A novel combination of sitagliptin and melatonin ameliorates T2D manifestations: studies on experimental diabetic models.

INTRODUCTION: Type 2 diabetes (T2D) is an endocrine disorder characterized by hyperglycemia, insulin resistance, dysregulated glucose and lipid metabolism, reduced pancreatic ß-cell function and mass, and a reduced incretin effect. Circadian rhythm disruption is associated with increased T2D risk. We have investigated the therapeutic potential of a combination of melatonin (M) and sitagliptin (S), a dipeptidyl peptidase IV (DPP-IV) inhibitor, in the amelioration of T2D manifestations in high-fat diet (HFD) induced T2D mouse model and also on ß-cell proliferation under gluco-lipotoxicity stress in vitro. METHODS: For in vivo study, mice were fed with HFD for 25 weeks to induce T2D and were treated with monotherapies and S + M for four weeks. For the in vitro study, primary mouse islets were exposed to normal glucose and high glucose + palmitate to induce gluco-lipotoxic stress. RESULTS: Our results suggest that monotherapies and S + M improve metabolic parameters and glyco-lipid metabolism in the liver and adipose tissue, respectively, and improve mitochondrial function in the skeletal muscle. Moreover, it increases peripheral insulin sensitivity. Our in vitro and in vivo studies suggest that ß-cell mass was preserved in all the drug-treated groups. CONCLUSION: The combination treatment is superior to monotherapies in the management of T2D.

Diagnostic disagreement between tests of evacuatory function: a prospective study of 100 constipated patients.

BACKGROUND: Evacuatory dysfunction (ED) is a common cause of constipation and may be sub-classified on the basis of specialist tests. Such tests may guide treatment e.g., biofeedback therapy for 'functional' defecatory disorders (FDD). However, there is no gold standard, and prior studies have not prospectively and systematically compared all tests that are used to diagnose forms of ED. METHODS: One hundred consecutive patients fulfilling Rome III criteria for functional constipation underwent four tests: expulsion of a rectal balloon distended to 50 mL (BE50 ) or until patients experienced the desire to defecate (BEDDV ), evacuation proctography (EP) and anorectal manometry. Yields and agreements between tests for the diagnosis of ED and FDD were assessed. KEY RESULTS: Positive diagnostic yields for ED were: BEDDV 18%, BE50 31%, EP 38% and anorectal manometry (ARM) 68%. Agreement was substantial between the two balloon tests (k = 0.66), only fair between proctography and BE50 (k = 0.27), poor between manometry and proctography (k = 0.01), and there was no agreement between the balloon tests and manometry (k = -0.07 for both BE50 and BEDDV ). For the diagnosis of FDD, there was only fair agreement between ARM and EP (k = 0.23), ARM ± BE50 and EP (k = 0.18), ARM and EP ± BE50 (k = 0.30) and ARM ± BE50 and EP ± BE50 (k = 0.23). CONCLUSIONS & INFERENCES: There is considerable disagreement between the results of various tests used to diagnose ED and FDD. This highlights the need for a reappraisal of both diagnostic criteria, and what represents the 'gold standard' investigation.

Traditional measures of normal anal sphincter function using high-resolution anorectal manometry (HRAM) in 115 healthy volunteers.

BACKGROUND: High-resolution anorectal manometry (HRAM) is a relatively new method for collection and interpretation of data relevant to sphincteric function, and for the first time allows a global appreciation of the anorectum as a functional unit. Historically, traditional anal manometry has been plagued by lack of standardization and healthy volunteer data of variable quality. The aims of this study were: (i) to obtain normative data sets for traditional measures of anorectal function using HRAM in healthy subjects and; (ii) to qualitatively describe novel physiological phenomena, which may be of future relevance when this method is applied to patients. METHODS: 115 healthy subjects (96 female) underwent HRAM using a 10 channel, 12F solid-state catheter. Measurements were performed during rest, squeeze, cough, and simulated defecation (push). Data were displayed as color contour plots and analysed using a commercially available manometric system (Solar GI HRM v9.1, Medical Measurement Systems). Associations between age, gender and parity were subsequently explored. KEY RESULTS: HRAM color contour plots provided clear delineation of the high-pressure zone within the anal canal and showed recruitment during maneuvers that altered intra-anal pressures. Automated analysis produced quantitative data, which have been presented on the basis of gender and parity due to the effect of these covariates on some sphincter functions. In line with traditional manometry, some age and gender differences were seen. Males had a greater functional anal canal length and anal pressures during the cough maneuver. Parity in females was associated with reduced squeeze increments. CONCLUSIONS & INFERENCES: The study provides a large healthy volunteer dataset and parameters of traditional measures of anorectal function. A number of novel phenomena are appreciated, the significance of which will require further analysis and comparisons with patient populations.

