A novel variant in the tropomyosin 3 gene presenting as an adult-onset distal myopathy - a case report.

BACKGROUND: We report a patient with a novel c.737 C > T variant (p.Ser246Leu) of the TPM3 gene presenting with adult-onset distal myopathy. CASE PRESENTATION: A 35-year-old Chinese male patient presented with a history of progressive finger weakness. Physical examination revealed differential finger extension weakness, together with predominant finger abduction, elbow flexion, ankle dorsiflexion and toe extension weakness. Muscle MRI showed disproportionate fatty infiltration of the glutei, sartorius and extensor digitorum longus muscles without significant wasting. Muscle biopsy and ultrastructural examination showed a non-specific myopathic pattern without nemaline or cap inclusions. Genetic sequencing revealed a novel heterozygous p.Ser246Leu variant (c.737C>T) of the TPM3 gene which is predicted to be pathogenic. This variant is located in the area of the TPM3 gene where the protein product interacts with actin at position Asp25 of actin. Mutations of TPM3 in these loci have been shown to alter the sensitivity of thin filaments to the influx of calcium ions. CONCLUSION: This report further expands the phenotypic spectrum of myopathies associated with TPM3 mutations, as mutations in TPM3 had not previously been reported with adult-onset distal myopathy. We also discuss the interpretation of variants of unknown significance in patients with TPM3 mutations and summarise the typical muscle MRI findings of patients with TPM3 mutations.

Systemic lupus erythematosus: latest insight into etiopathogenesis.

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder of unknown etiology. Multifactorial interaction among various susceptible factors such as environmental, hormonal, and genetic factors makes it more heterogeneous and complex. Genetic and epigenetic modifications have been realized to regulate the immunobiology of lupus through environmental modifications such as diet and nutrition. Although these interactions may vary from population to population, the understanding of these risk factors can enhance the perception of the mechanistic basis of lupus etiology. To recognize the recent advances in lupus, an electronic search was conducted among search engines such as Google Scholar and PubMed, where we found about 30.4% publications of total studies related to genetics and epigenetics, 33.5% publications related to immunobiology and 34% related to environmental factors. These outcomes suggested that management of diet and lifestyle have a direct relationship with the severity of lupus that influence via modulating the complex interaction among genetics and immunobiology. The present review emphasizes the knowledge about the multifactorial interactions between various susceptible factors based on recent advances that will further update the understanding of mechanisms involved in disease pathoetiology. Knowledge of these mechanisms will further assist in the creation of novel diagnostic and therapeutic options.

Interplay of redox imbalance with matrix gelatinases in neutrophils and their association with disease severity in rheumatoid arthritis patients.

Rheumatoid arthritis (RA) etiopathogenesis still remains complex, but involvement of several immune cells is evident. Present study focusses on evaluation of polymorphonuclear neutrophils (PMNs) in RA patients and healthy controls. From generation of oxidative species, release of inflammatory cytokines and matrix-degrading proteases, PMNs possess the ability to mediate immunological responses. Intracellular and mitochondrial ROS in PMNs and other oxidative parameters including catalase, superoxide dismutase, glutathione peroxidase, reduced glutathione and lipid peroxidation were measured in PMNs and serum samples. Gene regulation studies involved in oxidative (Keap1 and Nrf2) and degradative pathways (MMP2 and MMP9) were done using DNA methylation analysis. Intracellular expression levels of Keap1, Nrf2, Dnmt1, MMP2, and MMP9 were analyzed using flowcytometry in patients and controls. Moreover, serum levels of pro-inflammatory cytokines IL-1ß, IL-6, and TNF-α were also measured. Comparative measurements amongst patients and controls were statistically analyzed, and correlations were made with disease severity scores (DAS28 ESR).

Variations in the concentration, source activity, and atmospheric processing of PM2.5-associated water-soluble ionic species over Jammu, India.

