Did the gradual loss of GLUT2 cause a shift to diabetic disorders in the New Zealand obese mouse (NZO/Hl)?

The New Zealand obese mouse (NZO/Hl) is characterised by hereditary obesity and type-2 diabetes, including insulin resistance, hyperinsulinaemia, and glucose intolerance. In other diabetic models, it has been revealed that the proper functioning of the glucose transporter isoform 2 (GLUT2) is essential for adequate secretion of insulin. The aim of this study was to compare the distribution of islet cells and GLUT2, as well as the expression of GLUT2-mRNA, in the pancreas of NZO mice and metabolically unimpaired NMRI (Naval Medical Research Institute) mice. Pancreas tissue was obtained from different stages of development. For molecular determination of the expression level of GLUT2-mRNA, total-RNA was extracted from the pancreas and analysed by quantitative real-time RT-PCR. All investigated NZO mice displayed increased weight, elevated hyperinsulinaemia, and slightly enhanced blood glucose levels compared with the NMRI control mice. By means of immunofluorescence microscopy drastically reduced insulin levels were detected, which might be compensated by the observed islet cell hyperplasia and hypertrophy. Furthermore, the normally peripheral localisation of the alpha-cells within islets was disturbed. By contrast, there were no changes in somatostatin cell distribution. However, considerable differences appeared with regard to GLUT2: whereas the beta-cells of NMRI mice showed dense immunostaining of the GLUT2 transporter on the cell surface, in all age groups of NZO mice, GLUT2 on the plasma membranes was reduced and dispersed in the cytoplasm. These findings agree with the molecular biological results, which displayed decreased mRNA-expression of GLUT2. In summary, the observed alteration of islet morphology and of GLUT2 expression in diabetic mice complements our previous results from a superfusion protocol and further clarifies the mechanisms of diabetogenesis in NZO mice.     

Sniff nasal inspiratory pressure: what is the optimal number of sniffs?

Sniff nasal inspiratory pressure (SNIP) measurement is a volitional noninvasive assessment of inspiratory muscle strength. A maximum of 10 sniffs is generally used. The purpose of the present study was to investigate whether the maximum SNIP improved after the tenth sniff. In total, 20 healthy volunteers and 305 patients with various neuromuscular and lung diseases were encouraged to perform 40 and 20 sniffs, respectively. The best SNIP among the first 10 sniffs was lower than the best SNIP among the next 10 sniffs in the healthy volunteers and patients. The SNIP improvement after the twentieth sniff was marginal. In conclusion, a learning effect persists after the tenth sniff. The current authors suggest using 10 additional sniffs when the best result of the first 10 sniffs is slightly below normal, or when sniff nasal inspiratory pressure is used to monitor a progressive decline in inspiratory muscle strength.     

APOE2 allele increased in tardive dyskinesia.

Ninety-seven inpatients with tardive dyskinesia (average AIMS score = 13), the majority of whom were schizophrenic, were studied. Forty patients were Caucasian, and 57 were African-American. The APOE genotypes of these patients were compared to previously published genotypes of controls and with previously published studies of APOE genotypes in patients with schizophrenia. There were no significant differences in APOE allele frequencies comparing the African-American tardive dyskinesia population and the African-American control groups. In contrast, significant (< 0.05) P values were obtained comparing the Caucasian tardive dyskinesia population to the Caucasian controls, when comparing allele frequencies and genotypic frequencies. This study suggests that Caucasians bearing an APOE2 allele are at increased risk of developing tardive dyskinesia, whereas African-Americans are not. APOE genotype-specific risks of both tardive dyskinesia and Alzheimer's disease that vary across populations could be due to recruitment of patients or controls or could be due to modifying effects of differing genetic or environmental backgrounds. The mechanism by which the APOE2 allele increases risk of tardive dyskinesia is not known. Further information about the mechanisms of increased risk of tardive dyskinesia could result in stratification of prescribing practices weighing the costs of medications against the relative risk of side effects.     

Convergent Reliability and Validity of the Questions About Behavioral Function and the Motivation Assessment Scale: A Replication Study

This study compared key psychometric properties of the Motivation Assessment Scale (MAS) and the Questions About Behavioral Function (QABF) and explored their convergent validity. Twenty adults with mental retardation and problem behaviors (aggression, self-injury, or property destruction) and 31 respondents participated. Test–retest reliability of the subscales in both scales was good to excellent (Cicchetti, D. V., 1994, Psychol. Assess. 6: 284–290), and—except for 1 QABF subscale—internal consistency was good considering the small number of items and the purpose of the scale. Consistent with some earlier studies, interrater reliability was less satisfactory with both scales falling only into the fair to good range.Correlations between functionally equivalent subscales were statistically significant and were generally higher than correlations between nonequivalent subscales. The QABF and the MAS were found to be comparable in terms of the assessed reliabilities, and both instruments appear to be measuring very similar constructs.     

