Effect of surgical intervention on serum insulin-like growth factor 1 in patients with obstructive sleep apnoea.

OBJECTIVE: To evaluate the effect of surgical intervention on serum insulin-like growth factor 1 levels in patients with obstructive sleep apnoea. METHODS: A prospective study was conducted in a tertiary care hospital of adult patients with obstructive sleep apnoea for whom continuous positive airway pressure therapy failed or was refused. All patients underwent polysomnography and serum insulin-like growth factor 1 evaluation pre-operatively and at three months post-operatively. The site of surgery was determined using Müller's manoeuvre and ApneaGraph AG 200. RESULTS: Fifteen patients were included with a mean age of 38 years: 11 males and 4 females. The mean pre-operative Apnoea-Hypopnoea Index using polysomnography was 53.7 events per hour, and the mean post-operative Apnoea-Hypopnoea Index at three months was 15.3 events per hour (p = 0.0001). The mean pre-operative serum insulin-like growth factor 1 was 160.2 µg/l, while the mean post-operative value was 236.98 µg/l (p = 0.005). CONCLUSION: In adult patients with obstructive sleep apnoea for whom continuous positive airway pressure therapy fails, site-specific surgical intervention to treat the obstruction leads to an increase in serum insulin-like growth factor 1 levels.

Adaptation of the gut pathobiont Enterococcus faecalis to deoxycholate and taurocholate bile acids.

Enterococcus faecalis is a natural inhabitant of the human gastrointestinal tract. This bacterial species is subdominant in a healthy physiological state of the gut microbiota (eubiosis) in adults, but can become dominant and cause infections when the intestinal homeostasis is disrupted (dysbiosis). The relatively high concentrations of bile acids deoxycholate (DCA) and taurocholate (TCA) hallmark eubiosis and dysbiosis, respectively. This study aimed to better understand how E. faecalis adapts to DCA and TCA. We showed that DCA impairs E. faecalis growth and possibly imposes a continuous adjustment in the expression of many essential genes, including a majority of ribosomal proteins. This may account for slow growth and low levels of E. faecalis in the gut. In contrast, TCA had no detectable growth effect. The evolving transcriptome upon TCA adaptation showed the early activation of an oligopeptide permease system (opp2) followed by the adjustment of amino acid and nucleotide metabolisms. We provide evidence that TCA favors the exploitation of oligopeptide resources to fuel amino acid needs in limiting oligopeptide conditions. Altogether, our data suggest that the combined effects of decreased DCA and increased TCA concentrations can contribute to the rise of E. faecalis population during dysbiosis.

Facial neuritis in coronavirus disease 2019 associated mucormycosis: study on clinico-radiological correlates.

OBJECTIVE: To elucidate the aetiopathogenesis of facial neuritis in coronavirus disease 2019 associated mucormycosis. METHODS: A retrospective review was conducted of coronavirus disease 2019 associated mucormycosis patients who presented with peripheral facial nerve palsy from January 2021 to July 2021. The clinico-radiological details of four patients were assessed to examine the potential mechanism of facial nerve involvement. RESULTS: Serial radiological evaluation with contrast-enhanced computed tomography and contrast-enhanced magnetic resonance imaging revealed infratemporal fossa involvement in all cases, with the inflammation extending along fascial planes to reach the stylomastoid foramen. Ascending neuritis with an enhancement of the facial nerve was demonstrated in all cases. CONCLUSION: The likely explanation for facial palsy in patients with coronavirus disease 2019 associated mucormycosis, backed by radiology, is the disease abutting the facial nerve at the stylomastoid foramen and causing ascending neuritis of the facial nerve.

Design, characterization and in vitro evaluation of thin films enriched by tannic acid complexed by Fe(III) ions.

Materials based on carbohydrate polymers may be used for biomedical application. However, materials based on natural polymers have weak physicochemical properties. Thereby, there is a challenge to improve their properties without initiation of toxicity. The alternative method compared to toxic chemical agents' addition is the use of metal complexation method. In this study, chitosan/tannic acid mixtures modified by Fe(III) complexation are proposed and tested for potential applications as wound dressings. Thereby, surface properties, blood compatibility as well as platelet adhesion was tested. In addition, the periodontal ligament stromal cells compatibility studies were carried out. The results showed that the iron(III) addition to chitosan/tannic acid mixture improves properties due to a decrease in the surface free energy and exhibited a reduction in the hemolysis rate (below 5%). Moreover, cells cultured on the surface of films with Fe(III) showed higher metabolic activity. The current findings allow for the medical application of the proposed materials as wound dressings.

