Defining the Soluble and Extracellular Vesicle Protein Compartments of Plasma Using In-Depth Mass Spectrometry-Based Proteomics.

Plasma-derived extracellular vesicles (pEVs) are a potential source of diseased biomarker proteins. However, characterizing the pEV proteome is challenging due to its relatively low abundance and difficulties in enrichment. This study presents a streamlined workflow to identify EV proteins from cancer patient plasma using minimal sample input. Starting with 400 µL of plasma, we generated a comprehensive pEV proteome using size exclusion chromatography (SEC) combined with HiRIEF prefractionation-based mass spectrometry (MS). First, we compared the performance of HiRIEF and long gradient MS workflows using control pEVs, quantifying 2076 proteins with HiRIEF. In a proof-of-concept study, we applied SEC-HiRIEF-MS to a small cohort (12) of metastatic lung adenocarcinoma (LUAD) and malignant melanoma (MM) patients. We also analyzed plasma samples from the same patients to study the relationship between plasma and pEV proteomes. We identified and quantified 1583 proteins in cancer pEVs and 1468 proteins in plasma across all samples. While there was substantial overlap, the pEV proteome included several unique EV markers and cancer-related proteins. Differential analysis revealed 30 DEPs in LUAD vs the MM group, highlighting the potential of pEVs as biomarkers. This work demonstrates the utility of a prefractionation-based MS for comprehensive pEV proteomics and EV biomarker discovery. Data are available via ProteomeXchange with the identifiers PXD039338 and PXD038528.

Identification and optimization of pyridine carboxamide-based scaffold as a drug lead for Mycobacterium tuberculosis.

New drugs with novel mechanisms of action are urgently needed to tackle the issue of drug-resistant tuberculosis. Here, we have performed phenotypic screening using the Pathogen Box library obtained from the Medicines for Malaria Venture against Mycobacterium tuberculosis in vitro. We have identified a pyridine carboxamide derivative, MMV687254, as a promising hit. This molecule is specifically active against M. tuberculosis and Mycobacterium bovis Bacillus Calmette-Guérin (M. bovis BCG) but inactive against Enterococcus faecalis, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa, and Escherichia coli pathogens. We demonstrate that MMV687254 inhibits M. tuberculosis growth in liquid cultures in a bacteriostatic manner. Surprisingly, MMV687254 was as active as isoniazid in macrophages and inhibited M. tuberculosis growth in a bactericidal manner. Mechanistic studies revealed that MMV687254 is a prodrug and that its anti-mycobacterial activity requires AmiC-dependent hydrolysis. We further demonstrate that MMV687254 inhibits M. tuberculosis growth in macrophages by inducing autophagy. In the present study, we have also carried out a detailed structure-activity relationship study and identified a promising novel lead candidate. The identified novel series of compounds also showed activity against drug-resistant M. bovis BCG and M. tuberculosis clinical strains. Finally, we demonstrate that in contrast to MMV687254, the lead molecule was able to inhibit M. tuberculosis growth in a chronic mouse model of infection. Taken together, we have identified a novel lead molecule with a dual mechanism of action that can be further optimized to design more potent anti-tubercular agents.

Demographic analysis and biotic potential of Spodoptera frugiperda (J.E. Smith) (Lepidoptera: Noctuidae) on pea.

The fall armyworm (FAW), Spodoptera frugiperda (J.E. Smith) (Lepidoptera: Noctuidae) is a highly destructive polyphagous pest that primarily damages maize. Maize is considered a most versatile crop for growing intercrops due to the wide row it needs. Maize-pea intercropping is preferred by small and marginal farmers worldwide due to various advantages including higher yield and improved economic benefits. However, the success of this intercropping system may be hampered if pea could sustain the FAW population. Thus, to clarify the fitness and potential effect of S. frugiperda on pea, we analysed the survival and development of S. frugiperda fed on pea leaves in the laboratory and constructed age-stage and two-sex life tables. Results showed that FAW successfully completed its life cycle when fed on pea and produced fertile offspring. The pre-adult duration was significantly higher on pea than maize. The net reproductive rate, intrinsic and finite rate of population increase on pea (135.06 offspring per individual, 0.12 offspring per individual per day and 1.13 times per day) were all significantly different from those on maize (417.64 offspring per individual, 0.19 offspring per individual per day and 1.21 times per day). The probability of survival of S. frugiperda at each stage was lower when fed on pea leaves than that of maize-fed larvae. Due to the overlapping growth periods of the maize and pea, S. frugiperda can easily proliferate throughout the year by shifting between adjacent crops. Thus, this study revealed the adaptability of S. frugiperda for pea and provides the foundation for further assessment of FAW risk to other inter-crops.

