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The only place within the East African Rift System where seafloor spreading is being manifested along with new crust being formed is at the Afar triple junction, a seismically active area defined by latitude 9°N to 14°N and longitude 43E° to 49E°. Previous seafloor spreading studies have primarily concentrated on the Aden-Owen Carlsberg Ridge (AOCR). The AOCR defines the boundary between the Eastern Gulf of Aden and the Western Gulf of Aden. Although the previous studies have provided insight into seafloor spreading rates, the timing of seafloor spreading, particularly in the Western Gulf of Aden (encompassing the study area) remains unclear. This study seeks to estimate the rates of seafloor spreading by reviewing data from previous studies and integrating geophysical (paleomagnetic anomalies), geological data and systematically estimating seafloor spreading rates and determining the timing of the initial seafloor spreading in the Afar region using advanced geo-software (Gplates). The results from our modeling show that the initial seafloor spreading began approximately 16 million years ago, with spreading rates varying from 12.29 to 20.12 mm/yr (average = 15.75 mm/yr). The average seafloor spreading rates in the study area are nearly 1.5-fold lower than the average seafloor spreading in the Eastern Gulf of Aden (23 mm/yr). The predominant seafloor spreading in the study area is East-West. Further, the angular rotation of the Somalian plate against the Arabian plate has been estimated to be 0.5353°/Ma. The study enhances understanding of plate tectonics, seismic hazards, volcanism and hydrocarbon systems in the Afar region., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Duke Nyarera Nyangena reports financial support was provided by The KFW bank. Athanas Macheyeki reports a relationship with The University of Dodoma that includes: non-financial support. Zahirovic Sabin has patent issued to Duke Nyarera Nyangena., (© 2024 The Authors. Published by Elsevier Ltd.)

Mucuna pruriens (MP) which is commonly known as "Velvet Bean" is an underutilized legume traditionally used to treat Parkinson's disease and male fertility issues. Extracts of MP have also been identified for their antidiabetic, antioxidant, and antineoplastic effects. Commonly, the antioxidant and anticancer properties of a drug are linked together as antioxidants scavenge free radicals and prevent the cellular DNA damage which could result in cancer development. In this investigation, comparative assessment of the anticancer and antioxidant potentials of methanolic seed extracts from two common varieties of MP, Mucuna pruriens var. pruriens (MPP) and Mucuna pruriens var. utilis (MPU) against human colorectal cancer adenocarcinoma cells COLO-205, was carried out. The highest antioxidant potential was recorded with MPP with an IC 50 of 45.71 μg/ml. The in vitro antiproliferative effects of MPP and MPU on COLO-205 showed an IC 50 of 131.1 μg/ml and 246.9 μg/ml respectively. Our results revealed intervention of the MPP and MPU extracts in growth kinetics of the COLO-205 cells in concomitance with apoptosis induction up to 8.73- and 5.58-folds respectively. The AO/EtBr dual staining and the flow cytometry results also confirmed the better apoptotic efficacy of MPP over MPU. MPP at a concentration of 160 μg/ml exhibited highest apoptosis and cell cycle arrest. Furthermore, effect of the seed extracts on p53 expression was investigated by quantitative RT-PCR and a maximum upregulation of 1.12-fold was recorded with MPP., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Direct modulation of cardiac myosin function has emerged as a therapeutic target for both heart disease and heart failure. However, the development of myosin-based therapeutics has been hampered by the lack of targeted in vitro screening assays. In this study we use Artificial Intelligence-based virtual high throughput screening (vHTS) to identify novel small molecule effectors of human β-cardiac myosin. We test the top scoring compounds from vHTS in biochemical counter-screens and identify a novel chemical scaffold called 'F10' as a cardiac-specific low-micromolar myosin inhibitor. Biochemical and biophysical characterization in both isolated proteins and muscle fibers show that F10 stabilizes both the biochemical (i.e. super-relaxed state) and structural (i.e. interacting heads motif) OFF state of cardiac myosin, and reduces force and left ventricular pressure development in isolated myofilaments and Langendorff-perfused hearts, respectively. F10 is a tunable scaffold for the further development of a novel class of myosin modulators., (© 2023. The Author(s).)

The effects of a diesel engine combustion chamber geometries (PB1, PB2, PB3) and fuel injection pressure (FIP) (500, 750, and 1000 bar) with ternary fuel are discussed in this paper. It is observed that at maximum load as the FIP increased, the PB3 surpasses the PB1 and PB2 in brake thermal efficiency (4.86%) and hydrocarbon (7.2% decrease). However, a minor reduction in NO x (3%) is seen with increased FIP in the PB2. The NHRR (net heat release rate), peak pressure (in-cylinder), and ROPR (rate of pressure increases) all considerably increase with an enhancement in FIP in the case of PB3 by 2.96%, 3.86%, and 1.98%, respectively. It is discovered that altering the fuel injection pressure and piston shape concurrently offers a viable substitute for raising engine output and reducing emissions., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The large unmet demand for new heart failure therapeutics is widely acknowledged. Over the last decades the contractile myofilaments themselves have emerged as an attractive target for the development of new therapeutics for both systolic and diastolic heart failure. However, the clinical use of myofilament-directed drugs has been limited, and further progress has been hampered by incomplete understanding of myofilament function on the molecular level and screening technologies for small molecules that accurately reproduce this function in vitro. In this study we have designed, validated and characterized new high throughput screening platforms for small molecule effectors targeting the interactions between the troponin C and troponin I subunits of the cardiac troponin complex. Fluorescence polarization-based assays were used to screen commercially available compound libraries, and hits were validated using secondary screens and orthogonal assays. Hit compound-troponin interactions were characterized using isothermal titration calorimetry and NMR spectroscopy. We identified NS5806 as novel calcium sensitizer that stabilizes active troponin. In good agreement, NS5806 greatly increased the calcium sensitivity and maximal isometric force of demembranated human donor myocardium. Our results suggest that sarcomeric protein-directed screening platforms are suitable for the development of compounds that modulate cardiac myofilament function., (© 2023. The Author(s).)

