OBJECTIVE

This study evaluated the effects of 3 class-sparing antiretroviral therapy (ART) regimens on endothelial function in human immunodeficiency virus (HIV)-infected subjects participating in a randomized trial.

BACKGROUND

Endothelial dysfunction has been observed in patients receiving ART for HIV infection.

METHODS

This was a prospective, multicenter study of treatment-naive subjects who were randomly assigned to receive a protease inhibitor-sparing regimen of nucleoside reverse transcriptase inhibitors (NRTIs) + efavirenz, a non-nucleoside reverse transcriptase inhibitor-sparing regimen of NRTIs + lopinavir/ritonavir, or a NRTI-sparing regimen of efavirenz + lopinavir/ritonavir. The NRTIs were lamivudine + stavudine, zidovudine, or tenofovir. Brachial artery flow-mediated dilation (FMD) was determined by B-mode ultrasound before starting on ART, then after 4 and 24 weeks.

RESULTS

There were 82 subjects (median age 35 years, 91% men, 54% white). Baseline CD4 cell counts and plasma HIV ribonucleic acid (RNA) values were 245 cells/mm(3) and 4.8 log(10) copies/ml, respectively. At baseline, FMD was 3.68% (interquartile range [IQR] 1.98% to 5.51%). After 4 and 24 weeks of ART, plasma HIV RNA decreased by 2.1 and 3.0 log(10) copies/ml, respectively. FMD increased by 0.74% (IQR -0.62% to +2.74%, p = 0.003) and 1.48% (IQR -0.20% to +4.30%, p < 0.001), respectively, with similar changes in each arm (Kruskal-Wallis p value >0.600). The decrease in plasma HIV RNA at 24 weeks was associated with greater FMD (r(s) = -0.30, p = 0.017).

CONCLUSIONS

Among treatment-naive individuals with HIV, 3 different ART regimens rapidly improved endothelial function. Benefits were similar for all ART regimens, appeared quickly, and persisted at 24 weeks.

Neuropathy is often a major manifestation of systemic amyloidosis. It is most frequently seen in patients with hereditary transthyretin (TTR) amyloidosis, but is also present in 20% of patients with systemic immunoglobulin light chain (primary) amyloidosis. Familial amyloid polyneuropathy (FAP) is the most common form of inherited amyloidotic polyneuropathy, with clinical and electrophysiologic findings similar to neuropathies with differing etiologies (e.g., diabetes mellitus). Hereditary amyloidosis is an adult-onset autosomal-dominant disease with varying degrees of penetrance. It is caused by specific gene mutations, but demonstration that a patient has one such mutation does not confirm the diagnosis of amyloidosis. Diagnosis requires tissue biopsy with demonstration of amyloid deposits either by special histochemical stains or electron microscopy. Transthyretin amyloidosis is treated by liver transplantation, which eliminates the mutated transthyretin from the blood, but for some patients continued amyloid deposition can occur from wild-type (normal) transthyretin. Presently, a study is ongoing to determine whether amyloid deposition can be inhibited by small organic molecules that are hypothesized to affect the fibril-forming ability of transthyretin. Proposed gene therapy with antisense oligonucleotides (ASOs) to suppress hepatic transthyretin synthesis is effective in a transgenic mouse model but has not yet been tested in humans.

OBJECTIVE

To determine if particular components of antiretroviral drug regimens are associated with greater insulin resistance, dyslipidemia, and peripheral lipoatrophy.

METHODS

Metabolic and body composition variables were measured prospectively over 64 weeks in 334 antiretroviral-naive, HIV-infected subjects who were randomized to receive nelfinavir, efavirenz, or both, combined with zidovudine/lamivudine or didanosine/stavudine in a factorial design, multicenter trial. Subjects assigned to efavirenz (n = 110) were compared with those assigned to nelfinavir (n = 99); subjects assigned to zidovudine/lamivudine (n = 154) were compared with those assigned to didanosine/stavudine (n = 180). A subset of 157 subjects had serial dual-energy X-ray absorptiometry (DEXA) scans.

