Pharmacologic management of peripheral vascular disease

Although our understanding of the pathophysiology of atherosclerosis and peripheral vascular disease continues to grow, we have yet to discover a medication that can safely and efficaciously be given to most claudicants that will alleviate their symptoms to prevent disease progression. Many patients with intermittent claudication improve or remain stable without therapy if they attempt to alter their risk factors (e.g., control of diabetes, smoking cessation, lowering of cholesterol levels). However, many require concomitant drug therapy to alleviate symptoms of PVD, and some require surgical intervention. Even with the recent advances in therapeutic development and the promise of agents currently in clinical trials, the questions of who to treat, when treatment should begin, and which agent to use remain uncertain.     

Linking self-reported childhood behavioral inhibition to adolescent social phobia

OBJECTIVE: Behavioral inhibition in children has been hypothesized to be a risk factor for the later development of social phobia. However, this hypothesis has yet to be demonstrated in a prospective study. The purpose of the study presented here is to test whether behavioral inhibition in childhood constitutes a risk factor for social phobia during adolescence. METHOD: The sample consisted of 2,242 high school students assessed over a 4-year period. Assessments included self-report questionnaires, structured clinical interviews, and measurements of heart rate. Cox proportional hazards models were used to evaluate risk. RESULTS: Social avoidance, a component of behavioral inhibition, predicted onset of social phobia during high school. However, social avoidance was not related to depression in adolescence. Another component of behavioral inhibition, fearfulness, increased the risk for both social phobia and depression. Among subjects who were both socially avoidant and fearful, 22.3% developed social phobia--a risk more than four times greater than that for subjects with neither feature of behavioral inhibition. CONCLUSION: This prospective study demonstrates that behavioral inhibition in childhood increases the risk of social phobia in adolescence.     

Acute effects of cocaine on human brain activity and emotion

We investigated brain circuitry mediating cocaine-induced euphoria and craving using functional MRI (fMRI). During double-blind cocaine (0.6 mg/kg) and saline infusions in cocaine-dependent subjects, the entire brain was imaged for 5 min before and 13 min after infusion while subjects rated scales for rush, high, low, and craving. Cocaine induced focal signal increases in nucleus accumbens/subcallosal cortex (NAc/SCC), caudate, putamen, basal forebrain, thalamus, insula, hippocampus, parahippocampal gyrus, cingulate, lateral prefrontal and temporal cortices, parietal cortex, striate/extrastriate cortices, ventral tegmentum, and pons and produced signal decreases in amygdala, temporal pole, and medial frontal cortex. Saline produced few positive or negative activations, which were localized to lateral prefrontal cortex and temporo-occipital cortex. Subjects who underwent repeat studies showed good replication of the regional fMRI activation pattern following cocaine and saline infusions, with activations on saline retest that might reflect expectancy. Brain regions that exhibited early and short duration signal maxima showed a higher correlation with rush ratings. These included the ventral tegmentum, pons, basal forebrain, caudate, cingulate, and most regions of lateral prefrontal cortex. In contrast, regions that demonstrated early but sustained signal maxima were more correlated with craving than with rush ratings; such regions included the NAc/SCC, right parahippocampal gyrus, and some regions of lateral prefrontal cortex. Sustained negative signal change was noted in the amygdala, which correlated with craving ratings. Our data demonstrate the ability of fMRI to map dynamic patterns of brain activation following cocaine infusion in cocaine-dependent subjects and provide evidence of dynamically changing brain networks associated with cocaine-induced euphoria and cocaine-induced craving.     

