Efficacy and safety of fixed dose combination of Sitagliptin, metformin, and pioglitazone in type 2 Diabetes (IMPACT study): a randomized controlled trial.

BACKGROUND: Due to the progressive decline in ß-cell function, it is often necessary to utilize multiple agents with complementary mechanisms of action to address various facets and achieve glycemic control. Thus, this study aimed to evaluate the efficacy and safety of a fixed-dose combination (FDC) of metformin/sitagliptin/pioglitazone (MSP) therapy vs. metformin/sitagliptin (MS) in type 2 diabetes mellitus (T2DM). METHODS: In this phase 3, multicenter, double-blind study, patients with T2DM who exhibited inadequate glycemic control with HbA1c of 8.0-11.0% while taking ≥1500 mg/day metformin for at least 6 weeks were randomized to receive either FDC of MSP (1000/100/15 mg) or MS (1000/100 mg) per day for 24 weeks. The primary outcome measure was the change in HbA1c, and secondary outcomes included changes in fasting plasma glucose (FPG), postprandial plasma glucose (PPG), and body weight from baseline to 24 weeks along with safety and tolerability. RESULTS: Among the 236 patients randomized, 207 (87.71%) successfully completed the study. All baseline characteristics were comparable between the FDC of MSP and MS groups. There was a subsequent significant reduction of HbA1c in FDC of MSP (- 1.64) vs. MS (- 1.32); between groups was [- 0.32% (95% CI, - 0.59, - 0.05)], P = 0.0208. Similar reductions were found in FPG [- 13.2 mg/dL (95% CI, - 22.86, - 3.71)], P = 0.0068, and PPG [- 20.83 mg/dL (95% CI, - 34.11, - 7.55)], P = 0.0023. There were no significant changes in body weight. A total of 27 adverse effects (AEs) and one severe AE were reported, none of which were related to the study drug. CONCLUSION: The FDC of MSP demonstrated significant efficacy in managing glycemic indices and could serve as a valuable tool for physicians in the management of Indian patients with T2DM. TRIAL REGISTRATION: Clinical Trials Registry of India, CTRI/2021/10/037461.

Comparison of conventional fractionation (five fractions per week) and altered fractionation (six fractions per week) in stage I and II squamous cell carcinoma of oropharynx: An institutional study.

BACKGROUND: The radiotherapy (RT) dose and fractionation schedule for head and neck cancers for locoregional control and acceptable organ toxicity are still debatable. Accelerated RT includes administration of six fractions per week with the same dose per fraction. AIM: Comparison of conventional versus accelerated RT in terms of locoregional control, and acute and late radiation toxicity in squamous cell carcinoma oropharynx (stage I and II). SETTINGS AND DESIGN: Prospective, double arm, phase 2, randomized study. MATERIALS AND METHODS: Sixty patients of squamous cell carcinoma oropharynx (stage I and II) were randomized in two arms (accelerated fractionation, arm 1 and conventional fractionation, arm 2). All patients received RT dose of 66 Gray (Gy) in 33 fractions (#). The patients in arm 1 received six fractions per week with 2 Gy/# (Monday-Saturday) and in arm 2, five fractions per week with 2 Gy/# (Monday-Friday). No chemotherapy was administered. During and after the treatment, locoregional control, and acute and late radiation toxicity were assessed. RESULTS: At 1-year follow-up, 76% patients in arm 1 and 64% patients in arm 2 had complete response. The recurrence rate at the end of 1 year in arm 1 was 12% and it was 20% in arm 2.The acute Grade 2 and 3 toxicities were higher in the accelerated arm and no significant difference in late toxicities was found. SPSS version 4.0 was used for statistical analysis. CONCLUSION: Accelerated fractionation provides better locoregional control with higher but acceptable acute and equal late radiation toxicity in squamous cell carcinoma oropharynx.

Pattern of distant metastasis in molecular subtypes of carcinoma breast: An institutional study.