Capturing of neurotoxins causing diabetes stress and nervous breakdown in the aqueous medium by naphthazarin esters.

The fear of an increase in blood sugar can be very traumatic. Being diabetic either type I or type II leads to a disorder called diabetes distress having traits of stress, depression, and anxiety. Among risk factors of diabetes mellitus heavy and trace metal toxicity emerges as new risk factors reported in many studies. In this study we target toxic metals, viz., Ni2+, Zn2+, and Cu2+, involved in the pathogenesis of diabetes and diabetic stress with naphthazarin esters. The compounds C1-C3 isolated from the leaves and roots of Arnebia guttata were tested for their metal-binding ability in an aqueous medium in UV-Visible and nuclear magnetic resonance (NMR) studies. These probes are well-known naphthoquinones present in the Arnebia species. In the UV-Visible titrations of compounds C1-C3 with Na2+, K2+, Zn2+, Ca2+, Cu2+, Mg2+, Co2+, and Ni2+ ions, significant binding was observed with Ni2+, Cu2+, and Zn2+ ions in MeOH/H2O. There occurs a beautiful formation of red-shifted bands between the 520 to 620 nm range with a synergistic increase in absorbance. Also, the disappearance of proton peaks in the 1H NMR spectrum on addition of metal ions confirmed binding. Compounds C1-C3 isolated from A. guttata came out as potent Ni2+, Zn2+, and Cu2+ sensors that are reportedly involved in islet function and induction of diabetes.

Impact of Virtual Reality on Pain, ROM, Muscle Strength and Quality of Life among Breast Cancer Patients: An Integrative Review of Literature.

BACKGROUND: Breast cancer is the most commonly diagnosed cancer among women globally, with significant impacts on physical, emotional, and functional well-being. Traditional rehabilitation methods may not fully address the multifaceted challenges faced by breast cancer survivors (BCSs), prompting exploration into innovative approaches such as Virtual Reality (VR) technology. OBJECTIVE: The present review aims to assess the effectiveness of VR in alleviating pain, improving Range of Motion (ROM), enhancing muscle strength, and augmenting the overall quality of life in patients undergoing breast cancer rehabilitation. METHODS: A comprehensive review of existing literature was conducted, focusing on studies investigating the use of VR in breast cancer rehabilitation. PubMed, Scopus, PEDro and Google scholar were searched for articles addressing VR interventions targeting pain management, ROM improvement, muscle strength enhancement, and quality of life enhancement in breast cancer patients. RESULTS: Findings yielded total 12 articles matching the selection criteria. VR technology has shown promising results in addressing the multifaceted needs of breast cancer patients. VR also serves as a distraction tool, positively impacting psychological well-being and mitigating negative psychological symptoms associated with the disease. CONCLUSION: VR represents a non-pharmacological approach to pain management and rehabilitation in breast cancer patients. Its ability to engage emotional, cognitive, and attention processes contributes to its effectiveness in enhancing overall quality of life. Further research is warranted to elucidate the long-term benefits and optimal utilization of VR technology in breast cancer rehabilitation programs.

Optimizing wastewater treatment through artificial intelligence: recent advances and future prospects.

Artificial intelligence (AI) is increasingly being applied to wastewater treatment to enhance efficiency, improve processes, and optimize resource utilization. This review focuses on objectives, advantages, outputs, and major findings of various AI models in the three key aspects: the prediction of removal efficiency for both organic and inorganic pollutants, real-time monitoring of essential water quality parameters (such as pH, COD, BOD, turbidity, TDS, and conductivity), and fault detection in the processes and equipment integral to wastewater treatment. The prediction accuracy (R2 value) of AI technologies for pollutant removal has been reported to vary between 0.64 and 1.00. A critical aspect explored in this review is the cost-effectiveness of implementing AI systems in wastewater treatment. Numerous countries and municipalities are actively engaging in pilot projects and demonstrations to assess the feasibility and effectiveness of AI applications in wastewater treatment. Notably, the review highlights successful outcomes from these initiatives across diverse geographical contexts, showcasing the adaptability and positive impact of AI in revolutionizing wastewater treatment on a global scale. Further, insights on the ethical considerations and potential future directions for the use of AI in wastewater treatment plants have also been provided.