Anomalous pressure dependence of the electronic transport and anisotropy in SrIrO3 films.

Iridate oxides display exotic physical properties that arise from the interplay between a large spin-orbit coupling and electron correlations. Here, we present a comprehensive study of the effects of hydrostatic pressure on the electronic transport properties of SrIrO3 (SIO), a system that has recently attracted a lot of attention as potential correlated Dirac semimetal. Our investigations on untwinned thin films of SIO reveal that the electrical resistivity of this material is intrinsically anisotropic and controlled by the orthorhombic distortion of the perovskite unit cell. These effects provide another evidence for the strong coupling between the electronic and lattice degrees of freedom in this class of compounds. Upon increasing pressure, a systematic increase of the transport anisotropies is observed. The anomalous pressure-induced changes of the resistivity cannot be accounted for by the pressure dependence of the density of the electron charge carriers, as inferred from Hall effect measurements. Moreover, pressure-induced rotations of the IrO6 octahedra likely occur within the distorted perovskite unit cell and affect electron mobility of this system.

Public health crisis of road traffic accidents in India: Risk factor assessment and recommendations on prevention on the behalf of the Academy of Family Physicians of India.

Roads are considered a sign of development bringing colossal benefits to community as socioeconomic and logistic facilitator. Yet, growth of road network has brought road crashes leading to civic pain from premature deaths of productive age group. In 2017, 16 citizens were killed and 53 injured every hour on Indian roads as per officially reported data, while a fair number go unreported. This is unacceptably high when compared with international standards. Risk correlates of road traffic injuries (RTIs) need to be redefined so as to form a continuum with other confounding factors that impact to take lives on road. Risk factors impacting RTIs vary from human components to the roles and responsibilities of healthcare stakeholders. We should have made roads safer for all citizens because a large percentage of population - children, pedestrians, cyclists, motorcyclists, and the elderly - are most vulnerable. A taskforce was set up by the Academy of Family Physicians of India to scientifically analyze the literature available to assess risks and put forward appropriate recommendations.

Revision shoulder arthroplasty for failed surface replacement hemiarthroplasty.

PURPOSE: The aim of this study was to assess the reasons of failure of shoulder surface replacement hemiarthroplasty (SRH) and to evaluate the outcome of revision surgery. METHOD: The study group included 25 patients (26 shoulders) with failed SRHs. The mean time to revision surgery was 3.6 years. Their functional outcome was evaluated using adjusted Constant-Murley score at mean follow-up of 5.2 years (range 2-16 years). RESULT: Most common cause of failure was glenoid erosion (42%) and progressive failure of rotator cuff (31%). Median adjusted Constant-Murley score at mean follow-up of 5.2 years was 51.6. Median adjusted Constant-Murley score in patients who had primary diagnosis of osteoarthritis and had revision performed to anatomic TSA (14 shoulders) was 85 (range 40-100) at mean follow-up of 5 years compared to 36.3 (range 20-66.3) in the remaining patients at 5.4 years, p = 0.00008. CONCLUSION: Revision surgery for failed SRH can be technically challenging with variable results. Most common mode of failure was glenoid erosion. Functional outcomes are better in those with revision performed to anatomic TSA.

The clinical utility of cycle of threshold value of GeneXpert MTB/RIF (CBNAAT) and its diagnostic accuracy in pulmonary and extra-pulmonary samples at a tertiary care center in India.