Proximal load transfer with a stemless uncemented femoral implant

Bone stock preservation is crucial when performing total hip replacement in young patients. The aim is to save good bone stock for a possible revision procedure. Furthermore, there is an increasing demand from young and active patients to receive a new joint which allows a normal or nearly normal life style. With this in mind, we began, in 1993, to develop a new femoral implant. The purpose of this ultra-short stem was a physiologic strain distribution on the proximal femur with a proximal load transfer from the implant to the femoral bone. Main features were an almost complete absence of the diaphyseal portion of the stem, a well defined lateral flare with load transfer on the lateral column of the femur, and a very high femoral neck cut. These innovations resulted in a conservative implant on both the bone stock and the soft tissues. This implant, in the first years, was recommended only for young and active patients. Over the last thirteen years, this project has undergone several modifications but the basic principles of the implant have remained the same. In the present review, we present the rationale, the surgical technique and the clinical and experimental results so far obtained with this implant.     

Transplanting the Highly Sensitized Patient: The Emory Algorithm

Renal transplant patients sensitized to HLA antigens comprise nearly one-third of the UNOS wait-list and receive 14% of deceased donor (DD) transplants, a rate half that of unsensitized patients. Between 1999 and 2003, we performed 492 adult renal transplants from DD; 120 patients (approximately 25%) had a panel reactive antibody (PRA) of >30%, with nearly half (n = 58) having a PRA of >80%. Our approach is based upon high-resolution solid-phase HLA antibody analysis to identify class I/II antibodies and a 'virtual crossmatch' to predict compatible donor/recipient combinations. Recipients are excluded from the United Network for Organ Sharing match run if donors possess unacceptable antigens. Thus, when sensitized patients appear on the match run, they have a high probability of a negative final crossmatch. Here, we describe our 5-year experience with this approach. Five-year graft survival ranged from 66% to 70% among unsensitized (n = 272), moderately sensitized (PRA < 30%, n = 100) and highly sensitized (>30% PRA; n = 120) patients, equal to the average national graft survival (65.7%). The application of this approach (the Emory Algorithm) provides a logical and systematic approach to improve the access of sensitized patients to DD organs and promote more equitable allocation to a highly disadvantaged group of patients awaiting renal transplantation.     

Effect of Induction Therapy Protocols on Transplant Outcomes in Crossmatch Positive Renal Allograft Recipients Desensitized with IVIG

Here we retrospectively examine the efficacy of two antibody induction regimens using Zenapax or Thymoglobulin in patients with positive complement-dependent cytotoxicity crossmatches (CDC-CMXs) desensitized with IVIG (intravenous immunoglobulin). Between January 1999 and March 2005, 97 patients with (+) CDC-CMXs received kidney transplants (43 deceased donors/54 living donors). All patients received at least 2 g/kg IVIG (maximum four doses) until an acceptable CMX was obtained. Patients were divided into two groups: 1. IVIG + Zenapax (n = 58), 2. IVIG + Thymoglobulin (n = 39). A total of 94% of patients in Group 1 and 84% in G2 have at least 2 years of follow up. Patient and graft survival was 96%/84% in Group 1 and 100%/90% in Group 2, p = NS. The number and severity of AR episodes were similar (36% Group 1 vs. 31% Group 2, p = NS) as was the incidence of C4d (+) antibody-mediated rejection (AMR) (Banff Grade II/III) (22% Group 1 vs. 21% Group 2). Mean serum creatinines (SCrs) at 24 months were similar (Group 1: 1.4 +/- 0.7 vs. G2: 1.5 +/- 0.7 mg/dL). Induction therapy with Zenapax or Thymoglobulin results in excellent patient, graft survival and graft function at 2 years. There was no increased risk of viral infections or malignancies with either agent. Neither agent was effective in reducing the incidence of AMR.     