Concentrations, sources, and atmospheric processing of water-soluble ionic species associated with PM2.5 collected from 2015 to 2017 were studied in Jammu, an urban location in the North-Western Himalayan Region (NWHR). Being ecologically sensitive and sparsely studied for dynamics in PM2.5 and associated WSIS, the present study is important for developing robust air pollution abatement strategies for the air-shed of NWHR. Twenty-four hourly PM2.5 samples were collected on weekly basis at a receptor site and analyzed for WSIS using ion chromatography system. On annual basis, total sum of WSIS (ΣWSIS) contributed about 28.5% of PM2.5, where the contribution of sulfate-nitrate-ammonium, a proxy for secondary inorganic aerosols (SIA), was found to be 18.7% of PM2.5. The ΣWSIS and PM2.5 concentration showed a seasonal cycle with the maximum concentration during winters and the minimum in summers. Mass fraction of ΣWSIS in PM2.5 showed an anti-phase seasonal pattern indicating more source activity during summers. Season-wise, dominant WSIS constituting PM2.5 were NO3-, SO42-, NH4+, and K+ during winters; whereas summer was marked with dominant contributions from SO42-, NH4+, Ca2+, and K+. Seasonal variability exhibited among SIA constituents underscored the crucial role of air temperature and relative humidity regime. It was observed that nss-K+ + NH4+ were sufficient to neutralize most of the acidic species arising from precursor gases (NOx and SOx). Using principal component analysis, five major sources and processes, viz. (a) biomass burning activities, (b) secondary inorganic aerosol formation, (c) input from re-suspended dust, (d) transported dust, and (e) fertilizer residue, were identified for the emissions of PM2.5-associated WSIS over Jammu. In future studies, impacts of dry and/or wet deposition of aerosol-associated WSIS on the crop productivity in the region should be studied.

Apportionment of long-term trends in different sections of total ozone column over tropical region.

The additive time-series decomposition analysis was performed on National Oceanic and Atmospheric Administration Solar Backscatter Ultraviolet Instrument Merge satellite dataset version 8.6 for the period January 1979 to December 2019 with an objective to detect and apportion long-term trends present in the total ozone column (TOC) and the long-term trends exist in the respective ozone contents present in the vertical sub-columns constituting the TOC viz. upper, middle and lower stratosphere as well as near-surface for the tropical region. Linear regression analysis was performed on the deseasonalized monthly mean time series of TOC and corresponding ozone contents present in each partitioned layer for three different time spans, viz. 1979-2019 (complete time series), 1979-1998 (pre-inflection years), and 1999-2019 (post-inflection years), where 1998 was taken as inflection year. For the complete time-series, statistically significant negative trends were observed in TOC and corresponding ozone contents in the sub-columns over most of the tropical region. Expectedly, during pre-inflection years, strong negative trends were noted for TOC and ozone contents in the partitioned vertical layers. In contrast, during the post-inflection year time span, long-term trends in TOC were statistically insignificant over two-third of the tropical region, but one-third of the subtropical region exhibited negative trends in TOC. During this time span, positive trends were observed in the ozone contents present in the upper stratospheric sub-column. However, negative trends in ozone contents persisted in the middle and the lower stratosphere. It was interesting to note that the ozone contents confined in near-surface layer manifested strong negative trends during pre-inflection years and the same reversed into strong positive trends that in post-inflection span. The observed, contrasting, long-term trends and variability in the respective partitioned layer of the TOC confounded any clear sign of recovery in the TOC over the tropical region. The continuation of declining trends in the middle stratosphere and increasing trends in the near-surface layer of ozone contents is a matter of concern.

Altered redox regulation by Nrf2-Keap1 system in dendritic cells of systemic lupus erythematosus patients.

Systemic lupus erythematosus (SLE) is an autoimmune disorder associated with inflammation and multiple organ involvement. Individually, dendritic cells (DCs) and oxidative stress have been well discussed for their critical involvement in the pathogenesis of disease but the precise impact of oxidative stress on DCs in relation to SLE disease activity is yet to be scrutinized. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) pathway is the cellular mechanism to combat increased reactive oxygen species (ROS). The current study was framed in order to understand redox regulation in DCs along with an argument in context to disease activity. Here, 23 SLE patients along with 10 healthy controls were enrolled and disease activity was calculated as the recent change in SLEDAI score. We found the percentage of circulating plasmacytoid DCs (pDCs) was increased with an increase in disease activity. Altered DCs functionality along with disease activity was further supported with the differential concentration of Type I IFNs. The disease activity was positively associated with increased levels of ROS. A relevant reason for increased ROS was further explained with the decreased levels of transcription factor Nrf2. Hence, the present study suggests that SLE specific DCs displayed elevation in ROS and this outcome might be due to impaired free radical clearance by Nrf2. Correlation studies further established an association of disease activity with increased ROS, Type I IFNs levels and decreased activity of oxidative stress regulating enzymes.

