2 laminate, the traverse feed velocity was identified as the primary factor affecting the Kerf convergence ratio. In contrast, traverse feed velocity and Nozzle-to-substrate gap had the most significant influence on Surface irregularity. The findings also indicated that S, followed by Abrasive discharge proportion and traverse feed velocity, are the variables that have the most significant influence when cutting 6 wt% SiC filler particle fiber/metal laminate (H3 laminate). For Surface irregularity, the combination of traverse feed velocity and Nozzle-to-substrate gap had the most significant impact. To validate the optimization results, confirmatory tests was conducted, and the findings were very similar to the experimental values, indicating the accuracy and effectiveness of the optimization process. To better understand the manufacturing processes, a scanning electron microscope was used to examine the morphological features of the machined surfaces, such as delamination, fibre breakage, and fibre pull-out.

Phytochemical screening of ethanolic extracts of Cuminum cyminum L. seeds along with the evaluation of antidiabetic properties by molecular docking approach.

In this contribution, ethanolic extracts of Cuminum cyminum (C. cyminum) seeds were evaluated in terms of phytochemical content, total phenol and flavonoid contents. As far as the analytical techniques are concerned, UV-Vis, FTIR, HPLC, NMR (1H and 13C) and ESI-MS were performed. The binding capacity of five different antidiabetic enzymes was tested by in silico molecular docking studies. The HPLC, UV-Vis, FTIR, NMR and ESI-MS data highlighted the presence of seven biologically active molecules e.g. α-pinene, ß-pinene, Δ3-carene, ρ-cymene, α-terpineol, cuminaldehyde and linalool. The results coming from the in silico molecular docking studies showed that such phytochemicals present in the cumin seed extracts play an important role in the activity of key enzymes involved in carbohydrate metabolism. Therefore, C. cyminum is proven to be useful for the treatment of diabetes mellitus and its major secondary complications.

Treatment Patterns and Adverse Event-Related Hospitalization Among Patients with Epidermal Growth Factor Receptor (EGFR)-Mutated Metastatic Non-small Cell Lung Cancer After Treatment with EGFR Tyrosine Kinase Inhibitor and Platinum-Based Chemotherapy Regimens.

BACKGROUND: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR TKIs) are established first-line treatments among patients with metastatic non-small cell lung cancer harboring EGFR-sensitizing mutations. Upon EGFR TKI resistance, there are scant data supporting a standard of care in subsequent lines of therapy. OBJECTIVE: We aimed to characterize real-world treatment patterns and adverse events associated with hospitalization in later lines of therapy. METHODS: This retrospective analysis of administrative claims included adults with metastatic non-small cell lung cancer who initiated a next line of therapy (index line of therapy) following EGFR TKI and platinum-based chemotherapy discontinuation on/after 1 November, 2015. Treatment regimens and adverse event rates during the index line of therapy were described. RESULTS: Among 195 eligible patients (median age: 59 years; female: 60%), the five most common index line of therapy regimens were immune checkpoint inhibitor monotherapy (29%), EGFR TKI monotherapy (21%), platinum-based chemotherapy (19%), non-platinum-chemotherapy (13%), and EGFR TKI combinations (9%). The overall median (95% confidence interval) time to discontinuation of the index line of therapy was 2.8 (2.1-3.2) months. Common adverse events associated with hospitalizations included infection/sepsis, pneumonia/pneumonitis, and anemia (2.9, 2.8, and 2.0 per 100 person-months, respectively). CONCLUSIONS: Among EGFR TKI-resistant patients who discontinued platinum-based chemotherapy, the duration of the next line of therapy was short, treatment was highly variable, and re-treatment with EGFR TKIs and platinum-based regimens was common, suggesting a lack of standard of care in later lines. Adverse event rates associated with hospitalization were high, especially among platinum-treated patients. These results underscore the unmet need for new therapies in a later line of treatment to reduce the clinical burden among patients in this population.

Burden of Herpes Zoster Among Patients with Psoriasis in the United States.