In healthy hearts, myofilaments become more sensitive to Ca2+ as the myocardium is stretched. This effect is known as length-dependent activation and is an important cellular-level component of the Frank-Starling mechanism. Few studies have measured length-dependent activation in the myocardium from failing human hearts. We investigated whether ischemic and non-ischemic heart failure results in different length-dependent activation responses at physiological temperature (37°C). Myocardial strips from the left ventricular free wall were chemically permeabilized and Ca2+-activated at sarcomere lengths (SLs) of 1.9 and 2.3 µm. Data were acquired from 12 hearts that were explanted from patients receiving cardiac transplants; 6 had ischemic heart failure and 6 had non-ischemic heart failure. Another 6 hearts were obtained from organ donors. Maximal Ca2+-activated force increased at longer SL for all groups. Ca2+ sensitivity increased with SL in samples from donors (P < 0.001) and patients with ischemic heart failure (P = 0.003) but did not change with SL in samples from patients with non-ischemic heart failure. Compared with donors, troponin I phosphorylation decreased in ischemic samples and even more so in non-ischemic samples; cardiac myosin binding protein-C (cMyBP-C) phosphorylation also decreased with heart failure. These findings support the idea that troponin I and cMyBP-C phosphorylation promote length-dependent activation and show that length-dependent activation of contraction is blunted, yet extant, in the myocardium from patients with ischemic heart failure and further reduced in the myocardium from patients with non-ischemic heart failure. Patients who have a non-ischemic disease may exhibit a diminished contractile response to increased ventricular filling., (© 2023 Tanner et al.)

Background: Doctoral level board-certified clinical chemists play an invaluable role in many facets of laboratory medicine and healthcare. However, information concerning their total compensation is sparse., Content: A confidential self-reported compensation survey was conducted by the American Association for Clinical Chemistry's Society for Young Clinical Laboratorians (AACC SYCL) Core Committee from April 1 to April 17, 2018. Respondents provided information on geographic location, employment sector, gender, and years of experience to account for the influence of these variables on compensation. There were 199 respondents in total from the United States and Canada, however, only respondents employed in the United States with an earned doctoral degree and certification by the American Board of Clinical Chemistry (n = 133), were included in the full analysis. In comparison to compensation reported in AACC SYCL salary surveys conducted in 2010 and 2013, early career median salaries are trending upwards after correction for inflation., Summary: This survey is the first to collect the gender of respondents, and identify a pay gap for some geographic groups. However, this gap could be due in part to a difference in the years of experience, since males were highly represented in the group with >20 years of experience (25 out of 35, 71%). Future studies on compensation trends within clinical chemistry that do not rely on self-report are needed to ensure accuracy and completeness of the dataset., (© American Association for Clinical Chemistry 2020. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Competing Interests: There are no conflicts of interest.

Anaesthesia for pregnant patients presenting for non-obstetric surgery needs a thorough understanding of the physiological changes and altered pharmacokinetics of pregnancy. Considering the effects of surgery and anaesthesia on the foetus, only essential and emergency surgeries are performed during pregnancy. Surgical procedures in second trimester have the advantage of better foetal outcome. The primary concerns of maternal and foetal safety are achieved by a focused multidisciplinary team-based approach with respect to the surgical condition. Meticulous attention to preoperative patient counselling, airway management, haemodynamic stability, and thromboprophylaxis are the key factors in anaesthetic management. Choice of anaesthesia or anaesthetic drugs has minimal impact on the foetus provided utero-placental perfusion and uterine relaxation are maintained. Foetal monitoring when feasible and when done by a trained person enables to diagnose and treat the factors responsible for foetal heart rate variability. Anaesthetic technique needs to be modified according to the type of surgery., Competing Interests: There are no conflicts of interest.