A correlation between oxidative stress and diabetic retinopathy: An updated review.

Oxidative stress (OS) is a cytopathic outcome of excessively generated reactive oxygen species (ROS), down regulated antioxidant defense signaling pathways, and the imbalance between the produced radicals and their clearance. It plays a role in the genesis of several illnesses, especially hyperglycemia and its effects. Diabetic retinal illness, a micro vascular side effect of the condition, is the prime reason of diabetic related blindness. The OS (directly or indirectly) is associated with diabetic retinopathy (DR) and related consequences. The OS is responsible to induce and interfere the metabolic signaling pathways to enhance influx of the polyol cascades and hexosamine pathways, stimulate Protein Kinase-C (PKC) variants, and accumulate advanced glycation end products (AGEs). Additionally, the inequity between the scavenging and generation of ROS is caused by the epigenetic alteration caused by hyperglycemia that suppresses the antioxidant defense system. Induced by an excessive buildup of ROS, retinal changes in structure and function include mitochondrial damage, cellular death, inflammation, and lipid peroxidation. Therefore, it is crucial to comprehend and clarify the mechanisms connected to oxidative stress that underlie the development of DR.

Targeted Therapeutics for Transthyretin Amyloid Cardiomyopathy.

BACKGROUND: Deposition of wild-type or mutant transthyretin (TTR) amyloid fibrils in the myocardium causes TTR amyloid cardiomyopathy (ATTR-CM). Targeted therapeutics for ATTR-CM include TTR stabilizers (tafamidis and diflunisal) and oligonucleotide drugs (revusiran, patisiran, and inotersen). TTR stabilizers prevent dissociation of transthyretin tetramers. Transthyretin monomers can misfold and form amyloid fibrils. TTR stabilizers thereby limit amyloid fibrils development and deposition. Oligonucleotide drugs inhibit hepatic synthesis of transthyretin, which decreases transthyretin protein levels and thus the amyloid fibril substrate. AREAS OF UNCERTAINTY: To study the safety and efficacy of targeted therapeutics in patients with ATTR-CM, we performed a pooled analysis. A random-effects model with the Mantel-Haenszel method was used to pool the data. DATA SOURCES: A literature search was performed using PubMed, Cochrane CENTRAL, and Embase databases using the search terms "cardiac amyloidosis" AND "tafamidis" OR "patisiran" OR "inotersen" OR "revusiran" OR "diflunisal." THERAPEUTIC ADVANCES: We identified 6 studies that compared targeted therapeutics with placebo. One study was stopped prematurely because of increased mortality in the targeted therapeutics arm. Pooled analysis included 1238 patients, of which 738 patients received targeted therapeutics and 500 patients received placebo. When compared with placebo, targeted therapeutics significantly reduced all-cause mortality [OR 0.39, 95% confidence interval (CI): 0.16-0.97, P = 0.04]. Only 2 studies reported the effect on cardiovascular-related hospitalizations. There was a trend toward an improvement in global longitudinal strain (mean difference -0.69, 95% CI: -1.44 to 0.05, P = 0.07). When compared with placebo, there was no increase in serious adverse events with targeted therapeutics (OR 1.06, 95% CI: 0.78-1.44, P = 0.72). CONCLUSION: Evidence from the pooled analysis revealed targeted therapeutics improve survival and are well-tolerated. These findings suggest a potential role for targeted therapeutics in the treatment of patients with ATTR-CM.

Amino Appended Coumarin Composites for Pb2+ Capturing in Aqueous Medium.

The C1-C3 receptors were synthesized by using coumarin and amines viz., 1-butylpiperazine (1), cis-myrtanylamine (2), and 3-methyldiphenyl amine (3) at room temperature without using harsh conditions. All the probes show beautiful and strong binding with Pb2+ ions among all the tested essential elements of human body. The binding is clearly seen and confirmed in UV-visible, NMR and HPLC studies. Also, all the substituted amines (1-3) are well known bioactives viz., piperazine as anthelmintic, cis-myrtanyl use for cannabinoid receptor (CB2) antagonists, 3-methyldiphenyl is used in probes for selective detection of explosive nitroaromatic compounds further increases their sensitivity for use as Pb2+ sensor. As they are already well in use for research on human body metabolomics their future introduction as sensors in the human body for lead toxicity is highly favourable.

