Akhtar Khan - Academia.edu (original) (raw)

Papers by Akhtar Khan

Transplantation, 2010

Background. Because of the donor organ shortage, kidneys from smaller pediatric donors are being ... more Background. Because of the donor organ shortage, kidneys from smaller pediatric donors are being increasingly used. However, it is unclear whether small pediatric deceased donor kidneys should be used as single grafts or en bloc. We reviewed our outcomes of single kidney transplants from small pediatric donors into adult recipients. Methods. Kidneys equal to or more than 6 cm in length were transplanted as a single kidney in seven adult recipients weighing less than 80 kg. Creatinine clearance, kidney graft size, and glomerular size were followed up at 1, 3, 6, and 12 months after transplantation. Results. All patients and grafts, with the exception of one patient, are currently alive with functional grafts. Two kidneys were procured after cardiac death of the donors, but no delayed graft function was observed. A total of 57% (four of seven) patients developed BK viremia, and 29% (two of seven) patients developed BK virus nephropathy. The graft size significantly increased during follow-up by ultrasonography (Pϭ0.02). The renal allograft function by calculated creatinine clearance also significantly improved at 40.6Ϯ6.9 mL/min, 52.7Ϯ10.2 mL/min, and 66.2Ϯ9.7 mL/min at 1, 3, and 12 month after transplantation, respectively (Pϭ0.01). The size of glomeruli significantly increased from 122Ϯ8.4 m at 1 to 2 months to 169Ϯ22.5 m at 3 to 12 months after transplantation (PϽ0.01). Conclusions. Kidneys equal to or more than 6 cm from small pediatric donors can be successfully transplanted as a single kidney. Single pediatric kidney transplantation can provide adequate renal function with a speedy increase in allograft size.

Transplant International, 2011

The Journal of Steroid Biochemistry and Molecular Biology, 2008

Selective thyroid hormone receptor subtype-␤ (TR␤) agonists have received attention as potential ... more Selective thyroid hormone receptor subtype-␤ (TR␤) agonists have received attention as potential treatments for hypercholesterolemia and obesity, but have received less attention as treatments for diabetes, partly because this condition is not improved in thyroid hormone excess states. The TR␤ selective agonist KB-141 induces 5-10% increases in metabolic rate and lowering of plasma cholesterol levels without tachycardia in lean rats, unlike the major active thyroid hormone, T 3. In the current study, we determined whether KB-141 promotes weight loss in obese animals and whether it exhibits anti-diabetogenic effects. Body weight, adiposity (DEXA), and lipid levels were examined following p.o. administration of KB-141 to obese Zucker fa/fa rats at 0.00547-0.547 mg/kg/day for 21 days, and in ob/ob mice at 0.5 mg/kg/day KB-141 for 7 days. In rats, KB-141 reduced body weight by 6 and 8%, respectively, at 0.167 and 0.0547 mg/kg/day without tachycardia and adiposity was reduced at 0.167 mg/kg/day (5-6%). In ob/ob mice, KB-141 lowered serum cholesterol (35%), triacylglycerols (35%) and both serum and hepatic free fatty acids (18-20%) without tachycardia. Treatment of ob/ob mice with KB-141 (0.0547 or 0.328 mg/kg/day over 2 weeks) improved glucose tolerance and insulin sensitivity in a dose-dependent manner with no effect on heart rate. Thus, KB-141 elicits anti-obesity, lipid lowering and anti-diabetic effects without tachycardia suggesting that selective TR␤ activation may be useful strategy to attenuate features of the metabolic syndrome.

Molecular Endocrinology, 2006

In this study, we used ob/ob mice as a model to investigate the effects of long-term estradiol ad... more In this study, we used ob/ob mice as a model to investigate the effects of long-term estradiol administration on insulin sensitivity and to explore the mechanisms that underlie the antidiabetic effects of estrogen on mouse liver. Female ob/ob mice were randomly divided into two groups and given estradiol (100 g/kg⅐d) or vehicle alone for 4 wk. Estrogen administration improved glucose tolerance and insulin response to glucose in ob/ob mice. Moreover, insulin resistance and liver triglyceride levels were decreased in response to estrogen administration. Microarray analysis revealed that expression of genes involved in hepatic lipid biosynthesis was decreased in ob/ob mouse livers after estradiol treatment. Further searches for direct estrogen target genes revealed increased hepatic mRNA expression of signal transducer and activator of transcription 3 (Stat3) and several known Stat3 target genes in ob/ob livers after longterm estradiol treatment. Furthermore, Stat3 and phosphorylated Stat3 protein is induced in ob/ob mouse liver after long-term estrogen treatment. We also present data showing that Stat3 is rapidly induced by estradiol in mouse livers. This, together with data showing recruitment of ER␣ to the promoter of Stat3 in vivo, suggests that Stat3 is a direct target gene for estradiol. In conclusion, estradiol treatment improves glucose tolerance and insulin sensitivity in ob/ob mice. We propose that this may be mediated, at least partially, via estrogen stimulation of the hepatic expression of Stat3, leading to decreased expression of hepatic lipogenic genes, and thereby to antidiabetic effects.

