Fragment-based QSAR study to explore the structural requirements of DPP-4 inhibitors: a stepping stone towards better type 2 diabetes mellitus management.

Dipeptidyl peptidase-4 (DPP-4) inhibitors belong to a prominent group of pharmaceutical agents that are used in the governance of type 2 diabetes mellitus (T2DM). They exert their antidiabetic effects by inhibiting the incretin hormones like glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide which, play a pivotal role in the regulation of blood glucose homoeostasis in our body. DPP-4 inhibitors have emerged as an important class of oral antidiabetic drugs for the treatment of T2DM. Surprisingly, only a few 2D-QSAR studies have been reported on DPP-4 inhibitors. Here, fragment-based QSAR (Laplacian-modified Bayesian modelling and Recursive partitioning (RP) approaches have been utilized on a dataset of 108 DPP-4 inhibitors to achieve a deeper understanding of the association among their molecular structures. The Bayesian analysis demonstrated satisfactory ROC values for the training as well as the test sets. Meanwhile, the RP analysis resulted in decision tree 3 with 2 leaves (Tree 3: 2 leaves). This present study is an effort to get an insight into the pivotal fragments modulating DPP-4 inhibition.

Inclusivity and decolonisation of the post-graduate public health curriculum: Reflections from a student-led approach.

The future of successful public health practice requires public health students to be educated within a decolonised curriculum that challenges the historical biases and inequalities that are deeply embedded within global public health and society. In this commentary, we reflect on what it can mean and why it's important to decolonise and diversify a public health curriculum. We describe how we used a student-led approach to begin this process, and share recommendations that are applicable to national and international curricula.

Characterizing Agreement in the Level of Interarm Blood Pressure Readings of Adults in the Emergency Department (CALIBRATE Study).

Background: Increased interarm systolic blood pressure difference (IASBPD) is one of the major predictors of cardiovascular disease. An IASBPD of >10 mmHg is of clinical significance. However, studies have reported a high number of patients visiting the emergency department (ED) with high IASBPD and varying correlation of IASBPD to age, ethnic background, and comorbidities such as hypertension and diabetes. Objective: The CALIBRATE study aimed to measure the IABPDs in the multiethnic patient population presenting to the ED in Qatar and to assess the distribution of IASBPD in this population. Methods: In a sitting position, two consecutive blood pressure (BP) measurements were recorded from the right and left arms for each participant using a calibrated automated machine and appropriate cuff sizes. The data were recorded using predefined data fields, including patient demographics, past medical, and social and family history. The continuous variables were reported as mean or median based on the distribution of data. The data were analyzed using Stata MP 14.0. Results: A total of 1800 patients, with a mean age of 34 (10) years, were prospectively recruited from the ED. The median absolute systolic BP difference (ΔSBP) between the right and left arms was 6 (3-10) mmHg, and it was the same for the first (ΔSBP1) and the second readings (ΔSBP2). The absolute average of ΔSBP1 and ΔSBP2 was 7 (4-10) mmHg. The difference in systolic BP difference (SBP) of < 20 mmHg for interarm blood pressure was seen in the 95th percentile of the population. No meaningful association could be detected between the IABPD and the study variables such as age, demographics, regions of interest, and risk factors. Conclusion: In population presenting to the ED, the IASBPD of at least 20 mmHg reached at the 95th percentile, validating the known significant difference. The utility of SBP difference can be improved further by taking the average of two individual readings.

Peripherally administered KP-10 prevents development of insulin-induced hypoglycemic shock in diabetic rhesus monkeys.

AIM: This study investigated whether kisspeptin-10 (KP-10) prevents diabetic rhesus monkeys from insulin-induced hypoglycemic shock. MATERIALS AND METHODS: Thirty-six adult male rhesus monkeys were used, six in each group. Diabetes was induced with streptozotocin (45 mg/kg b.w.; single dose i.v.). Groups were as: saline control, insulin alone, pre-insulin (treated with KP-10, 30 min before insulin), post-insulin (treated with KP-10, 30 min after insulin), treated with premix dose of KP-10 (50 µg) and insulin, and the group treated with the kisspeptin antagonist P234 (50 µg). Following an overnight fast, each animal was subjected to respective treatment, and blood glucose concentrations were recorded every 30-min interval for 3 h. RESULTS: Intergroup comparisons demonstrated that treatment with KP-10 prior to insulin administration and kisspeptin-insulin premix treatment allowed blood glucose levels to rise to significantly higher levels (p < 0.001) by 180 min in diabetic and healthy animals compared to treatment with insulin alone. However, intragroup comparisons revealed a significant decrease in blood glucose level in diabetic animals only. Treatment with P234 antagonist followed by insulin administration abolished the preventive action of kisspeptin, whereby blood glucose decreased significantly (p < 0.001) in both diabetic and healthy animals. KP-10 post-insulin treatment, however, remained ineffective and led, instead, to significantly decreased glucose concentrations by 180 min in both diabetic and healthy animals when compared to animals treated with insulin alone. CONCLUSIONS: KP-10 bears therapeutic potential to prevent hypoglycemic shock that may sometimes occur during intensive insulin therapy. Several pharmacological aspects of its interaction with insulin and other drugs, however, remain to be investigated.

