Type 2 Diabetes mellitus (T2DM) is characterized by peripheral insulin resistance, impaired insulin secretion, and reduced β-cell mass. Mechanisms that underlie β-cell failure include glucotoxicity, lipotoxicity, endoplasmic reticulum (ER) stress, and oxidative stress. This study was designed to assess the protective effect of trigonelline and diosgenin against changes in ER stress-associated apoptotic proteins CHOP, Caspase12, and Caspase3 and antioxidant levels in pancreas as well as adipose tissue PPARγ mRNA in T2DM rats. Markers of diabetes and obesity such as serum glucose, insulin, free fatty acid (FFA), TNF-α, IL-6, and leptin were also assessed. T2DM rats showed significantly elevated levels of pancreatic ER stress proteins and lipid peroxidation, while the antioxidants were significantly reduced. Histological examination also confirmed T2DM-associated damage in pancreas. In addition, a significant increase in serum FFA, TNF-α, IL-6, and decrease in leptin levels along with significantly decreased adipose mass and reduced PPARγ expression were observed in T2DM rats. On the other hand, trigonelline and diosgenin treatment independently brought about significant improvement in serum parameters, decrease in apoptotic ER stress proteins, and reinforced antioxidant status in pancreas. Histological examination of pancreas showed normal morphology. Treated groups also showed increased adipose tissue mass and enhanced PPARγ expression. Data from docking studies indicated good interaction of both compounds with PPARγ, and diosgenin showed better binding efficiency. These findings suggest that the insulin-sensitizing effects of trigonelline and diosgenin are mediated through moderation of ER stress and oxidative stress in pancreas as well as by PPARγ activation in adipose tissue.

Abstract. Syzygium cumini (SC) is well known for its anti-diabetic potential, but the mechanism underlying its amelioration of type 2 diabetes is still elusive. Therefore, for the first time, we investigated whether SC aqueous seed extract (100, 200, or 400 mg/kg) exerts any beneficial effects on insulin resistance (IR), serum lipid profile, antioxidant status, and/or pancreatic β-cell damage in high-fat diet / streptozotocin-induced (HFD-STZ) diabetic rats. Wistar albino rats were fed with HFD (55% of calories as fat) during the experiment to induce IR and on the 10th day were injected with STZ (40 mg/kg, i.p.) to develop type 2 diabetes. Subsequently, after confirmation of hyperglycemia on the 14th day (fasting glucose level > 13.89 mM), diabetic rats were treated with SC for the next 21 days. Diabetic rats showed increased serum glucose, insulin, IR, TNF-α, dyslipidemia, and pancreatic thiobarbituric acid-reactive substances with a concomitant decrease in β-cell function and pancreatic superoxide dismutase, catalase, and glutathione peroxidase antioxidant enzyme activities. Microscopic examination of their pancreas revealed pathological changes in islets and β-cells. These alterations reverted to near-normal levels after treatment with SC at 400 mg/kg. Moreover, hepatic tissue demonstrated increased PPARγ and PPARα protein expressions. Thus, our study demonstrated the beneficial effect of SC seed extract on IR and β-cell dysfunction in HFD-STZ-induced type 2 diabetic rats.

Multiply transfused patients of severe aplastic anemia are at increased risk of graft rejection. Five such patients underwent peripheral blood stem cell transplantation from HLA-identical siblings with a fludarabine-based protocol. The conditioning consisted of fludarabine 30 mg/m 2 / day  6 days, cyclophosphamide 60 mg/kg/day  2 days and horse antithymocyte globulin (ATG)  4 days. Two different ATG preparations were used: ATGAM (dose 30 mg/kg/day  4 days) or Thymogam (dose 40 mg/kg/ day  4 days). Engraftment: median time to absolute neutrophil count (ANC) 40.5  10 9 /l was 11 days (range: 8-17) and median time to platelet count 420  10 9 /l was 11 days (range: 9-17). At a median follow-up of 171 days (range: 47-389), there has been no graft rejection and all patients are in complete remission. Acute GVHD (grade 1) occurred in one patient only. Chronic GVHD developed in two patients (extensive in one and limited in another). The transplants were performed in non-HEPA filter rooms. In only one patient, systemic antifungal therapy (voriconazole) was used. The use of Thymogam brand of ATG for conditioning is being reported for the first time. Our experience suggests that this fludarabine-based protocol allows rapid sustained engraftment in high-risk patients without significant immediate toxicity.

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Posterior reversible encephalopathy syndrome (PRES) has diverse etiologies and is closely linked to hematopoietic stem cell transplant (HSCT). Headache and seizures are the most common clinical presentations. Although near total recovery is seen in the majority of patients with appropriate management, the implications of its occurrence in the setting of an HSCT is much more than the residual neurological deficits. Graft rejection and occurrence of graft versus host disease has been reported. We analyzed retrospectively our data of 35 pediatric HSCT recipients over the last 2 years at our center. In total, 17% (n=6) patients developed PRES. Headache and seizures were the most common clinical presentations. All patients were on calcineurin inhibitors at the onset of symptoms. The median time after HSCT to the onset of PRES was 21 days. In total, 34% (n=2) patients developed residual neurological deficit. One patient died of acute graft versus host disease at a later date, and 50% (n=3) patients had graft rejection and return to transfusion dependence. The implications of PRES on HSCT outcomes are grave, and better immunosuppression transition protocols need to be developed.

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Peripheral blood stem cell mobilization with cytokines for autologous stem cell transplant in multiple myeloma is adversely affected by initial induction therapy consisting of either Lenalidomide or cytotoxic drugs, with failure rates of up to 45%. The use of Plerixafor with G-CSF for PBSC mobilisation significantly improves the chances of a successful mobilization. Plerixafor is a costly therapy and increases the overall costs of ASCT which can affect the number of patients being taken up for ASCT in resource limited settings. We prospectively studied the impact of single dose preemptive Plerixafor for PBSC mobilization in patients with prior Lenalidomide exposure. 26 patients who had received Lenalidomide based induction protocol underwent PBSC mobilisation during the study period with G-CSF 10 μg/kg/day SC for 4 days and single dose preemptive Plerixafor 240 μg/kg SC stat 11 h before the scheduled PB stem cell harvest on D5, based on a D4 PB CD34+ counts of <20/μL. A median of 07 cycles of Lenalidomide based combination therapy was used for induction therapy prior to ASCT. 84% patients underwent successful mobilization with one sitting of stem cell harvest post a single dose of Inj Plerixafor. 7.6% patients failed to mobilise the predefined minimum cell dose of CD34 and could not be taken up for ASCT. The median CD34% of the harvest bag sample was 0.33% (0.1-0.97%). Injection site erythema (34%), paresthesia's (34%) and nausea (30%) were the commonest adverse events reported post Inj Plerixafor. We did a real-world cost analysis for a resource limited setting for PBSC mobilization and found significant cost savings for the preemptive Plerixafor group.