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Frequent use of antibiotics and the growth of industry lead to the pollution of several natural resources which is one of the major consequences for fatality to human health. Exploration of smart sensing materials is highly anticipated for ultrasensitive detection of those hazardous organics. The robust porous hydrogen bonded network encompassing a free-NH

Decrease in sunlight exposure during periods of social distancing during the COVID-19 pandemic increased the risk of severe manifestations of vitamin D deficiency (VDD) in a particular "high-risk" population. Our objective was to highlight the importance of vitamin D screening in youth with autism spectrum disorder (ASD) and restrictive eating.We describe 3 adolescent male patients with ASD who developed severe manifestations of VDD and hypocalcemia in late 2020 during the COVID-19 pandemic. All spent less time outdoors than in prior years because of isolation at home during the pandemic. Presenting symptoms included seizures and atraumatic fractures. All 3 were found to have hypocalcemia and severe VDD. Limited sun exposure because of isolation indoors during the COVID-19 pandemic was a likely contributing factor to the severity of VDD. All 3 were treated with intravenous calcium acutely, followed by oral calcium and vitamin D. Laboratory tests performed post-treatment showed biochemical resolution of hypocalcemia and VDD.These cases highlight the importance of screening "at-risk" youth for VDD. Clinicians should be cognizant that children and adolescents with ASD and restricted eating can have severe manifestations of hypocalcemia and VDD. Decreased sun exposure because of isolating indoors during the COVID-19 pandemic increased their risk for this.

Purpose The aim of this study was to examine current practice patterns in pediatric total body irradiation (TBI) techniques among COG member institutions. Methods and Materials Between November 2019 and February 2020, a questionnaire containing 52 questions related to the technical aspects of TBI was sent to medical physicists at 152 COG institutions. The questions were designed to obtain technical information on commonly used TBI treatment techniques. Another set of 9 questions related to the clinical management of patients undergoing TBI was sent to 152 COG member radiation oncologists at the same institutions. Results Twelve institutions were excluded because TBI was not performed in their institutions. A total of 88 physicists from 88 institutions (63% response rate) and 96 radiation oncologists from 96 institutions (69% response rate) responded. The anterior-posterior/posterior-anterior (AP/PA) technique was the most common technique reported (49 institutions [56%]); 44 institutions (50%) used the lateral technique, and 14 (16%) used volumetric modulated arc therapy or tomotherapy. Midplane dose rates of 6 to 15 cGy/min were most commonly used. The most common specification for lung dose was the midlung dose for both AP/PA techniques (71%) and lateral techniques (63%). Almost all physician responders agreed with the need to refine current TBI techniques, and 79% supported the investigation of new TBI techniques to further lower the lung dose. Conclusions There was no consistency in the practice patterns, methods for dose measurement, and reporting of TBI doses among COG institutions. The lack of standardization precludes meaningful correlation between TBI doses and clinical outcomes including disease control and normal tissue toxicity. The COG radiation oncology discipline is currently undertaking several steps to standardize the practice and dose reporting of pediatric TBI using detailed questionnaires and phantom-based credentialing for all COG centers.

Purpose: Identification of nonresponders prior to anti-vascular endothelial growth factor (anti-VEGF) therapy would help in the judicious clinical management of diabetic macular edema (DME) patients. Thus, a systematic study was initiated to identify nonresponding DME patient population undergoing ranibizumab treatment to figure out additional inflammatory components that may contribute to their nonresponsiveness to anti-VEGF therapy. Methods: A total of 40 patients recruited to this investigator-initiated trial received intravitreal ranibizumab monthly for 3 months. The fourth- and fifth-month injections were according to PRN protocol and the sixth-month injection was mandatory. Best-corrected visual acuity (BCVA), central macular thickness (CMT), and VEGF in aqueous humor were measured for all the patients. Patients were grouped into responders/nonresponders on the formulated criteria and the levels of key pro-inflammatory cytokines were also measured between the two groups at baseline, 2 month and 5 months using cytometric bead array (CBA). Results: Eleven patients were categorized (29.72%) as responders and 10 patients (27.02%) as nonresponders. Nonresponders showed poorer BCVA (P = 0.024, 0.045, and 0.048 for 4, 5, and 6 months) and higher CMT (P = 0.021, 0.0008 and

The organometallic compounds are prospective candidates in the row of developing metallochemotherapeutics with the aim of overcoming the limitations of platinum drugs. In order to explore the anticancer properties of organometallic compounds with the natural medicines, two Ru(II)

Targeted photodynamic therapy (PDT) is one of the promising approaches for the selective killing of cancerous cells without affecting the normal cells, and hence designing new strategies for targeted PDT is extremely important. Herein we report the design and synthesis of a new class of nanosheets derived from the self-assembly of the iodo-BODIPY-biotin conjugate as a photosensitizer for targeted PDT applications. The nanosheet exhibits a high extinction coefficient in the NIR region, high singlet oxygen efficiency, no toxicity in the dark and cell targeting ligands (biotin) on the surface, which are necessary features required for an ideal photosensitizer. Overexpression of sodium-dependent multivitamin transporters (SMVTs) in HeLa and A549 (biotin receptor positive cell lines) is explored for the selective uptake of the nanophotosensitizer through receptor mediated endocytosis (interaction between biotin and SMVT). Control experiments using a biotin receptor negative cell line (WI-38) are also carried out to confirm that the specific interaction between the SMVTs and biotin is mainly responsible for the selective uptake of the photosensitizer. Efficient killing of cancerous cells is demonstrated upon light irradiation through the generation of singlet oxygen and other reactive oxygen species around the cellular environment.

This article provides a comprehensive overview of hand tendon injuries. It has been tailored towards healthcare professionals who will be the first to assess these injuries and instigate appropriate management. It discusses the essential hand anatomy to be aware of, how to assess tendon injuries, their initial management and also the definitive surgical interventions used, if required. Rehabilitation techniques are also discussed, as this is also key to good functional outcomes. Missed injuries, or delay in their diagnosis and referral to specialist hand surgeons, can cause a large amount of morbidity for patients and therefore it is important that they are picked up in a timely manner.

Objective Writer’s cramp (WC) is a focal task-specific dystonia characterized by abnormal posturing of the hand muscles during handwriting, but not during other tasks that involve the same set of muscles and objects such as sharpening a pencil. Our objective was to investigate the pathophysiology underlying the task specificity of this disorder using EEG. We hypothesized that premotor-parietal connectivity will be lower in WC patients specifically during handwriting and motor imagery of handwriting. Methods We recruited 15 WC patients and 15 healthy controls. EEG was recorded while participants performed 4 tasks – writing with a pencil, sharpening a pencil, imagining writing and imagining sharpening. We determined the connectivity changes between relevant brain regions during these tasks. Results We found reduced interhemispheric alpha coherence in the sensorimotor areas in WC patients exclusively during handwriting. WC patients also showed less reduction of task-related beta spectral power and a trend for reduced premotor-parietal coherence during motor tasks. Conclusion We could not confirm an abnormality in premotor-parietal connectivity specific to handwriting by this method. However, there was a task-specific reduction in interhemispheric alpha connectivity in WC patients, whose behavioral correlate remains unknown. Significance Interhemispheric alpha connectivity can be a potential interventional target in WC.

