Response of Male Reproductive System Against Ionizing Radiation and Available Radio-protective Agents: Cellular and Molecular Insight.

BACKGROUND: The reproductive organ, housing spermatogonial stem cells (SSCs), undergoes ongoing division impacted by the irradiation dosage and exposure duration. Within the male reproductive organ, germ stem cells (spermatogonia) and somatic cells (Sertoli and Leydig cells) are present. Lower doses of ionizing (>4-6 Gy) and non-ionizing radiation (radiofrequency and microwave range 900 MHz - 2.45 GHz) may cause sperm-related issues, while higher doses (15 Gy) may affect Leydig cells and testosterone production. Response to radiation varies with age and pubescence. Spermatogonial stem cells, crucial for regenerating the spermatogenic lineage, express molecular markers like Estrogen receptor, FSH (Follicular Stimulating Hormone) receptor, TLR-4 (Toll-like Receptor-4), TLR-5 (Toll-like Receptor-5), FGF2 (Fibroblast Growth Factor-2), KIT (Receptor Tyrosine Kinase), AT-1 (Angiotensin II Type-1 Receptor), LXRs-γ (Liver X Receptor-γ), TNF-ß (Tumor Necrosis Factor-ß), and PCNA (Proliferating Cell Nuclear Antigen), influencing stem cell activity in testes. OBJECTIVE: This study aimed to review the various available radioprotective agents and their efficacy in targeting the male reproductive system from the available literature. RESULT: Various radioprotective herbal/synthetic/microbial/metallic extracts/formulations/ drugs [Septilin, Silymarin, Organic Turmeric, Oestrogen, Melatonin, Febuxostat, SQGD (Semiquinone glucoside derivative), Rapamycin, Entolimod, Zinc, Selenium, etc.] have been investigated up to exposure, but owing to effectiveness issues, they are unable to fulfil the aim to the fullest of restoring male fertility and normal testosterone levels during such eventuality. CONCLUSION: Further study is needed to optimize these tactics and fill knowledge gaps. Also, the effective components of herbal, synthetic drugs, etc., should be isolated and tested up to clinical levels, paving the way for successful radioprotection and radiomitigation strategies in the male reproductive system.

Evaluation and comparison of three-dimensional finite element analysis of stress distribution in immediately placed and loaded conventional and customized three-dimensional printed dental implants.

Aim: The aim of this study was to evaluate and compare the stress distribution patterns in immediately placed and loaded conventional and customized three-dimensional (3D) printed dental implants by 3D finite element analysis. Materials and Methods: Twelve 3D finite element models [Group A-3 models; Group B-9 models] with 72 test conditions which were modeled and compared from customized 3D printed dental implants [Group A] and 3 commercially available implant systems [Group B] (Straumann, Ankylos, and Astratech) using "SolidWorks". All models were embedded in extraction socket models of the maxillary central incisor (CI) and Canine (C), Mandibular 1st Premolar. An occlusal loading by axial and nonaxial force of 100 N and 150 N at 30° and 45° was applied on the abutment using the "ANSYS" Suite. Customized 3D printed dental implant (Group A) for maxilla (Max.) CI, Max. C, and mandibular 1st premolar (PM) socket model was compared with three commercial available dental implant systems (Group B) for Max. CI, Max. C, and mandible (Mand.) 1st PM socket model to understand the stress distribution patterns. Results: With increasing oblique loads, von Mises stresses were reduced for the customized group as compared to conventional implants. Increased axial loads caused proportionate increase in the stresses for both groups, yet remained under the physiologic limits in all test conditions. Higher stresses were observed in cortical bone than in cancellous bone at bone-implant contact in general. Marked reduction in von Mises stress was observed at the boundary between compact and cancellous bone. Customized 3D printed implants performed better for oblique loads and comparable for axial load stress distribution in comparison to conventional implant systems in Max. CI and C, Mand. 1st PM. Conclusion: Thus, customized 3D printed implants appear a promising alternative for immediately placed immediately loaded protocols, with additional benefits in specific clinical situations.

Long-Term Efficacy and Safety of Repeated Rituximab to Maintain Remission in Idiopathic Childhood Nephrotic Syndrome: An International Study.

