Serum IL-6: a candidate biomarker for intracranial pressure elevation following isolated traumatic brain injury.

BACKGROUND: Increased intracranial pressure (ICP) is a serious, life-threatening, secondary event following traumatic brain injury (TBI). In many cases, ICP rises in a delayed fashion, reaching a maximal level 48-96 hours after the initial insult. While pressure catheters can be implanted to monitor ICP, there is no clinically proven method for determining a patient's risk for developing this pathology. METHODS: In the present study, we employed antibody array and Luminex-based screening methods to interrogate the levels of inflammatory cytokines in the serum of healthy volunteers and in severe TBI patients (GCS RESULTS: Consistent with previous reports, we observed sustained increases in IL-6 levels in TBI patients irrespective of their ICP status. However, the group of patients who subsequently experienced ICP >or= 25 mm Hg had significantly higher IL-6 levels within the first 17 hours of injury as compared to the patients whose ICP remained 128 pg/ml correctly identified 85% of isolated TBI patients who subsequently developed elevated ICP, and values between these cut-off values correctly identified 75% of all patients whose ICP remained CONCLUSIONS: Our results suggest that serum IL-6 can be used for the differential diagnosis of elevated ICP in isolated TBI.

Amyotrophic lateral sclerosis and Parkinsonism-dementia complex of Guam: Descriptive epidemiology, secular trends, and birth cohort effects on incidence, 1950--1989

This study describes the patterns of occurrence of amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia complex (PDC) of Guam during 1950-1989. Both ALS and PDC occur with high frequency among the indigenous Chamorro population, first recognized in the early 1950's. Reports in the early 1980's indicated that both ALS and PDC were disappearing, due to a purported reduction in exposure to harmful environmental factors as a result of the dramatic changes in lifestyle that took place after World War II. However, this study provides compelling evidence that ALS and PDC have not disappeared on Guam and that rates for both are higher during 1980-1989 than previously reported.^ The patterns of occurrence for both ALS and PDC overlap in most respects: (1) incidence and mortality are decreasing; (2) median age at onset is increasing; (3) males are at increased risk for developing disease; (4) risk is higher for those residing in the south compared to the non-south; and (5) age-specific incidence is decreasing over time except in the oldest age groups.^ Age-specific incidence of ALS and PDC, separately and together, is generally higher for cohorts born before 1920 than for those born after 1920. A significant birth cohort effect on the incidence of PDC for the 1906-1915 birth cohort was found, but not for ALS and for ALS and PDC together. Whether or not a cohort effect, period effect, or both are associated with incidence of ALS and PDC cannot be determined from the data currently available and will require additional follow-up of individuals born after 1920.^ The epidemiological data amassed over this 40-year period provide evidence that supports an environmental exposure model for disease occurrence as opposed to a simple genetic or infectious disease model. Whether neurodegenerative disease in this population occurs as a consequence of a single exposure or is explained by a multifactorial model such as a genetic predisposition with some environmental interaction is yet to be determined. However, descriptive studies such as this can provide clues concerning timing and location of potential adverse exposures but cannot determine etiology, underscoring the urgent need for analytic studies of ALS and PDC to further investigate existing etiologic hypotheses and to test new hypotheses. ^

Changing epidemiology of trauma deaths leads to a bimodal distribution

Introduction. Injury mortality was classically described with a tri-modal distribution, with immediate deaths at the scene, early deaths due to hemorrhage, and late deaths from organ failure. We hypothesized that trauma systems development have improved pre-hospital care, early resuscitation, and critical care, and altered this pattern. ^ Methods. This is a population-based study of all trauma deaths in an urban county with a mature trauma system (n=678, median age 33 years, 81% male, 43% gunshot, 20% motor vehicle crashes). Deaths were classified as immediate (scene), early (in hospital, ≤ 4 hours from injury), or late (>4 hours post injury). Multinomial regression was used to identify independent predictors of immediate and early vs. late deaths, adjusted for age, gender, race, intention, mechanism, toxicology and cause of death. ^ Results. There were 416 (61%) immediate, 199 (29%) early, and 63 (10%) late deaths. Immediate deaths remained unchanged and early deaths occurred much earlier (median 52 minutes vs. 120). However, unlike the classic trimodal distribution, there was no late peak. Intentional injuries, alcohol intoxication, asphyxia, and injuries to the head and chest were independent predictors of immediate deaths. Alcohol intoxication and injuries to the chest were predictors of early deaths, while pelvic fractures and blunt assaults were associated with late deaths. ^ Conclusion. Trauma deaths now have a bimodal distribution. Elimination of the late peak likely represents advancements in resuscitation and critical care that have reduced organ failure. Further reductions in mortality will likely come from prevention of intentional injuries, and injuries associated with alcohol intoxication. ^

