Head injury outcome prediction in the emergency department: a role for protein S-100B?

BACKGROUND: Biochemical markers released after head injury may reflect the degree of brain damage, which is related to subsequent disability. If the serum level of a marker were found to be related to outcome, then earlier identification and intervention would be possible. OBJECTIVE: To investigate the potential of the serum marker S-100B protein to predict the outcome after head injury. METHODS: Blood samples for S-100B concentrations were taken from 148 adults within six hours of a head injury (initial Glasgow coma score 4-15). Patients were recruited from the emergency departments of four hospitals in Greater Manchester, United Kingdom. Outcome was assessed in 119 patients (80%) at one month using the extended Glasgow outcome scale (GOSE). RESULTS: A significant inverse correlation between serum S-100B level and GOSE was found (Spearman's rho = -0.349, p < 0.0001). A serum S-100B concentration of > 0.32 micro g/l predicted severe disability (GOSE < 5) at one month with a sensitivity of 93% (95% confidence interval 68% to 100%), a specificity of 72% (54% to 79%), and a negative predictive value of 99% (93% to 100%). CONCLUSION: Serum S-100B concentration can be used in the emergency department to identify patients with head injury who are most likely to have a poor outcome at one month.

Non-transmitted maternal HLA DQ2 or DQ8 alleles and risk of Type I diabetes in offspring: the importance of foetal or post partum exposure to diabetogenic molecules.

AIMS/HYPOTHESIS: Type I (insulin-dependent) diabetes mellitus results from an immune-mediated destruction of pancreatic beta cells for which HLA haplotypes DR3-DQ2 and DR4-DQ8 represent the strongest genetic risk markers. Mothers of patients with rheumatoid arthritis carry more frequently the HLA DR4-DQ8 haplotype as non-transmitted haplotype than mothers of healthy control subjects. As maternal cells have been shown to persist in their offspring up to 30 years after birth, we investigated whether the association of HLA DR3-DQ2 and DR4-DQ8 with Type I diabetes is purely a genetic effect acting through inheritance or whether it can also act as an environmental factor, for example through foetal exposure in utero to maternal circulating cells. METHODS: We analysed the non-transmitted parental HLA DQ alleles of 464 families (1367 subjects) with a Type I diabetic offspring. HLA DQ alleles were assessed using sequence-specific primers and allele-specific oligonucleotides hybridisation. A chi-square test was done to compare allele and transmission frequencies in the respective subsets of families. RESULTS: The non-transmitted HLA DR3-DQ2 and DR4-DQ8 were more frequent in mothers than in fathers of all non- DQ2/DQ8 heterozygous diabetic offspring ( p=0.0001) as well as in offspring not carrying any HLA high-risk allele ( p=0.0243). In patients with either risk allele alone, more maternal than paternal non-transmitted risk alleles complemented the constellation to DQ2/DQ8 ( p<0.0099). CONCLUSION/INTERPRETATION: HLA high risk alleles were more frequent among maternal non-inherited (but possibly exposed) alleles than among paternal non-inherited alleles. These results indicate that HLA DR-DQ is an environmental risk factor for Type I diabetes.

A recently described polymorphism in the CD28 gene on chromosome 2q33 is not associated with susceptibility to type 1 diabetes.

Type 1 diabetes mellitus is an autoimmune disease with a strong genetic background. The CTLA4 gene region (IDDM12) has been implicated in genetic susceptibility to type 1 diabetes by genome scanning and both family- and population-based analyses. As the genes encoding the costimulatory molecules CTLA4 and CD28, which compete for the receptor B7, reside close together on chromosome 2q33 and have high sequence homology, we investigated a recently described polymorphism in intron 3 of the CD28 gene and the CLTA4 codon 17 polymorphism in 176 patients with type 1 diabetes and 220 healthy controls. Whereas CTLA4 was found to be associated with type 1 diabetes, the frequency of the CD28 polymorphism did not differ between patients and controls, either in the entire sample or after stratification for CTLA4 genotype. Thus, the CD28 intron 3 polymorphism does not appear to be associated with susceptibility to type 1 diabetes.

A retroviral long terminal repeat adjacent to the HLA DQB1 gene (DQ-LTR13) modifies Type I diabetes susceptibility on high risk DQ haplotypes.

AIMS/HYPOTHESIS: HLA-DQ genes, located in the human leukocyte antigen region on chromosome 6 p, are the main inherited factors predisposing to Type I (insulin-dependent) diabetes mellitus. Endogenous retroviral long-terminal repeats are integrated at several sites within this region, one of which is known to enhance susceptibility for Type I diabetes. We examined another LTR within the HLA-region as an additional genetic risk marker. METHODS: We investigated the segregation of one long-terminal repeat (DQ-LTR13), located 1.3 kb upstream of HLA DQB1 with different HLA-DQ haplotypes, and its transmission to patients. A total of 284 Caucasian families (203 German and 81 Belgian) with at least one diabetic offspring were genotyped for DQA1, DQB1 and DQ-LTR13. RESULTS: DQ8/LTR13(+) was preferentially transmitted (139 transmitted vs 28 not transmitted; P(TDT) = 1.67 x 10(-14)) whereas no deviation from expected transmission frequencies was observed for DQ8/LTR13(-) (20 transmitted vs 17 not transmitted; P(TDT) = 1.00). DQ8/LTR13(+) alleles conferred a significantly higher risk for Type I diabetes than DQ8/LTR13(-) alleles (p chi(2) = 2.58 x 10(-14)). This difference remained significant even after DRB1 subtyping (p chi(2) = 0.02). Also, there was a significant difference when comparing the transmission of DQ2/LTR13(+) and DQ2/LTR13(-) alleles (p chi(2) = 0.01), the latter conferring an increased risk. The transmission of DQ-LTR13(+) haplotypes did not show any differences regarding paternal, maternal or gender-related stratification. However, DQ8/LTR13(-) was significantly more often transmitted from mothers (p chi(2) = 0.01) and to female patients (p chi(2) = 0.04). CONCLUSION/INTERPRETATION: We conclude that DQ-LTR13 marks additional genetic risk for Type I diabetes on predisposing DRB1(*)0401- DQ8 and DQ2 haplotypes and will help to further define susceptibility in this gene region.