Predictors of Five-Year Readmission to an Inpatient Service among Patients with Alcohol Use Disorders: Report from a Low-Middle Income Country.

BACKGROUND: Alcohol use disorder (AUD) is a relapsing-remitting disease that accounted for a sizable proportion of all-cause adult inpatient stays. OBJECTIVES: To determine the predictors of any and multiple readmissions to inpatient care for AUD within 5 years of the index admission. METHODS: This retrospective, register-based cohort study assessed consecutive patients with AUD admitted to a publicly-funded inpatient service between January 2007 and December 2014. Binary logistic regression was used to determine independent predictors for readmissions based on relevant demographic, clinical, and treatment variables that showed significant differences (p < 0.05) on univariate analysis. RESULTS: Among 938 patients (age 35.9 ± 10.3 years; duration of alcohol use 159.6 ± 104.5 months; dual diagnosis 19%; comorbidity of substance use disorder 49.3%; medical disorder 34.8%, 299 (31.9%) and 115 (12.3%) had any and multiple readmissions, respectively. Comorbid "severe mental illness" (Odds ratio [OR] 1.99, 95% confidence interval [CI] 1.11-3.57) and urban residence (OR 1.58, 95% CI 1.13-2.18) increased the odds of any readmission; "Improved" status at discharge (OR 0.51, 95% CI 0.35-0.72) during index hospitalization reduced odds of readmission. Additionally, any medical or psychiatric comorbidities increased (OR 2.23, 95% CI 1.26-3.97), and comorbid substance use disorder decreased (OR 0.41, 95% CI 0.19-0.89) risk of multiple readmissions. CONCLUSIONS: Clinicians could identify patients at-risk for any and multiple readmissions during the index hospitalization. A policy aimed at reducing the risk of rehospitalization, healthcare cost, and stigma should pay attention to the predictors of readmission. Such policy should further benefit resource-limited settings.

Molecular characterization of Clostridioides difficile by multi-locus sequence typing (MLST): A study from tertiary care center in India.

OBJECTIVES: Clostridioides difficile is an important pathogen responsible for antibiotic-associated diarrhoea (AAD). This study was aimed to perform multi-locus sequence typing (MLST) of C. difficile isolates from AAD cases and to understand the clonal relationship between these C. difficile strains. METHODS: Thirty five strains and a standard strain C.difficile ATCC 9689 were characterized by polymerase chain reaction assay (PCR) for toxin genes (tcdA and tcdB gene) detection and MLST. RESULTS: MLST results revealed that the most common sequence types were ST-17, ST-54, ST-63. The cluster analysis revealed that strains isolated from AAD patients generated 12 MLST sequence types grouped into two distinct evolutionary lineages. CONCLUSIONS: ST 17 is most prominent sequence type. This is the first report of MLST based study of C. difficile from India. Further studies from diverse geographical regions can help better understand the epidemiology of CDI in India.

Evaluation of Immature Granulocyte Count as the Earliest Biomarker for Sepsis.

Background: Diagnosing sepsis early is important for its successful management. Various biomarkers are being used currently, but mostly they are either expensive or not readily available. This study aims to evaluate usefulness of automated immature granulocyte count (IG#) and immature granulocyte percentage (IG%) as early diagnostic markers of sepsis and compares it to other established predictive markers. Patients and methods: In this prospective observational study, 137 eligible, critically ill, nonseptic intensive care unit patients were analyzed for automated IG#, IG%, serum procalcitonin (PCT), and blood lactate (Lac), daily for 7 days after recruitment. Patients were followed for the development of sepsis, defined by the new Sepsis-3 criteria. The study was divided into four time periods of 24 hours each with respect to the day of developing organ dysfunction. Using area under receiver operator characteristic and diagnostic odds ratio (DOR) methods, the best biomarker for the prediction of sepsis in each time period was calculated. Results: IG# and IG% were the earliest biomarkers to have a significant discriminating value with area under the curve of 0.81 and 0.82, respectively, as early as 24 hours before clinical sepsis is diagnosed by Sepsis-3 criteria. Both IG# and IG% have a high DOR of 34.91 and 18.11, respectively, when compared to others like PCT and Lac having a DOR of 27.06 and 4.78, respectively. Conclusion: IG# and IG% are easily available, rapid, and inexpensive tools to differentiate between septic and nonseptic patients with high specificity and sensitivity. It is the earliest biomarker to show a significant rise in patients developing sepsis. How to cite this article: Bhansaly P, Mehta S, Sharma N, Gupta E, Mehta S, Gupta S. Evaluation of Immature Granulocyte Count as the Earliest Biomarker for Sepsis. Indian J Crit Care Med 2022;26(2):216-223.

