DRD2 Dopamine Receptor Genotype, Linkage Disequilibrium, and Alcoholism in American Indians and Other Populations

We defined interpopulation differences in the frequency of the dopamine D2 receptor DRD2/Taq1 A1 allele, which has previously been associated with alcoholism. Frequencies of the A1 allele in unrelated subjects were 0.18 to 0.20 (se = 0.02 to 0.03) in several Caucasian populations previously assessed, 0.38 (±0.05) in American Blacks ( n = 44), 0.63 (±0.07) in Jemez Pueblo Indians ( n = 23), and 0.80 (± 0.04) in Cheyenne Indians ( n = 52). The existence of large interpopulation differences in the frequency of the Taq1 alleles suggests that associations to disease status could readily be generated or masked if disease and control groups were uneven in ethnic composition. To address the possibility that the 4-fold higher frequency of the A1 allele in Cheyenne Indians was related to an increased vulnerability to alcoholism in that population, 47 Cheyenne Indians were psychiatrically interviewed and blind-rated. However, there was no significant difference between interviewed controls (0.73 ± 0.06, n = 24), subjects with alcoholism and/or drug abuse (0.74 ± 0.06, n = 23) and noninterviewed population controls (0.87 ± 0.05, n = 20). Legitimate association of the DRD2/Taq1 allele to alcoholism would presumably require it to be in linkage disequilibrium (nonrandom association) with a functional mutation at DRD2 or elsewhere. The level of disequilibrium would vary between populations and could place an upper bound on the strength of an association. To provide a model for the extent and variation of disequilibrium at DRD2, the level of linkage disequilibrium between the Taq1 RFLP and a second DRD2 polymorphism, the SSCP variant in the immediate 3'region of the gene, was determined in three populations. The normalized disequilibrium values were 0.36 In U.S. Caucasians ( n = 48), 0.34 in Finns ( n = 86), and 0.78 in Cheyenne Indians ( n = 34).     

Genetic and environmental effects on fasting and postchallenge plasma glucose and serum insulin values in Finnish twins

The aim of this study was to evaluate genetic and environmental effects on plasma glucose, insulin secretion, and resistance in Finnish twins. Altogether 151 randomly selected twin pairs were examined by the oral glucose tolerance test; 66 twin pairs were monozygotic and 85 like-sexed dizygotic. We estimated the intraclass correlation coefficients and variance components of genetic and environmental effects on waist circumference, plasma glucose, and serum insulin. For fasting insulin, the proportion of total variation accounted for by additive genetic effects (A) and nonshared environmental effects (E) were 43 and 57%, respectively. As to postchallenge insulin and waist circumference, A effects were stronger in female twins (51 and 70%, respectively) than male twins in whom no significant evidence for genetic variance was found. Of the variation in fasting glucose, A and E effects accounted for 45 and 55%, respectively. Of the variation in postchallenge glucose, E effects had a greater role (65%), compared with A effects (35%); A effects on pre- and postchallenge insulin levels were highly correlated (genetic correlation coefficient = 0.81). In conclusion, additive genetic effects are important for the insulin secretion, whereas nonshared environmental effects contribute strongly to peripheral insulin resistance.     

Impact of Intracranial Pressure Monitor–Guided Therapy on Neurologic Outcome After Spontaneous Nontraumatic Intracranial Hemorrhage

Objectives: Intracranial pressure (ICP) monitors have been used in some patients with spontaneous intracranial hemorrhage (ICH) to provide information to guide treatment without clear evidence for its use in this population. We assessed the impact of ICP monitor placement, including external ventricular drains and intraparenchymal monitors, on neurologic outcome in this population.Materials and MethodsIn this secondary analysis of the Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation III trial, the primary outcome was poor outcome (modified Rankin Scale score 4-6) and the secondary outcome was death, at 1 year from onset. We compared outcomes in patients with or without an ICP monitor using unadjusted and adjusted logistic regression models. The analyses were repeated in a balanced cohort created with propensity score matching.ResultsSeventy patients underwent ICP monitor placement and 424 did not. Poor outcome was seen in 77.1% of patients in the ICP-monitor subgroup compared with 53.8% in the no-monitor subgroup (p<0.001). Of patients in the ICP-monitor subgroup, 31.4% died, compared with 21.0% in the no-monitor subgroup (p=0.053). In multivariate models, ICP monitor placement was associated with a >2-fold greater risk of poor outcome (odds ratio 2.76, 95% CI 1.30–5.85, p=0.008), but not with death (p=0.652). Our findings remained consistent in the propensity score-matched cohort.ConclusionThese results question whether ICP monitor–guided therapy in patients with spontaneous nontraumatic ICH improves outcome. Further work is required to define the causal pathway and improve identification of patients that might benefit from invasive ICP monitoring.     