INTRODUCTION: Patients with psoriasis (PsO) are at increased risk of herpes zoster (HZ), but recent data on the incidence of HZ among patients with PsO and the impact of HZ on healthcare resource use (HRU) and costs for patients with PsO have not been described. METHODS: This retrospective, longitudinal, cohort study estimated HZ incidence in cohorts of adults with vs without PsO (PsO + vs PsO-) and HRU and costs among those with PsO, with vs without HZ (PsO + /HZ + vs PsO + /HZ-) using Optum's de-identified Clinformatics Data Mart Database during 2015-2020. Patients with psoriatic arthritis were excluded from all four cohorts. Comparisons between cohorts used generalized linear models to adjust outcomes based on various baseline characteristics. RESULTS: The incidence rate of HZ was significantly higher in the PsO + (n = 144,115) vs PsO- (n = 23,837,237) cohorts at 11.35 vs 7.67 per 1000 patient-years; adjusted incidence rate ratio (aIRR): 1.21, 95% confidence interval (CI): 1.16-1.25. HRU (outpatient, emergency department, and inpatient) was significantly higher in the PsO + /HZ + (n = 1859) vs PsO + /HZ- (n = 78,664) cohorts during 1 month and 3 months after HZ diagnosis (e.g., outpatient visits during month: 2.83 vs 1.30 per patient; aIRR: 1.96; 95% CI 1.86-2.06). Mean all-cause costs were also significantly higher in the PsO + /HZ + vs PsO + /HZ- cohort during both month ($5020 vs $2715 per patient; adjusted cost difference: $1390; 95% CI $842-$1964) and 3 months ($12,305 vs $8256; adjusted cost difference: $1422; 95% CI $280-$2889) after HZ diagnosis. CONCLUSION: These findings show the increased incidence of HZ among patients with PsO and the clinical and economic burdens of HZ in this population. Considering the high prevalence of PsO, insights into the impact of HZ in these patients provide valuable evidence to inform clinical decision-making.

Psoriasis is an inflammatory condition that causes flaky, scaly skin. Herpes zoster (shingles) causes a painful rash, usually on the abdomen. However, recent data on the proportion of patients with psoriasis who develop herpes zoster is lacking. Furthermore, little is known about the healthcare resources that are used or the costs of care for patients with psoriasis who develop herpes zoster. We found that patients with psoriasis were 21% more likely to have herpes zoster than patients without psoriasis. Among patients with psoriasis, those who developed herpes zoster had twice as many doctor's visits, 3 times as many emergency department visits, and twice as many inpatient hospital stays during the month after a herpes zoster diagnosis as patients without herpes zoster. This resulted in an additional cost of $1390 per patient with psoriasis and herpes zoster compared with those with psoriasis but without herpes zoster. Overall, patients with psoriasis are at increased risk of developing herpes zoster and the healthcare resource use and associated cost of treating herpes zoster in patients with psoriasis is substantial.

Health care costs and resource utilization among commercially insured adult patients with hemophilia A managed with FVIII prophylaxis in the United States.