Purpose The purpose of this study is to evaluate the clinical profile, visual, anatomical and survival outcome of patients with endogenous endophthalmitis. Methods Retrospective chart review of consecutive cases with endogenous endophthalmitis presenting from 2009-2016. Results In our study, 41 eyes of 34 patients were included. Most common co-morbidity associated with endogenous endophthalmitis was Diabetes Mellitus (70.7%) and most common infective foci was UTI (73.2%). Among the culture positive cases, fungi and bacteria were evenly distributed, 76.93% were Gram positive bacteria and 23.07% were Gram negative. Fungal endogenous endophthalmitis was more commonly seen in immunosuppressed state (72.7%) and bilateral cases (66.7%). The mean presenting vision (log MAR) of patients who died during the study were poor compared to those who survived (P = 0.014) Poor mean visual acuity at presentation was associated with more death (P = 0.014). Eyes with poor presenting vision, fungal isolates, culture positivity and immune suppression had poor visual and survival outcome. Poor visual outcome was observed more frequently in eyes with Aspergillus infection (85.7%) compared to Candida (75%) and bacteria (58.3%). Evisceration was done for 5 out of 41 eyes (12.2%). Vitrectomy rate was 53.7% in our study, with 40% of them showing overall improvement in vision. Conclusion Endogenous endophthalmitis is a sight threatening condition associated with high mortality particularly when caused by Aspergillus spp. in immunocompromised patients. Contrary to the prior published reports of endogenous endophthalmitis outside India, we found an equal distribution of fungal and bacterial organisms among our cases, with predominance of Aspergillus among fungal isolates and Gram-positive organism among bacteria. Fungal infections, especially with Aspergillus spp., resulted in poor visual and survival outcome.

BACKGROUND: The acute vascular disease deep vein thrombosis (DVT) requires oral anticoagulants to prevent progression. Monitoring therapeutic efficacy of direct oral anticoagulants (DOAC), including rivaroxaban, is problematic as no reliable test is available. Advances in rheometry have led to the development of a functional coagulation biomarker using Gel Point (GP) analysis which assesses clot structure formation. The biomarker measures incipient clot formation time (TGP) and quantifies fibrin clot structure in terms of fractal dimension (df). OBJECTIVE: This study aimed to investigate clot structure formation in first time DVT and the effect of rivaroxaban treatment. METHODS: This prospective observational cohort study measured the GP and standard laboratory markers at three sample points: pre-treatment and at 20 and 60 days following 15 mg BD and 20 mg OD rivaroxaban respectively. RESULTS: Forty DVT patients (mean age 64 years [SD±14.8]; 23 males, 17 female) were recruited. The results show that DVT vs non-DVT patients did not have a significantly different GP profile (df: 1.72±0.06 vs 1.70±0.06 and TGP: 267±68 sec vs 262±73 sec) with both within the defined healthy index. In addition, rivaroxaban therapy increased TGP to 392 s (±135 s) after 20 days, and subsequently increased to 395 s (±194 s) at 60 days but did not significantly increase df (from 1.69±0.05 to 1.71±0.06). CONCLUSIONS: The results indicate in this cohort of DVT patients there was no underlying hypercoagulable effect as determined by gel point analysis. Furthermore, the anticoagulant effect of rivaroxaban prolonged clotting, suggesting a protective effect against clot formation, without significantly reducing clot microstructural properties.

Summary Objectives The advent of direct-acting antivirals (DAAs) has revealed high rates of sustained virological response at 12 weeks (SVR 12) in Hepatitis C (HCV) treatment. Since the introduction of DAAs, in our centre, 42% of patients treated for HCV are HIV co-infected. Our study aimed to identify the SVR 12 rates between this group and HCV mono-infected patients. Methods Retrospective data analysis of HCV mono-infection and HIV-HCV co-infection patients between 1st July 2015 and 30th November 2018, who had a SVR at 12 weeks post treatment. Co-infected patients were only referred for HCV treatment if they had well controlled HIV. Patients treated with Pegylated Interferon and Ribavirin were excluded. Results During this period, 724 patients were treated for HCV and had data on SVR 12. Of those, 303 (41.8%) were co-infected with HIV. The SVR 12 was achieved in 386 (91.6%) of the HIV negative patients and 288 (95%) of the HIV positive patients (χ²= 3.10 p = 0.078). Cirrhotic patients had poorer SVR 12 in both groups (90% in co-infection and 88.4% in HCV mono-infection). Conclusions Our results demonstrate a higher SVR 12 in co-infected patients compared to patients with HCV mono-infection. We hypothesise that adherence to HIV treatment could increase compliance and success of HCV treatment.

Children with ADHD show developmentally abnormal levels of mirror overflow-unintentional movements occurring symmetrically opposite of intentional movements. Because mirror overflow correlates with ADHD behavioral symptoms, the study of disinhibition in motor control may shed light on physiologic mechanisms underlying impaired behavioral/cognitive control. This is a case-controlled study of EEG recording from 25 children with ADHD and 25 typically developing (TD) controls performing unilateral sequential finger tapping, with overflow movements measured using electronic goniometers. Consistent with previously published findings, children with ADHD showed increased mirror overflow as compared with TD peers. EEG findings revealed less lateralized alpha modulation (event-related desynchronization; ERD) and decreased magnitude of beta ERD in ADHD; both alpha and beta ERD reflect cortical activation. Moderation analysis revealed a significant association between beta ERD and overflow, independent of diagnosis; and an equivocal (p = .08) effect of diagnosis on the relationship between alpha ERD and overflow, with a significant effect in children with ADHD but not TD children. These results suggest two mechanisms involved with mirror overflow: one reflected in beta ipsilateral to the intentional movement and relevant to both children with ADHD and controls, and the other seemingly more specific to ADHD (alpha, contralateral to movement).

Autism spectrum disorder (ASD) consists of altered performance of a range of skills, including social/communicative and motor skills. It is unclear whether this altered performance results from atypical acquisition or learning of the skills or from atypical "online" performance of the skills. Atypicalities of skilled actions that require both motor and cognitive resources, such as abnormal gesturing, are highly prevalent in ASD and are easier to study in a laboratory context than are social/communicative skills. Imitation has long been known to be impaired in ASD; because learning via imitation is a prime method by which humans acquire skills, we tested the hypothesis that children with ASD show alterations in learning novel gestures via imitation. Eighteen participants with ASD and IQ > 80, ages 8-12.9 years, and 19 typically developing peers performed a task in which they watched a video of a model performing a novel, meaningless arm/hand gesture and copied the gesture. Each gesture video/copy sequence was repeated 4-6 times. Eight gestures were analyzed. Examination of learning trajectories revealed that while children with ASD made nearly as much progress in learning from repetition 1 to repetition 4, the shape of the learning curves differed. Causal modeling demonstrated the shape of the learning curve influenced both the performance of overlearned gestures and autism severity, suggesting that it is in the index of learning mechanisms relevant both to motor skills and to autism core features. Autism Res 2020, 13: 777-784.. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Imitation is a route by which humans learn a wide range of skills, naturally and in therapies. Imitation is known to be altered in autism spectrum disorder (ASD), but learning via imitation has not been rigorously examined. We found that the shape of the learning curve is altered in ASD, in a way that has a significant impact both on measures of autism severity and of other motor skills.

BACKGROUND: Plethora of efforts fails to yield a single drug to reverse the pathogenesis of Parkinson's disease (PD) and related α-synucleopathies. METHODS: Using chemical biology, we identified a small molecule inhibitor of c-abl kinase, PD180970 that could potentially clear the toxic protein aggregates. Genetic, molecular, cell biological and immunological assays were performed to understand the mechanism of action. In vivo preclinical disease model of PD was used to assess its neuroprotection efficacy. FINDINGS: In this report, we show the ability of a small molecule inhibitor of tyrosine kinases, PD180970, to induce autophagy (cell lines and mice midbrain) in an mTOR-independent manner and ameliorate the α-synuclein mediated toxicity. PD180970 also exerts anti-neuroinflammatory potential by inhibiting the release of proinflammatory cytokines such as IL-6 (interleukin-6) and MCP-1 (monocyte chemoattractant protein-1) through reduction of TLR-4 (toll like receptor-4) mediated NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) activation. In vivo studies show that PD180970 is neuroprotective by degrading the toxic protein oligomers through induction of autophagy and subsiding the microglial activation. INTERPRETATION: These protective mechanisms ensure the negation of Parkinson's disease related motor impairments. FUND: This work was supported by Wellcome Trust/DBT India Alliance Intermediate Fellowship (500159-Z-09-Z), DST-SERB grant (EMR/2015/001946), DBT (BT/INF/22/SP27679/2018) and JNCASR intramural funds to RM, and SERB, DST (SR/SO/HS/0121/2012) to PAA, and DST-SERB (SB/YS/LS-215/2013) to JPC and BIRAC funding to ETA C-CAMP. ispartof: EBIOMEDICINE vol:50 pages:260-273 ispartof: location:Netherlands status: published

