The Mo-Se active site of nicotinate dehydrogenase

Nicotinate dehydrogenase (NDH) from Eubacterium barkeri is a molybdoenzyme catalyzing the hydroxylation of nicotinate to 6-hydroxynicotinate. Reactivity of NDH critically depends on the presence of labile (nonselenocysteine) selenium with an as-yet-unidentified form and function. We have determined the crystal structure of NDH and analyzed its active site by multiple wavelengths anomalous dispersion methods. We show that selenium is bound as a terminal MoSe ligand to molybdenum and that it occupies the position of the terminal sulfido ligand in other molybdenum hydroxylases. The role of selenium in catalysis has been assessed by model calculations, which indicate an acceleration of the critical hydride transfer from the substrate to the selenido ligand in the course of substrate hydroxylation when compared with an active site containing a sulfido ligand. The MoO(OH)Se active site of NDH shows a novel type of utilization and reactivity of selenium in nature.     

Serum PCB levels and congener profiles among US construction workers

Background  

The presence of PCB in caulking (sealant) material found in masonry buildings has been well-documented in several countries. A recent investigation of 24 buildings in the greater Boston area found that 8 buildings had high PCB levels in caulking materials used around window frames and in joints between masonry blocks. Workers removing caulking material have been shown to have elevated serum PCB levels.     

Dandy-Walker syndrome: a review of fifteen cases evaluated by prenatal sonography

Fifteen cases of the Dandy-Walker syndrome evaluated by prenatal sonography were reviewed retrospectively. A posterior fossa cyst communicating with the fourth ventricle was a feature in each case. Hydrocephalus was present in 53% of fetuses. Extracranial congenital malformations were documented in 60% of cases. Cardiac, genitourinary, gastrointestinal, and skeletal anomalies were noted. Of 12 available karyotypes, 4 (33%) were abnormal, including two cases of trisomy 18. Excluding terminated pregnancies, there was an overall mortality of 55%. Associated congenital defects contributed to 83% of the postnatal deaths. The Dandy-Walker syndrome can be accurately diagnosed in utero by sonographic demonstration of characteristic morphologic changes in the fetal posterior fossa. The prenatal examination should include an evaluation of associated supratentorial and extracranial defects. Coexisting structural and chromosomal anomalies occur frequently and adversely affect survival.     

Retinal nerve fibre layer loss in patients with type 1 diabetes mellitus without retinopathy

BACKGROUND/AIM: There is evidence suggesting the occurrence of neurovisual abnormalities in patients with diabetes without retinopathy. However, the determination of abnormalities in the neural and glial elements in vivo is difficult. The aim of this study was to investigate whether a retinal nerve fibre layer (RNFL) defect (as determined by scanning laser polarimetry, SLP) is present in patients without clinical manifestations of diabetic retinopathy. METHODS: 12 patients with type 1 diabetes mellitus (DM) without retinopathy or other diabetes induced microvascular complications, underwent a complete ophthalmological examination, including automated perimetry and RNFL measurements with a nerve fibre layer analyser GDx. The data were compared with a normal control group matched for age and sex. RESULTS: The superior segment retardation in patients with diabetes was lower than in the control group, based on the superior integral (0.19 (SD 0.06) v 0.23 (0.04) mm(2), p=0.03) and the superior average (71.0 (11.05) v 84.27 (10.56) microm, p=0.007) parameters. CONCLUSION: This finding may be indicative of significant nerve fibre loss in the superior segment of the retina in patients with type 1 diabetes mellitus but without retinopathy. The meaning of intraretinal differences in RNFL retardation, indicating asymmetric NFL loss, in patients with diabetes is yet not understood.     

A phase II study of Irofulven (MGI 114) in patients with stage IV melanoma

Sixteen patients with stage IV melanoma,who were heavily pretreated, received11 mg/m²/day of intravenous Irofulvenfor five consecutive days every 28 days.There were no objective tumor responses,although one patient exhibited stabledisease after 4 cycles. The most commontoxicities were grade 1/2 nausea, vomiting,fatigue, anemia, and thrombocytopenia. Onepatient required a dose reduction for anelevated creatinine while another patientrequired cessation of treatment because ofacute ataxia that may have been related toIrofulven. Based upon these data, Irofulvendoes not demonstrate significant antitumoractivity to warrant further investigationin advanced melanoma.     