Metabolism, 1998

The hypothalamus and cortex from ob/ob mice and their lean littermates were sonicated and then in... more The hypothalamus and cortex from ob/ob mice and their lean littermates were sonicated and then incubated with glucose-6-phosphate (glucose-6-P) and glycerol phosphate (glycerol-P). The difference between the rates of hydrolysis of glucose-6-P and glyceroI-P was taken as the measure of glucose-6-phosphatase activity. The activity was much higher in the hypothalamus from ob/ob mice versus their lean littermates. Activity was undetected in the cortex. These findings raise the possibility that a defect in the regulation of glucose-6-phosphatase activity in a portion of the hypothalamus may relate to the mechanism underlying obesity in the ob/ob mouse. However, obese gene product administration to ob/ob mice, while reducing the body weight, did not alter the glucose-6-phosphatase activity.

Endocrinology, 1998

Islets from Goto-Kakizaki (GK) rats from our colony, despite marked impairment of glucose-induced... more Islets from Goto-Kakizaki (GK) rats from our colony, despite marked impairment of glucose-induced insulin release, used glucose and produced CO2 at a rate 3 times that of islets from control Wistar rats. Almost all glucose used was accounted for in CO2 and lactate production. The percentages of glucose carbon used collected in CO2 and lactate were similar for control and GK islets. GK islets also oxidized 40% more acetate and leucine to CO2 than did control islets. The fraction of carbon leaving the Krebs cycle relative to CO2 production was the same in GK and control islets. The capacities of mitochondria from GK islets to generate ATP from glutamate and malate were similar and that to generate ATP from succinate and rotenone was somewhat less from GK islets. The reason for the enhanced utilization of substrates by islets of the GK rat is not apparent. In conclusion, there is no decrease in islet glucose utilization, glucose oxidation, Krebs cycle function, or the electron transpor...

Clinical Transplantation, 2011

Immunosuppression management in post-transplant malignancy is challenging because of a lack of ob... more Immunosuppression management in post-transplant malignancy is challenging because of a lack of objective immunologic assessment tools. The ImmuKnow assay measures the ATP level from CD4 T cells, quantifying cell-mediated immunity and providing an insight into the immune status of transplant recipients. Its potential use in patients with post-transplant de novo malignancy was evaluated. Thirteen adult transplant patients with de novo malignancy were divided into survivors (n = 9) and non-survivors (n = 4) after malignancy treatment. Tacrolimus and the ImmuKnow levels were monitored before, during, and after malignancy treatment. The ImmuKnow level in non-survivors group was significantly lower before and after malignancy treatment compared to survivors group (p = 0.013 and 0.0014 respectively). In survivor group, the ImmuKnow level was significantly decreased during malignancy treatment (p = 0.019) but recovered to the initial level after the treatment. However, in non-survivor group, the ImmuKnow level remained suppressed throughout the observed period despite a reduction in immunosuppressive drug levels. The ImmuKnow assay can be an objective means evaluating immune status of patients with de novo malignancy. The ImmuKnow assay can express the degree of immune suppression induced by chemotherapeutic or radiation therapy and may be a useful tool in optimizing the timing of reintroduction of immunosuppression after malignancy treatment.

Bioscience Reports, 1994

The present study shows that the calmodulin antagonist calmidazolium inhibited influx of Ca2+ thr... more The present study shows that the calmodulin antagonist calmidazolium inhibited influx of Ca2+ through voltage-gated Ca2+-channels in clonal insulin producing RINm5F-cells. The mechanism of inhibition may involve both Ca2+-calmodulin-dependent protein kinases and direct binding of calmidazolium to the Ca2+-channel. Calmidazolium did not affect uptake of Ca2+ into intracellular Ca2+-pools, inositol 1,4,5-trisphosphate (InsP3) formation or action on intracellular Ca2+-pools. The calmodulin inhibitor also did not affect glucose utilization or oxidation in RINm5F-cells, speaking against an unspecific toxic effect of the compound. KCl-and ATP-stimulated insulin release from RINm5F-cells was attenuated by calmidazolium, whereas basal hormone secretion was unaffected.