Purpose: To study the late toxicities of treatment and its impact on Breast cancer survivors among Indian patients. Materials and Methods: Our study recruited 152 curatively treated non metastatic carcinoma breast patients. The baseline demographic details, disease related and treatment related information were collected. The late effects included breast cancer related lymphedema, shoulder dysfunction, treatment induced bone loss, hypothyroidism, cardiac dysfunction, and chemotherapy induced cognitive dysfunction and Quality of life. Results: The median age was 47 years (range 27 -72 years). The cumulative frequency of BCRL and shoulder dysfunction was 31.57% and 34.86% respectively. The improvement in BCRL with corrective intervention was not statistically significant. The BCRL was significantly associated with shoulder dysfunction. The frequency of loss of bone mineral density was 38.15%. There was statistically significant improvement in bone mineral density with interventions. The cumulative rate of hypothyroidism and cardiac dysfunction was 14.47 % and 2.17% respectively which improved after corrective therapy. We did not find any delayed cognitive dysfunction. There was improvement in global health, physical function, role function, fatigue, Nausea, vomiting, pain scores, insomnia, Loss of appetite, diarrhea and arm symptoms over time with intervention. Conclusion: Our study has shown that nearly half of the survivors were suffering from at least one of the late effects. The intervention helped in improving the loss of bone mineral density, hypothyroidism, cardiac dysfunction and quality of life in Breast cancer survivors.

Anemia is a common finding and important cause of morbidity in patients with acute lymphoblastic leukemia (ALL) at diagnosis or during the course of its protracted treatment. We studied profile of anemia in ALL patients on maintenance therapy and evaluated specific micronutrients as cause of this anemia.ALL patients who were on maintenance therapy and had grade ≥ 2 anemia were recruited for the study. Serum iron studies, folate, and vitamin B12 were done to identify micronutrient deficiency and to initiate supplementation with specific components if found to be deficient. Toxicities, improvement of anemia, micronutrient levels, and disease outcome were studied after 3 months.From March 2015 to September 2016, 105 ALL patients were found to be on maintenance fulfilling the inclusion criteria. Overall, the proportion of anemia was 80%(N = 84). Majority had normocytic normochromic anemia (71%). Macrocytic anemia was seen in 18% and microcytic hypochromic in 9.5%. In patients with anemia of grade ≥ 2 (N = 84), 38 patients (45%) had biochemical deficiency of serum folate, and 7 (8%) had vitamin B12 deficiency. No biochemical evidence of iron deficiency was found. Supplementation of deficient micronutrients improved anemia: mean hemoglobin significantly increased from 8.06 ± 1.63 to 10.78 ± 1.53 (p 0.001) at 3 months; and reduced treatment toxicities, mean number of febrile neutropenia episodes (p = 0.007), and treatment interruptions of 2 weeks (p = 0.002) were lowered. Patients with anemia had significantly more relapses (N = 14,64%) compared to patients without anemia (N = 8,36%), (p = 0.040).Timely identification and correction of micronutrient deficiencies causing anemia in ALL patients on maintenance can enhance treatment outcomes.

Cardiotoxic manifestation associated with breast cancer treatment by anthracycline regimen increases patients’ susceptibility to myocardial injury, reduction in left ventricular ejection fraction and complications associated with heart failure. There is currently no standardized, minimally invasive, cost effective and clinically verified procedure to monitor cardiotoxicity post-anthracycline therapy initiation, and to detect early onset of irreversible cardiovascular complications. This study aims to create a panel of novel biomarkers and circulating miRNAs associated with cardiotoxicity, further assessing their correlation with cardiac injury specific markers, troponin I and T, and demonstrate the development of cardiac dysfunction in breast cancer patients. Blood obtained from West Virginian females clinically diagnosed with breast cancer and receiving anthracyclines showed upregulated level of biomarkers and circulating miRNAs after 3 and 6 months of chemotherapy initiation with increased levels of cardiac troponin I and T. These biomarkers and miRNAs significantly correlated with elevated troponins. Following 6 months of anthracycline-regimens, 23% of the patient population showed cardiotoxicity with reduced left ventricular ejection fraction. Our results support the clinical application of plasma biomarkers and circulating miRNAs to develop a panel for early diagnosis of chemotherapy related cardiac dysfunction which will enable early detection of disease progression and management of irreversible cardiac damage.

Summary The N6-methyladenosine (m6A) RNA modification is used widely to alter the fate of mRNAs. Here we demonstrate that the C. elegans writer METT-10 (the ortholog of mouse METTL16) deposits an m6A mark on the 3′ splice site (AG) of the S-adenosylmethionine (SAM) synthetase pre-mRNA, which inhibits its proper splicing and protein production. The mechanism is triggered by a rich diet and acts as an m6A-mediated switch to stop SAM production and regulate its homeostasis. Although the mammalian SAM synthetase pre-mRNA is not regulated via this mechanism, we show that splicing inhibition by 3′ splice site m6A is conserved in mammals. The modification functions by physically preventing the essential splicing factor U2AF35 from recognizing the 3′ splice site. We propose that use of splice-site m6A is an ancient mechanism for splicing regulation., Graphical abstract, Highlights • m6A deposited at 3′ splice site by worm METT-10 inhibits splicing • Methylation blocks 3′ splice site recognition by splicing factor U2AF35 • Methylation and splicing inhibition is a response to change in worm diet • Splicing inhibition by 3′ splice site m6A is conserved in mammals, m6A methylation of a 3ʹ splice site blocks its recognition by splicing factors to inhibit pre-mRNA splicing in nematodes and mammals. In worms, this mechanism is used to modulate splicing in response to a change in diet.

PURPOSE Chemotherapy-induced nausea and vomiting (CINV) is a significant toxicity of chemotherapy. Olanzapine is recommended in adult patients for the prevention of CINV but has not been prospectively investigated in children. METHODS This investigator-initiated, randomized, open-label trial evaluated olanzapine in children (ages 5-18 years) scheduled to receive the first cycle of highly emetogenic chemotherapy (HEC). All participants received aprepitant, ondansetron, and dexamethasone during and 2 days after chemotherapy. Participants in the study group additionally received oral olanzapine 0.14 mg/kg/day (rounded to the nearest 2.5 mg; maximum, 10 mg) during the chemotherapy block and 3 days postchemotherapy. The primary objective was to compare complete response (CR) rates (no vomiting and no rescue medication) between the groups in the acute, delayed, and overall periods. Nausea comparison and safety evaluation were secondary and additional objectives, respectively. The collection of outcomes and adverse events was performed daily until the completion of the overall period. RESULTS A total of 240 patients underwent randomization. We performed a modified intention-to-treat analysis on 231 patients (116 in the control group and 115 in the study group). A higher proportion of patients in the olanzapine group achieved CR in the acute period (78% v 59%; P = .001), delayed period (74% v 47%; P < .001) and overall period (64% v 38%; P < .001) than in the control group. The proportion of patients with no nausea was significantly higher in the olanzapine group in the acute period (74% v 52%; P < .001), delayed period (74% v 47%; P < .001), and overall period (64% v 37%; P < .001). Grade 1/2 somnolence was greater in the olanzapine group (35% v 11%; P < .001). There was no grade 3/4 somnolence reported. CONCLUSION Olanzapine significantly improved CR rates for vomiting in children receiving the first cycle of HEC.

