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: Introduction: There is paucity of data related to potential gender differences in the use of interventions to prevent and treat cardiovascular disease (CVD) among HIV‐positive individuals. We investigated whether such differences exist in the observational D:A:D cohort study. Methods: Participants were followed from study enrolment until the earliest of death, six months after last visit or February 1, 2015. Initiation of CVD interventions [lipid‐lowering drugs (LLDs), angiotensin‐converting enzyme inhibitors (ACEIs), anti‐hypertensives, invasive cardiovascular procedures (ICPs) were investigated and Poisson regression models calculated whether rates were lower among women than men, adjusting for potential confounders. Results: Women (n = 12,955) were generally at lower CVD risk than men (n = 36,094). Overall, initiation rates of CVD interventions were lower in women than men; LLDs: incidence rate 1.28 [1.21, 1.35] vs. 2.40 [2.34, 2.46]; ACEIs: 0.88 [0.82, 0.93] vs. 1.43 [1.39, 1.48]; anti‐hypertensives: 1.40 [1.33, 1.47] vs. 1.72 [1.68, 1.77] and ICPs: 0.08 [0.06, 0.10] vs. 0.30 [0.28, 0.32], and this was also true for most CVD interventions when exclusively considering periods of follow‐up for which individuals were at high CVD risk. In fully adjusted models, women were less likely to receive CVD interventions than men (LLDs: relative rate 0.83 [0.78, 0.88]; ACEIs: 0.93 [0.86, 1.01]; ICPs: 0.54 [0.43, 0.68]), except for the receipt of anti‐hypertensives (1.17 [1.10, 1.25]). Conclusion: The use of most CVD interventions was lower among women than men. Interventions are needed to ensure that all HIV‐positive persons, particularly women, are appropriately monitored for CVD and, if required, receive appropriate CVD interventions., Introduction HIV‐positive individuals are known to be at increased risk of cardiovascular disease (CVD) compared to the general population, partly due to an increased prevalence of some CVD risk factors, [...]

Background: The development of efficacious combination antiretroviral therapy (cART) has led to a dramatic decrease in mortality in HIV-positive patients. Specific data on the impact in HIV/hepatitis B virus (HBV)-coinfected patients are lacking. In this study, all-cause and cause-specific mortality risks stratified per era of diagnosis are investigated., Methods: Data were analyzed from HIV/HBV-coinfected patients enrolled in the ATHENA cohort between January 1, 1998, and December 31, 2017. Risk for (cause-specific) mortality was calculated using Cox proportional hazard regression analysis, comparing patients diagnosed before 2003 with those diagnosed ≥2003. Risk factors for all-cause and liver-related mortality were also assessed using Cox proportional hazard regression analysis., Results: A total of 1301 HIV/HBV-coinfected patients were included (14 882 person-years of follow-up). One-hundred ninety-eight patients (15%) died during follow-up. The adjusted hazard ratio (aHR) for all-cause mortality in patients diagnosed in or after 2003 was 0.50 (95% CI, 0.35-0.72) relative to patients diagnosed before 2003. Similar risk reduction was observed for liver-related (aHR, 0.29; 95% CI, 0.11-0.75) and AIDS-related mortality (aHR, 0.44; 95% CI, 0.22-0.87). Use of a tenofovir-containing regimen was independently associated with a reduced risk of all-cause and liver-related mortality. Prior exposure to didanosine/stavudine was strongly associated with liver-related mortality. Ten percent of the population used only lamivudine as treatment for HBV., Conclusions: All-cause, liver-related, and AIDS-related mortality risk in HIV/HBV-coinfected patients has markedly decreased over the years, coinciding with the introduction of tenofovir. Tenofovir-containing regimens, in absence of major contraindications, should be strongly encouraged in this population., (© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