The increasing use of nanoparticles and their occurrence in the environment has made it imperative to elucidate their impact on the environment. Although several studies have advanced the authors' understanding of nanoparticle-plant interactions, their knowledge of the exposure of plants to nanoparticles and their effects on edible crop plants remain meager and is often paradoxical. The aim of this study was to increase their knowledge on the effect of zinc oxide (ZnO) nanoparticles on eggplant seed germination and seedling growth. ZnO nanoparticles had a negative effect on the growth of eggplant in plant tissue-culture conditions, as the growth of seedlings decreased with the increase in the concentration of ZnO nanoparticles. In contrast, ZnO nanoparticles enhanced eggplant growth under greenhouse conditions. The accumulation of ZnO nanoparticles in various parts of eggplant was observed through scanning electron microscopy of both plant tissue-culture and greenhouse-raised eggplant seedlings. To the best of their knowledge, this is the first study to report on ZnO nanoparticle accumulation in eggplant and its effect on seed germination and seedling growth.

Failure of spinal anaesthesia for caesarean section may have deleterious consequences for the mother as well as the newborn baby. In this article, we discuss the mechanisms of failure of spinal anaesthesia as well as the approach to a failed block. We performed a literature search in Google Scholar, PubMed, and Cochrane databases for original and review articles concerning failed spinal anaesthesia and caesarean section. Strategies for a failed spinal anaesthetic include manoeuvers to salvage the block, repeating the block, epidural anaesthesia or a combined spinal-epidural (CSE) technique, or resorting to general anaesthesia. Factors influencing the choice of these alternative options are discussed. A "failed spinal algorithm" can guide the anaesthesiologist and help reduce morbidity and mortality., Competing Interests: There are no conflicts of interest.

Background: Obesity is one of the major causes for development of T2DM. Metabolic surgery has been proved to be a successful and cost-effective treatment modality for managing the patients with obesity and T2DM. Many scoring systems and models have been described in literature to predict the outcome of T2DM after metabolic surgery. The aim of this study is to compare the efficacy of Diarem, DRS, and ABCD score in predicting the T2DM remission., Methods: A total number of 102 diabetic patients, who underwent LMGB/LOAGB, were selected for this study. A retrospective analysis of the three scoring systems when applied to these patients and their predictive abilities were analyzed., Results: At 1 year after surgery, 72 (70.59%) patients achieved remission of T2DM. Though the pairwise comparisons between AUC on ROC analysis of ABCD, Diarem, and DRS scores does not show statistically significant difference between them, Diarem score has the maximum relative area under ROC curves. By multivariate analysis, it was found that factors significantly associated with T2DM remission were duration of T2DM, C-peptide, and Pre-Op HbA1c., Conclusions: Among the three scoring systems, though DiaRem score has the best sensitivity and specificity and maximum AUC, no statistically significant difference was found in their diabetes remission predicting abilities. A shorter duration of T2DM, a lower HbA1C, and higher levels of C-peptide were significantly associated with a higher chance of T2DM remission.

Objectives: Laparoscopic sleeve gastrectomy (LSG) is one of the most popular bariatric procedure. One anastomosis gastric bypass (OAGB) is rapidly emerging as a safe and effective metabolic procedure. This study aims at comparing the 1-year follow-up results of OAGB and LSG in terms of excess weight loss, complications, resolution of comorbidities, and quality of life., Methods: A prospective randomized study of results between 100 LSG and 101 OAGB patients was done from 2012 to 2015. The results were compared regarding operative outcomes, percentage of excess weight loss, complications, resolution of comorbidities, and quality of life (BAROS score)., Results: The mean BMI for the OAGB and LSG group was 44.31 and 43.75 kg/m 2 , respectively. Percentage of excess weight loss (%EWL) for OAGB vs LSG was 66.87 ± 10.87 vs 63.97 ± 13.24 at 1 year (p > 0.05), respectively. Diabetes remission was 83.63 % in OAGB patients and 76.58 % in LSG patients. Remission of hypertension is 64.15 % in OAGB patients and 66.07 % in LSG patients. Bariatric Analysis Reporting and Outcome System (BAROS) was 3.71 in LSG and 3.96 in OAGB., Conclusions: In our study, there was no significant difference between LSG and OAGB in outcome at 1 year follow-up in % excess weight loss, remission of HTN, and quality of life. OAGB has marginally better outcome in T2 DM remission. However, a longer follow-up is required to establish a correct comparative result.