RESULTS

Lipid measures increased in all groups. Greater increases in high density lipoprotein (HDL) cholesterol occurred with efavirenz than with nelfinavir. Greater increases in total cholesterol, non-HDL cholesterol and HDL cholesterol occurred with stavudine and didanosine than with zidovudine/lamivudine. There were no differences in insulin resistance in the comparisons. After initial increases in the first 16 weeks, median limb fat decreased. Greater changes in percentage changes in limb fat occurred with didanosine/stavudine (-16.8%) than with zidovudine/lamivudine (+4.0%; P < 0.001 for overall change from baseline) and with nelfinavir (-13.1%) compared with efavirenz (+1.8%; P = 0.003).

CONCLUSIONS

Over 64 weeks, all regimens were associated with increases in lipids but insulin resistance did not differ between groups. Regimens containing didanosine/stavudine and regimens containing nelfinavir were associated with greater loss of limb fat.

BACKGROUND

The Cystic Fibrosis Questionnaire-Revised (CFQ-R) is a validated patient-reported outcome (PRO) containing both generic scales and scales specific to cystic fibrosis (CF). The minimal clinically important difference (MCID) score for a PRO corresponds to the smallest clinically relevant change a patient can detect. MCID scores for the CFQ-R respiratory symptom (CFQ-R-Respiratory) scale were determined using data from two 28 day, open-label, tobramycin inhalation solution (TIS) studies in patients with CF and chronic Pseudomonas aeruginosa airway infection. At study enrollment, patients in the study 1-exacerbation had symptoms indicative of pulmonary exacerbation (n = 84; < 14 years of age, 31 patients;>> or = 14 years of age, 53 patients); patients in study 2-stable had stable respiratory symptoms (n = 140; < 14 years of age, 14 patients;>> or = 14 years, 126 patients).

METHODS

The anchor-based method utilized a global rating-of-change questionnaire (GRCQ) that assessed patients' perceptions of change in their respiratory symptoms after TIS treatment. The mean change from baseline CFQ-R-Respiratory scores were mapped onto the GRCQ to estimate the MCID. The two distribution-based methods were as follows: (1) 0.5 SD of mean change in CFQ-R-Respiratory scores (baseline to end of TIS treatment); and (2) 1 SEM for baseline CFQ-R-Respiratory scores. Triangulation of these three estimates defined the MCIDs.

RESULTS

MCID scores were larger for patients in study 1-exacerbation (8.5 points) than for those in study 2-stable (4.0 points), likely reflecting differences in patient disease status (exacerbation/stable) between these studies.

CONCLUSIONS

Patient benefit from new and current CF therapies can be evaluated using changes in CFQ-R-Respiratory scores. Using the MCID provides a systematic way to interpret these changes, and facilitates the identification of CF treatments that improve both symptoms and physiologic variables, potentially leading to better treatment adherence and clinical outcomes. Trial registration (study 1-exacerbation): Australian-New Zealand Clinical Trials Registry Identifier: ACTRN 12605000602628 Trial registration (study 2-stable): ClinicalTrials.gov Identifier: NCT00104520.

The chemokine receptors (CCRs) CCR4 and CCR10, and the cutaneous lymphocyte antigen (CLA), have each been proposed as critical mediators of skin-specific TH lymphocyte homing in mice and humans. CLA initiates skin homing by mediating E-selectin-dependent tethering and rolling within cutaneous venules, but the specific roles of CCR4 and CCR10 are unclear. We have generated an antihuman CCR10 monoclonal antibody (mAb; 1B5) to illuminate the individual contributions of these molecules. This mAb allows us to compare CCR10, CCR4, and CLA expression within human TH populations. The mAb 1B5 recognizes functional CCR10 expression, as chemotactic responsiveness to cutaneous T-cell-attracting chemokine (CTACK)/CCL27 (a CCR10 ligand) parallels the staining of TH subsets. We find CCR10 expressed by only a minority (approximately 30%) of blood-borne, skin-homing (CLA+/CCR4+) TH cells. However, essentially all members of the relatively small "effector" (CLA+/CCR4+/CD27-/CCR7-) skin-homing TH population express CCR10. Most skin-infiltrating lymphocytes in allergic delayed-type hypersensitivity (DTH) and bacterial chancroid skin lesions express both CCR4 and CLA, but only about 10% express CCR10. This suggests for the 2 models of TH skin homing studied here that CCR10+ TH cells have no advantage over other CLA+/CCR4+ TH cells in homing to cutaneous sites. We conclude that the skin-homing TH compartment is itself divided into distinct subpopulations, the smaller of which expresses both CCR4 and CCR10, and the larger of which expresses only CCR4. Thus, CCR10 is unlikely to be necessary for cutaneous homing of TH cells in the models studied here. CCR10 may instead play a role in the movement of specialized "effector" cutaneous TH cells to and/or within epidermal microenvironments.