Freezability of water buffalo bull (Bubalus bubalis) spermatozoa is improved with the addition of curcumin (diferuoyl methane) in semen extender.

Effects of curcumin as antioxidant in extender were evaluated on freezability of buffalo spermatozoa. Semen from each of the five bulls (n = 3 replicates, six ejaculates/bull, a total of 30 ejaculates) was diluted in Tris-citric acid extender containing curcumin (0.5, 1.0, 1.5 or 2.0 mM) or control. At pre-freezing and post-thawing, total antioxidant contents (µM/L) and lipid peroxidation levels (µM/ml) were higher (p < .05) and lower (p < .05) respectively, with 1.5 and 2.0 mM compared to 0.5 and 1.0 mM curcumin and control. At post-thawing, progressive motility (PM, %) and rapid velocity (RV, %) were higher (p < .05) with 1.5 mM compared to other doses of curcumin and control (except in case of RV, 1.5 was similar with 1.0 mM). Kinematics (average path velocity, µm/s; straight-line velocity, µm/s; curved-line velocity, µm/s; straightness, %; linearity, %), in vitro longevity (%, PM and RV) and DNA integrity (%) at post-thawing were higher (p < .05) with 1.5 mM compared to control. At post-thawing, supravital plasma membrane integrity (%) and viable spermatozoa with intact acrosome (%) were higher with 1.5 compared to 2.0 mM curcumin and control. We concluded that freezability of water buffalo spermatozoa is improved with the addition of 1.5 mM curcumin in extender.

Clinical implications of eye deviation on admission CT examination of acute ischaemic stroke patients.

AIM: To determine the frequency and prognostic value of eye deviation detected on the admission computed tomography (CT) of acute ischaemic stroke patients. MATERIALS AND METHODS: The clinical and imaging data from the Albumin in Acute Stroke (ALIAS) Trials 1 and 2 were analysed. Two reviewers evaluated all admission CT images for the presence of eye deviation, and Alberta Stroke Program Early CT Score (ASPECTS). The admission National Institutes of Health Stroke Scale (NIHSS) scores and 3-month modified Rankin scale (mRs) scores were ascertained. Disability or death was defined as mRS score >2, at 3-month follow-up. RESULTS: Of 1,223 patients included in the present series, 352 (28.8%) had rightward and 331 (27.1%) had leftward eye deviation on admission CT. Patients with eye deviation on CT had higher admission NIHSS score and larger middle cerebral artery (MCA) territory infarct volume (based on ASPECTS). The presence of eye deviation on CT was associated with higher rates of haemorrhagic transformation at 24 hours (19.8% versus 13.5%, p=0.004), and higher rates of disability or death at 3-month follow-up (53.1% versus 35.7%, p<0.001). Mediation analysis showed that radiological eye deviation relation with higher rate of disability or death is predominantly due to its association with higher admission NIHSS scores, lower ASPECTS, and to a lesser extent patients' older age. CONCLUSIONS: The presence of eye deviation on CT examination of acute ischaemic stroke patients is associated with larger anterior circulation stroke volumes, higher risk of 24-hour haemorrhagic transformation, and 3-month disability or death.

Effect of equilibration times, freezing, and thawing rates on post-thaw quality of buffalo (Bubalus bubalis) bull spermatozoa.