Evacuation proctography: a reappraisal of normal variability.

AIM: Interpretation of evacuation proctography (EP) images is reliant on robust normative data. Previous studies of EP in asymptomatic subjects have been methodologically limited. The aim of this study was to provide parameters of normality for both genders using EP. METHOD: Evacuation proctography was prospectively performed on 46 healthy volunteers (28 women). Proctograms were independently analysed by two reviewers. All established and some new variables of defaecatory structure and function were assessed objectively: anorectal dimensions; anorectal angle changes; evacuation time; percentage contrast evacuated; and incidence of rectal wall morphological 'abnormalities'. RESULTS: Normal ranges were calculated for all main variables. Mean end-evacuation time was 88 s (95% CI: 63-113) in male subjects and 128 s (95% CI: 98-158) in female subjects; percentage contrast evacuated was 71% (95% CI: 63-80) in male subjects and 65% (95% CI: 58-72) in female subjects. Twenty-six (93%) of 28 female subjects had a rectocoele with a mean depth of 2.5 cm (upper limit = 3.9 cm). Recto-rectal intussusception was found in nine subjects (approximately 20% of both genders); however, recto-anal intussusception was not observed. Only rectal diameter differed significantly between genders. Qualitatively, three patterns of evacuation were present. CONCLUSION: This study defines normal ranges for anorectal dimensions and parameters of emptying, as well as the incidence and characteristics of rectal-wall 'abnormalities' observed or derived from EP. These ranges can be applied clinically for subsequent disease comparison.

Systematic review of the clinical effectiveness of neuromodulation in the treatment of faecal incontinence.

BACKGROUND: Over the past 18 years neuromodulation therapies have gained support as treatments for faecal incontinence (FI); sacral nerve stimulation (SNS) is the most established of these. A systematic review was performed of current evidence regarding the clinical effectiveness of neuromodulation treatments for FI. METHODS: The review adhered to the PRISMA framework. A comprehensive search of the literature included PubMed, MEDLINE, Embase and Evidence-Based Medicine Reviews. Methodological quality assessment and data extraction were completed in a systematic fashion. RESULTS: For SNS, 321 citations were identified initially, of which 61 studies were eligible for inclusion. Of studies on other neuromodulation techniques, 11 were eligible for review: seven on percutaneous tibial nerve stimulation (PTNS) and four on transcutaneous tibial nerve stimulation (TTNS). On intention-to-treat, the median (range) success rates for SNS were 63 (33-66), 58 (52-81) and 54 (50-58) per cent in the short, medium and long terms respectively. The success rate for PTNS was 59 per cent at the longest reported follow-up of 12 months. SNS, PTNS and TTNS techniques also resulted in improvements in Cleveland Clinic Incontinence Score and quality-of-life measures. Despite significant use of neuromodulation in treatment of FI, there is still no consensus on outcome reporting in terms of measures used, aetiologies assessed, length of follow-up or assessment standards. CONCLUSION: Emerging data for SNS suggest maintenance of its initial therapeutic effect into the long term. The clinical effectiveness of PTNS is comparable to that of SNS at 12 months, although there is no evidence to support its continued effectiveness after this period. PTNS may be a useful treatment before SNS. The clinical effectiveness of TTNS is still uncertain owing to the paucity of available evidence. A consensus to standardize the use of outcome measures is recommended in order that further reports can be compared meaningfully.

Memory metamaterials.

The resonant elements that grant metamaterials their distinct properties have the fundamental limitation of restricting their useable frequency bandwidth. The development of frequency-agile metamaterials has helped to alleviate these bandwidth restrictions by allowing real-time tuning of the metamaterial frequency response. We demonstrate electrically controlled persistent frequency tuning of a metamaterial, which allows the lasting modification of its response by using a transient stimulus. This work demonstrates a form of memory capacitance that interfaces metamaterials with a class of devices known collectively as memory devices.

Anaesthesiological considerations on tocolytic and uterotonic therapy in obstetrics.