BACKGROUND: There are knowledge gaps in the in-depth analysis of the most promising and robust diagnostic tool, GeneXpert MTB/RIF (CBNAAT). The cycle of threshold (CT) value of the CBNAAT test and its clinical implications has not been explored much. AIMS AND OBJECTIVES: The study aimed at (a) estimating the diagnostic accuracy and incremental yield of Xpert MTB/RIF in various specimens (b) establishing the association between CT value category (high, medium, low, very low) and culture time-to-positivity (TTP). METHODS: A total of 1000 samples, both pulmonary and extra-pulmonary were collected from presumptive TB cases in a large tertiary care hospital. Sensitivity and specificity of CBNAAT was calculated with culture as the gold standard. The association of CT value with culture TTP was also studied. RESULTS: The overall sensitivity of CBNAAT was 88.5%, with bronchial washing specimen being the most sensitive (92.3%) and pleural fluid being the least (66.7%). In smear negative individuals, the sensitivity of CBNAAT was 80.9%. The additional yield of CBNAAT over smear microscopy was 10.9%. It was observed that as we move from high to very low CT category, culture positivity decreases significantly (p<0.001), whereas time taken for culture growth increases (p<0.001). CONCLUSION: CBNAAT is a robust test for accurate diagnosis of tuberculosis both pulmonary and extra-pulmonary, smear negative as well, especially in resource-limited settings. The correlation between CT value and culture TTP has potential in predicting bacillary load, though further studies are required.

Direct-acting Antiviral Agents in Hepatitis C Virus-infected Renal Allograft Recipients: Treatment and Outcome Experience from Single Center.

Hepatitis C virus (HCV) infection in renal allograft recipient is associated with increased morbidity and mortality. At present, only few studies related to treatment and outcomes of HCV-infected renal allograft recipients with DAAs have been published. We aimed the study to assess the efficacy and safety of sofosbuvir-based regimens in HCV-infected renal allograft recipients. We analyzed data of 22 eligible HCV-infected renal allograft recipients (14 genotype-3, 6 genotype-1, one each genotype-2 and 4) who were treated with DAAs at our institute. DAA regimen included sofosbuvir and ribavirin with or without ledipasvir or daclatasvir for 12-24 weeks. Patients were followed up for 24 weeks after completion of treatment. A rapid viral response of 91%, end of therapy response of 100%, and sustained viral response at 12 and 24 weeks of 100% with rapid normalization of liver enzymes were observed. Therapy was well tolerated except for ribavirin-related anemia. A significant decrease in tacrolimus trough levels was observed and most patients required increase in tacrolimus dose during the study. Treatment with newer DAAs is effective and safe for the treatment of HCV-infected renal allograft recipients.

Efficacy and Safety of Cyclosporine versus Tacrolimus in Steroid and Cyclophosphamide Resistant Nephrotic Syndrome: A Prospective Study.

Calcineurin inhibitors (CNIs) are the preferred drugs for treatment of childhood steroid-resistant nephrotic syndrome (SRNS) who are also resistant to cyclophosphamide (CYC). Although few studies have shown a benefit of one over the other, efficacy and safety of either CNIs (tacrolimus [TAC] or cyclosporine [CSA]) in this special population remained to be assessed in long-term studies. Forty-five children with SRNS who were also resistant to CYC (CYC-SRNS) from January 2006 to June 2011, were included in the study. Patients were treated with CNI either TAC or CSA based on 1:1 allocations and were prospectively observed. Patients who were nonresponsive to CNIs had been treated with mycophenolate mofetil. Outcomes were measured in terms of remission of NS, adverse effects of drugs, and progression of disease. After 6 months of treatment, 16/23 (69.5%) patients on CSA achieved remission and 18/22 (81.8%) on TAC achieved remission (P = 0.3). The side effects hypertrichosis, and gum hyperplasia were significantly less in TAC group as compared to CSA group (P < 0.001). The 1-, 2-, 3-, 4-, and 5-year estimated renal survival (doubling of serum creatinine as event) in CSA group was 96%, 91%, 85%, 54%, and 33% and in TAC group was 96%, 95%, 90%, 89%, and 79%, respectively (P = 0.02). Although TAC and CSA are equally efficacious, TAC has significantly less side effects. The long-term outcome of renal function was significantly better in patients who were treated with TAC as compared to CSA.

CHronic Rhinosinusitis Outcome MEasures (CHROME), developing a core outcome set for trials of interventions in chronic rhinosinusitis.