For  n , d , w ∈ N , let  A ( n ,  d ,  w ) denote the maximum size of a binary code of word length  n , minimum distance  d and constant weight  w . Schrijver recently showed using semidefinite programming that A ( 23 , 8 , 11 ) = 1288 , and the second author that  A ( 22 , 8 , 11 ) = 672 and  A ( 22 , 8 , 10 ) = 616 . Here we show uniqueness of the codes achieving these bounds. Let  A ( n ,  d ) denote the maximum size of a binary code of word length  n and minimum distance  d . Gijswijt et al. showed that  A ( 20 , 8 ) = 256 . We show that there are several nonisomorphic codes achieving this bound, and classify all such codes with all distances divisible by 4., (© The Author(s) 2018.)

Despite advances in medical care, mortality due to cerebral Nocardia abscesses remains unacceptably high. The case of a typical immunocompromised patient, who deteriorated clinically despite optimal antimicrobial treatment, is reported here. Adjuvant immunotherapy with interferon-gamma resulted in partial restoration of the immune response and a corresponding clinical and radiographic recovery., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: As a result of effective combination antiretroviral therapy (cART) and advanced supportive healthcare, a growing number of human immunodeficiency virus (HIV)-infected children survive into adulthood. The period of transition to adult care is often associated with impaired adherence to treatment and discontinuity of care. We aimed to evaluate virological and social outcomes of HIV-infected adolescents and young adults (AYAs) before and after transition, and explore which factors are associated with virological failure., Methods: We included 59 HIV-infected AYAs from the Netherlands who had entered into pediatric care and transitioned from pediatric to adult healthcare. We used HIV RNA load and cART data from the Dutch Stichting HIV Monitoring database (1996-2014), and collected social and treatment data from patients' medical records from all Dutch pediatric HIV treatment centers and 14 Dutch adult treatment centers involved. We evaluated risk factors for virological failure (VF) in a logistic regression model adjusted for repeated measurements., Results: HIV VF occurred frequently during the study period (14%-36%). During the transition period (from 18 to 19 years of age) there was a significant increase in VF compared with the reference group of children aged 12-13 years (odds ratio, 4.26 [95% confidence interval, 1.12-16.28]; P = .03). Characteristics significantly associated with VF were low educational attainment and lack of autonomy regarding medication adherence at transition., Conclusions: HIV-infected AYAs are vulnerable to VF, especially during the transition period. Identification of HIV-infected adolescents at high risk for VF might help to improve treatment success in this group., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Amphotericin B deoxycholate (AmBd) is the recommended induction treatment for HIV-associated cryptococcal meningitis (CM). Its use is hampered by toxicities that include electrolyte abnormalities, nephrotoxicity, and anemia. Protocols to minimize toxicity are applied inconsistently. In a clinical trial cohort of AmBd-based CM induction treatment, a standardized protocol of preemptive hydration and electrolyte supplementation was applied. Changes in blood counts, electrolyte levels, and creatinine levels over 14 days were analyzed in relation to the AmBd dose, treatment duration (short course of 5 to 7 days or standard course of 14 days), addition of flucytosine (5FC), and outcome. In the 368 patients studied, the hemoglobin levels dropped by a mean of 1.5 g/dl (95% confidence interval [CI], 1.0 to 1.9 g/dl) following 7 days of AmBd and by a mean of 2.3 g/dl (95% CI, 1.1 to 3.6 g/dl) after 14 days. Serum creatinine levels increased by 37 μmol/liter (95% CI, 30 to 45 μmol/liter) by day 7 and by 49 μmol/liter (95% CI, 35 to 64μmol/liter) by day 14 of AmBd treatment. Overall, 33% of patients developed grade III/IV anemia, 5.6% developed grade III hypokalemia, 9.5% had creatinine levels that exceeded 220 μmol, and 6% discontinued AmBd prematurely. The addition of 5FC was associated with a slight increase in anemia but not neutropenia. Laboratory abnormalities stabilized or reversed during the second week in patients on short-course induction. Grade III/IV anemia (adjusted odds ratio [aOR], 2.2; 95% CI, 1.1 to 4.3; P = 0.028) and nephrotoxicity (aOR, 4.5; 95% CI, 1.8 to 11; P = 0.001) were risk factors for 10-week mortality. In summary, routine intravenous saline hydration and preemptive electrolyte replacement during AmBd-based induction regimens for HIV-associated CM minimized the incidence of hypokalemia and nephrotoxicity. Anemia remained a concerning adverse effect. The addition of flucytosine was not associated with increased neutropenia. Shorter AmBd courses were less toxic, with rapid reversibility., (Copyright © 2015 Bicanic et al.)

