Effect of Linagliptin on Incretin-axis and Glycaemic Variability in T1DM.

BACKGROUNDS AND OBJECTIVES: Short-term studies have demonstrated potential therapeutic efficacy of dipeptidyl peptidase 4 inhibitors (DPP4 inhibitors) in patients with poorly controlled T1DM. In this study we evaluated the effect of DPP4 inhibitor, linagliptin, on glycaemic control and variability, and incretinaxis in well controlled T1DM patients to mitigate the effect of glucotoxicity on incretin secreting cells. METHODS: Twenty T1DM patients were randomized to receive either linagliptin (10 patients, dose-5 mg/day) or placebo (10 patients), in addition to insulin for 3 months. HbA1C, continuous glucose monitoring (CGM) and mixed meal test (MMT) were performed before and at the end of the study period. RESULTS: HbA1C reduction and change in glycaemic variability and insulin requirement in the linagliptin group did not attain the level of statistical significance. The increase in AUC GLP1 (Area under curve for GLP1) and decrease in AUC glucagon (Area under curve for glucagon) during the MMT in linagliptin group were also statistically insignificant. INTERPRETATIONS AND CONCLUSIONS: Linagliptin is not effective in reducing HbA1C and glycaemic variability in relatively well controlled T1DM patients.

Magnitude of foot problems in diabetes in the developing world: a study of 1044 patients.

AIM: To gain insight into the prevalence of peripheral neuropathy, foot care practices, foot at risk and foot ulcers in patients with diabetes mellitus at a tertiary care centre. METHODS: A prospective case study involving 1044 patients with diabetes mellitus attending the diabetes clinic of a tertiary care centre in north India from January 2007 to May 2008. All subjects underwent a detailed clinical assessment including vibration perception threshold (VPT) and ankle brachial pressure index (ABI), along with metabolic parameters, and were categorized into ulcer, foot at risk and patients with no risk factors. Foot care practices were assessed with a questionnaire. Peripheral neuropathy was defined as VPT score > or = 25 V. Peripheral vascular disease (PVD) was defined as ABI < 0.9. One hundred and forty-nine patients with foot at risk were followed up for 9.0 +/- 2.3 months (range 5-13 months). RESULTS: The prevalence of peripheral neuropathy was 34.9% and of PVD 12.6%. Two thirds of the patients were at risk for foot ulceration; 9% had an ulcer and 20.2% of them required amputation. Correct foot care practices were followed by 214 (20.5%) subjects of the whole study population and by only 135 (19.3%) of the patients with foot at risk. Improvement in glycaemic control in the patients on follow-up was associated with improvement or stabilization of VPT score. Five (3.4%) patients developed new ulcers on follow-up. CONCLUSION: The high prevalence of neuropathy and PVD, coexisting with poor adherence to foot care practices predisposes to foot problems in people with diabetes in our study population.

Carbon fiber based electrochemical sensor for sweat cortisol measurement.

This study examines the use of a conductive carbon fiber to construct a flexible biosensing platform for monitoring biomarkers in sweat. Cortisol was chosen as a model analyte. Functionalization of the conductive carbon yarn (CCY) with ellipsoidal Fe2O3 has been performed to immobilize the antibodies specific to cortisol. 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) and N-Hydroxysuccinimide (NHS) chemistry has been used to immobilize the antibodies onto the Fe2O3 modified CCY. Crystallinity, structure, morphology, flexibility, surface area, and elemental analysis were studied using X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), Raman spectroscopy, Field emission scanning electron microscopy with energy dispersive X-ray spectroscopy (FE-SEM/EDS) and Brunauer-Emmett-Teller (BET) analysis. Mechanical properties of the fiber such as tensile strength, young's modulus have also been investigated. Under optimal parameters, the fabric sensor exhibited a good linearity (r2 = 0.998) for wide a linear range from 1 fg to 1 µg with a detection limit of 0.005 fg/mL for the sensitive detection of cortisol. Repeatability, reliability, reproducibility, and anti-interference properties of the current sensor have been investigated. Detection of cortisol levels in human sweat samples has also been investigated and the results were validated with commercial chemiluminescence immunoassay (CLIA) method.

