The GLP-1 Receptor Agonist Liraglutide Increases Myocardial Glucose Oxidation Rates via Indirect Mechanisms and Mitigates Experimental Diabetic Cardiomyopathy

BackgroundType 2 diabetes (T2D) increases risk for cardiovascular disease. Of interest, liraglutide, a therapy for T2D that activates the glucagon-like peptide-1 receptor to augment insulin secretion, reduces cardiovascular-related death in people with T2D, though it remains unknown how liraglutide produces these actions. Notably, the glucagon-like peptide-1 receptor is not expressed in ventricular cardiac myocytes, making it likely that ventricular myocardium-independent actions are involved. We hypothesized that augmented insulin secretion may explain how liraglutide indirectly mediates cardioprotection, which thereby increases myocardial glucose oxidation.MethodsC57BL/6J male mice were fed either a low-fat diet (lean) or were subjected to experimental T2D and treated with either saline or liraglutide 3× over a 24-hour period. Mice were subsequently euthanized and had their hearts perfused in the working mode to assess energy metabolism. A separate cohort of mice with T2D were treated with either vehicle control or liraglutide for 2 weeks for the assessment of cardiac function via ultrasound echocardiography.ResultsTreatment of lean mice with liraglutide increased myocardial glucose oxidation without affecting glycolysis. Conversely, direct treatment of the isolated working heart with liraglutide had no effect on glucose oxidation. These findings were recapitulated in mice with T2D and associated with increased circulating insulin levels. Furthermore, liraglutide treatment alleviated diastolic dysfunction in mice with T2D, which was associated with enhanced pyruvate dehydrogenase activity, the rate-limiting enzyme of glucose oxidation.ConclusionsOur data demonstrate that liraglutide augments myocardial glucose oxidation via indirect mechanisms, which may contribute to how liraglutide improves cardiovascular outcomes in people with T2D.     

Hypertriglyceridemia: a possible diagnostic marker of disease severity in visceral leishmaniasis

Purpose

Visceral leishmaniasis (VL), a protozoan disease, is 100 % fatal if left untreated. Anemia is common in VL which plays a role in expression of clinically overt VL disease. Laboratory clues are scarce for strengthening clinical suspicion for severity in VL. Hypertriglyceridemia has emerged as a new concept for the diagnosis and prognosis in VL. The present study is aimed at correlating the magnitude of hypertriglyceridemia with the severity in VL.

Materials and methods

A retrospective case–control study was conducted between January 2012 to December 2013 among 124 patients coming for treatment from VL endemic areas, who had fever of more than 15 days and did not respond to antimalarials and antibiotics. The parasitologically confirmed VL cases (n = 87) were categorized as mild/moderate (n = 60) and severe (n = 27) groups according to WHO classification for anemia and parasite burden. Serum triglycerides were assayed in VL groups along with controls (n = 37).

Results

Serum triglyceride level was significantly higher in VL than controls [mean values were 173.50 ± 47.67 versus 127.1 ± 53.79 mg/dl, respectively (p < 0.0001)]. Triglyceride level was significantly higher in severe than in mild/moderate group of VL [211.3 ± 50.2 mg/dl versus 134 ± 45.09 mg/dl, respectively (p < 0.0001)]. Hypertriglyceridemia (>161.7 mg/dl) was noted in all severe VL patients, compared to 31.66 % of mild or moderate group (p < 0.0001). There was no significant difference between mild/moderate VL and controls.

Conclusions

It is hypothesized that hypertriglyceridemia could be of additional diagnostic benefit to assess the probability and severity of VL in endemic areas.

     

Pheochromocytoma: a 10-year experience in a tertiary care North Indian hospital.

