Central institutional ethics committee needed to facilitate timely review of multicenter clinical trials.

A multicenter trial in India undergoes review by Institutional Ethics Committees (IECs) of all participating institutions. The failure to obtain approval even from a single institution's IEC creates a situation of inequitable access to clinical trials. The dichotomy in decisions of different IECs is attributed to lack of standardization and accountability in their functioning. The registration of IECs with Central Drugs Standard Control Organization notwithstanding, the current model of IEC review has failed to ensure uniformity in IEC decisions in multicenter trials. Alternative models that allow central review of multicenter clinical trials should be explored.

Development and quality evaluation of dehydrated chicken meat rings using spent hen meat and different extenders.

It is recommended that for effective utilization of spent hen meat, it should be converted into value added or shelf stable meat products. Since we are lacking in cold chain facilities, therefore there is imperative need to develop shelf stable meat products. The present study was envisaged with the objective to develop dehydrated chicken meat rings utilizing spent hen meat with different extenders. A basic formulation and processing conditions were standardized for dehydrated chicken meat rings. Extenders such as rice flour, barnyard millet flour and texturized soy granule powder at 5, 10 and 15 % levels were incorporated separately replacing the lean meat in pre standardized dehydrated chicken meat ring formulation. On the basis of physico-chemical properties and sensory scores optimum level of incorporation was adjudged as 10 %, 10 % and 5 % for rice flour, barnyard millet flour and texturized soy granule powder respectively. Products with optimum level of extenders were analysed for physico-chemical and sensory attributes. It was found that a good quality dehydrated chicken meat rings can be prepared by utilizing spent hen meat at 90 % level, potato starch 3 % and refined wheat flour 7 % along with spices, condiments, common salt and STPP. Addition of an optimum level of different extenders such as rice flour (10 %), barnyard millet flour (10 %) and TSGP (5 %) separately replacing lean meat in the formulation can give acceptable quality of the product. Rice flour was found to be the best among the three extenders studied as per the sensory evaluation.

Development and evaluation of Fusarium wilt-resistant and high-yielding chickpea advanced breeding line, KCD 11.

Fusarium wilt (FW) is the most severe soil-borne disease of chickpea that causes yield losses up to 100%. To improve FW resistance in JG 11, a high-yielding variety that became susceptible to FW, we used WR 315 as the donor parent and followed the pedigree breeding method. Based on disease resistance and yield performance, four lines were evaluated in station trials during 2017-2018 and 2018-2019 at Kalaburagi, India. Further, two lines, namely, Kalaburagi chickpea desi 5 (KCD 5) and KCD 11, which possesses the resistance allele for a specific single-nucleotide polymorphism marker linked with FW resistance, were evaluated across six different locations (Bidar, Kalaburagi, Raichur, Siruguppa, Bhimarayanagudi and Hagari) over a span of 3 years (2020-2021, 2021-2022 and 2022-2023). KCD 11 exhibited notable performance, showcasing yield advantages of 8.67%, 11.26% and 23.88% over JG 11, and the regional checks Super Annigeri 1 (SA 1) and Annigeri 1, respectively, with enhanced FW resistance in wilt sick plot. Further, KCD 11 outperformed JG 11, SA 1 and Annigeri 1 in multi-location trials conducted across three seasons in the North Eastern Transition Zone, North Eastern Dry Zone, and North Dry Zones of Karnataka. KCD 11 was also tested in trials conducted by All India Coordinated Research Project on chickpea and was also nominated for state varietal trials for its release as a FW-resistant and high-yielding variety. The selected line is anticipated to cater the needs of chickpea growers with the dual advantage of yield increment and disease resistance.

Chromosomal rearrangements in lymphocytes of head and neck squamous cell carcinoma treated with chemotherapeutic agents.

