Binding of Nucleotide Inhibitors to the NS5 RdRp of the ZIKA Virus in the Replication Initiation State.

INTRODUCTION: The bindings of several ribonucleoside triphosphate (NTP) inhibitors to the RNA-dependent RNA polymerase (RdRp) of the Zika virus (ZIKV) are studied herein to identify potential drug-like candidates that can inhibit the replication of the viral genome by RdRp. METHOD: In this study, a guanosine triphosphate (GTP) bound RdRp structure is generated to model the replication initiation state of RdRp. Subsequently, the bindings of 30 NTP inhibitors to the GTP binding site of RdRp are studied in detail by using the molecular docking method. Based on the docking scores, four NTP inhibitors, such as 2'-Cmethyl- adenosine-5'-triphosphate (mATP), 7-deaza-2'-C-methyladenosine-TP (daza-- mATP), 1-N6-Ethenoadenosine-5'-triphosphate (eATP), and Remdesivir-5'-triphosphate (RTP) are shortlisted for further analysis by employing molecular dynamics simulations and binding free-energy methods. RESULTS: These inhibitors are found to bind to RdRp quite strongly, as evident from their relative binding free energies that lie between -31.54±4.54 to -89.46±4.58 kcal/- mol. As the binding of RTP to the GTP site of RdRp generates the most stable complex, which is about 45 kcal/mol more stable than the binding of GTP to RdRp, it is most likely that RTP may inhibit the replication of the Zika viral genome efficiently. CONCLUSION: However, experimental studies are required to measure the potency of RTP and other drugs before their clinical use.

Repurposing of antiparasitic drugs against the NS2B-NS3 protease of the Zika virus.

To date, no approved drugs are available to treat the Zika virus (ZIKV) infection. Therefore, it is necessary to urgently identify potential drugs against the ZIKV infection. Here, the repurposing of 30 antiparasitic drugs against the NS2B-NS3 protease of the ZIKV has been carried out by using combined docking and molecular dynamics- (MD) simulations. Based on the docking results, 5 drugs, such as Amodiaquine, Primaquine, Paromomycin, Dichlorophene, and Ivermectin were screened for further analysis by MD simulations and free energy calculations. Among these drugs, Amodiaquine and Dichlorophen are found to produce the most stable complexes and possess relative binding free energies of about -44.3 ± 3.7 kcal/mol and -41.1 ± 5.3 kcal/mol respectively. Therefore, they would act as potent small-molecule inhibitors of the ZIKV protease.However, evaluations of biological and safety activities of these drugs against the ZIKV protease are required before their clinical use.Communicated by Ramaswamy H. Sarma.

Short-course Palliative Hypofractionated Radiotherapy in Patients with Poor-prognosis High-grade Glioma: Survival and Quality of Life Outcomes from a Prospective Phase II Study.

AIMS: To report longitudinal quality of life (QoL) outcomes and survival in patients with poor-prognosis high-grade glioma (HGG) treated with palliative hypofractionated radiotherapy. MATERIALS AND METHODS: Patients with poor-prognosis HGG were accrued on a prospective study of short-course palliative hypofractionated radiotherapy (35 Gy/10 fractions/2 weeks). The European Organization for Research and Treatment of Cancer QoL core questionnaire (QLQ-C30) and brain cancer module (BN20) were used in English or validated Indian vernacular languages (Hindi and Marathi) for QoL assessment at baseline (before radiotherapy), the conclusion of radiotherapy, 1 month post-radiotherapy and subsequently at 3-monthly intervals until disease progression/death. Baseline QoL scores were compared with corresponding scores from a historical HGG cohort. Summary QoL scores were compared longitudinally over time by related samples Friedman's two-way test. Progression-free survival and overall survival were calculated using the Kaplan-Meier method and reported as 1-year estimates with 95% confidence intervals. RESULTS: Forty-nine (89%) of 55 patients completed the planned course of hypofractionated radiotherapy. Longitudinal QoL data were available in 42 (86%) of 49 patients completing radiotherapy, comprising the present cohort. The median age of included patients, comprised mainly of glioblastoma patients (81%), was 57 years, with an interquartile range (IQR) of 50-66 years and a median baseline Karnofsky score of 60 (IQR = 50-60). Baseline QoL scores were significantly worse for several domains compared with a historical institutional cohort of HGG patients treated previously with conventionally fractionated radiotherapy, indicating negative selection bias. QoL scores remained stable for most domains after palliative hypofractionated radiotherapy, with statistically significant improvements in fatigue (P = 0.032), dyspnoea (P = 0.042) and motor dysfunction (P = 0.036) over time. At a median follow-up of 8 months, Kaplan-Meier estimates of 1-year progression-free survival and overall survival were 33.3% (95% confidence interval 21.7-51.1%) and 38.1% (95% confidence interval 25.9-56%), respectively. CONCLUSION: Short-course palliative hypofractionated radiotherapy in patients with poor-prognosis HGG is associated with stable and/or improved QoL scores in several domains, making it a viable resource-sparing regimen.

