Evidence for linkage between regulatory enzymes in glycolysis and schizophrenia in a multiplex sample.

Observations of impaired glucose regulation in schizophrenia are long-standing, although their pathological and etiological significance is uncertain. One approach to the issue that minimizes environmental variables (e.g., medication and diet) is to determine whether genes related to glucose regulation show genetic linkage to schizophrenia. We examined the potential role of glucose metabolism in schizophrenia through a genome scan of affection status in schizophrenia and an empirical method for deriving P-values. Data were utilized from the NIMH Genetics Initiative for Schizophrenia dataset, which comprises a total sample consisting of 71 pedigrees containing 218 nuclear families and 987 individuals. A genome scan with 459 markers spaced at an average of 10 cM intervals was conducted using the linkage analysis program Genehunter separately for European- and African-American groups. Enzymes that regulate glycolysis were identified and the genes regulating these enzymes were located through the Online Mendelian Inheritance in Man (OMIM) website. The focus in this study was on genes located near previously reported schizophrenia susceptibility regions. The genome-wide significance of these genes to schizophrenia was assessed using permutation testing. When results were adjusted for multiple testing within and across ethnic groups, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 (PFKFB2; chromosome 1q32.2) achieved genome-wide significance (P = 0.04). In addition, hexokinase 3 (HK3; chromosome 5q35.3) was also suggestive of linkage (P = 0.09). For the European-American sample, PFKFB2 (1q32.2), hexokinase 3 (HK3; 5q35.3), and pyruvate kinase 3 (PK3; chromosome 15q23) achieved significance at the 0.05 level. None of the genes showed significance in the African-American sample. Our results provide further support for the view that genes that regulate glucose metabolism may also influence susceptibility to schizophrenia. More generally, they support the view that relationships between glucose dysregulation and schizophrenia are inherent to the disorder, and are not merely epiphenomena related to medication or other treatment factors.     

Physician contributions to disparities in HIV/AIDS care: The role of provider perceptions regarding adherence

Racial/ethnic minorities in the United States are disproportionately affected by HIV/AIDS. In addition to having higher rates of HIV/AIDS, minorities with HIV/AIDS have higher mortality rates than others in the United States. Disparities in the care received by minorities living with HIV/AIDS contribute to these higher mortality rates. This article provides a review of HIV/AIDS health care disparities and explores providers’ contributions to these disparities. An important source of provider contribution to disparities appears to be differential prescribing based on perceptions and assumptions that minority patients may have lower adherence to highly active antiretroviral therapy. Literature regarding this topic is reviewed and strategies for reducing disparities are suggested.     

Homozygosity mapping of achromatopsia to chromosome 2 using DNA pooling

Achromatopsia is an autosomal recessive disease of the retina, characterized clinically by an inability to distinguish colors, impaired visual acuity, nystagmus and photophobia. A genome-wide search for linkage was performed using an inbred Jewish kindred from Iran. To facilitate the genome-wide search, we utilized a DNA pooling strategy which takes advantage of the likelihood that the disease in this inbred kindred is inherited by all affected individuals from a common founder. Equal molar amounts of DNA from all affected individuals were pooled and used as the PCR template for short tandem repeat polymorphic markers (STRPs). Pooled DNA from unaffected members of the kindred was used as a control. A reduction in the number of alleles in the affected versus control pool was observed at several loci. Upon genotyping of individual family members, significant linkage was established between the disease phenotype and markers localized on chromosome 2. The highest LOD score observed was 5.4 (theta = 0). When four additional small unrelated families were genotyped, the combined peak LOD score was 8.2. Analysis of recombinant chromosomes revealed that the disease gene lies within a 30 cM interval which spans the centromere. Additional fine-mapping studies identified a region of homozygosity in all affected individuals, narrowing the region to 14 cM. A candidate gene for achromatopsia was excluded from this disease interval by radiation hybrid mapping. Linkage of achromatopsia to chromosome 2 is an essential first step in the identification of the disease-causing gene.      

