Detrimental effects of continued illicit drug use on the treatment of HIV-1 infection.

OBJECTIVE: To identify the effects of substance abuse status (active, former, and never) on utilization of highly active antiretroviral therapy (HAART), medication adherence, and virologic and immunologic responses to therapy. DESIGN: Prospective cohort study of 764 HIV-1-infected patients who attended an urban HIV clinic and participated in a standardized interview. MAIN OUTCOME MEASURES: Past utilization of HAART, self-reported nonadherence with antiretroviral therapy, and changes in HIV-1 RNA level and CD4+ lymphocyte count relative to prior peak and nadir, respectively. RESULTS: Forty-four percent of active drug users failed to utilize HAART compared with 22% of former drug users and 18% of non-drug users (p <.001 for both comparisons). Among participants who were taking antiretroviral therapy when interviewed, active drug users were more likely to report medication nonadherence (34% vs. 24% of nonusers and 17% of former users), had a smaller median reduction in HIV-1 RNA from baseline (0.8 log10 copies/ml vs. 1.7 in nonusers and 1.6 in former users), and had smaller median increases in CD4+ lymphocyte count from baseline (65 cells/mm3 vs. 116 in nonusers and 122 in former users) (p <.05 for all comparisons with active users). CONCLUSIONS: Active drug use was strongly associated with underutilization of HAART, nonadherence, and inferior virologic and immunologic responses to therapy, whereas former drug users and non-drug users were similar in all outcomes. Effective strategies are needed that integrate HIV-1 and substance abuse treatments.

Update on adherence to HIV therapy.

AIDS: The Clinical Practices for Treatment of HIV Infection convened a 35-member panel in 1997 to examine clinical practice issues regarding HIV/AIDS treatment, resulting in a document on treatment guidelines. The controversial issues and the most likely sources of change that may occur during revisions of the document are reviewed. The issues that are reviewed include what constitutes no detectable virus in determining regimen effectiveness, what changes should be made in drug regimens that are considered failures, what to do when patients who are taking two nucleoside reverse transcriptase inhibitors have achieved the goal of undetectable virus, how to address the problems surrounding salvage therapy and the concept of class resistance among protease inhibitors, and the point at which antiretroviral therapy should be discontinued.^ieng

To take or not to take that mound of medicine.

AIDS: Patient adherence to dosing schedules is critically important for the long-term success of antiviral therapy, but a question remains regarding how much adherence is enough for therapy to be successful. Aggressive therapy is hard to maintain, and results of a study measuring patient adherence were reported. Results demonstrate the clear association between adherence and viral suppression, although it is noted that even highly adherent patients can suffer virologic failure. Factors associated with non-adherence include depression and race. Predicting which patients are most likely to be adherent remains difficult, but adherence may improve if more effective interventions are developed.^ieng

Primary invasive cutaneous Microsporum canis infections in immunocompromised patients.

Two cases of primary invasive cutaneous infections caused by the zoophilic dermatophytic species Microsporum canis are presented. The first case occurred in a liver transplant recipient who was receiving immunosuppressive therapy. Multiple erythematous papules were seen on both legs, and a biopsy revealed invasive fungal hyphae. The second case was diagnosed in a human immunodeficiency virus-positive individual with a CD4 lymphocyte count of 81 mm3. Raised red nodules were seen on her scalp and face. Histopathology was consistent with bacillary angiomatosis, and in addition, invasive septate hyphae were observed. The two strains recovered from the biopsy specimens from both individuals had colony morphologies consistent with that of M. canis, but it was difficult to induce production of macroconidia. These cases serve to increase the awareness of this unusual infection, reinforce the need for cultures, and raise some interesting questions about the potential virulence of this dermatophyte species.

Habituation of neurosecretory responses to extracellular ATP in PC12 cells.

Neuronally differentiated PC12 cells have been used as a model for habituation. These cells secrete norepinephrine in response to extracellular ATP, as well as other stimulants, and the response is diminished with repetitive stimulation. This loss of neurosecretory responsiveness displays characteristics commonly associated with habituative learning. These include an increase in both the rate and the relative degree of response loss with either increasing stimulation frequency or decreasing stimulus intensity, and selective generalization of the decreased responsiveness to heterologous stimuli. In PC12 cells, the loss of neurosecretory responsiveness appears to be entirely caused by stimulation-dependent inactivation of the ATP-gated cation channel. Several unusual properties of this channel apparently allow its regulation to produce the behaviors associated with short-term habituation. Recovery of the ATP-gated channel requires several minutes, allowing habituation of responses to repetitive stimuli given at intervals of several minutes. Inactivation of the ATP-gated channel may be proportionately faster in response to lower ligand concentrations, allowing habituation to be more rapid in response to stimuli of weaker intensity.

Human EBV-transformed lymphocytes of patients with Schistosoma japonicum infection secrete idiotypically related immunoregulatory antibodies.

Lymphocytes derived from the peripheral blood of individuals infected with Schistosoma japonica were transformed in vitro with Ebstein-Barr virus (EBV). Serological characterization of antibody molecules revealed both antigen reactive (idiotypic) and anti-idiotypic transformants. One idiotypic EBV transformant, LO2C2, describes a major cross-reactive idiotype associated with anti-antigen binding molecules. Other antibody populations expressing idiotypic cross-reactivity were derived from separate individuals showing shared idiotypy in S. japonicum field study populations in the Republic of Philippines. Both idiotypic and anti-idiotypic molecules suppressed parasite antigen-driven blastogenesis of heterologous human peripheral blood lymphocytes. The data show a serologically related immunoregulatory immune network in patients in the Republic of the Philippines which is serologically distinct from idiotypy expressed in other selected S. japonicum endemic areas in the Far East.