BACKGROUND: Standard of care for patients with severe hemophilia A (HA) is life-long prophylaxis with factor VIII (FVIII) concentrate or other hemostatic agents. Published literature highlights a wide range of treatment costs for patients with HA. OBJECTIVE: To estimate average annual health care costs and resource utilization for a cross-section of adult patients managed with FVIII concentrate prophylaxis using recent data from a large US commercial claims database. METHODS: Adult males with 1 or more claim with HA diagnosis, continuous commercial plan enrollment, and 4 or more FVIII prescription dispenses during 12 months were identified from IBM MarketScan Research Database from January 2013 to September 2019, excluding those with FVIII inhibitors, an HIV/AIDS diagnosis, or diagnosis and treatment for hepatitis B or C. Patients were classified as using FVIII prophylaxis if they met any of the following definitions: (1) 6 or more FVIII dispenses, (2) a gap of 60 days or less between dispenses, and (3) at least 273 days supply in the 12-month period. Additionally, subgroups of patients meeting each individual definition were examined, with some patients included in all 3 subgroups. RESULTS: The overall cohort included 411 patients who met 1 or more of the 3 definitions, with a mean age of 28.9 years. Subgroups of 401, 325, and 237 patients met the first, second, and third FVIII prophylaxis definitions, respectively. Per-patient mean (SD) annual all-cause health care costs were $654,571 ($380,762) in the overall cohort and ranged from $650,065 ($382,196) to $759,661 ($387,040) among subgroups. Cost of FVIII concentrate accounted for more than 96% of total costs in the overall cohort and in each subgroup. Cost of FVIII in the overall cohort varied according to type of concentrate, with the highest among patients who were treated with both standard and extended half-life (SHL and EHL) FVIII ($784,945), followed by EHL FVIII only ($708,928), SHL FVIII only ($647,800), and plasma-derived FVIII ($535,614). The most common treatment type was SHL FVIII only (45.7% of all patients). In the overall cohort, the majority had 1 or more outpatient visits (94.9%), while emergency department visits, hospital admissions, and home health visits occurred less frequently (27.0%, 7.1%, and 7.1%, respectively). CONCLUSIONS: Commercially insured patients with HA incur substantial all-cause annual health care costs, with FVIII concentrate accounting for a majority of costs. DISCLOSURES: This study was funded by BioMarin Pharmaceutical Inc, which was involved in the protocol development, analysis plan development, data interpretation, manuscript preparation, and publication decisions. All authors contributed to protocol development, analysis plan development, data interpretation, and manuscript development and maintained control over the final content. Thornburg has received professional fees from BioMarin Pharmaceutical, CSL Behring, Genentech, Novo Nordisk, Sanofi Genzyme, HEMA Biologics, and Spark Therapeutics and institutional research funding from BioMarin Pharmaceutical, Novo Nordisk, and Sanofi Genzyme. Adamski, Cook, and Sendhil are employees of Analysis Group, a consulting company that was contracted by BioMarin Pharmaceutical to conduct this study and develop the manuscript. Vembusubramanian is a former employee of Analysis Group. Hinds, Chen, and Sammon are employees and shareholders of BioMarin Pharmaceutical. Solari is a former employee of BioMarin Pharmaceutical. Garrison has received consulting fees from BioMarin Pharmaceutical and Analysis Group. Croteau has received professional fees from BioMarin Pharmaceutical, Bayer, CSL Behring, HEMA Biologics, and Pfizer and institutional research funding from Novo Nordisk and Spark Therapeutics.

Efficacy of avapritinib versus best available therapy in the treatment of advanced systemic mastocytosis.

Advanced systemic mastocytosis (AdvSM) is a rare myeloid neoplasm associated with poor overall survival (OS). This study (NCT04695431) compared clinical outcomes between patients with AdvSM treated with avapritinib in the Phase 1 EXPLORER (NCT0256198) and Phase 2 PATHFINDER (NCT03580655) trials (N = 176) and patients treated with best available therapy (BAT; N = 141). A multi-center, observational, retrospective chart review study was conducted at six study sites (four European, two American) to collect data from patients with AdvSM who received BAT; these data were pooled with data from EXPLORER and PATHFINDER. Comparisons between outcomes of OS, duration of treatment (DOT), and maximum reduction in serum tryptase were conducted between the treatment cohorts, with adjustment for key covariates. The results indicated that the avapritinib cohort had significantly better survival (adjusted hazard ratio (HR) (95% confidence interval (CI)): 0.48 (0.29, 0.79); p = 0.004) and significantly longer DOT (HR: 0.36 (0.26, 0.51); p < 0.001) compared to the BAT cohort. Additionally, the mean difference in percentage maximum reduction in serum tryptase levels was 60.3% greater in the avapritinib cohort (95% CI: -72.8, -47.9; p < 0.001). With no randomized controlled trials comparing avapritinib to BAT, these data offer crucial insights into the improved efficacy of avapritinib for the treatment of AdvSM.

3-(4-Chloro-phen-yl)-1-phenyl-1H-pyrazole-4-carbaldehyde.