Structures and dynamics of peptide and peptidomimetic inhibitors bound to the NS2B-NS3 protease of the ZIKA virus.

Infections caused by the Zika virus (ZIKV) have detrimental effects on human health, in particular on infants. As no potent drug or vaccine is available to date to contain this viral disease, it is necessary to design inhibitors that can target the NS2B-NS3 protease of the ZIKV, which is mainly responsible for the proliferation of the virus inside the host cells . Here, molecular dynamics (MD) simulation and molecular mechanics energies combined with the generalized Born and surface area continuum solvation model (MM/GBSA) are used to understand the binding modes and stabilities of R, KR, KKR, WKR, WKKR, YKKR, and FKKR peptide inhibitors bound to the NS3-NS2B protease. The results are compared with the corresponding results obtained for covalent (compound 1) and non-covalent (compound 4*) peptidomimetic inhibitors . It is revealed that peptide inhibitors can bind strongly with the ZIKV protease with the ΔGbind ranging from -12 kcal/mol to -73 kcal/mol. Among these peptides, YKKR is found to make the most stable complex with the protease and fully occupy the electrostatically active substrate binding site. Hence, it would inhibit the protease activities of ZIKV strongly. The residue-wise decomposition of ΔGbind indicates that Asp75, Asp129, Tyr130, Ser135, Gly151, Asn152, Glys153, and Tyr161 of NS3 and Ser81, Asp83, and Phe84 of NS2B play a prominent role in the inhibitor binding. Therefore, any future design of inhibitors should be aimed to target these residues.

Public Awareness and Attitude towards COVID-19 Infection and Vaccines: A cross-sectional national survey in Nepal.

Background To combat COVID-19, high vaccination rates are essential. However, challenges such as vaccine denial, lack of knowledge, and negative attitudes hinder progress. Assessing public understanding of vaccination is crucial to promote acceptance and reducing reluctance. Objective To understand people's awareness and attitude regarding COVID-19 infection and vaccines in Nepal. Method A cross-sectional web-based survey was conducted among the Nepali population of age 18 years and above in April 2021 during the early phase of vaccination deployment. A structured questionnaire was used to collect awareness data, and a five-point Likert scale was employed to assess participants' attitudes. The survey categorized participants into two groups based on whether their awareness level or attitude score was above or below the mean. The secondary outcome was the association between socio-demographic factors and COVID-19 awareness or attitude. Result Of 475 eligible participants, 46% had a low level of awareness on COVID-19 infection whereas 56% had low awareness on COVID-19 vaccines. Every six out of ten participants had a positive attitude towards the national COVID-19 vaccination program. Most of the participants had high awareness of COVID-19 symptoms and preventive measures (hand hygiene, physical distancing, mask), but two-thirds had a false perception of vaccine safety and contraindications. People's education status, occupation, province, and current/prior COVID-19 infection status were found to be significantly associated with their awareness regarding COVID-19 disease or vaccines. Conclusion The study revealed limited COVID-19 awareness among the Nepali population but a positive attitude toward the national vaccination program. Regular updates on COVID-19 and vaccines are important as new variants and vaccines emerge.

