Unveiling Potential Targeted Therapeutic Opportunities for Co-Overexpressed Targeting Protein for Xklp2 and Aurora-A Kinase in Lung Adenocarcinoma.

Lung adenocarcinoma (LUAD) is one of the most prevalent and leading causes of cancer deaths globally, with limited diagnostic and clinically significant therapeutic targets. Identifying the genes and processes involved in developing and progressing LUAD is crucial for developing effective targeted therapeutics and improving patient outcomes. Therefore, the study aimed to explore the RNA sequencing data of LUAD from The Cancer Genome Atlas (TCGA) and gene expression profile datasets involving GSE10072, GSE31210, and GSE32863 from the Gene Expression Omnibus (GEO) databases. The differential gene expression and the downstream analysis determined clinically significant biomarkers using a network-based approach. These therapeutic targets predominantly enriched the dysregulation of mitotic cell cycle regulation and revealed the co-overexpression of Aurora-A Kinase (AURKA) and Targeting Protein for Xklp2 (TPX2) with high survival risk in LUAD patients. The hydrophobic residues of the AURKA-TPX2 interaction were considered as the target site to block the autophosphorylation of AURKA during the mitotic cell cycle. The tyrosine kinase inhibitor (TKI) dacomitinib demonstrated the strong binding potential to hinder TPX2, shielding the AURKA destabilization. This in silico study lays the foundation for repurposing targeted therapeutic options to impede the Protein-Protein Interactions (PPIs) in LUAD progression and aid in future translational investigations.

Macrophage Cx43 Is Necessary for Fibroblast Cytosolic Calcium and Lung Fibrosis After Injury.

Macrophages are paracrine signalers that regulate tissular responses to injury through interactions with parenchymal cells. Connexin hemichannels have recently been shown to mediate efflux of ATP by macrophages, with resulting cytosolic calcium responses in adjacent cells. Here we report that lung macrophages with deletion of connexin 43 (MacΔCx43) had decreased ATP efflux into the extracellular space and induced a decreased cytosolic calcium response in co-cultured fibroblasts compared to WT macrophages. Furthermore, MacΔCx43 mice had decreased lung fibrosis after bleomycin-induced injury. Interrogating single cell data for human and mouse, we found that P2rx4 was the most highly expressed ATP receptor and calcium channel in lung fibroblasts and that its expression was increased in the setting of fibrosis. Fibroblast-specific deletion of P2rx4 in mice decreased lung fibrosis and collagen expression in lung fibroblasts in the bleomycin model. Taken together, these studies reveal a Cx43-dependent profibrotic effect of lung macrophages and support development of fibroblast P2rx4 as a therapeutic target for lung fibrosis.

Comparative evaluation of the analgesic efficacy of ultrasound-guided erector spinae plane block versus intrathecal morphine in patients undergoing percutaneous nephrolithotomy surgery: A prospective randomized pilot study.

OBJECTIVES: Existing research on erector spinae plane block and intrathecal morphine in patients undergoing percutaneous nephrolithotomy surgery is limited. METHODS: In this prospective, randomized study, 60 patients aged between 18 and 60 years were randomized into two groups (erector spinae plane block and intrathecal morphine). In the erector spinae plane block group, ultrasound-guided erector spinae plane block was performed, following which a mixture of 20 mL of 0.375% ropivacaine and 0.5 mcg/kg of clonidine was injected. In the intrathecal morphine group, 150 mcg preservative-free morphine with 2 mL of normal saline was administered intrathecally. The primary outcome was to evaluate the perioperative opioid consumption in the first 24 h. The secondary outcomes were to evaluate hemodynamic response to surgical stimulus, visual analogue scale score, time to first analgesic requirement, postoperative nausea and vomiting, postoperative opioid consumption, urethral irritation, and incidence of drug-related adverse effects. RESULTS: Total perioperative opioid consumption in the erector spinae plane block group was 355.0 (265.0, 485.0) µg and 240.0 (145.0, 370.0) µg in the intrathecal morphine group (P = 0.09). However, the patients in the erector spinae plane block group had significantly greater postoperative fentanyl consumption (235.0 [120.0, 345.0] µg) compared with those in the intrathecal morphine group (105.0 [30.0, 225.0] µg). There were no statistically significant differences noted for intraoperative opioid consumption, postoperative visual analogue scale score, time to first analgesic request, postoperative nausea and vomiting, and catheter irritation between the two groups. CONCLUSIONS: Although no statistically significant difference in intraoperative opioid consumption was seen between the erector spinae plane block and intrathecal morphine groups, postoperative opioid consumption was significantly higher in the erector spinae plane block group than in the intrathecal morphine group in patients undergoing percutaneous nephrolithotomy surgery.