External fixation of unstable pelvic ring fractures: comparative rigidity of some current frame configurations

The effectiveness of external fixation in the stabilisation of pelvic ring fractures was studied in a laboratory cadaveric series. Shearing displacements occurring at sacroiliac joint and symphysis pubis dislocation sites, due to simplified longitudinal loading of the sacrum in an Instron unit, were monitored using variable-impedence transducers. The rigidity of fixation was compared for the Slätis and the Bonnel single anterior frames, for coupled and uncoupled double anterior frames, and for combined anterior-plus-posterior fixation achieved with separate transfixation pin clusters, with through-and-through pin clusters, or with a posterior screw plate. The data showed that the use of posterior fixation provided greatly enhanced stabilisation compared to that achieved with anterior fixation alone. The complex double anterior frames performed only slightly better than did the simpler single anterior frames. In no case, however, was it possible to recover rigidity levels approaching those of the intact pelvis. The results suggest that the transfixation pin arrangement is the most important determinant of pelvic fixation stability, and that further investigation of posterior screw-plate fixation is warranted.     

Pharmacological analysis of extracellular dopamine and metabolites in the striatum of conscious as/agu rats, mutants with locomotor disorder

The as/agu rat is a spontaneously occurring mutation which exhibits locomotor abnormalities, reduced tyrosine hydroxylase levels in the substantia nigra and lower extracellular levels of dopamine. The animal could represent a model of some human locomotor disorders. High-potassium medium evoked a 460% rise of dopamine levels in control rats but double this in mutants. Amphetamine increased extracellular dopamine by 710% in controls and 1480% in mutants. Clorgyline produced a small increase of dopamine levels in controls but an 1170% increase in mutants. The uptake inhibitor nomifensine increased dopamine levels by 910% in controls but only 270% in mutants. After treatment with benserazide plus L-DOPA, an acute injection of L-DOPA evoked a release of dopamine which was twice as large in the as/agu rats compared with controls. The results show reduced extracellular dopamine in as/agu rats when the locomotor disorder is apparent, but there has been little loss of tyrosine hydroxylase. The responses to drugs are qualitatively different from those obtained using 6-hydroxydopamine.Overall, the effects of compounds affecting aminergic neurons suggest that one possible mechanism for the neuronal abnormality in as/agu rats is a defective regulation of dopamine release from striatal terminals.     

Exaggerated respiratory chemosensitivity and association with SaO2 level at 3568 m in obesity

To investigate whether obesity is associated with alterations in respiratory chemosensitivity, we compared the ventilatory response to hypoxia (HVR) and hypercapnia (HCVR) in 9 obese men (BMI: 37.0+/-4.3 kg m(-2)) and 10 lean men (BMI: 25.8+/-4.8 kg m(-2)). HVR (DeltaVE, L min(-1) per DeltaSaO2, %) was measured by a progressive isocapnic hypoxia technique, and HCVR (DeltaVE/DeltaPETCO2, L min(-1)Torr(-1)) was measured by a progressive hypercapnic method. HCVR, was greater (p<0.001) in the obese men (2.68+/-0.78) than in the lean men (1.4+/-0.45) as was HVR (p<0.05) (1.26+/-0.65 versus 0.71+/-0.43, respectively). The difference (DeltaSaO2, 4.30+/-3.69 and 10.54+/-3.45 in the lean and obese men, respectively, p<0.01) between daytime (86+/-1 and 86+/-1%) and nighttime SaO2 (81+/-3 and 76+/-4%) at a simulated altitude of 3658 m was significantly (p<0.05) correlated with both HVR (r=0.51) and HCVR (r=0.48). These results suggest that chemosensitivity in mildly obese men is increased, not blunted. Furthermore, otherwise healthy, obese individuals have the potential for significant desaturation during sleep at high altitude possibly due to exaggerated sleep-disordered breathing.     

Congenital tracheal stenosis in Pfeiffer syndrome

We report an infant with Pfeiffer syndrome (acrocephalosyndactyly type V) and a solid cartilaginous trachea lacking rings. This airway abnormality has been reported in a child with Crouzon syndrome but has not been described in Pfeiffer syndrome.