OBJECTIVE

The aim of the study was to examine serum markers of bone turnover at 6 and 18 months after Roux-en-Y gastric bypass surgery.

METHODS

Ten women and 10 men [body mass index (BMI), 50.2 +/- 8.4 kg/m(2)] were studied at 6 months; 10 women and nine men (BMI, 47.2 +/- 6.6 kg/m(2)) were studied at 18 months after surgery.

METHODS

Serum osteocalcin, bone specific alkaline phosphatase (BAP), N-telopeptide of type 1 collagen (NTX), PTH, 25-hydroxy vitamin D, and leptin were measured.

RESULTS

BMI was reduced 32.7 +/- 6.2% at 6 months after surgery. Serum osteocalcin (6.9 +/- 2.4 to 10.9 +/- 2.6 ng/ml; P < 0.0001), BAP (14.2 +/- 3.7 to 16.4 +/- 4.5 ng/ml; P = 0.04), and NTX (10.9 +/- 1.7 to 19.6 +/- 5.3 nm bone collagen equivalents; P < 0.0001) were increased. Calcium, phosphate, and PTH were unchanged, but 25-hydroxy vitamin D increased (16.0 +/- 8.9 vs. 26.9 +/- 10.6 ng/ml; P <0.0001). The increase in NTX correlated with reduction in serum leptin (r = 0.58; P = 0.007). BMI was reduced 40.9 +/- 7.5% at 18 months after surgery. Serum BAP (17.6 +/- 5.3 to 22.2 +/- 7.8 ng/ml; P = 0.0017) and NTX (10.8 +/- 2.7 to 16.9 +/- 5.5 nm bone collagen equivalents; P < 0.0001) were increased. Calcium, phosphate, and PTH were unchanged, but 25-hydroxy vitamin D increased (17.7 +/- 7.6 to 25.6 +/- 6.8 ng/ml; P < 0.0001). The increase in NTX correlated with reduction in BMI (r = 0.58; P = 0.009) and leptin (r = 0.45; P = 0.04) and the increase in serum 25-hydroxy vitamin D (r = 0.43; P = 0.05). In multiple regression (adjusted model R(2) 0.263; P = 0.013), reduction in leptin was a significant predictor of increase in NTX (P = 0.016), but changes in BMI and 25-hydroxy vitamin D were not.

CONCLUSIONS

Weight loss after bariatric surgery is associated with long-term increase in serum markers of bone turnover. The increase in NTX is related to the decrease in leptin, which may signal caloric restriction to the skeleton.

OBJECTIVE

Inhaled nitric oxide (iNO) reduces the use of extracorporeal membrane oxygenation (ECMO)/incidence of death in term and near-term neonates with severe hypoxic respiratory failure. We conducted a randomized, double masked, multicenter trial to determine whether administration of iNO earlier in respiratory failure results in additional reduction in the incidence of these outcomes.

METHODS

Neonates who were born at>> or =34 weeks' gestation were enrolled when they required assisted ventilation and had an oxygenation index (OI)>> or =15 and <25 on any 2 measurements in a 12-hour interval. Infants were randomized to early iNO or to simulated initiation of iNO (control). Infants who had an increase in OI to 25 or more were given iNO as standard therapy.

RESULTS

The trial enrollment was halted after 75% of target sample size was reached because of decreasing availability of eligible patients. The 150 infants who were given early iNO and 149 control infants had similar baseline characteristics. Arterial oxygen tension increased by >20 mm Hg in 73% of early iNO and 37% of control infants after study gas initiation. Control infants received standard iNO and deteriorated to OI >40 more often than infants who were given early iNO. The incidence of death (early iNO, 6.7% vs control, 9.4%), ECMO (10.7% vs 12.1%), and their combined incidence (16.7% vs 19.5%) were similar in both groups.