Indian goose berry fortified, anti-oxidant rich bael (Aegle marmelos) fermented beverage.

Bael (Aegle marmelos Correa), an important fruit of Indian subtropics, traditionally utilized in the preparation of preserve, candy, squash, RTS, etc. has immense therapeutic potential. An attempt was made to develop a bael based low alcoholic sweet fermented beverage ( may be called as bael cider), anti-oxidant fortified with 0.25 per cent bael leaf or 10 per cent Indian goose berry (Emblica officinalis Gaertn.) juice in separate batches. Unfortified bael pulp based drink was kept as control. The ameliorated pulp was fermented at 30 ± 2ºC using Saccharomyces cerevisiae. The gooseberry blended bael fermented beverage had higher anti-oxidant content in the form of phenolics (323 mg/100 ml) than leaf extract added fermented beverage (265 mg/100 ml) and control (266 mg/100 ml). Sensory evaluation of product revealed that gooseberry blended fermented beverage scored higher (8.2/10) than bael leaf blended fermented beverage (7.9/10) and control (7.0/10). Twelve months maturation study of beverage revealed increase in reducing sugars and decrease in phenolic content in all the treatments. Bael fermented beverage with gooseberry blend retained highest phenolic content (257 mg/100 ml) and sensory score 7.8/10. The study inferred that an acceptable quality fermented drink could be prepared from bael-gooseberry blend, which could be stored for one year with higher antioxidant value and minimum deterioration in the quality.

Central Placenta Previa With Coexisting Central Cervical Fibroid in Pregnancy: An Obstetrician's Nightmare.

Pregnancy with central placenta praevia and a coexistent cervical fibroid is infrequently encountered in clinical practice. A patient with this unusual combination is a nightmare for any clinician, especially if she presents with obstetric emergencies. In this scenario, there is a high chance of catastrophic obstetric hemorrhage during the peripartum period leading to a fatal outcome. We report a case of a 27-year-old lady at term pregnancy, who was brought to emergency in labor pain with antepartum hemorrhage. Subsequently, she was diagnosed to have central placenta praevia along with a large central cervical fibroid. An emergency cesarean section was performed to deliver the child. Intraoperatively, she had a major postpartum hemorrhage which was successfully managed with intrauterine balloon tamponade, hemostatic sutures, and uterine artery ligation. We could avoid cesarean hysterectomy by precise anticipation, meticulous planning, and step-wise protocol-driven management.

Selective Activation of MST1/2 Kinases by Retinoid Agonist Adapalene Abrogates AURKA-Regulated Septic Arthritis.

Septic arthritis is a chronic inflammatory disorder caused by Staphylococcus aureus invasion of host synovium, which often progresses to impairment of joint functions. Although it is known that disease progression is intricately dependent on dysregulated inflammation of the knee joint, identification of molecular events mediating such imbalance during S. aureus-induced septic arthritis still requires detailed investigation. In this article, we report that Aurora kinase A (AURKA) responsive WNT signaling activates S. aureus infection-triggered septic arthritis, which results in inflammation of the synovium. In this context, treatment with adapalene, a synthetic retinoid derivative, in a mouse model for septic arthritis shows significant reduction of proinflammatory mediators with a simultaneous decrease in bacterial burden and prevents cartilage loss. Mechanistically, adapalene treatment inhibits WNT signaling with concomitant activation of HIPPO signaling, generating alternatively activated macrophages. Collectively, we establish adapalene as a promising strategy to suppress S. aureus-induced irreversible joint damage.

A De novo Peptide from a High Throughput Peptide Library Blocks Myosin A -MTIP Complex Formation in Plasmodium falciparum.