Lineage- and stage-specific expressed CYCD7;1 coordinates the single symmetric division that creates stomatal guard cells.

Plants, with cells fixed in place by rigid walls, often utilize spatial and temporally distinct cell division programs to organize and maintain organs. This leads to the question of how developmental regulators interact with the cell cycle machinery to link cell division events with particular developmental trajectories. In Arabidopsis leaves, the development of stomata, two-celled epidermal valves that mediate plant-atmosphere gas exchange, relies on a series of oriented stem cell-like asymmetric divisions followed by a single symmetric division. The stomatal lineage is embedded in a tissue in which other cells transition from proliferation to postmitotic differentiation earlier, necessitating stomatal lineage-specific factors to prolong competence to divide. We show that the D-type cyclin, CYCD7;1, is specifically expressed just prior to the symmetric guard cell-forming division, and that it is limiting for this division. Further, we find that CYCD7;1 is capable of promoting divisions in multiple contexts, likely through RBR1-dependent promotion of the G1/S transition, but that CYCD7;1 is regulated at the transcriptional level by cell type-specific transcription factors that confine its expression to the appropriate developmental window.

Optimizing pediatric peripheral blood stem cell collection.

INTRODUCTION: Pediatric PBSC harvests pose specific challenges during apheresis and a knowledge of the same and variables affecting PBSC collection are very important in planning these procedures. In the present study safety profile of pediatric PBSC procedures and variables influencing the successful collection were analyzed. METHOD: Pediatric PBSC harvest data for 3 years was reviewed for donor, procedural and product parameters and any specific challenges faced during the procedures. Successful PBSC collection was defined when CD34 dose obtained was ≥2 × 106 cells/Kg of recipients' body weight. RESULTS: 85 PBSC collections performed on 46 children (age range 1.5-15 years) were included. Sixty-two procedures were on autologous donors and 23 on allogenic donors. The median CD34+ cell dose in the PBSC product per procedure was 2.12 × 106 cells/Kg for autologous procedures and 4.6 × 106 cells/Kg for allogenic procedures. Systemic adverse reaction was observed during only one procedure (0.01 %) and was managed conservatively. Successful dose was collected in 52 procedures (61.17 %) and was significantly associated with CD34+ count of more than 19.7/µL, monocyte count of more than 1.65 × 106/µL, allogenic collection and female gender (p = 0.00001, p = 0.011, p = 0.00052, and p = 0.0001, respectively). CONCLUSION: PBSC collection is safe in pediatric age groups and pre-procedure CD34 count of ≥20/µL on the day of collection may result in successful collection of stem cell dose. It is important to identify factors associated with failed collection for appropriate counselling and justifying pre-emptive use of stem cell mobilizing agents.

The Effectiveness of Non-Benzodiazepine, Non-Barbiturate Medications for Alcohol Withdrawal Syndrome: A Rapid Systematic Review.

