HIV Neuropathogenesis in the Presence of a Disrupted Dopamine System

Antiretroviral therapy (ART) has transformed HIV into a chronic condition, lengthening and improving the lives of individuals living with this virus. Despite successful suppression of HIV replication, people living with HIV (PLWH) are susceptible to a growing number of comorbidities, including neuroHIV that results from infection of the central nervous system (CNS). Alterations in the dopaminergic system have long been associated with HIV infection of the CNS. Studies indicate that changes in dopamine concentrations not only alter neurotransmission, but also significantly impact the function of immune cells, contributing to neuroinflammation and neuronal dysfunction. Monocytes/macrophages, which are a major target for HIV in the CNS, are responsive to dopamine. Therefore, defining more precisely the mechanisms by which dopamine acts on these cells, and the changes in cellular function elicited by this neurotransmitter are necessary to develop therapeutic strategies to treat neuroHIV. This is especially important for vulnerable populations of PLWH with chemically altered dopamine concentrations, such as individuals with substance use disorder (SUD), or aging individuals using dopamine-altering medications. The specific neuropathologic and neurocognitive consequences of increased CNS dopamine remain unclear. This is due to the complex nature of HIV neuropathogenesis, and logistical and technical challenges that contribute to inconsistencies among cohort studies, animal models and in vitro studies, as well as lack of demographic data and access to human CNS samples and cells. This review summarizes current understanding of the impact of dopamine on HIV neuropathogenesis, and proposes new experimental approaches to examine the role of dopamine in CNS HIV infection.

HIV Neuropathogenesis in the Presence of a Disrupted Dopamine System. Both substance abuse disorders and the use of dopaminergic medications for age-related diseases are associated with changes in CNS dopamine concentrations and dopaminergic neurotransmission. These changes can lead to aberrant immune function, particularly in myeloid cells, which contributes to the neuroinflammation, neuropathology and dysfunctional neurotransmission observed in dopamine-rich regions in HIV+ individuals. These changes, which are seen despite the use antiretroviral therapy (ART), in turn lead to further dysregulation of the dopamine system. Thus, in individuals with elevated dopamine, the bi-directional interaction between aberrant dopaminergic neurotransmission and HIV infection creates a feedback loop contributing to HIV associated neurocognitive dysfunction and neuroHIV. However, the distinct contributions and interactions made by HIV infection, inflammatory mediators, ART, drugs of abuse, and age-related therapeutics are poorly understood. Defining more precisely the mechanisms by which these factors influence the development of neurological disease is critical to addressing the continued presence of neuroHIV in vulnerable populations, such as HIV-infected older adults or drug abusers. Due to the complexity of this system, understanding these effects will require a combination of novel experimental modalities in the context of ART. These will include more rigorous epidemiological studies, relevant animal models, and in vitro cellular and molecular mechanistic analysis.

     

Serodiagnosis of invasive amebiasis using a recombinant Entamoeba histolytica protein

One hundred eight serum samples from 106 patients were examined by Western blot analysis for the presence of antibodies to a recombinant fusion protein containing the sequence of the newly described serine-rich Entamoeba histolytica protein (SREHP). Among patients with invasive amebiasis from Durban, Republic of South Africa; San Diego, Calif; Mexico City, Mexico; and St Louis, Mo, 53 (82%) of 65 had antibodies to SREHP. In contrast, only one patient (2%) of 43 without acute invasive amebiasis had antibodies to SREHP. The predictive value of a positive test for anti-SREHP antibodies in the detection of acute invasive amebiasis was most marked when analyzed in the patients from Durban, where 11 (92%) of 12 patients who were seropositive for SREHP had acute invasive amebiasis vs 17 (65%) of 26 patients who had a positive serologic diagnosis as determined by agar gel diffusion. The use of a serologic test based on the recombinant SREHP fusion protein may be a useful adjunct to the diagnosis of acute invasive amebiasis in endemic regions.     

The role of somatic complaints in the diagnosis of depression in children and adolescents

The question of whether somatic complaints are a significant feature of depression independent of anxiety was explored. Structured interview (Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children) and Child Behavior Checklist data from depressed and nondepressed psychiatric controls were analyzed to explore the interaction of somatic complaints, anxiety, and depression. Seventy percent of the children who met criteria for depression also had significant somatic complaints in contrast to 34% of the controls. Findings revealed that frequency of somatic complaints increased with severity of depression regardless of coexisting anxiety.     

Surface behavior of axolemma monolayers: Physico-chemical characterization and use as supported planar membranes for cultured Schwann cells

The axolemma membrane forms a stable and reproducible monomolecular layer at the air-aqueous interface. The major lipids and proteins are present in this monolayer in molar ratios similar to the original membrane. Acetylcholinesterase and Na-K-ATPase activities are preserved in the monolayer to levels of 64% and 25%, respectively. The total lipid fraction forms a homogeneously mixed phase. The presence of proteins in the monolayer introduces surface inhomogeneties. Among other features, this is revealed by the presence of two values of lateral pressure at which the monolayer shows partial or total collapse: a broad partial collapse at surface pressures between 13 to 30 mN/m and a sharp collapse point at 46 mN/m. The average molecular areas, the broad collapse point, and the variation of the surface potential per molecule suggest the relocation of protein components at surface pressures between 13 to 30 mN/m. The behavior is consistent with the extrusion and exposure of proteins toward the aqueous medium that depends on the lateral pressure. Schwann cells grown on coverslips coated with axolemma monolayers at 13 mN/m (beginning of the broad collapse) and 34 mN/m (above the broad collapse) recognize the difference in the surface organization of axolemma caused by the lateral pressure which affects their proliferation, morphology, and spatial pattern of organization. Our results show for the first time that response of Schwann cells depends on the intermolecular organization of the axolemma surface with which they interact. These results suggest that the local expression of putative surface molecules of axolemma that may mediate membrane recognition and the signalling of morphological and proliferative changes can be modulated by long range supramolecular properties. © 1993 Wiley-Liss, Inc.     

