Inflammation-based scores in a large cohort of adrenocortical carcinoma and adrenocortical adenoma: role of the hormonal secretion pattern.

BACKGROUND: Serum inflammation-based scores can predict clinical outcome in several cancer types, including adrenocortical carcinoma (ACC). It is unclear whether the extent of inflammation-based scores alterations in ACC reflects malignancy, steroid excess, or both. METHODS: We investigated a large retrospective cohort of adrenocortical adenomas (ACA, n = 429) and ACC (n = 61) with available baseline full blood count and hormonal evaluation. We examined the relationship between different inflammation-based scores [neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), systemic immune-inflammation index (SII), and prognostic nutrition index (PNI)] and both malignancy and steroid secretion patterns. RESULTS: All inflammation-based scores differed between ACC and ACA: patients with ACC had higher NLR, PLR, SII and lower LMR and PNI levels compared to ACA (all p values < 0.001). NLR showed a positive correlation with cortisol levels after overnight 1 mg-dexamethasone suppression test (1 mg-DST), both in ACC and ACA (p < 0.01). The ROC curve analysis determined NLR > 2.6 as the best cut-off to discriminate ACC from ACA [AUC = 0.846, p < 0.01]. At multivariable analysis, NLR > 2.6 was independently associated with ACC, 1 mg-DST cortisol levels and age, but not with tumour size. Considering the ACC, NLR and SII were higher and PNI was lower in patients with cortisol excess compared to those without cortisol excess (p = 0.002, p = 0.007, and p = 0.044 respectively). Finally, LMR and NLR differed between inactive-ACC (n = 10) and inactive-ACA (n = 215) (p = 0.040 and p = 0.031, respectively). CONCLUSION: Inflammation-based scores are related to steroid secretion both in ACC and ACA. ACCs present a higher grade of inflammation regardless of their hormonal secretion, likely as a feature of malignancy itself.

The pace of biological aging helps explain the association between insomnia and chronic low back pain.

Chronic low back pain (cLBP) is associated with insomnia and advanced age. Emerging evidence suggests that the severity of both sleep disorders (like insomnia) and chronic pain are associated with a faster pace of biological aging. We aimed to determine whether the pace of biological age mediates the relationship between insomnia and the impact of cLBP in a sample of community-dwelling adults ages 19 to 85 years. Participants (49 with no pain, 32 with low-impact pain, and 37 with high-impact pain) completed sociodemographic, pain, insomnia, and short physical performance battery assessments. We calculated the pace of biological aging using DunedinPACE from blood leukocyte DNA. On average, individuals with high-impact cLBP had significantly faster biological aging than those with low-impact and no chronic pain (p < .001). Bivariate associations of DunedinPACE scores with insomnia severity and functional performance were significant at p < .01 (rs = 0.324 and -0.502, respectively). After adjusting for race and sex, the association of insomnia severity and the impact of cLBP was partially mediated by the pace of biological aging (ß = 0.070, p < .001). Also, the association of insomnia severity with functional performance was partially mediated by the pace of biological aging (ß = -0.105, p < .001). Thus, insomnia remains strongly predictive of cLBP outcomes, and the pace of biological aging helps explain this association. Future prospective studies with repeated assessments are needed to uncover the directionality of these complex relationships and ultimately develop interventions to manage cLBP.

Efficacy of a pediatric headache infusion center: A single-center experience.

