Glucose levels in the normal range predict incident diabetes in families with premature coronary heart disease

PURPOSE: Little is known about excess risk of incident diabetes conferred by fasting plasma glucose (FPG) within the normal range (<5.6 mmol/l) for high risk families. METHODS: Healthy 30-59 year old non-diabetic siblings (N = 542) of index cases with documented premature coronary disease were followed prospectively for type 2 diabetes. RESULTS: During 8.7+/-3 years of follow-up, incident diabetes was identified in 7.8%. Rates were incremental with baseline non-diabetes FPG thresholds of 5.0, 5.6, 6.1, and 6.7 mmol/l (p for trend < 0.0001). FPG was the strongest predictor of incident diabetes even across levels within the normal range. The multivariable adjusted relative risk was 14.9 (95% CI = 3.4-65.2) at FPG thresholds > or =5.0 mmol/l versus FPG <5.0 mmol/l. The maximal diagnostic efficiency for FPG was 5.50 mmol/l; with sensitivity and specificity 0.782. All FPG thresholds in the normal range between 5.0 and 5.6 mmol/l showed efficiency levels >0.74. The overall area under the ROC curve predicting incident diabetes for normal and prediabetes ranges of FPG was 0.867. CONCLUSION: Higher FPG levels within the designated "normal" range in high risk families are a potent independent risk factor for type 2 diabetes and may serve as a sentinel to trigger primary preventive interventions.     

Gastric Cancer Occurring After Vertical Banded Gastroplasty

A case of gastric cancer after vertical banded gastroplasty (VBG) is presented. A 44-year-old man presented with vomiting and weight loss 6 years after VBG. Endoscopy revealed a poorly differentiated gastric adenocarcinoma. The patient underwent a Whipple pancreaticoduodenectomy and received chemotherapy. He expired 6 months later. From our case and review of the literature, development of gastric cancer after VBG is very rare. The authors suggest that patients undergoing VBG be monitored by endoscopy after the operation.     

MRI of mouse models of neurological disorders

MRI has contributed to significant advances in the understanding of neurological diseases in humans. It has also been used to evaluate the spectrum of mouse models spanning from developmental abnormalities during embryogenesis, evaluation of transgenic and knockout models, through various neurological diseases such as stroke, tumors, degenerative and inflammatory diseases. The MRI techniques used clinically are technically more challenging in the mouse because of the size of the brain; however, mouse imaging provides researchers with the ability to explore cellular and molecular imaging that one day may translate into clinical practice. This article presents an overview of the use of MRI in mouse models of a variety of neurological disorders and a brief review of cellular imaging using magnetically tagged cells in the mouse central nervous system.     

"They should come out here ...": research findings on lack of local palliative care services for Australian aboriginal people

Although Aboriginal Australians experience morbidity and mortality rates far greater than that of the wider Australian population, to date, their access to culturally appropriate palliative care services has remained unexplored. This article provides findings from an Australian National Health and Medical Research funded study that documents the availability of palliative care services to Aboriginal peoples of the Northern Territory, Australia. The data were collected through a series of open-ended, qualitative interviews with a cross section of Aboriginal peoples and health professionals conducted during a 2-year period. The findings provide an overview of the palliative care services that are presently available and reflect a serious lack of local, culturally appropriate palliative care services. This research shows the similarities in the struggles and difficulties faced by Australian Aboriginals and Indigenous peoples worldwide. The hope is that the suggestions put forward for improvement will one day be useful for the world's Indigenous peoples.     

Three common polymorphisms in the CYBA gene form a haplotype associated with decreased ROS generation

NOX enzymes are reactive oxygen species (ROS)‐generating NADPH oxidases. Several members of the NOX family depend on the p22^phox subunit, encoded by the CYBA gene. CYBA is highly polymorphic, and has been widely studied as a potential risk factor for various diseases, with conflicting results. In the present study, we used Epstein‐Barr (EBV)‐transformed B‐lymphocytes from 50 healthy unrelated individuals to analyze their CYBA mRNA sequence and NOX2‐dependent ROS generation. Seven single‐nucleotide polymorphisms (SNPs) were identified (five previously described, two novel). The combination of these SNPs yielded 11 distinct haplotypes, which could be grouped into seven haplogroups (A–G). Haplogroup C (c.214T>C, c.521T>C, and c.^*24G>A) showed a significantly lower ROS generation, as compared to the most frequent haplogroup, A. CYBA variants from the seven haplogroups were transduced into p22^phox‐deficient B‐lymphocytes. The haplogroup C variant showed significantly lower ROS production. c.214T>C and c.521T>C lead to nonsynonymous codon changes, while c.^*24G>A lies within the 3′UTR. Using a luciferase/3′UTR construct, we showed that the ^*24A allele led to decreased reporter gene activity. These results help to unravel the complex nature of how genetic variations in CYBA influence NOX2 activity, and indicate that haplotypes, rather than individual SNPs, define the effect on ROS generation. Hum Mutat 30:1–11, 2009. © 2009 Wiley‐Liss, Inc.     