CONCLUSIONS

iNO improves oxygenation but does not reduce the incidence of ECMO/mortality when initiated at an OI of 15 to 25 compared with initiation at >25 in term and near-term neonates with respiratory failure.

OBJECTIVE

The authors examined the developmental impact and temporal characteristics of risperidone-associated weight change.

METHODS

Weight change was measured for 63 children and adolescents with autism treated with risperidone for 6 months. Change in serum leptin levels after 2 months was examined as a predictor of final weight gain in mixed regression models that controlled for site, gender, age, and risperidone dose.

RESULTS

Age- and gender-standardized weight increased after 6 months of treatment (gross: mean=5.6 kg [SD=3.9]; standardized: mean=0.6 z [SD=0.5]) and was positively correlated with weight gained after 1 month. Change in leptin levels after 2 months of treatment (mean=-0.3 ng/ml, SD=6.2) (N=48) did not predict final weight gain.

CONCLUSIONS

Chronic risperidone exposure in children with autism causes weight gain in excess of developmentally expected norms that follows a curvilinear trajectory and decelerates over time. Serum leptin change does not reliably predict risperidone-associated weight gain.

BACKGROUND

Several genome-wide association studies (GWAS) have been performed to identify genes contributing to bone mineral density (BMD), typically in samples of elderly women and men.

OBJECTIVE

The objective of the study was to identify genes contributing to BMD in premenopausal women.

METHODS

GWAS using the Illumina 610Quad array in premenopausal European-American (EA) women and replication of the top 50 single-nucleotide polymorphisms (SNPs) for two BMD measures in African-American (AA) women.

METHODS

Subjects included 1524 premenopausal EA women aged 20-45 yr from 762 sibships and 669 AA premenopausal women aged 20-44 yr from 383 sibships.

METHODS

There were no interventions.

METHODS

BMD was measured at the lumbar spine and femoral neck by dual-energy x-ray absorptiometry. Age- and weight-adjusted BMD values were tested for association with each SNP, with P values determined by permutation.

RESULTS

SNPs in CATSPERB on chromosome 14 provided evidence of association with femoral neck BMD (rs1298989, P = 2.7 x 10(-5); rs1285635, P = 3.0 x 10(-5)) in the EA women, and some supporting evidence was also observed with these SNPs in the AA women (rs1285635, P = 0.003). Genes identified in other BMD GWAS studies, including IBSP and ADAMTS18, were also among the most significant findings in our GWAS.

CONCLUSIONS

Evidence of association to several novel loci was detected in a GWAS of premenopausal EA women, and SNPs in one of these loci also provided supporting evidence in a sample of AA women.

BACKGROUND

Potent antiretroviral treatment has drastically reduced mortality in HIV-infected patients but may accelerate atherosclerotic disease, which could be partially mediated via endothelial dysfunction.

METHODS

In 8 HIV-negative healthy males, leg blood flow responses to intraartery infusions of methacholine chloride (Mch), sodium nitroprusside, and NG-mono-methyl-L-arginine (L-NMMA) were measured before and after 4 weeks of daily oral indinavir. In the same subjects, we also assessed the effect of indinavir on lipids, insulin sensitivity, markers of inflammation, as well as oxidative stress.

RESULTS

After 4 weeks of indinavir, the endothelium-dependent response to methacholine chloride was impaired (195% +/- 38% vs 83% +/- 13%, P < .05), the response to NG-mono-methyl-L-arginine (nitric oxide-dependent tone) was nearly abrogated (-30% +/- 4% vs -1% +/- 11%, P < .05), whereas the endothelium-independent response to sodium nitroprusside remained unchanged. Fasting insulin levels increased from 5.8 +/- 1.2 to 7.0 +/- 1.4 microU/mL (P < .05), and HOMA-IR scores increased from 1.3 +/- 0.3 to 1.6 +/- 0.3 U (P < .05). There were no changes in blood pressure, lipids, markers of inflammation, or oxidative stress.

CONCLUSIONS

Four weeks of the HIV-1 protease inhibitor indinavir, in the absence of HIV-1 infection, causes vascular dysfunction most likely at the level of endothelial nitric oxide production. The vascular dysfunction may be mediated partially by the concomitant induction of insulin resistance but other mechanisms cannot be ruled out.