Enhanced thermoelectric properties of lightly Nb doped SrTiO3 thin films.

Novel thermoelectric materials developed for operation at room temperature must have similar or better performance along with being as ecofriendly as those commercially used, e.g., Bi2Te3, in terms of their toxicity and cost. In this work, we present an in-depth study of the thermoelectric properties of epitaxial Nb-doped strontium titanate (SrTi1-x Nb x O3) thin films as a function of (i) doping concentration, (ii) film thickness and (iii) substrate type. The excellent crystal quality was confirmed by high resolution transmission electron microscopy and X-ray diffraction analysis. The thermoelectric properties were measured by the three-omega method (thermal conductivity) and van der Pauw method (electrical resistivity), complemented by Seebeck coefficient measurements. A maximum power factor of 8.9 × 10-3 W m-1 K-2 and a thermoelectric figure of merit of 0.49 were measured at room temperature in 50 nm-thick films grown on lanthanum strontium aluminate. The mechanisms behind this high figure of merit are discussed in terms of a possible two-dimensional electron gas, increase of the effective mass of the electrons, electron filtering and change in strain due to different substrates. The overall enhancement of the thermoelectric properties suggests that SrTi1-x Nb x O3 is a very promising n-type candidate for room- to high-temperature applications.

Cell culture monitoring by impedance mapping using a multielectrode scanning impedance spectroscopy system (CellMap).

We report on the impedance mapping of in vitro cellular morphology by electrical impedance spectroscopy, using microelectrodes. A micro multielectrode system was designed, fabricated, assembled, tested and demonstrated for the monitoring of anchorage-dependent cell behavior and morphology. This system allowed continuous, label-free, quantitative monitoring and visualization of cell adhesion, spreading, proliferation and detachment due to cell cycle processes as well as cell-drug interaction, with spatio-temporal resolution. OvCa429 ovarian cancer cells were monitored in vitro over a period of 70 hours by inoculating the cell suspension directly on the multielectrode device. The phase angle of impedance was observed to develop a distinctive shape as a result of cell attachment and proliferation. The shape of the phase angle curve reverted back to the pre-attachment shape upon detachment of cells from the substrate, caused by the addition of trypsin to the cell culture medium. The impedance data of the cell culture were then successfully modeled as a multi-parametric equivalent circuit. The model incorporated both interfacial and cell-layer impedance parameters. Upon addition of trypsin, the cell-layer parameters showed a marked decline and were eventually eliminated from the multi-parametric model, confirming the correlation of the model to the electrode-cell-electrolyte system. These experiments demonstrate the applicability of the impedance mapping technique in visualizing and quantifying physiological changes in the cell layer due to cellular processes as well as the effect of external chemical stimulus on cells (cell-drug interaction).

Evaluation of the monothermal caloric test.

In 1970, Torok reported that patients with labyrinthine disease showed vestibular recruitment and that patients with retrolabyrinthine disease showed vestibular decruitment on the monothermal caloric test. Other investigators have failed to confirm these findings; however, their studies did not precisely replicate Torok's test procedure. Following Torok's procedure exactly, the monothermal caloric test was administered to normal individuals and to patients with well-documented vestibular lesions. Nine of ten normal persons showed normal responses and one person showed borderline decruitment. Six of eight patients who had lesions of the vestibular nerve or central vestibular pathways showed decruitment. Two patients with active Meniere's disease showed recruitment and one showed asymmetry. Two patients with Meniere's disease who had undergone endolymphatic sac operations showed normal responses. These findings support Torok's claim that the monothermal caloric test discriminates between labyrinthine and retrolabyrinthine vestibular pathology.

Fluorescein use in the detection of perilymphatic fistula: a study in cats.