(1) Background: Nonalcoholic fatty liver disease (NAFLD) is primarily characterized by the presence of fatty liver, hepatic inflammation and fibrogenesis eventually leading to nonalcoholic steatohepatitis (NASH) or cirrhosis. Obesity and diabetes are common risk factors associated with the development and progression of NAFLD, with one of the highest prevalence of these diseased conditions in the West Virginia population. Currently, the diagnosis of NAFLD is limited to radiologic studies and biopsies, which are not cost-effective and highly invasive. Hence, this study aimed to develop a panel and assess the progressive levels of circulatory biomarkers and miRNA expression in patients at risk for progression to NASH to allow early intervention strategies. (2) Methods: In total, 62 female patients were enrolled and blood samples were collected after 8&ndash, 10 h of fasting. Computed tomography was performed on abdomen/pelvis following IV contrast administration. The patients were divided into the following groups: Healthy subjects with normal BMI and normal fasting blood glucose (Control, n = 20), Obese with high BMI and normal fasting blood glucose (Obese, n = 20) and Obese with high fasting blood glucose (Obese + DM, n = 22). Based on findings from CT, another subset was created from Obese + DM group with patients who showed signs of fatty liver infiltration (Obese + DM(FI), n = 10). ELISA was performed for measurement of plasma biomarkers and RT-PCR was performed for circulating miRNA expression. (3) Results: Our results show significantly increased levels of plasma IL-6, Leptin and FABP-1, while significantly decreased level of adiponectin in Obese, Obese + DM and Obese + DM(FI) group, as compared to healthy controls. The level of CK-18 was significantly increased in Obese + DM(FI) group as compared to control. Subsequently, the expression of miR-122, miR-34a, miR-375, miR-16 and miR-21 was significantly increased in Obese + DM and Obese + DM(FI) group as compared to healthy control. Our results also show distinct correlation of IL-6, FABP-1 and adiponectin levels with the expression of miRNAs in relation to the extent of NAFLD progression. (4) Conclusion: Our results support the clinical application of these biomarkers and miRNAs in monitoring the progression of NAFLD, suggesting a more advanced diagnostic potential of this panel than conventional methods. This panel may provide an appropriate method for early prognosis and management of NAFLD and subsequent adverse hepatic pathophysiology, potentially reducing the disease burden on the West Virginia population.

Cell migration is a universal and crucial mechanism for life. It is required in a series of physiological processes, in wound repair and immune response and is involved in several pathological conditions, including cancer and virus dissemination. Among the several biochemical and biophysical routes, changing cell membrane elasticity holds the promise to be a universal strategy to alter cell mobility. Due to their affinity with cell membranes, ionic liquids (ILs) may play an important role. This work focuses on the effect of subtoxic amounts of imidazolium-ILs on the migration of the model cancer cell line MDA-MB-231. Here we show that ILs are able to enhance cell mobility by reducing the elasticity of the cellular lipid membrane, and that both mobility and elasticity can be tuned by IL-concentration and IL-cation chain length. This biochemical-physical mechanism is potentially valid for all mammalian cells, and its impact in bionanomedicine and bionanotechnology is discussed.

Hepatic fibrosis has been associated with a series of pathophysiological processes causing excessive accumulation of extracellular matrix proteins. Several cellular processes and molecular mechanisms have been implicated in the diseased liver that augments fibrogenesis, fibrogenic cytokines and associated liver complications. Liver biopsy remains an essential diagnostic tool for histological evaluation of hepatic fibrosis to establish a prognosis. In addition to being invasive, this methodology presents with several limitations including poor cost-effectiveness, prolonged hospitalizations, and risks of peritoneal bleeding, while the clinical use of this method does not reveal underlying pathogenic mechanisms. Several alternate noninvasive diagnostic strategies have been developed, to determine the extent of hepatic fibrosis, including the use of direct and indirect biomarkers. Immediate diagnosis of hepatic fibrosis by noninvasive means would be more palatable than a biopsy and could assist clinicians in taking early interventions timely, avoiding fatal complications, and improving prognosis. Therefore, we sought to review some common biomarkers of liver fibrosis along with some emerging candidates, including the oxidative stress-mediated biomarkers, epigenetic and genetic markers, exosomes, and miRNAs that needs further evaluation and would have better sensitivity and specificity. We also aim to elucidate the potential role of cardiotonic steroids (CTS) and evaluate the pro-inflammatory and profibrotic effects of CTS in exacerbating hepatic fibrosis. By understanding the underlying pathogenic processes, the efficacy of these biomarkers could allow for early diagnosis and treatment of hepatic fibrosis in chronic liver diseases, once validated.

(1) Introduction. A recent viral outbreak of novel coronavirus (CoVID-19) was declared as a pandemic by the World Health Organization (WHO) due to its global public health concern. There has been an aggressive growth in the number of emerging cases suggesting rapid spread of the virus. Since the first reported case of CoVID-19, there has been vast progress in understanding the dynamics of CoVID-19. However, there is an increasing evidence of epidemiological disparity in disease burden between urban and rural areas, with rural areas having minimal pandemic preparedness and their own healthcare challenges. Therefore, this review aims to provide insight on the pathogenesis and the transmission dynamics of CoVID-19 along with pharmacological and non-pharmacological intervention strategies to mitigate the clinical manifestation of this virus. This review also aims to assess existing challenges of the CoVID-19 pandemic in rural areas based on past pandemic experiences and the effect on rural population. (2) Methods. A literature review was conducted using databases such as PubMed, Science Direct, Academic Search Premier, ProQuest, and Google Scholar, along with information from governmental organizations such as Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO). (3) Results. The causative virus, with its likely zoonotic origin, has demonstrated high pathogenicity in humans through increasing human-to-human transmission leading to extensive mitigation strategies, including patient quarantine and mass “social distancing” measures. Although the clinical manifestation of symptoms is mild in majority of the virus-inflicted population, critical patients may present with pneumonia and acute respiratory distress syndrome, exacerbated by pre-existing comorbidities, eventually leading to death. While effective coronavirus disease (CoVID-19)-specific vaccines and drugs are under clinical trials, several pharmacological and non-pharmacological interventions have been adapted to manage symptoms and curtail the effect of the virus to prevent increasing morbidity and mortality. Several persisting challenges have been noted for mitigating CoVID-19 in rural areas, including the poor healthcare infrastructure, health literacy, pandemic preparedness along with the fact that majority of rural population are frail subjects with pre-existing comorbidities. (4) Discussion. The increasing rate of incidence of CoVID-19 presents its own challenges, burdening healthcare institutions and the global economy, and impacting the physical and mental health of people worldwide. Given the clinical insights into CoVID-19 and the challenges presented in this review for the U.S. rural population, mitigation strategies should be designed accordingly to minimize the morbidity and mortality of this contagion.

Most proteins associate into multimeric complexes with specific architectures(1,2), which often have functional properties such as cooperative ligand binding or allosteric regulation(3). No detailed knowledge is available about how any multimer and its functions arose during evolution. Here we use ancestral protein reconstruction and biophysical assays to elucidate the origins of vertebrate haemoglobin, a heterotetramer of paralogous alpha- and beta-subunits that mediates respiratory oxygen transport and exchange by cooperatively binding oxygen with moderate affinity. We show that modern haemoglobin evolved from an ancient monomer and characterize the historical 'missing link' through which the modern tetramer evolved-a noncooperative homodimer with high oxygen affinity that existed before the gene duplication that generated distinct alpha- and beta-subunits. Reintroducing just two post-duplication historical substitutions into the ancestral protein is sufficient to cause strong tetramerization by creating favourable contacts with more ancient residues on the opposing subunit. These surface substitutions markedly reduce oxygen affinity and even confer cooperativity, because an ancient linkage between the oxygen binding site and the multimerization interface was already an intrinsic feature of the protein's structure. Our findings establish that evolution can produce new complex molecular structures and functions via simple genetic mechanisms that recruit existing biophysical features into higher-level architectures.