Apicomplexan parasites, through their motor machinery, produce the required propulsive force critical for host cell-entry. The conserved components of this so-called glideosome machinery are myosin A and myosin A Tail Interacting Protein (MTIP). MTIP tethers myosin A to the inner membrane complex of the parasite through 20 amino acid-long C-terminal end of myosin A that makes direct contacts with MTIP, allowing the invasion of Plasmodium falciparum in erythrocytes. Here, we discovered through screening a peptide library, a de-novo peptide ZA1 that binds the myosin A tail domain. We demonstrated that ZA1 bound strongly to myosin A tail and was able to disrupt the native myosin A tail MTIP complex both in vitro and in vivo. We then showed that a shortened peptide derived from ZA1, named ZA1S, was able to bind myosin A and block parasite invasion. Overall, our study identified a novel anti-malarial peptide that could be used in combination with other antimalarials for blocking the invasion of Plasmodium falciparum.

Clinical Profile, Surgical Approach and Outcome of Complicated Genital Fistulae in Urban Population of a Developing Nation.

OBJECTIVES: To study aetiology and management of complicated genital fistulae and to evaluate the outcome of the treatment. METHODS: This observational study enrolled patients with complicated genital fistulae from September 2008 to August 2018 at Sant Parmanand Hospital, Delhi. Patients underwent a reparative surgery or ureteric stenting after a detailed preoperative workup. Patients were followed up for the assessment of outcomes. RESULTS: A total of 16 patients were recruited: Ten (62.5%) patients had fistulae secondary to gynaecological surgeries (seven laparoscopic and three abdominal hysterectomies) and six (37.5%) patients had obstetric fistulae. At a mean follow-up of 5.8 years among obstetric fistulae and 7.3 years among post-operative fistulae, 100% success rate was maintained with the first attempt of reparative surgery or ureteric stenting. There were no major complications. Two patients had recurrent urinary tract infections, and one patient had transient urinary incontinence for 4 weeks. CONCLUSION: The study demonstrates that complicated genital fistulae occur more commonly secondary to gynaecological surgeries as compared to obstetric complications in a contemporary cohort from a metropolitan city. A 100% success rate of reparative surgery could be achieved with a transperitoneal approach. Good outcome in ureteric fistulae can be achieved with conservative approach, after proper case selection.

The Therapeutic and Preventive Efficacy of Curcumin and Its Derivatives in Esophageal Cancer

Esophageal cancer is the eighth most common occurring cancer type worldwide and 6th most common among the cancer related deaths of which the most common type is squamous cell carcinoma which comprise about 90% of esophageal cancer cases. The standard of care for esophageal cancer is neoadjuvant concurrent chemotherapy and radiation (NACRT) followed by surgery however the prognosis remains dismal with 5 year survival a meager 10-15%. The treatment modalities for esophageal cancer is associated with both long term and short term toxicities. Curcumin has been explored as a therapeutic modality as a chemo adjuvant in different cancers due to its low toxicity profile and potent anticancer effect however despite lot of promising preclinical data it has not progressed from bench side to bed side. The primary reason that has obstructed its application in clinic has been its low bioavailability which was seen in different clinical trials but there has been tremendous progress in developing formulations of curcumin which have significantly increased its bioavailability and are being tested in clinical trials. Esophageal cancer is associated with inflammation that's why curcumin being a natural antioxidant offer a potential avenue to reduce toxicity of current therapeutic modalities in a chemo adjuvant setting while simultaneously targeting different pro oncogenic pathways. The present review tries to cover in depth different aspects of curcumin application in treatment of esophageal cancer and progress of this potent anticancer agent in its treatment and prevention.

Plasmodium palmitoylation machinery engineered in E. coli for high-throughput screening of palmitoyl acyl-transferase inhibitors.