A stained or colored perilymph would be a valuable tool to otologists for the detection of a perilymph fistula. We studied the effect of intravenously injected fluorescein on the inner ear in seven cats. Still and video photography was used to clearly document our findings. Intravenously injected fluorescein appeared within the soft tissue in less than 1 minute and stayed there for at least 3 1/2 hours. Fluorescence around the round window niche resulted from soft tissue (mucosal) fluorescence and extravasation of interstitial fluid (transudate). No fluorescence of perilymph was detected. Because of this, we do not believe intravenously injected fluorescein is useful in the detection of perilymph fistula. Intrathecal injection caused quick and intense staining of labyrinthine fluid.

Current status of electronystagmography testing.

ENG testing, whether computerized or not, remains the most useful means of assessing the vestibular system. The caloric test provides invaluable site-of-lesion information that objectively documents a peripheral vestibular lesion. Double (bithermal) caloric irrigation of each ear provides a more thorough and wider range test of inner ear function than a single caloric irrigation because the vestibular system is both excited and inhibited, causing responses in opposite directions, which are important in evaluating patients with underlying spontaneous nystagmus. In an age in which economically efficient and clinically effective diagnostic methods are in high demand, ENG testing remains the gold standard of vestibular function tests.

Intraoperative electrocochleography during endolymphatic sac surgery: clinical results.

Thirty-eight patients who underwent endolymphatic shunt surgery with intraoperative electrocochleography were questioned regarding control of symptoms. The average follow-up period was 2 years (range, 7 to 40 months). Sixteen (42%) patients showed improvement in the intraoperative electrocochleography potential, 12 (32%) showed worsening, and 10 (26%) showed no change. Complete or substantial control of dizziness was achieved in 36 (95%) patients, and insignificant control in only 2 (5%) patients. Hearing improvement was noted in 4 (11%) patients, and hearing loss in 13 (34%). No correlation was found between intraoperative electrocochleography improvement and dizziness control. However, three of the four patients who had hearing improvement also had the greatest improvement in intraoperative electrocochleography recording. Intraoperative electrocochleography may help the surgeon more accurately identity the true endolymphatic sac and duct.

Oscillopsia in patients with loss of vestibular function.

Contrary to standard teaching, many patients with bilateral vestibular loss clearly deny oscillopsia or imbalance in darkness. In an attempt to characterize these patients within the larger population of all patients with bilateral vestibular loss, the rotation and posturography test results of 22 patients with bilateral vestibular loss were reviewed. In addition, dynamic visual acuity was assessed with an eye chart test. There was a poor relationship between oscillopsia and dynamic visual acuity or rotation testing. There were three patterns of response on rotation testing, and loss of high-frequency gain was seen in as many patients who reported oscillopsia as did not. There were some patients with normal gain values at all frequencies tested who reported oscillopsia. It may be that the change in the VOR, rather than the absolute VOR loss, is responsible for the production of oscillopsia. On the basis of this and other studies, treatment strategies for patients with bilateral vestibular loss are suggested.

Vestibular effects of chronic perilymph fistula in the cat.

Chronic, unilateral perilymph fistulae were created in cats by removal of the round window membrane and placement of a tympanostomy tube into the round window. Rotary chair, fistula, caloric, and vestibulospinal tests were performed before and after fistulization, and periodically for 2 weeks. At 2 weeks, patency of the fistula was documented by fluorescein injection into the spinal fluid and visualization of leakage into the middle ear bulla via the fistula. All the cats had a patent fistula at 2 weeks, but one of the three cats had a greater perilymph leak than the others. The cat with the more active leak had a spontaneous nystagmus toward the side of the fistula on the first postoperative day; this changed to nystagmus toward the opposite side by the third postoperative day. The other cats had a spontaneous nystagmus toward the opposite side from the first postoperative day. Most abnormal test results returned to normal in the first week after fistulization. Histologic study of the temporal bones revealed that the cat with the greater leak had a wider cochlear aqueduct than the other cats.