Overexpression of the LAR (leukocyte antigen-related) protein-tyrosine phosphatase in muscle causes insulin resistance.

Previous reports indicate that the expression and/or activity of the protein-tyrosine phosphatase (PTP) LAR are increased in insulin-responsive tissues of obese, insulin-resistant humans and rodents, but it is not known whether these alterations contribute to the pathogenesis of insulin resistance. To address this question, we generated transgenic mice that overexpress human LAR, specifically in muscle, to levels comparable to those reported in insulin-resistant humans. In LAR-transgenic mice, fasting plasma insulin was increased 2.5-fold compared with wild-type controls, whereas fasting glucose was normal. Whole-body glucose disposal and glucose uptake into muscle in vivo were reduced by 39-50%. Insulin injection resulted in normal tyrosyl phosphorylation of the insulin receptor and insulin receptor substrate 1 (IRS-1) in muscle of transgenic mice. However, phosphorylation of IRS-2 was reduced by 62%, PI3' kinase activity associated with phosphotyrosine, IRS-1, or IRS-2 was reduced by 34-57%, and association of p85alpha with both IRS proteins was reduced by 39-52%. Thus, overexpression of LAR in muscle causes whole-body insulin resistance, most likely due to dephosphorylation of specific regulatory phosphotyrosines on IRS proteins. Our data suggest that increased expression and/or activity of LAR or related PTPs in insulin target tissues of obese humans may contribute to the pathogenesis of insulin resistance.

Vitamin D receptor allele combinations influence genetic susceptibility to type 1 diabetes in Germans.

Vitamin D has been shown to exert manifold immunomodulatory effects. Because type 1 diabetes is regarded to be immune-mediated and vitamin D prevents the development of diabetes in the NOD mouse, we investigated the role of the vitamin D receptor (VDR) gene as a candidate for type 1 diabetes susceptibility. A total of 152 Caucasian families with at least one affected offspring were genotyped for four VDR restriction-site polymorphisms (FokI, BsmI, ApaI, and TaqI). Whereas the BsmI, ApaI, and TaqI polymorphisms are in strong linkage disequilibrium with each other, no significant linkage disequilibrium with the FokI site was observed. Extended transmission disequilibrium testing (ETDT) was used to detect preferential transmission of allelic combinations to affected offspring. We found significant haplotype-wise ETDT results for the BsmI/ApaI/TaqI (chi2 = 18.886, df = 7, P = 0.0086), the BsmI/TaqI (chi2 = 8.373, df = 3, P = 0.0389), and theApaI/TaqI (chi2 = 17.182, df = 3, P = 0.0006) haplotypes. The "At" and "Bt" alleles confer an increased risk, whereas "AT" and "at" are protective. The combination with the strongest susceptibility was the "BAt" haplotype (64% transmitted, P = 0.0106). Analysis of the FokI site does not provide more information on susceptibility (FokI/BsmI/ApaI/TaqI [chi2 = 24.702, df = 15, P = 0.0541]). These findings suggest a linkage of VDR itself or a nearby gene with type 1 diabetes susceptibility in Germans, confirming respective observations previously made in Indian Asians.

Digging the genome for diabetes mellitus: the 2nd ADA Research Symposium on the Genetics of Diabetes, San Jose, CA, USA, 17-19 October 1999.

The diabetes genetics community recently met in California to discuss the impact that the latest findings in susceptibility mapping might have on our understanding of the pathophysiology of diabetes mellitus and its long-term complications. Organized by Ralph DeFronzo (San Antonio, TX) and Alan Permutt (St Louis, MO) the symposium covered the genetics of type 1 and type 2 diabetes, obesity, approaches to population selection and stratification, quantitative trait analysis, epidemiological tools and technological advances in genotyping.

Vitamin D binding protein alleles and susceptibility for type 1 diabetes in Germans.

Vitamin D has been shown to modulate the immune system thereby preventing the development of diabetes in NOD mice. Since the vitamin D binding protein (DBP) is the main transporter for vitamin D and DBP has immunomodulatory properties itself, we investigated three polymorphic sites within the DBP gene as candidates for type 1 diabetes susceptibility for the first time. 152 Caucasian families with at least one affected offspring were genotyped for intron 8 [(TAAA)n repeat] and exon 11 (HaeIII, StyI) polymorphisms. Transmission disequilibrium testing was used to detect preferential transmission to affected offspring. We found no significant transmission disequilibrium for DBP alleles. The strongest deviation from expected values was observed for the "10" allele (relative risk = 0.57, transmitted 13 of 36 times (corrected p = 0.249)). Although we cannot exclude an association of the studied DBP alleles with type 1 diabetes at present, these data do not suggest their contribution to this disease in Germans.