AIM: There are potential clinical, ethical and legal concerns with overdosing benzodiazepines (or barbiturates) for the treatment of moderate to severe alcohol withdrawal symptoms (AWS) through telemedicine or ambulatory outpatients. A rapid systematic review to (a) qualitatively summarize the non-benzodiazepine treatment alternatives, (b) evaluate the quality of evidence for the same to effectively manage moderate to severe AWS. METHODS: We conducted searches on PubMed (January 1990 to 31 March 2020), Cochrane Central Register of Controlled Trials, and Google Scholar. We selected the English language randomized controlled trials (RCTs) assessing the efficacy and adverse effects of non-benzodiazepine and non-barbiturate medications among adults with a diagnosis of AWS. Data extraction was done in a predefined format. Risk of bias (RoB) assessment and qualitative synthesis of evidence was done with the RoB2 tool and Grading of Recommendations Assessment, Development, and Evaluation (GRADE) proGDT. RESULTS: Thirty-four RCTs were included. Gabapentin (n = 6), carbamazepine (n = 5), baclofen (n = 5), valproate (n = 3), clonidine/lofexidine (n = 3) and acamprosate (n = 2) had more than one trial with a particular comparison group. Four studies were found to have a low ROB. The GRADE evidence summary showed gabapentin had a 'moderate' level of evidence against standard benzodiazepine treatments for reducing the severity of AWS. The level of certainty was 'low' for carbamazepine, baclofen and valproate and 'very low' for acamprosate and clonidine/lofexidine. Reported adverse events between these alternative medications and benzodiazepines or placebo were generally unremarkable. CONCLUSIONS: Although benzodiazepines remain the treatment of choice for AWS, during particular circumstances, gabapentin could be an alternative although like benzodiazepines is not without risk when used in the community. Future RCTs must aim to improve upon the quality of evidence.

Stability and sub-cellular localization of DNA polymerase ß is regulated by interactions with NQO1 and XRCC1 in response to oxidative stress.

Protein-protein interactions regulate many essential enzymatic processes in the cell. Somatic mutations outside of an enzyme active site can therefore impact cellular function by disruption of critical protein-protein interactions. In our investigation of the cellular impact of the T304I cancer mutation of DNA Polymerase ß (Polß), we find that mutation of this surface threonine residue impacts critical Polß protein-protein interactions. We show that proteasome-mediated degradation of Polß is regulated by both ubiquitin-dependent and ubiquitin-independent processes via unique protein-protein interactions. The ubiquitin-independent proteasome pathway regulates the stability of Polß in the cytosol via interaction between Polß and NAD(P)H quinone dehydrogenase 1 (NQO1) in an NADH-dependent manner. Conversely, the interaction of Polß with the scaffold protein X-ray repair cross complementing 1 (XRCC1) plays a role in the localization of Polß to the nuclear compartment and regulates the stability of Polß via a ubiquitin-dependent pathway. Further, we find that oxidative stress promotes the dissociation of the Polß/NQO1 complex, enhancing the interaction of Polß with XRCC1. Our results reveal that somatic mutations such as T304I in Polß impact critical protein-protein interactions, altering the stability and sub-cellular localization of Polß and providing mechanistic insight into how key protein-protein interactions regulate cellular responses to stress.

Guggulsterone ameliorates ethidium bromide-induced experimental model of multiple sclerosis via restoration of behavioral, molecular, neurochemical and morphological alterations in rat brain.

Multiple Sclerosis (MS) is a progressive neurodegenerative disease with clinical signs of neuroinflammation and the central nervous system's demyelination. Numerous studies have identified the role of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) overexpression and the low level of peroxisome proliferator-activated receptor-gamma (PPAR-γ) in MS pathogenesis. Guggulsterone (GST), an active component derived from 'Commiphora Mukul,' has been used to treat various diseases. Traditional uses indicate that GST is a suitable agent for anti-inflammatory action. Therefore, we assessed the therapeutic potential of GST (30 and 60 mg/kg) in ethidium bromide (EB) induced demyelination in experimental rats and investigated the molecular mechanism by modulating the JAK/STAT and PPAR-γ receptor signaling. Wistar rats were randomly divided into six groups (n = 6). EB (0.1%/10 µl) was injected selectively in the intracerebropeduncle (ICP) region for seven days to cause MS-like manifestations. The present study reveals that long-term administration of GST for 28 days has a neuroprotective effect by improving behavioral deficits (spatial cognition memory, grip, and motor coordination) associated with lower STAT-3 levels. While elevating PPAR-γ and myelin basic protein levels in rat brains are consistent with the functioning of both signaling pathways. Also, GST modulates the neurotransmitter level by increasing Ach, dopamine, serotonin and by reducing glutamate. Moreover, GST ameliorates inflammatory cytokines (TNF, IL-1ß), and oxidative stress markers (AchE, SOD, catalase, MDA, GSH, nitrite). In addition, GST prevented apoptosis, as demonstrated by the reduction of caspase-3 and Bax. Simultaneously, Bcl-2 elevation and the restoration of gross morphology alterations are also recovered by long-term GST treatment. Therefore, it can be concluded that GST may be a potential alternative drug candidate for MS-related motor neuron dysfunctions.

