Antisense knockdown of the Shaker-like Kv1.1 gene abolishes the central stimulatory effects of amphetamines in mice and rats.

Amphetamine (AMPH) is an indirect sympathomimetic compound classified as a substrate-type releaser that distinguishes it from other stimulants that act as uptake 1 blockers, such as cocaine (COC). In mammals, AMPH elicits central stimulation, hypermotility, anorexia, analgesia and analeptic activity, mainly through the increase of extracellular brain dopamine (DA). The inversion of vesicular transporters and/or intravesicular alkalinization is assumed to have a role in AMPH-induced exocytosis. However, the action mechanism of this compound has not yet been completely clarified. Recent evidence on the action of AMPHs indicates potassium channel-blocking properties in peripheral tissues. We investigated the possible involvement of a Shaker-like Kv1.1 channel subtype in the central effects of AMPH, using an antisense oligodeoxyribonucleotide (aODN) that specifically and reversibly inhibits the expression of these channels in the brain. The effect of aODN pretreatments was studied by evaluating the modification of behavioral effects induced in mice through the intracerebroventricular administration of AMPH, COC, or other compounds. The aODN in mice almost completely blocked the stimulatory effects of AMPH and other releasers but was ineffective in reducing the central activity of COC. In aODN-pretreated rats a strong reduction of the AMPH, but not of the COC-stimulated DA efflux from nucleus accumbens was observed. Our results suggest that the stimulant effects of AMPH and chemically related compounds, but not COC, require the presence of functionally active Kv1.1 channels in the brain.     

Pilot study to enhance HIV care using needle exchange-based health services for out-of-treatment injecting drug users

The introduction of highly active antiretroviral therapy (HAART) has resulted in marked reductions in mortality and acquired immunodeficiency syndrome (AIDS) incidence across all risk groups; however, the proportionate decrease among injecting drug users (IDUs) has been less impressive. Much of the disparity in benefit to IDUs has been a consequence of decreased access to and receipt of potent antiretroviral combinations. Strategies to increase access to and utilization of HAART have included entry into drug treatment and abstinence. Unfortunately, as few as 15%–20% of active drug users in the United States, and in many other countries, are in drug treatment at any one time. We report a pilot project among out-of-drug treatment IDUs infected with human immunodeficiency virus (HIV); HIV therapy was successfully provided to active heroin injectors using the Community Health Care Van (CHCV) at sites of needle exchange. Subjects were willing to initiate, but were not receiving, recommended HIV therapy and were not interested in formal drug treatment. Antiretroviral therapy regimens were selected and linked to heroin injection timing. Weekly visits were scheduled by CHCV staff to assess adverse side effects and encourage adherence. Of the 13 participants, the mean baseline HIV-1 RNA level and CD4 lymphocyte count were 162,369 (log 5.21) copies per milliliter and 265 cells per milliliter, respectively. By 6 months, the proportion whose HIV-1 RNA was below the limits of detection (<400 copies/mL) was 85% (N=11); 77% (N=10) had nondetectable levels by 9 months. By 12 months, 54% (N=7) had a persistently nondetectable viral load, and the net increase in CD4 lymphocyte count was 150 cells per milliliter. As an additional and unintended benefit of this pilot project, 9 (69%) subjects chose to enter drug treatment after achieving a nondetectable viral load. Entry into drug treatment was associated with durability of viral suppression. This small pilot study suggests that health services based on needle exchange may enhance access to HAART among out-of-treatment HIV-infected IDUs. In addition, it demonstrates that this population can benefit from this therapy with the support of a nontraditional, community-based health intervention.     

Neurocysticercosis in Persons with Epilepsy in Medellín,Colombia

Summary: Purpose: A prospective series of 643 persons with epilepsy attending a reference neurologic center in Medellin, Colombia, was examined by computed tomography (CT scan) or serology or both with the enzyme-linked immunoelectrotransfer blot assay (EITB) to assess the prevalence of Taenia solium cysticercosis. Methods: All presenting patients were consecutively enrolled in the study. Five hundred forty-six persons underwent cerebral CT scans; 376 of them also had serum EITB performed. Results: Prevalence of neurocys@ercosis by CT scan was 13.92%. Overall prevalence of T. solium antibodies with EITB was 9.82%, but for those with late-onset epilepsy (onset after age 30 years), prevalence increased to 17.5% and 19% for those who originated from outside urban Medellin. Seroprevalence in individuals with mixed lesions (cysts and calcifications) was 88.2% and 64.10% in those with live cysts. Conversely, only 2.72% of persons with CT findings not related to neurocysticercosis had positive EITB tests. Conclusions: Our study shows that an important proportion of individuals with epilepsy have radiologic or serologic evidence of T. solium infection, suggesting that neurocysticercosis is an important etiology for epilepsy in Colombia.     