BACKGROUND: The study was carried out to highlight the clinical and biochemical profile of patients with pheochromocytoma in a tertiary care center of North India. METHODS AND RESULTS: Thirty consecutive cases of pheochromocytoma admitted over a period of 10 years to our Institute were analyzed. The chief clinical complaints of these 30 patients (17 males and 13 females, mean age 24+/-7 years) were palpitation (80%), headache (77%), sweating (60%), breathlessness (67%) and flushing (56%). The clinical triad of headache, flushing and sweating occurred in 26.7% of cases. On clinical examination, 97% of the patients were hypertensive and 16.6% presented with malignant hypertension. Laboratory measurements showed that the levels of 24-hour urinary vanillylmandelic acid were elevated in 80% of cases. Levels of plasma adrenaline and noradrenaline were raised in 78% and 79% of cases, respectively. Anatomical localization of the tumor on computerized tomographic scan showed the presence of an adrenal tumor in 80% and extra-adrenal tumor in 20%. Surgical removal of the tumor could be carried out in 28 cases following control of the blood pressure with antihypertensive drugs including alpha and beta adrenoreceptor blockers. CONCLUSIONS: Pheochromocytoma should be suspected in all young hypertensive persons. The appropriate therapy for this tumor is surgical removal preceded by adequate blood pressure control including the use of alpha and beta adrenoreceptor antagonists.     

Putative roles of a proline–glutamic acid-rich protein (PE3) in intracellular survival and as a candidate for subunit vaccine against Mycobacterium tuberculosis

The proline–glutamic acid (PE) protein family of Mycobacterium tuberculosis (Mtb) plays diverse roles in the pathogenesis and modulation of host immune responses. The uniqueness of conserved regions of PE proteins may be useful to test and validate their corresponding functions. Hence, the present study has been undertaken to demonstrate the role of PE3 (Rv0159c) for persistence, host immune response and immunoprophylaxis. We have expressed Mtb-specific PE3 gene in M. smegmatis (MS) and used the strain to infect J774A.1 macrophage cells and BALB/c mice. It was observed that during the infection, the MS expressing PE3 showed higher bacterial load when compared to infection with wild-type MS. In hypoxic condition, the expression level of PE3 gene was induced in Mtb, which further showed its relevance in the cell survival during hypoxia-induced persistence. The expression level of PE3 in Mtb was markedly induced during chronic stage of murine infection, which reiterated its importance in mycobacterial persistence in the host. The immunization of mice with recombinant PE3 protein stimulated the secretion of TNF, IL-6 and IL-2 cytokines and generated strong protective immunity against challenge with live mycobacteria, which was evidenced by decreased viable bacilli in the lungs, histopathological changes and increased survival of PE3 immunized mice. Conclusively, the results indicated that PE3 plays significant roles in mycobacterial persistence during infection, modulate host immune response and hence could be a prospective candidate for the development of subunit vaccine against tuberculosis.     

Anatomical basis of antropyloric transposition for fecal incontinence in humans: the infrapyloric approach

Purpose

Antropylorus transposition in the perineum for end-stage anal incontinence has shown to be feasible in humans. Vascular anatomy of the antro-pyloro-duodenal area is critical in preventing complications and increasing pyloric graft survival. This study was undertaken to examine the vascular anatomy of antro-pyloro-duodenal area in an attempt to safeguard the graft blood supply and improve its survival.

Methods

After obtaining preoperative CT angiography to delineate the infrapyloric artery (IP a.), bench dissection of resected pancreaticoduodenectomy specimens was performed in 12 patients. Ex vivo angiography of these specimens were also performed. Subsequent to the information obtained from these dissections, the method of antropylorus mobilization during transposition was modified in terms of the site of division of the right gastroepiploic a. (Rt GEA). Perioperative outcomes (graft related complications, fecal incontinence scores, Doppler flow studies, and manometry studies of the graft) were compared between the two groups.

Results

IP a. originated only from the Rt GEA in 8 cases (66 %) and from both the gastroduodenal a. and the Rt GEA in the rest. However, its origin solely from the gastroduodenal a. was not observed. The pyloric graft survival, pyloric valve pressures and Doppler flow velocities were significantly (p < 0.05) better when the infrapyloric a. was preserved following this refinement. However, no immediate significant difference in incontinence scores was observed.

Conclusions

Careful preservation of the pyloric valve vascularity by preserving the IP a. by dividing the Rt GEA at its origin increases vascularity, survival and contractility of the pyloric graft in perineum.     