The diagnoses provided by a standard indirect test of vasopressin function were compared with those obtained by radioimmunoassay of plasma vasopressin in 24 patients with nonglucosuric polyuria. All seven cases of severe neurogenic diabetes insipidus diagnosed by the indirect tests were confirmed by the vasopressin assay. However, two of six patients with partial neurogenic diabetes insipidus by indirect criteria had normal vasopressin secretion by the direct assay; one was found to have primary polydipsia, and the other nephrogenic diabetes insipidus. Moreover, three of 10 patients diagnosed as having primary polydipsia by the indirect test had clear evidence of partial vasopressin deficiency by the direct assay. The inability of the indirect test to distinguish accurately between partial neurogenic diabetes insipidus and primary polydipsia may be explained by increased sensitivity to low concentrations of vasopressin in the former disorder and a reduction of maximal concentrating ability in both. We conclude that the incorporation of a vasopressin assay improves accuracy in the differential diagnosis of polyuria.

Na(+) reabsorption by the epithelial Na(+) channel (ENaC) in cortical collecting duct provides the final renal adjustment to Na(+) balance, there being no further downstream Na(+) transport system. This fact coupled with the responsiveness of ENaC to aldosterone, which conveys stimulation inversely proportional to the state of Na(+) balance, places ENaC in a pivotal position to influence the risk for hypertension. Although several molecular variants of ENaC subunits have been identified, there has been no consistent demonstration of an association of any of the variants with hypertension. More compelling is the notion that ENaC activity does not fully adjust to an increase in Na(+) reabsorption occurring elsewhere in the nephron, there being overstimulation by inappropriately elevated aldosterone levels. Additional evidence that the maintenance of hypertension can be dependent on ENaC is derived from the observed responses to the treatment of hypertensive individuals with inhibitors of ENaC. Described is a clinical trial in which black hypertensive individuals who did not fully respond to more traditional therapy were given amiloride, spironolactone, a combination of the two drugs, or placebo. Treatment with either of the active inhibitors of ENaC resulted in a substantial improvement in BP. In conclusion, evidence to date is supportive of the concept that an increase in Na(+) transport by ENaC may be a common and requisite component of salt-dependent forms of hypertension.

Blacks develop a higher peak bone mass than whites which is associated with a reduced risk for bone fracture. The physiological basis for the difference in bone mass was investigated by metabolic balance and calcium kinetic studies in adolescent black and white girls. The hypothesis that the greater peak bone mass in blacks compared with whites is due to suppressed bone resorption was tested. Subjects were housed in a supervised environment for 3 wk during which time they consumed a controlled diet and collected all excreta. Subjects were given stable calcium isotopes orally and intravenously after 1 wk adaptation. Blacks have greater calcium retention (mean +/- SD, 11.5 +/- 6.1 vs. 7.3 +/- 4.1 mmol/d, P < 0.05) consistent with greater bone formation rates (49.4 +/- 13.5 vs. 36.5 +/- 13.6 mmol/d, P < 0.05) relative to bone resorption rates (37.4 +/- 13.2 vs. 29.4 +/- 10.9 mmol/d, P = 0.07), increased calcium absorption efficiency (54 +/- 19 vs. 38 +/- 18%, P < 0.05) and decreased urinary calcium (1.15 +/- 0.95 vs. 2.50 +/- 1.35 mmol/d, P < 0.001), compared with whites. The racial differences in calcium retention in adolescence can account for the racial differences in bone mass of adults.

BACKGROUND

Small, priming doses of alcohol enhance desire to drink, and thus play a role in the loss of control of alcohol consumption. Using functional magnetic resonance imaging (fMRI), we previously showed that alcoholic drink odors (AO; subjects' drinks of choice) induce greater nucleus accumbens (NAc) activity than non-appetitive odors (NApO; grass, leather) in subjects at risk for alcoholism. Here we hypothesized that priming exposure to alcohol would enhance responses to AO in the NAc and orbitofrontal cortex in comparison to NApO (grass, leather) and to the appetitive control odors (ApCO) of chocolate and grape.