Mechanism of alpha-2 adrenergic modulation of canine cardiac Purkinje action potential

We reported recently that stimulation of postjunctional alpha-2 adrenergic receptors prolongs the action potential durations (APD) of isolated canine Purkinje fibers. With standard microelectrode techniques, we examined the ionic mechanism through which alpha-2 adrenergic stimulation prolonged Purkinje APD, by measuring the effects of inhibitors of the various plateau currents on the alpha-2-mediated prolongation of APD. The alpha-2-specific agonist UK 14,304 (0.1 microM) prolonged the Purkinje APD at 50% repolarization and the APD at 90% repolarization, and these effects were inhibited by yohimbine (0.1 microM). The Purkinje APD at 50% repolarization and the APD at 90% repolarization were prolonged significantly with the transient outward potassium current inhibitor 4-aminopyridine (1 mM), the rapid component of delayed rectifier potassium current inhibitor d-sotalol (10 microM), the slow component of delayed rectifier potassium current inhibitor indapamide (0.1 microM) and the chloride current inhibitor mefenamic acid (10 nM) and were shortened significantly with the calcium current inhibitor nifedipine (0.3 microM). Prolongation of Purkinje APD at 50% repolarization and APD at 90% repolarization by UK 14,304 remained intact in the presence of d-sotalol, indapamide, mefenamic acid and nifedipine. All of these UK 14,304 effects were significantly reversed by yohimbine. Only in the presence of 4-aminopyridine did UK 14,304 fail to prolong Purkinje APD. The phase 1 magnitudes of Purkinje action potentials were also significantly inhibited by UK 14,304. This effect was completely abolished only in the presence of 4-aminopyridine. These results suggest that inhibition of the 4-aminopyridine-sensitive transient outward potassium current is the major ionic mechanism by which alpha-2 adrenergic stimulation prolongs Purkinje APD.     

Severity distribution of atopic dermatitis in the community and its relationship to secondary referral

A case of cutaneous leishmaniasis in a traveller from Belize, Central America is reported. Leishmaniasis presents rarely in Australia and delays in diagnosis and treatment often occur. A high index of suspicion in a patient who has returned from an endemic region is required. Subsequent confirmation of a diagnosis of cutaneous leishmaniasis is best achieved by demonstration of the organism on skin biopsy, aspiration or smear. The histology is variable and depends on geographic, parasite species and host factors. Speciation of New World disease as either Leishmania braziliensis or Leishmania mexicana is important to determine the risk of later development of mucosal disease, which normally only occurs with L. braziliensis infection, and for optimal treatment. Several different modes of treatment have been suggested, but antimonials, such as sodium stibogluconate, remain the treatment of choice in New World cutaneous leishmaniasis.     

Virus-associated hemophagocytic syndrome. Diagnosis and treatment

Virus-associated haemophagocytic syndrome (VAHS) is a rare disease characterized by fever, splenomegaly, cytopenia and histiocytic proliferation with haemophagocytosis in the reticuloendothelial system. The clinical course of VAHS can be dramatic and the prognosis is often poor. The pathogenesis of VAHS is not well understood. Many believe that viral infection provokes an abnormal immune response in predisposed individuals leading to hyperactivation of Th1 helper cells, macrophage proliferation and secretion of large amounts of cytokines. The resultant hypercytokinaemia may be responsible for the clinical and biochemical manifestations of VAHS. In this article the clinical features, presumed pathogenesis, diagnostic criteria and treatment of VAHS are discussed.     

Pulmonary manifestations of Sj?gren's syndrome

Sj?gren's syndrome is one of the most common systemic rheumatic diseases. Pulmonary disease is prevalent in Sj?gren's syndrome; respiratory manifestations include chronic cough, obstructive airways disease, pulmonary lymphoma, and interstitial lung disease that may progress to severe pulmonary fibrosis.     

In vivo and in vitro immune variables in patients with narcolepsy and HLA-DR2 matched controls

We investigated cytokine levels (interleukin [IL]-1beta, IL-1ra, IL-2, IL-6, tumor necrosis factor [TNF]-alpha, TNF-beta) in plasma and secreted by mitogen-stimulated blood monocytes and lymphocytes; T-cell subsets; and natural killer cell activity in patients with narcolepsy and in human leukocyte antigen (HLA)-DR2 matched controls. The only significant finding was higher IL-6 secretion by monocytes of patients than by those of the HLA-DR2-positive controls. In conclusion, we found no major abnormalities of T-cell function in patients with narcolepsy, but slight alterations of monocyte function deserving further investigation.