OBJECTIVE: To evaluate the efficacy of a pediatric headache infusion center (HIC) in alleviating the symptoms and preventing future visits to the emergency department (ED). BACKGROUND: Headache is a common reason for visits to the pediatric ED. ED visits are associated with inordinate costs of care and are conceived by parents to be avoidable if adequate alternatives are available. An infusion center for acute treatment of intractable headache in children with chronic migraine may be an effective alternative to an ED visit. METHODS: This was a retrospective analysis of data from a single-center cohort of patients with a known history of chronic migraine, presenting to Dayton Children's HIC with an acute migraine from June 1, 2017 to June 1, 2020. Patients were treated according to established protocols divided into two pathways. Patient demographics, clinical characteristics, pre- and postinfusion pain scores, ED visits and inpatient admissions within 2 weeks of HIC visit, and ED visits 1 year prior and 1 year after the HIC visit were noted. RESULTS: A total of 297 HIC visits were analyzed from 201 patients. The HIC was effective in controlling symptoms with a significant reduction in pain score (median [interquartile range; IQR] 7.0 [2.0] preinfusion vs. 1.0 [2.0] postinfusion, p < 0.001). Only 25/297 (8.4%) patients came to the ED within 2 weeks of the HIC visit, and an even smaller number of patients (20/297, 6.7%) were admitted as inpatients within 2 weeks of the HIC visit. The number of ED visits was significantly reduced in the year after the HIC visit compared with the year prior (median [IQR] 1.0 [2.0] before vs. 0.0 [1.0] after, p < 0.001). CONCLUSION: A pediatric HIC is effective in alleviating the symptoms and preventing ED visits. These centers should be considered as standard of care at children's hospitals.

Selective exclusion and selective binding both contribute to ion selectivity in KcsA, a model potassium channel.

The selectivity filter in potassium channels, a main component of the ion permeation pathway, configures a stack of binding sites (sites S1-S4) to which K+ and other cations may bind. Specific ion binding to such sites induces changes in the filter conformation, which play a key role in defining both selectivity and permeation. Here, using the potassium channel KcsA as a model, we contribute new evidence to reinforce this assertion. First, ion binding to KcsA blocked by tetrabutylammonium at the most cytoplasmic site in the selectivity filter (S4) suggests that such a site, when in the nonconductive filter conformation, has a higher affinity for cation binding than the most extracellular S1 site. This filter asymmetry, along with differences in intracellular and extracellular concentrations of K+versus Na+ under physiological conditions, should strengthen selection of the permeant K+ by the channel. Second, we used different K+ concentrations to shift the equilibrium between nonconductive and conductive states of the selectivity filter in which to test competitive binding of Na+ These experiments disclosed a marked decrease in the affinity of Na+ to bind the channel when the conformational equilibrium shifts toward the conductive state. This finding suggested that in addition to the selective binding of K+ and other permeant species over Na+, there is a selective exclusion of nonpermeant species from binding the channel filter, once it reaches a fully conductive conformation. We conclude that selective binding and selective exclusion of permeant and nonpermeant cations, respectively, are important determinants of ion channel selectivity.

Differential binding of monovalent cations to KcsA: Deciphering the mechanisms of potassium channel selectivity.

This work explores whether the ion selectivity and permeation properties of a model potassium channel, KcsA, could be explained based on ion binding features. Non-permeant Na+ or Li+ bind with low affinity (millimolar KD's) to a single set of sites contributed by the S1 and S4 sites seen at the selectivity filter in the KcsA crystal structure. Conversely, permeant K+, Rb+, Tl+ and even Cs+ bind to two different sets of sites as their concentration increases, consistent with crystallographic evidence on the ability of permeant species to induce concentration-dependent transitions between conformational states (non-conductive and conductive) of the channel's selectivity filter. The first set of such sites, assigned also to the crystallographic S1 and S4 sites, shows similarly high affinities for all permeant species (micromolar KD's), thus, securing displacement of potentially competing non-permeant cations. The second set of sites, available only to permeant cations upon the transition to the conductive filter conformation, shows low affinity (millimolar KD's), thus, favoring cation dissociation and permeation and results from the contribution of all S1 through S4 crystallographic sites. The differences in affinities between permeant and non-permeant cations and the similarities in binding behavior within each of these two groups, correlate fully with their permeabilities relative to K+, suggesting that binding is an important determinant of the channel's ion selectivity. Conversely, the complexity observed in permeation features cannot be explained just in terms of binding and likely relates to reported differences in the occupancy of the S2 and S3 sites by the permeant cations.

