The prevalence of thrombophilia in patients with chronic venous leg ulceration

BACKGROUND: Thrombophilia is increasingly recognized as a risk factor for deep venous thrombosis (DVT), which in turn is a major risk factor for chronic venous ulceration (CVU). However, the relationship between thrombophilia and CVU remains unknown. The aim of this study was to define the prevalence of thrombophilia in patients with CVU and to determine whether this is associated with a history or duplex scan evidence of DVT. METHODS: Eighty-eight patients with CVU were prospectively studied. The patients underwent clinical assessment and duplex ultrasound scanning. Blood was drawn for antithrombin, proteins C and S, activated protein C resistance, factor V Leiden, prothrombin 20210A, lupus anticoagulant, and anticardiolipin antibodies. RESULTS: The study included 35 men with a median age of 61 years (interquartile range, 45 to 72 years) and 53 women with a median age of 76 years (interquartile range, 69 to 82 years). Thirty-six percent of the patients had either a history or duplex scan evidence suggestive of previous DVT. The following abnormalities were detected: four, five, and six cases of antithrombin, protein C, and protein S deficiencies, respectively; 14 cases of activated protein C resistance; 11 cases of factor V Leiden mutation; three cases of prothrombin 20210A mutation; eight cases of lupus anticoagulant; and 12 cases of anticardiolipin antibodies. Thrombophilia was not significantly related to previous DVT, deep reflux, or disease severity. CONCLUSION: Patients with CVU have a 41% prevalence rate of thrombophilia. This rate is two to 30 times higher than the rate of the general population but is similar to that reported for patients with previous DVT. However, in patients with CVU, thrombophilia does not appear to be related to a history of DVT, a pattern of reflux, or severity of disease. Many patients with CVU may have unsuspected postthrombotic disease.     

Late effects of TNF-alpha-induced inflammation on the microcirculation of cremaster muscle flaps under intravital microscopy

In order to understand the microcirculatory changes and regulatory mechanisms governing passage of neutrophils from the vascular bed to the interstitial tissue during ischemia/reperfusion (I/R) injury, a key component of this injury, tumor necrosis factor-alpha (TNF-alpha)-induced inflammation was analyzed. Twenty-four Sprague-Dawley rats were divided into four groups, containing six animals in each. The effect of TNF-alpha-induced inflammation was studied at two different time points, early sequential and late. In the early-effect Groups 1 and 2, animals were given TNF-alpha and vehicle, respectively. Microcirculatory changes were recorded for 6 hr continuously. In the late-effect Groups 3 and 4, following TNF-alpha injection and vehicle, microcirculatory changes were measured 16 hr later. In the early-effect groups, the number of rolling and adhering leukocytes was increased immediately following TNF-alpha injection and remained elevated for the first 3 hr (p<0.05). The number of transmigrated leukocytes remained significantly increased throughout the first 6 hr (p<0.05) and returned to normal at 16 hr. In delayed-effect groups, a second peak in the number of rolling leukocytes was noted at 16 hr (p<0.05). The numbers of rolling and adhering lymphocytes, although remained at the baseline for the first 6 hr, was increased 2- and 1.5-fold at 16 hr, respectively (p<0.05). The number of perfused capillaries gradually decreased over time in the TNF-alpha-induced inflammation groups. A vasodilatory response was noted at the third and fourth order arterioles within the first 3 hr of measurement (p<0.05), but returned to normal afterward. The detrimental effects of TNF-alpha-induced inflammation during I/R injury could be prolonged up to 16 hr at the microcirculatory level of the muscle flaps.     

Amyotrophic lateral sclerosis and hopelessness: psychosocial factors

The purpose of this study was to investigate the relationship of psychosocial factors to the presence of hopelessness among patients with amyotrophic lateral sclerosis (ALS). Secondary cross-sectional analyses were conducted with data collected from 136 ALS patients. Primary research questions were examined using hierarchical multiple regression procedures. Results showed that health locus of control and purpose in life were significant predictors of hopelessness among ALS patients. Other factors, including socioeconomic and demographic variables, variables measuring length and severity of illness, and additional psychosocial variables (social support satisfaction and degree to which spiritual beliefs help to cope with ALS) were not significant predictors of hopelessness. Results are discussed in light of the benefit to ALS patients of psychosocial interventions in disease management.     

Distinct domain responses of R-state human hemoglobins A,C, and S to anions

Anionic regulation of hemoglobin (Hb) is of increasing interest for the design of Hb-based oxygen carriers. Even "external" amino-acid substitutions can alter the nature and extent of anionic control. This was shown by evaluation of the anion sensitivities of liganded, R-state, forms of HbA, HbC (beta6 Glu --> Lys) and HbS (beta6 Glu --> Val). The beta6 mutants differ in the anion-sensitivity of their central cavities, alpha1beta2 interfaces, and heme and beta93 Cys environments. The mutant Hbs also exhibit increased anion-dependent oxidation and surface denaturation. Moreover, differential chloride effects on oxygen binding by Hbs C, S compared to HbA occur after R-state stabilization by fluoresceination of beta93 Cys. It is concluded that the "external" substitutions in the mutant Hbs have structural consequences that are propagated to varying extents to other domains as a result of anion binding, and that these anion-dependent changes may underlie mechanisms leading to the observed increase in oxidation propensity and surface denaturation.     