The effects of equilibration times (E1, 2 h; E2, 4 h; E3, 6 h), freezing rates (FR1, manual, 5 cm above liquid nitrogen (LN2 ) for 10 min, plunging in LN2 ; FR2, programmable ultra-fast, holding at +4 °C for 2 min, from 4 to -10 °C at -10 °C/min, from -10 to -20 °C at -15 °C/min, from -20 to -120 °C at -60 °C/min, holding at -120 °C for 30 sec, plunging in LN2 ), and thawing rates (T1, 37 °C for 30 sec; T2, 50 °C for 15 sec; T3, 70 °C for 7 sec) were evaluated on quality of buffalo bull spermatozoa. Progressive motility (%), rapid velocity (%), average path velocity (VAP, µm/s), straight line velocity (VSL, µm/s), and mitochondrial transmembrane potential (%) were higher (p < 0.05) with E2, FR2, and T3 compared to other groups. Sperm curved line velocity (VCL, µm/s) was higher (p < 0.05) with E2 and FR2 compared to other groups. Sperm straightness (%) and linearity (LIN, %) were higher (p < 0.05) with E2 compared to other groups. Sperm LIN was affected (p < 0.05) with T3 compared to other groups. Supravital-plasma membrane integrity (%), viability and acrosome integrity (%) of spermatozoa were higher (p < 0.05) with E2 and FR2 compared to other groups. Sperm DNA integrity (%) was higher (p < 0.05) with FR2 and T1 compared to other groups. We concluded that inclusion of 4 h-equilibration time, programmable ultra-fast freezing rate, and rapid thawing at 70 °C for 7 sec in cryopreservation protocol improves the post-thaw quality of buffalo bull spermatozoa.

Correction of faulty sensors in phased array radars using symmetrical sensor failure technique and cultural algorithm with differential evolution.

Three issues regarding sensor failure at any position in the antenna array are discussed. We assume that sensor position is known. The issues include raise in sidelobe levels, displacement of nulls from their original positions, and diminishing of null depth. The required null depth is achieved by making the weight of symmetrical complement sensor passive. A hybrid method based on memetic computing algorithm is proposed. The hybrid method combines the cultural algorithm with differential evolution (CADE) which is used for the reduction of sidelobe levels and placement of nulls at their original positions. Fitness function is used to minimize the error between the desired and estimated beam patterns along with null constraints. Simulation results for various scenarios have been given to exhibit the validity and performance of the proposed algorithm.

Differential immunolocalization of sulfonylurea receptors in mouse and rat ureters.

The receptors for sulphonylurea (SURs) are known to be expressed in the mouse kidney, but their expression in the ureter is undefined. Owing to the physiological and pharmacological significance of SURs, the localization of SUR in ureters of adult mice and rats was investigated through immunohistochemistry. Animals were perfused transcardially with 4% paraformaldehyde and tissues were processed for immunohistochemistry using polyclonal antisera against SUR2A and SUR2B (SUR1) receptor proteins. Sections were incubated with primary and secondary antisera and developed with aminoethylcarbazole as a chromogen. A differentiated localized staining pattern of SUR proteins in rat and mouse ureters is demonstrated. In the mouse, immunoreactivity of SUR2A was predominantly confined to the cytoplasmic portion of epithelial cells and blood vessels, with comparatively low-level staining found in smooth muscle. In contrast, SUR2B (SUR1) immunoreactivity was absent in mouse ureters. In rats, SUR2A immunoreactivity was localized only in the blood vessels, while SUR2B (SUR1) immunoreactivity was localized in the epithelial cell cytoplasm. Tissue specificity of SUR is demonstrated in the two species of rodents and suggests a role of SUR proteins in urinary metabolism pertaining possibly to salt handling and maintenance of the smooth muscle tone.

One-year chronic oral toxicity with combined reproduction toxicity study of a novel probiotic, Bacillus coagulans, as a food ingredient.

Some strains of Bacillus coagulans can survive extremes of heat, stomach acid and bile acids, to which commonly consumed probiotics are susceptible. A toxicological safety assessment was published in 2009 on a proprietary preparation of B. coagulans - GanedenBC(30)™ - a novel probiotic. It was concluded that GanedenBC(30)™ is safe for chronic human consumption based upon scientific procedures, supported by a safe history of use (Endres et al., 2009). A one-year chronic oral toxicity study combined with a one-generation reproduction study was conducted to further investigate safety of long-term consumption. The one-year study of GanedenBC(30)™ administered to male and female HsdBrlHan: Wistar rats in their diet showed no signs of toxicity at the highest dose tested. The conclusion from the reproduction toxicity study is that administration of GanedenBC(30)™ in the diet caused no signs of toxicity in the parental generation (male or female) nor the F1 offspring. Using the lowest NOEL of 1948 mg/kg concluded at the end of the 1-year feeding study, a 100-fold safety factor, a test article concentration of 6.88×10(10) CFU (colony forming units) per gram, and an average 70 kg human, it is determined that GanedenBC(30)™ is safe for chronic consumption at up to 9.38×10(10) CFUs per day.

Toxicological evaluation of a dietary supplement formulated for male sexual health prior to market release.