Competing Lipid-Protein and Protein-Protein Interactions Determine Clustering and Gating Patterns in the Potassium Channel from Streptomyces lividans (KcsA).

There is increasing evidence to support the notion that membrane proteins, instead of being isolated components floating in a fluid lipid environment, can be assembled into supramolecular complexes that take part in a variety of cooperative cellular functions. The interplay between lipid-protein and protein-protein interactions is expected to be a determinant factor in the assembly and dynamics of such membrane complexes. Here we report on a role of anionic phospholipids in determining the extent of clustering of KcsA, a model potassium channel. Assembly/disassembly of channel clusters occurs, at least partly, as a consequence of competing lipid-protein and protein-protein interactions at nonannular lipid binding sites on the channel surface and brings about profound changes in the gating properties of the channel. Our results suggest that these latter effects of anionic lipids are mediated via the Trp(67)-Glu(71)-Asp(80) inactivation triad within the channel structure and its bearing on the selectivity filter.

Detergent-labile, supramolecular assemblies of KcsA: relative abundance and interactions involved.

In this work, we illustrate the ability of the prokaryotic potassium channel KcsA to assemble into a variety of supramolecular clusters of defined sizes containing the tetrameric KcsA as the repeating unit. Such clusters, particularly the larger ones, are markedly detergent-labile and thus, disassemble readily upon exposure to the detergents commonly used in protein purification or conventional electrophoresis analysis. This is a reversible process, as cluster re-assembly occurs upon detergent removal and without the need of added membrane lipids. Interestingly, the dimeric ensemble between two tetrameric KcsA molecules are quite resistant to detergent disassembly to individual KcsA tetramers and along with the latter, are likely the basic building blocks through which the larger clusters are organized. As to the proteins domains involved in clustering, we have observed disassembly of KcsA clusters by SDS-like alkyl sulfates. As these amphiphiles bind to inter-subunit, "non-annular" sites on the protein, these observations suggest that such sites also mediate channel-channel interactions leading to cluster assembly.

The Pace of Biological Aging Predicts Nonspecific Chronic Low Back Pain Severity.

This study aimed to determine if and how the pace of biological aging was associated with nonspecific chronic low back pain (cLBP) and compare what measure of epigenetic age acceleration most strongly predicts cLBP outcomes. We used the Dunedin Pace of Aging from the Epigenome (DunedinPACE), Horvath's, Hannum's, and PhenoAge clocks to determine the pace of biological aging in 69 cLBP, and 49 pain-free controls (PFCs) adults, ages 18 to 85 years. On average, participants with cLBP had higher DunedinPACE (P < .001) but lower Horvath (P = .04) and Hannum (P = .02) accelerated epigenetic age than PFCs. There was no significant difference in PhenoAge acceleration between the cLBP and PFC groups (P = .97). DunedinPACE had the largest effect size (Cohen's d = .78) on group differences. In univariate regressions, a unit increase in DunedinPACE score was associated with 265.98 times higher odds of cLBP than the PFC group (P < .001). After controlling for sex, race, and body mass index (BMI), the odds ratio of cLBP to PFC group was 149.62 (P < .001). Furthermore, among participants with cLBP, DunedinPACE scores positively correlated with pain severity (rs = .385, P = .001) and interference (rs = .338, P = .005). Epigenetic age acceleration from Horvath, Hannum, and PhenoAge clocks were not significant predictors of cLBP. The odds of a faster pace of biological aging are higher among adults with cLBP, and this was associated with greater pain severity and disability. Future interventions to slow the pace of biological aging may improve cLBP outcomes. PERSPECTIVE: Accelerated epigenetic aging is common among adults with nonspecific cLBP. Higher DunedinPACE scores positively correlate with pain severity and interference, and better predict cLBP than other DNA methylation clocks. Interventions to slow the pace of biological aging may be viable targets for improving pain outcomes.