Growth and Aging of Proximal Femoral Bone: A Study With Women Spanning Three Generations

Osteoporotic hip fracture is a serious clinical event associated with high morbidity and mortality. Understanding femoral growth patterns is important for promoting bone health in the young and preventing fractures in later life. In this study, growth patterns of areal bone mineral density (aBMD) and geometric properties of the proximal femur were measured by dual‐energy X‐ray absorptiometry. They were studied in 251 girls from premenarche (11.2 ± 0.7 years) to late adolescence (18.3 ± 1.1 years) and compared with their premenopausal mothers (n = 128, aged 44.9 ± 4.1 years) and postmenopausal grandmothers (n = 128, aged 70.0 ± 6.3 years). Hip axis length (HAL) was the first to reach peak growth velocity (?10.5 months before menarche), followed by neck diameter (ND) and neck cross‐sectional area (CSA), (?7.1 and ?4.1 months before menarche, respectively). Both neck‐shaft angle (NSA) and aBMD of neck and total hip peaked at menarche. At 18 years (7‐year follow‐up), girls already had higher femoral neck aBMD but similar HAL and NSA compared with their mothers. Grandmothers had the longest HAL, narrowest NSA, widest ND but lowest aBMD and CSA. Hip strength index (HSI), an index of femoral neck strength during a fall, dropped rapidly after menarche in girls but thereafter remained relatively constant. Grandmothers had lower HSI than either mothers or girls. In conclusion, differences in proximal femoral bone mass and structure in adulthood are largely established before menarche, indicating that heritable factors are responsible for most of the individual variance. The development of geometric properties precedes aBMD in puberty, resulting in relatively constant hip strength after menarche. This asynchronous growth leads to adaptation of bone strength to the imposed loads, avoiding fractures in a biologically efficient manner. Both deterioration of aBMD and inadequate compensatory change in bone geometry after menopause contribute to the increased fracture risk later in life. © 2014 American Society for Bone and Mineral Research.     

The mediating role of C-reactive protein and handgrip strength between obesity and walking limitation

OBJECTIVES: To study the association between different obesity indicators and walking limitation and to examine the role of C‐reactive protein (CRP) and handgrip strength in that association. DESIGN: A cross‐sectional, population‐based study. SETTING: The Health 2000 Survey with a representative sample of the Finnish population. PARTICIPANTS: Subjects aged 55 and older with complete data on body composition, CRP, handgrip strength, and walking limitation (N=2,208). MEASUREMENTS: Body composition, anthropometrics, CRP, medical conditions, handgrip strength, and maximal walking speed were measured in the health examination. Walking limitation was defined as maximal walking speed less than 1.2 m/s or difficulty walking half a kilometer. RESULTS: The two highest quartiles of body fat percentage and CRP and the two lowest quartiles of handgrip strength were all significantly associated with greater risk of walking limitation when chronic diseases and other covariates were taken into account. In addition, high CRP and low handgrip strength partially explained the association between high body fat percentage and walking limitation, but the risk of walking limitation remained significantly greater in persons in the two highest quartiles than in those in the lowest quartile of body fat percentage (odds ratio (OR)=1.75, 95% confidence interval (CI)=1.19–2.57 and OR=2.80, 95% CI 1.89–4.16). The prevalence of walking limitation was much higher in persons who simultaneously had high body fat percentage and low handgrip strength (61%) than in those with a combination of low body fat percentage and high handgrip strength (7%). Using body mass index and waist circumference as indicators of obesity yielded similar results as body fat percentage. CONCLUSION: Low‐grade inflammation and muscle strength may partially mediate the association between obesity and walking limitation. Longitudinal studies and intervention trials are needed to verify this pathway.     