Background: Cryptococcal meningitis (CM) is a leading cause of HIV-associated mortality globally. High fungal burden in cerebrospinal fluid (CSF) at diagnosis and poor fungal clearance during treatment are recognized adverse prognostic markers; however, the underlying pathogenic factors that drive these clinical manifestations are incompletely understood. We profiled a large set of clinical isolates for established cryptococcal virulence traits to evaluate the contribution of C. neoformans phenotypic diversity to clinical presentation and outcome in human cryptococcosis., Methods: Sixty-five C. neoformans isolates from clinical trial patients with matched clinical data were assayed in vitro to determine murine macrophage uptake, intracellular proliferation rate (IPR), capsule induction, and laccase activity. Analysis of the correlation between prognostic clinical and host immune parameters and fungal phenotypes was performed using Spearman's r, while the fungal-dependent impact on long-term survival was determined by Cox regression analysis., Results: High levels of fungal uptake by macrophages in vitro, but not the IPR, were associated with CSF fungal burden (r = 0.38, P = 0.002) and long-term patient survival (hazard ratio [HR] 2.6, 95% CI 1.2-5.5, P = 0.012). High-uptake strains were hypocapsular (r = -0.28, P = 0.05) and exhibited enhanced laccase activity (r = 0.36, P = 0.003). Fungal isolates with greater laccase activity exhibited heightened survival ex vivo in purified CSF (r = 0.49, P < 0.0001) and resistance to clearance following patient antifungal treatment (r = 0.39, P = 0.003)., Conclusion: These findings underscore the contribution of cryptococcal-phagocyte interactions and laccase-dependent melanin pathways to human clinical presentation and outcome. Furthermore, characterization of fungal-specific pathways that drive clinical manifestation provide potential targets for the development of therapeutics and the management of CM., Funding: This work was made possible by funding from the Wellcome Trust (WT088148MF), the Medical Research Council (MR/J008176/1), the NIHR Surgical Reconstruction and Microbiology Research Centre and the Lister Institute for Preventive Medicine (to R.C. May), and a Wellcome Trust Intermediate fellowship (089966, to T. Bicanic). The C. neoformans isolates were collected within clinical trials funded by the British Infection Society (fellowship to T. Bicanic), the Wellcome Trust (research training fellowships WT069991, to A.E. Brouwer and WT081794, to J.N. Jarvis), and the Medical Research Council, United Kingdom (76201). The funding sources had no role in the design or conduct of this study, nor in preparation of the manuscript.