STATEMENT OF PROBLEM: Evaluating the effectiveness of treatments in chronic rhinosinusitis (CRS) have been limited by both a paucity of high quality randomised trials, and the heterogeneity of outcomes in those that have been reported. Core outcome sets (COS) are an agreed, standardized set of outcomes that should be measured and reported by future trials as a minimum and will facilitate future meta-analysis of trial results in systematic reviews (SRs). We set out to develop a core outcome set for interventions for adults with CRS. METHOD(S) OF STUDY: A long-list of potential outcomes was identified by a steering group utilising a literature review, thematic analysis of a wide range of stakeholders' views and systematic analysis of currently available Patient Reported Outcome Measures (PROMs). A subsequent e-Delphi process allowed 110 patients and healthcare practitioners to individually rate the outcomes in terms of importance, on a Likert scale. MAIN RESULTS: After 2 rounds of the iterative Delphi process, the 54 initial outcomes were distilled down to a final core-outcome set of 15 items, over 4 domains. PRINCIPAL CONCLUSIONS: The authors hope inclusion of these core outcomes in future trials will increase the value of research on interventions for CRS in adults. It was felt important to make recommendations regarding how these outcomes should be measured, although additional work is now required to further develop and revalidate existing outcome measures.

Evaluation of Surface Roughness of Nanofilled Composite Restorations after Simulated Tooth Brushing using Various Dentifrices.

Background Teeth restored with direct composite resin are constantly exposed to specific challenges of the oral cavity. These challenges can modify the material properties and, when associated with daily brushing, eventually change its surface roughness, allowing bacterial growth and retention of extrinsic pigments. Dentifrices plays an important role in dental wear (abrasion) and over time, can also cause an increase in the surface roughness of restorative materials. Objective To assess the effect of dentifrices on the longevity of direct nanofilled composite resins restorations as far as wear and roughness is concerned. Method Class V cavity were prepared on 90 extracted human teeth and restored with Filtek Z350 composite. Teeth were randomly divided into 6 experimental groups of 15 each labelled as Group-1 (Colgate Dental cream) Group-2 (Colgate Active Salt toothpaste), Group-3 (Pepsodent Regular toothpaste), Group-4 (Dabur red toothpaste), Group-5 (Dabur Lal tooth powder) and Group-6 Control (water). The samples were fixed on tooth brushing machine and subjected to mechanical tooth brushing using various dentifrices according to respective groups in 3 phases and reading of surface roughness (Ra) was recorded. Result Surface roughness (Ra) had increased in following order: Group 6 < Group 3 < Group 2 < Group 1 < Group 4 < Group 5. All the tooth pastes were compared, their behaviour was found to be similar as there was no statistically significant difference amongst them. Though all of them were inferior to control group and the difference was statistically significant. Whereas the only tooth powder Dabur lal tooth powder gave the maximum roughness when compared with the other tooth pastes and the difference was statistically significant. Conclusion With increase in time of brushing there was increase in surface roughness in all the 5 dentifrices among them Ra was maximum for Dabur lal tooth powder.

Association and expression of the antigen-processing gene PSMB8, coding for low-molecular-mass protease 7, with vitiligo in North India: case-control study.

BACKGROUND: Vitiligo is a multifactorial, autoimmune, depigmenting disorder of the skin where aberrant presentation of autoantigens may have a role. OBJECTIVES: To study the association of two antigen-processing genes, PSMB8 and PSMB9, with vitiligo. METHODS: In total 1320 cases of vitiligo (1050 generalized and 270 localized) and 752 healthy controls were studied for the PSMB9 exon 3 G/A single-nucleotide polymorphism (SNP), PSMB8 exon 2 C/A SNP and PSMB8 intron 6 G/T SNP at site 37 360 using polymerase chain reaction (PCR)-restriction fragment length polymorphism. Real-time PCR was used for transcriptional expression of PSMB8 and cytokines. Expression of ubiquitinated proteins and phosphorylated-p38 (P-p38) was studied by Western blotting. RESULTS: Significant increases in PSMB8 exon 2 allele A (P < 2.07 × 10-6 , odds ratio 1·93) and genotypes AA (P < 1.03 × 10-6 , odds ratio 2·51) and AC (P < 1.29 × 10-6 , odds ratio 1·63) were observed in patients with vitiligo. Interferon-γ stimulation induced lower expression of PSMB8 in peripheral blood mononuclear cells of cases compared with controls, suggesting impaired antigen processing, which was confirmed by accumulation of ubiquitinated proteins in both lesional and nonlesional skin of patients with vitiligo. Expression of proinflammatory cytokines - interleukin (IL)-6, IL-1ß and IL-8 - was higher in the lesional skin. P-p38 expression was variable but correlated with the amount of ubiquitinated proteins in the lesional and nonlesional skin, suggesting that the inflammatory cytokine responses in lesional skin could be a result of both P-p38-dependent and -independent pathways. CONCLUSIONS: The PSMB8 exon 2 SNP is significantly associated with vitiligo. Accumulation of ubiquitinated proteins in skin of cases of vitiligo suggests their aberrant processing, which may promote the development of the disease.