Squamous cell carcinoma especially of oral cavity is one of the most prevalent diseases in the world. Chromosomal rearrangements are known to play important role in the pathogenesis of many diseases including cancer. In case of Head and Neck Squamous Cell Carcinoma, chromosomal changes are detectable at all stages of tumor development providing excellent opportunity for chromosomal prognosis and therapy. The present work aimed to study the frequency and pattern of chromosomal aberrations in human peripheral blood lymphocyte culture of freshly diagnosed Head and Neck squamous cell carcinoma patients. Further In vitro anticancer drugs (5-Fluorouracil {5-FU } and Cisplatin) effects were studied for clastogenicity. Results indicated significant impact of chemotherapeutic agents on the frequency of different types of chromosomal rearrangements.

Ungual and transungual drug delivery.

Topical therapy is desirable in treatment of nail diseases like onychomycosis (fungal infection of nail) and psoriasis. The topical treatment avoids the adverse effects associated with systemic therapy, thereby enhancing the patient compliance and reducing the treatment cost. However the effectiveness of the topical therapies has been limited due to the poor permeability of the nail plate to topically applied therapeutic agents. Research over the past one decade has been focused on improving the transungual permeability by means of chemical treatment, penetration enhancers, mechanical and physical methods. The present review is an attempt to discuss the different physical and chemical methods employed to increase the permeability of the nail plate. Minimally invasive electrically mediated techniques such as iontophoresis have gained success in facilitating the transungual delivery of actives. In addition drug transport across the nail plate has been improved by filing the dorsal surface of the nail plate prior to application of topical formulation. But attempts to improve the trans-nail permeation using transdermal chemical enhancers have failed so far. Attempts are on to search suitable physical enhancement techniques and chemical transungual enhancers in view to maximize the drug delivery across the nail plate.

Modelling asthma in macaques: longitudinal changes in cellular and molecular markers.

The aim of the present study was to determine whether systemic sensitisation and chronic aeroallergen challenge in macaques replicate the classical and emerging immunology and molecular pathology of human asthma. Macaques were immunised and periodically challenged over 2 yrs with house dust mite allergen. At key time-points, serum, bronchoalveolar lavage (BAL) and bronchial biopsies were assayed for genes, proteins and lymphocyte subpopulations relevant to clinical asthma. Immunisation and periodic airway challenge induced changes in immunoglobulin E, airway physiology and eosinophilia consistent with chronic, dual-phase asthma. Sensitisation increased interleukin (IL)-1ß and -6 concentrations in serum, and IL-13 expression in BAL cells. Airway challenge increased: early expression of IL-5, -6, -13 and -19, and eotaxin; and variable late-phase expression of IL-4, -5 and -13, and thymus- and activation-regulated chemokine in BAL cells. CD4+ lymphocytes comprised 30% of the CD3+ cells in BAL, increasing to 50% in the late phase. Natural killer T-cells represented <3% of the CD3+ cells. Corticosteroid treatment reduced serum histamine levels, percentage of CD4+ cells and monocyte-derived chemokine expression, while increasing CD3+ and CD8+ cells in BAL. Sensitisation and periodic aeroallergen challenge of cynomolgus macaques results in physiological, cellular, molecular and protein phenotypes, and therapeutic responses observed in human asthma, providing a model system useful in target and biomarker discovery, and translational asthma research.

A hospital based study of prevalence of gestational diabetes mellitus in an urban population of India.

OBJECTIVE: A cross-sectional institutional-based study was undertaken to know the prevalence of Gestational Diabetes Mellitus (GDM) among Indian pregnant women. SUBJECTS AND METHODS: 325 pregnant women were screened for evidence of diabetes who were previously not known to be diabetic. They underwent 75 g, 2 hour, oral glucose tolerance test (OGTT). Chi-square test was done for statistically association of variables in GDM. RESULTS AND CONCLUSIONS: The results of this study indicate that bad obstetrics history, obese patient on high calorie diet especially non vegetarian diet with less physical activity are highly prone to develop GDM.

