Chronic inflammatory effects of interleukin-1 on the blood-retina barrier.

The chronic effects of human recombinant IL-1 (hrIL-1) on the specialized vasculature of the central nervous system (CNS) and on the CNS itself have been examined over a 35-day period in the rabbit retina. A single intraocular injection of physiological levels of hrIL-1 (300 units) induced a biphasic inflammatory reaction with well-defined acute and chronic phases in the challenged eye. Quantitative histopathological examination of the vascularized portion of the retina in the IL-1-challenged eye documented a persistent mononuclear (MN) cell response that peaked 7-14 days post-challenge. Included in the MN cell count were perivascular plasma cells. Elevated protein levels in the vitreous persisted throughout the time points studied and alterations in vascular permeability of the epiretinal vessels were demonstrated by tracer leakage at 2 weeks post-challenge. The results show that exposure of the CNS-vasculature to IL-1 induces long-lasting inflammatory changes typical of a chronic inflammatory reaction.     

Pathophysiologic effect of interleukin-1b in the rabbit retina.

Interleukin-1 is a potent immunomodulator and has been shown to initiate many aspects of the inflammatory response. To determine the effects of IL-1b in the central nervous system (CNS), the rabbit retina was used, adjacent to which factors can be injected with minimal trauma and both pathologic and physiologic effects can be monitored. Intravitreal injection of 300 units of IL-1b induced an alteration in the visual evoked potentials (VEP) that was associated with marked intravascular red blood cell accumulations, hemorrhage, and cellular inflammation of the epiretinal vessels. Analysis of these events showed slowing and occasional hyper-excitability of the compound action potential of the optic tract and of the cortical VEP that correlate with the maximum inflammatory response. Histologic studies show the following: no apparent response occurs within the first 1.5 hours after intraocular challenge; and between 3 and 6 hours after injection an extensive intravascular red blood cell accumulation and progressive hemorrhage is accompanied by an increase in the number of mononuclear (MN) cells and the appearance of polymorphonuclear (PMN) cells. Polymorphonuclear cells continue to increase with time to give a single wave of inflammation that peaks 24 hours after injection, while the number of MN cells steadily increases. These events are associated with changes in the permeability of the blood-brain barrier and correlate with the electrophysiologic dysfunctions. Forty-one hours after injection, MN inflammation, reactive gliosis, and residual PMN inflammation are evident. Neutralization with specific antibody inhibited the responses through 6 hours after injection. It is concluded that the rabbit retina provides a valuable model for the in vivo analysis of CNS inflammation.     

Mechanisms of edema formation in experimental autoimmune encephalomyelitis. The contribution of inflammatory cells.

Most of the central nervous system (CNS) endothelium regulates the passage of solutes and functions as a blood-brain barrier (BBB). During experimental autoimmune encephalomyelitis (EAE), an inflammatory demyelinating disease of the CNS, loss of BBB function occurs. The authors have previously shown an increase in endothelial transcytotic activity associated with decreased mitochondrial content as evidence of BBB dysfunction in EAE. These changes occurred in the capillary bed and correlated with CNS edema and clinical signs. In the present report, a fixation procedure before infusion of the intravascular tracer horseradish peroxidase (HRP) in rats at the height of clinical EAE has been used. In these animals, tracer leakage was only noted in inflamed venules with diameters of 12 to 19 mu. The authors detected several mechanisms of passive leakage: 1) increased junctional permeability; 2) increased interendothelial space; 3) leakage alongside migrating inflammatory cells. Some small capillaries showed necrotic changes with minimal tracer leakage. This report demonstrates that BBB disruption also occurs via nonendocytic mechanisms that may be induced by inflammatory cells.     

Quantitative analysis of amino acid oxidation and related gluconeogenesis in humans.