Novel polymorphisms in the somatostatin receptor 5 (SSTR5) gene associated with bipolar affective disorder

The somatostatin receptor 5 (SSTR5) gene is a candidate gene for bipolar affective disorder (BPAD) as well as for other neuropsychiatric disorders. The gene is positioned on chromosome 16p13.3, a region that has been implicated by a few linkage studies to potentially harbor a disease susceptibility gene for BPAD. Recent evidence shows that the dopamine D2 receptor (DRD2) and SSTR5 interact physically to form heterodimers with enhanced functional activity. Brain D2 dopamine receptors are one of the major targets of neuroleptic treatments in psychiatric disorders. In this study we systematically screened the promoter and coding region of the SSTR5 gene for genetic variation that could contribute to the development of neuropsychiatric disorders. Eleven novel single nucleotide polymorphisms (SNPs) were identified including four missense SNPs, Leu48Met, Ala52Val, Pro109Ser and Pro335Leu. We carried out an association study of BPAD using 80 Danish cases and 144 control subjects, and replication analysis using 55 British cases and 88 control subjects. For the Danish population, association was suggested between silent SNP G573A and BPAD (P = 0.008). For the British population we found association to BPAD with missense mutation Leu48Met (P = 0.003) and missense mutation Pro335Leu (P = 0.004). The statistical significance of the association was, however, greatly reduced after correcting for multiple testing. When combining genotypes from Leu48Met and Pro335Leu into haplotypes, association to BPAD was found in the British population (P = 0.0007). This haplotype association was not replicated in the Danish population. Our results may indicate that the SSTR5 gene is involved in the etiology of BPAD or may exist in linkage disequilibrium with a susceptibility gene close to SSTR5. However, given the marginal statistical significance and the potential for false-positive results in association studies with candidate genes, further studies are needed to clarify this hypothesis.     

The association between APOE and dementia does not seem to be mediated by vascular factors

OBJECTIVE: The effect of APOE on dementia may be mediated through dyslipidemia and atherogenesis through its effect on cholesterol metabolism. The authors investigated this possibility among aged survivors from the UK Medical Research Council Trial of the Treatment of Hypertension in Older Adults. DESIGN: A total of 370 of 657 survivors from an initial cohort of 1,088 recruited into the trial between 1983 and 1985 were traced in 1994 and agreed to be screened for dementia. Blood samples were analyzed for APOE genotype and serum fibrinogen. Cholesterol level, smoking behavior, blood pressure, body mass index, and EKG recordings had been measured at recruitment 10 to 12 years earlier. Odds ratios (ORs) for the association between APOE epsilon4/* and both AD and dementia were estimated and adjusted incrementally for the effect of age and premorbid intelligence, cholesterol, other risk factors for vascular disease, and EKG evidence of cardiovascular disease. RESULTS: The authors diagnosed 24 cases of National Institute of Neurological and Communicative Disorders and Stroke AD from 41 cases of dementia. The crude OR for the association between APOE epsilon4/* and AD was 3.40 (95% CI 1.30 to 8.91). APOE genotype was associated with serum cholesterol level, and there was a nonsignificant trend for an association with smoking behavior. After adjusting for these and all other vascular risk factors and vascular disease variables listed earlier, the OR for the association between APOE epsilon4/* and AD increased to 4.81 (1.60 to 14.4). CONCLUSION: Presence of APOE epsilon4/* seems to increase the risk for dementia and AD independently of its effect on dyslipidemia and atherogenesis.     

"Is there life on dialysis?": time and aging in a clinically sustained existence

Increasingly, in the United States, lives are being extended at ever-older ages through the implementation of routine medical procedures such as renal dialysis. This paper discusses the lives and experiences of a number of individuals 70 years of age and older at two dialysis units in California. It considers what kind of life it is that is being sustained and prolonged in these units, the meanings of the time gained through (and lost to) dialysis for older people, and the relationship of "normal" life outside the units to an exceptional state on the inside that some patients see as not-quite-life. Highlighting the unique dimensions of gerontological time on chronic life support, the article offers a phenomenology of the end of life as that end is drawn out, deferred by technological means, and effaced by the ethos and experiential course of dialysis treatment.