Objective: Cognitive impairment (CI) and major depressive disorder (MDD) remain prevalent in treated HIV-1 disease; however, the pathogenesis remains elusive. A possible contributing mechanism is immune-mediated degradation of tryptophan (TRP) via the kynurenine (KYN) pathway, resulting in decreased production of serotonin and accumulation of TRP degradation products. We explored the association of these biochemical pathways and their relationship with CI and MDD in HIV-positive (HIV+) individuals., Methods: In a cross-sectional analysis, concentrations of neopterin (NEO), tumor necrosis factor-alpha, TRP, KYN, KYN/TRP ratio, phenylalanine (PHE), tyrosine (TYR), PHE/TYR ratio, and nitrite were assessed in the cerebrospinal fluid (CSF) and plasma of HIV+ ( n = 91) and HIV-negative (HIV-) individuals ( n = 66). CI and MDD were assessed via a comprehensive neuropsychological test battery. A Global Deficit Score ≥0.5 was defined as CI. Nonparametric statistical analyses included Kruskal-Wallis and Mann-Whitney U tests, and multivariate logistic regression., Results: Following Bonferroni correction, NEO concentrations were found to be greater in CSF and TRP concentration was found to be lower in the plasma of HIV+ versus HIV- individuals, including a subgroup of aviremic (defined as HIV-1 RNA <50 cps/mL) HIV+ participants receiving antiretroviral therapy ( n = 44). There was a nonsignificant trend toward higher KYN/TRP ratios in plasma in the HIV+ group ( P = 0.027; Bonferroni corrected α = 0.0027). In a logistic regression model, lower KYN/TRP ratios in plasma were associated with CI and MDD in the overall HIV+ group ( P = 0.038 and P = 0.063, respectively) and the aviremic subgroup ( P = 0.066 and P = 0.027, respectively), though this observation was not statistically significant following Bonferroni correction (Bonferroni corrected α = 0.0031)., Conclusions: We observed a trend toward lower KYN/TRP ratios in aviremic HIV+ patients with CI and MDD., Competing Interests: MRK is employed by, and owns shares in, ViiV Healthcare Ltd. AW discloses honoraria, research grants, or consultancy fees from, or a role as an investigator in clinical trials sponsored by, Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Janssen-Cilag, Roche, Pfizer and ViiV Healthcare, all outside the work presented here. SLL discloses lecture honorarium, unpaid consultancy and a research grant paid to his institution from Gilead Sciences; consultancy and a research grant paid to his institution from ViiV Healthcare; consultancy for Merck & Co. Inc.; and lecture honorarium from Janssen, all unrelated to the work presented here. Other authors disclose no potential conflicts of interest.

This manuscript reports a new approach for the synthesis of one dimensional gold nanostructure (AuNs) and its application in the development of cholesterol biosensor. Au nanostructures have been synthesized by exploiting β-diphenylalanine (β-FF) as an sacrificial template, whereas the Au nanoparticles (AuNPs) were synthesized by ultrasound irradiation. X-ray diffractometer (XRD), scanning electron microscope (SEM) and energy dispersive analysis of X-rays (EDAX) have been employed to characterize the morphology and composition of the prepared samples. With the aim to develop a highly sensitive cholesterol biosensor, cholesterol oxidase (ChOx) was immobilized on AuNs which were appended on the graphite (Gr) electrode via chemisorption onto thiol-functionalized graphene oxide (GO-SH). This Gr/GO-SH/AuNs/ChOx biosensor has been characterized using cyclic voltammetry (CV), electrochemical impedance spectroscopy and chronoamperometry. CV results indicated a direct electron transfer between the enzyme and the electrode surface. A new potentiostat intermitant titration technique (PITT) has been studied to determine the diffusion coefficient and maxima potential value. The proposed biosensor showed rapid response, high sensitivity, wide linear range and low detection limit. Furthermore, our AuNs modified electrode showed excellent selectivity, repeatability, reproducibility and long term stability. The proposed electrode has also been used successfully to determine cholesterol in serum samples., (Copyright © 2016 Elsevier B.V. All rights reserved.)

In a patient with tetralogy of Fallot (TOF) and pulmonary atresia, treating the cardiac problem or the associated congenital illness is always a challenge. We describe the challenges and successful initial management of bilateral cataract to prevent visual loss in an infant with TOF with pulmonary atresia.

In this paper, a simple and innovative electrochemical hydrogen peroxide biosensor has been proposed using catalase (CATpp) derived from Pichia pastoris as bioelectrocatalyst. The model biocomponent was immobilized on gold nanoparticle nanotubes (AuNPNTs) and polythiophene composite using 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide and N-hydroxysuccinimide (EDC-NHS) coupling reagent. In this present work, we have successfully synthesized gold nanoparticles (AuNPs) by ultrasonic irradiation. The tubular gold nanostructures containing coalesced AuNPs were obtained by sacrificial template synthesis. The assembly of AuNPNTs onto the graphite (Gr) electrode was achieved via S-Au chemisorption. The latter was pre-coated with electropolymerized thiophene (PTh) to enable S groups to bind AuNPNTs. The combination of AuNPNTs-PTh, i.e., an inorganic-organic hybrid, provides a stable enzyme immobilization platform. The physical morphology of the fabricated biosensor Gr/PTh/AuNPNTs/EDC-NHS/CATpp was investigated using scanning electron microscopy and energy-dispersive microscopy. The analytical performance of the bioelectrode was examined using cyclic voltammetry, differential pulse voltammetry and chronoamperometry. Operational parameters such as working potential, pH, and thermal stability of the modified electrode were examined. The beneficial analytical characteristics of the proposed electrode were demonstrated. Our results indicate that the Gr/PTh/AuNPNTs/EDC-NHS/CATpp bioelectrode exhibits a wide linear range from 0.05 mM to 18.5 mM of H2O2, fast response time of 7 s, excellent sensitivity of 26.2 mA mM(-1) cm(-2), good detection limit of 0.12 μM and good Michaelis-Menten constant of 1.4 mM. In addition, the bioelectrode displayed good repeatability, high stability and acceptable reproducibility, which can be attributed to the AuNPNTs-PTh composite that provides a biocompatible micro-environment.