A phase 1b study of crenigacestat (LY3039478) in combination with gemcitabine and cisplatin or gemcitabine and carboplatin in patients with advanced or metastatic solid tumors.

BACKGROUND: Notch signaling plays an integral role in development and tissue homeostasis. Inhibition of Notch signaling has been identified as a reasonable target for oncotherapy. Crenigacestat (LY3039478) is a potent Notch inhibitor that decreases Notch signaling and its downstream biologic effects. METHODS: I6F-MC-JJCD was a multicenter, nonrandomized, open-label, phase 1b study with 5 separate, parallel dose escalations in patients with advanced or metastatic cancer from a variety of solid tumors followed by a dose-confirmation phase in pre-specified tumor types. This manuscript reports on 2 of 5 groups. The primary objective was to determine the recommended phase 2 dose of crenigacestat combined with other anticancer agents (gemcitabine/cisplatin or gemcitabine/carboplatin). Secondary objectives included evaluation of safety, tolerability, preliminary efficacy, and pharmacokinetics. RESULTS: Patients (N = 31) received treatment between November 2016 and July 2019. Dose-limiting toxicities occurred in 6 patients. The recommended phase 2 dose for crenigacestat was 50 mg TIW in Part 1 (combined with gemcitabine/cisplatin) and not established in Part 2 (combined with gemcitabine/carboplatin) due to poor tolerability. Patients had at least one treatment-emergent adverse event (TEAE), and most had Grade ≥ 3 TEAEs. Over 50% of the patients experienced gastrointestinal disorders (Grade ≥ 3). No patient had complete response; 5 patients had a partial response. Disease control rates were 62.5% (Part 1) and 60.0% (Part 2). CONCLUSION: This study demonstrated that the Notch inhibitor, crenigacestat, combined with different anticancer agents (gemcitabine, cisplatin, and carboplatin) was poorly tolerated and resulted in disappointing clinical activity in patients with advanced or metastatic solid tumors. CLINICALTRIALS: gov Identification Number: NCT02784795.

Machine learning for detection of stenoses and aneurysms: application in a physiologically realistic virtual patient database.

This study presents an application of machine learning (ML) methods for detecting the presence of stenoses and aneurysms in the human arterial system. Four major forms of arterial disease-carotid artery stenosis (CAS), subclavian artery stenosis (SAS), peripheral arterial disease (PAD), and abdominal aortic aneurysms (AAA)-are considered. The ML methods are trained and tested on a physiologically realistic virtual patient database (VPD) containing 28,868 healthy subjects, adapted from the authors previous work and augmented to include disease. It is found that the tree-based methods of Random Forest and Gradient Boosting outperform other approaches. The performance of ML methods is quantified through the [Formula: see text] score and computation of sensitivities and specificities. When using six haemodynamic measurements (pressure in the common carotid, brachial, and radial arteries; and flow-rate in the common carotid, brachial, and femoral arteries), it is found that maximum [Formula: see text] scores larger than 0.9 are achieved for CAS and PAD, larger than 0.85 for SAS, and larger than 0.98 for both low- and high-severity AAAs. Corresponding sensitivities and specificities are larger than 90% for CAS and PAD, larger than 85% for SAS, and larger than 98% for both low- and high-severity AAAs. When reducing the number of measurements, performance is degraded by less than 5% when three measurements are used, and less than 10% when only two measurements are used for classification. For AAA, it is shown that [Formula: see text] scores larger than 0.85 and corresponding sensitivities and specificities larger than 85% are achievable when using only a single measurement. The results are encouraging to pursue AAA monitoring and screening through wearable devices which can reliably measure pressure or flow-rates.

Neuropsychiatric manifestations in General Paralysis of Insane (GPI).

General paralysis of insane is a form of neurosyphilis which brings parenchymatous changes in the central nervous system. Its manifestations include a variety of neuropsychiatric symptoms ranging from cognitive impairment to overt psychosis. Clinicians face difficulties in proper diagnosis as variety of symptoms changes from one form to other within a short period of time. Rarity of the disease at this modern era of penicillin is also another factor in timely diagnosis and management of such cases. Here we present a case of general paralysis of insane who presented with variety of neuropsychiatric symptoms and have had great difficulties to reach into the diagnosis.

