SARS-CoV-2 Omicron BA.1 and BA.2 are attenuated in rhesus macaques as compared to Delta

Since the emergence of SARS-CoV-2, five different variants of concern (VOCs) have been identified: Alpha, Beta, Gamma, Delta, and Omicron. Due to confounding factors in the human population, such as pre-existing immunity, comparing severity of disease caused by different VOCs is challenging. Here, we investigate disease progression in the rhesus macaque model upon inoculation with the Delta, Omicron BA.1, and Omicron BA.2 VOCs. Disease severity in rhesus macaques inoculated with Omicron BA.1 or BA.2 was lower than those inoculated with Delta and resulted in significantly lower viral loads in nasal swabs, bronchial cytology brush samples, and lung tissue in rhesus macaques. Cytokines and chemokines were upregulated in nasosorption samples of Delta animals compared to Omicron BA.1 and BA.2 animals. Overall, these data suggests that in rhesus macaques, Omicron replicates to lower levels than the Delta VOC, resulting in reduced clinical disease.

Age-related differences in immune dynamics during SARS-CoV-2 infection in rhesus macaques

Advanced age is a key predictor of severe COVID-19. To gain insight into this relationship, particularly with respect to immune responses, we utilized the rhesus macaque model of SARS-CoV-2 infection. Two cohorts of eight older (16-23 years) and eight younger (3-5 years) rhesus macaques were inoculated with SARS-CoV-2. Animals were evaluated using viral RNA quantification, clinical observations, thoracic radiographs, single-cell transcriptomics, multiparameter flow cytometry, multiplex immunohistochemistry, cytokine detection, and lipidomics analysis at pre-defined timepoints in various tissues. Differences in clinical signs, pulmonary infiltrates, and virus replication dynamics were limited between age cohorts. Transcriptional signatures of inflammation-associated genes in cells isolated from bronchoalveolar lavage fluid at 3 dpi revealed efficient mounting of innate immune defenses in both younger and older animals. These findings suggested that age did not substantially skew major facets of acute disease in this model. However, age-specific divergence of immune responses emerged during the post-acute phase of infection (7-21 dpi). Older animals exhibited sustained local inflammatory innate responses while local effector T-cell responses were induced earlier in the younger animals. Circulating lipid mediator and cytokine levels highlighted increased repair-associated signals in the younger animals, in contrast to persistent pro-inflammatory responses in the older animals. In summary, despite similar disease outcomes, multi-omics profiling in SARS-CoV-2-infected rhesus macaques suggests that age may delay or impair the induction of anti-viral cellular immune responses and delay efficient return to immune homeostasis following acute infection.

Subtle differences in the pathogenicity of SARS-CoV-2 variants of concern B.1.1.7 and B.1.351 in rhesus macaques

The emergence of several SARS-CoV-2 variants has caused global concerns about increased transmissibility, increased pathogenicity, and decreased efficacy of medical countermeasures. Animal models can be used to assess phenotypical changes in the absence of confounding factors that affect observed pathogenicity and transmissibility data in the human population. Here, we studied the pathogenicity of variants of concern (VOC) B.1.1.7 and B.1.351 in rhesus macaques and compared it to a recent clade B.1 SARS-CoV-2 isolate containing the D614G substitution in the spike protein. The B.1.1.7 VOC behaved similarly to the D614G with respect to clinical disease, virus shedding and virus replication in the respiratory tract. Inoculation with the B.1.351 isolate resulted in lower clinical scores in rhesus macaques that correlated with lower virus titers in the lungs, less severe histologic lung lesions and less viral antigen detected in the lungs. We observed differences in the local innate immune response to infection. In bronchoalveolar lavages, cytokines and chemokines were upregulated on day 4 in animals inoculated with D614G and B.1.1.7 but not in those inoculated with B.1.351. In nasal samples, we did not detect upregulation of cytokines and chemokines in D614G or B.1.351-inoculated animals. However, cytokines and chemokines were upregulated in the noses of B.1.1.7-inoculated animals. Taken together, our comparative pathogenicity study suggests that ongoing circulation under diverse evolutionary pressure favors transmissibility and immune evasion rather than an increase in intrinsic pathogenicity.

Phase I/II trial of vorinostat combined with temozolomide and radiation therapy for newly diagnosed glioblastoma: results of Alliance N0874/ABTC 02.