Sphingomyelinase-Like Phosphodiesterase 3b Expression Levels Determine Podocyte Injury Phenotypes in Glomerular Disease

Diabetic kidney disease (DKD) is the most common cause of ESRD in the United States. Podocyte injury is an important feature of DKD that is likely to be caused by circulating factors other than glucose. Soluble urokinase plasminogen activator receptor (suPAR) is a circulating factor found to be elevated in the serum of patients with FSGS and causes podocyte αVβ₃ integrin-dependent migration in vitro. Furthermore, αVβ₃ integrin activation occurs in association with decreased podocyte-specific expression of acid sphingomyelinase-like phosphodiesterase 3b (SMPDL3b) in kidney biopsy specimens from patients with FSGS. However, whether suPAR-dependent αVβ₃ integrin activation occurs in diseases other than FSGS and whether there is a direct link between circulating suPAR levels and SMPDL3b expression in podocytes remain to be established. Our data indicate that serum suPAR levels are also elevated in patients with DKD. However, unlike in FSGS, SMPDL3b expression was increased in glomeruli from patients with DKD and DKD sera-treated human podocytes, where it prevented αVβ₃ integrin activation by its interaction with suPAR and led to increased RhoA activity, rendering podocytes more susceptible to apoptosis. In vivo, inhibition of acid sphingomyelinase reduced proteinuria in experimental DKD but not FSGS, indicating that SMPDL3b expression levels determined the podocyte injury phenotype. These observations suggest that SMPDL3b may be an important modulator of podocyte function by shifting suPAR-mediated podocyte injury from a migratory phenotype to an apoptotic phenotype and that it represents a novel therapeutic glomerular disease target.     

Treatment of renal angiomyolipoma: pooled analysis of individual patient data

Epididymal anomalies and patent processus vaginalis are frequently found in boys with cryptorchidism or hydrocele. We conducted this study to evaluate the association between epididymal anomalies and testicular location or patent processus vaginalis in boys with undescended testis or hydrocele. Children undergoing surgery with undescended testis (group A, 136 boys and 162 testes) or communicating hydrocele (group B, 93 boys and 96 testes) were included. Testicular locations and epididymal anomalies were investigated prospectively. An anomalous epididymis was defined as anomalies of epididymal fusion that consisted of loss of continuity between the testis, the epididymis, and the long looping epididymis. The epididymis was considered normal when a normal, firm attachment between the testis, the caput, and the cauda epididymis was present. The mean ages of groups A and B were 24.6 ± 19.7 (range, 8–52 months) and 31.4 ± 20.6 months (range, 10–59 months). The incidence of epididymal anomalies was significantly higher in group A than that in group B (65.4 % vs. 13.5 %, P < 0.001). The incidence of epididymal anomalies in boys with undescended testis was significantly different according to testis location. Epididymal anomalies were observed in 100 %, 91.4 %, and 39.3 % of cases when the testis was located in the abdomen, inguinal canal, and distal to the external inguinal ring, respectively (P < 0.001). We conclude that epididymal anomalies were more frequent in boys with undescended testis than in boys with hydrocele, and that these anomalies were more frequent when undescended testis was at a higher level. These results suggest that testicular location is associated with epididymal anomalies rather than patent processus vaginalis.     

Left ventricular mass regression in the LIFE study: effect of previous antihypertensive treatment

BACKGROUND: Whether to include only those patients who have not had prior hypertension treatment in clinical trials of left ventricular (LV) mass reduction is controversial. Accordingly, our aim was to study the relationship between prior treatment and both baseline and 1-year echocardiographic LV mass in subjects enrolled in the Losartan Intervention For Endpoint reduction (LIFE) study. METHODS: We studied clinical and baseline echocardiographic data on 960 patients with electrocardiographically confirmed left ventricular hypertrophy enrolled in the electrocardiographic substudy of the LIFE study, 847 of whom had LV mass remeasured after 1 year of blinded treatment. The majority (75%) of these patients had prior medical treatment for hypertension. RESULTS: In multivariable regression analysis, controlling for age, sex, blood pressure (BP), body mass index, and indices of pump and myocardial function, prior antihypertensive treatment was not associated with either greater LV mass or relative wall thickness on the baseline study. Moreover, there was no significant difference between the 637 subjects who were previously treated and the 210 who were not treated with regard to the mean reduction in systolic or diastolic pressures (-25 +/- 17 v -24 +/- -16 and -13 +/- 9 mm Hg v -12 +/- 9 mm Hg), LV mass (-27 +/- 38 v -29 +/- 34 g), or LV mass/body surface area (-14 +/- 20 v -15 +/- 18 g/m(2)), all P >.05. CONCLUSIONS: Prior treatment is not associated with either greater LV mass or greater relative wall thickness when age, body mass index, sex, systolic BP, heart rate, or indices of LV volume load and systolic function are taken into account. In addition, prior treatment is not associated with lesser degrees of LV mass reduction. For design of future clinical trials, restriction of inclusion criteria to only previously untreated patients does not appear to be necessary when the selection criterion is electrocardiographically determined left ventricular hypertrophy.