Lipid-based palmitoylation is a post-translation modification (PTM) which acts as a biological rheostat in life cycle progression of a deadly human malaria parasite, Plasmodium falciparum. P. falciparum palmitoylation is catalyzed by 12 putative palmitoyl acyl-transferase enzymes containing the conserved DHHC-CRD (DHHC motif within a cysteine-rich domain) which can serve as a druggable target. However, the paucity of high-throughput assays has impeded the design of drugs targeting palmitoylation. We have developed a novel strategy which involves engineering of Escherichia coli, a PTM-null system, to enforce ectopic expression of palmitoyl acyl-transferase in order to study Plasmodium-specific palmitoylation and screening of inhibitors. In this study, we have developed three synthetic E. coli strains expressing Plasmodium-specific DHHC proteins (PfDHHC7/8/9). These cells were used for validating acyl-transferase activity via acyl-biotin exchange (ABE) and clickable chemistry methods. E. coli proteome was found to be palmitoylated in PfDHHC-expressing clones, suggesting that plasmodium DHHC can catalyze palmitoylation of E. coli proteins. Upon treatment with generic inhibitor 2-bromopalmitate (2-BMP), a predominant reduction in palmitic acid incorporation is detected. Overall, these findings suggest that synthetic E. coli strains expressing PfDHHCs can enforce global palmitoylation in the E. coli proteome. Interestingly, this finding was corroborated by our in silico palmitoylome profiling, which revealed that out of the total E. coli proteome, 108 proteins were predicted to be palmitoylated as represented by the presence of three cysteine consensus motifs (cluster type I, II, III). In summary, our study reports a proof of concept for screening of chemotherapeutics targeting the palmitoylation machinery using a high-throughput screening platform.

Deregulated AUF1 Assists BMP-EZH2-Mediated Delayed Wound Healing during Candida albicans Infection.

Tissue repair is a complex process that necessitates an interplay of cellular processes, now known to be dictated by epigenetics. Intriguingly, macrophages are testimony to a large repertoire of evolving functions in this process. We identified a role for BMP signaling in regulating macrophage responses to Candida albicans infection during wound repair in a murine model. In this study, the RNA binding protein, AU-rich element-binding factor 1, was posttranslationally destabilized to bring about ubiquitin ligase, NEDD4-directed activation of BMP signaling. Concomitantly, PI3K/PKCδ mobilized the rapid phosphorylation of BMP-responsive Smad1/5/8. Activated BMP pathway orchestrated the elevated recruitment of EZH2 at promoters of genes assisting timely wound closure. In vivo, the repressive H3K27 trimethylation was observed to persist, accompanied by a robust upregulation of BMP pathway upon infection with C. albicans, culminating in delayed wound healing. Altogether, we uncovered the signaling networks coordinated by fungal colonies that are now increasingly associated with the infected wound microbiome, resulting in altered wound fate.

Identification and Characterization of a Novel Palmitoyl Acyltransferase as a Druggable Rheostat of Dynamic Palmitoylome in L. donovani.

Palmitoylation has been recently identified as an important post-translational rheostat for controlling protein function in eukaryotes. However, the molecular machinery underlying palmitoylation remains unclear in the neglected tropical parasite, Leishmania donovani. Herein, we have identified a catalog of 20 novel palmitoyl acyltransferases (PATs) and characterized the promastigote-specific PAT (LdPAT4) containing the canonical Asp-His-His-Cys (DHHC) domain. Immunofluorescence analysis using in-house generated LdPAT4-specific antibody demonstrated distinct expression of LdPAT4 in the flagellar pocket of promastigotes. Using metabolic labeling-coupled click chemistry method, the functionality of this recombinant enzyme could be authenticated in E. coli strain expressing LdPAT4-DHHC domain. This was evident by the cellular uptake of palmitic acid analogs, which could be successfully inhibited by 2-BMP, a PAT-specific inhibitor. Using CSS-Palm based in-silico proteomic analysis, we could predict up to 23 palmitoylated sites per protein in the promastigotes, and further identify distinctive palmitoylated protein clusters involved in microtubule assembly, flagella motility and vesicular trafficking. To highlight, proteins such as Flagellar Member proteins (FLAM1, FLAM5), Intraflagellar Transport proteins (IFT88), and flagellar motor assembly proteins including the Dynein family were found to be enriched. Furthermore, analysis of global palmitoylation in promastigotes using Acyl-biotin exchange purification identified a set of S-palmitoylated proteins overlapping with the in-silico proteomics data. The attenuation of palmitoylation using 2-BMP demonstrated several phenotypic alterations in the promastigotes including distorted morphology, reduced motility (flagellar loss or slow flagellar beating), and inefficient invasion of promastigotes to host macrophages. These analyses confirm the essential role of palmitoylation in promastigotes. In summary, the findings suggest that LdPAT4 acts as a functional acyltransferase that can regulate palmitoylation of proteins involved in parasite motility and invasion, thus, can serve as a potential target for designing chemotherapeutics in Visceral Leishmaniasis.