Thyrotoxicosis--surgical management in the era of evidence-based medicine: experience in western India with 752 cases.

The three modalities of treatment of thyrotoxicosis, antithyroid therapy (ATT), radio-iodine (I131) therapy and surgery are not cause-specific. In this paper, we describe our evolving experience with 752 thyrotoxic patients who underwent surgery during the last 40 years and discuss the current scenario with evidence-based data and observations wherever possible. Thyroidectomy was performed in 428 patients with Grave's disease (GD), 299 patients with toxic multinodular goitre, and 25 with toxic solitary nodules (TSN). Whereas 289 patients with GD had surgery for failed ATT, the other 139 had primary surgery for controversial or debatable indications such as poor socio-economic status, desire for early pregnancy, poor drug compliance and severe ophthalmopathy. Preoperatively, all patients were administered carbimazole or propylthiouracil. Non-selective b-blocker propranolol and Lugol's iodine were routinely given. In the 25 patients with TSN, hemithyroidectomy was performed. In all others, subtotal thyroidectomy (STT), was performed leaving behind 4 to 8 g of thyroid tissue: a larger amount was left behind in those with higher antithyroid antibody titres. During the last decade, 80 patients received near total thyroidectomy (NTT), mainly to minimize recurrence of thyrotoxicosis and to ameliorate severe eye signs. Because of our increasing experience, no significant increase in postoperative morbidity was encountered with NTT compared to STT. Transient hoarseness was observed in 53 patients with STT and only in two patients with NTT. Three patients with STT and one with NTT developed permanent hoarseness due to recurrent laryngeal nerve palsy; voice in these four was normalized by intraglottic injection of Teflon paste 6 months after the operation. In patients undergoing STT, transient hypoparathyroidism was encountered in 63, and permanent hypoparathyroidism in five. The corresponding figures for NTT were 12 and one, respectively. Of the 500 patients monitored for 1 year or more, hypothyroidism was observed in 135 and recurrent thyrotoxicosis in nine. In the same group of 500, exophthalmos was ameliorated in 130 of the 265 with positive eye signs. Nineteen glands exhibited features of severe Hashitoxicosis with marked destruction of acini and considerable lymphoid aggregates and follicles. Carcinoma was observed in three other thyroid glands.

Arterial embolization for control of bleeding in advanced head and neck carcinoma.

There are a number of patients with unresectable recurrent carcinoma of the head and neck who continue to lead a relatively functional life despite advanced local disease. For these patients bleeding from tumor represents a devastating complication that can abruptly terminate the course of an otherwise chronic disease, albeit a uniformly fatal one. The technique we describe renders a relatively safe and effective treatment that seems to control this problem. We report on our experience with three patients whose tumor bleeding was controlled by permanent intra-arterial embolization with Ivalon, a polyvinyl alcohol-based foam. The technique, indications, and complications are discussed.

Perilymph fistula.

PLF is an enigmatic otologic disease that may be congenital or acquired through surgery, trauma, neoplasm, or infection. The exact incidence of PLF is unknown, primarily because it is difficult to diagnose. A careful, thorough history is important in recognizing PLF. If a PLF exists, repair can be effected simply and quickly and may be very beneficial to the patient. There is a small but real risk of total hearing loss with operation to repair any PLF. Currently, the most useful diagnostic tests for PLF involve the vestibular system, and further studies of vestibular responses to PLF hold promise in improving our diagnostic ability.

Combined 2D and 3D-QSAR, molecular modelling and docking studies of pyrazolodiazepinones as novel phosphodiesterase 2 inhibitors.