METHODS

Ten hazardous drinkers (mean age = 22.7; SD = 2.9, average drinks per drinking day = 5.9, SD = 2.3; drinking days/90 days = 50.4, SD = 13.7) were scanned on a 1.5 T GE Signa MR scanner during intravenous infusion of lactated Ringer's or 6% ethanol in lactated Ringer's that was pharmacokinetically modeled to achieve a constant breath alcohol concentration (BrAC) of 50 mg% throughout imaging. During scanning, subjects sniffed AO, NApO, and ApCO.

RESULTS

Alcohol infusion enhanced the contrast between AO and NApO in the NAc, and in orbitofrontal, medial frontal, and precuneus/posterior cingulate regions. The contrast between AO and appetitive control odors (ApCO; chocolate and grape) was similarly larger in the orbital, medial frontal, precuneus, and posterior cingulate/retrosplenial areas, with the most robust finding being a potentiated response in the posterior cingulate/retrosplenial area. The orbital region is similar to an area previously shown to manifest satiety-related decreases in activity induced by food cues.

CONCLUSIONS

The results suggest that priming exposure to alcohol renders a limbic network more responsive to alcohol cues, potentially enhancing desire to drink.

OBJECTIVE

We sought to determine the vascular risk factors and demographic features associated with the severity and location of intracranial stenosis.

METHODS

Data on patients enrolled in the Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial were used for the analyses. Demographic features and vascular risk factors were compared in patients with moderate stenosis (n=336) versus severe stenosis (n=225) and according to the location of intracranial stenosis (middle cerebral, internal carotid, basilar, or vertebral artery).

RESULTS

History of a lipid disorder (77% in severe vs 67% in moderate, P=0.01), metabolic syndrome (63% in severe vs 53% in moderate, P=0.05), and diabetes (43% in severe vs 35% in moderate, P=0.04) were more common in patients with severe intracranial stenosis by univariate analyses. A history of a lipid disorder was independently associated with severe stenosis (odds ratio=1.62; 95% CI, 1.09 to 2.42; P=0.02). The distribution of stenosis location differed among age groups (P=0.0015), sexes (P=0.0001), races (P=0.0243), qualifying events (P=0.0156), diabetes (P=0.0030), coronary artery disease (P=0.0030), and hyperlipidemia (P=0.054). Patients with basilar artery stenoses were older and more likely to have hyperlipidemia. Patients with middle cerebral artery stenoses were more likely to be women and black. Patients with internal carotid artery stenoses were more likely to have diabetes. Patients with vertebral artery stenoses were more likely to have coronary artery disease.

CONCLUSIONS

History of a lipid disorder had the strongest association with severity of intracranial stenosis and should be the target of prevention therapies. Different locations of intracranial stenoses are associated with different vascular risk factors and demographic features, suggesting that there may be a difference in the underlying pathophysiology of stenoses among the intracranial arteries.

BACKGROUND

Data on the quality of life (QOL) of children with non-alcoholic fatty liver disease (NAFLD) are needed to estimate the true burden of illness in children with NAFLD.

OBJECTIVE

To characterize QOL and symptoms of children with NAFLD and to compare QOL in children with NAFLD with that in a sample of healthy children.

METHODS

Quality of life and symptoms were assessed in children with biopsy-proven NAFLD enrolled in the NASH Clinical Research Network. PedsQL scores were compared with scores from healthy children. For children with NAFLD, between-group comparisons were made to test associations of demography, histological severity, symptoms and QOL.

RESULTS

A total of 239 children (mean age 12.6 years) were studied. Children with NAFLD had worse total (72.8 vs. 83.8, P < 0.01), physical (77.2 vs. 87.5, P < 0.01) and psychosocial health (70.4 vs. 81.9, P < 0.01) scores compared with healthy children. QOL scores did not significantly differ by histological severity of NAFLD. Fatigue, trouble sleeping and sadness accounted for almost half of the variance in QOL scores. Impaired QOL was present in 39% of children with NAFLD.

CONCLUSIONS

Children with NAFLD have a decrement in QOL. Symptoms were a major determinant of this impairment. Interventions are needed to restore and optimize QOL in children with NAFLD.