BACKGROUND: Molecular subtypes of carcinoma breast show a particular pattern of distant metastasis, the knowledge of which can help to diagnose and intervene early in the course of the disease. AIM: The aim of this study was to investigate and establish an association between the molecular subtypes of carcinoma breast and the pattern of distant metastasis. SETTINGS AND DESIGN: Single arm, retrospective study. MATERIALS AND METHODS: Totally 400 patients of carcinoma breast (Stage I and II) were selected who were treated between January 2010 and December 2013. All these patients were treated with the standard treatment protocol for breast cancer. The estrogen receptor, progesterone receptor, human epidermal growth factor receptor-2 (HER-2) Neu status, and Ki-67 were done, and patients were classified into luminal A/B, HER-2 enriched, luminal/HER-2, and triple-negative subtypes. All patients were followed up until December 2015, and the pattern of local failure as well as distant metastasis was correlated with the molecular subtypes. RESULTS: A total of 143 patients developed distant metastasis and local recurrence. Bone was the most common site of metastasis overall. It was the most common type of metastasis in luminal A/B (53.3%) and luminal-HER (57.1%). Brain metastasis was most common in HER-2-enriched subtype (30.3%), whereas liver was the most common site of metastasis in HER-2-enriched subtype (45.45%). The incidence of brain metastasis was comparatively lower in luminal A/B subtype. Local recurrence was most common in HER-2-enriched subtype. The results were statistically significant for lung metastasis and local recurrence (with P = 0.004 and 0.047, respectively). CONCLUSION: A strong association exists between the molecular subtypes and the site of distant metastasis in breast cancer which can be used for greater vigilance to detect site-specific distant metastasis beforehand.

Squamous Cell Carcinoma of Skin after 20 Years of Renal Transplantation.

Solid organ transplant recipients are at high risk of developing malignancies due to the prolonged use of immunosuppressant drugs. Squamous cell carcinoma of skin can occur in these patients even after decades of organ transplant. A 45-year-old male underwent renal transplant for end-stage renal disease 23 years ago and was on immunosuppressive drugs since then. The patient was on regular follow-up. Three years back, he developed squamous cell carcinoma of both forearms and hands, which was treated with radiation therapy using 8 MeV electrons, by parallel opposed fields to a dose of 60 Gy/30 fractions. Complete response to treatment was achieved at 3 months posttreatment. The patient is currently on follow-up and asymptomatic for skin lesions. Hence, these patients require longer follow-up, active surveillance, and screening for early diagnosis and prompt treatment of the premalignant and malignant conditions.

Genetic diversity trend in Indian rice varieties: an analysis using SSR markers.

BACKGROUND: The knowledge of the extent and pattern of diversity in the crop species is a prerequisite for any crop improvement as it helps breeders in deciding suitable breeding strategies for their future improvement. Rice is the main staple crop in India with the large number of varieties released every year. Studies based on the small set of rice genotypes have reported a loss in genetic diversity especially after green revolution. However, a detailed study of the trend of diversity in Indian rice varieties is lacking. SSR markers have proven to be a marker of choice for studying the genetic diversity. Therefore, the present study was undertaken with the aim to characterize and assess trends of genetic diversity in a large set of Indian rice varieties (released between 1940-2013), conserved in the National Gene Bank of India using SSR markers. RESULT: A set of 729 Indian rice varieties were genotyped using 36 HvSSR markers to assess the genetic diversity and genetic relationship. A total of 112 alleles was amplified with an average of 3.11 alleles per locus with mean Polymorphic Information Content (PIC) value of 0.29. Cluster analysis grouped these varieties into two clusters whereas the model based population structure divided them into three populations. AMOVA study based on hierarchical cluster and model based approach showed 3 % and 11 % variation between the populations, respectively. Decadal analysis for gene diversity and PIC showed increasing trend from 1940 to 2005, thereafter values for both the parameters showed decreasing trend between years 2006-2013. In contrast to this, allele number demonstrated increasing trend in these varieties released and notified between1940 to 1985, it remained nearly constant during 1986 to 2005 and again showed an increasing trend. CONCLUSION: Our results demonstrated that the Indian rice varieties harbors huge amount of genetic diversity. However, the trait based improvement program in the last decades forced breeders to rely on few parents, which resulted in loss of gene diversity during 2006 to 2013. The present study indicates the need for broadening the genetic base of Indian rice varieties through the use of diverse parents in the current breeding program.