In the title compound, C(16)H(11)ClN(2)O, the chloro-substituted phenyl ring is disordered over two positions with refined site occupancies of 0.503 (2) and 0.497 (2). The dihedral angle between the pyrazole and phenyl rings is 7.93 (7)°. The pyrazole ring also forms dihedral angles of 24.43 (9)° and 28.67 (9)° with the disordered chloro-substituted benzene ring. In the crystal, mol-ecules are linked by inter-molecular C-H⋯O hydrogen bonds, generating R(2) (1)(7) and R(2) (2)(10) ring motifs. π-π inter-actions between the pyrazole and phenyl rings [centroid-centroid distance = 3.758 (1) Å] further stabilize the crystal structure.

Unusual antibiotic resistance pattern among blood culture isolates of Salmonella Paratyphi A.

INTRODUCTION: With increasing fluoroquinolone resistance, extended spectrum cephalosporins are recommended for the treatment of invasive Salmonella infections. However, Extended spectrum beta-lactamases (ESBL) producing Salmonella Paratyphi A causing enteric fever is on the rise and constitutes a major therapeutic challenge. Hence, we aimed to assess the incidence of ESBL production, fluoroquinolone resistance in S. Paratyphi A and to compare the fluoroquinolone resistance detection methods. METHODOLOGY: Seventeen blood-culture isolates of S. Paratyphi A were tested for susceptibility to ampicillin, chloramphenicol, co-trimoxazole, streptomycin and tetracycline (ACCuST), fluoroquinolones, azithromycin and ceftriaxone by disk diffusion method. We compared and correlated between disk diffusion of ciprofloxacin and pefloxacin with ciprofloxacin MIC. Combined disk test was employed to determine ESBL production. RESULTS: In this study, 13(76.5%) isolates were nalidixic acid resistant (NAR), 16 (94.1%) were pefloxacin resistant, while 7 (41.2%), 9 (52.9%) exhibited resistance and intermediate susceptibility to ciprofloxacin respectively. The MIC50, MIC90 of ciprofloxacin was 1 µg/mL, 2 µg/mL respectively. Among the NAR, 76.92% were DSC (MIC 0.5-1 µg/mL) and 23.08% had an MIC of 2-4 µg/mL. Of note, 4 isolates with DSC were NAS. Of the 17 S. Paratyphi A isolates, 14 (82.4%) were ESBL producers and 11 (64.7%) isolates were ceftriaxone susceptible. CONCLUSIONS: Multidrug resistant (AmpRChlRSxtR) S. Paratyphi A with combined resistance to fluoroquinolones and ESBL production is a cause of concern. We found S. Paratyphi A isolates with a relatively unusual phenotype: nalidixic acid susceptible but exhibited DSC; pefloxacin susceptible but ciprofloxacin resistant. Of note one multidrug resistant (AmpRChlRSxtR) isolate, an ESBL producer exhibited resistance to azithromycin, cephalosporins and fluoroquinolones but was susceptible to carbapenems and streptomycin.

Effect of Bacillus subtilis PB6, a natural probiotic on colon mucosal inflammation and plasma cytokines levels in inflammatory bowel disease.

The pathophysiology of inflammatory bowel disease (IBD) involves the production of diverse lipid mediators, namely eicosanoid, lysophospholipids, and platelet-activating factor, in which phospholipase A2 (PLA2) is the key enzyme. Thus, it has been postulated that control of lipid mediators production by inhibition of PLA2 would be useful for the treatment of IBD. This hypothesis has been tested in the present study by examining the therapeutic effect of a novel natural probitic Bacillus subtilis PB6 (ATCC- PTA 6737). B. subtilis PB6 is found to secrete surfactins (cyclic lipopeptides) which have anti-bacterial potential. These surfactins inhibit PLA2, a rate-limiting enzyme involved in the arachidonic acid associated inflammatory pathway and could downregulate the inflammatory response by regulating the eicosanoid and cytokine pathways. With this concept, an experimental animal trial has been conducted in a rat model of 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-induced colitis. The oral administration of PB6 suppresses the colitis as measured by mortality rate, changes in the weight gain, colon morphology and the levels of plasma cytokines. The animals treated orally with PB6 at 1.5 x 10(8) CFU/kg thrice daily from day 4 to 10 significantly improve gross pathology of the colon and regain the colon weight to normal (p < 0.05), compared to TNBS-induced positive control. The plasma levels of pro-inflammatory cytokines (TNF-alpha, 1L-1beta, IL-6 and IFN-gamma) are also significantly lowered (p < 0.05) and anti-inflammatory cytokine (IL-I0 and TGF-beta) significantly (p < 0.05) increased after the oral administration of PB6 on day 11. The present study supports the concept that PB6 inhibits PLA2 by the secreting surfactins. In a clinical investigation, it is found to be well tolerated by all the healthy volunteers.