BACKGROUND: Long-term outcomes after multiple courses of rituximab among children with frequently relapsing, steroid-dependent nephrotic syndrome (FRSDNS) are unknown. METHODS: A retrospective cohort study at 16 pediatric nephrology centers from ten countries in Asia, Europe, and North America included children with FRSDNS who received two or more courses of rituximab. Primary outcomes were relapse-free survival and adverse events. RESULTS: A total of 346 children (age, 9.8 years; IQR, 6.6-13.5 years; 73% boys) received 1149 courses of rituximab. A total of 145, 83, 50, 28, 22, and 18 children received two, three, four, five, six, and seven or more courses, respectively. Median (IQR) follow-up was 5.9 (4.3-7.7) years. Relapse-free survival differed by treatment courses (clustered log-rank test P<0.001). Compared with the first course (10.0 months; 95% CI, 9.0 to 10.7 months), relapse-free period and relapse risk progressively improved after subsequent courses (12.0-16.0 months; HRadj, 0.03-0.13; 95% CI, 0.01 to 0.18; P<0.001). The duration of B-cell depletion remained similar with repeated treatments (6.1 months; 95% CI, 6.0 to 6.3 months). Adverse events were mostly mild; the most common adverse events were hypogammaglobulinemia (50.9%), infection (4.5%), and neutropenia (3.7%). Side effects did not increase with more treatment courses nor a higher cumulative dose. Only 78 of the 353 episodes of hypogammaglobulinemia were clinically significant. Younger age at presentation (2.8 versus 3.3 years; P=0.05), age at first rituximab treatment (8.0 versus 10.0 years; P=0.01), and history of steroid resistance (28% versus 18%; P=0.01) were associated with significant hypogammaglobulinemia. All 53 infective episodes resolved, except for one patient with hepatitis B infection and another with EBV infection. There were 42 episodes of neutropenia, associated with history of steroid resistance (30% versus 20%; P=0.04). Upon last follow-up, 332 children (96%) had normal kidney function. CONCLUSIONS: Children receiving repeated courses of rituximab for FRSDNS experience an improving clinical response. Side effects appear acceptable, but significant complications can occur. These findings support repeated rituximab use in FRSDNS.

Paediatric hypertension for the primary care provider: What you need to know.

The prevalence of hypertension has increased in the paediatric and adolescent populations, and is estimated between 1% and 2% in Canada. Paediatric and adolescent hypertension differs from adult hypertension in many ways, and primary care providers may not be up to date with current guidelines and recommendations. Recently, the American Academy of Pediatrics updated and published guidelines on the diagnosis, evaluation, and management of hypertension in children and adolescents. This paper summarizes these new guidelines in addition to the existing Canadian guidelines in a simple four-step approach, catered to a primary care setting, detailing the diagnosis, evaluation, workup, and management of hypertension in children and adolescents.

Both the rituximab dose and maintenance immunosuppression in steroid-dependent/frequently-relapsing nephrotic syndrome have important effects on outcomes.

Rituximab is an effective treatment for steroid-dependent/ frequently-relapsing nephrotic syndrome (SDFRNS) in children. However, the optimal rituximab regimen remains unknown. To help determine this we conducted an international, multicenter retrospective study at 11 tertiary pediatric nephrology centers in Asia, Europe and North America of children 1-18 years of age with complicated SDFRNS receiving rituximab between 2005-2016 for 18 or more months follow-up. The effect of rituximab prescribed at three dosing levels: low (375mg/m2), medium (750mg/m2) and high (1125-1500mg/m2), with or without maintenance immunosuppression (defined as concurrent use of corticosteroids, mycophenolate motile or calcineurin inhibition at first relapse or for at least six months following the rituximab treatment) was examined. Among the 511 children (median age 11.5 year, 67% boys), 191, 208 and 112 received low, medium and high dose rituximab, respectively. Within this total cohort of 511 children, 283 (55%) received maintenance immunosuppression. Renal biopsies were performed in 317 children indicating the predominant histology was minimal change disease (74%). Without maintenance immunosuppression, low-dose rituximab had a shorter relapse-free period and a higher relapse risk (8.5 months) than medium (12.7 months; adjusted hazard ratio, 0.62) and high dose (14.3 months; adjusted hazard ratio, 0.50; all significant). With maintenance immunosuppression, the relapse-free survival in low-dose rituximab (14 months) was similar to medium (10.9 months; adjusted hazard ratio, 1.23) and high dose (12.0 months; adjusted hazard ratio, 0.92; all non-significant). Most adverse events were mild. Thus, children receiving low-dose rituximab without maintenance immunosuppression had the shortest relapse-free survival. Hence, both rituximab dose and maintenance immunosuppression have important effects on the treatment outcomes.