Altered oxidative stress markers in relation to T cells, NK cells & killer immunoglobulin receptors that are associated with disease activity in SLE patients.

Systemic Lupus Erythematosus is an autoimmune disease with symptoms pervasive to all organ systems. It affects more females as compared to males (in the ratio 9:1). Oxidative stress plays a major role in the pathogenesis of SLE and other autoimmune diseases. In order to understand the relationship between cell specific oxidative stress and the severity of SLE, this research study involving the estimation of intracellular ROS accumulation in T and NK cell was conducted on SLE patients of North Indian Population. At the same time, to estimate anti-oxidant defense, Keap1 and Nrf2 levels were estimated in these cell types. The relationship between the expression of Killer immunoglobulin receptors i.e., KIR2DL4 & KIR3DL1 and oxidative stress was also evaluated as these receptors are imperative for the function and self-tolerance of NK cells.Oxidative stress was raised along with Keap1 and Nrf2 in T and NK cell subsets in SLE patients. The expression of KIR2DL4 was raised and that of KIR3DL1 was reduced in the NK cells of patients. The intensity of change in expression and its significance varied among the subsets. Nrf2 expression was raised in these species against oxidative stress as the antioxidant defense mechanism pertaining to Keap1-Nrf2 pathway, but the adequacy of response needs to be understood in further studies. The expression of KIR2DL4 and KIR3DL1 varied among the patient and healthy controls and the expression of the latter was found to have a significant positive relationship with plasma Glutathione(reduced) concentration.

Aerosol-associated n-alkanes over Dhauladhar region of North-Western Himalaya: seasonal variations in sources and processes.

Particulate n-alkanes are major constituents of organic aerosols (OA). Being primary in origin, chemically stable and thus long-lived, n-alkanes retains source signatures and along with diagnostic parameters have extensively been used to identify source(s) of OA. Systematic, yearlong study was carried out in the Dhauladhar region of North-Western Himalaya (NWH) to investigate dynamics in the composition and concentration of aerosol-associated n-alkanes. PM10 samples were collected for 24 h, once every week, at an urban mid-altitude location (Dharamshala) and a rural low-altitude site (Pohara). Particulate bound n-alkanes were identified and quantified using thermal desorption gas chromatography mass spectrometry (TD-GCMS). Annual mean concentrations of total n-alkanes (TNA) were 211 ± 99 ng m-3 and 223 ± 83 ng m-3, while mass fractions of TNA in PM10 were 4410 ± 1759 ppm and 3622 ± 1243 ppm at Dharamshala and Pohara, respectively. At both sites, a slight dominance of odd carbon-numbered n-alkanes was noticed. The TNA concentration and associated diagnostic parameters indicated unique source profiles at rural and urban locations. Significant seasonal variations were attributed to the contrasting land-use settings and meteorological variations. Influence of petrogenic contributions at urban location and predominance of biogenic contributions at rural location were observed in spring and autumn seasons. Preliminary insights on sources of organic aerosols are presented here. The diagnostic parameters allowed apportionment of biogenic and petrogenic sources. Biogenic emissions from agricultural practices viz. harvesting and threshing were predominant in the rural settings, while tourism-led anthropogenic contributions significantly add to petrogenic contributions in urban environment of the NWH region.

Deciphering multi-temporal scale dynamics in the concentration, sources and processes of near surface ozone over different climatic regions of India.