Movements in animals arise through concerted action of neurons and skeletal muscle. General anaesthetics prevent movement and cause loss of consciousness by blocking neural function. Anaesthetics of the amino amide-class are thought to act by blockade of voltage-gated sodium channels. In fish, the commonly used anaesthetic tricaine methanesulphonate, also known as 3-aminobenzoic acid ethyl ester, metacaine or MS-222, causes loss of consciousness. However, its role in blocking action potentials in distinct excitable cells is unclear, raising the possibility that tricaine could act as a neuromuscular blocking agent directly causing paralysis. Here we use evoked electrical stimulation to show that tricaine efficiently blocks neural action potentials, but does not prevent directly evoked muscle contraction. Nifedipine-sensitive L-type Cav channels affecting movement are also primarily neural, suggesting that muscle Nav channels are relatively insensitive to tricaine. These findings show that tricaine used at standard concentrations in zebrafish larvae does not paralyse muscle, thereby diminishing concern that a direct action on muscle could mask a lack of general anaesthesia.

Hyaluronan (HA) is a naturally occurring linear, negatively charged polysaccharide that plays a vital role in the organization and function of pericellular coats and extracellular matrices in vertebrates, and that is becoming increasingly popular in biomedical applications. To gain insight into the physical phenomena that govern the mechanical behavior of HA assemblies, we have studied the response of films of end-grafted HA to compression over a large range of ionic strength. Compression forces were measured as a function of the absolute distance between a colloidal probe and the planar surface on which the HA film was constructed, using a combined atomic force microscopy and reflection interference contrast microscopy setup. The HA films were well-defined in the sense that they are made of chains with a narrow size distribution that are grafted at controlled density to a solid support. Detailed comparison of the experimental data with analytical expressions derived from polymer and polyelectrolyte brush theory reveals that films of end-grafted HA behave as strongly charged polyelectrolyte brushes. To quantitatively reproduce the experimental data, intrinsic excluded volume interactions and chain stiffness of the polymer backbone must be taken into account. At low ionic strength, chains become almost fully stretched. In our experimental system, several micrometer thick films are formed that reach a hydration of up to 99.98%, and the brush thickness decreases by more than 5-fold with increasing ionic strength. More generally, the study provides quantitative theoretical predictions for the film thickness and compressive response as a function of HA length, grafting density and ionic strength.

We describe a method that combines colloidal probe atomic force microscopy (AFM) and reflection interference contrast microscopy (RICM) to characterize the mechanical properties of thin and solvated polymer films. When analyzing polymer films, a fundamental problem in colloidal probe AFM experiments is to determine the distance at closest approach between the probe and the substrate on which the film is deposited. By combining AFM and RICM in situ, forces and absolute distances can be measured simultaneously. Using the combined setup, we quantify the compressive mechanics of films of the polysaccharide hyaluronan that is end-grafted to a supported lipid bilayer. The experimental data, and comparison with polymer theory, show that hyaluronan films are well-described as elastic, very soft and highly solvated polymer brushes. The data on these well-defined films should be a useful reference for the investigation of the more complex hyaluronan-rich coats that surround many living cells.

The state-of-the-art cultured podocyte is conditionally immortalized by expression of a temperature-sensitive mutant of the SV40 large-T antigen. These cultures proliferate at 33°C and differentiate at 37°C into arborized cells that more closely resemble in vivo podocytes. However, the degree of resemblance remains controversial. In this study, several parameters were measured in podocyte cell lines derived from mouse (JR, KE), human (MS), and rat (HK). In all lines, the quantities of NEPH1 and podocin proteins and NEPH1 and SYNPO mRNAs were comparable to glomeruli, while synaptopodin and nephrin proteins and NPHS1 and NPHS2 mRNAs were <5% of glomerular levels. Expression of Wilms' tumor-1 (WT1) mRNA in mouse lines was comparable to glomeruli, but rat and human lines expressed little WT1. Undifferentiated human and mouse lines had similar proliferation rates that decreased after differentiation, while the rate in rat cells remained constant. The motility of different lines varied as measured by both general motility and wound-healing assays. The toxicity of puromycin aminonucleoside was MS ∼ JR >> KE, and of doxorubicin was JR ∼ KE > MS, while HK cells were almost unaffected. Process formation was largely a result of contractile action after formation of lamellipodia. These findings demonstrate dramatic differences in marker expression, response to toxins, and motility between lines of podocytes from different species and even between similarly-derived mouse lines.

Objective: The study objective was to explore the biological basis for link between antipsychotic-induced weight gain and therapeutic response in schizophrenia by examining longitudinal changes in serum leptin level after antipsychotic treatment., Methods: We examined serum leptin in schizophrenia patients at antipsychotic-naive baseline status as well as after 3 months of antipsychotic treatment. For baseline analyses, the patients were compared with healthy controls matched for anthropometric measures and physical activity., Results: At baseline, schizophrenia patients had significantly lower levels of leptin in comparison with controls. After treatment, body mass index and levels of leptin increased significantly in patients. The magnitude of increase in leptin had a significant positive correlation with magnitude of increase in body mass index; the magnitude of reduction in SANS total score showed significant positive correlation with the magnitude of increase in leptin level., Conclusion: The study findings suggest a potential role for leptin to mediate the link between antipsychotic-induced weight gain and beneficial therapeutic response in schizophrenia.