Unpleasant Subjective Emotional Experiencing of Pain

The field of pain medicine that once began as a supportive and compassionate care, adding value to the management of acute and chronic ailments, has now transformed into a vital and essential specialty with structured training programs and service units with professionals dedicating their careers to it. The expansion of understanding of the direct relationship of pain relief to the quality of life, uncovering of neuronal pathways, and technological advances in imaging as well as in interventional techniques have all contributed to this phenomenal growth. However, there is a growing concern whether the training programs and the specialized practitioners are gradually limiting their skilled inputs primarily within the sensory realm of the pain experience with sophisticated interventional techniques and relegating its subjective and emotional dimensions to perfunctory realms within the schema of service provision. While the specialty is still young, if we can understand the inherent aspect of these dimensions within the pain experience and acknowledge the gaps in service provision, it may be possible to champion development of truly comprehensive pain relief programs that responds effectively and ethically to a patient''s felt needs. This article attempts to position the subjectivity of pain experience in context and surface the need to design complete systems of pain relief services inclusive of this dimension. It presents authors’ review of literature on perspectives of ‘unpleasant subjective emotional experiencing of the pain” to elucidate possible clinical implications based on the evidences presented on neuro-biology and neuro-psychology of the pain experience; the aim being to inspire systems of care where this dimension is sufficiently evaluated and managed.     

Association of UGT1A6 gene polymorphism with clinical outcome in pediatric epileptic patients on sodium valproate monotherapy

Pediatric epilepsy comprises chronic neurological disorders characterized by recurrent seizures. Sodium valproate is one of the common antiseizure medications used for treatment. Glucuronide conjugation is the major metabolic pathway of sodium valproate, carried out by the enzyme uridine 5′-diphosphate (UDP) glucuronosyl transferase (UGT) whose gene polymorphisms may alter the clinical outcome. The objective of this study was to assess the association between UGT1A6 genetic polymorphism and clinical outcome in terms of efficacy and tolerability in pediatric epileptic patients on sodium valproate monotherapy. Pediatric epileptic patients (n=65) aged 2-18 years receiving sodium valproate monotherapy for the past one month were included. Genetic polymorphism patterns of UGT1A6 (T19G, A541G, A552C) were evaluated by PCR-RFLP. Clinical outcome was seizure control during the 6 months observation period. Tolerability was measured by estimating the hepatic, renal, and other lab parameters. Out of 65 patients, TT (40%), TG (57%), and GG (3%) patterns were observed in UGT1A6 (T19G) gene, AA (51%), AG (40%), and GG (9%) in (A541G) gene, and AA (43%), AC (43%), and CC (14%) in (A552C) gene. No statistical difference in clinical outcome was found for different UGT1A6 genetic polymorphism patterns. We concluded that different patterns of UGT1A6 genetic polymorphism were not associated with the clinical outcome of sodium valproate in terms of efficacy and tolerability. Sodium valproate was well-tolerated among pediatric patients with epilepsy and can be used as an effective antiseizure medication.     

Anterior segmental osteotomies without orthodontics: practicability of the correction of dentoalveolar deformities

We designed this study to determine the efficiency and stability of anterior segmental osteotomies (ASO) without orthodontics for various dentofacial deformities. Records of patients treated with maxillary or mandibular ASO, or both, without orthodontics in the past 15 years were analysed. The assessment included postoperative analysis of patients’ aesthetics and functional satisfaction using a questionnaire and grading (score 0 - 4) system, and the amount of relapse calculated from 12-month postoperative cephalograms. A total of 26 ASO subjects (age range 13- 31 years) were studied (14 maxillary, two mandibular, and 10 bimaxillary). Long-term stability was acceptable in all cases with no significant relapse (p>0.05). No major complications were encountered. All patients reported good to excellent (score = 3 to 4) satisfaction following surgery. Using meticulous planning and a careful surgical technique, ASO without orthodontics is a simple, quick, safe, and stable option for the correction of dentofacial deformities.