This study aims to investigate the factors influencing seasonal and long-term (2003-2021) changes in the near surface ozone (850 hpa) concentrations over different climatic sub-regions of India. Detailed comparison of daily (2019-2021) near surface ozone values of ERA-5 and CAAQMS (Continuous Ambient Air Quality Monitoring Stations) ground-based measurements revealed that ERA-5 is temporally in phase with CAAQMS measurements falling indifferent climatic sub-regions of India. ERA-5 near surface ozone shows statistically significant long-term (2003-2021) positive trends [2-4 percent per decade (ppd)] over most of the climatic sub-regions, over Indo-Gangetic Planes (IGPs), Southern and Central India trends are particularly strong. Trends were also estimated for each season separately, which were largely positive (2-6 ppd) over Central and Southern India in the Autumn and Winter seasons. Extensive climatological analysis reveals that the reversal of winds in the Indian monsoonal system plays a vital role in such trend patterns across the Indian subcontinent. South-westerly winds from June through September presumably bring ozone deficit air of marine origin, thus causing a dilution effect while the North-easterly winds during late Autumn and early Winters plausibly bring ozone-rich air from the stratospheric-tropospheric efflux dominated Himalayan region. It allows near surface ozone enhancement over Central and Southern India. Seasonal Principal component analysis (PCA) revealed that precursor gases (CH4 and NO2) and climatic variables especially specific humidity (SH) are the primary drivers of near surface ozone variability in the Winter season, while in Spring, climatic variables like boundary layer height (BLH), temperature (T) and SH have a significant role. Principal component regression (PCR) reveals a long-term increase in near surface ozone levels mostly dominated by precursor concentration over IGPs and Southern sub-regions. Whereas, BLH, T and SH significantly explain near surface ozone trends over North-eastern and Coastal India.

Short-term treatment with cholestyramine increases long-acting anticoagulant rodenticide clearance from rabbits without affecting plasma vitamin K1 levels or blood coagulation.

Administration of high-dose vitamin K1 (VK1) overcomes coagulopathy and bleeding elicited by acute poisoning with long-acting anticoagulant rodenticides (LAARs). However, long-term (months) treatment is required due to long LAAR biological half-lives that may lead to poor compliance and recurrent coagulopathy. The half-lives of LAARs are extended by slow metabolism, and similar to warfarin, are thought to undergo enterohepatic recirculation. We now show that treatment with the bile acid sequestrant cholestyramine (CSA) administered concomitantly with VK1 decreases plasma LAAR levels and increases LAAR fecal excretion. Daily CSA treatment for 14 days did not reduce plasma VK1 levels, or increase prothrombin time. Collectively, these data show that CSA accelerates LAAR clearance from rabbits without adverse effects on VK1 anticoagulation, and could provide an additional therapeutic option for treatment of LAAR poisoning.

Bisphenol-A (BPA) Impairs Hippocampal Neurogenesis via Inhibiting Regulation of the Ubiquitin Proteasomal System.

The ubiquitin-proteasome system (UPS) controls protein homeostasis to maintain cell functionality and survival. Neurogenesis relies on proteasome function, and a defective proteasome system during brain development leads to neurological disorders. An endocrine-disrupting xenoestrogen bisphenol-A (BPA) used in plastic products adversely affects human health and causes neurotoxicity. Previously, we reported that BPA reduces neural stem cells (NSCs) proliferation and differentiation, impairs myelination and mitochondrial protein import, and causes excessive mitochondrial fragmentation leading to cognitive impairments in rats. Herein, we examined the effect(s) of prenatal BPA exposure on UPS functions during NSCs proliferation and differentiation in the hippocampus. Rats were orally treated with 40 µg/kg body weight BPA during day 6 gestation to day 21 postnatal. BPA significantly reduced proteasome activity in a cellular extract of NSCs. Immunocytochemistry exhibited a significant reduction of 20S proteasome/Nestin+ and PSMB5/Nestin+ cells in NSCs culture. BPA decreased 20S/Tuj1+ and PSMB5/Tuj1+ cells, indicating disrupted UPS during neuronal differentiation. BPA reduced the expression of UPS genes, 20S, and PSMB5 protein levels and proteasome activity in the hippocampus. It significantly reduced overall protein synthesis by the loss of Nissl substances in the hippocampus. Pharmacological activation of UPS by a bioactive triterpenoid 18α-glycyrrhetinic acid (18α GA) caused increased proteasome activities, significantly increased neurosphere size and number, and enhanced NSCs proliferation in BPA exposed culture, while proteasome inhibition by MG132 further aggravates BPA-mediated effects. In silico studies demonstrated that BPA strongly binds to catalytic sites of UPS genes (PSMB5, TRIM11, Parkin, and PSMD4) which may result in UPS inactivation. These results suggest that BPA significantly reduces NSCs proliferation by impairing UPS, and UPS activation by 18α GA could suppress BPA-mediated neurotoxicity and exerts neuroprotection.