Summary Adoptive therapy using chimeric antigen receptor-modified T cells (CAR-T cells) is effective in hematologic but not epithelial malignancies, which cause the greatest mortality. In breast and lung cancer patients, CAR-T cells targeting the tumor-associated antigen receptor tyrosine kinase-like orphan receptor 1 (ROR1) infiltrate tumors poorly and become dysfunctional. To test strategies for enhancing efficacy, we adapted the KrasLSL-G12D/+;p53f/f autochthonous model of lung adenocarcinoma to express the CAR target ROR1. Murine ROR1 CAR-T cells transferred after lymphodepletion with cyclophosphamide (Cy) transiently control tumor growth but infiltrate tumors poorly and lose function, similar to what is seen in patients. Adding oxaliplatin (Ox) to the lymphodepletion regimen activates tumor macrophages to express T-cell-recruiting chemokines, resulting in improved CAR-T cell infiltration, remodeling of the tumor microenvironment, and increased tumor sensitivity to anti-PD-L1. Combination therapy with Ox/Cy and anti-PD-L1 synergistically improves CAR-T cell-mediated tumor control and survival, providing a strategy to improve CAR-T cell efficacy in the clinic.

Purpose: To study the incidence and risk factors of raised intraocular pressures (IOPs) in the follow-up of transconjunctival sutureless vitrectomy (TSV). Methods: A retrospective observational study was performed on 635 patients who underwent TSV under a single surgeon. The IOPs were recorded using a calibrated non-contact tonometer at seven postoperative visits, viz., day 1, 7 and 1, 3, 6 months, and 1 day and 1 month following silicone oil removal. Results: IOP rise was seen in 24.25% (154) out of the 635 eyes studied. Among patients under 50 years of age, 37.73% had an IOP rise, compared to 21.55% above 50 years (Odds Ratio 2.206). Among males, 30.32% had an IOP rise, as compared to 15.98% females (OR 2.287). In eyes with retinal detachment, 49.16% had raised IOP (OR 5.435), and 24.05% with proliferative diabetic retinopathy (OR 1.780), as opposed to 15.38% with macular hole and 12.32% with epiretinal membrane. This was statistically significant (P < 0.001). In eyes with silicone oil, 34.9% developed a rise in IOP (OR 2.738) as compared to 11.94% of other surgeries (OR 0.697). This was statistically significant (P < 0.001). Conclusion: We observed an increase in IOP postoperatively, more in those under 50 years, males and patients undergoing surgery for RD and PDR.

A retrospective case series.The aim of this study was to report the immunosuppression and secondary bacterial infection after dengue viral infection and the predilection of these infections in the spine. This can trigger further research in to this fact. The possibility of change in the serotype of dengue virus, which are neurotropic, may be looked into.This is the largest case series of epidural abscess with or without spondylodiscitis within 6 weeks following dengue virus infection.We performed a retrospective review of all the eight cases treated for epidural abscess with or without spondylodiscitis within 6 weeks following dengue virus infection in our center during the period of 3 months from June 2017 to August 2017.Of the eight cases, three of them were infected with Methicillin Resistant Saphylococcus Aureus and all of them grew the bug in the blood culture. Three of them had Methicillin Sensitive Staphylococcus Aureus (MSSA), one with MSSA septicemia, and one had associated Elizabeth Kingia meningoseptica infection and one patient had positive Acid Fast Bacilli stained in smears. Two patients were infected with pseudomonas. Some patients had multiple site abscess and epidural abscess without spondylodiscitis. Five of them had neurological deficit, which recovered with abscess drainage and antibiotic treatment. The Erythrocyte Sedimentation rate, C-Reactive Protein, and serum ferritin were elevated in these patients.This is a large case series of epidural abscess with or without spondylodiscitis within 6 weeks following dengue virus infection. The predilection of dengue virus for the neural tissue should be further investigated. Post dengue immunosuppression also needs further study.4.

Background The Direct Observation of Treatment (DOT) is an important component of the country's TB Control strategy. Standards of TB care in India and the End TB strategy emphasised the importance of a patient-centered approach to foster adherence. A qualitative study was conducted to explore the perception of people with Tuberculosis in Kerala regarding DOT, mechanisms to make the treatment of TB more patients centered and to identify the preferable mechanisms to ensure adherence. Methods Six focus group discussions were conducted – two among people with TB from rural area, two among people with TB in urban area, one among multipurpose health workers of rural area and one among key field staff of TB control in urban area. Results Patients who were on a strict DOT were unhappy about the issues of confidentiality, patient inconvenience and provider centered approach . A flexible, patient centered approach were a family member can act as the DOT provider with guidance from a trained health worker was evolved as the most acceptable and comfortable mode of treatment to majority of the TB patients. They felt that a strict external monitor as a DOT provider was not a necessity in majority of the cases. Only practical way to effectively incorporate ICT in monitoring patient compliance in current scenario was identified as daily phone call reminders. Patients also expressed their concerns in keeping the medicines for entire duration at home. Conclusion A flexible patient wise individualized system based on patient's behavior, literacy and awareness along with attitude of family members is needed to ensure adherence to anti TB drugs.

The concept of substrate inhibition to prevent its phosphorylation has potential in drug discovery and is envisioned to treat the autoimmune disorder multiple sclerosis (MS). Glia maturation factor-β (GMF-β) Ser83 phosphorylation by protein kinase A (PKA) is pivotal in the activation of GMF-β-p38MAPK-NFκB biochemical pathway towards proinflammatory response induction in experimental autoimmune encephalomyelitis (EAE). Using structure-based drug design, we identified the small molecule inhibitor 1-H-indazole-4yl methanol (GMFBI.1) that specifically blocked Ser83 phosphorylation site on GMF-β substrate. Using in vitro and in vivo techniques, molecular mechanism of action of GMFBI.1’s direct interaction with GMF-β substrate and prevention of its Ser83 phosphorylation was established. GMFBI.1 down regulated p38MAPK phosphorylation and NFκB expression essential for proinflammatory response. Further, GMFBI.1 administration at peak of EAE reversed clinical symptoms, immunopathology, proinflammatory cytokine response and up regulated the anti-inflammatory cytokines. Present strategy of substrate inhibition against the key immunomodulatory target has immense therapeutic potential in MS.

The 5' end of eukaryotic mRNAs is protected by the m

Translin, a highly conserved, DNA/RNA binding protein, is abundantly expressed in brain, testis and in certain malignancies. It was discovered initially in the quest to find proteins that bind to alternating polypurines-polypyrimidines repeats. It has been implicated to have a role in RNA metabolism (tRNA processing, RNAi, RNA transport, etc.), transcription, DNA damage response, etc. Studies from human, mice, drosophila and yeast have revealed that it forms an octameric ring, which is important for its function. Translin is a cytoplasmic protein, but under genotoxic stress, it migrates into the nucleus, binds to the break point hot spots and therefore, thought to be involved in chromosomal translocation events as well as DNA damage related response. Its structure is known and DNA binding regions, GTP binding region and regions responsible for homotypic and heterotypic interaction are known. It forms a ball like structure with open central channel for accommodating the substrate nucleic acids. Besides this, translin protein binds to 3' and 5' UTR of certain mRNAs and probably regulates their availability for translation. It is also involved in mRNA transport and cell cycle progression. It forms a heteromeric complex with translin associated factor-X (TRAX) to form C3PO complex which is involved in RNA silencing process. Recently, it has been shown that translin is upregulated under starvation conditions in Drosophila and is involved in the integration of sleep and metabolic rate of the flies. Earlier studies classified translin as a DNA repair protein; however subsequent studies showed that it is a multifunctional protein. With this background, in this review we have summarized the translin biochemical activities, cellular function as well as structural properties of this important protein.