Distribution of therapeutic proteins into thoracic lymph after intravenous administration is protein size-dependent and primarily occurs within the liver and mesentery.

Therapeutic proteins can facilitate the targeting and treatment of lymphatic diseases (such as cancer metastases, infections and inflammatory diseases) since they are cleared via the lymphatics following interstitial (SC or IM) administration. However, therapeutic proteins are often administered intravenously (IV). Recently therapeutic proteins have been found to access the thoracic lymph in surprisingly high quantities after IV administration. The aim of this study was to determine, for the first time, the major sites of thoracic lymph access of therapeutic proteins, and the protein properties that enhance lymph access, after IV administration. In order to achieve this, novel methods were developed or optimized to collect hepatic, mesenteric or thoracic lymph from male SD rats. Four different sized PEGylated or non-PEGylated therapeutic proteins (native interferon α2b (IFN, 19kDa), PEGylated interferon α2b (IFN-PEG12, 31kDa), PEGylated interferon α2a (IFN-PEG40, 60kDa) or trastuzumab (150kDa)) were then administered via short IV infusion, and plasma and lymph concentrations of the proteins determined via ELISA. The recovery of the therapeutic proteins in the thoracic lymph duct, which collects lymph from most of the body, was significantly greater for trastuzumab, IFN-PEG40 and IFN-PEG12 (all >3% dose over 8h) when compared to native IFN (0.9% dose). Conversely, the thoracic lymph/plasma (L/P) concentration ratio and thus efficiency of extravasation and transport through the interstitium to lymph was highest for the smaller proteins IFN and IFN-PEG12 (at 90-100% vs 15-30% for trastuzumab and IFN-PEG40). The lower total recovery of IFN and IFN-PEG12 in thoracic lymph reflected more rapid systemic clearance and thus lower systemic exposure. For all therapeutic proteins, the majority (>80%) of lymph access occurred via the hepatic and mesenteric lymphatics. This lymphatic distribution pattern was supported by quantitative imaging of the lymph node distribution of IV administered Cy5 labelled trastuzumab. Optimizing the properties of IV administered therapeutic proteins represents a viable approach to better target and treat pathological states involving the lymphatics, particularly in the liver and mesentery. This includes cancer metastases, infections and inflammatory diseases. Successful development of the novel technique to collect hepatic lymph will also enable future work to evaluate tissue-specific lymph transport in health and disease.

Transversus Abdominis Plane Block for Inguinal Hernia Repair in a Premature Infant: A Case Report.

In this report, we describe the case of a premature infant (36 weeks' postgestational age) who underwent left inguinal hernia repair under general anesthesia without the use of any airway device. Anesthesia was induced and maintained with sevoflurane in oxygen and nitrous oxide. An ultrasound-guided transversus abdominis plane block was performed that provided effective analgesia, obviating the need for opioids in the intraoperative period. The infant's hemodynamics remained stable throughout the surgery. This report also briefly explains the advantages of using a transversus abdominis plane block, compared with neuraxial blockade, for hernia repair surgery.

Neurofilament depletion improves microtubule dynamics via modulation of Stat3/stathmin signaling.

In neurons, microtubules form a dense array within axons, and the stability and function of this microtubule network is modulated by neurofilaments. Accumulation of neurofilaments has been observed in several forms of neurodegenerative diseases, but the mechanisms how elevated neurofilament levels destabilize axons are unknown so far. Here, we show that increased neurofilament expression in motor nerves of pmn mutant mice, a model of motoneuron disease, causes disturbed microtubule dynamics. The disease is caused by a point mutation in the tubulin-specific chaperone E (Tbce) gene, leading to an exchange of the most C-terminal amino acid tryptophan to glycine. As a consequence, the TBCE protein becomes instable which then results in destabilization of axonal microtubules and defects in axonal transport, in particular in motoneurons. Depletion of neurofilament increases the number and regrowth of microtubules in pmn mutant motoneurons and restores axon elongation. This effect is mediated by interaction of neurofilament with the stathmin complex. Accumulating neurofilaments associate with stathmin in axons of pmn mutant motoneurons. Depletion of neurofilament by Nefl knockout increases Stat3-stathmin interaction and stabilizes the microtubules in pmn mutant motoneurons. Consequently, counteracting enhanced neurofilament expression improves axonal maintenance and prolongs survival of pmn mutant mice. We propose that this mechanism could also be relevant for other neurodegenerative diseases in which neurofilament accumulation and loss of microtubules are prominent features.