Disruption of NAD(P)H:quinone oxidoreductase 1 gene in mice leads to 20S proteasomal degradation of p63 resulting in thinning of epithelium and chemical-induced skin cancer.

This corrects the article DOI: 10.1038/onc.2010.491.

Stress-induced NQO1 controls stability of C/EBPα against 20S proteasomal degradation to regulate p63 expression with implications in protection against chemical-induced skin cancer.

This corrects the article DOI: 10.1038/onc.2011.600.

Cellular stress induces TRB3/USP9x-dependent Notch activation in cancer.

Expression of the Notch ligand JAG1 and Notch pathway activation promote poor prognosis, basal-like breast cancer. We have recently shown that the pseudokinase Tribbles homolog 3 (TRB3) regulates JAG1 expression in this malignancy. TRB3 is a stress and metabolic sensor, and here we show that nutrient deprivation or endoplasmic reticulum stress markedly upregulate TRB3, which serves as a scaffold for the deubiquitinase USP9x. USP9x in turn stimulates JAG1 activity through two mechanisms: (1) through TRB3 deubiquitination and stabilization, and (2) through deubiquitination and activation of Mind Bomb 1, an E3 ligase required for JAG1 ubiquitination-mediated endocytosis and Notch activation. These USP9x activities are confined to the signal-sending cell of a cell pair undergoing Notch signaling. We demonstrate that USP9x is required for TRB3 upregulation and Notch activation in response to cellular stress in basal-like breast cancer cells. These data suggest that TRB3 functions as a sensor of tumor microenvironmental stress and together with USP9x induces the cell survival and tumor-promoting activities of Notch. These findings identify a novel mechanism by which cancer cells survive in their hostile environment and provide potential therapeutic targets in breast cancer.

Subcranial craniofacial resection for advanced sinonasal malignant tumours involving the anterior skull base.

BACKGROUND: The subcranial approach is a modification of traditional craniofacial resection. It provides similar broad access to the anterior skull base, but with lower mortality and morbidity. It has been the surgical technique of choice at our institution since 2006 for treating advanced stage sinonasal tumours (American Joint Committee on Cancer stage III or above). This paper reports our experience and outcomes. METHOD AND RESULTS: Eighteen patients underwent subcranial craniofacial resection over a seven-year period, this being combined with a second adjunctive procedure in 89 per cent of cases. Forty per cent of patients required reconstruction of the primary defect. No peri-operative deaths occurred. One patient had a transient cerebrospinal fluid leak. The major complication rate was 33 per cent, of which 67 per cent were directly related to soft tissue reconstruction. Tumour recurrence rate was 17 per cent and the five-year disease-free survival estimate was 40 per cent. CONCLUSION: The subcranial approach is a safe and effective technique that may be used to successfully treat advanced sinonasal malignancies with anterior skull base extension.

Mucopolysaccharidosis I; Parental beliefs about the impact of disease on the quality of life of their children.