Background: Vorinostat, a histone deacetylase (HDAC) inhibitor, has shown radiosensitizing properties in preclinical studies. This open-label, single-arm trial evaluated the maximum tolerated dose (MTD; phase I) and efficacy (phase II) of vorinostat combined with standard chemoradiation in newly diagnosed glioblastoma. Methods: Patients received oral vorinostat (300 or 400 mg/day) on days 1-5 weekly during temozolomide chemoradiation. Following a 4- to 6-week rest, patients received up to 12 cycles of standard adjuvant temozolomide and vorinostat (400 mg/day) on days 1-7 and 15-21 of each 28-day cycle. Association between vorinostat response signatures and progression-free survival (PFS) and overall survival (OS) was assessed based on RNA sequencing of baseline tumor tissue. Results: Phase I and phase II enrolled 15 and 107 patients, respectively. The combination therapy MTD was vorinostat 300 mg/day and temozolomide 75 mg/m2/day. Dose-limiting toxicities were grade 4 neutropenia and thrombocytopenia and grade 3 aspartate aminotransferase elevation, hyperglycemia, fatigue, and wound dehiscence. The primary efficacy endpoint in the phase II cohort, OS rate at 15 months, was 55.1% (median OS 16.1 mo), and consequently, the study did not meet its efficacy objective. Most common treatment-related grade 3/4 toxicities in the phase II component were lymphopenia (32.7%), thrombocytopenia (28.0%), and neutropenia (21.5%). RNA expression profiling of baseline tumors (N = 76) demonstrated that vorinostat resistance (sig-79) and sensitivity (sig-139) signatures had a reverse and positive association with OS/PFS, respectively. Conclusions: Vorinostat combined with standard chemoradiation had acceptable tolerability in newly diagnosed glioblastoma. Although the primary efficacy endpoint was not met, vorinostat sensitivity and resistance signatures could facilitate patient selection in future trials.

Ethnopharmacological based Evaluation of Anogeissus pendula Edgew Extracts for Antioxidant and Hepatoprotective Potential.

BACKGROUND: Anogeissus pendula has various reported ethnomedicinal uses and is reported to contain phenolic compounds which have antioxidant potential. AIM: The present study was undertaken to evaluate the in vitro antioxidant potential and in vivo hepatoprotective activity along with the oxidative stress parameters of stem bark and leaves of Anogeissus pendula for the first time. SETTINGS AND DESIGN: Albino rats were divided into seven groups of six animals each. Healthy control (Group I) and toxic control (Group II) received the vehicle. Group III, IV, V, VI and VII were treated with silymarin (100 mg/kg body weight, orally) and two hydro-alcoholic extracts i.e., APB (stem bark) and APL (leaves) at doses of 200 and 400 mg/kg b. w., orally, respectively. Hepatotoxicity was induced by allyl alcohol. MATERIALS AND METHODS: Albino Wistar rats of either sex between 8-12 weeks old were used. The plant parts were collected from Sawai Madhopur (Rajasthan, India) and extracted with hydro-alcoholic solvent to get two extracts i.e., APB (stem bark) and APL (leaves) which were investigated for the in vitro antioxidant potential through DPPH radical and H2O2 scavenging assay along with in vivo hepatoprotective potential through allyl alcohol induced hepatotoxicity. STATISTICAL ANALYSIS: Statistical comparisons between different groups were done by using one-way ANOVA followed by the Bonferroni test. P < 0.05 was considered significant. RESULTS AND CONCLUSIONS: APB showed more potent activity than APL in case of in vitro antioxidant potential with IC50 of 44.29 µg/ml in DPPH radical scavenging activity and 53.09 µg/ml in hydrogen peroxide scavenging assay. Both the extracts revealed antioxidant and hepatoprotective potentials in a dose dependent manner but more significant results were obtained in case of APB at 400 mg/kg. More amounts of phytoconstituents might be the reason behind the more significant activity of extract of stem bark than that of the leaves.

CAPD Catheter Exit-Site and Tunnel Infection with Fungal Etiology-Treatment and Catheter Reinsertion for an Extremely Rare Complication.

Fungal infection is an extremely rare etiology of exit-site and tunnel infection in patients on continuous ambulatory peritoneal dialysis (CAPD). There are few data available regarding its management-especially choice of antifungals, duration of therapy, and removal of catheter. There are no guidelines pertaining to reinsertion of the CAPD catheter following fungal exit-site and tunnel infection. This case report highlights Candida albicans as a rare cause of exit-site and tunnel infection of the CAPD catheter. The catheter was removed and the patient received appropriate antifungal therapy followed by reinsertion of the CAPD catheter and re-initiation on CAPD.

SDH with Bleeding Diathesis-a Management Protocol.

Chronic subdural hematoma (SDH) is one of the leading causes of morbidity and mortality in elderly. Patients taking antiplatelets and/or anticoagulants have increased risk of bleeding during the perioperative period. Precise dose blood products and specific surgical technique have been effective in preventing hemorrhagic complications perioperatively. From Jan 2010 to Dec 2012, 25 patients who were on antiplatelets and/or oral anticoagulants underwent emergency surgery for chronic or acute on chronic SDH. Patients were divided into three groups: group I-patients on antiplatelets, group II-patients on oral anticoagulants, and group III-patients taking both. Of these, 21 patients underwent minicraniotomy with microsurgical membranectomy and 4 patients underwent burr hole craniostomy. Random donor platelet concentrate (RDPC) and fresh frozen plasma (FFP) were used depending on whether patient was on antiplatelets or oral anticoagulants. Results were evaluated on the basis of ease of intraoperative hemostasis, incidence of rebleeding in postoperative period, postoperative imaging, and reversal of neurological deficits. Group I, group II, and group III had 16, 4, and 5 patients, respectively. Group I received a mean of 7 units of RDPC. Group II received a mean of 4 units of FFP. Group III received a mean of 7 units of RDPC and 4 units FFPs. There was no problem with intraoperative hemostasis and no incidence of rebleeding. We suggest specific dose protocol for reversal of antiplatelet and anticoagulant effect and specific surgical procedure in preventing intraoperative bleeding and postoperative rebleeding in the above group of patients.