Biochemical and Biophysical Research Communications, 2002

Exocytosis is regulated by exocytotic proteins, which are present in insulin-secreting beta-cells... more Exocytosis is regulated by exocytotic proteins, which are present in insulin-secreting beta-cells and play regulatory roles in insulin secretion. Non-insulin dependent diabetes mellitus (type 2 diabetes) is a disease characterized by impaired insulin secretion and insulin resistance. Exocytotic protein immunoreactivities were studied in pancreatic islets of type 2 diabetic Goto-Kakizaki (GK) rats using immunofluorescence histochemistry. The immunoreactivities for vesicle-associated membrane protein-2 (VAMP-2), synaptotagmin III, cysteine string protein (CSP), mammalian homologue of the unc-18 gene (Munc-18), alpha-soluble N-ethylmaleimide-sensitive attachment protein (alpha-SNAP), N-ethylmaleimide-sensitive factor (NSF) and synaptosomal-associated protein of 25 kDa (SNAP-25) exhibited weaker immunofluorescence intensity in islets of GK rats as compared to control Wistar rats. Insulin immunoreactivity was also decreased in GK rat beta-cells, whereas no detectable alterations in the expression of actin immunoreactivity could be detected. The data suggest that reduced expression of exocytotic proteins and decreased insulin content may contribute to the diabetic syndrome in the GK rat.

Biochemical and Biophysical Research Communications, 2003

Glucose-6-phosphatase (G6Pase) is a multicomponent enzyme system which regulates the catalysis of... more Glucose-6-phosphatase (G6Pase) is a multicomponent enzyme system which regulates the catalysis of glucose-6-phosphate (G6P) to glucose and inorganic phosphate. G6Pase can antagonize glucose phosphorylation, a step prerequisite in the regulation of insulin secretion from pancreatic b cells, and G6Pase activity is increased in islets isolated from animal models of type II diabetes. Using RT-PCR with hepatic G6Pase catalytic subunit primers, we demonstrate that the sizes of amplified products from ob/ob mouse islets are identical to those from liver cDNA. This was confirmed by PCR-based cloning and sequencing of the hepatic G6Pase catalytic subunit open reading frame from islet cDNA. The expression in islets of the G6P transporter, G6PT1, was also demonstrated, suggesting that all of the identified hepatic G6Pase system genes are expressed in pancreatic islets. Finally, the expression of isletspecific G6Pase-related protein (IGRP) in pancreatic islets was confirmed and its expression in liver was also observed.

American Journal of Physiology-Endocrinology and Metabolism, 2008

The high-fat diet (HFD)-fed mouse is a model of obesity, impaired glucose tolerance, and insulin ... more The high-fat diet (HFD)-fed mouse is a model of obesity, impaired glucose tolerance, and insulin resistance. The main objective of this study was to elucidate the molecular mechanisms underlying the antidiabetogenic and weight-lowering effects of 17β-estradiol (E2) in this mouse model. C57BL/6 female mice (8 wk old) were fed on a HFD for 10 mo. E2, given daily (50 μg/kg sc) during the last month of feeding, decreased body weight and markedly improved glucose tolerance and insulin sensitivity. Plasma levels of insulin, leptin, resistin, and adiponectin were decreased. We demonstrated that E2treatment decreased the expression of genes encoding resistin and leptin in white adipose tissue (WAT), whereas adiponectin expression was unchanged. Furthermore, in WAT we demonstrated decreased expression levels of sterol regulatory element-binding protein 1c (SREBP1c) and its lipogenic target genes, such as fatty acid synthase and stearoyl-CoA desaturase 1 (SCD1). In the liver, the expression l...

Human Immunology, 2008

Donor specific antibodies (DSA) are a risk factor for antibody mediated rejection (AMR). DSA to H... more Donor specific antibodies (DSA) are a risk factor for antibody mediated rejection (AMR). DSA to HLA A, B, DR, and DQ are primarily implicated in AMR. Because cells express less HLA C compared to A or B, HLA C mismatch is not considered a risk factor for transplant rejection. We explored the etiology of an episode of late rejection in a 42 year old man (A2 B8,62 Cw3,7 DR4,17,52,53 DQ2,3) that occurred four years after deceased-donor kidney transplant (A2,66 B27,41 Cw2,17 DR9,13,52,53 DQ3,3). Methods: Kidney biopsy was performed. Patient sera were tested for anti-donor HLA class I and II by Luminex single antigen beads. T and B cell Flow cross-matches were performed on three surrogate donors. Results: Biopsy showed linear capillary loop staining of IgG, IgA, IgM, complement in glomeruli and peritubular capillaries, and C4d in peritubular capillaries consistent with AMR. Luminex testing showed antidonor HLA Cw2 and 17. The T or B cell XM was positive against the Cw17 donors and negative against a non-Cw2,17 donor. The patient received 5 courses of plasmapheresis/IVIG over 14 days. Anti-donor antibody decreased by Luminex and Flow cytometric assays post treatment. Serum Cr pre and post treatment was 4.1 and 2.7 mg/dl. Conclusions: This case report illustrates that antibody to the HLA Cw loci can result in AMR. One should consider testing for anti-donor HLA C in cases of suspected AMR, particularly when no donor-specific HLA-A, B, DR, or DQ antibodies can be found through standard testing. Furthermore, typing for HLA C may be important in working up cases of AMR.