Genetic epidemiology of gallbladder disease in Mexican Americans and cholesterol 7$\alpha$-hydroxylase gene sequence variation

Among Mexican Americans, the second largest minority group in the United States, the prevalence of gallbladder disease is markedly elevated. Previous data from both genetic admixture and family studies indicate that there is a genetic component to the occurrence of gallbladder disease in Mexican Americans. However, prior to this thesis no formal genetic analysis of gallbladder disease had been carried out nor had any contributing genes been identified.^ The results of complex segregation analysis in a sample of 232 Mexican American pedigrees documented the existence of a major gene having two alleles with age- and gender-specific effects influencing the occurrence of gallbladder disease. The estimated frequency of the allele increasing susceptibility was 0.39. The lifetime probabilities that an individual will be affected by gallbladder disease were 1.0, 0.54, and 0.00 for females of genotypes "AA", "Aa", and "aa", respectively, and 0.68, 0.30, and 0.00 for males, respectively. This analysis provided the first conclusive evidence for the existence of a common single gene having a large effect on the occurrence of gallbladder disease.^ Human cholesterol 7$\alpha$-hydroxylase is the rate-limiting enzyme in bile acid synthesis. The results of an association study in both a random sample and a matched case/control sample showed that there is a significant association between cholesterol 7$\alpha$-hydroxylase gene variation and the occurrence of gallbladder disease in Mexican Americans males but not in females. These data have implicated a specific gene, 7$\alpha$-hydroxylase, in the etiology of gallbladder disease in this population.^ Finally, I asked whether the inferred major gene from complex segregation analysis is genetically linked to the cholesterol 7$\alpha$-hydroxylase gene. Three pedigrees predicted to be informative for linkage analysis by virtue of supporting the major gene hypothesis and having parents with informative genotypes and multiple offspring were selected for this linkage analysis. In each of these pedigrees, the recombination fractions maximized at 0 with a positive, albeit low, LOD score. The results of this linkage analysis provide preliminary and suggestive evidence that the cholesterol 7$\alpha$-hydroxylase gene and the inferred gallbladder disease susceptibility gene are genetically linked. ^