Unique Clinical, Radiological and Histopathological Characteristics of a Southeast Asian Cohort of Patients with Limb-Girdle Muscular Dystrophy 2G/LGMD-R7-Telethonin-Related.

AIM: We describe a cohort of five patients with limb-girdle muscular dystrophy (LGMD) 2G/LGMD-R7 in a South-east Asian cohort. BACKGROUND: LGMD2G/LGMD-R7-telethonin-related is caused by mutations in the TCAP gene that encodes for telethonin. METHODS: We identified consecutive patients with LGMD2G/LGMD-R7-telethonin-related, diagnosed at the National Neuroscience Institute (NNI) and National University Hospital (NUH) between January 2000 and June 2021. RESULTS: At onset, three patients presented with proximal lower limb weakness, one patient presented with Achilles tendon contractures, and one patient presented with delayed gross motor milestones. At last follow up, three patients had a limb girdle pattern of muscle weakness and two had a facioscapular humeral pattern of weakness. Whole body muscle MRI performed for one patient with a facioscapular-humeral pattern of weakness showed a pattern of muscle atrophy similar to facioscapular-humeral dystrophy. One patient had histological features consistent with myofibrillar myopathy; electron microscopy confirmed the disruption of myofibrillar architecture. One patients also had reduced staining to telethonin antibody on immunohistochemistry. CONCLUSION: We report the unique clinical and histological features of a Southeast Asian cohort of five patients with LGMD2G/LGMD-R7-telethonin-related muscular dystrophy and further expand its clinical and histopathological spectrum.

Bisphenol-A Mediated Impaired DRP1-GFER Axis and Cognition Restored by PGC-1α Upregulation Through Nicotinamide in the Rat Brain Hippocampus.

The regulatory network of mitochondrial biogenesis and dynamics is vital for mitochondrial functions and cellular homeostasis. Any impairment in the mitochondrial network leads to neurodegenerative disorders. Our earlier studies suggest that environmental toxicant Bisphenol-A (BPA) exposure reduces neurogenesis by abnormal mitochondrial dynamics and mitochondrial biogenesis through impairment of mitochondrial fission factor dynamin-related protein (DRP1) and mitochondrial import protein GFER, which leads to demyelination, neurodegeneration, and cognitive deficits in the rats. In the present study, we found that chronic BPA exposure reduces PGC-1α levels (master regulator of mitochondrial biogenesis), alters mitochondrial localization of DRP1 and GFER, and reduces the number of PGC-1α/NeuN+ and PGC-1α/ß-tubulin+ neurons in the rat hippocampus, suggesting reduced PGC-1α-mediated neurogenesis. Nicotinamide significantly increased PGC-1α protein levels, PGC-1α/NeuN+ co-labeled cells in BPA-treated rat hippocampus and PGC-1α/ß-tubulin+ co-labeled cells in neuron culture derived from hippocampal neural stem cells. Interestingly, PGC-1α upregulation by nicotinamide also resulted in increased GFER levels and restored mitochondrial localization of GFER (increased GFER/TOMM20 co-labeled cells) in vitro and in vivo following BPA treatment. Nicotinamide also reduced DRP1 levels and prevented DRP1 mitochondrial localization in BPA-treated neuronal cultures and hippocampus, suggesting reduced mitochondrial fission. This resulted in reduced cytochrome c levels in neuronal culture and reduced hippocampal neurodegeneration (reduced caspase-3/NeuN+ co-labeled neurons) following nicotinamide treatment in BPA-treated group. Consequently, activation of PGC-1α by nicotinamide restored BPA-mediated cognitive deficits in rats. Results suggest that the treatment of nicotinamide has therapeutic potential and rescues BPA-mediated neuronal death and cognitive deficits by upregulating the PGC-1α and GFER-DRP1 link, thus balancing mitochondrial homeostasis.

Imaging update in arthroplasty.