Race-specific associations: inflammatory mediators and chronic low back pain.

ABSTRACT: Chronic low back pain (cLBP) is a global health crisis that disproportionately burdens non-Hispanic Black (NHB) individuals, compared with those who identify as non-Hispanic White (NHW). Despite the growing personal and societal impact of cLBP, its biological underpinnings remain poorly understood. To elucidate the biological factors that underlie the racial disparities in cLBP, this study sought to determine whether inflammatory mediators associated with pain interference (PI), pain at rest (PAR), and movement-evoked pain (MEP) differ as a function of racial identity. Blood samples were collected from 156 individuals with cLBP (n = 98 NHB participants, n = 58 NHW participants). Enzyme-linked immunosorbent assay and multiplex assays were used to quantify concentrations of proinflammatory (fibrinogen, C-reactive protein [CRP], serum amyloid A, tumor necrosis factor α [TNF-α], and interleukin [IL]-1α, IL-1ß, and IL-6) and anti-inflammatory markers (IL-4 and IL-13). Spearman rho correlations were used to assess associations among markers of inflammation and PI, PAR, and MEP using the Brief Pain Inventory-Short Form. Analyses revealed that for NHW patients, CRP, serum amyloid A, and IL-6 were positively associated with cLBP outcomes and IL-4 was inversely associated with PAR and MEP. However, for NHB patients, only IL-1α was positively associated with PAR. Our findings suggest that, while there are associations between inflammation and cLBP outcomes, the biomarkers that underlie the inflammation could very well differ as a function of racialized minority group. However, more research with racially inclusive samples is needed to elucidate the mechanisms that may contribute to racial disparities in cLBP.

Adverse Childhood Experiences and Chronic Low Back Pain in Adulthood: The Role of Emotion Regulation.

Chronic low back pain (cLBP) is characterized by biopsychosocial determinants that collectively result in a substantial burden at the individual, community, and health care system levels. A growing body of literature suggests that childhood adversity is longitudinally associated with the development and maintenance of various chronic pain conditions in adulthood. Little research has investigated the psychological processes that might underlie the association between adverse childhood experiences (ACEs) and cLBP. Emotion regulation comprises a substantive part of the subjective experience of pain and may be a potential mechanism through which ACEs contribute to cLBP etiology and maintenance. Thus, the current study examined the extent to which emotion dysregulation mediated the relationship between ACEs and pain severity (pain at rest and movement-evoked pain) in adults with cLBP. Participants included 183 adults (53.0% female, 62.5% non-Hispanic Black) between the ages of 18 and 85 with cLBP. Participants self-reported on ACEs, pain, difficulties in emotion regulation (DER), depression, and completed brief physical function tasks. In data analytic models, sociodemographic variables were included as covariates. Analyses revealed that emotion regulation mediated the relationship between ACEs and cLBP severity at rest (indirect effect = .15 [95% CI {.06-.25}]) and with movement (indirect effect = 1.50 [95% CI {.69-2.57}]). Findings suggest ACEs are linked to cLBP severity in adulthood through DER. This aligns with research demonstrating that childhood maltreatment can lead to DER, which perpetuate over the lifespan to impact adult health outcomes. PERSPECTIVE: This study presents emotion dysregulation as a psychological pathway through which childhood adversity may contribute to cLBP in adulthood. This work may bolster our understanding of social experiences as risk factors for chronic pain, while identifying targets for clinical intervention. TRIAL REGISTRATION: This study utilized baseline data collected as part of a parent trial titled "Examining Racial and SocioEconomic Disparities in Chronic Low Back Pain" (ClinicalTrials.gov ID: NCT03338192).

Healthcare Practitioners' Quality of Life in Rural and Urban Areas of Saudi Arabia.