Sensitivity and Specificity of Lateral Flow Antigen Test Kits for COVID-19 in Asymptomatic Population of Quarantine Centre of Province 3.

Background Nearly after 6 months of the spread of Corona Virus Disease 19, along with the world Nepal is still trying to control the spread and prevent general population from acquiring it. With limited resources in manpower, technology and evidence it has been a difficult battle. But with time and more understanding of the virus new technology to detect the virus are coming up. It is a major breakthrough in the diagnostic field as this helps us in not only detecting the virus but also helps us to mobilize our human resources. This comes in a time where the cases are increasing at an alarming rate. Although numbers of Polymerase Chain Reaction testing have increased but due to the time consuming and the cost wise, we need a faster and equally reliable alternative. Antigen test approved by different countries can be used for point of care, screening and surveillance depending upon the requirements after calculating its sensitivity, specificity and accuracy. Objective To find out sensitivity and specificity of the Antigen test kit for COVID-19. Method Antigen tests were compared with Reverse Transcription Polymerase Chain Reaction as a reference standard in calculated sample size of 113 subjects in a high risk population. Both Reverse Transcription Polymerase Chain Reaction and antigen test were performed in a same subject with in maximum of 2 days' interval. Convenience sampling technique was used to select the subjects. Ethical approval was taken from Nepal Health Research Council before data collection. Study was done from August to September 2020 from Quarantine center of Province 3. Result There were total of 113 test carried out, among those 47 were positive and 66 were negative in Reverse Transcription Polymerase Chain Reaction. After preparing two by two table, Sensitivity and specificity of the tested was calculated which came out to be 85% and 100% respectively, with accuracy of 93.80%. Conclusion Even though the sensitivity and specificity came to be higher, this test should be interpreted cautiously depending upon the prevalence of Corona Virus Disease 19 in that particular community and the clinical and epidemiological context of the person who has been tested. When in doubt by clinical correlation should be confirmed with Reverse Transcription Polymerase Chain Reaction.

Management of Different Types of Pneumothorax at Dhulikhel Hospital, Kathmandu University Hospital.

Background Pneumothorax is defined as the presence of air in the pleural cavity. Pneumothorax can be classified as Spontaneous and Traumatic according to the etiology. Spontaneous pneumothorax is further classified as Primary and Secondary. Objective This study was conducted to know the management of different types of pneumothorax at Dhulikhel Hospital, Kathmandu University Hospital. Method This was a hospital based retrospective study conducted at Dhulikhel Hospital, Kathmandu University Hospital. Patients admitted in Surgery Ward with diagnosis of Pneumothorax from January 2018 to December 2019 were included in this study. Result This study included 144 patients with pneumothorax age ranging from 14 years to 94 years. Most of the patients were male with male:female ratio of 3.8:1. Eighty-four (58.03%) patients had Traumatic pneumothorax followed by Secondary spontaneous pneumothorax in 53(36.08%) patients and Primary spontaneous pneumothorax in seven (4.86%) patients. Among 144 patients, chest tube drain was required in 135 patients and nine patients were managed conservatively. One patient underwent Video Assisted Thoracoscopic Surgery (VATS) with Bullectomy and mechanical pleurodesis. Sixteen patients had persistent pneumothorax, among which six patients required chemical pleurodesis, two patients required negative suction therapy and five patients required both chemical pleurodesis and negative suction therapy. Conclusion This study showed pneumothorax to be more common in male population. Traumatic pneumothorax was the most common type followed by Secondary spontaneous pneumothorax and Primary spontaneous pneumothorax.

Treatment sequencing in metastatic colorectal cancer.