Abuse liability of flunitrazepam among methadone-maintained patients

Abuse liability and acute subjective and psychomotor effects of flunitrazepam were assessed in ten methadone-maintained males with history of benzodiazepine and alcohol use, who voluntarily participated in a double-blind, controlled, cross-over, randomized clinical trial. There were six experimental sessions in which a single oral dose of flunitrazepam 1, 2, and 4 mg; triazolam 0.5 and 0.75 mg; and placebo was given. Evaluations included physiological measures; psychomotor performance tasks (simple reaction time, Digit Symbol Substitution Test, balance task, Maddox-wing device); and self-administered subjective effects questionnaires [Addiction Research Center Inventory (ARCI), Profile of Mood States (POMS), a series of visual analog scales (VAS)]. All drugs but flunitrazepam 1 mg caused an impairment of psychomotor tasks. Effects were more evident with the highest doses of both drugs. Only flunitrazepam 4 mg produced a significant decrease in balance time. Triazolam 0.75 mg induced increases in sedation measured by ARCI-PCAG, depression in POMS, and VAS-drowsiness scores. Flunitrazepam 4 mg caused euphoria-related effects as measured by increases in ARCI-MBG and “high” scores in the VAS. Our findings of flunitrazepam-induced euphoria in methadone-maintained subjects together with epidemiological evidence of flunitrazepam abuse by opioid dependents, suggest that it may be included in the group of benzodiazepines with a relatively high abuse potential. Received: 13 February 1998/Final version: 1 May 1998     

Effect of lead on postnatal development of the bank vole (Clethrionomys glareolus)

Female bank voles (Clethnonomys glareolus Schreber, 1780) were given lead-contaminated food (2.5, 60, 380, and 730 g g^–1 of lead) after giving birth to litters. The concentrations of lead in bodies of young voles were determined after 5th, 10th, 15th, and 20th days of life. The concentrations of lead in the offspring increased with elevation of lead level in the diet of mothers. Lead accumulation became remarkable after 15th day, particularly in the bodies of the young born to mothers given 380 and 730 g g^–1 of dietary lead. The adverse effect of lead on the growth of young voles (declining weight increments) was observed in groups receiving highly contaminated food. The mortality among the young was also monitored. It occurred in whole litters as well as individuals and attained the highest values in groups given 730 g g^–1 of dietary lead.     

Search for poliovirus long-term excretors among patients affected by agammaglobulinemia

Patients with agammaglobulinemia may excrete enteroviruses, including vaccine-derived poliovirus, for prolonged periods of time. This poses a risk to the patients but it also may pose a risk to the population after eradication of poliovirus and the cessation of routine vaccination. To assess this risk, a pilot study was performed to identify potential poliovirus long-term excretors in a cohort of 38 patients with a definite/presumptive diagnosis of X-linked agammaglobulinemia (XLA). Stool samples were analyzed to detect any polio or other enteroviruses replicating in the gut and neutralizing antibodies against polioviruses were measured in the sera. No viruses were isolated from the stool samples and most sera had neutralizing antibody levels against all three poliovirus serotypes considered by the WHO to be protective in immunocompetent individuals. This suggests that long-term excretion of enteroviruses in patients with agammaglobulinemia is relatively uncommon.     

Wilson disease: novel mutations in the ATP7B gene and clinical correlation in Brazilian patients

Wilson disease (WD) is a rare inherited autosomal recessive disorder caused by a defect in a metal transporting P-type ATPase, resulting in copper overload in various tissues and cells. The aim was to assess both the phenotype in Brazilian WD patients and the corresponding ATP7B genotype. Sixty subjects belonging to 46 pedigrees diagnosed as WD were included in this study. Direct sequencing of all 21 exons within ATP7B and their flanking introns was performed. Demographic, clinical, laboratory and histopathological data at the time of diagnosis were obtained. We identified twenty-five mutations, twelve of them reported for the first time. The c.3402delC mutation had the highest allelic frequency (30.8%), followed by the c.2123T>C (p.L708P) (16.7%). Exons 8 and 15 were the site of 62.5% of the mutations. The common European mutation c.3207C>A (p.H1069Q) was not present at all. Phenotype varied greatly among individuals with the same ATP7B genotype. Our data confirm the heterogeneity of ATP7B genotype in Brazilian WD patients. The mutational spectrum is compatible with the Brazilian history of Mediterranean immigration; however, new mutations, and different frequencies and phenotype associated with the previously known mutations characterize this population. Exons 8 and 15 should be preferentially screened in WD cases from Brazil. Phenotype variation among subjects with the same ATP7B genotype suggests that modifying factors play an additional role in the pathogenesis of WD.     

HIV seroincidence among patients at clinics for sexually transmitted diseases in nine cities in the United States

Although the numbers of newly reported diagnoses of AIDS decreased in the 1990s, it is not clear whether they reflect a decreasing number of new HIV infections. Direct measurement of HIV incidence through follow-up cohort studies is difficult and costly. We estimated HIV incidence and trends in incidence among men who have sex with men (MSM) and heterosexual men and women at clinics for sexually transmitted diseases (STDs) by using a recently developed serologic testing algorithm that requires only a single blood specimen. Cross-sectional anonymous serosurveys were conducted at 13 STD clinics in nine cities in the United States from 1991 through 1997. Before anonymous HIV testing, demographic and clinical information was abstracted. Of 129,774 specimens tested, 362 (0.28%) were from persons estimated to be recently infected. Incidence among MSM was 7.1% (95% confidence interval (CI): 4.8-10.3), 14 times higher than that among heterosexuals, which was 0.5% (CI: 0.4- 0.7). Incidence among MSM and heterosexuals remained unchanged during the time studied. Decreasing rates of new AIDS diagnoses in the 1990s do not reflect stable rates of new HIV infections among MSM and heterosexual patients attending these clinics.