INTRODUCTION: The quality of care delivered by healthcare practitioners (HCPs) is crucial in promoting optimal health and quality of life (QOL) for a population. To achieve this, understanding the factors that affect the quality of life of healthcare practitioners is essential for governments to develop sustainable healthcare systems. Developed countries have a major role to play in this aspect, as the misallocation of healthcare providers to the wrong geographic regions can significantly impact their performance.  Aim: This study aims to evaluate the factors associated with healthcare practitioners' (HCP) quality of life (QOL) and provide workforce planning with knowledge of the level of QOL among HCPs and its factors in Saudi Arabia in 2021. METHODS: This is an observational, descriptive, cross-sectional study conducted in both rural and urban areas of Saudi Arabia. The study population includes all healthcare practitioners practicing in Saudi Arabia. A probability-stratified random sampling technique was used to recruit healthcare practitioners into the study, with a requirement of at least 380 practitioners to achieve 95% confidence and a 5% margin of error. To assess the quality of life of healthcare practitioners in Saudi Arabia, the study used a national online self-administered questionnaire that was designed by the research team. The data collection process took place from June 2021 to October 2021, and responses were obtained randomly. For analysis, the study used descriptive statistics such as frequency, percentages, mean or median, and standard deviation or interquartile range. The statistical significance was set at p<0.05, and independent sample T-tests and Chi-square tests were calculated to determine any significant differences between groups. RESULTS: A total of 439 participants completed the questionnaire and were included in the final analysis. The participants had a mean age of 38.8 years (SD = 10.173), with 232 (52.8%) male and 207 (47.2%) female. Regarding marital status, 28% were single, 68.6% were married, and 3.4% were divorced or widowed. The prevalence of chronic diseases in the cohort was 9.1%, with hypertension being the most commonly reported. Of the participants, 362 (82.5%) were living in a society considered urban, while 77 (17.5%) were living in rural areas. Urban healthcare practitioners expressed higher levels of satisfaction with safety and security, internet availability and speed, and city infrastructure compared to their rural counterparts. However, rural practitioners reported greater satisfaction with the cost of living, and transportation quality was a point of concern for both groups. CONCLUSION: The study shows that people living in urban and rural areas are all satisfied with their living conditions based on many factors mentioned in the results section. This indicates that there is no significant difference. The most important factor that affects satisfaction with living is health status. The rate of satisfaction is very high for all factors, including security and safety, environmental health, city infrastructure, cost of living, internet availability, and sports activity-all of which are related to the city itself. For factors related to the individual, such as emotional support from family and friends, personal relationships, overall health, and body appearance, the rate of satisfaction is also high.

Integrated BATF transcriptional network regulates suppressive intratumoral regulatory T cells.

Human regulatory T cells (Tregs) are crucial regulators of tissue repair, autoimmune diseases, and cancer. However, it is challenging to inhibit the suppressive function of Tregs for cancer therapy without affecting immune homeostasis. Identifying pathways that may distinguish tumor-restricted Tregs is important, yet the transcriptional programs that control intratumoral Treg gene expression, and that are distinct from Tregs in healthy tissues, remain largely unknown. We profiled single-cell transcriptomes of CD4+ T cells in tumors and peripheral blood from patients with head and neck squamous cell carcinomas (HNSCC) and those in nontumor tonsil tissues and peripheral blood from healthy donors. We identified a subpopulation of activated Tregs expressing multiple tumor necrosis factor receptor (TNFR) genes (TNFR+ Tregs) that is highly enriched in the tumor microenvironment (TME) compared with nontumor tissue and the periphery. TNFR+ Tregs are associated with worse prognosis in HNSCC and across multiple solid tumor types. Mechanistically, the transcription factor BATF is a central component of a gene regulatory network that governs key aspects of TNFR+ Tregs. CRISPR-Cas9-mediated BATF knockout in human activated Tregs in conjunction with bulk RNA sequencing, immunophenotyping, and in vitro functional assays corroborated the central role of BATF in limiting excessive activation and promoting the survival of human activated Tregs. Last, we identified a suite of surface molecules reflective of the BATF-driven transcriptional network on intratumoral Tregs in patients with HNSCC. These findings uncover a primary transcriptional regulator of highly suppressive intratumoral Tregs, highlighting potential opportunities for therapeutic intervention in cancer without affecting immune homeostasis.