The dietary supplement, 112 Degrees, was formulated with the goal of supporting sexual functioning in men. Due to rampant problems with drug adulteration for this category of products, a comprehensive screening for active pharmaceutical agents, with an emphasis on drugs prescribed for erectile dysfunction such as type 5 phosphodiesterase (PDE-5) inhibitors, and known unapproved PDE-5 drug analogues, was performed along with preclinical toxicology studies prior to the introduction of this product into the marketplace. 112 Degrees was found to be free of all pharmaceutical adulterants tested, and was not mutagenic, clastogenic, or genotoxic as demonstrated by the Ames test, chromosomal aberration assay, and mouse micronucleus assay, respectively. The LD(50) in the 14-day acute oral toxicity study was greater than 5000 mg/kg, the highest dose tested.

Cost benefit with early operative fixation of unstable ankle fractures.

INTRODUCTION: Ankle fractures are common and many require surgical intervention. It has been well documented that a delay in fracture fixation results in increased length of hospital stay and increased complication rate. Initial delay can also allow swelling or blistering to develop which may necessitate a further delay in operative fixation for up to 1 week. The aim of the current study was to review the length of hospital in-patient stay for operative ankle fractures over the previous 12-month period at our hospital and compare this to the length of hospital stay following the introduction of a fast-track system for the fixation of these fractures (all fractures fixed within 48 h). PATIENTS AND METHODS: A retrospective review of all ankle fractures managed by open reduction and internal fixation over a 12-month period was undertaken. A protocol was then agreed to openly reduce and fix these fractures at the earliest possible opportunity over the next 6-month period. We then collected the data on all ankle fractures that needed open reduction and internal fixation over this 6-month period. The pre-protocol and post-protocol groups were then compared for total hospital length of stay and complication rate. RESULTS: In the 12-month retrospective review, there were 83 ankle fractures that required surgical intervention. Sixty-two of these had surgery within 48 h (mean length of stay, 5.4 days), and 21 had surgery after 48 h (mean length of stay, 9.5 days). There were 39 ankle fractures in the post-protocol group who all had surgery within 48 h (mean length of stay, 5 days). There was no increase in complication rate after implementation of the fast-track system. CONCLUSIONS: This study shows that early operative intervention for ankle fractures reduces the length of hospital stay. Intensive physiotherapy and co-ordinated discharge planning are also essential ingredients for early discharge. Early operative fixation for unstable ankle fractures has substantial cost-saving implications with no increase in complication rate.

Fission track estimation of uranium concentrations in drinking water from Azad Kashmir, Pakistan.

The analysis of uranium in water samples can be very helpful for providing guidelines to the general public regarding necessary remedial measures. A fission-track technique has been applied for the estimation of the uranium concentration in drinking water collected from natural springs of Muzaffarabad and hilly areas of Reshian, Azad Kashmir. The technique involved simultaneous irradiation with thermal neutrons of a sample and a standard in contact with a track detector, and the counting of the fission tracks in the detector from the (n, f) nuclear reaction. Uranium concentrations of the samples were determined by comparing fission-track density with that of a standard of known uranium concentration. Uranium concentration in water samples from the Muzaffarabad and Reshian area varied from 0.03 +/- 0.01 microgL(-1) to 6.67 +/- 0.14 microgL(-1) with an average of 1.36 +/- 0.05 microgL(-1). The observed concentrations of uranium in drinking water were found to be less than the Maximum Acceptable Concentration levels of 9-30 microgL(-1). Thus, the observed values are within safe limits as far as uranium related health hazards are concerned.

Acute idiopathic scrotal oedema in an adult: a case report.

In the evaluation of a patient of any age presenting with an acute scrotal swelling, a surgical emergency should be carefully excluded. However, acute idiopathic scrotal oedema must be considered to avoid unnecessary surgical exploration.

Artificial neural networks for blur identification and restoration of nonlinearly degraded images.

In this paper, an image restoration algorithm is proposed to identify noncausal blur function. Image degradation processes include both linear and nonlinear phenomena. A neural network model combining an adaptive auto-associative network with a random Gaussian process is proposed to restore the blurred image and blur function simultaneously. The noisy and blurred images are modeled as continuous associative networks, whereas auto-associative part determines the image model coefficients and the hetero-associative part determines the blur function of the system. The self-organization like structure provides the potential solution of the blind image restoration problem. The estimation and restoration are implemented by using an iterative gradient based algorithm to minimize the error function.

Complications of thyroidectomy for benign disease.