Characterization of the expression of variant and standard CD44 in prostate cancer cells: identification of the possible molecular mechanism of CD44/MMP9 complex formation on the cell surface.

CD44 is a glycosylated adhesion molecule and osteopontin is one of its ligand. CD44 undergoes alternative splicing to produce variant isoforms. Our recent studies have shown an increase in the surface expression of CD44 isoforms (sCD44 and v4-v10 variant CD44) in prostate cancer cells over-expressing osteopontin (PC3/OPN). Formation of CD44/MMP9 complex on the cell surface is indispensable for MMP9 activity. In this study, we have characterized the expression of variant CD44 using RT-PCR, surface labeling with NHS-biotin, and immunoblotting. Expression of variant CD44 encompassing v4-v10 and sCD44 at mRNA and protein levels are of the same levels in PC3 and PC3/OPN cells. However, an increase in the surface expression of v6, v10, and sCD44 in PC3/OPN cells suggest that OPN may be a ligand for these isoforms. We then proceeded to determine the role of sCD44 in MMP9 activation. Based on our previous studies in osteoclasts, we hypothesized that phosphorylation of CD44 has a role on its surface expression and subsequent activation of MMP9. We have prepared TAT-fused CD44 peptides comprising unphosphorylated and constitutively phosphorylated serine residues at positions Ser323 and Ser325. Transduction of phosphopeptides at Ser323 and Ser323/325 into PC3 cells reduced the surface levels of CD44, MMP9 activity, and cell migration; but had no effect on the membrane localization of MMP9. However, MMP9 knock-down PC3 cells showed reduced CD44 at cellular and surface levels. Thus we conclude that surface expression of CD44 and activation of MMP9 on the cell surface are interdependent.

QT/QTc safety and efficacy evaluation of teneligliptin in Indian type 2 diabetes mellitus patients: the "thorough QT/QTc" study (Q-SET study).

Background: Newer therapies, such as dipeptidyl peptidase-IV inhibitors, are increasingly being used in the treatment of type 2 diabetes mellitus (T2DM). Teneligliptin, a DPP4 inhibitor, currently commonly used as monotherapy or as add-on therapy, was generally well tolerated in patients with T2DM during clinical trials. No AEs related to QT prolongation were detected with 40 mg/day of teneligliptin, but were seen at a supratherapeutic dose of 160 mg/day. Aims and objective: To evaluate the safety of teneligliptin in type 2 diabetes patients with respect to QTc prolongation. Methodology: This was an open-label, prospective, multi-centric trial conducted in patients with T2DM aged ≥18 to ≤65 years with a hemoglobin A1c (HbA1c) ≥7.0% and gliptin naïve. Teneligliptin 20 mg once a day was added to the standard treatment. The dose of teneligliptin was increased to 40 mg once a day if required, on the basis of glycemic parameters. Twelve-lead ECG was recorded at baseline and follow-up visits. The QTc was calculated by using the Bazett's formula (QTc=QT/√RR). Results: The mean QT interval at screening (Visit 1, Day 0, baseline ECG) was 0.33±0.07 seconds, while at visit 2 (Day 1, post 2 hours of Teneligliptin dosing) it was 0.32±0.04 seconds, at visit 3 (Day 15) it was 0.32±0.04 seconds, and at visit 4 (Day 90) it was 0.32±0.03 seconds. The mean QTc interval at baseline was 0.37±0.04 seconds, while at visit 2 it was 0.37±0.04 seconds, at visit 3 it was 0.37±0.03 seconds, and at visit 4 it was 0.37±0.03 seconds. There was a significant reduction in fasting blood glucose (P=0.002), postprandial blood glucose (P<0.001), and HbA1c (P<0.001) at the end of the 3 months as compared to baseline. Conclusion: Teneligliptin at a therapeutic dose of 20 mg/day or 40 mg/day improved glycemic parameters significantly and did not cause QT/QTc interval prolongation.

Predicting QT prolongation in humans during early drug development using hERG inhibition and an anaesthetized guinea-pig model.