Metastatic colorectal cancer (mCRC) remains incurable in most cases, but survival has improved with advances in cytotoxic chemotherapy and targeted agents. However, the optimal use and sequencing of these agents across multiple lines of treatment is unclear. Here, we review current treatment approaches and optimal treatment sequencing across the first-, second- and third-line settings in mCRC, including biological aspects affecting sequencing and rechallenge. Effective first-line therapy is a key determinant of treatment outcomes and should be selected after considering both clinical factors and biological markers, notably RAS and BRAF. The second-line regimen choice depends on the systemic therapies given in first-line. Anti-angiogenic agents (e.g. bevacizumab, ramucirumab and aflibercept) are indicated for most patients, whereas epidermal growth factor receptor (EGFR) inhibitors do not improve survival in the second-line setting. Molecular profiling is important in third-line treatment, with options in RAS wild-type patients including EGFR inhibitors (cetuximab or panitumumab), regorafenib and trifluridine/tipiracil. Immunotherapy with pembrolizumab or nivolumab ± ipilimumab may be considered for patients with high microsatellite instability disease. Targeting HER2/neu amplification shows promise for the subset of CRC tumours displaying this abnormality. Sequencing decisions are complicated by the potential for any treatment break or de-escalation to evoke a distinct clinical progression type. Ongoing trials are investigating the optimal sequencing and timing of therapies for mCRC. Molecular profiling has established new targets, and increasing knowledge of tumour evolution under drug pressure will possibly impact on sequencing.

Analysis of porcine body size variation using re-sequencing data of miniature and large pigs.

BACKGROUND: Domestication has led to substantial phenotypic and genetic variation in domestic animals. In pigs, the size of so called minipigs differs by one order of magnitude compared to breeds of large body size. We used biallelic SNPs identified from re-sequencing data to compare various publicly available wild and domestic populations against two minipig breeds to gain better understanding of the genetic background of the extensive body size variation. We combined two complementary measures, expected heterozygosity and the composite likelihood ratio test implemented in "SweepFinder", to identify signatures of selection in Minipigs. We intersected these sweep regions with a measure of differentiation, namely FST, to remove regions of low variation across pigs. An extraordinary large sweep between 52 and 61 Mb on chromosome X was separately analyzed based on SNP-array data of F2 individuals from a cross of Goettingen Minipigs and large pigs. RESULTS: Selective sweep analysis identified putative sweep regions for growth and subsequent gene annotation provided a comprehensive set of putative candidate genes. A long swept haplotype on chromosome X, descending from the Goettingen Minipig founders was associated with a reduction of adult body length by 3% in F2 cross-breds. CONCLUSION: The resulting set of genes in putative sweep regions implies that the genetic background of body size variation in pigs is polygenic rather than mono- or oligogenic. Identified genes suggest alterations in metabolic functions and a possible insulin resistance to contribute to miniaturization. A size QTL located within the sweep on chromosome X, with an estimated effect of 3% on body length, is comparable to the largest known in pigs or other species. The androgen receptor AR, previously known to influence pig performance and carcass traits, is the most obvious potential candidate gene within this region.

Short communication: Uncovering quantitative trait loci associated with resistance to Mycobacterium avium ssp. paratuberculosis infection in Holstein cattle using a high-density single nucleotide polymorphism panel.

Mycobacterium avium ssp. paratuberculosis (MAP) is the etiological agent of Johne's disease in cattle. Johne's disease is a disease of significant economic, animal welfare, and public health concern around the globe. Therefore, understanding the genetic architecture of resistance to MAP infection has great relevance to advance genetic selection methods to breed more resistant animals. The objectives of this study were to perform a genome-wide association study of previously analyzed 50K genotypes now imputed to a high-density single nucleotide polymorphism panel (777K), aiming to validate previously reported associations and potentially identify additional single nucleotide polymorphisms associated with antibody response to MAP infection. A principal component regression-based genome-wide association study revealed 15 putative quantitative trait loci (QTL) associated with the MAP infection phenotype (serum or milk ELISA tests) on 9 different chromosomes (Bos taurus autosomes 5, 6, 7, 10, 14, 15, 16, 20, and 21). These results validated previous findings and identified new QTL on Bos taurus autosomes 15, 16, 20, and 21. The positional candidate genes NLRP3, IFi47, TRIM41, TNFRSF18, and TNFRSF4 lying within these QTL were identified. Further functional validation of these genes is now warranted to investigate their roles in regulating the immune response and, consequently, cattle resistance to MAP infection.