KARABAY, OGUZ/0000-0003-1514-1685; Kaya, Sehnaz/0000-0003-0002-1517; Gan, Chin Seng/0000-0002-6758-4798; Valderrama, Sandra/0000-0003-1833-1599; Abouqal, Redouane/0000-0002-6117-4341; Unal, Necmettin/0000-0002-9440-7893; Yousef, Reham H. A./0000-0003-4004-3008; Horhat, Florin George/0000-0001-6133-0204 WOS: 000522628200013 PubMed: 31676155 Background: We report the results of International Nosocomial Infection Control Consortium (INICC) surveillance study from January 2012 to December 2017 in 523 intensive care units (ICUs) in 45 countries from Latin America, Europe, Eastern Mediterranean, Southeast Asia, and Western Pacific. Methods: During the 6-year study period, prospective data from 532,483 ICU patients hospitalized in 242 hospitals, for an aggregate of 2,197,304 patient days, were collected through the INICC Surveillance Online System (ISOS). The Centers for Disease Control and Prevention-National Healthcare Safety Network (CDC-NHSN) definitions for device-associated health care-associated infection (DA-HAI) were applied. Results: Although device use in INICC ICUs was similar to that reported from CDC-NHSN ICUs, DA-HAI rates were higher in the INICC ICUs: in the medical-surgical ICUs, the pooled central line-associated bloodstream infection rate was higher (5.05 vs 0.8 per 1,000 central line-days); the ventilator-associated pneumonia rate was also higher (14.1 vs 0.9 per 1,000 ventilator-days,), as well as the rate of catheter-associated urinary tract infection (5.1 vs 1.7 per 1,000 catheter-days). From blood cultures samples, frequencies of resistance, such as of Pseudomonas aeruginosa to piperacillin-tazobactam (33.0% vs 18.3%), were also higher. Conclusions: Despite a significant trend toward the reduction in INICC ICUs, DA-HAI rates are still much higher compared with CDC-NHSN's ICUs representing the developed world. It is INICC's main goal to provide basic and cost-effective resources, through the INICC Surveillance Online System to tackle the burden of DA-HAIs effectively. (C) 2019 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved. International Nosocomial Infection Control Consortium Surveillance Online System Funding for the design, development, maintenance, technical support, data validation, and report generation of the International Nosocomial Infection Control Consortium Surveillance Online System, and the activities carried out at the International Nosocomial Infection Control headquarters were provided by Victor D. Rosenthal, and the Foundation to Fight against Nosocomial Infections.

Summary: RNA polymerase II transcripts receive a protective 5ʹ,5ʹ-triphosphate-linked 7-methylguanosine (m7G) cap, and its removal by decapping enzymes like DCP2 is critical for initiation of RNA decay. Alternative RNA caps can be acquired when transcription initiation uses metabolites like nicotinamide adenine dinucleotide (NAD), generating NAD-RNAs. Here, we identify human NUDT12 as a cytosolic NAD-RNA decapping enzyme. NUDT12 is active only as homodimers, with each monomer contributing to creation of the two functional catalytic pockets. We identify an ∼600-kDa dodecamer complex between bleomycin hydrolase (BLMH) and NUDT12, with BLMH being required for localization of NUDT12 to a few discrete cytoplasmic granules that are distinct from P-bodies. Both proteins downregulate gene expression when artificially tethered to a reporter RNA in vivo. Furthermore, loss of Nudt12 results in a significant upregulation of circadian clock transcripts in mouse liver. Overall, our study points to a physiological role for NUDT12 in the cytosolic surveillance of NAD-RNAs. : Wu et al. identify NUDT12 as a decapping enzyme for NAD-capped RNAs and demonstrate a role for the enzyme in regulation of circadian clock transcripts in mice. They reveal the existence of a BLMH-NUDT12 complex that facilitates localization of NUDT12 to distinct cytoplasmic granules. Keywords: human NUDT12, BLMH, NAD-RNA, m7G, RNA decay, deNADding, circadian clock

The androgen receptor (AR) is a driver of cellular differentiation and prostate cancer development. An extensive body of work has linked these normal and aberrant cellular processes to mRNA transcription, however, the extent to which AR regulates post-transcriptional gene regulation remains unknown. Here, we demonstrate that AR uses the translation machinery to shape the cellular proteome. We show that AR is a negative regulator of protein synthesis and identify an unexpected relationship between AR and the process of translation initiation in vivo. This is mediated through direct transcriptional control of the translation inhibitor 4EBP1. We demonstrate that lowering AR abundance increases the assembly of the eIF4F translation initiation complex, which drives enhanced tumor cell proliferation. Furthermore, we uncover a network of pro-proliferation mRNAs characterized by a guanine-rich cis-regulatory element that is particularly sensitive to eIF4F hyperactivity. Using both genetic and pharmacologic methods, we demonstrate that dissociation of the eIF4F complex reverses the proliferation program, resulting in decreased tumor growth and improved survival in preclinical models. Our findings reveal a druggable nexus that functionally links the processes of mRNA transcription and translation initiation in an emerging class of lethal AR-deficient prostate cancer.

Propolis is a natural resinous substance produced by honey bees. The antimicrobial effects of glass ionomer cement have been shown to improve with the addition of propolis; however its effect on the physicomechanical properties of the cement is not known. Aim: The purpose of this study was to evaluate the compressive strength and solubility of conventional restorative glass ionomer cement following the addition of propolis. Study design: Twenty half cylindrical samples were prepared with conventional restorative glass ionomer cement formed the control group. Another twenty samples were prepared with propolis added to conventional restorative glass ionomer cement formed the experimental group. The compressive strength was assessed using universal testing machine. To assess solubility, the samples were immersed in deionised water at room temperature, for 7 days. The solubility was measured as a difference in the weight of the sample; prior to immersion and following immersion at the end of each day. Results: The control group had a significantly higher mean compressive strength of 146.26 Mpa as compared to the experimental group (135.06 Mpa). The solubility between the groups was significant. Conclusion: In comparison to the control group, incorporation of propolis to conventional restorative glass ionomer cement decreased the compressive strength significantly. The solubility of the cement in the experimental group increased significantly over 7day period as compared to the control group.

Flu immunity shows its age As we age, our immune systems change; in many ways not for the better. For instance, the elderly account for 90% of influenza deaths annually. Pillai et al. now report that influenza-infected human monocytes, a type of immune cell, exhibit reduced antiviral activity. In influenza-infected mice, two innate immune sensing pathways work together to promote antiviral immunity to influenza. Mice lacking antiviral immunity (similar to the situation in elderly people) had elevated bacterial burdens in their lungs and increased inflammatory responses, which both contributed to their increased susceptibility to influenza. Science , this issue p. 463

Background Intraoperative radiotherapy (IORT) was implemented at our institution for early stage breast cancer patients including those with geographic or medical co-morbidity limitations to whole breast radiation therapy (WBRT). Methods Retrospective review of patients (n = 127) who underwent IORT from 2009 to 2016 for breast cancer. Demographics, pathology, toxicity, and recurrences were ascertained. Results The median age was 67 years (interquartile range: 62–73). At median follow-up (49.6 months), 5 patients (4%) had ipsilateral breast tumor recurrence with median time to recurrence of 36.8 months. Acute and late grade ≥3 skin toxicities were observed in 3.1% and 4.7% of patients, respectively. A subset (n = 7) who received prior ipsilateral WBRT was found to have no subsequent local recurrence, one case of acute grade 3 skin toxicity, and no late toxicity. Conclusions IORT is a safe and effective alternative to whole breast radiotherapy, and serves as a suitable alternative to completion mastectomy in locally recurrent breast cancer.