BACKGROUND AND PURPOSE: Drug-induced prolongation of the QT interval can lead to torsade de pointes, a life-threatening ventricular arrhythmia. Finding appropriate assays from among the plethora of options available to predict reliably this serious adverse effect in humans remains a challenging issue for the discovery and development of drugs. The purpose of the present study was to develop and verify a reliable and relatively simple approach for assessing, during preclinical development, the propensity of drugs to prolong the QT interval in humans. EXPERIMENTAL APPROACH: Sixteen marketed drugs from various pharmacological classes with a known incidence -- or lack thereof -- of QT prolongation in humans were examined in hERG (human ether a-go-go-related gene) patch-clamp assay and an anaesthetized guinea-pig assay for QT prolongation using specific protocols. Drug concentrations in perfusates from hERG assays and plasma samples from guinea-pigs were determined using liquid chromatography-mass spectrometry. KEY RESULTS: Various pharmacological agents that inhibit hERG currents prolong the QT interval in anaesthetized guinea-pigs in a manner similar to that seen in humans and at comparable drug exposures. Several compounds not associated with QT prolongation in humans failed to prolong the QT interval in this model. CONCLUSIONS AND IMPLICATIONS: Analysis of hERG inhibitory potency in conjunction with drug exposures and QT interval measurements in anaesthetized guinea-pigs can reliably predict, during preclinical drug development, the risk of human QT prolongation. A strategy is proposed for mitigating the risk of QT prolongation of new chemical entities during early lead optimization.

Passive and iontophoretic permeation of glipizide.

In vitro iontophoretic delivery of glipizide across the pigskin was investigated. The experiment was carried out at three different donor drug concentrations using cathodal iontophoresis (current density 0.5 mA cm(-2)) with corresponding passive controls. At all concentration levels, iontophoresis showed enhanced permeation rate compared to passive controls (P<0.01). For passive permeation, the steady-state flux significantly increased with the increase in donor drug concentration (P<0.01). Passive process followed zero-order profile while the profile was nonlinear in iontophoresis. Competition by chloride ions released in the cathode compartment could be the reason. Flux enhancement was highest at the lowest drug load and lowest at the highest drug load. The target flux of glipizide was calculated to be 0. 4147 micromol h(-1). As the highest flux obtained was 0.2727 micromol cm(-2) h(-1), it can be said that glipizide is a promising candidate for iontophoretic delivery.

Influence of beta-cyclodextrin complexation on glipizide release from hydroxypropyl methylcellulose matrix tablets.

Glipizide was complexed with beta-cyclodextrin in an attempt to enhance the drug solubility. The phase solubility diagram was classified as A(L) type, which was characterized by an apparent 1:1 stability constant that had a value of 413.82 M(-1). Fourier transform infrared spectrophotometry, differential scanning calorimetry, powder x-ray diffractometry and proton nuclear magnetic resonance spectral analysis indicated considerable interaction between the drug and beta-cyclodextrin. A 2(3) factorial design was employed to prepare hydroxypropyl methylcellulose (HPMC) matrix tablets containing the drug or its complex. The effect of the total polymer loads (X1), levels of HPMC K100LV (X9), and complexation (X3) on release at first hour (Y1), 24 h (Y2), time taken for 50% release (Y3), and diffusion exponent (Y4) was systematically analyzed using the F test. Mathematical models containing only the significant terms (P < 0.05) were generated for each parameter by multiple linear regression analysis and analysis of variance. Complexation was found to exert a significant effect on Y1, Y2, and Y3, whereas total polymer loads significantly influenced all the responses. The models generated were validated by developing two new formulations with a combination of factors within the experimental domain. The experimental values of the response parameters were in close agreement with the predicted values, thereby proving-the validity of the generated mathematical models.

Human immunodeficiency virus type 1 (HIV-1) Vpr-regulated cell death: insights into mechanism.