Conserved roles of Osiris genes in insect development, polymorphism and protection.

Much of the variation among insects is derived from the different ways that chitin has been moulded to form rigid structures, both internal and external. In this study, we identify a highly conserved expression pattern in an insect-only gene family, the Osiris genes, that is essential for development, but also plays a significant role in phenotypic plasticity and in immunity/toxicity responses. The majority of Osiris genes exist in a highly syntenic cluster, and the cluster itself appears to have arisen very early in the evolution of insects. We used developmental gene expression in the fruit fly, Drosophila melanogaster, the bumble bee, Bombus terrestris, the harvester ant, Pogonomyrmex barbatus, and the wood ant, Formica exsecta, to compare patterns of Osiris gene expression both during development and between alternate caste phenotypes in the polymorphic social insects. Developmental gene expression of Osiris genes is highly conserved across species and correlated with gene location and evolutionary history. The social insect castes are highly divergent in pupal Osiris gene expression. Sets of co-expressed genes that include Osiris genes are enriched in gene ontology terms related to chitin/cuticle and peptidase activity. Osiris genes are essential for cuticle formation in both embryos and pupae, and genes co-expressed with Osiris genes affect wing development. Additionally, Osiris genes and those co-expressed seem to play a conserved role in insect toxicology defences and digestion. Given their role in development, plasticity, and protection, we propose that the Osiris genes play a central role in insect adaptive evolution.

TAK-228 (formerly MLN0128), an investigational dual TORC1/2 inhibitor plus paclitaxel, with/without trastuzumab, in patients with advanced solid malignancies.

PURPOSE: This phase I trial evaluated the safety, pharmacokinetic profile, and antitumor activity of investigational oral TORC1/2 inhibitor TAK-228 plus paclitaxel, with/without trastuzumab, in patients with advanced solid malignancies. METHODS: Sixty-seven patients received TAK-228 6-40 mg via three dosing schedules; once daily for 3 days (QDx3d QW) or 5 days per week (QDx5d QW), and once weekly (QW) plus paclitaxel 80 mg/m2 (dose-escalation phase, n = 47) and with/without trastuzumab 2 mg/kg (expansion phase, n = 20). Doses were escalated using a modified 3 + 3 design, based upon dose-limiting toxicities in cycle 1. RESULTS: TAK-228 pharmacokinetics exhibited dose-dependent increase in exposure when dosed with paclitaxel and no apparent differences when administered with or 24 h after paclitaxel. Dose-limiting toxicities were dehydration, diarrhea, stomatitis, fatigue, rash, thrombocytopenia, neutropenia, leukopenia, and nausea. The maximum tolerated dose of TAK-228 was determined as 10-mg QDx3d QW; the expansion phase proceeded with 8-mg QDx3d QW. Overall, the most common grade ≥3 drug-related toxicities were neutropenia (21%), diarrhea (12%), and hyperglycemia (12%). Of 54 response-evaluable patients, eight achieved partial response and six had stable disease lasting ≥6 months. CONCLUSION: TAK-228 demonstrated a safety profile consistent with other TORC inhibitors and promising preliminary antitumor activity in a range of tumor types; no meaningful difference was noted in the pharmacokinetics of TAK-228 when administered with or 24 h after paclitaxel. These findings support further investigation of TAK-228 in combination with other agents including paclitaxel, with/without trastuzumab, in patients with advanced solid tumors. CLINICALTRIALS. GOV IDENTIFIER: NCT01351350.

Evaluation of abrin induced nephrotoxicity by using novel renal injury markers.

