When a Sibling Has Autism: Narrative Review of Interventions for Typically Developing Siblings.

Being a typically developing sibling to a child with autism spectrum disorder (ASD-Sib) can be associated with several behavioral and mental health problems. With this understanding, researchers are beginning to focus on sibling-oriented interventions. This review seeks to evaluate the current literature on such interventions. We searched digital databases and identified eight relevant studies. The sample (n = 247) had an age range of 4-16 years. The outcomes were generally positive, with improvements in different facets of ASD-Sibs. Results differed due to varied intervention styles, outcome variables, methods, and samples. Our findings highlight the potential for improvement in ASD-Sib's knowledge of autism and their psychological functioning and hence call for further research with robust methods.

Pathways to care and barriers in treatment among patients with Dissociative disorders.

INTRODUCTION: Dissociative disorder patients often present with sudden and embarrassing symptoms, and it is difficult for the patient and care giver to understand initially, recognize the need for help and reach for appropriate treatment timely. This can result in high risk of engaging in dangerous behaviors such as self-harm and suicidal acts, impaired global functioning, and poor quality of life. Knowledge about the types of barriers which are there in treatment seeking, can help in planning strategies for their removal and to facilitate the treatment process. METHODS: Cross-sectional study among patients (n=133) with Dissociative disorders which were recruited from January 2023 to June 2023 in a tertiary care hospital. Pathways to care and barriers in treatment for Dissociative disorders were assessed by interviewing patients using semi-structured proforma. The Dissociative Experience Scale and World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0)) were used to assess disease severity and impact of illness on various domains of life respectively. Group comparison was made to assess differences in social- clinical profile of patients choosing different modalities of treatment. RESULTS: 133 patients of Dissociative disorders with mean age 29.6±9.2, showed their first-choice of help seeking from general practitioner/ neurologist (40.6%), traditional faith healers (35.3%), psychiatrist (18.1%) and 5.2% preferred alternative treatments. This trend changed with 2nd and 3rd contact of help seeking with greater preference for psychiatrist in their 2nd (n=45, 33.8%) and 3rd (n=69, 51.8%) contact. The median duration of untreated illness was 56 weeks (IQR 24-182 weeks). Social-clinical profile of patients varied with their choice of treatment, having lower education level (P = 0.013), longer duration of untreated illness (p=0.003), more severity of symptoms (p=0.032) and greater disability scores(p=0.002) in patients whose first treatment choice was traditional faith healers. More than 70% patients faced availability barriers, stigma, unawareness about mental illness and influence of others in treatment of choice as barriers in initiating and continuing treatment. CONCLUSION: Patients with Dissociative disorders seek treatment from a multitude of healthcare providers including traditional faith healers, general physicians, and alternative medicine practitioners before reaching psychiatrist and undergoes various barriers in treatment. There is need to implement necessary measures for sensitization and awareness about Dissociative disorders to prevent prolonged and undue delays in initiation of appropriate management.

Comparative study between dynamic susceptibility contrast magnetic resonance imaging and arterial spin labelling perfusion in differentiating low-grade from high-grade brain tumours.

Purpose: Our aim was to distinguish between low-grade and high-grade brain tumours on the basis of dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) perfusion and arterial spin labelling (ASL) perfusion and to compare DSC and ASL techniques. Material and methods: Forty-one patients with brain tumours were evaluated by 3-Tesla MRI. Conventional and perfusion MRI imaging with a 3D pseudo-continuous ASL (PCASL) and DSC perfusion maps were evaluated. Three ROIs were placed to obtain cerebral blood value (CBV) and cerebral blood flow (CBF) in areas of maximum perfusion in brain tumour and normal grey matter. Histopathological diagnosis was considered as the reference. ROC analysis was performed to compare the diagnostic performance and to obtain a feasible cut-off value of perfusion parameters to differentiate low-grade and high-grade brain tumours. Results: Normalised perfusion parameters with grey matter (rCBF or rCBV lesion/NGM) of malignant lesions were significantly higher than those of benign lesions in both DSC (normalised rCBF of 2.16 and normalised rCBV of 2.63) and ASL (normalised rCBF of 2.22) perfusion imaging. The normalised cut-off values of DSC (rCBF of 1.1 and rCBV of 1.4) and ASL (rCBF of 1.3) showed similar specificity and near similar sensitivity in distinguishing low-grade and high-grade brain tumours. Conclusions: Quantitative analysis of perfusion parameters obtained by both DSC and ASL perfusion techniques can be reliably used to distinguish low-grade and high-grade brain tumours. Normalisation of these values by grey matter gives us more reliable parameters, eliminating the different technical parameters involved in both the techniques.