Background:  Cryptococcal meningitis (CM) is a leading cause of death in individuals infected with human immunodeficiency virus (HIV). Identifying factors associated with mortality informs strategies to improve outcomes., Methods:  Five hundred one patients with HIV-associated CM were followed prospectively for 10 weeks during trials in Thailand, Uganda, Malawi, and South Africa. South African patients (n = 266) were followed for 1 year. Similar inclusion/exclusion criteria were applied at all sites. Logistic regression identified baseline variables independently associated with mortality., Results:  Mortality was 17% at 2 weeks and 34% at 10 weeks. Altered mental status (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.7-5.9), high cerebrospinal fluid (CSF) fungal burden (OR, 1.4 per log10 colony-forming units/mL increase; 95% CI, 1.0-1.8), older age (>50 years; OR, 3.9; 95% CI, 1.4-11.1), high peripheral white blood cell count (>10 × 10(9) cells/L; OR, 8.7; 95% CI, 2.5-30.2), fluconazole-based induction treatment, and slow clearance of CSF infection were independently associated with 2-week mortality. Low body weight, anemia (hemoglobin <7.5 g/dL), and low CSF opening pressure were independently associated with mortality at 10 weeks in addition to altered mental status, high fungal burden, high peripheral white cell count, and older age. In those followed for 1 year, overall mortality was 41%. Immune reconstitution inflammatory syndrome occurred in 13% of patients and was associated with 2-week CSF fungal burden (P = .007), but not with time to initiation of antiretroviral therapy (ART)., Conclusions:  CSF fungal burden, altered mental status, and rate of clearance of infection predict acute mortality in HIV-associated CM. The results suggest that earlier diagnosis, more rapidly fungicidal amphotericin-based regimens, and prompt immune reconstitution with ART are priorities for improving outcomes.

The heart is involved in up to 50% of all patients with Churg-Strauss syndrome, but vasculitis of the coronary arteries has only been rarely documented. We present a young patient with severe coronary aneurysms and stenotic lesions due to a Churg-Strauss vasculitis. Prompt therapy with prednisone and cyclophosphamide resulted in the complete resolution of all lesions.

After an imported case of Marburg hemorrhagic fever was reported in 2008 in the Netherlands, control measures to prevent transmission were implemented. To evaluate consequences of these measures, we administered a structured questionnaire to 130 contacts classified as either having high-risk or low-risk exposure to body fluids of the case-patient; 77 (59.2%) of 130 contacts responded. A total of 67 (87.0%) of 77 respondents agreed that temperature monitoring and reporting was necessary, significantly more often among high-risk than low-risk contacts (p<0.001). Strict compliance with daily temperature monitoring decreased from 80.5% (62/77) during week 1 to 66.2% (51/77) during week 3. Contacts expressed concern about development of Marburg hemorrhagic fever (58.4%, 45/77) and infecting a family member (40.2%, 31/77). High-risk contacts had significantly higher scores on psychological impact scales (p<0.001) during and after the monitoring period. Public health authorities should specifically address consequences of control measures on the daily life of contacts.

The global burden of HIV-associated cryptococcal meningitis is estimated at nearly one million cases per year, causing up to a third of all AIDS-related deaths. Molecular epidemiology constitutes the main methodology for understanding the factors underpinning the emergence of this understudied, yet increasingly important, group of pathogenic fungi. Cryptococcus species are notable in the degree that virulence differs amongst lineages, and highly-virulent emerging lineages are changing patterns of human disease both temporally and spatially. Cryptococcus neoformans variety grubii (Cng, serotype A) constitutes the most ubiquitous cause of cryptococcal meningitis worldwide, however patterns of molecular diversity are understudied across some regions experiencing significant burdens of disease. We compared 183 clinical and environmental isolates of Cng from one such region, Thailand, Southeast Asia, against a global MLST database of 77 Cng isolates. Population genetic analyses showed that Thailand isolates from 11 provinces were highly homogenous, consisting of the same genetic background (globally known as VNI) and exhibiting only ten nearly identical sequence types (STs), with three (STs 44, 45 and 46) dominating our sample. This population contains significantly less diversity when compared against the global population of Cng, specifically Africa. Genetic diversity in Cng was significantly subdivided at the continental level with nearly half (47%) of the global STs unique to a genetically diverse and recombining population in Botswana. These patterns of diversity, when combined with evidence from haplotypic networks and coalescent analyses of global populations, are highly suggestive of an expansion of the Cng VNI clade out of Africa, leading to a limited number of genotypes founding the Asian populations. Divergence time testing estimates the time to the most common ancestor between the African and Asian populations to be 6,920 years ago (95% HPD 122.96 - 27,177.76). Further high-density sampling of global Cng STs is now necessary to resolve the temporal sequence underlying the global emergence of this human pathogen.