Imaging of metal implants has historically been difficult, regardless of the applied modality. The number of primary arthroplasties is increasing over the years. With it, we expect the number of symptomatic complications to increase as well. Acquiring accurate imaging for diagnosis and treatment planning for these cases is of paramount importance. Significant advancements have been made to reduce artifacts, leading to better imaging representation of arthroplasty. This review article would give a background on the current ways of imaging arthroplasty and metal implants, covering recent advances in imaging techniques.

Multifocal retroperitoneal and pelvic PEComas mimicking liposarcoma: A case report and review of literature.

Perivascular epithelioid cell neoplasms (PEComa) constitute a rare, but increasingly recognized family of seemingly distinct mesenchymal tumors which can occur in any part of the body. Due to their rarity, radiological descriptions of PEComas in the current literature are few and non-specific, making diagnosis difficult, though some common imaging features have been reported. We present an unusual case of multifocal retroperitoneal and pelvic PEComas, mimicking liposarcoma, subsequently treated with open surgery.

Nanomedicine against Alzheimer's and Parkinson's Disease.

Alzheimer's and Parkinson's are the two most rampant neurodegenerative disorders worldwide. Existing treatments have a limited effect on the pathophysiology but are unable to fully arrest the progression of the disease. This is due to the inability of these therapeutic molecules to efficiently cross the blood-brain barrier. We discuss how nanotechnology has enabled researchers to develop novel and efficient nano-therapeutics against these diseases. The development of nanotized drug delivery systems has permitted an efficient, site-targeted, and controlled release of drugs in the brain, thereby presenting a revolutionary therapeutic approach. Nanoparticles are also being thoroughly studied and exploited for their role in the efficient and precise diagnosis of neurodegenerative conditions. We summarize the role of different nano-carriers and RNAi-conjugated nanoparticle-based therapeutics for their efficacy in pre-clinical studies. We also discuss the challenges underlying the use of nanomedicine with a focus on their route of administration, concentration, metabolism, and any toxic effects for successful therapeutics in these diseases.

Particulate bound polycyclic aromatic hydrocarbons over Dhauladhar region of the north-western Himalayas.

A systematic yearlong study was carried out in Dhauladhar region of the North-Western Himalayas to investigate dynamics in the composition and concentration of particulate bound polycyclic aromatic hydrocarbons (PAHs) and their source(s) activity. PM10 samples were collected for 24 h, once every week during January 2015-January 2016, at an urban mid-altitude site (Dharamshala) and a rural low-altitude site (Pohara). PAHs were identified and quantified using high performance liquid chromatography coupled with UV-detector. Seasonal average concentration of total PAHs followed a pattern: Summer > Winter > Autumn > Spring in the region. Seasonal average values of molecular diagnostic ratios indicated significant contribution from non-traffic (biomass burning and coal combustion) sources also during winter and spring season, whereas, traffic emissions (gasoline and diesel) were the dominant source at both the locations throughout the year in the region. The Principal Component Analysis deciphered a) emissions from gasoline driven vehicles b) diesel engine exhaust emissions c) biomass/wood burning source d) coal combustion and e) waste incineration and burning of oil/tar as major sources of PAHs in the region. Annual mean values of total Benzo(a)Pyrene Equivalent were much higher than 1 ng.m-3 over both the locations indicating higher lung cancer risk to the people living in this part of the Himalayas.

Cypermethrin Impairs Hippocampal Neurogenesis and Cognitive Functions by Altering Neural Fate Decisions in the Rat Brain.

Neurogenesis is a developmental process that involves fine-tuned coordination between self-renewal, proliferation, and differentiation of neural stem cells (NSCs) into neurons. However, early-life assault with environmental toxicants interferes with the regular function of genes, proteins, and other molecules that build brain architecture resulting in attenuated neurogenesis. Cypermethrin is a class II synthetic pyrethroid pesticide extensively used in agriculture, veterinary, and residential applications due to its low mammalian toxicity, high bio-efficacy, and enhanced stability. Despite reports on cypermethrin-mediated behavioral and biochemical alterations, till now, no study implicates whether cypermethrin exposure has any effect on neurogenesis. Therefore, the present study was undertaken to comprehend the effects of cypermethrin treatment on embryonic and adult neurogenesis. We found that cypermethrin exposure led to a considerable decrease in the BrdU/Sox-2+, BrdU/Dcx+, and BrdU/NeuN+ co-labeled cells indicating that cypermethrin treatment decreases NSC proliferation and generation of mature and functional neurons. On the contrary, the generation of BrdU/S100ß+ glial cells was increased resulting in neurogliogenesis imbalance in the hippocampus. Further, cypermethrin treatment also led to an increased number of BrdU/cleaved caspase-3+ and Fluoro-Jade B+ cells suggesting an induction of apoptosis in NSCs and increased degeneration of neurons in the hippocampus. Overall, these results explicate that cypermethrin exposure not only reduces the NSC pool but also disturbs the neuron-astrocyte ratio and potentiates neurodegeneration in the hippocampus, leading to cognitive dysfunctions in rats.