An improved model of type 2 diabetes with effects on glucose tolerance, neuropathy and retinopathy with and without obesity.

RATIONALE: Type 2 diabetes (T2D) costs billions of dollars annually, is also associated with pain (diabetic neuropathy), as well as retinopathy, lower urinary tract/urinary bladder dysfunction, depression, and systemic inflammation, affecting quality of life for patients. To that end, animal models are utilized to explore potential treatments, but may not reflect the complexity of the condition. OBJECTIVE: We aimed to test an improved model of T2D that more closely mimics the clinical mechanisms and symptoms in an outbred strain of mouse. FINDINGS: Male and female CD-1 mice (n = 72) were fed one of four diets: regular chow (REG), our Standard American Diet (SAD), a revised SAD (SAD2), or the commonly-used high-fat diet (HFD). Overall, HFD- and SAD-fed mice had significant weight gain and increased fat mass. Following injury, the SAD- and SAD2-fed mice showed protracted recovery, but the HFD-fed mice did not. Similarly, SAD- and SAD2-fed mice showed impaired retinal function compared to REG-fed mice, but the HFD-fed mice did not. CONCLUSIONS: The SAD and SAD2 more closely model the problematic dietary intake and subsequent clinical symptoms associated with T2D. POTENTIAL IMPACT OF STUDY: The adjusted SAD2 may be a better representation of a human-translatable diet than the SAD and HFD, and may allow for increased advances in the investigation of T2D-related symptoms.

Racial Differences in 25-Hydroxy Vitamin D and Self-Reported Pain Severity in a Sample of Individuals Living with Non-Specific Chronic Low Back Pain.

Introduction: Considerable evidence suggests that there are significant ethnic/racial differences in the experience of pain among individuals suffering from chronic musculoskeletal conditions. Additionally, low levels of vitamin D have been associated with pain severity. Further, vitamin D deficiency is more prevalent in Non-Hispanic Black (NHB) individuals compared to Non-Hispanic Whites (NHW). Objective: The aim of this study was to investigate the associations among race, pain severity, and serum levels of vitamin D in a sample of patients with chronic low back pain (cLBP). Methods: All study participants (n = 155) self-identified their race/ethnicity as either NHB or NHW. Blood samples were collected to assess circulating levels of serum 25- hydroxy vitamin D. Vitamin D levels were categorized as optimal (≥20 ng/mL), insufficient (12-19 ng/mL) or deficient (<12 ng/mL). Participants then self-reported their pain severity using the Brief Pain Inventory - Short Form. Results: Results showed that a greater proportion of NHB versus NHW participants were categorized as Vitamin D deficient (χ 2 (2, N = 155) = 16.79, p < 0.001). An analysis of covariance (ANCOVA) revealed that NHBs reported significantly greater pain severity relative to NHWs (F(1150) = 6.45) p = 0.012. Further, self-reported pain severity significantly differed according to Vitamin D clinical categories (F(2150) = 4.19, p = 0.013). Participants with deficient vitamin D reported significantly greater pain severity in comparison to participants with optimal vitamin D (F(1101) = 7.28, p = 0.008). Conclusion: The findings suggest that Vitamin D deficiency may be linked to greater pain severity in a sample of individuals with cLBP, especially for those who identify as NHB.

Peroxisomal catalases from the yeasts Pichia pastoris and Kluyveromyces lactis as models for oxidative damage in higher eukaryotes.