Polyglutamine-induced ion channels: a possible mechanism for the neurotoxicity of Huntington and other CAG repeat diseases

CAG repeats resulting in long polyglutamine tracts have been implicated in the pathogenesis of at least eight neurodegenerative diseases including Huntington. Expression of polyglutamine repeats is required for disease and increasing length of the repeats leads to earlier onset of illness (anticipation). Expression of polyglutamine repeats in cultured neurons leads to deposition of intracellular aggregates resembling those found in amyloid diseases, and to neurotoxicity. We report here that polyglutamine can induce large (19-220 pS), long-lived, (lifetime = 6 sec), non-selective (P(cation) = P(anion)) ion channels in planar phospholipid bilayer membranes, and that channel formation is enhanced by acidic pH. We propose that channel formation may be a mechanism of cellular toxicity in Huntington and other CAG repeat disease.     

Phase I clinical and pharmacokinetic study of NSC 655649, a rebeccamycin analogue, given in both single-dose and multiple-dose formats.

PURPOSE: NSC 655649 was given in both single- and multiple-dose formats, to characterize maximum tolerated dose (MTD), toxicity, and pharmacokinetic profile. Experimental Design: Patients with advanced malignancies were treated with escalating doses of NSC 655649 in either a single-dose format (step 1) or a multiple-dose format (step 2). In step 1, NSC 655649 was given as a 30-60 min infusion. In step 2, the NSC 655649 dose was divided into three consecutive daily doses. Plasma and urine were sampled to assess the pharmacokinetic and excretory characteristics of NSC 655649. A total of 12 patients were enrolled at the MTD for the purpose of gender equity. RESULTS: Forty-three patients were treated with NSC 655649 for a total of 108 cycles in step 1, and 26 patients were treated for a total of 41 cycles in step 2. The MTD for both steps 1 and 2 was determined to be 572 mg/m(2). Myelosuppression was the dose-limiting toxicity. Local venous irritation was generally grade 1-2 in severity but could only be adequately prevented by administration of study drug through central i.v. access. One patient with adenocarcinoma of unknown primary experienced a partial response on step 1. Four patients experienced stable disease of >100 days duration. CONCLUSIONS: NSC 655649 may be safely given at an MTD of 572 mg/m(2) in both single-dose and multiple-dose formats. Optimally, this drug should be administered through central i.v. access.     

Further evidence of association between behavioral inhibition and social anxiety in children

OBJECTIVE: The authors sought to examine psychopathological correlates of behavioral inhibition in young offspring of parents with panic disorder and/or major depression. METHOD: Behavioral inhibition, determined by using standard laboratory observations, was assessed in four groups of children (age 2-6 years): 129 children of parents with both panic disorder and major depression, 22 children of parents with panic disorder alone, 49 children of parents with major depression alone, and 84 comparison children of parents with neither panic disorder nor major depression. Psychopathology in children > or =5 years was compared between children with behavioral inhibition (N=64) and without (N=152). RESULTS: Social anxiety disorder (social phobia or avoidant disorder) was significantly more likely to be found in the children with behavioral inhibition (17%) than in those without (5%). Noninhibited children were significantly more likely than inhibited children to have disruptive behavior disorders (20% versus 6%, respectively) and had higher scores on the attention problems scale of the Child Behavior Checklist (mean=52.1 versus 50.8). CONCLUSIONS: This study adds to the growing literature suggesting an association between behavioral inhibition and social anxiety disorder and an inverse relationship between inhibition and disruptive behavior disorders.     

Efficacy of a mixed amphetamine salts compound in adults with attention-deficit/hyperactivity disorder

BACKGROUND: We report on a controlled trial of a mixed amphetamine salts compound (Adderall, dextroamphetamine sulfate, dextro-, levoamphetamine sulfate, dextroamphetamine aspartate, levoamphetamine aspartate, and dextroamphetamine saccharate) in the treatment of adult attention-deficit/hyperactivity disorder (ADHD). METHODS: This was a 7-week, randomized, double-blind, placebo-controlled, crossover study of Adderall in 27 well-characterized adults satisfying full DSM-IV criteria for ADHD of childhood onset and persistent symptoms into adulthood. Medication was titrated up to 30 mg twice a day. Outcome measures included the ADHD Rating Scale and the Clinical Global Impression Score. Comorbid psychiatric disorders were assessed to test for potential effects on treatment outcome. RESULTS: Treatment with Adderall at an average oral dose of 54 mg (administered in 2 daily doses) was effective and well tolerated. Drug-specific improvement in ADHD symptoms was highly significant overall (42% decrease on the ADHD Rating Scale, P<.001), and sufficiently robust to be detectable in a parallel groups comparison restricted to the first 3 weeks of the protocol (P<.001). The percentage of subjects who improved (reduction in the ADHD rating scale of > or =30%) was significantly higher with Adderall treatment than with a placebo (70% vs 7%; P =.001). CONCLUSIONS: Adderall was effective and well tolerated in the short-term treatment of adults with ADHD. More work is needed to evaluate the long-term effects of Adderall, or other amphetamine compounds, in the treatment of adults with ADHD.