Models and approaches to comprehend and address glial inflammation following spinal cord injury.

Spinal cord injury (SCI) culminates in chronic inflammation and glial scar formation driven by the activation of microglia and astrocytes. Current anti-inflammatory strategies to treat glial activation associated with SCI have several limitations. Existing in vitro and ex vivo models studying molecular mechanisms associated with inflammation focus only on the acute phase. However, the progression of glial cell-derived inflammation over the acute-to-chronic phases has not been assessed. Understanding this progression will help establish a framework for evaluating therapeutic strategies. Additionally, new models could be useful as high-throughput screening (HTS) platforms. This review aims to highlight currently available models and future methods that could facilitate screening of novel therapeutics for SCI.

Statistically-aided development of protein A affinity chromatography for enhancing recovery and controlling quality of a monoclonal antibody.

Protein A chromatography is widely used for isolation of monoclonal antibodies (mAbs) from cell culture components. In this study, the effect of different process parameters of the Protein A purification namely, binding pH, elution pH, flow rate, neutralization pH and tween concentration, on the concentration and quality of the purified mAb were evaluated. Using design of experiments approach, the critical process parameters of protein A chromatography were identified and experimentally optimized. Their impact on quality attributes, such as size variants and charge variants, of the mAb was studied. Multivariate data analysis was subsequently performed using multiple linear regression and partial least squares regression methods. It was observed that the elution pH primarily governed the concentration of the purified mAb and the content of monomers and aggregates, while the tween concentration primarily influenced the main peak of the charge variants. This is the first study that evaluates the impact of tween concentration in buffers on the protein A chromatography purification step. These studies helped in identifying the design space and defining the target robust and optimal setpoints of the responses, which were subsequently verified experimentally. These setpoints not only passed the target criteria but also resulted in the highest recoveries during the investigation. Through this statistically-aided approach, an optimized and robust protein A chromatography process was rationally developed for purification of mAbs, while achieving the desired product quality. This study highlights the influence of multiple parameters of the protein A purification process on critical quality attributes of mAbs, such as the size and charge variants, which has been a very scarcely explored area.

Insights into the mechanism of oligodendrocyte protection and remyelination enhancement by the integrated stress response.

central nervous system (CNS) inflammation triggers activation of the integrated stress response (ISR). We previously reported that prolonging the ISR protects remyelinating oligodendrocytes and promotes remyelination in the presence of inflammation. However, the exact mechanisms through which this occurs remain unknown. Here, we investigated whether the ISR modulator Sephin1 in combination with the oligodendrocyte differentiation enhancing reagent bazedoxifene (BZA) is able to accelerate remyelination under inflammation, and the underlying mechanisms mediating this pathway. We find that the combined treatment of Sephin1 and BZA is sufficient to accelerate early-stage remyelination in mice with ectopic IFN-γ expression in the CNS. IFN-γ, which is a critical inflammatory cytokine in multiple sclerosis (MS), inhibits oligodendrocyte precursor cell (OPC) differentiation in culture and triggers a mild ISR. Mechanistically, we further show that BZA promotes OPC differentiation in the presence of IFN-γ, while Sephin1 enhances the IFN-γ-induced ISR by reducing protein synthesis and increasing RNA stress granule formation in differentiating oligodendrocytes. Finally, pharmacological suppression of the ISR blocks stress granule formation in vitro and partially lessens the beneficial effect of Sephin1 on disease progression in a mouse model of MS, experimental autoimmune encephalitis (EAE). Overall, our findings uncover distinct mechanisms of action of BZA and Sephin1 on oligodendrocyte lineage cells under inflammatory stress, suggesting that a combination therapy may effectively promote restoring neuronal function in MS patients.

Potential of cinnamaldehyde essential oil as a possible antimicrobial against fowl typhoid in layers.