Hematologically important mutations: The autosomal recessive forms of chronic granulomatous disease (second update)

Chronic granulomatous Disease (CGD) is an immunodeficiency disorder affecting about 1 in 250,000 individuals. The disease is caused by mutations in the genes encoding the components of the leukocyte NADPH oxidase. This enzyme produces superoxide, which is essential in the process of intracellular pathogen killing by phagocytic leukocytes. Four of the five genes involved in CGD are autosomal; these are CYBA, encoding p22-phox, NCF2, encoding p67-phox, NCF1, encoding p47-phox, and NCF4, encoding p40-phox. This article lists all mutations identified in these genes in the autosomal forms of CGD. Moreover, polymorphisms in these genes are also given, which should facilitate the recognition of future disease-causing mutations.     

GT repeat polymorphism in the 5' flanking region of the human growth hormone receptor gene

A polymorphic GT dinucleotide repeat sequence has been identified in the 5' flanking region of the human growth hormone receptor (hGHR) gene on chromosome 5p13.1-p12, within the promoter region of the V9 5'UTR exon. Thirteen alleles have been identified in 50 non-related individuals, with an observed heterozygosity of 52%. The major allele contains 24 repeats, although a range of 19-32 repeats has been observed. Codominant segregation was demonstrated in five two-generation and two three-generation families. This marker may be useful in analysing the role of the hGHR gene in pre- and postnatal growth disorders.     

Localisation and surgical treatment of insulinomas

Most insulinomas are solitary, benign and functional neuroendocrine pancreatic tumours which give rise to manifold symptoms. Their preoperative localisation is often unclear, but the cure rate after their excision is very high. It was the aim of this study to analyse and evaluate our group of patients with regard to preoperative tumour localisation and overall surgical results. Twelve patients with a biochemical diagnosis of organic hyperinsulinism were surgically treated. Diagnosis was made with the combination of magnetic resonance imaging, computed tomography, selective angiography and intraoperative portal vein sampling. In five patients, the tumour was enucleated, in three patients Whipple procedure was performed; while three patients underwent left pancreatectomy with spleen preserving in two cases. The twelfth patient underwent total pancreatectomy following Whipple procedure performed elsewhere. There was no postoperative death. The complications were two pancreatic fistulas and two wound infections. The fasting pre- and postoperative plasma glucose mean value was 2.8 mm/l and 4.9 mm/l, respectively; while the pre- and postoperative plasma insulin mean value was 282 pm/l and 72 pm/l, respectively. Accurate diagnosis, preoperative localisation and diligent surgical exploration by experienced surgeons are the key to a successful outcome in patients with insulinomas.     

Viral capsids as MRI contrast agents.

Viral capsids have the potential for combined cell/tissue targeting, drug delivery, and imaging. Described here is the development of a viral capsid as an efficient and potentially relevant MRI contrast agent. Two approaches are outlined to fuse high affinity Gd(3+) chelating moieties to the surface of the cowpea chlorotic mottle virus (CCMV) capsid. In the first approach, a metal binding peptide has been genetically engineered into the subunit of CCMV. In a second approach gadolinium-tetraazacyclododecane tetraacetic acid (GdDOTA) was attached to CCMV by reactions with endogenous lysine residues on the surface of the viral capsid. T(1) and T(2) ionic relaxivity rates for the genetic fusion particle were R1 = 210 and R2 = 402 mM(-1)s(-1) (R2 at 56 MHz) and for CCMV functionalized with GdDOTA were R1 = 46 and R2 = 142 mM(-1)s(-1) at 61 MHz. The relaxivities per intact capsid for the genetic fusion were R1 = 36,120 and R2 = 69,144 mM(-1)s(-1) (R2 at 56 MHz) and for the GdDOTA CCMV construct were R1 = 2,806 and R2 = 8,662 mM(-1)s(-1) at 61 MHz. The combination of high relaxivity, stable Gd(3+) binding, and large Gd(3+) payloads indicates the potential of viral capsids as high-performance contrast agents.