Catalases are among the main scavengers of reactive oxygen species (ROS) present in the peroxisome, thereby preventing oxidative cellular and tissular damage. In human, multiple diseases are associated with malfunction of these organelles, which causes accumulation of ROS species and consequently the inefficient detoxification of cells. Despite intense research, much remains to be clarified about the precise molecular role of catalase in cellular homeostasis. Yeast peroxisomes and their peroxisomal catalases have been used as eukaryotic models for oxidative metabolism, ROS generation and detoxification, and associated pathologies. In order to provide reliable models for oxidative metabolism research, we have determined the high-resolution crystal structures of peroxisomal catalase from two important biotechnology and basic biology yeast models, Pichia pastoris and Kluyveromyces lactis. We have performed an extensive functional, biochemical and stability characterization of both enzymes in order to establish their differential activity profiles. Furthermore, we have analyzed the role of the peroxisomal catalase under study in the survival of yeast to oxidative burst challenges combining methanol, water peroxide, and sodium chloride. Interestingly, whereas catalase activity was induced 200-fold upon challenging the methylotrophic P. pastoris cells with methanol, the increase in catalase activity in the non-methylotrophic K. lactis was only moderate. The inhibitory effect of sodium azide and ß-mercaptoethanol over both catalases was analyzed, establishing IC50 values for both compounds that are consistent with an elevated resistance of both enzymes toward these inhibitors. Structural comparison of these two novel catalase structures allows us to rationalize the differential susceptibility to inhibitors and oxidative bursts. The inherent worth and validity of the P. pastoris and K. lactis yeast models for oxidative damage will be strengthened by the availability of reliable structural-functional information on these enzymes, which are central to our understanding of peroxisomal response toward oxidative stress.

Revisiting the Prevalence of Autism Spectrum Disorder among Omani Children: A multicentre study.

OBJECTIVES: This study aimed to provide an updated estimate of the prevalence of autism spectrum disorder (ASD) among Omani children. METHODS: This retrospective descriptive study was conducted from December 2011 to December 2018. Data were retrieved from the three main autism diagnostic centres in Oman: Sultan Qaboos University Hospital, Royal Hospital and Al-Massarah Hospital. The ASD diagnosis was made by experienced clinicians based on the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). The overall population prevalence estimates per 10,000 children aged 0-14 years old in Oman were calculated using the denominator of the mid-period population data. RESULTS: A total of 1,705 ASD cases were identified with the majority of cases being male (78.1%). The overall prevalence rate of ASD was estimated at 20.35 per 10,000 children (95% confidence interval: 19.39-21.32) between 2012-2018. Boys were found to have a 3.4-fold higher prevalence of ASD than girls (31.23/10,000 versus 9.07/10,000). Regionally, the majority of cases were found in the capital, Muscat, where the highest prevalence was 36.51 cases per 10,000 children. CONCLUSION: The prevalence of ASD among Omani children is 15-fold higher than estimates from 2011. This increase can be attributed to improvements in diagnostic services, increased awareness of ASD, better screening programmes and changes in diagnostic criteria. In addition, this increase in prevalence suggests a need for a registry of developmental disabilities and more extensive diagnostic and rehabilitation services in Oman.

Transformation of inorganic and organic arsenic by Alkaliphilus oremlandii sp. nov. strain OhILAs.

Alkaliphilus oremlandii sp. nov. strain OhILAs is a mesophilic, spore-forming, motile, low mole%GC gram positive. It was enriched from Ohio River sediments on a basal medium with 20 mM lactate and 5 mM arsenate and isolated through passage on medium with increased arsenic concentration (10 and 20 mM), tindalization, and serial dilution. The pH optimal for growth was 8.4 and 16S rRNA gene sequence analysis indicated it is most closely related to species in the genus Alkaliphilus (A. crotonoxidans 95%, A. auruminator 95%, A. metalliredigens, 94%). A strict anaerobe, it can ferment lactate via the acrylate pathway as well as fructose and glycerol. A. oremlandii also has respiratory capability, as it is able to use arsenate and thiosulfate as terminal electron acceptors with acetate, pyruvate, formate, lactate, fumarate, glycerol, or fructose as the electron donor. A respiratory arsenate reductase, which is constitutively expressed, has been identified through biochemical and Western blot analyses and confirmed by cloning and sequencing of the gene encoding the structural subunit arrA. The entire arr operon as well as the ars operon have also been identified in the fully annotated genome. A. oremlandii also transforms the organoarsenical 3-nitro-4-hydroxy benzene arsonic acid (roxarsone). Growth experiments and genomic analysis suggest that it couples the reduction of the nitro group of the organoarsenical to the oxidation of either lactate or fructose in a dissimilatory manner, generating ATP via a sodium dependent ATP synthase.