Laparoscopic adjustable gastric banding for patients with body mass index of ≤35 kg/m

BACKGROUND: Many mild-to-moderately obese individuals (body mass index [BMI] 30-35 kg/m(2)) have serious diseases related to their obesity. Nonoperative therapy is ineffective in the long term, yet surgery has never been made widely available to this population. METHODS: Between 1996 and 2004, 93 patients with a BMI of 30-35 kg/m(2) underwent laparoscopic adjustable gastric banding with the LAP-BAND. All patients were referred by their primary physician, entered into a comprehensive bariatric surgery program at one Australian center, and operated on by one surgeon. Data on all patients were collected prospectively and entered into an electronic registry. The study parameters included preoperative age, gender, BMI, presence of co-morbidities, percentage of excess weight loss, and resolution of co-morbidities. RESULTS: The mean age was 44.6 years (range 16-76), mean weight was 98 kg, and the mean BMI was 32.7 kg/m(2) (range 30-34). Of the 93 patients, 42 (45%) had co-morbidities, including asthma, diabetes, hypertension, and sleep apnea. The proportion of patients in follow-up was 79%, 85%, and 89% at 1, 2, and 3 years, respectively. The mean weight was reduced to 71 kg at 1 year, 72 kg at 2 years, and 72 kg at 3 years. The mean BMI was reduced to 27.2 +/- 2.2, 27.3 +/- 3.1, and 27.6 +/- 3.7 kg/m(2), respectively, and the mean percentage of excess weight loss was 57.9% +/- 24.5%, 57.6 +/- 29.3%, and 53.8% +/- 32.8% at 1, 2, and 3 years, respectively. At 3 years, the BMI was 18-24 kg/m(2) in 34%, 25-29 kg/m(2) in 51%, and 30-35 kg/m(2) in 10%. At 3 years, the percentage of excess weight loss was <25% in 10%, 25-50% in 24%, 50-75% in 51%, and >75% in 10%. The co-morbidities improved or completely resolved in most patients. No mortality occurred. CONCLUSION: We are very encouraged by this series of low BMI patients treated with the LAP-BAND. Their weight loss has been good, the complications have been minimal, and the co-morbidities have partially or wholly resolved. With additional study, it is reasonable to expect the weight guidelines for bariatric surgery to be altered to include patients with a BMI of 30-35 kg/m(2).     

Surgical Complications and Long-Term Outcome of Different Biliary Reconstructions in Liver Transplantation for Primary Sclerosing Cholangitis—Choledochoduodenostomy versus Choledochojejunostomy

Choledochojejunostomy (CJS) is commonly used for biliary reconstruction in liver transplantation for primary sclerosing cholangitis (PSC). We alternatively performed choledochoduodenostomy (CDS) and side-to-side choledochodocholedochstomy in a large cohort of patients. Fifty-one patients with PSC, transplanted between 1988 and 2000, were analyzed retrospectively. Biliary reconstruction was CDS in 25 (49%), CJS in 20 (39%) and CC in 6 transplantations (12%). Biliary leaks occurred in the early follow-up (< or =41 days) only in CDS patients (20%). However, in the late follow-up (>4 months), stricturing of anastomosis was found once in CDS (4%) and CJS (5%). Later (>9 months), intrahepatic bile duct strictures were diagnosed in four CDS (16%), one CJS (5%) and one CC (17%) patient(s). In 48% of CDS (12/25), 60% of CJS (12/20) and 17% of CC (1/6) at least one incidence of cholangitis was observed. Overall, biliary complication rates were significantly higher in CDS (40%) than CJS (10%) and CC (17%); of those none in CC and 12% in CDS were anastomosis-related. Graft/patient survival showed no significant differences among groups. Based on our results we consider CJS the standard method for biliary reconstruction in PSC; however, in selected cases where CJS is difficult to accomplish because of previous surgery or for retransplantation, CDS may present an alternative technique.     

Analysis of insulin signaling pathways through comparative genomics. Mapping mechanisms for insulin resistance in type 2 (non-insulin-dependent) diabetes mellitus.

The precise molecular cause of insulin resistance has not yet been elucidated. Resistance to the normal action of insulin contributes to the pathogenesis of a number of common human disorders, including type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus, hypertension, and the Metabolic Syndrome X, thus constituting a major public health problem. A disease program aimed at combating this disorder should focus on the identification of targets for therapeutic intervention which may overcome insulin resistance and hence the associated metabolic consequences characteristic of the Metabolic Syndrome. Although the primary defect in the pathogenesis of type 2 diabetes is unknown, genetic and environmental factors are likely to contribute to the manifestation of this progressive metabolic disorder, which is usually not clinically apparent until mid-life. Defects at the level of glucose uptake/phosphorylation characterize insulin resistance in skeletal muscle of type 2 diabetic patients. Identification of putative components of the insulin receptor-signaling pathway may offer insights into mechanisms involved in insulin resistance. Enhanced flux of free fatty acids due to impaired lipid metabolism may contribute to impaired insulin secretion and peripheral insulin resistance. Genes regulating lipolysis are prime candidates for susceptibility towards the metabolic syndrome. Here we describe pathways constituting complex interactions that control glucose homeostasis. We will be considering (1) regulation of glucose uptake by the insulin receptor signaling pathway, and (2) control of adipogenesis and insulin sensitivity by the sterol response element binding protein (SREBP) pathway.