Fowl typhoid (FT) is an economically significant bacterial disease of layers leading to a drastic drop in egg production. Due to increased public health concerns about antibiotics in poultry feed, a search for new safe antimicrobials for treating fowl typhoid is crucial. The antimicrobial effect of cinnamaldehyde essential oil (CnEO) against fowl typhoid in layers was investigated in this experiment. The 60-week-old BV300-layer birds (n = 100) were divided into five groups: the non-challenged control group A, only cinnamaldehyde-treated group B (CnEO @ 1:8000 dilutions through drinking water for 60 days), the challenged group C, challenged plus cinnamaldehyde therapy group D (CnEO @ 1:8000 dilutions through drinking water from 16 to 30 dpi), and challenged plus antibiotic therapy group E (chloramphenicol @ 1 gm/5lit through drinking water from 16 to 30 dpi). Hens from all challenged groups were challenged with Salmonella Gallinarum (VTCCBAA588) @ 1 × 108 CFU/ml orally. Various parameters such as clinical signs, mortality, egg production and egg weight, colony-forming unit (CFU) count of cecal content, eggshell surface, and egg yolk were evaluated all through 60 days of an experimental trial. Results indicated that, in the case of the cinnamaldehyde therapeutic group, there was a significant improvement in egg production, mild clinical signs, lower feed conversion ratio (FCR), and a significantly lower bacterial count in ceca and on the eggshell surface compared to the control challenge group. Thus, CnEO @ 1:8000 dilutions through drinking water can be a potential antimicrobial for controlling fowl typhoid.

Insights into the mechanism of oligodendrocyte protection and remyelination enhancement by the integrated stress response.

CNS inflammation triggers activation of the integrated stress response (ISR). We previously reported that prolonging the ISR protects remyelinating oligodendrocytes and promotes remyelination in the presence of inflammation (Chen et al., eLife , 2021). However, the exact mechanisms through which this occurs remain unknown. Here, we investigated whether the ISR modulator Sephin1 in combination with the oligodendrocyte differentiation enhancing reagent bazedoxifene (BZA) is able to accelerate remyelination under inflammation, and the underlying mechanisms mediating this pathway. We find that the combined treatment of Sephin1 and BZA is sufficient to accelerate early-stage remyelination in mice with ectopic IFN-γ expression in the CNS. IFN-γ, which is a critical inflammatory cytokine in multiple sclerosis (MS), inhibits oligodendrocyte precursor cell (OPC) differentiation in culture and triggers a mild ISR. Mechanistically, we further show that BZA promotes OPC differentiation in the presence of IFN-γ, while Sephin1 enhances the IFN-γ-induced ISR by reducing protein synthesis and increasing RNA stress granule formation in differentiating oligodendrocytes. Finally, the ISR suppressor 2BAct is able to partially lessen the beneficial effect of Sephin1 on disease progression, in an MS mouse model of experimental autoimmune encephalitis (EAE). Overall, our findings uncover distinct mechanisms of action of BZA and Sephin1 on oligodendrocyte lineage cells under inflammatory stress, suggesting that a combination therapy may effectively promote restoring neuronal function in MS patients.

A case study: Correlation of the nutrient composition in Chinese Hamster Ovary cultures with cell growth, antibody titre and quality attributes using multivariate analyses for guiding medium and feed optimization in early upstream process development.

In this case-study, we demonstrate an approach for identifying correlations between nutrients/metabolites in the spent medium of CHO cell cultures and cell growth, mAb titre and critical quality attributes, using multivariate analyses, which can aid in selection of targets for medium and feed optimization. An extensive LC-MS-based method was used to analyse the spent medium composition. Partial least squares (PLS) model was used to identify correlations between nutrient composition and cell growth and mAb titre and orthogonal projections to latent structures (OPLS) model was used to determine the effect of the changing nutrient composition during the culture on critical quality attributes. The PLS model revealed that the initial concentrations of several amino acids as well as pyruvic acid and pyridoxine, governed the early cell growth, while the concentrations of TCA cycle intermediates and several vitamins highly influenced the stationary phase, in which mAb production was maximum. For the first time, with the help of the OPLS model, we were able to draw correlations between nutrients/metabolites during the culture and critical quality attributes, for example, optimizing the supply of certain amino acids and vitamins could reduce impurities while simultaneously increasing desirable glycoforms. The unique correlations obtained from such an exploratory analysis, utilizing conditions that are commonly adopted in early process development, present opportunities for optimizing the compositions of the growth media and the feed media for enhancing cell growth, mAb production and quality, thereby proving to be a useful preliminary step in bioprocess optimization. Supplementary Information: The online version contains supplementary material available at 10.1007/s10616-022-00561-z.

An insight into new glycotherapeutics in glial inflammation: Understanding the role of glycosylation in mitochondrial function and acute to the chronic phases of inflammation.