Chromones and their derivatives as radical scavengers: a remedy for cell impairment.

Chromones (1-benzopyran-4-ones) are natural occurring compounds present in representative amounts in a normal human diet and are associated with interesting physiological activities such as antiinflammatory, antidiabetic, antitumor, anticancer etc. These biological activities are thought to be related to the antioxidant properties of chromones i.e. to neutralize active oxygen and to cut off free radicals processes that can delay or inhibit cell impairment which leads to various diseases. In this review, we have summarized the literature reports published in about 70 research articles during the period January 2004 to March 2014 on more than 400 naturally as well as the synthetically derived chromone derivatives having antioxidant potential. The literature reports suggest that the double bond, a carbonyl group of chromone and 3´,4´-dihydroxy group (catechol) in ring B along with the C-3 and C-5 hydroxyl groups are important for radical scavenging activity. In turn, a decrease in the radical scavenging potential has been observed upon methylation / glycosylation of the hydroxyl groups on chromone nucleus.

The Fas/Fas ligand apoptotic pathway is involved in abrin-induced apoptosis.

Abrin is a plant glycoprotein toxin from the seeds of Abrus precatorius, sharing similarity in structure and properties with ricin. Abrin is highly toxic, with an estimated human fatal dose of 0.1-1 µg/kg, causing death after accidental or intentional poisoning. It is a potent biological toxin warfare agent. There is no chemical antidote available against the abrin. The elucidation of molecular mechanism of abrin-induced cell death is important for development of therapy. Intrinsic pathway-mediated apoptosis has been well established in abrin-induced cell death. However, the detailed mechanism especially extrinsic receptor-mediated pathway remains uncharacterized. To assess whether some of the apoptosis known to occur after abrin exposure might be mediated by Fas/Fas ligand (Fas L) interactions, we analyzed effect of abrin on Fas pathway in Jurkat cells. Here, we report that activation of the Fas pathway is involved in abrin-induced apoptosis. Following treatment of abrin, Fas L was induced, which stimulated the Fas pathway by cross-linking Fas receptor (Fas R). Apoptosis was mediated by cleavage of the Fas R proximal caspase-8 and the downstream caspase-3, resulting in activation of the prototype caspase substrate poly-(ADP-ribose) polymerase and caspase-activated DNase. Blocking Fas L/Fas R interaction by using Fas inhibitor reduced abrin-induced apoptosis, further confirms involvement of Fas pathway. Activation of components of Fas pathway and caspases upon abrin treatment was also found in splenocytes in mice. Our findings offer new perspective for understanding the fundamental mechanism in abrin-induced apoptotic mechanism and may have implication in developing novel therapeutic strategies in the management for abrin-induced complications.

T-2 toxin induced skin inflammation and cutaneous injury in mice.

T-2 toxin is one of the most toxic among several trichothecenes involved in both human and animal poisoning cases. We investigated the biochemical and histological alterations behind inflammation and cutaneous injury caused by T-2 toxin. Swiss albino mice were exposed to T-2 toxin topically at doses of 0.5, 1 and 2 LD50 (2.97, 5.94 and 11.88 mg/kg respectively) and observed till 3, 24 and 72 h. Topical application of T-2 toxin resulted in skin oxidative stress in terms of increased reactive oxygen species generation, lipid peroxidation and neutrophil mediated myeloperoxidase activity. The histological alterations include degenerative changes like vacuolation, ballooning of basal keratinocytes and infiltration of inflammatory cells in dermis. The mRNA levels of skin pro-inflammatory cytokines TNF-α, IL-6, and IL-1ß showed significant up regulation. Anti-inflammatory cytokines IL-10 showed significant up regulation at 24h whereas IL-4 showed down regulation for all the doses and time points. Gelatin zymography and immunoblot analysis of matrix metalloproteinases (MMP)-9 and 2 indicated MMP activation and their role in degenerative skin histological changes. Time dependent increase in inducible nitric oxide synthase levels was seen. Immunoblot analysis revealed significant increase in the levels of phosphorylated p38 mitogen activated protein kinase (MAPK). Flow cytometry analysis of propidium iodide stained epidermal cells showed increase in sub-G1 population at all the doses and time points indicating apoptosis. In summary, T-2 toxin induced skin inflammation and cutaneous injury is mediated through oxidative stress, activation of myeloperoxidase, MMP activity, increase in inflammatory cytokines, activation of p38 MAPK and apoptosis of epidermal cells leading to degenerative skin histological changes.