Bioresolution of racemic phenyl glycidyl ether by a putative recombinant epoxide hydrolase from Streptomyces griseus NBRC 13350.

In order to produce enantiomerically pure epoxides for the synthesis of value-added chemicals, a novel putative epoxide hydrolase (EH) sgeh was cloned and overexpressed in pET28a/Escherichia coli BL21(DE3). The 1047 bp sgeh gene was mined from Streptomyces griseus NBRC 13350 genome sequence. The recombinant hexahistidyl-tagged SGEH was purified (16.6-fold) by immobilized metal-affinity chromatography, with 90% yield as a homodimer of 100 kDa. The recombinant E. coli whole cells overexpressing SGEH could kinetically resolve racemic phenyl glycidyl ether (PGE) into (R)-PGE with 98% ee, 40% yield, and enantiomeric ratio (E) of 20. This was achieved under the optimized reaction conditions i.e. cell/substrate ratio of 20:1 (w/w) at pH 7.5 and 20 °C in 10% (v/v) dimethylformamide (DMF) in a 10 h reaction. 99% enantiopure (R)-PGE was obtained when the reaction time was prolonged to 12 h with a yield of 34%. In conclusion, an economically viable and environment friendly green process for the production of enantiopure (R)-PGE was developed by using wet cells of E. coli expressing recombinant SGEH.

An Overview on the Enhancement of Enantioselectivity and Stability of Microbial Epoxide Hydrolases.

Epoxide hydrolases (EHs; 3.3.2.x) catalyze the enantioselective ring opening of racemic epoxides to the corresponding enantiopure vicinal diols and remaining equivalent unreacted epoxides. These epoxides and diols are used for the synthesis of chiral drug intermediates. With an upsurge in the methods for identification of novel microbial EHs, a lot of EHs have been discovered and utilized for kinetic resolution of racemic epoxides. However, there is still a constraint on the account of limited EHs being successfully applied on the preparative scale for industrial biotransformations. This limitation has to be overcome before application of identified functional EHs on large scale. Many strategies such as optimizing reaction media, immobilizing EHs and laboratory-scale directed evolution of EHs have been adopted for enhancing the industrial potential of EHs. In this review, these approaches have been highlighted which can serve as a pathway for the enrichment of already identified EHs for their application on an industrial scale in future studies.

Bioefficacy evaluation and dissipation pattern of nanoformulation versus commercial formulation of pyridalyl in tomato (Solanum lycopersicum).

A study was undertaken to evaluate the decline of the residues of pyridalyl in tomatoes grown in two different cultivation systems: open field (conventional cultivation) and net house (pot experiment). Field experiment was conducted with commercial (10 EC) and nanoformulation of pyridalyl on tomato crop. Tomato plants were subjected to pesticide spray, when fruits were close to ripeness. Fruit samples were taken periodically and cleaned up using QuEChERS methodology, and the residue of pyridalyl was analyzed by ultrahigh-performance liquid chromatography (UHPLC). It dissipated in tomato fruit following the first-order kinetics. In field, average initial deposit of pyridalyl in tomato was observed to be 0.222 and 0.371 µg g(-1) at recommended and double the recommended application rate, respectively, using nanoformulation while it was 0.223 and 0.393 µg g(-1) on using commercial formulation, respectively. The half-life (t1/2) value of nanopyridalyl in tomato fruit was 2.8 and 3.2 days while for commercial formulation, it was 2.5 and 2.6 days for recommended and double the recommended dose, respectively. In India, maximum residue limit (MRL) on tomato has not been fixed for pyridalyl but its residues were always below European MRLs (5 µg g(-1)) on tomato at both application rates. The results of terminal residue showed that pyridalyl residues were below the available MRL. Low residues in tomatoes suggested that this pesticide is safe to use under the recommended dosage. No statistical differences were observed between the cultivation systems in relation to the residue levels of pyridalyl.