Morphological Parameters of the Thoracic Pedicle in an Asian Population: A Magnetic Resonance Imaging-Based Study of 3324 Pedicles.

STUDY DESIGN: A cross-sectional magnetic resonance imaging (MRI)-based anatomical study. OBJECTIVES: Instrumentation of the thoracic spine may be challenging due to the unique pedicle morphology and the proximity of vital structures. As prior morphological studies have mostly been done in Caucasians, our study aims to determine the optimal pedicle screw size for transpedicular fixation in an Asian population. METHODS: A retrospective analysis of 400 patients who had undergone MRI of the thoracic spine was performed. A total of 3324 pedicles were included. Pedicle morphology was graded qualitatively based on the size of its cancellous channel, and quantitatively with the following parameters: pedicle transverse diameter, pedicle screw path length, and pedicle angle. Subgroup analysis based on gender was performed. RESULTS: Mean pedicle transverse diameter was the narrowest at the T4 (2.9 ± 1 mm) and T5 (3.1 ± 1.1 mm) level. The mean pedicle screw path length progressively increased from T1 (34 ± 4.6 mm) to T12 (47 ± 4.6 mm). The mean pedicle angle was the largest at T1 (34° ± 7.9°) and decreased caudally, to 9.4° ± 3.8° at the T12 level. Females had significantly lower mean pedicle diameter and screw path length than males at every vertebral level; however, they had a larger pedicle angle at T8 to T10. The most common size of the pedicle cancellous channel was more than 4 mm. CONCLUSION: Morphological differences in the Asian pedicle suggest that caution needs to be taken during thoracic spine instrumentation, particularly in Asian females who have significantly smaller pedicles. In such cases, the use of alternative techniques or intraoperative navigation may be useful.

Bisphenol-A inhibits mitochondrial biogenesis via impairment of GFER mediated mitochondrial protein import in the rat brain hippocampus.

Mitochondrial biogenesis relies on different protein import machinery, as mitochondrial proteins are imported from the cytosol. The mitochondrial intermembrane space assembly (MIA) pathway consists of GFER/ALR and CHCHD4/Mia40, responsible for importing proteins and their oxidative folding inside the mitochondria. The MIA pathway plays an essential role in complex IV (COX IV) biogenesis via importing copper chaperone COX17, associated with the respiratory chain. BPA, an environmental toxicant, found in consumable plastics, causes neurotoxicity via impairment in mitochondrial dynamics, neurogenesis, and cognitive functions. We studied the levels of key regulatory proteins of mitochondrial import pathways and mitochondrial biogenesis after BPA exposure in the rat hippocampus. BPA caused a significant reduction in the levels of mitochondrial biogenesis proteins (PGC1α, and TFAM) and mitochondrial import protein (GFER). Immunohistochemical analysis showed reduced co-localization of NeuN with GFER, PGC-1α, and TFAM suggesting impaired mitochondrial biogenesis and protein import. BPA exposure resulted in damaged mitochondria with distorted cristae in neurons and caused a significant reduction in GFER localization inside IMS as depicted by immunogold electron microscopy. The reduced levels of GFER resulted in defective COX17 import. The translocation of cytochrome c into the cytosol and increased cleaved caspase-3 levels triggered apoptosis due to BPA toxicity. Overall, our study implicates GFER as a potential target for impaired mitochondrial protein machinery, biogenesis, and apoptosis against BPA neurotoxicity in the rat hippocampus.