Pb2+ sensing by coumarin sulphonamide hybrids in aqueous medium.

Metals play an important role in various metabolic activities in the human body, but above desired concentrations, a role reversal occurs that causes deadly outcomes viz., cancer. Metals cannot be cracked down and are non-biodegradable. It is the bioaccumulation of toxic metals inside the biomatrices, that further intensifies the research on different means of metal detoxification from different matrices. Among heavy toxic metals lead is a brutal carcinogen that requires pitiless sensors for its capturing. The use of heterocycles for metal sensing in supramolecular chemistry is preferred due to the strong chelation they offer to toxic metals. The C1-C3 probes were synthesized and studied for their Pb2+ binding ability. All the probes were prepared by treating bromoacetyl coumarin with camphor sulphonamide, 5-dimethylamino-1-naphthalene sulphonamide, and methyl-2-amino-sulphonyl benzoate at room temperature. The probes show selective binding with Pb2+ ions in aqueous acetonitrile among different tested metal ions viz., Cu2+ , Zn2+ , Ni2+ , Mn2+, and Pb2+ ions as shown in ultraviolet (UV)-visible, nuclear magnetic resonance (NMR), and high-performance liquid chromatography (HPLC) studies. These sulphur-containing probes bind very well with Pb2+ ions by offering selectivity in binding positions that capture lead ions at their minimum possible concentration.

Lenalidomide and Vorinostat Maintenance after Autologous Transplantation in Multiple Myeloma: Long- Term Follow-Up.

Post-autologous stem cell transplantation (ASCT) maintenance therapy with lenalidomide is standard of care for patients with multiple myeloma (MM). Effective and tolerable drug combinations may further enhance the clinical response post-ASCT. Vorinostat, a histone deacetylase inhibitor, induces antiproliferative and proapoptotic effects in patients with MM. We hypothesized that combination maintenance therapy would further prolong the clinical response achieved from transplantation. We previously reported that the combination of lenalidomide and vorinostat as maintenance post-ASCT was tolerable in 16 patients with MM. We now present the long-term follow up of these patients. Progression-free survival (PFS) and overall survival (OS) outcomes were characterized using the Kaplan-Meier method. Five patients (31%) had high-risk disease, and the median number of lines of therapy before ASCT was 1 (range, 1 to 5). With a median follow-up of 89.8 months from ASCT, the median PFS was 64.3 months (range, 21.7 months to not reached [NR]), and OS was not reached (median, 53.0 months to NR). At the time of this report, 5 patients remained on the study. The combination of vorinostat and lenalidomide as maintenance post-ASCT is tolerable and induces a durable response. A phase III randomized study of lenalidomide versus a combination with vorinostat is warranted.

A Prospective, Randomized, Interventional Study of Oral Iron Supplementation Comparing Daily Dose with Alternate Day Regimen Using Hepcidin as a Biomarker in Iron Deficiency Anemia.

AIM: To assess effect of daily vis-a-vis alternate day oral iron therapy in terms of hemoglobin, reticulocyte hemoglobin equivalent (RET-He) and GI side effects using hepcidin as a biomarker. METHODS: A hospital based randomized interventional two-arm analytical study was done among patients of IDA (20 in each group). The study population was divided into two groups by randomisation. Group 1 received oral iron supplements on alternate day and Group 2 received iron supplements daily. Hemoglobin, RET-He, Serum ferritin and Hepcidin level were assessed. RESULTS: On day 2nd, the rise in Hepcidin was not significant from base line in alternate day therapy group but was significantly increased in daily therapy group. On day 3, the rise in hepcidin was significant from base line in both the groups but the mean change in hepcidin was more in daily therapy group. RET-He began increasing on day 2nd in both the groups. In alternate day therapy group, the rise in RET-He was significant from base line from the day 2nd onwards while the rise in RET-He in daily therapy group was not significant even on day 3. In alternate day iron therapy group, the mean increase in hemoglobin on day 21th (1.58 ±0.53 gm/dl) was significantly more than mean increase among daily therapy (0.41 ± 0.25 gm/dl, P <0.05). CONCLUSION: Alternate day single tablet dosing schedule of oral iron therapy (60mg of elemental iron, ferrous sulfate) was more effective and better tolerated (gastrointestinal side effects) compared to daily supplementation in IDA.