Significant gaps remain in our knowledge of the pathways of amino acid catabolism in humans. Further quantitative data describing amino acid metabolism in the kidney are especially needed as are further details concerning the pathways utilized for certain amino acids in liver. Sufficient data do exist to allow a broad picture of the overall process of amino acid oxidation to be developed along with approximate quantitative assessments of the role played by liver, muscle, kidney, and small intestine. Our analysis indicates that amino acids are the major fuel of liver, i.e., their oxidative conversion to glucose accounts for about one-half of the daily oxygen consumption of the liver, and no other fuel contributes nearly so importantly. The daily supply of amino acids provided in the diet cannot be totally oxidized to CO2 in the liver because such a process would provide far more ATP than the liver could utilize. Instead, most amino acids are oxidatively converted to glucose. This results in an overall ATP production during amino acid oxidation very nearly equal to the ATP required to convert amino acid carbon to glucose. Thus gluconeogenesis occurs without either a need for ATP from other fuels or an excessive ATP production that could limit the maximal rate of the process. The net effect of the oxidation of amino acids to glucose in the liver is to make nearly two-thirds of the total energy available from the oxidation of amino acids accessible to peripheral tissues, without necessitating that peripheral tissues synthesize the complex array of enzymes needed to support direct amino acid oxidation. As a balanced mixture of amino acids is oxidized in the liver, nearly all carbon from glucogenic amino acids flows into the mitochondrial aspartate pool and is actively transported out of the mitochondria via the aspartate-glutamate antiport linked to proton entry. In the cytoplasm the aspartate is converted to fumarate utilizing urea cycle enzymes; the fumarate flows via oxaloacetate to PEP and on to glucose. Thus carbon flow through the urea cycle is normally interlinked with gluconeogenic carbon flow because these metabolic pathways share a common step. Liver mitochondria experience a severe nonvolatile acid load during amino acid oxidation. It is suggested that this acid load is alleviated mainly by the respiratory chain proton pump in a form of uncoupled respiration.(ABSTRACT TRUNCATED AT 400 WORDS)     

Copolymer effects on microglia and T cells in the central nervous system of humanized mice

The random amino acid copolymers FYAK and VWAK ameliorate EAE in a humanized mouse model expressing both a human transgenic myelin basic protein (MBP)85-99-specific T cell receptor and HLA-DR2. Here we show that microglia isolated from the central nervous system (CNS) of humanized mice with EAE induced by MBP85-99 and treated with these copolymers had reduced expression of HLA-DR, and thus reduced capacity to present MBP85-99 and activate transgenic T cells. In vitro microglia up-regulated empty HLA-DR2 upon activation with GM-CSF with or without LPS or IFN-gamma, but not with IL-4 or IL-10. Correspondingly, gene chip arrays showed that the CNS of untreated and YFAK-treated mice differentially expressed pro- and anti-inflammatory molecules during MBP85-99-induced EAE. Interestingly, microglia expressed the full-length gammabeta and alphabeta subunits of the tetrameric adaptor protein complexes AP-1 and AP-2 respectively, but after treatment with GM-CSF these complexes were cleaved, as had been found in immature dendritic cells derived from bone marrow. Strikingly, in vivo the perivascular lymphocyte infiltration seen in untreated mice immunized with MBP85-99 was composed of equal numbers of hVbeta2+ MPB85-99-specific transgenic and hVbeta2- endogenous T cells, while the much smaller infiltration seen after treatment with YFAK was composed predominantly of hVbeta2- endogenous T cells.     

Texting Lost-to-follow-up PrEP Patients from a San Francisco Sexual Health Clinic