Neurodevelopmental pathogenesis of schizophrenia might be mediated by abnormalities in Insulin-like Growth Factor-1 (IGF-1). Developmental disturbances like obstetric complications, by themselves, as well as through the resultant hypercortisolemia due to hypothalamic-pituitary-adrenal (HPA) axis hyperactivity, can lead to deficient IGF-1 level. The relevance of IGF-1-Cortisol interactions in schizophrenia, especially in the context of antipsychotic treatment, is yet to be explored. In this study, thirty-three antipsychotic-naïve schizophrenia patients (13-men) were examined for serum IGF-1 and cortisol levels at baseline and after 3months of antipsychotic treatment. For baseline analyses, the patients were compared with 33 healthy controls matched for age, sex, socio-economic status, and physical activity. Symptoms were assessed using Scale for Assessment of Positive Symptoms (SAPS) and Scale for Assessment of Negative Symptoms (SANS). At baseline, schizophrenia patients had significantly lower levels of IGF-1 [t=4.6; p<0.0001] and higher levels of cortisol [t=3.9; p=0.0002] in comparison with healthy controls. Following treatment, IGF-1 level increased significantly [t=4.5; p<0.0001] whereas cortisol decreased significantly [t=2.5; p=0.02] in patients. There was a significant positive correlation between magnitude of increase in IGF-1 level and the magnitude of reduction in cortisol level [r=0.52; p=0.002]. Also, the greater the increase in IGF-1 the greater was the reduction in SAPS score [r=0.39; p=0.02]. Our study findings demonstrate that antipsychotic treatment can result in significant elevation of serum IGF-1 possibly mediated by reduction in cortisol levels. These observations suggest a possible link between HPA axis abnormalities and IGF-1 deficits in the neurodevelopmental pathogenesis of schizophrenia., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)

Oxidative stress abnormalities have been proposed to explain the pathogenesis of schizophrenia. The present study examined neopterin and oxidative stress abnormalities in schizophrenia patients before and after treatment. Serum neopterin, total anti-oxidants, nitrites and thiols in antipsychotic-naïve schizophrenia patients (n=45) were assessed at baseline before treatment in comparison with healthy controls (n=43). The schizophrenia patients on treatment were followed up for 3months and these parameters were reassessed (n=32). In comparison to healthy controls, schizophrenia patients had significantly higher levels of neopterin and nitrites and significantly lower levels of anti-oxidants before treatment. During follow-up assessments in schizophrenia patients after treatment with antipsychotics, there was a significant decrease in the neopterin levels and significant increase in anti-oxidant levels. Our study observations support increased oxidative stress in schizophrenia that improves with antipsychotic treatment.

Background: It is well established that there is mutual interaction between the neuroendocrines and immune systems and that the disturbance in any one system could affect the function of the other. While there is a large body of evidence suggesting negative impact of human immunodeficiency virus type 1B (HIV-1B) infection on both immune and neuroendocrine systems, the consequence of HIV-1 clade C infection (with structural differences from HIV-1B virus) on these systems is not clearly understood., Methods: We carried out a 2-year longitudinal study on plasma profile of adrenocorticosteroids, including cortisol and DHEAS and their relationship with declining CD4+ cell counts in neurologically asymptomatic HIV-C infected individuals (N=84) in order to understand the impact of HIV-1 clade C infection on adrenocortical dysfunction and its relationship with the progressive decline in the cell mediated immunity., Results: We found that while plasma cortisol levels increased significantly at baseline in HIV-1C infected individuals compared to those in HIV-negative controls (HIV-1C+, 9.83+/-0.39 vs controls, 8.04+/-0.45; p<0.01), there was a significant decrease in DHEAS in HIV-1C+ individuals, compared to that in HIV-negative controls (81.02+/-4.9 vs 185.1+/-12.03, p<0.001), and consequently a significant increase in cortisol:DHEAS ratio in HIV-1 clade C infected persons (0.19+/-0.002 vs control 0.058+/-0.006; p<0.001). Moreover, in HIV-1C infected individuals, there was a strong positive correlation between DHEAS and CD4 cells (r=0.2; p<0.05), and a strong negative correlation between cortisol, as well as cortisol:DHEAS ratio and CD4 cells (r=-0.25; p<0.01; and r=-0.31; p<0.001, respectively)., Conclusions: These findings suggest the persistent and progressive adrenocortical dysfunction during the asymptomatic phase of HIV infection, and that the evaluation of increase in plasma cortisol, a decrease in DHEAS, and an increase in cortisol:DHEAS ratio may serve as important biomarkers preceding the impending down regulation of CD4 cell counts and progressive decline in the immune system function in HIV-1C infection. Furthermore, these findings may indicate the dysregulation of 3beta-hydroxysteroid dehydrogenase (3beta-HSD) activity, the enzyme involved in the biosynthesis of cortisol and DHEA through the pregnenolone-progesterone pathway, and that it may offer an opportunity for drug discovery targeting re-regulation of 3beta-HSD activity for potential therapeutic application in HIV-1C infection.