AIM: Significant side effects of tocolytic and uterotonic substances may be of concern to the anaesthesiologist. Recently, new drugs have been introduced having less side effects for both the mother and the neonate. METHODS: A literature search was undertaken mainly focusing on meta-analyses, to review the possible side effects that might affect the course of anaesthesia and to suggest which precautions should be considered to prevent the occurrence of significant interactions with anaesthetic manipulations and drugs. RESULTS: Magnesium sulphate has a proven benefit in lowering systolic blood pressure and preventing the occurrence of eclampsia, but not as a tocolytic. beta-adrenergic agonists are being abandoned due to the availability of tocolytic agents causing less side effects. Calcium channel blockers (CCB) are frequently used but can cause major maternal cardiovascular complications. Nitroglycerin seems to be appreciated as an acute tocolytic rather than a routine substance during pre-term labour. Cyclo-oxygenase-2 inhibitors are still under investigation but their tocolytic benefit is questionable mainly due to foetal side effects. Atosiban is considered the first-choice tocolytic. With respect to oxytocic drugs, oxytocine, prostaglandines and methylergometrine may all cause serious side effects especially when combined. The cardiovascular side effects of prostaglandins and methylergometrine can be life-threatening. Both oxytocin and carbetocin have a rather low risk for maternal complications. CONCLUSION: Atosiban and CCB are at least as effective tocolytic agents as beta-mimetics but have significantly less side effects. Magnesium sulphate can cause neuromuscular blockade, especially when combined with CCB. Concerning oxytocic agents, short-acting oxyctocin and long-acting carbetocin have the least side effects as compared with prostaglandins and methylergometrine.

Progress in chip-scale photonic sensing.

Chip-scale integrated planar photonic sensing systems for portable diagnostics and monitoring are emerging, as photonic components are integrated into systems with silicon (Si), Si complementary metal-oxide semiconductor, and fluidics. This paper reviews progress in these areas. Medical and environmental applications, candidate photonic sensors, integration methodologies, integrated subsystem demonstrations, and challenges facing this emerging field are discussed in this paper.

Regional anaesthesia for primary caesarean section in patients with preterm HELLP syndrome: a review of 102 cases.

OBJECTIVE: To determine the feasibility and the safety of combined spinal/epidural and spinal anaesthetic techniques for primary caesarean section in case of preterm HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome. METHODS: A retrospective study was carried out in a tertiary centre including all patients who underwent primary caesarean section for HELLP syndrome. The immediate preoperative and the lowest thrombocyte count, the method of anaesthesia and eventual complications were recorded. Patients were categorised as having antepartum or postpartum HELLP syndrome. RESULTS: A total number of 102 charts was reviewed. Mean gestational age was 30.6 weeks (SD 2.7, range 23-36 weeks). There were seven (6.9%) patients with postpartum HELLP and 95 with antepartum HELLP. In case of antepartum HELLP in 37 (36.3%) general anaesthesia was selected; in 53 (52.0%) combined spinal epidural anaesthesia and in 12 (11.8%) single dose spinal anaesthesia. Preoperative thrombocyte count was significantly higher (p < 0.01) in the combined spinal epidural group (113,000/mm3) while there was no difference between general (88,000/mm3) and spinal anaesthesia (95,000/mm3). There were no cases of epidural haematoma. Two patients received a combined spinal epidural although their immediate preoperative thrombocyte count was < 50,000/mm3. CONCLUSIONS: Our data demonstrate that combined spinal/epidural is feasible and safe in selected cases of HELLP syndrome.

Purification and characterization of maltooligosaccharide-forming amylase from Bacillus circulans GRS 313.

A maltooligosaccharide-forming amylase that hydrolyzes starch into maltotriose and maltopentaose was found in the culture filtrate of a strain of Bacillus circulans GRS 313 isolated from local soil. The enzyme was purified by organic solvent fractionation, Sephadex G-100 gel filtration and CM-Sephadex column chromatography. Optimum pH and temperature of amylase were evaluated using response surface methodology (RSM) and were found to be 48 degrees C and 4.9, respectively. The enzyme was stable up to 60 degrees C and its pH stability was in the range of 5.0-8.0. The Km and Vmax of the amylase with starch were 11.66 mg/ml and 68.97 U, respectively, and the energy of activation, Ea, was 7.52 kcal/mol. Dextrin inhibited the enzyme competitively, with a Ki of 6.1 mg/ml, and glucose caused noncompetitive inhibition with a Ki of 9.5 mg/ml. The enzyme was inhibited by Hg2+, Mn2+, Fe3+ and Cu2+ and enhanced by Co2+ and Mg2+. EDTA reversed the inhibitory effect of the metals. Paper chromatographic and high-performance liquid chromatography analysis of the products of the amylolytic reaction showed the presence of maltotriose, maltotetraose, maltopentaose, maltose and glucose in the starch hydrolysate.