The destruction of CD4(+) T cells and eventual induction of immunodeficiency is a hallmark of the human immunodeficiency virus type 1 infection (HIV-1). However, the mechanism of this destruction remains unresolved. Several auxiliary proteins have been proposed to play a role in this aspect of HIV pathogenesis including a 14 kDa protein named viral protein R (Vpr). Vpr has been implicated in the regulation of various cellular functions including apoptosis, cell cycle arrest, differentiation, and immune suppression. However, the mechanism(s) involved in Vpr-mediated apoptosis remains unresolved, and several proposed mechanisms for these effects are under investigation. In this review, we discuss the possibility that some of these proposed pathways might converge to modulate Vpr's behavior. Further, we also discuss caveats and future directions for investigation of the interesting biology of this HIV accessory gene.

Two-dimensional echocardiography in double orifice mitral valve.

In a patient with endocarditis and significant aortic insufficiency, two-dimensional echocardiography revealed an abnormal mitral valve configuration with division of the valve into two separate orifices. At autopsy, a double orifice mitral valve with two sets of valve leaflets was observed. Appreciation of this echocardiographic abnormality is important because double orifice mitral valve is associated with other congenital anomalies and this echocardiographic configuration may be confused with other cardiac abnormalities.

Evaluation of the role of lipoprotein metabolism genes in systemic cationic liposome-mediated gene transfer in vivo.

Germ line gene disruption and gene insertion are often used to study the function of selected genes in vivo. We used selected knockout and transgenic mouse models to attempt to identify lipoprotein-related genes and gene products that regulate the process of intravenous cationic liposome-DNA complex (CLDC)-based gene delivery. Several observations suggested that proteins involved in lipoprotein metabolism might be important in influencing the delivery and/or expression of CLDC. First, in vitro transfection of either K562 or CHO cells by CLDCs was enhanced by the presence of a functional low-density lipoprotein receptor (LDLR). Second, pretreatment of mice with 4-aminopyrazolopyrimidine (4APP), an agent that alters lipoprotein profiles in mice, significantly decreased expression of luciferase (luc) after intravenous injection of CLDC-luc complexes in mice. Therefore, we tested mouse model systems either deficient for, or overexpressing, selected genes involved in lipoprotein metabolism, for their potential to regulate intravenous, CLDC-based gene delivery. Although homozygous knockout mutation in the apoE gene caused a significant decrease in gene expression in many tissues of apoE-deficient mice, mice with homozygous deletion of both the apoE and LDLR genes showed wild-type levels of gene transfer efficiency. Thus, a secondary event, produced by homozygous deletion of apoE, but compensated for by the concomitant deletion of LDLR, and/or effects resulting from strain-related, genetic background differences, appeared to play a significant role in mediating intravenous, CLDC-based gene delivery. Secondary alterations resulting from germ line knockouts, as well as epigenetic effects produced by strain differences, may limit the ability to assign specific, gene transfer-related functions to the deleted gene.

Effects of pituitary adenylate cyclase-activating polypeptide on hormone secretion by human pituitary adenomas in vitro.