Improved hepatic differentiation strategies for human induced pluripotent stem cells.

Based on their almost unlimited self-renewal capacity and their ability to differentiate into derivatives of all three germ layers, human induced pluripotent stem cells (hiPSCs) might serve as a preferable source for hepatic transplants in metabolic liver disorders or acute liver failure. Furthermore, the generation of patient specific hiPSCs might facilitate the development of innovative therapeutic strategies by accurately modelling disease in vitro. In our study, we aimed for an efficient hepatic differentiation protocol that is applicable for both human embryonic stem cells (hESCs) and hiPSCs. We attempted to accomplish this goal by using a cytokine and small molecule-based protocol for direct differentiation of hESCs and hiPSCs into hepatic cells. Selecting differentiated hepatic cells was possible using an albumin promoter-driven G418 resistance system. Due to IRES-dependent dTomato reporter expression, we were able to track hepatic differentiated cells and we evaluated the most efficient time frame for G418 selection. The status of hepatic differentiation was determined by qRT-PCR comparing the expression of hepatic markers such as AFP, ALB, SOX17, and HNF4 to standard hepatic cells. Functional analysis of the hepatic phenotype was obtained by measuring secreted albumin levels and by analysis of cytochrome P450 type 1A1 activity (EROD). The percentage of differentiated cells was quantified by FACS analysis. In conclusion, our improved protocol demonstrates that both pluripotent cell sources (hESC and hiPSC) can efficiently be differentiated into mature hepatic cells with functional characteristics similar to those of standard hepatic cell lines such as HepG2.

Quality parameters of mango and potential of non-destructive techniques for their measurement - a review.

The king of fruits "Mango" (Mangifera indica L.) is very nutritious and rich in carotenes. India produces about 50% of the total world's mango. Many researchers have reported the maturity indices and quality parameters for determination of harvesting time and eating quality. The methods currently used for determination of quality of mango are mostly based on the biochemical analysis, which leads to destruction of the fruits. Numerous works are being carried out to explore some non-destructive methods such as Near Infrared (NIR), Nuclear Magnetic Resonance (NMR), X-ray and Computed Tomography (CT), electronic nose, machine vision and ultrasound for quality determination of fruits. This paper deals with some recent work reported on quality parameters, harvesting and post-harvest treatments in relation to quality of mango fruits and reviews on some of the potential non-destructive techniques that can be explored for quality determination of mango cultivars.

Allergic contact dermatitis in patients with atopic dermatitis: A clinical study.

BACKGROUND: Atopic dermatitis (AD) is a chronically relapsing dermatitis with no known cure. Due to the chronic nature of the condition, frequent and long term topical therapy is used. This may lead to sensitization, resulting in allergic contact dermatitis (ACD). AIMS: The aim of the study was to observe the frequency of ACD in atopic patients in this part of the country using Indian standard battery. METHODS: A total number of 30 cases of AD were taken for the study. Diagnosis of AD cases was based on the criteria of Hannifin and Rajka (1980). All the selected cases of AD had mild to moderate grade of severity. All these cases were treated and patch tested during the remission period. The duration of the study was 12 months. RESULTS: Out of the 30 AD cases, 7 cases showed positive ACD with patch test allergens. CONCLUSION: This study shows that ACD is not uncommon amongst atopic individuals.

Topical lincomycin gel in acne vulgaris: a multicentric placebo controlled study.

INTRODUCTION: Acne vulgaris is commonly treated with topical antibacterials. We evaluated lincomycin gel, a new topical formulation for mild to moderate acne. MATERIAL AND METHODS: A multicentric, randomized, double blind, placebo controlled, clinical trial was conducted with lincomycin hydrochloride in 2% gel form in 200 patients with grade II and grade III acne. The severity of acne lesions was noted at baseline and after 4 weeks. RESULTS: About 70% cases in the study group showed a good to excellent response, which was significantly more as compared to 23% in the placebo group. The frequency and severity of adverse reactions in the two groups were similar. CONCLUSION: Lincomycin hydrochloride gel is an effective and safe treatment option for mild to moderate acne vulgaris.