INTRODUCTION: Glycosylation plays a critical role during inflammation and glial scar formation upon spinal cord injury (SCI) disease progression. Astrocytes and microglia are involved in this cascade to modulate the inflammation and tissue remodeling from acute to chronic phases. Therefore, understating the glycan changes in these glial cells is paramount. METHOD AND RESULTS: A lectin microarray was undertaken using a cytokine-driven inflammatory mixed glial culture model, revealing considerable differential glycosylation from the acute to the chronic phase in a cytokine-combination generated inflamed MGC model. It was found that several N- and O-linked glycans associated with glia during SCI were differentially regulated. Pearson's correlation hierarchical clustering showed that groups were separated into several clusters, illustrating the heterogenicity among the control, cytokine combination, and LPS treated groups and the day on which treatment was given. Control and LPS treatments were observed to be in dense clusters. This was further confirmed with lectin immunostaining in which GalNAc, GlcNAc, mannose, fucose and sialic acid-binding residues were detected in astrocytes and microglia. However, the sialyltransferase inhibitor inhibited this modification (upregulation of the sialic acid expression), which indeed modulates the mitochondrial functions. CONCLUSIONS: The present study is the first functional investigation of glycosylation modulation in a mixed glial culture model, which elucidates the role of the glycome in neuroinflammation in progression and identified potential therapeutic targets for future glyco therapeutics in neuroinflammation.

Proton magnetic resonance spectroscopy-based evaluation of metabolic abnormalities in the right dorsolateral prefrontal cortex and caudate nucleus in treatment-naïve patients with obsessive-compulsive disorder.

Background: Obsessive-compulsive disorder (OCD) is a common psychiatric disorder whose underlying pathophysiology is insufficiently understood. The pathophysiology of OCD may be related to abnormalities in the biochemistry of neurotransmitters. Aim: The aim of the present study was to measure the absolute concentration of various metabolites in the right dorsolateral prefrontal cortex (DLPFC) and caudate nucleus (CN) in treatment-naive patients with OCD and compare it with healthy controls (HCs). Methods: The present study investigated the metabolic profile of two brain regions, namely right DLPFC and CN, by using single voxel in-vivo proton magnetic resonance spectroscopy (1H MRS) in drug-naive patients with OCD (n = 17, mean age = 30.71 ± 10.104 years) and compared it with healthy controls (n = 13, mean age = 30.77 ± 5.449 years). The patients with OCD were recruited after appropriate psychometric assessments. The 1H-MRS experiments were performed using the 3 Tesla (3T) human MR scanner, and absolute concentrations of metabolites were estimated using the LC model. Results: Significantly lower concentration of tNAA in the right DLPFC was observed in the patients with OCD compared to the controls, which may be indicative of neurodegeneration in this region. However, no significant differences were observed in the concentrations of the metabolites between the patients and controls in the CN region. The level of tNAA in DLPFC significantly correlated with the disability level (WHO-DAS) of the patients. Conclusions: The present study demonstrates abnormalities in the metabolic profile of an important region, DLPFC of the CSTC circuit, which is suggestive of neurodegeneration in the region in OCD patients.

CuH-Catalyzed Enantioselective Desymmetrization of Cyclic 1,3-Diketones.

Herein, we report a CuH-catalyzed asymmetric desymmetrization of prochiral cyclopentane-1,3-diones to access cyclic 3-hydroxy ketones having an all-carbon quaternary center with high diastereoselectivity via hydrosilylation using PMHS as an inexpensive hydride source. This reaction displays high functional group tolerance including reducible alkyne, alkene, and ester groups with a broad substrate scope. The importance of chiral cyclic 3-hydroxy ketone building blocks was also demonstrated through the synthesis of (-)-estrone, the toxicodenane E core, and fused indoles.

Versatility of Anabolic Androgenic Steroid-Induced Hepatotoxicity.

The modified derivatives of testosterone, termed as androgenic steroids are indicated in the management of hypogonadism, visceral obesity and metabolic disorders. Anabolic androgenic steroids (AASs) however are surreptitiously used by athletes and body builders for cosmetic purpose owing to their anabolic effects on muscle mass and strength. The unsurveilled use of AASs subjects these users to various side effects involving multiple systems such as the endocrine, genitourinary, hepatobiliary, central nervous, musculoskeletal and psychosocial system. The liver is a hormone-sensitive organ owing to abundance of androgen receptors and is vulnerable to a wide array of hepatotoxicity ranging from asymptomatic liver enzyme elevation to life-threatening subacute liver failure. The type of drug-induced liver injury (DILI) due to AASs can be hepatocellular injury, cholestasis, fatty liver disease, chronic vascular injury and neoplastic disease. Herein, we report three cases of AAS-related DILI associated with AAS abuse.

Self-stigma in patients with major depressive disorder: An exploratory study from India.