Residue, dissipation, and safety evaluation of pyridalyl nanoformulation in Okra (Abelmoschus esculentus [L] Moench).

A comparative study on residues and rate of dissipation of a new nanoformulation of pyridalyl and commercial pyridalyl was carried out on okra under net house and field conditions. Okra crop was sprayed with commercial and nanoformulation of pyridalyl at recommended (75 g a. i./ha) and double the recommended dose (150 g a. i./ha) at the time of fruiting. Quantitation of residues of pyridalyl in okra was done by ultra high performance liquid chromatography over a period of 15 days, and recovery of the method ranged from 79 to 87 %. The half life calculated from the dissipation pattern of pyridalyl on okra for commercial and developed nanoformulation proved that residues of nanopyridalyl did not persist much longer than that of conventional formulation in net house as well as in field trials. The risk quotient value of pyridalyl in okra was significantly lower than 1, implying its negligible risk to the humans.

Trigger factor assisted folding of the recombinant epoxide hydrolases identified from C. pelagibacter and S. nassauensis.

Epoxide hydrolases (EHs), are enantioselective enzymes as they catalyze the kinetic resolution of racemic epoxides into the corresponding enantiopure vicinal diols, which are useful precursors in the synthesis of chiral pharmaceutical compounds. Here, we have identified and cloned two putative epoxide hydrolase genes (cpeh and sneh) from marine bacteria, Candidatus pelagibacter ubique and terrestrial bacteria, Stackebrandtia nassauensis, respectively and overexpressed them in pET28a vector in Escherichia coli BL21(DE3). The CPEH protein (42kDa) was found to be overexpressed as inactive inclusion bodies while SNEH protein (40kDa) was found to form soluble aggregates. In this study, the recombinant CPEH was successfully transformed from insoluble aggregates to the soluble and functionally active form, using pCold TF vector, though with low EH activity. To prevent the soluble aggregate formation of SNEH, it was co-expressed with GroEL/ES chaperone and was also fused with trigger factor (TF) chaperone at its N-terminus. The TF chaperone-assisted correct folding of SNEH led to a purified active EH with a specific activity of 3.85µmol/min/mg. The pure enzyme was further used to biocatalyze the hydrolysis of 10mM benzyl glycidyl ether (BGE) and α-methyl styrene oxide (MSO) with an enantiomeric excess of the product (eep) of 86% and 73% in 30 and 15min, respectively. In conclusion, this is the first report about the heterologous expression of epoxide hydrolases using TF as a molecular chaperone in pCold TF expression vector, resulting in remarkable increase in the solubility and activity of the otherwise improperly folded recombinant epoxide hydrolases.

Use of complementary and alternative medicine for work related musculoskeletal disorders associated with job contentment in dental professionals: Indian outlook.

BACKGROUND: High prevalence rates of work-related musculoskeletal disorders (WRMSD) among dentists have been reported. Complementary and alternative medicine (CAM) therapies can be helpful in managing and preventing work-related musculoskeletal disorders. The purpose of this study was to determine if dental professionals are using CAM for work-related musculoskeletal disorders. Who have greater job satisfaction: dentist who uses Complementary and alternative medicine (CAM) or conventional therapy (CT) as a treatment modality for WRMSD. METHOD: Dentists who registered in Uttar Pradesh state, India under Indian Dental Council, Uttar Pradesh branch (n=1134) were surveyed. Data were analyzed using univariate and bivariate analyses and logistic regression. RESULT: A response rate of 53% (n=601) was obtained, revealing that 82% (n=487) of the respondents suffered from work-related musculoskeletal disorders. The use of complementary and alternative medicine or conventional therapy was reported among 80% (n=390) of the dentists with work-related musculoskeletal disorders. Complementary and alternative medicine users reported greater overall health compared to conventional therapy users (P<0.001). Of those with work-related musculoskeletal disorders, 35.5% (n=172) considered a career change for once, and 4.0% (n=19) reported having left dentistry. CONCLUSION: Complementary and alternative medicine therapies may improve quality of life, reduce work disruptions and enhance job satisfaction for dentists who suffer from work-related musculoskeletal disorders. It is important that dentists incorporate complementary and alternative medicine strategies into practice to facilitate musculoskeletal health that will enable longer and healthier careers, increase productivity, provide safer workplace and prevent musculoskeletal disorders.