Drug advertisements published in Indian Medical Journals: Are they ethical?

CONTEXT: It is observed in studies done for western medical journals that insufficient information related to drug is usually provided in the drug advertisements published in them. AIMS: As data for advertisements published in Indian Medical Journals were lacking, this study was designed with the aim of evaluating drug advertisements published in Indian Medical Journals for adequacy of information on drug and references given to support the claim made in the advertisements. SETTINGS AND DESIGN: Cross-sectional survey. METHODS AND MATERIALS: All medical journals related to clinical practice subscribed by the Central Library of Government Medical College, Surat, (Indian Journal of Pediatrics [IJP], Indian Pediatrics [IP], Journal of the Association of Physicians of India [JAPI], Journal of Indian Medical Association [JIMA], Indian Journal of Critical Care Medicine [IJCCM], Indian Journal of Medical and Pediatric Oncology [IJMPO], Indian Journal of Gastroenterology [IJG], Indian Journal of Ophthalmology [IJO], and Journal of Obstetrics and Gynecology of India [JOGI] were evaluated for adequacy of reporting of various parameters in drug advertisements published in these journals on the basis of "World Heath Organization (WHO)" criteria. References mentioned to support claims were also evaluated. STATISTICAL ANALYSIS USED: Descriptive statistics was used to describe data as frequencies, percentages, and 95% confidence interval around the percentage. RESULTS: Generic name was mentioned in 90% advertisements. Indications were mentioned in 84% advertisements. Dose, precautions, and contraindications were mentioned in 24%, 17%, and 16% advertisements, respectively. Adverse effects and postal address of pharmaceutical company was mentioned in 19% and 74% advertisements, respectively. Price was mentioned in only 5% advertisements. Only 28% claims were supported by references. Most common references were Journal articles (75%). CONCLUSION: Drug advertisements published in Indian Medical Journals are poor in reporting various parameters according to WHO criteria.

Effects of combined exposure to dichlorvos and monocrotophos on blood and brain biochemical variables in rats.

Dichlorvos (DDVP) and monocrotophos (MC) are systemic insecticides and known to produce cholinergic and non-cholinergic effects. Individual toxic effects of these chemicals are known but their combined effects have not been studied. We studied the effect of concomitant exposure to DDVP and MC on selected biochemical variables suggestive of liver damage, changes in whole brain biogenic amines levels, acetylcholinesterase (AchE) and monoamine oxidase (MAO) activities in rats. Female rats were exposed to DDVP (2.5 mg/kg subcutaneously) and MC (1.8 mg/kg oral) either individually or in combination for 4 weeks. We observed significant decrease in more pronounced depletion in norepinephrine (NE) and dopamine (DA) levels during co-exposure to DDVP and MC. Brain AChE activity increased and activity of MAO showed significant depletion on co-exposure to DDVP and MC. Brain glutathione (GSH) and oxidized glutathione (GSSG) ratio decreased significantly during exposure to DDVP or MC while co-exposure to these toxicants led to a more pronounced depletion of GSH: GSSG ratio. Serum aspartate amino transferase (AST) and alkaline phosphatase (ALP) activities increased significantly on exposure to MC suggesting liver injury, while DDVP alone had no effect on these variables. There were no effects of DDVP and MC exposure on haematological biochemical variables except for depletion in serum glucose level after MC exposure which was more pronounced DDVP + MC during co-exposure. It can be concluded that only moderate synergistic effects occur between MC and DDVP during co-exposure. A more detailed study with variable doses, prolonged exposure and alterations in different brain regions is recommended.