It is critical to understand what happens when PrEP patients are lost-to-follow-up (LTFU) and, where appropriate, attempt to re-engage them in care with the goal of preventing future human immunodeficiency virus (HIV) acquisition. We evaluated the benefits and limitations of using text-based outreach to re-engage with LTFU PrEP patients and offer re-initiation of PrEP care. Using text-messaging, we surveyed San Francisco City Clinic patients who started PrEP from January 2015 to October 2019 and were LTFU by October 1, 2020. Our goals were to better understand (1) whether our patients remained on PrEP through another provider or source, (2) why patients choose to discontinue PrEP, and (3) whether text-based outreach could successfully re-engage such patients in care. Multiple-choice survey questions were analyzed quantitatively to determine the proportion of respondents selecting each option; free-text responses were analyzed qualitatively using an inductive approach to identify any additional recurring themes. Of 846 eligible survey recipients, 130 responded (overall response rate 15.4%). Forty-two respondents (32.3%) were still on PrEP through another provider while 88 (67.7%) were not. Common reasons for stopping PrEP included: COVID-19–related changes in sex life (32.3% of responses), concerns regarding side effects (17.7%), and the need to take a daily pill (8.3%). Free text responses revealed additional concerns regarding risk compensation. While 32 participants agreed to be contacted by City clinic staff for PrEP counseling, only 6 were reached by phone and none of the six subsequently restarted PrEP. We learned that text messaging is a possible approach to survey certain PrEP program participants to determine who is truly LTFU and off PrEP, and to better understand reasons for PrEP discontinuation. While such information could prove valuable as programs seek to address barriers to PrEP retention, efforts to improve acceptability and increase response rates would be necessary. We were less successful in re-engaging LTFU patients in PrEP care, suggesting that text-messaging may not be the optimal strategy for this purpose.

     

Differential chemokine induction by the mouse adenovirus type-1 in the central nervous system of susceptible and resistant strains of mice

Mouse adenovirus-type 1 (MAV-1) has recently been shown to cause a fatal hemorrhagic encephalopathy in certain strains of mice whereas other strains are resistant. Morbidity is associated with a productive infection of cerebrovascular endothelial cells, resulting in necrosis of the vasculature, infarction, hemorrhage and death within 4 - 6 days. Previous studies were not able to define a role for the innate or acquired immune response. In the current study we have addressed the effect of MAV-1 on chemokine and chemokine receptor expression in the central nervous system (CNS) and spleen of susceptible (C57BL/6) and resistant (BALB/c) strains of mice. Intra-peritoneal infection with MAV-1 in C57BL/6 animals resulted in early and prominent induction of IP-10/crg-2 in the spleen and CNS. Increased expression of MCP-1, MIP-1alpha, MIP-1beta and RANTES was also noted in the CNS of MAV-1-infected C57BL/6 animals commencing around 72 h post-infection. In contrast, chemokine expression in BALB/c animals was more restricted with prominent upregulation only of MIP-2 in the CNS. In situ hybridization identified the vascular endothelium and CNS glia as the principal site of IP-10/crg-2 production in the C57BL/6 animals. The chemokine receptors CCR1-5 were upregulated in the CNS of both strains of mice. These data show that productive infection of the CNS with MAV-1 leads to the upregulation of a characteristic pattern of chemokines and their receptors, which may point to a role for these factors in disease pathogenesis.     

Adolescents with Autism Spectrum Disorder Show a Circumspect Reasoning Bias Rather than ‘Jumping-to-Conclusions’

People with autism spectrum disorders (ASD) often take longer to make decisions. The Autism-Psychosis Model proposes that people with autism and psychosis show the opposite pattern of results on cognitive tasks. As those with psychosis show a jump-to-conclusions reasoning bias, those with ASD should show a circumspect reasoning bias. Jumping-to-conclusions was assessed in a sample of 20 adolescents with ASD and 23 age-matched controls using the jumping-to-conclusions beads task. Both groups demonstrated equivalent levels of confidence in decision-making, however the ASD group required more beads than controls before making their decision. Furthermore, there was a positive correlation between the beads required and degree of autism symptoms. Consistent with the Autism-Psychosis Model, a more circumspect reasoning bias was evident in ASD.     

Adverse dermatologic effects of cardiovascular drug therapy: part III

Cardiovascular disease is common, affecting an increasing number of persons as the population ages. To combat this growing health problem, physicians use a multitude of medications in the treatment of their patients. Although pharmacologic therapy greatly enhances quality of life for a majority of patients, there is always the potential for an unfavorable reaction. For example, cardiovascular drugs can induce a vast array of adverse dermatologic responses. This article reviews the various cutaneous reaction patterns that can occur as a result of treatment with vasodilators and other antihypertensive drugs, anticoagulants and antiplatelet drugs, thrombolytic agents, and lipid-lowering agents.