Three men with primary mediastinal germ-cell tumors subsequently developed a malignant hematologic disorder characterized by pancytopenia and marrow infiltration with hematopoietic blast cells. Two of these patients were classified as having acute megakaryocytic leukemia and the third was believed to have a myelodysplastic syndrome with a prominent megakaryocytic component. Analysis of clinical characteristics of these patients and review of the literature suggest that the proximate association of mediastinal germ-cell tumors with malignant hematologic disorders is neither a coincidence nor a consequence of chemotherapy given for the germ-cell tumor. We believe this association represents the evolution of a neoplastic disorder that initially involves a totipotent germ cell. These germ cells, when located in the mediastinum, apparently acquire hematologic phenotypes and are manifested clinically as a hematologic malignancy.

BACKGROUND

There is limited evidence to support the recommendation that patients with heart failure (HF) restrict sodium intake. The purpose of this study was to compare differences in cardiac event-free survival between patients with sodium intake above and below 3 g.

METHODS

A total of 302 patients with HF (67% male, 62 ± 12 years, 54% New York Heart Association [NYHA] Class III/IV, ejection fraction 34 ± 14%) collected a 24-hour urine sodium (UNa) to indicate sodium intake. Patients were divided into 2 groups using a 3-g UNa cutpoint and stratified by NYHA Class (I/II vs. III/IV). Event-free survival for 12 months was determined by patient or family interviews and medical record review. Differences in cardiac event-free survival were determined by Kaplan-Meier survival curve with log-rank test and Cox hazard regression.

RESULTS

The Cox regression hazard ratio for 24-hour UNa ≥ 3 g in NYHA Class I/II was 0.44 (95% confidence interval [CI] = 0.20-0.97) and 2.54 (95% CI = 1.10-5.84) for NYHA III/IV after controlling for age, gender, HF etiology, body mass index, ejection fraction, and total comorbidity score.

CONCLUSIONS

These data suggest that 3 g dietary sodium restriction may be most appropriate for patients in NYHA functional Classes III and IV.

This report examined the effect of methylphenidate on social communication and self-regulation in children with pervasive developmental disorders and hyperactivity in a secondary analysis of RUPP Autism Network data. Participants were 33 children (29 boys) between the ages of 5 and 13 years who participated in a four-week crossover trial of placebo and increasing doses of methylphenidate given in random order each for one week. Observational measures of certain aspects of children's social communication, self-regulation, and affective behavior were obtained each week. A significant positive effect of methylphenidate was seen on children's use of joint attention initiations, response to bids for joint attention, self-regulation, and regulated affective state. The results go beyond the recent literature and suggest that methylphenidate may have positive effects on social behaviors in children with PDD and hyperactivity.

Longitudinal studies of neurocognitive function in prediagnosis Huntington disease (pre-HD) have been few, and duration of follow-up has been brief. In this study, 155 individuals at-risk for HD completed a battery of cognitive and motor tasks at two study visits approximately 10 years apart. Participants were classified as: (1) at-risk, without the CAG expansion (healthy controls, NC; n = 112), or (2) CAG expanded (CAG+; n = 43). To examine the rate of decline at different stages of the pre-HD period, participants in the CAG+ group were further characterized as converters (i.e., individuals who developed manifest HD over the course of the study; n = 21) or nonconverters (n = 22), and their performances were compared. The CAG+ group exhibited faster rates of neurocognitive decline over the course of the study, relative to the NC group. In addition, more rapid decline was associated with closer proximity to estimated age of disease onset in the CAG+ group. Faster rates of motor and psychomotor decline were observed in the CAG+ converter group, relative to the nonconverters. These findings suggest that neurocognitive decline in pre-HD, particularly in motor and psychomotor domains, begins insidiously and accelerates as individuals approach disease onset.

Atypical antipsychotics are increasingly prescribed to children and adolescents with neuropsychiatric disorders. Although their profile of potent antagonism at specific serotonin and dopamine receptors offers certain advantages compared with typical antipsychotics, their use has been associated with various adverse effects, including significant weight gain. This adverse effect is of particular concern in children and adolescents, secondary to the immediate and long-term health risks associated with weight gain, including obesity, diabetes mellitus, and hyperlipidemia. Indeed, from 1963 to 1991, the prevalence of obesity has approximately doubled in youth. Prior to selecting an atypical antipsychotic, a detailed review of the predictors of weight gain is necessary for every child and adolescent. Published data suggest that clozapine and olanzapine are associated with considerable weight gain, whereas risperidone and quetiapine have a moderate risk. Alternatively, ziprasidone and aripiprazole may exhibit a low risk for this adverse effect. Whereas behavioral and pharmacologic measures are available to manage weight gain associated with atypical antipsychotics, research is needed to establish more effective and safe interventions for this adverse effect in children and adolescents.