Hyponatremia is defined as serum sodium level135 meq/L. It is the most common electrolyte abnormality seen in hospital admissions worldwide. The proportion is even higher in the ICU setting. A wide variety of factors influence the outcome of the hyponatremic patient. Present study is designed to approach to analyse etiology, clinical features, co-morbid factors, severity of hyponatremia, rate of correction, and impact of treatment on outcome of these diverse group of patients in ICU.1) To find proportion of patients presenting with hyponatremia and requiring medical ICU admission in a tertiary care set up. 2) To study the etiology and clinical features of hyponatremia in patients requiring ICU admission. 3) To compare and study the effect of various factors on the outcome of hyponatremic patients in the ICU.This study was a cross-sectional observational study in tertiary care hospital. All indoor general medicine ward admissions over a period of 18 months were screened for the presence of hyponatremia and patients requiring Medical ICU care and satisfying inclusion criteria were studied. Serial serum electrolytes and urine sodium were tested for all patients in the ICU satisfying the inclusion criteria. Type of fluid given and daily correction of serum sodium of all patients were noted. Outcome was measured in terms of mortality, duration of stay in ICU, number of days required for sodium correction and complications of treatment if any. Patients were followed up till hospital discharge or death..In this study, 5.2% of total admissions had hyponatremia. Among the ICU admissions, the different symptoms attributed to hyponatremia included nausea (69.3%), malaise (80%), drowsiness (61.3%), confusion (41.3%), lethargy (24%), frequent falls (1.3%), convulsions (2.7%), altered sensorium (41.3%) and delirium (9.3%). SIADH was the most common cause of hyponatremia in these patients (32%). Serum sodium levels of patients on admission ranged from 82 - 133 meq/L, with average serum sodium being 124meq/L. Overall mortality among the hyponatremic ICU admissions was 26/75, 34.6%, which was higher than the total ICU mortality of 26% in same duration (p = 0.1). There was a significant increase in duration of stay in ICU in patients with various co-morbidities (p=0.003). There was a significant association between Glasgow Coma Scale (GCS) and serum sodium levels, (p = 0.002). Blood pressure and hydration status did not significantly influence outcome. Lower serum sodium on admission was associated with a lower survival (p= 0.041). Sodium correction of5 m eq/day was associated with an increased mortality(p = 0.04), whereas sodium correction of10 m eq/day was not associated with increased mortality, but an increased risk of EPM, which was seen in one patient.Most common cause of hyponatremia in ICU patients is SIADH. Longer duration of stay is seen in the presence of different co-morbidities. A lower GCS and a lower serum sodium on admission is associated with lower survival. Type of fluid used for hyponatremia correction did not influence the outcome. Under correction of hyponatremia in first 24 hours or inadequate correction was associated with a poorer outcome. Overcorrection was not associated with any survival benefit, but was associated with risk of EPM.

Several studies have suggested that bone marrow stromal steam cells (BMSC) exist in a quiescent state (G0) within the in vivo niche; however, an explicit analysis of the biology of G0 state-BMSC has not been reported. We hypothesized that induction of G0 in BMSC might enhance their stem cell properties. Thus, we induced quiescence in BMSC in vitro by (a) suspension culture in a viscous medium or (b) culture on soft polyacrylamide substrate; and examined their molecular and functional phenotype. Induction of G0 was confirmed by bromo-deoxyuridine (BrdU) labelling and analysis of cell cycle gene expression. Upon reactivation and re-entry into cell cycle, G0 state-BMSC exhibited enhanced clonogenic self-renewal, preferential differentiation into osteoblastic rather than adipocytic cells and increased ectopic bone formation when implanted subcutaneously in vivo in immune-deficient mice, compared to asynchronous proliferating (pre-G0) BMSC. Global gene expression profiling revealed reprogramming of the transcriptome during G0 state including significant alterations in relevant pathways and expression of secreted factors, suggesting altered autocrine and paracrine signaling by G0 state-BMSC and a possible mechanism for enhanced bone formation. G0 state-BMSC might provide a clinically relevant model for understanding the in vivo biology of BMSC. Keywords: Quiescence (G0), BMSC, Transcriptome, Suspension culture, Adhesion, Substrate stiffness, Cell cycle, Osteoblastic differentiation, Reprogramming

ObjectiveTo validate a newly introduced cartilage rim augmented temporalis fascia tympanoplasty technique by statistically comparing it with the morphological and audiological outcomes of traditional temporalis fascia tympanoplasty.MethodsA retrospective comparative study was conducted on 115 patients who underwent tympanoplasty during 2013 and 2015. Fifty-eight patients underwent temporalis fascia tympanoplasty and 57 underwent cartilage rim augmented fascia tympanoplasty.ResultsIn the cartilage fascia group, graft healing was achieved in 94.7 per cent of cases; in the temporalis fascia group, the graft take-up rate was 70 per cent. In those with a normal ossicular chain, the post-operative air–bone gap was within 20 dB in 92.6 per cent of cartilage fascia group cases and in 69.7 per cent of the temporalis fascia group cases, which was a statistically significant difference. Among the defective ossicular chain cases, the post-operative air–bone gap was within 20 dB in 76.9 per cent in the cartilage fascia group, as against 57.1 per cent in the temporalis fascia group.ConclusionCartilage rim augmented temporalis fascia tympanoplasty has a definite advantage over the temporalis fascia technique in terms of superior graft take up and statistically significant hearing gain in those with normal ossicular mobility.

We present six patients with Gilles de la Tourette syndrome (TS) who are also deaf. TS has been observed previously, but rarely reported in deaf people, and to date, so called "unusual" phenomenology has been highlighted. TS occurs almost worldwide and in all cultures, and the clinical phenomenology is virtually identical. In our cohort of deaf patients (we suggest another culture) with TS, the phenomenology is the same as in hearing people, and as in all other cultures, with classic motor and vocal/phonic tics, as well as associated phenomena including echo-phenomena, pali-phenomena and rarer copro-phenomena. When "words" related to these phenomenon (e.g. echolalia, palilalia, coprolalia or mental coprolalia) are elicited in deaf people, they occur usually in British Sign Language (BSL): the more "basic" vocal/phonic tics such as throat clearing are the same phenomenologically as in hearing TS people. In our case series, there was a genetic predisposition to TS in all cases. We would argue that TS in deaf people is the same as TS in hearing people and in other cultures, highlighting the biological nature of the disorder.

The present study aims to develop the correlation between in vitro and in vivo skin permeation of lidocaine in its transdermal patch. In order to minimize the run-to-run variability during in vitro skin permeation studies, release normalized cumulative percent (%Ct n) was calculated. A suitable polynomial mathematical model was used to establish a correlation between time and %Ct n. Percent in vivo absorbed was calculated by using numerical deconvolution (NDC) and non-compartmental analysis (NCA) methods. Pharmacokinetic (PK) parameters such as AUC last and C max were predicted with the established in vitro-in vivo correlation (IVIVC) models. The minimum prediction errors in NDC method for C max were found to be -30.9 and -25.4% for studies I (in vivo study in human volunteers with one batch of Lidoderm patch; internal validation) and II (in vivo study in human volunteers with another batch of Lidoderm patch; external validation), respectively, whereas minimum prediction errors in NCA method were relatively low (3.9 and 0.03% for studies I and II, respectively) compared to those in NDC method. The prediction errors for AUC last were found to be less than 2% for both methods and studies. The established method in this study could be a potential approach for predicting the bioavailability and/or bioequivalence for transdermal drug delivery systems.

Adult stem cell quiescence is critical to ensure regeneration while minimizing tumorigenesis. Epigenetic regulation contributes to cell cycle control and differentiation, but few regulators of the chromatin state in quiescent cells are known. Here we report that the tumor suppressor PRDM2/RIZ, an H3K9 methyltransferase, is enriched in quiescent muscle stem cells in vivo and controls reversible quiescence in cultured myoblasts. We find that PRDM2 associates with >4400 promoters in G0 myoblasts, 55% of which are also marked with H3K9me2 and enriched for myogenic, cell cycle and developmental regulators. Knockdown of PRDM2 alters histone methylation at key promoters such as Myogenin and CyclinA2 (CCNA2), and subverts the quiescence program via global de-repression of myogenesis, and hyper-repression of the cell cycle. Further, PRDM2 acts upstream of the repressive PRC2 complex in G0. We identify a novel G0-specific bivalent chromatin domain in the CCNA2 locus. PRDM2 protein interacts with the PRC2 protein EZH2 and regulates its association with the bivalent domain in the CCNA2 gene. Our results suggest that induction of PRDM2 in G0 ensures that two antagonistic programs-myogenesis and the cell cycle-while stalled, are poised for reactivation. Together, these results indicate that epigenetic regulation by PRDM2 preserves key functions of the quiescent state, with implications for stem cell self-renewal.