Experimental dermatophytosis in mice: correlation between light and electron microscopic changes in primary, secondary and chronic infections

The histopathological and electron microscopic features of experimental dermatophytosis due to Trichophyton quinckeanum in Balb/c mice have been studied in animals with primary, secondary and chronic infections. Infected animals all showed pathological changes with adherence of microconidia to keratinocytes within 4 h of infection. Other features were the early infiltration of neutrophils, the formation of a mycelial mass (scutulum) in the epidermis, and epidermal oedema. Increased thickness of the epidermis was measured within 3 days of infection, although this was mainly due to oedema. The main differences seen in secondary infections were the paucity of fungal elements, even after 24 h, a sustained increase in epidermal thickness, and the dense dermal infiltrate of mononuclear cells. Chronically infected animals showed similar changes to those at the peak of a primary infection, but in addition there were large numbers of mast cells in the dermis. Cells carrying Ia markers were identified in the epidermis (Langerhans cells) and the dermis (macrophages) in all infections and their distribution did not appear to change. Although recovery from infection has been correlated previously with T lymphocyte mediated responses an increase in the number of cell layers of the epidermis and a dense infiltrate of neutrophils at the zone of infection were both seen within 2 days of infection. It is suggested that neutrophil killing of fungi and increased epidermal proliferation, not dependent on T cell activation, may also be implicated in host defence against dermatophytes.     

Production of specific retinal S antigen antibodies in patients with retinal detachment

One hundred patients with retinal detachment (61 primary operations and 39 reoperations) were studied for titers of autoantibodies to human retinal S antigen using the enzyme-linked immunosorbent assay technique (ELISA). There was no statistically significant difference when comparing the group of patients with primary retinal detachment with the control group. However, a statistically significant increase in anti-S titers was recorded when a comparison was made between the group of reoperated patients and the control group (²,P < 0.001) and between the group of reoperated subjects and the group of patients operated on for the first time (²,P < 0.005).Presented at the XVth Meeting of the Club Jules Gonin, Copenhagen, 10–15 August 1986     

M protein gene type distribution among group A streptococcal clinical isolates recovered in Mexico City,Mexico, from 1991 to 2000, and Durango,Mexico, from 1998 to 1999: overlap with type distribution within the United States

To examine the type distribution of pathogenic group A streptococcal (GAS) strains in Mexico, we determined the emm types of 423 GAS isolates collected from ill patients residing in Mexico (Durango or Mexico City). These included 282 throat isolates and 107 isolates from normally sterile sites. Of the other isolates, 38 were recovered from other miscellaneous infections. A total of 31 different emm types were found, revealing a broad overlap between commonly occurring emm types in Mexico and the United States. The information obtained in this study is consistent with the possibility that multivalent, M type-specific vaccines prepared for GAS strain distribution within the United States could theoretically protect against the majority of GAS strains causing disease in the two cities surveyed in Mexico.     

Phosphatidylinositol turnover and calcium movement in the rat pancreas

Carbamylcholine, bombesin, pancreozymin, and pentagastrin elicited a similar increase in amylase secretion and phosphatidylinositol turnover in rat pancreatic fragments. The concentration of each secretagogue that provoked half-maximal stimulation of amylase secretion was three to six times lower than that which induced half-maximal stimulation of phosphatidylinositol turnover. The increased turnover of phosphatidylinositols due to carbamylcholine or pancreozymin, but not the secretory response, persisted in a calcium-free medium or in 90% heavy water. The replacement of the media Na+ with Li+ increased an atropine-resistant turnover of phosphatidylinositols, but did not stimulate secretion. The ionophore A-23187 (in a medium containing 2.5 mM Ca2+) and 10 mM NaF induced a high secretory response, but exerted no effect on phosphatidylinositol turnover. K+ at a 70 mM concentration provoked a phosphatidylinositol effect and hypersecretion. Secretin, vasoactive intestinal peptide, dibutyryl cAMP, dibutyryl cGMP, 8-bromo cGMP, and N2-monobutyryl cGMP stimulated amylase secretion without an increased turnover of phosphatidylinositols. It is concluded that, in the rat pancreas, the increased turnover of phosphatidylinositols was directly associated with secretagogues inducing calcium movements.     

Activation of the alternative and classical complement pathways by Entamoeba histolytica

Entamoeba histolytica HM1 supported the activation of human alternative and classical complement pathways in the absence of ameba-reactive antibodies. Nonimmune serum depleted of C1q and factor D (NHS s C1q + D) and reconstituted with C1q was able to specifically deposit C3b onto trophozoites and produce lysis. This activity was not modified by the absorption of serum on E. histolytica. Serum depleted of factor B allowed C3b binding to amebae. Serum devoid of C4 effected only small amounts of C3 uptake. The kinetics of lysis of E. histolytica by serum in the presence of Mg-EGTA [ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid] (lacking classical pathway function) or by NHS s C1q + D and reconstituted with factor D was slow and only produced one-half the amount of lysis produced by NHS s C1q + D supplemented with C1q. These results indicate that the surface of the ameba can promote complement activation by the classical pathway, without the participation of specific antibodies, and that the magnitude of this activation is greater than that induced by the alternative pathway.