Hormone release in culture in response to pituitary adenylate cyclase-activating polypeptide (PACAP) was examined in 28 human pituitary adenomas: 10 null cell adenomas, 4 gonadotropin-, 6 GH-, 6 ACTH-, and 2 PRL-producing adenomas. The effects of PACAP38 were compared with those of the classical hypothalamic releasing hormones and other activators of intracellular signaling pathways. PACAP38 significantly stimulated GH release from 1 somatotrope tumor (125 +/- 3% of control; P < 0.05) and ACTH release from 3 corticotrope tumors (134 +/- 6%, 136 +/- 7%, and 137 +/- 9% of control; P < 0.05). The effects of PACAP38 were less potent than either GHRH on GH release in the somatotrope tumor or CRH on ACTH release in the corticotrope tumors but similar to the responses seen with the cAMP analog 8-bromo-cAMP (8-Br-cAMP). No detectable effects of PACAP38 on hormone release from null cell, gonadotropin-, or PRL-producing adenomas were observed. Of the 5 somatotrope tumors that failed to respond to PACAP38, all also failed to respond to either 8-Br-cAMP, TRH, or GHRH. Of the corticotrope tumors that failed to respond, 2 of the 3 also failed to respond to CRH. In addition to eliciting hormone release appropriate to the tumor type, PACAP38 also stimulated glycoprotein hormone alpha-subunit (alpha SU) release from one somatotrope tumor (229 +/- 35% of control, P < 0.01) and one corticotrope tumor (149 +/- 4% of control; P < 0.01). This response was not mimicked by 8-Br-cAMP in the somatotrope tumor, but in the corticotrope tumor a significant alpha SU release was also seen after stimulation with the protein kinase C activator 12-O-tetradecanoyl-phorbol-13-acetate and 8-Br-cAMP. These results suggest that the novel hypothalamic peptide PACAP38 has a modest role in the regulation of GH, ACTH, and alpha SU secretion from some human tumourous pituitary corticotropes and somatotropes. Further studies are needed to elucidate the intracellular signaling pathways that mediate the effects of PACAP on hormone secretion by these tumor types.

Psychogenic seizures. A study of 42 attacks in six patients, with intensive monitoring.

Intractable complex partial seizures and seizures of unknown type were studied in 78 patients, six of whom were found to have psychogenic seizures. Evaluation by intensive monitoring included simultaneous six-hour telemetered EEG and videotape recordings and daily determination of plasma antiepileptic drug levels. Diagnosis was determined by assessment of four major criteria: deviation of seizures from characteristics of known seizure types, absence of epileptiform activity in the ictal EEG, absence of slowing in the postictal EEG, and relation of seizure frequency to decreasing plasma concentrations of antiepileptic drugs. No single criterion is sufficient for an unequivocal diagnosis of psychogenic seizures.

Epilepsy in prison: elevated prevalence and no relationship to violence.

The epidemiologic, clinical, and social characteristics of epilepsy were investigated in men entering the Illinois prison system and compared with a matched control group of prisoners without epilepsy. The prevalence of epilepsy was 2.4%, four times higher than the prevalence among men aged 20 to 39 in Rochester, MN. Head trauma was the probable cause of epilepsy among 45% of the prisoners with epilepsy, a much higher percentage than that reported in studies of other populations. In comparison with an age- and race-matched group of prisoners without epilepsy, the epilepsy group was not convicted of more serious or more violent crimes.

Disposition of mephenytoin and its metabolite, nirvanol, in epileptic patients.

We investigated the conversion of mephenytoin to nirvanol in five patients with uncontrolled complex partial seizures. After a 50-mg single oral dose, mean peak mephenytoin level was 0.48 microgram/ml and nirvanol 0.37 microgram/ml. After 400 mg, peak mephenytoin level was 3.9 micrograms/ml and nirvanol 2.5 micrograms/ml. On 400 mg daily, mephenytoin reached a mean steady-state level of 1.5 micrograms/ml. Nirvanol mean steady-state level was 18 micrograms/ml. Mean plasma half-life was 17 hours for mephenytoin and 114 hours for nirvanol. Two patients had reduced seizures during mephenytoin therapy and one a transient increase during drug withdrawal. No toxicity was seen, but mephenytoin was not more effective than phenytoin.

Synthesis of 15-keto-6beta, 7beta-methyleneprogesterone. Effect of the 6beta, 7beta-methylene group on mineralocorticoid activity.

15-Ketoprogesterone is as active as spironolactone in blocking the mineralocorticoid effect of deoxycorticosterone acetate. This activity is reduced when a methylene group is attached to the 6beta, 7beta position. The title compound was prepared from 15alpha-acetoxy-6-dehydroprogesterone. Methylenation of the delta6 double bond with dimethyloxosulfonium methylide proceeds steroselectively from the beta side of the molecule.