Association between the HOXA1 A218G polymorphism and increased head circumference in patients with autism.

BACKGROUND: The HOXA1 gene plays a major role in brainstem and cranial morphogenesis. The G allele of the HOXA1 A218G polymorphism has been previously found associated with autism. METHODS: We performed case-control and family-based association analyses, contrasting 127 autistic patients with 174 ethnically matched controls, and assessing for allelic transmission disequilibrium in 189 complete trios. RESULTS: A, and not G, alleles were associated with autism using both case-control (chi(2) = 8.96 and 5.71, 1 df, p <.005 and <.025 for genotypes and alleles, respectively), and family-based (transmission/disequilibrium test chi(2) = 8.80, 1 df, p <.005) association analyses. The head circumference of 31 patients carrying one or two copies of the G allele displayed significantly larger median values (95.0th vs. 82.5th percentile, p <.05) and dramatically reduced interindividual variability (p <.0001), compared with 166 patients carrying the A/A genotype. CONCLUSIONS: The HOXA1 A218G polymorphism explains approximately 5% of the variance in the head circumference of autistic patients and represents to our knowledge the first known gene variant providing sizable contributions to cranial morphology. The disease specificity of this finding is currently being investigated. Nonreplications in genetic linkage/association studies could partly stem from the dyshomogeneous distribution of an endophenotype morphologically defined by cranial circumference.     

Freiberg’s Infraction in Identical Twins: A Case Report

Freiberg's infraction is an ostechondrosis of a lesser metatarsal head resulting in degeneration of the metatarsophalangeal joint. Several mechanisms have been suggested in its pathenogenesis. Freiberg first described the entity and believed single impact trauma was the underlying cause. Repetitive biomechanical microtrauma is the most widely accepted etiologic theory. Other factors contributing to its development include aseptic necrosis, ischemia, and a congenital predisposition. We present a case report of Freiberg's infraction occurring in identical twins involving multiple metatarsals in various stages of degeneration. One of the twins was affected unilaterally whereas the other twin was affected bilaterally. Both twins had involvement of the second metatarsal on the same side extremity. The occurrence of Freiberg's infraction in identical twins suggests that an underlying congenital predisposition to the condition may play more of a role than previously considered.     

Changes in CSF neurotransmitters in infantile spasms

Cerebrospinal fluid (CSF) from 7 patients with infantile spasms (mean age: 6.7 months) was collected before and after treatment with adrenocorticotropic hormone (ACTH). The concentration of neurotransmitter metabolites was analyzed using high-performance liquid chromatography and compared to the metabolite concentration in the CSF from 7 age-matched controls (mean age: 6.1 months). Pretreatment levels of CSF 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid, 3-methoxy-4-hydroxyphenyl glycol (MHPG), and kynurenine were significantly lower in infantile spasm patients compared to controls. Following treatment, marked increases in 5-HIAA and decreases in kynurenine levels were observed in the CSF of the 5 infants whose seizures were eliminated or reduced by ACTH. In the 2 nonresponders 5-HIAA levels decreased. The level of MHPG was reduced slightly in 5 infants, including the 2 nonresponders, and was increased in 2 responders. CSF homovanillic acid levels increased in 4 infantile spasm infants and decreased in 3 following ACTH. These data demonstrate that the presence of seizures in infantile spasms is associated with a significant decrease in serotonergic activity and that elimination of seizures by ACTH is accompanied by increased serotonin turnover. The simultaneous increase of 5-HIAA and decrease of kynurenine, an alternate metabolite of tryptophan, suggests an underlying disturbance of tryptophan metabolism in infantile spasms. The possibility that elimination of seizures by ACTH may be related to decreased production of certain kynurenine metabolites, particularly quinolinic acid, is discussed.     

Loss of breast cancer metastasis suppressor 1 protein expression predicts reduced disease-free survival in subsets of breast cancer patients.

PURPOSE: This study aims to determine the effect of loss of breast cancer metastasis suppressor 1 (BRMS1) protein expression on disease-free survival in breast cancer patients stratified by estrogen receptor (ER), progesterone receptor (PR), or HER2 status, and to determine whether loss of BRMS1 protein expression correlated with genomic copy number changes. EXPERIMENTAL DESIGN: A tissue microarray immunohistochemical analysis was done on tumors of 238 newly diagnosed breast cancer patients who underwent surgery at the Cleveland Clinic between January 1, 1995 and December 31, 1996, and a comparison was made with 5-year clinical follow-up data. Genomic copy number changes were determined by array-based comparative genomic hybridization in 47 breast cancer cases from this population and compared with BRMS1 staining. RESULTS: BRMS1 protein expression was lost in nearly 25% of cases. Patients with tumors that were PR negative (P=0.006) or HER2 positive (P=0.039) and <50 years old at diagnosis (P=0.02) were more likely to be BRMS1 negative. No overall correlation between BRMS1 staining and disease-free survival was observed. A significant correlation, however, was seen between loss of BRMS1 protein expression and reduced disease-free survival when stratified by either loss of ER (P=0.008) or PR (P=0.029) or HER2 overexpression (P=0.026). Overall, there was poor correlation between BRMS1 protein staining and copy number status. CONCLUSIONS: These data suggest a mechanistic relationship between BRMS1 expression, hormone receptor status, and HER2 growth factor. BRMS1 staining could potentially be used in patient stratification in conjunction with other prognostic markers. Further, mechanisms other than genomic deletion account for loss of BRMS1 gene expression in breast tumors.     

Comparison of trichloroethylene and enflurane as adjuncts to nitrous oxide and relaxant anaesthesia

Forty women who underwent gynaecological surgery were randomly allocated to receive trichloroethylene, enflurane, or enflurane plus fentanyl as adjuncts to nitrous oxide/relaxant anaesthesia with controlled ventilation. No serious cardiac dysrhythmias were seen in any group. Each patient was observed postoperatively for 4 hours by a nurse blind to the technique used, and questioned at 24 hours by a similarly blinded anaesthetist. Recovery after trichloroethylene was not significantly prolonged although postoperative analgesia by visual analogue was better, opiate analgesia was required less frequently and there was less nausea and vomiting than in either of the enflurane groups. We argue for the continued use of trichloroethylene by this technique, because it costs one hundred times less than enflurane and because of the potential morbidity of the postoperative opiate dosage required after enflurane.     

Longitudinal,population-based study of racial/ethnic differences in colorectal cancer survival: impact of neighborhood socioeconomic status,treatment and comorbidity

Background  

Colorectal cancer, if detected early, has greater than 90% 5-year survival. However, survival has been shown to vary across racial/ethnic groups in the United States, despite the availability of early detection methods.     

Multiphase radon generation and transport in porous materials

Radon generation and transport in porous materials involve solid, liquid, and gas phases in the processes of emanation, diffusion, advection, absorption, and adsorption. Oversimplifications, such as representing moist soil systems by air-phase emanation and transport models, cause theoretical inconsistencies and biases in resulting calculations. Detailed Rn rate balance equations for solid, liquid, and gas phases were analyzed and combined using phase equilibrium constants to derive a single diffusive-advective rate balance equation in the traditional form. The emanation, diffusion, and permeability coefficients in the new equation have expanded definitions and interpretations to include Rn phase transfer. Radon adsorption was characterized by an exponential moisture dependence, and diffusion and permeability constants utilized previous moisture relationships. Correct boundary and interface conditions were defined, and the unified theoretical approach was applied to field data from a diffusion-dominated system and to laboratory data from an advection-dominated system. Measured 222Rn fluxes and concentrations validated the modeled values within the measurement variability in both applications.