Bisphosphonates for metastatic bone disease in lung cancer

Bisphosphonates have proven effectiveness in preventing skeletal-related events (SREs) in advanced breast cancer, prostate cancer and multiple myeloma. The purpose of this study was to assess efficacy of bisphosphonates in preventing SREs, in controlling pain, and in increasing life expectancy in lung cancer patients with bone metastases.^ We performed an electronic search in MEDLINE, EMBASE, Web of Science, and Cochrane library databases up to April 4, 2010. Hand searching and searching in clinicaltrials.gov were also performed. Two independent reviewers selected all clinical trials that included lung cancer patients with bone metastases treated with bisphosphonates. We excluded articles that involved cancers other than lung, patients without bone metastasis and treatment other than bisphosphonates. Outcome questions answered were efficacy measured as overall pain control, overall improvement in survival and reduction in skeletal-related events or SREs (fracture, cord compression, radiation or surgery to the bone, hypercalcemia of malignancy). The quality of each study was evaluated using the Cochrane Back Review group questionnaire to assess risk of bias (0-worst to 11-best). Data extraction and quality assessments were independently performed by two assessors. Meta-analyses were performed where more than one study with similar outcomes were found.^ We identified eight trials that met our inclusion criteria. Three studies evaluated zoledronic acid, three pamidronate, three clodronate and two ibandronate. Two were placebocontrol trials while two had multi-group comparisons (radiotherapy, radionucleotides, and chemotherapy) and two had different bisphosphonate as active controls. Quality scores ranged from 1-4 out of 11 suggesting high risk of bias. Studies failed to report adequate explanation of randomization procedures, concealment of randomization and blinding. Metaanalysis showed that patients treated with zoledronic acid alone had lower rates of developing SREs compared to placebo at 21 months (RR=0.80, 95% CI=0.66-0.97, p=0.02). Meta-analyses also showed increased pain control when a bisphosphonate was added to the existing treatment modality like chemotherapy or radiation (RR=1.17, 95% CI=1.03-1.34, p=0.02). However, pain control was not statistically significantly different among various bisphosphonates when other treatment modalities were not present. Despite improvement in SRE and pain control, bisphosphonates failed to show improvement in overall survival (Difference in means=109.1 days, 95% CI= -51.52 – 269.71, p=0.183).^ Adding biphosphonates to standard care improved pain control and reduced SREs. Biphosphonates did not improve overall survival. Further larger studies with higher quality are required to stengthen the evidence.^ Keywords/MeSH terms Bisphosphonates/diphosphonates: generic, chemical and trade names.^

The epidemiology of left ventricular outflow tract obstruction defects in Texas, 2002-2008: An update and assessment of effect heterogeneity

Left ventricular outflow tract (LVOT) defects are an important group of congenital heart defects (CHDs) because of their associated mortality and long-term complications. LVOT defects include aortic valve stenosis (AVS), coarctation of aorta (CoA), and hypoplastic left heart syndrome (HLHS). Despite their clinical significance, their etiology is not completely understood. Even though the individual component phenotypes (AVS, CoA, and HLHS) may have different etiologies, they are often "lumped" together in epidemiological studies. Though "lumping" of component phenotypes may improve the power to detect associations, it may also lead to ambiguous findings if these defects are etiologically distinct. This is due to potential for effect heterogeneity across component phenotypes. ^ This study had two aims: (1) to identify the association between various risk factors and both the component (i.e., split) and composite (i.e., lumped) LVOT phenotypes, and (2) to assess the effect heterogeneity of risk factors across component phenotypes of LVOT defects. ^ This study was a secondary data analysis. Primary data were obtained from the Texas Birth Defect Registry (TBDR). TBDR uses an active surveillance method to ascertain birth defects in Texas. All cases of non complex LVOT defects which met our inclusion criteria during the period of 2002–2008 were included in the study. The comparison groups included all unaffected live births for the same period (2002–2008). Data from vital statistics were used to evaluate associations. Statistical associations between selected risk factors and LVOT defects was determined by calculating crude and adjusted prevalence ratio using Poisson regression analysis. Effect heterogeneity was evaluated using polytomous logistic regression. ^ There were a total of 2,353 cases of LVOT defects among 2,730,035 live births during the study period. There were a total of 1,311 definite cases of non-complex LVOT defects for analysis after excluding "complex" cardiac cases and cases associated with syndromes (n=168). Among infant characteristics, males were at a significantly higher risk of developing LVOT defects compared to females. Among maternal characteristics, significant associations were seen with maternal age > 40 years (compared to maternal age 20–24 years) and maternal residence in Texas-Mexico border (compared to non-border residence). Among birth characteristics, significant associations were seen with preterm birth and small for gestation age LVOT defects. ^ When evaluating effect heterogeneity, the following variables had significantly different effects among the component LVOT defect phenotypes: infant sex, plurality, maternal age, maternal race/ethnicity, and Texas-Mexico border residence. ^ This study found significant associations between various demographic factors and LVOT defects. While many findings from this study were consistent with results from previous studies, we also identified new factors associated with LVOT defects. Additionally, this study was the first to assess effect heterogeneity across LVOT defect component phenotypes. These findings contribute to a growing body of literature on characteristics associated with LVOT defects. ^