Mechanical and structural property analysis of bacterial cellulose composites.

Bacterial cellulose (BC) exhibits unique properties including high mechanical strength and high crystallinity. Improvement in the mechanical properties of BC is sought for many applications ranging from food to structural composites to biomedical materials. In this study, different additives including carboxymethyl cellulose (CMC), pectin, gelatin, cornstarch, and corn steep liquor were included in the fermentation media to alter the BC produced. Three different concentrations (1%, 3% and 5%) were chosen for each of the additives, with no additive (0%) as the control. The produced BC was then analyzed to determine tensile and compression modulus. Amongst the tested additives, BC produced in media containing 3% (w/v) pectin had the maximum compressive modulus (142kPa), and BC produced in media containing 1% (w/v) gelatin exhibited the maximum tensile modulus (21MPa). Structural characteristics of BC and BC-additive composites were compared using X-Ray diffraction (XRD). The crystal size and crystallinity of BC was reduced when grown in the presence of CMC and gelatin while pectin only decreased the crystallite size. This suggested that CMC and gelatin may be incorporated into the BC fibril structure. The field emission scanning electron microscopy (FESEM) images showed the increased micro-fibril aggregation in BC pellicles grown in the presence of additives to the culture media.

Effect of occupation on lipid peroxidation and antioxidant status in coal-fired thermal plant workers.

BACKGROUND: Air pollution from coal-fired power units is large and varied, and contributes to a significant number of negative environmental and health effects. Reactive oxygen species (ROS) have been implicated in the pathogenesis of coal dust-induced toxicity in coal-fired power plants. AIM: The aim of the study was to measure free radical damage and the antioxidant activity in workers exposed to varying levels of coal dust. MATERIAL AND METHODS: The study population consisted of workers in coal handling unit, turbine unit, and boiler unit (n = 50 each), working in thermal power plant; and electricians (n = 50) from same department were taken as controls. Lipid peroxidation was measured by malondialdehyde (MDA) levels and antioxidant activity was determined by superoxide dismutase (SOD) and glutathione peroxidase (GPx) levels. Statistical analysis was carried out by Student's unpaired t-test. RESULT: MDA levels showed significant increase (P > 0.001) in the thermal power plant workers than the electricians working in the city. The levels of SOD and GPx were significantly higher (P > 0.001) in electricians as compared to subjects working in thermal plant. Among the thermal plant workers, the coal handling unit workers showed significant increase (P > 0.001) in MDA and significant decrease in SOD and GPx than the workers of boiler and turbine unit workers. CONCLUSION: Oxidative stress due to increase in lipid peroxidation and decrease in antioxidant activity results from exposure to coal dust and coal combustion products during thermal plant activities.

Effect of media components on cell growth and bacterial cellulose production from Acetobacter aceti MTCC 2623.

Acetobacter aceti MTCC 2623 was studied as an alternative microbial source for bacterial cellulose (BC) production. Effect of media components on cell growth rate, BC production and cellulose characteristics were studied. FTIR results showed significant variations in cellulose characteristics produced by A. aceti in different media. Results have shown the role of fermentation time on crystallinity ratio of BC in different media. Further, effect of six different media components on cell growth and BC production was studied using fractional factorial design. Citric acid was found to be the most significant media component for cell growth rate (95% confidence level, R(2)=0.95). However, direct role of these parameters on cellulose production was not established (p-value>0.05).

A rare posterior cranial fossa tumor.

Among tumors of the central nervous system, tumors of the mixed glioneuronal type form an important recognized subset. Some of the examples for mixed glioneuronal tumors include gangliocytoma, dysembryoplastic neuroepithelial tumor (DNT), ganglioglioma, anaplastic ganglioglioma, and central neurocytoma. The rosette-forming glioneuronal tumor (RGNT) of the fourth ventricle is a new entity that has only slowly emerged in the literature due to its prior classification with other low-grade mixed glial and neuronal tumors. These tumors are relatively infrequent lesions, and therefore, they can be challenging to diagnose for the practicing pathologist. This is a rare biphasic tumor with clearly defined neurocytic and glial components. The tumor is found exclusively in the posterior fossa, where it arises in the midline, usually occupying a substantial fraction of the fourth ventricle, and it is observed by magnetic resonance imaging (MRI) as a circumscribed, solid mass with heterogeneous contrast enhancement. We describe here a case of RGNT occurring in a 22-year-old male.