Retention of habituation in PC12 cells.

The time course of habituation and recovery of neurotransmitter release was measured in neuronally differentiated PC12 cells stimulated with either acetylcholine or ATP. The release of norepinephrine in response to either stimulant declined exponentially with repeated presentation of that stimulant. When the stimulus was withheld, the cells' ability to respond recovered to initial levels with an exponential time course. The rate of response recovery depended on the stimulant used and, in the case of stimulation with acetylcholine, on the number of previous stimuli. After habituation and recovery, or partial recovery, of norepinephrine release, the response to a second series of repetitive stimuli declined more rapidly than in the naive case. This increase in habituation rate was dependent on the number of previous stimuli and, in the case of stimulation with acetylcholine, was stable with time for at least 90 min after stimulation. These phenomena are analogous to characteristics of short- and long-term memories of habituative learning observed in behavioral studies. Kinetic equations based on a putative reversible stimulation-dependent inactivation of the cellular response mechanism were used to analyze the rates of habituation and response recovery.

An outbreak of human Leishmania (Viannia) braziliensis infection

The occurence of acute cutaneous leishmaniasis among inhabitants of 10 farms within 10 Km of the hamlet of Corte de Pedra, Bahia, Brazil was studied prospectively from 1984-l989. A mean population of 1,056 inhabitants living in 146 hourses were visited every 6 months and the numberof sKin ulcers recorded. A leishmanin skin test survey was done people with suggestive skin scars or active disease in l984. The incidence of skin ulcers due to Leishmania (Viannia) brasiliensis (Vlb) reached 83/1,000 inhabitants but declined sharply in the subsequent 2 years. Retrospective data shows that leishamiasis is a sporadic endemic disease. Although the reasons for this epidemic are unclear some possible aetiological factors are discussed

An outbreak of human Leishmania (Viannia) braziliensis infection.

The occurrence of acute cutaneous leishmaniasis among inhabitants of 10 farms within 10 Km of the hamlet of Corte de Pedra, Bahia, Brazil was studied prospectively from 1984-1989. A mean population of 1,056 inhabitants living in 146 houses were visited every 6 months and the number of skin ulcers recorded. A leishmanin skin test survey was done people with suggestive skin scars or active disease in 1984. The incidence of skin ulcers due to Leishmania (Viannia) braziliensis (Lvb) reached 83/1,000 inhabitants but declined sharply in the subsequent 2 years. Retrospective data shows that leishmaniasis is a sporadic endemic disease. Although the reasons for this epidemic are unclear some possible aetiological factors are discussed.

A protein kinase C isozyme is translocated to cytoskeletal elements on activation.

Protein kinase C (PKC)1 isozymes comprise a family of related cytosolic kinases that translocate to the cell particulate fraction on stimulation. The activated enzyme is thought to be on the plasma membrane. However, phosphorylation of protein substrates occurs throughout the cell and is inconsistent with plasma membrane localization. Using an isozyme-specific monoclonal antibody we found that, on activation, this PKC isozyme translocates to myofibrils in cardiac myocytes and to microfilaments in fibroblasts. Translocation of this activated PKC isozyme to cytoskeletal elements may explain some of the effects of PKC on cell contractility and morphology. In addition, differences in the translocation site of individual isozymes--and, therefore, phosphorylation of different substrates localized at these sites--may explain the diverse biological effects of PKC.

Chronic ethanol causes heterologous desensitization of receptors by reducing alpha s messenger RNA.

One of the biochemical results of ethanol exposure is a change in the amount of the intracellular second messenger cyclic AMP (cAMP) produced in response to receptor stimulation. In general, acute ethanol exposure increases the amount of cAMP produced on stimulation of receptors coupled to the enzyme adenylyl cyclase via the GTP-binding protein Gs, whereas chronic ethanol exposure has the opposite effect (results for receptors coupled via Gi have been more variable). We previously reported that adaptation to continuous ethanol exposure reduces receptor-stimulated cAMP production by 25-35% in a neuroblastoma cell line (NG108-15), and an even greater reduction of 75% was observed in lymphocytes taken from actively-drinking alcoholics. This reduction in receptor-stimulated cAMP levels was recently confirmed in platelets from alcoholics. None of these studies, however, determined whether more than one receptor coupled to adenylyl cyclase activity was affected in the same cell. Here we report that chronic ethanol exposure causes desensitization of heterologous receptors coupled to Gs as cAMP production mediated by prostaglandin E1 as well as by adenosine is reduced by approximately 30% in NG108-15 cells. We show that, after chronic ethanol exposure, the activity of the alpha subunit of Gs is decreased by 29%, the amount of alpha s protein is decreased by 38.5%, and alpha s messenger RNA is decreased by 30%. Thus, cellular adaptation to ethanol involves a reduction in alpha s mRNA and, as a consequence, reduced cAMP production by heterologous receptors coupled to Gs. Such changes in cAMP production may account for the tolerance and physical dependence on ethanol in alcoholism.