Anaesthetic considerations for a child with combined Prader-Willi syndrome and mitochondrial myopathy.

We report the anaesthetic management of a child with Prader-Willi syndrome and mitochondrial myopathy for open heart surgery. We used ketamine, fentanyl, rocuronium and caudal morphine together with a propofol infusion with no untoward effects. The implications of both conditions for anaesthesia are discussed.

Dual AV nodal pathway physiology after injury with radiofrequency energy in a patient without a history of reentrant tachycardia.

Radiofrequency (RF) atrioventricular (AV) nodal modification has been reported to occasionally produce a proarrhythmic effect. Dual AV nodal pathway physiology in patients without reentrant tachychardia has also been reported. This case describes AV nodal modification with RF energy in an anatomically intermediate area resulting in the appearance of discontinuous antegrade conduction curves and reentry in a patient in which these were previously not present. This suggests that AV nodal injury may be a mechanism for acquired AV nodal reentry.

Reversible shear-mediated platelet dysfunction during cardiac surgery as assessed by the PFA-100 platelet function analyzer.

We undertook this investigation to assess alterations in shear-mediated platelet function during cardiac surgery and to determine the potential for the PFA-100 to predict post-operative bleeding. Platelet aggregation and PFA-100 closure times were determined in 18 adult patients at five intervals during cardiac surgery. Associations between post-operative bleeding and closure times were examined in an additional 58 patients. Statistical analysis consisted of Student's t, Wilcoxon signed rank, and Spearman correlation tests. All results are reported as mean +/- SEM. Collagen/epinephrine closure times were prolonged prior to and throughout surgery. Collagen/adenosine-5'-diphosphate (ADP) closure times were significantly prolonged by heparin administration, 141 +/- 15 s versus 115 +/- 10 s (P = 0.01), and subsequent initiation of cardiopulmonary bypass (CPB), 203 +/- 12 s (P= 0.0001); however, 15 min after protamine administration, closure times returned to near pre-operative values, 138 +/- 12 s (P = not significant). In contrast, platelet aggregation in response to ADP remained impaired in 17 of 19 patients after CPB. Neither ex vivo correction of sample hematocrits nor supplementation with Humate P affected closure times. Positive and negative predictive values for post-CPB collagen/ADP closure times to predict bleeding were 18 and 96%, respectively. These results suggest that factors both intrinsic and extrinsic to the platelet contribute to reversible shear-mediated platelet dysfunction during CPB, and that the PFA-100 may prove useful after CPB to identify patients unlikely to benefit from platelet transfusions.

ANP, BNP, and CNP enhance bradycardic responses to cardiopulmonary chemoreceptor activation in conscious sheep.

We demonstrated previously that atrial natriuretic peptide (ANP) enhances reflex bradycardia to intravenous serotonin [5-hydroxytryptamine (5-HT)] (von Bezold-Jarisch reflex) in rats. To determine whether 1) ANP affects this cardiopulmonary vagal reflex in another species and 2) B-type (BNP) and C-type (CNP) natriuretic peptides share with ANP the ability to modulate this reflex, we used intravenous phenylbiguanide (PBG), a 5-HT(3) agonist, as the stimulus to evoke a von Bezold-Jarisch reflex (dose-related, reproducible bradycardia) in conscious adult sheep (n = 5). Three doses of PBG (13 +/- 3, 20 +/- 3, and 31 +/- 4 microg/kg) injected into the jugular vein caused reflex cardiac slowing of -7 +/- 1, -15 +/- 2, and -36 +/- 3 beats/min, respectively, under control conditions. These doses of PBG were repeated during infusions of ANP, BNP, or CNP (10 pmol. kg(-1). min(-1) iv), or vehicle (normal saline). Each of the natriuretic peptides significantly (P < 0.05) enhanced the sensitivity of bradycardic responses to PBG by 94 +/- 8% (ANP), 142 +/- 55% (BNP), and 61 +/- 16% (CNP). Thus not only did ANP sensitize cardiopulmonary chemoreceptor activation in a species with resting heart rate close to that in humans, but BNP and CNP also enhanced von Bezold-Jarisch reflex activity in conscious sheep.