In an earlier cross-sectional study, we reported antipsychotic-naive schizophrenia patients to have significantly elevated beta2-microglobulin (beta2M) level suggestive of its potential association with the pathogenesis of schizophrenia. In this study, we present the follow-up analyses of beta2M in 31 patients from the previous study who were re-assessed after 92.1+/-7.2 days of antipsychotic treatment. Compared to baseline, there was a further significant elevation of beta2M in schizophrenia patients following treatment, especially in those who were treated with risperidone. Also, there was a significant negative correlation between beta2M level and total psychopathology score during follow-up in risperidone group. The study findings extend further support the role for beta2M in the pathogenesis of schizophrenia strengthening the case for immune dysregulation. Moreover, the observations suggest the possibility that the mechanism of action of antipsychotics might involve alteration of immune parameters.

Studies examining immune dysfunction in schizophrenia have reported decreased type-1 T-helper cell specific immunity (Th1) and increased type-2 T-helper cell specific immunity (Th2) and related abnormalities in inflammatory system. Beta2-Microglobulin (beta2M) influences the development of dendritic cells, which play a significant role in regulating the differentiation of naive CD4+ T cells into Th1 or Th2 lineages. The present study examined serum beta2M in antipsychotic-naïve schizophrenia patients (n=43) in comparison with age, sex, handedness and socioeconomic status matched healthy controls (n=43). Serum beta2M was significantly higher in schizophrenia patients (1692.6+/-354.4 ng/mL) than healthy controls (1409.6+/-246.9 ng/mL) (t=4.3; p<0.0001). There was a significant positive correlation between beta2M level and total psychopathology score (r=0.32; p=0.035). These novel observations suggest that beta2M abnormalities might have a potential association with the pathogenesis of schizophrenia.

Human immunodeficiency virus type 1 (HIV-1) infection causes a wide spectrum of abnormalities in neurological, neuropsychological, and neuroendocrinological functions. Several studies report disturbance in autonomic nervous system (ANS) and hypothalamic pituitary-adrenal (HPA) axis function in HIV-1B infected individuals. However, no such investigations on the effect of HIV-1 clade C infection, particularly during the initial phase of the disease progression, have been reported. The present investigations were carried out longitudinally over a 2-year period at 12 monthly intervals in clinically asymptomatic HIV-1 clade C seropositive patients (n=120) and seronegative control subjects (n=29). We determined both the basal levels and the dynamic changes in plasma levels of norepinephrine (NE), epinephrine (E), adrenocorticotrophic hormone (ACTH) and cortisol (CORT). Studies were also extended longitudinally (at three separate yearly visits of each participant), to evaluate the response of autonomic and HPA axis to mirror star tracing challenge test (MSTCT) and the values were determined as area under the curve (AUC, corrected for baseline levels of NE, E, ACTH, and CORT). The findings show that the values of basal plasma NE levels, as well as NE response to MSTCT (AUC) at the first visit of HIV-1 seropositive individuals did not differ from those found in the control subjects (NE, pg/ml, HIV-1C=313.5+/-12.7 vs. controls=353.0+/-21.3; p=NS; AUC, HIV-1C=225+/-14.75 vs. controls=232.7+/-19.34; p=NS, respectively). At the subsequent two visits of HIV-1 positive patients however, NE response to MSTCT challenge was progressively attenuated (AUC=235+/-19.5 and 162.7+/-13.6; p<0.01 and 0.05, respectively) compared to that found at the first visit. On the other hand, plasma levels of E as well as E response to MSTCT at the first visit were significantly lower in HIV-1C seropositive individuals compared to those in the control subjects (pg/ml, HIV-1C=77.30+/-5.7 vs. controls=119.1+10.5; p<0.05; AUC, HIV-1C =83.29+/-7.5 vs. controls=172.3+/-18.9; p<0.001), but no further change was observed in AUC of E in response to MSTCT at the two subsequent yearly visits. The basal plasma levels of ACTH in HIV-1C seropositives were not different than in the control subjects (pg/ml: HIV-1C=20.0+/-0.9 vs. controls=23.1+/-1.6; p=NS), but ACTH response to MSTCT in HIV-1C seropositive patients at the first visit was lower than in the controls (AUC, HIV-1C=23.57+/-1.5 vs. controls=30.94+/-3.5; p<0.05), and fluctuated between high and low at the second and third visits (AUC, 28.89+/-2.3 and 21.69+/-2.36, respectively). However, the baseline plasma levels of cortisol as well as the response of cortisol to MSTCT (AUC) in HIV-1C seropositive individuals were higher than in the control subjects at the first visit (mug/dl, HIV-1C=9.83+/-0.39 vs. controls=6.3+/-0.56; p<0.05; AUC, HIV-1C=12.31+/-0.7 vs. control=9.18+/-0.9; p<0.05), and remained high at the two subsequent yearly follow up visits of HIV-1C (AUC, 11.8+/-0.86 and 11.98+/-0.77, respectively). These findings demonstrate attenuated autonomic functions, a disconnection between response of ACTH and cortisol to the MSTCT challenge, and an inverse relationship between plasma levels of catecholamine(s) and cortisol. Since plasma catecholamines and cortisol are the peripheral mediators of the autonomic and HPA axis function, the findings of this study reflect the overall adverse effect of HIV-1C infection on autonomic as well as HPA axis functions. The findings, apart from being the first to demonstrate the progressive dysregulation of autonomic nervous system and HPA axis function among HIV-1C infected seropositive individuals much ahead of the onset of acquired immunodeficiency syndrome (AIDS), also suggest that MSTCT, involving visuoconstructive cognitive abilities, is an effective stressor for unraveling the underlying dysfunctions in the neuroendocrine functions in health and disease.