The general prevalence of the familial multi-organ tumor disorder, von Hippel-Lindau syndrome (VHL), was estimated to be 1 in 25-40,000 in western studies two decades back. Few studies were done in Indian sub-continent, amidst a surge in clinical reports on VHL specific manifestations. The syndrome is correlated with mutations of the gene VHL (located in Chr 3p25.3). We aimed to conduct a prospective case series describing phenotypic and genotypic characteristics in Indian population. The VHL-specific clinical and radiological features were collected from patients and family members. Genotypic changes such as deletion/duplication or point mutation in the VHL locus were identified using sequencing and MLPA. Thirty-one subjects, from fifteen families with diagnosed VHL, were included in the study. Multicystic pancreas was found in 71% (22/31), CNS hemangioblastoma in 68% (21/31), renal cell carcinoma and retinal angiomas in 23% (7/31) each, pheochromocytoma in 9.7% (3/31) of the population and endolymphatic sac tumor in one subject. Four families (9 subjects) had full length deletion of VHL, three families (4 subjects) had a deletion of exon 3, eight families (18 subjects) had different exonic, splice-site and intronic point mutations and one subject had a de novo in-frame indel in exon 1. Multicystic pancreas and CNS hemangioblastomas were the most common manifestations in our population. The phenotypic expression patterns in terms of tumorigenesis, tissue tropism and penetrance in comparison to the genotypic features were found to be different from previous correlative studies.

Testing drugs for anti-aging effects has historically been conducted in mouse life-span studies, but are costly and time consuming, and more importantly, difficult to recapitulate in humans. In addition, life-span studies in mice are not well suited to testing drug combinations that target multiple factors involved in aging. Additional paradigms for testing therapeutics aimed at slowing aging are needed. A new paradigm, designated as the Geropathology Grading Platform (GGP), is based on a standardized set of guidelines developed to detect the presence or absence of low-impact histopathological lesions and to determine the level of severity of high-impact lesions in organs from aged mice. The GGP generates a numerical score for each age-related lesion in an organ, summed for total lesions, and averaged over multiple mice to obtain a composite lesion score (CLS). Preliminary studies show that the platform generates CLSs that increase with the age of mice in an organ-dependent manner. The CLSs are sensitive enough to detect changes elicited by interventions that extend mouse life span, and thus help validate the GGP as a novel tool to measure biological aging. While currently optimized for mice, the GGP could be adapted to any preclinical animal model.

Beta lactams are standard empirical therapy for febrile neutropenia (FN). The aim of this study was to evaluate the efficacy and safety of cefepime monotherapy compared with cefoperazone/sulbactam plus amikacin (CS + A) for empirical treatment of high risk FN. One hundred seventy-five patients with 336 FN episodes were randomized to receive either cefepime (2 g q8h for adults and 50 mg/kg q8h for children) or CS (2 g q8h for adults and 50 mg/kg q8h for children) plus amikacin (15 mg/kg once a day). Positive response was defined as afebrile within 72 h of starting antibiotics, persistent afebrile status more than 48 h and no requirement of second-line antibiotics and antifungal agents. Three hundred thirty-six episodes were assessable for efficacy (168 cefepime, 168 CS + A). The positive response to antibiotics was identical for cefepime (53%) and CS + A (53%). Positive response was similar in MDI (microbiologically documented infection), 50 vs. 35% (p = 0.248), CDI (clinically documented infection), 50 vs. 35% (p = 0.259), combination CDI + MDI, 25 vs. 15% (p = 0.400), FUO (fever of unknown origin), 68 vs. 72% (p = 0.577) respectively in the two groups. The successful discontinuation of antibiotics at 72 h in FUO was similar in both groups (60 vs. 59%, p = 0.544). Total drug-related adverse events were similar in both groups (8 vs. 6%) except renal dysfunction was high in CS + A (1 vs. 7 events). Mortality was the same between two groups (8 vs 7%). Cefepime monotherapy and CS + A had similar efficacy as first-line therapy for FN. Discontinuation of empirical antibiotics is safe and feasible approach in selected group of FUO patients.

Background: Achilles tendon injuries are common, and present a challenge in the acute and chronic setting. There is significant morbidity associated with the injury and the numerous management strategies, as well as financial implications to the patient and the health service. To date, repair tissue from all methods of management fail to achieve the same functional and biomechanical properties as the native tendon. Objective: The use of tissue engineering technology may reduce morbidity, improve the biomechanical properties of repair tissue and reduce the financial burden. The goal is to produce completely integrated tendon repair tissue that has the functional and mechanical properties of the native tendon. This review evaluates the role of stem cells in tissue engineering for tendon reconstruction and the various sources for harvesting stem cells. Results: They can be obtained from the embryo, foetus or adult, and require the correct conditions for proliferation and differentiation. There remain many ethical concerns with the use of embryo or foetus harvested stem cells, thus the focus remains on adult sources, haematopoietic and non-haematopoietic. The improving knowledge of the role of growth factors is addressed, as is their effect on animal models for tendon repair. Growth factors include bone morphogenic proteins, transforming growth factor, insulin-like growth factor and platelet derived growth factor. The role of scaffolds in human and animal models is reviewed, both naturally derived and synthetic scaffolds. Whilst numerous animal studies have reported encouraging results, further work is required. Conclusions: The ideal source of MSCs still has not been agreed upon, and little is known regarding the signalling pathways involved in tenogenesis of MSCs. Whilst current studies have shown encouraging results with regards to improved biomechanical and histological properties, further work is required to ascertain the growth factors, biomaterials and source of stem cells required for tendon regeneration.

Obesity is a multifaceted pathophysiological condition that has been associated with lipid accumulation, adipocyte dysfunction, impaired mitochondrial biogenesis and an altered metabolic profile. Redox imbalance and excessive release of inflammatory mediators have been intricately linked in obesity-associated phenotypes. Hence, understanding the mechanisms of redox signaling pathways and molecular targets exacerbating oxidative stress is crucial in improving health outcomes. The activation of Na/K-ATPase/Src signaling, and its downstream pathways, by reactive oxygen species (ROS) has been recently implicated in obesity and subsequent nonalcoholic steatohepatitis (NASH), which causes further production of ROS creating an oxidant amplification loop. Apart from that, numerous studies have also characterized antioxidant properties of heme oxygenase 1 (HO-1), which is suppressed in an obese state. The induction of HO-1 restores cellular redox processes, which contributes to inhibition of the toxic milieu. The novelty of these independent mechanisms presents a unique opportunity to unravel their potential as molecular targets for redox regulation in obesity and NASH. The attenuation of oxidative stress, by understanding the underlying molecular mechanisms and associated mediators, with a targeted treatment modality may provide for improved therapeutic options to combat clinical disorders.

The cellular transport process of DNA is hampered by cell membrane barriers, and hence, a delivery vehicle is essential for realizing the potential benefits of gene therapy to combat a variety of genetic diseases. Virus-based vehicles are effective, although immunogenicity, toxicity and cancer formation are among the major limitations of this approach. Cationic polymers, such as polyethyleneimine are capable of condensing DNA to nanoparticles and facilitate gene delivery. Lack of biodegradation of polymeric gene delivery vehicles poses significant toxicity because of the accumulation of polymers in the tissue. Many attempts have been made to develop biodegradable polymers for gene delivery by modifying existing polymers and/or using natural biodegradable polymers. This review summarizes mechanistic aspects of gene delivery and the development of biodegradable polymers for gene delivery.