Incidence of incisional hernias following single-incision versus traditional laparoscopic surgery: a meta-analysis.

PURPOSE: To compare, using a meta-analysis of randomized controlled trials, the risk of incisional hernia in patients undergoing single-incision laparoscopic surgery to those undergoing traditional laparoscopic surgery. METHODS: MEDLINE and EMBASE databases were searched. Randomized controlled trials comparing single-incision laparoscopic surgery to traditional laparoscopic surgery and which reported incisional hernias over a minimum 6-month follow-up period were eligible. Risk of bias was assessed as outlined in the Cochrane Handbook. Pooled odds ratios were calculated using RevMan. RESULTS: Of 309 identified studies, 22 were included in this meta-analysis. Pooled results showed higher odds of incisional hernia following single-incision laparoscopic surgery relative to traditional laparoscopic surgery (odds ratio 2.83, 95% CI 1.34-5.98, p = 0.006, I2 = 0%). There was no difference in the odds of incisional hernias requiring surgical repair (p = 0.10). Subgroup analysis found no difference in the odds of incisional hernias based on procedure type (p = 0.69) or method of follow-up (p = 0.85). The quality of evidence was determined to be moderate. CONCLUSION: Single-incision laparoscopic surgery is associated with a threefold increase in the odds of incisional hernia compared with traditional laparoscopic surgery.

p-cresol and oleic acid as reliable biomarkers of estrus: evidence from synchronized Murrah buffaloes.

Successful reproductive management in buffaloes depends on effective estrus detection. Urinary pheromones identified from natural estrous cycle have been reported to decipher estrus phase. However, its presence has not been analyzed in the urine after synchronization. Thus, our present investigation was to investigate the influence of synchronized estrus urine in bulls and to examine the presence of estrus-specific compounds ascertained in natural estrus in synchronized buffaloes. Mid-stream urine was collected from six synchronized buffaloes during various phases of estrous cycle and volatiles were examined using GC-MS. Sexual provocation in bulls was established by displaying persistent flehmen and frequent mounting towards estrus urine from synchronized animals. Totally forty-two volatile compounds were identified from three phases of estrous cycle, more specifically 4-methyl phenol (p-cresol) and 9-octadecenoic acid (oleic acid) in estrus urine of synchronized animal as similar to natural estrus. Hence, these chemical cues in buffalo urine might be employed as potential marker candidates for the development of an estrus detection aid.

DomIns: a web resource for domain insertions in known protein structures.

Proteins can be formed by single or multiple domains. The process of recombination at the molecular level has generated a wide variety of multi-domain proteins with specific domain organization to cater to the functional requirements of an organism. The functional and structural costs of inserting a domain into another means that multi-domain proteins are usually formed by covalently linking the N-terminus of one domain to the C-terminus of the preceding domain. While this is true in a large proportion of multi-domain proteins, we find a significant fraction of proteins that are the result of domain insertion. The inserted domain breaks the sequence contiguity of the domain into which it is inserted leading to a novel domain organization. This web resource aims to document domain insertions in known protein structures that are classified in the SCOP database. The web server can be accessed from http://stash.mrc-lmb.cam. ac.uk/DomIns/.

Determination of glucocerebroside, sphingomyelin, free fatty acid and total lipid by thin-layer chromatography and charring-scintillation quenching.