Prominence of symptoms and level of stigma among depressed patients in Calcutta.

A pilot study of 29 patients for research on clinical depression employed the framework of cultural epidemiology to examine illness-related experience, meaning, behaviour with a Bengali version of the explanatory Model Interview Catalogue (EMIC). This report examined patterns of distress and stigma with reference to the most troubling patient-specified symptom. All subjects were psychiatric outpatients in the Institute of Psychiatry, Calcutta, and met Diagnostic and Statistical Manual (DSM)-IV criteria for a major depressive episode. Only 5 patients (17.2%) identified sadness as the most troubling problem, and 48.3% specified pains and other somatic symptoms instead. An internally consistent stigma scale with Cronbach's alpha of .67, comprised 13 items, was used to assess stigma. In addition to the scale score for each subject, the contribution of each item was reported and compared. A suggestive, though not significantly lower value of the stigma score for patients reporting somatic symptoms as most troubling, compared with sadness, was consistent with findings from prior studies showing a positive relationship between the magnitude of depression and stigma. These findings are discussed with reference to their impact on recognition and help seeking among patients, and recognition and management of depression by general practitioner. Culturally distinctive presentations and social contexts of depression and other mental illnesses should be addressed in professional training and public health communications.

Chronic arsenic toxicity in Bangladesh and West Bengal, India--a review and commentary.

Fifty districts of Bangladesh and 9 districts in West Bengal, India have arsenic levels in groundwater above the World Health Organization's maximum permissible limit of 50 microg/L. The area and population of 50 districts of Bangladesh and 9 districts in West Bengal are 118,849 km2 and 104.9 million and 38,865 km2 and 42.7 million, respectively. Our current data show arsenic levels above 50 microg/ L in 2000 villages, 178 police stations of 50 affected districts in Bangladesh and 2600 villages, 74 police stations/blocks of 9 affected districts in West Bengal. We have so far analyzed 34,000 and 101,934 hand tube-well water samples from Bangladesh and West Bengal respectively by FI-HG-AAS of which 56% and 52%, respectively, contained arsenic above 10 microg/L and 37% and 25% arsenic above 50 microg/L. In our preliminary study 18,000 persons in Bangladesh and 86,000 persons in West Bengal were clinically examined in arsenic-affected districts. Of them, 3695 (20.6% including 6.11% children) in Bangladesh and 8500 (9.8% including 1.7% children) in West Bengal had arsenical dermatological features. Symptoms of chronic arsenic toxicity developed insidiously after 6 months to 2 years or more of exposure. The time of onset depends on the concentration of arsenic in the drinking water, volume of intake, and the health and nutritional status of individuals. Major dermatological signs are diffuse or spotted melanosis, leucomelanosis, and keratosis. Chronic arsenicosis is a multisystem disorder. Apart from generalized weakness, appetite and weight loss, and anemia, our patients had symptoms relating to involvement of the lungs, gastrointestinal system, liver, spleen, genitourinary system, hemopoietic system, eyes, nervous system, and cardiovascular system. We found evidence of arsenic neuropathy in 37.3% (154 of 413 cases) in one group and 86.8% (33 of 38 cases) in another. Most of these cases had mild and predominantly sensory neuropathy. Central nervous system involvement was evident with and without neuropathy. Electrodiagnostic studies proved helpful for the diagnosis of neurological involvement. Advanced neglected cases with many years of exposure presented with cancer of skin and of the lung, liver, kidney, and bladder. The diagnosis of subclinical arsenicosis was made in 83%, 93%, and 95% of hair, nail and urine samples, respectively, in Bangladesh; and 57%, 83%, and 89% of hair, nail, and urine samples, respectively in West Bengal. Approximately 90% of children below 11 years of age living in the affected areas show hair and nail arsenic above the normal level. Children appear to have a higher body burden than adults despite fewer dermatological manifestations. Limited trials of 4 arsenic chelators in the treatment of chronic arsenic toxicity in West Bengal over the last 2 decades do not provide any clinical, biochemical, or histopathological benefit except for the accompanying preliminary report of clinical benefit with dimercaptopropanesulfonate therapy. Extensive efforts are needed in both countries to combat the arsenic crisis including control of tube-wells, watershed management with effective use of the prodigious supplies of surface water, traditional water management, public awareness programs, and education concerning the apparent benefits of optimal nutrition.