BACKGROUND: Hematopoietic stem cell transplants, alongside enzyme replacement therapy and good multi-disciplinary care, have dramatically improved the life expectancy in children with Mucopolysaccharidosis (MPS) I, with better objective and functional outcomes. Despite these improvements, children with both the attenuated (non-Hurler) and severe (Hurler) variants of the disease have marked residual morbidity. Children with MPS I suffer with head and neck disease including obstructive sleep apnoea and hearing loss. The impact of these on quality of life has been poorly researched and no previous work has been published looking at patients' perception of their own health, an important domain when considering the impact of treatment. METHODS: This exploratory qualitative study aimed to discover the effect of head and neck disease, alongside that of MPS I as a whole, on the quality of life of affected children. A grounded theory approach was used to conduct this study. Children and their parents were invited to participate in semi-structured interviews. The transcribed interviews were coded and emergent themes explored until saturation occurred. RESULTS: The families of eleven children with MPS I were interviewed, five with Hurler's and six with the attenuated non-Hurler's. Important themes to emerge were- the fear of dying associated with obstructive sleep apnoea, difficulties communicating at school due to the delayed acquisition of language, chronic pain and restricted mobility, physical differences and restricted participation in social activities such as sports secondary to the musculoskeletal disease burden. The overall theme running through the analysis was the desire to fit in with ones peers. CONCLUSION: Parents and children with MPS 1 worry about 'fitting-in' with broader society. The presence of airway disease has a profound impact on the emotional well being of parents whilst language delay and musculoskeletal disease have the biggest impact on the quality of life of the children themselves. It is important to understand the impact of MPS I on the quality of life of children and their families so that we may improve future treatment and management of this sub-group of children who have an increasing life span.

Cancer stem cell drugs target K-ras signaling in a stemness context.

Cancer stem cells (CSCs) are considered to be responsible for treatment relapse and have therefore become a major target in cancer research. Salinomycin is the most established CSC inhibitor. However, its primary mechanistic target is still unclear, impeding the discovery of compounds with similar anti-CSC activity. Here, we show that salinomycin very specifically interferes with the activity of K-ras4B, but not H-ras, by disrupting its nanoscale membrane organization. We found that caveolae negatively regulate the sensitivity to this drug. On the basis of this novel mechanistic insight, we defined a K-ras-associated and stem cell-derived gene expression signature that predicts the drug response of cancer cells to salinomycin. Consistent with therapy resistance of CSC, 8% of tumor samples in the TCGA-database displayed our signature and were associated with a significantly higher mortality. Using our K-ras-specific screening platform, we identified several new candidate CSC drugs. Two of these, ophiobolin A and conglobatin A, possessed a similar or higher potency than salinomycin. Finally, we established that the most potent compound, ophiobolin A, exerts its K-ras4B-specific activity through inactivation of calmodulin. Our data suggest that specific interference with the K-ras4B/calmodulin interaction selectively inhibits CSC.

Immunoprotective responses of T helper type 1 stimulatory protein-S-adenosyl-L-homocysteine hydrolase against experimental visceral leishmaniasis.

It is well known that a patient in clinical remission of visceral leishmaniasis (VL) remains immune to reinfection, which provides a rationale for the feasibility of a vaccine against this deadly disease. In earlier studies, observation of significant cellular responses in treated Leishmania patients as well as in hamsters against leishmanial antigens from different fractions led to its further proteomic characterization, wherein S-adenosyl-L-homocysteine hydrolase (AdoHcy) was identified as a helper type 1 (Th1) stimulatory protein. The present study includes immunological characterization of this protein, its cellular responses [lymphoproliferation, nitric oxide (NO) production and cytokine responses] in treated Leishmania-infected hamsters and patients as well as prophylactic efficacy against Leishmania challenge in hamsters and the immune responses generated thereof. Significantly higher cellular responses were noticed against recombinant L. donovani S-adenosyl-L-homocysteine hydrolase (rLdAdoHcy) compared to soluble L. donovani antigen in treated samples. Moreover, stimulation of peripheral blood mononuclear cells with rLdAdoHcy up-regulated the levels of interferon (IFN)-γ, interleukin (IL)-12 and down-regulated IL-10. Furthermore, vaccination with rLdAdoHcy generated perceptible delayed-type hypersensitivity response and exerted considerably good prophylactic efficacy (∼70% inhibition) against L. donovani challenge. The efficacy was confirmed by the increased expression levels of inducible NO synthase and Th1-type cytokines, IFN-γ and IL-12 and down-regulation of IL-4, IL-10 and transforming growth factor (TGF)-ß. The results indicate the potentiality of rLdAdoHcy protein as a suitable vaccine candidate against VL.