A previously described method has been extended to various specific lipids of liver and brain. The basic method involves thin-layer chromatography followed by charring to reveal the bands. The intensity of each band is determined by suspending the silica gel in a radioactive scintillation gel and measuring the optically quenched activities. The lipids are extracted with hexane/isopropanol and, in the case of total lipid determinations, the extract is simply applied to a silica gel plate and charred without use of a development step. For brain cerebroside, the extract is applied to the plate and developed in the usual way. For liver cerebroside, the dried lipid extract is fractionated with a silica gel column to purify the glycolipid, which is then purified further by development with a plate. For sphingomyelin the ester type lipids in the extract are cleaved by alkali for 1 min and the resultant lipids are applied directly to the thin-layer plate. Free fatty acids are chromatographed and measured after a preliminary solvent partitioning to remove most lipids. The method is useful for samples of 5-40 micrograms. Methods for quantitative application of samples to plates are described. A modification of the Camag sample streaker is described which yields precise 1-cm streaks.

Domain insertions in protein structures.

Domains are the structural, functional or evolutionary units of proteins. Proteins can comprise a single domain or a combination of domains. In multi-domain proteins, the domains almost always occur end-to-end, i.e., one domain follows the C-terminal end of another domain. However, there are exceptions to this common pattern, where multi-domain proteins are formed by insertion of one domain (insert) into another domain (parent). Here, we provide a quantitative description of known insertions in the Protein Data Bank (PDB). We found that 9% of domain combinations observed in non-redundant PDB are insertions. Although 90% of all insertions involve only one insert, proteins can clearly have multiple (nested, two-domain and three-domain) inserts. We also observed correlations between the structure and function of a domain and its tendency to be found as a parent or an insert. There is a bias in insert position towards the C terminus of parents. We observed that the atomic distance between the N and C terminus of an insert is significantly smaller when compared to the N-to-C distance in a parent context or a single domain context. Insertions are found always to occur in loop regions of parent domains. Our observations regarding the relationship between domain insertions and the structure, function and evolution of proteins have implications for protein engineering.

Synthesis of biologically important neutral amylo-ß peptide by using improved Fmoc solid-phase peptide synthetic strategy.

The 10 amino acid sequence of the biologically important neutral amylo-ß peptide has equally hydrophilic and hydrophobic properties, which reduces the coupling efficiency during its synthesis and reduces the final yield of the peptide, and is therefore classified as a "difficult peptide sequence." The method presented here minimizes the synthetic problems by the introduction of improved Fmoc chemistry and effective hydroxybenzotriazole (HoBt), diisopropylcarbodiimide (DIC)-coupling and activation strategies. In addition, we developed a PS-TPGD resin as a solid support for the synthesis of specific neutral peptides, which is still a challenge to peptide chemistry. The most essential biologically active neutral amylo-ß peptide (KVKRIILARS) was successfully synthesized, and some synthetic modification was performed using the Fmoc solid-phase peptide synthesis (SPPS) method for purity and yield improvement. Graphical abstractᅟ.

Effect of oral methionine on blood lipid peroxidation and antioxidants in alloxan-induced diabetic rats.

Supplementation of thiol compounds has been suggested to protect against the toxic effects of reduced oxygen species by contributing to the thiol pool of the cell. The present study was designed to determine whether supplementation of methionine in the diet of diabetic animals protected against the oxidative stress in diabetic pathology. Oral methionine was administered at a dosage of 330 mg/100 g feed to diabetic rats. The effect was compared with the effect of insulin administration. Levels of lipid peroxides were measured in plasma, erythrocytes, and erythrocyte membrane. Anti-oxidants were measured in plasma. Diabetic condition was associated with increased lipid peroxidation and depletion in antioxidant levels. Although methionine did not affect the level of blood glucose and some of the antioxidants, it lowered the lipid peroxide content in blood. Erythrocyte lipid peroxidation activity was unaffected by methionine treatment. Administration of insulin lowered both plasma and erythrocyte lipid peroxide levels.