Abrin is a potent plant toxin analogous to ricin that is derived from the seeds of Abrus precatorius plant. It belongs to the family of type II ribosome-inactivating proteins and causes cell death by irreversibly inactivating ribosomes through site-specific depurination. In this study we examined the in vivo nephrotoxicity potential of abrin toxin in terms of oxidative stress, inflammation, histopathological changes and biomarkers of kidney injury. Animals were exposed to 0.5 and 1.0 LD50 dose of abrin by intraperitoneal route and observed for 1, 3, and 7 day post-toxin exposure. Depletion of reduced glutathione and increased lipid peroxidation levels were observed in abrin treated mice. In addition, abrin also induced inflammation in the kidneys as observed through expression of MMP-9 and MMP-9/NGAL complex in abrin treated groups by using zymography method. Nephrotoxicity was also evaluated by western blot analysis of kidney injury biomarkers including Clusterin, Cystatin C and NGAL, and their results indicate severity of kidney injury in abrin treated groups. Kidney histology confirmed inflammatory changes due to abrin. The data generated in the present study clearly prove the nephrotoxicity potential of abrin.

Prevalence of Sensory Neuropathy in Type 2 Diabetes Mellitus and Its Correlation with Duration of Disease.

Background Peripheral neuropathy is one of the most common and distressing late complication of diabetes mellitus. Ignorance of the complications may develop foot ulcers and gangrene requiring amputation. Objective The main objective of this study is to find out the prevalence of sensory neuropathy in type 2 diabetes mellitus and to compare it with the duration of disease. Method Two hundred seventy one patients with type 2 diabetes mellitus of both gender age 30 years and above willing to participate were included in this study. Patients having hypothyroidism, rheumatoid arthritis, B12 deficiency, cerebrovascular disease, chronic musculoskeletal disease, Parkinson's disease, alcohol abuse, chronic renal or liver failure and cancer were excluded from the study. Touch, pin prick and vibration sensation were tested. Vibration perception threshold was recorded from six different sites of the sole of each foot using Biothesiometer. Result Two hundreds seventy one type 2 diabetic outpatients were studied. The mean age was 59.81±22.85 years. The overall prevalence of diabetic sensory neuropathy in the study population was 58.70%. A rising trend of diabetic sensory neuropathy with increasing age and duration of diabetes was observed. Neuropathy was found more in patients having urinary microalbuminuria. Burning and pins and needles sensation were most common symptoms. Conclusion The overall prevalence of diabetic sensory neuropathy in the study population was 58.70% (mean age 59.81±22.85 yrs), and its prevalence increased with duration of diabetes and increasing age. Its prevalence was found more in patients having microalbuminuria.

Prophylactic efficacy of S-2(2-aminoethylamino)ethyl phenyl sulfide (DRDE-07) against sulfur mustard induced lung toxicity in mice.

OBJECTIVE: The present study was planned to investigate the prophylactic efficacy of S-2(2-aminoethylamino)ethyl phenyl sulfide (DRDE-07), against topically applied SM induced pulmonary toxicity in mouse. MATERIALS AND METHODS: Animals were pretreated with S-2(2-aminoethylamino)ethyl phenyl sulfide (DRDE-07) (249.4 mg/kg by oral gavage) 30 minutes before SM exposure. The SM (6.48 mg/kg) was applied on hair clipped dorsocaudal region (percutaneous) of the animal. The animals were sacrificed on day 1, 3, 5 and 7. The biochemical changes those were observed in the bronchoalveolar lavage (BAL) fluid and lung tissue included protein, LDH, MPO, ß-glucuronidase, MMP-2, MMP-9, activated macrophages, reduced glutathione and lipid peroxidation level. RESULTS AND DISCUSSION: Pretreatment with DRDE-07 (0.2 LD50) attenuated SM-induced changes at all time point tested. BAL fluid biochemical endpoints indicated epithelial and endothelial cell damages as evidenced by increase in BAL protein, LDH level and increased number of activated macrophages. The increased myeloperoxidase activity and ß-glucuronidase level exhibited the degranulation of neutrophils due to SM toxicity in lung. The zymogrphy analysis of BAL fluid showed a significant increase in matrix metalloproteases (MMP) activity due to inflammatory cells accumulation. CONCLUSION: Thirty minutes pretreatment with DRDE-07 decreased vascular permeability reduced the inflammation and oxidative stress, hence may be recommended as a potential prophylactic agent for SM intoxication.