Selective inhibition of phosphodiesterase 2 (PDE2) in cells where it is located elevates cyclic guanosine monophosphate (cGMP) and acts as novel analgesic with antinociceptive activity. Three-dimensional quantitative structure-activity relationship (QSAR) studies for pyrazolodiazepinone inhibitors exhibiting PDE2 inhibition were performed using comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA) and Topomer CoMFA, and two-dimensional QSAR study was performed using a Hologram QSAR (HQSAR) method. QSAR models were generated using training set of 23 compounds and were validated using test set of nine compounds. The optimum partial least squares (PLS) for CoMFA-Focusing, CoMSIA-SDH, Topomer CoMFA and HQSAR models exhibited good 'leave-one-out' cross validated correlation coefficient (q(2)) of 0.790, 0.769, 0.840 and 0.787, coefficient of determination (r(2)) of 0.999, 0.964, 0.979 and 0.980, and high predictive power (r(2)(pred)) of 0.796, 0.833, 0.820 and 0.803 respectively. Docking studies revealed that those inhibitors able to bind to amino acid Gln859 by cGMP binding orientation called 'glutamine-switch', and also bind to the hydrophobic clamp of PDE2 isoform, could possess high selectivity for PDE2. From the results of all the studies, structure-activity relationships and structural requirements for binding to active site of PDE2 were established which provide useful guidance for the design and future synthesis of potent PDE2 inhibitors.

Population pharmacokinetics of inhaled tobramycin powder in cystic fibrosis patients.

Tobramycin powder for inhalation (TOBI Podhaler or TIP) is approved for the treatment of Pseudomonas aeruginosa airway infection in patients with cystic fibrosis (CF). A population pharmacokinetic model for tobramycin inhalation powder (TIP) in CF patients was developed to characterize the effect of covariates including body mass index (BMI) and lung function (forced expiratory volume in 1 s as percent of the predicted value (FEV1% predicted) at baseline) on the serum exposure parameters.A two-compartment model with first-order elimination and first-order absorption was developed. Across a range of baseline demographic values in the study population, the predicted mean values for the maximum (Cmax) and trough (Ctrough) plasma concentrations at steady state were at least 7.5 and 5-fold lower, respectively, than the recommended thresholds for tobramycin toxicity (12 µg/ml for Cmax and 2 µg/ml for Ctrough). This model adequately described the tobramycin serum concentration-time course in CF patients following inhalation of TIP. The results indicate that no BMI- or FEV1-based dose adjustment is needed for use of TIP in CF patients.

Prevalence and risk factors of diabetes in a community-based study in North India: the Chandigarh Urban Diabetes Study (CUDS).

AIMS: As there have been few studies in North India of the prevalence of diabetes within the past decade, this study aimed to assess the prevalence and risk factors associated with diabetes in the North Indian city of Chandigarh. METHODS: This cross-sectional survey of 2227 subjects (response rate: 94%), aged ≥20 years and representative of the urban Chandigarh population, was conducted from April 2008 to June 2009. Fasting plasma glucose (FPG) and 2-h plasma glucose (2hPG) following ingestion of 75 g of an anhydrous glucose equivalent were estimated by glucometer in all subjects except those with known diabetes, in whom only FPG was measured. Diagnosis of diabetes was based on 1999 WHO criteria. The collected prevalence data was age-standardized for the Chandigarh population, and multivariate logistic-regression analysis was used to correlate risk factors with the presence of diabetes. RESULTS: A total of 349 subjects (15.7%, 95% CI: 13.9-16.9) were diabetic, comprising 210 (9.4%) with known diabetes and 139 (6.2%) with newly diagnosed diabetes, and 344 (15.4%, 95% CI: 14.3-17.1) subjects were prediabetic. The age-standardized prevalence of diabetes and prediabetes were 11.1% (95% CI: 9.7-12.4) and 13.2% (95% CI: 11.8-14.6), respectively. Age ≥50 years, a family history of diabetes, BMI ≥23 kg/m(2), abdominal obesity and hypertension were significantly and positively associated with the presence of diabetes, whereas educational status was negatively associated with diabetes (P<0.001 for all). CONCLUSION: The age-standardized prevalence of diabetes and prediabetes were 11.1% and 13.2%, respectively. Older age, family history of diabetes, obesity and hypertension were positively related, while educational status was negatively related, to the presence of diabetes.