Fetal ECG extraction from single-channel maternal ECG using singular value decomposition.

The extraction of fetal electrocardiogram (ECG) from the composite maternal ECG signal obtained from the abdominal lead is discussed. The proposed method employs singular value decomposition (SVD) and analysis based on the singular value ratio (SVR) spectrum. The maternal ECG (M-ECG) and the fetal ECG (F-ECG) components are identified in terms of the SV-decomposed modes of the appropriately configured data matrices, and elimination of the M-ECG and determination of F-ECG are achieved through selective separation of the SV-decomposed components. The unique feature of the method is that only one composite maternal ECG signal is required to determine the F-ECG component. The method is numerically robust and computationally efficient.

Chromosomal aberrations induced by cobaltous chloride in mice in vivo.

The effects of cobaltous chloride in inducing chromosomal aberrations were observed on laboratory bred mice in vivo after single oral administration of different fractions (1/10, 1/20, 1/40) of the lethal toxic dose of the salt. Bone marrow cells were flushed out and processed for chromosome studies following colchicine, hypotonic, giemsa, air drying procedure. The parameters screened were chromosomal aberrations, with and without gaps and break per cell. Slides were screened after the expiry of 6, 12, 18, and 24 h. Statistical analysis indicated the clastogenic effects of the salt. The degree of chromosome damage was directly related to the concentration, and also to the period after administration. The different stages of the cell cycle were affected.

Cytotoxic effects of cobalt chloride on mouse bone marrow cells in vivo.

Various dilutions (1/10, 1/20, 1/40) of the lethal toxic dose of cobalt chloride, a non-carcinogenic salt, were found to be clastogenic to bone marrow cells of mice when administered orally in vivo. The clastogenic effects, mainly chromosome breaks, increased significantly with increasing concentration. The frequency of cell division was affected only by higher concentrations of the salt.

Comparative efficacy of chlorophyllin in reducing cytotoxicity of some heavy metals.

The potential of chlorophyllin in reducing clastogenicity was studied against two concentrations of each of three potent metallic clastogens (cesium chloride, mercuric chloride and cobalt chloride) in bone marrow cells of mice in vivo. The respective salts and chlorophyllin were administered orally to mice by gavaging in different combinations. Simultaneous administration of chlorophyllin with both concentrations of each salt reduced the clastogenic effects in the order Cs greater than Hg greater than Co. Chlorophyllin could not decrease the clastogenic effects when administered 2 h before the salts.

MODIFICATION OF THE CLASTOGENIC EFFECTS OF COBALT BY CALCIUM IN BONE MARROW CELLS OF MICE IN VIVO.

THE INTERACTION BETWEEN COBALTOUS CHLORIDE AND CALCIUM CHLORIDE WAS OBSERVED USING AS ENDPOINTS MITOTIC INDEX AND FREQUENCY OF CHROMOSOMAL ABNORMALITIES. THE TWO SALTS WERE ADMINISTERED ORALLY TO LABORATORY-BRED MALE MICE IN VIVO SINGLY OR ONE FOLLOWED BY THE OTHER OR BOTH SIMULTANEOUSLY. CHROMOSOMES WERE STUDIED FROM BONE MARROW PREPARATIONS AFTER 24 HR. IN ALL CASES, THE ADMINISTRATION OF CACL2 TWO HOURS BEFORE COCL2 PROTECTED AGAINST THE CLASTOGENIC EFFECTS OF THE LATTER TO A SIGNIFICANT EXTENT. SIMULTANEOUS FEEDING OF THE TWO SALTS REDUCED THE DAMAGE BY COCL2 ONLY WHEN CACL2 WAS GIVEN IN A HIGHER CONCENTRATION. THE REDUCTION OF CLASTOGENICITY OF CATIONIC COBALT BY CALCIUM HAS BEEN ATTRIBITED TO THE COMPETITION BETWEEN THE TWO IONS. THIS REPORT OF THE USE OF CA(2+) IN REDUCING THE CLASTOGENICITY OF CO(2+) IS A NEW ONE.

Iron in sickle cell disease.

Iron deficiency anaemia was detected in 23% of cases with homozygous sickle cell disease. The aetiology of iron deficiency was similar to the other population in the community. High serum ferritin level was detected in 15.4% of the cases and was well correlated to the number of transfusions. Tissue haemosiderosis was not detected in any case. Patients with heterozygous sickle cell had either normal or low serum ferritin levels.