Objective: The purpose of this study was to examine the evidence for the insulin-like growth factor-1 (IGF-1) deficiency hypothesis in the pathogenesis of schizophrenia., Method: The authors examined the fasting plasma levels of glucose, insulin, IGF-1, and cortisol in antipsychotic-naive schizophrenia patients (N=44) relative to age- and sex-matched healthy comparison subjects (N=44). Patients and comparison subjects were also matched for anthropometric measures and physical activity., Results: Schizophrenia patients had a significantly higher mean plasma insulin level as well as a significantly higher mean insulin resistance score relative to healthy comparison subjects. The mean plasma IGF-1 level was significantly lower in patients. IGF-1 levels had a significant negative correlation with plasma insulin levels. The total positive symptoms score as well as the hallucinations subscore had a significant inverse relationship with IGF-1 levels., Conclusions: Deficient IGF-1 might underlie insulin resistance in schizophrenia. The IGF-1 deficit in antipsychotic-naive schizophrenia patients and its significant correlation with psychopathology scores suggest that IGF-1 might be potentially involved in the pathogenesis of schizophrenia.

Background: Plasma adenosine deaminase and its isoenzymes(s) activities have been used as diagnostic marker for intracellular parasitism, including HIV infection, and malignancy of immune cells. HIV infection being primarily targeted against CD4 cells, it would be of interest to relate the activity of total plasma ADA and isoenzymes fractions to immune status and antiretroviral therapy., Methods: In the present study, plasma total ADA activity (ADAT) including ADA1 and ADA2 isoenzyme(s) were assayed among HIV seropositive Clade C (n=90) comprising both asymptomatic (n=71) and symptomatic (n=19) and compared with that of HIV seronegatives (n=35)., Results: A significant increase in the activity of ADAT (16.30+/-0.80 v/s 6.18+/-0.30) as well as ADA1 (6.50+/-0.42 v/s 2.34+/-0.16) and ADA2 (9.79+/-0.53 v/s 3.85+/-0.23) isoenzyme(s) among the asymptomatic as well as the symptomatic subjects as compared to respective controls was noted. Increase in plasma ADAT activity, including ADA1 and ADA2 isoenzyme(s), were found to have negative correlation with CD4 counts (r, -0.273; p<0.05). The increased plasma ADAT activity among the asymptomatic HIV seropositive with CD4 counts>500 (13.2+/-1.65; p<0.01) as well as those who were on antiretroviral therapy (19.31+/-1.36; p<0.001) was evident., Conclusions: These findings suggest that plasma ADA can be a sensitive marker of an ongoing biological insult to host tissues either because of infection and/or side effects of medication. Measurement of plasma ADA activity, along with serological evidence for HIV infection may provide an alternate laboratory tool to monitor intracellular parasitism including secondary infection vis a vis the after effects of therapeutic outcome.

A disturbance in the activity of the hypothalamic-pituitary-adrenal (HPA) axis has been reported among individuals with HIV-1 infection. However, these studies have been carried out in the West where the infecting clade is clade B. HIV-1 infection is rapidly spreading in various parts of South East Asia, including India, where the HIV-1 infecting clade is largely clade C. An investigation of HPA axis activity in this type of infection is warranted since there are many structural differences between clades B and C. This study was carried out to investigate whether HIV-1 infection clade C interferes with the functions of the hippocampus and thereby affects the HPA axis. We tested the hypothesis that when hippocampus activity is disturbed, it leads to the development of neuropathogenesis in HIV-1 C-clade infected individuals. This study included asymptomatic HIV-1 seropositive individuals (n=117) and, age-matched, HIV-1 seronegative controls (n=29). Neuroendocrine function of the HPA axis was evaluated using plasma levels of cortisol, ACTH, and DHEA-S, both in the morning (0800-1000 hr) and evening (2000-2200 hr). A significant elevation of cortisol levels during A.M. and P.M. hours was observed in HIV-1 infected individuals when compared to the controls. Interestingly, no significant change in ACTH level was observed in HIV-1 seropositive subjects, either during A.M or P.M. Elevated levels of cortisol in HIV-1 seropositive subjects appear to be independent of ACTH and may be the result of a defective negative feedback mechanism. On the other hand, a significant decrease in the plasma levels of DHEA-S was observed during A.M. and P.M. hours in HIV-1 infected individuals, leading to an increased cortisol to DHEA-S ratio. Since increased levels of cortisol and decreased levels of DHEA-S are related to the development of neuropathogenesis, it is hypothesized that a study of the development of neurocognitive deficits among HIV-1 seropositive individuals in India is warranted.