BACKGROUND: One of the barriers to effective care in patients with depression is stigma associated with having a mental disorder, which also acts as a barrier to recovery and increases the disability. AIMS: To study the stigma and disabilities experienced by the patients with depressive disorders seeking treatment in a tertiary care hospital. METHODOLOGY: Fifty patients diagnosed to have depressive disorder as per ICD-10 were recruited by convenient sampling. To measure the stigma, the Discrimination and Stigma Scale -12 was applied. The severity of depression was determined by applying Hamilton Depression Rating Scale (HAMD). The disability was calculated by using WHO Disability Assessment Schedule 2.0. RESULTS: Fifty percentages of the participants reported unfair treatment and they experienced discrimination in at least one life domain. There was significant positive correlation between unfair treatment subscale of stigma and disability. Around one fourth of the participants reported to be treated unfairly by their own families. Seventy percent reported to have concealed their mental health problems, 54% have stopped themselves from having a close personal relationship and 32% didn't apply for work in anticipating discrimination. Experienced and anticipated discrimination were significantly associated with concealing the mental health problem. CONCLUSION: Stigma due to having depression acts as a barrier to vocational & social integration and functional recovery. Concealment of the diagnosis of depression is itself barrier for help seeking and to receiving appropriate treatment. Small sample size and adopting the purposive sampling method are the limitations of the study.

Hereditary Persistence of Alpha-Fetoprotein in Chronic Liver Disease-Confusing Genes!

Alpha-fetoprotein (AFP) is a glycoprotein secreted by the embryonic liver and is expressed in tumours with high mitotic index such as hepatocellular carcinoma (HCC) and germ cell tumours. Detection of elevated AFP is strongly associated with underlying HCC or occasionally germ cell tumour. Modest elevation of AFP can be observed in patients with chronic viral hepatitis particularly with active replication. Very rarely, incidental detection of raised AFP in a genetically susceptible individuals has been reported in the absence of the underlying malignant process. This condition is termed as hereditary persistence of AFP (HPAFP), a rare disorder with an autosomal dominant pattern of inheritance. HPAFP should be suspected in patients with high AFP in the absence of radiological evidence of HCC or germ cell tumour. The diagnosis is confirmed by the identification of AFP gene mutation. AFP gene is located in the long arm of chromosome 4. The most common single-nucleotide polymorphism in HPAFP is 119 G > A, rs587776861, interestingly reported only in six family clusters worldwide. Despite being described as a benign disorder, its implication in patients with underlying chronic liver disease needs further clarification. Here, we describe 3 patients in their forties with chronic liver disease and persistently elevated levels of AFP, where genetic studies confirmed HPAFP. None of our patients had HCC despite extensive investigations.

In Vitro Model to Investigate Communication between Dorsal Root Ganglion and Spinal Cord Glia.

Chronic discogenic back pain is associated with increased inflammatory cytokine levels that can influence the proximal peripheral nervous system, namely the dorsal root ganglion (DRG). However, transition to chronic pain is widely thought to involve glial activation in the spinal cord. In this study, an in vitro model was used to evaluate the communication between DRG and spinal cord glia. Primary neonatal rat DRG cells were treated with/without inflammatory cytokines (TNF-α, IL-1ß, and IL-6). The conditioned media were collected at two time points (12 and 24 h) and applied to spinal cord mixed glial culture (MGC) for 24 h. Adult bovine DRG and spinal cord cell cultures were also tested, as an alternative large animal model, and results were compared with the neonatal rat findings. Compared with untreated DRG-conditioned medium, the second cytokine-treated DRG-conditioned medium (following medium change, thus containing solely DRG-derived molecules) elevated CD11b expression and calcium signal in neonatal rat microglia and enhanced Iba1 expression in adult bovine microglia. Cytokine treatment induced a DRG-mediated microgliosis. The described in vitro model allows the use of cells from large species and may represent an alternative to animal pain models (3R principles).

Design, synthesis and application of spiro[4.5]cyclohexadienones via one-pot sequential p-hydroxybenzylation/oxidative dearomatization.

One-pot sequential p-hydroxybenzylation/oxidative dearomatization/spiroannulation has been designed for the efficient construction of tetrahydrofuran containing spiro-cyclohexadienones. This reaction proceeds through the p-hydroxybenzylation of 1,3-diketones with p-hydroxybenzyl alcohol via quinone methide formation followed by oxidative dearomatization/spiroannulation with suitable alcohols. The Friedel-Crafts alkylation of spiro[4.5]cyclohexadienones with indoles provided a broad array of highly diastereoselective C-3 alkylated spirocycles and cyclohepta[b]indoles depending upon the ring size of the fused cyclic ketones.