Synthesis, crystallographic, spectroscopic studies and biological activity of new cobalt(II) complexes with bioactive mixed sulindac and nitrogen-donor ligands.

Four novel complexes [Co(H2O)4(sul)2] 1, [Co(2-ampy)2(sul)2] 2, [Co(H2O)2(1,10-phen) (sul)2] 3 and [Co(2,9-dimephen)(sul)2] 4 (sul = sulindac, 2-ampy = 2-amino pyridine, 1,10-phen = 1,10-phenanthroline and 2,9-dimeph = 2,9-dimethyl-1,10-phenanthroline) were prepared and characterized by IR, UV-Visible spectroscopy and magnetic properties. The crystal structures of complexes 1 and 4 were determined by single-crystal X-ray diffraction. In-vitro anti-bacterial activity for the prepared complexes against Gram-positive (Staphylococcus epidermidis, Staphylococcus aureus) and Gram-negative (Bordetella, Escherichia coli) bacteria and Yeast species (Saccharomyces and Candida) were performed using agar well-diffusion method. Only complex 4 showed reasonable activity against yeast. All compounds showed more anti-bacterial activity against Gram-positive bacteria than Gram-negative. Graphical abstract This work reports synthesis, crystallographic, spectroscopic studies and biological activity of new cobalt(II) complexes with bioactive mixed sulindac and nitrogen-donor ligands. The crystal structures of complexes 1 and 4 were determined using single-crystal X-ray diffraction. In-vitro anti-bacterial activity of the prepared complexes and their parent ligands were investigated against different Gram-positive and Gram-negative bacteria using agar diffusion method.

The Influential Role of BCL2 Family Members in Synovial Sarcomagenesis.

Synovial sarcomas are deadly soft tissue malignancies associated with t(X;18) balanced chromosomal translocations. Expression of the apoptotic regulator BCL2 is prominent in synovial sarcomas and has prompted the hypothesis that synovial sarcomagenesis may depend on it. Herein, it is demonstrated that Bcl2 overexpression enhances synovial sarcomagenesis in an animal model. Furthermore, we determined increased familial clustering of human synovial sarcoma patients with victims of other BCL2-associated malignancies in the Utah Population Database. Conditional genetic disruption of Bcl2 in mice also led to reduced sarcomagenesis. Pharmacologic inhibition specific to BCL2 had no demonstrable efficacy against human synovial sarcoma cell lines or mouse tumors. However, targeting BCLxL in human and mouse synovial sarcoma with the small molecule BH3 domain inhibitor, BXI-72, achieved significant cytoreduction and increased apoptotic signaling. Thus, the contributory role of BCL2 in synovial sarcomagenesis does not appear to render it as a therapeutic target, but mitochondrial antiapoptotic BCL2 family members may be.Implications: The association of BCL2 expression with synovial sarcoma is found to fit with a subtle, but significant, impact of its enhanced presence or absence during early tumorigenesis. However, specific pharmacologic inhibition of BCL2 does not demonstrate a persistent dependence in fully developed tumors. Conversely, inhibition of the BCL2 family member BCLxL resulted in nanomolar potency against human synovial sarcoma cell lines and 50% tumor reduction in a genetically engineered mouse model. Mol Cancer Res; 15(12); 1733-40. ©2017 AACR.