OBJECTIVE

We sought to determine if patients with intracranial stenosis who have a transient ischemic attack or stroke on antithrombotic therapy are at particularly high risk for recurrent stroke.

METHODS

We compared baseline features and the rates of stroke or vascular death and stroke in the territory of the symptomatic artery between patients ON (n=299) versus OFF (n=269) antithrombotics at the time of their qualifying event for the Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial.

RESULTS

In univariate analyses, there was no difference in the rates of stroke or vascular death (21% versus 23%; hazard ratio [ON/OFF], 0.91; 95% CI, 0.64 to 1.29; P=0.59) or stroke in territory (13% versus 14%; hazard ratio [ON/OFF], 0.90; 95% CI, 0.57 to 1.39; P=0.61) between patients ON versus OFF antithrombotics at the time of their qualifying event. A multivariable analysis adjusted for the difference in risk factors between patients ON and OFF antithrombotic therapy also showed no significant differences in the combined end point of stroke or vascular death (hazard ratio [ON/OFF], 0.86; 95% CI, 0.55 to 1.34; P=0.51) or stroke in territory (hazard ratio [ON/OFF], 1.01; 95% CI, 0.58 to 1.77; P=0.97) between patients ON versus OFF antithrombotic therapy at the time of the qualifying event.

CONCLUSIONS

Patients with intracranial stenosis who fail antithrombotic therapy are not at higher risk of stroke than those who do not fail antithrombotic therapy. Given our finding that patients ON and OFF antithrombotic therapy are both at high risk for stroke in the territory, intracranial stenting trials should not be limited to just those who fail antithrombotic therapy.

Amyloid fibrils were isolated from cardiac tissue of two brothers who died from familial amyloidotic polyneuropathy (FAP) type II. Sequence analysis on peptides derived from proteolytic cleavage with trypsin and fragmentation with cyanogen bromide reveal that the fibril subunit protein is derived from plasma transthyretin (prealbumin). About two-thirds of the fibril subunit protein was found to contain an amino acid substitution at position 84 where the normal isoleucine residue has been replaced by serine. Sequence analysis of the plasma transthyretin (prealbumin) from the two brothers as well as two clinically diagnosed FAP type II family members and two of four children of affected individuals showed the presence of serine at position 84. The presence of this substitution also correlates with low serum levels of retinol-binding protein and thus transthyretin (prealbumin) position 84 may be involved with the interaction of these two proteins.

Blacks have a greater tendency to retain Na than whites. The present study sought evidence for ethnic differences in parameters reflective of Na uptake by the Na,K,2Cl cotransporter in the thick ascending limb, namely, the urine concentration and urinary excretion of certain cations before and after furosemide administration (40 mg IV). Subjects were healthy (ages 18 to 36 years). During the preceding overnight period, urine volume was lower, and osmolality was higher in blacks than in whites, an ethnic difference that disappeared when water intake was restricted to infused normal saline (60 mL/h). Plasma vasopressin levels were higher in black males than in other sex/ethnic groups. Baseline urinary excretion rates of K, Ca, and Mg were significantly lower in blacks than in whites. After furosemide (0 to 1 hour), K and Ca excretion rates increased, but the proportionate ethnic difference decreased from 44% to 22% and from 22% to 10%, respectively, consistent with blacks having more basal Na,K,2Cl cotransporter activity to inhibit. During a later postfurosemide period (1 to 5 hours), urinary concentrations of Ca and Mg recovered more slowly in blacks, consistent with greater reuptake in the thick ascending limb. In summary, there were distinct ethnic differences in renal handling of Ca and Mg basally and in response to furosemide that were consistent with a more active Na,K,2Cl cotransporter in the thick ascending limb in blacks. An increase in vasopressin levels appeared to explain greater urine concentrations in black males but not black females.