BACKGROUND: Goitre is a common ailment seen in mountainous regions, like the periphery of Abbottabad. Thyroidectomies are very common in our center. METHODS: This study was done to find out the complication rate of thyroidectomies. RESULTS: 189 cases were operated in Ayub Hospital Complex, Abbottabad during July 96 and Dec. 99. All patients were with benign disease and any case found to have malignancy were excluded from the study. The overall complication rate for all the categories was 15%. In total 5 patients died within one month of surgery.

The stomach divalent ion-sensing receptor scar is a modulator of gastric acid secretion.

Divalent cation receptors have recently been identified in a wide variety of tissues and organs, yet their exact function remains controversial. We have previously identified a member of this receptor family in the stomach and have demonstrated that it is localized to the parietal cell, the acid secretory cell of the gastric gland. The activation of acid secretion has been classically defined as being regulated by two pathways: a neuronal pathway (mediated by acetylcholine) and an endocrine pathway (mediated by gastrin and histamine). Here, we identified a novel pathway modulating gastric acid secretion through the stomach calcium-sensing receptor (SCAR) located on the basolateral membrane of gastric parietal cells. Activation of SCAR in the intact rat gastric gland by divalent cations (Ca(2+) or Mg(2+)) or by the potent stimulator gadolinium (Gd(3+)) led to an increase in the rate of acid secretion through the apical H+,K+ -ATPase. Gd(3+) was able to activate acid secretion through the omeprazole-sensitive H+,K+ -ATPase even in the absence of the classical stimulator histamine. In contrast, inhibition of SCAR by reduction of extracellular cations abolished the stimulatory effect of histamine on gastric acid secretion, providing evidence for the regulation of the proton secretory transport protein by the receptor. These studies present the first example of a member of the divalent cation receptors modulating a plasma membrane transport protein and may lead to new insights into the regulation of gastric acid secretion.

Carnitine transport by organic cation transporters and systemic carnitine deficiency.

The intracellular homeostasis is controlled by different membrane transporters. Organic cation transporters function primarily in the elimination of cationic drugs, endogenous amines, and other xenobiotics in tissues such as the kidney, intestine, and liver. Among these molecules, carnitine is an endogenous amine which is an essential cofactor for mitochondrial beta-oxidation. Recently, a new family of transporters, named OCT (organic cation transporters) has been described. In this minireview, we present the recent knowledge about OCT and focus on carnitine transport, more particularly by the OCTN2. The importance of this sodium-dependent carnitine cotransporter, OCTN2, comes from various recently reported mutations in the gene which give rise to the primary systemic carnitine deficiency (SCD; OMIM 212140). The SCD is an autosomal recessive disorder of fatty acid oxidation characterized by skeletal myopathy, progressive cardiomyopathy, hypoglycemia and hyperammonemia. Most of the OCTN2 mutations identified in humans with SCD result in loss of carnitine transport function. Identifying these mutations will allow an easy targeting of the SCD syndrome. The characteristics of the juvenile visceral steatosis (jvs) mouse, an animal model of SCD showing similar symptoms as humans having this genetic disorder, are also described. These mice have a mutation in the gene encoding the mouse carnitine transporter octn2. Although various OCTN carnitine transporters have been identified and functionally characterized, their membrane localization and regulation are still unknown and must be investigated. This knowledge will also help in designing new drugs that regulate carnitine transport activity.

Hepatic mitochondrial proteins in congenitally hyperammonemic spf mice: effect of acetyl-L-carnitine.

The sparse-fur (spf) mutant mouse has an X-linked deficiency of hepatic ornithine transcarbamylase (OTC), and develops hyperammonemia immediately after weaning and maintains it throughout its life span. We have studied the effects of acetyl-L-carnitine (ALCAR) on the hepatic mitochondrial proteins of the chronically hyperammonemic spf mice. Two different age groups of mice were studied, the weanlings (3 weeks) and the adult mice (8 weeks). Our results indicate that in the mitochondrial matrix, the untreated chronic hyperammonemia induced a significant increase in the quantity of 54.4-kDa protein in spf adult mice. After ALCAR treatment, in spf adult mice, the quantities of the 54.4-kDa, 63.8-kDa, and 129-kDa matrix proteins were significantly increased. In the mitochondrial inner membrane fraction of the spf weanling mice, a 53.5-kDa protein was significantly increased by ALCAR treatment. Our results show that: (a) chronic hyperammonemia has altered the mitochondrial matrix protein profile in spf mice, that (b) ALCAR has a modulating effect on various matrix and inner membrane proteins, and that (c) there was no effect of hyperammonemia or ALCAR treatment on the outer membrane proteins.