Background: Progress in therapy for cryptococcal meningitis has been slow because of the lack of a suitable marker of treatment response. Previously, we demonstrated the statistical power of a novel endpoint, the rate of clearance of infection, based on serial quantitative cultures of cerebrospinal fluid, to differentiate the fungicidal activity of alternative antifungal drug regimens. We hypothesized that the rate of clearance of infection should also be a clinically meaningful endpoint., Methods: We combined data from cohorts of patients with human immunodeficiency virus-associated cryptococcal meningitis from Thailand, South Africa, and Uganda, for whom the rate of clearance of infection was determined, and clinical and laboratory data prospectively collected, and explored the association between the rate of clearance of infection and mortality by Cox survival analyses., Results: The combined cohort comprised 262 subjects. Altered mental status at presentation, a high baseline organism load, and a slow rate of clearance of infection were independently associated with increased mortality at 2 and 10 weeks. Rate of clearance of infection was associated with antifungal drug regimen and baseline cerebrospinal fluid interferon-gamma levels., Conclusions: The results support the use of the rate of clearance of infection or early fungicidal activity as a means to explore antifungal drug dosages and combinations in phase II studies. An increased understanding of how the factors determining outcome interrelate may help clarify opportunities for intervention.

Objectives: To assess impact of serial lumbar punctures on association between cerebrospinal fluid (CSF) opening pressure and prognosis in HIV-associated cryptococcal meningitis; to explore time course and relationship of opening pressure with neurological findings, CSF fungal burden, immune response, and CD4 cell count., Design: Evaluation of 163 HIV-positive ART-naive patients enrolled in three trials of amphotericin B-based therapy for cryptococcal meningitis in Thailand and South Africa., Methods: Study protocols required four lumbar punctures with measurements of opening pressure over the first 2 weeks of treatment and additional lumbar punctures if opening pressure raised. Fungal burden and clearance, CSF immune parameters, CD4 cell count, neurological symptoms and signs, and outcome at 2 and 10 weeks were compared between groups categorized by opening pressure at cryptococcal meningitis diagnosis., Results: Patients with higher baseline fungal burden had higher baseline opening pressure. High fungal burden appeared necessary but not sufficient for development of high pressure. Baseline opening pressure was not associated with CD4 cell count, CSF pro-inflammatory cytokines, or altered mental status. Day 14 opening pressure was associated with day 14 fungal burden. Overall mortality was 12% (20/162) at 2 weeks and 26% (42/160) at 10 weeks, with no significant differences between opening pressure groups., Conclusion: Studies are needed to define factors, in addition to fungal burden, associated with raised opening pressure. Aggressive management of raised opening pressure through repeated CSF drainage appeared to prevent any adverse impact of raised opening pressure on outcome in patients with cryptococcal meningitis. The results support increasing access to manometers in resource-poor settings and routine management of opening pressure in patients with cryptococcal meningitis.

In a randomized controlled trial of amphotericin B-based therapy for human immunodeficiency virus (HIV)-associated cryptococcal meningitis in Thailand, we also compared the mycological efficacy, toxicity, and pharmacokinetics of oral versus intravenous flucytosine at 100 mg/kg of body weight/day for the initial 2 weeks. Half of 32 patients assigned to the two arms containing flucytosine were randomized to oral and half to intravenous flucytosine. Early fungicidal activity was determined from serial quantitative cultures of cerebrospinal fluid (CSF), and toxicity was assessed by clinical and laboratory monitoring. Flucytosine and fluorouracil concentrations in plasma and CSF were measured by high-performance liquid chromatography. No significant bone marrow or hepatotoxicity was seen, there was no detectable difference in bone marrow toxicity between patients on intravenous and those on oral formulation, and no patients discontinued treatment. In patients receiving intravenous flucytosine, the median 24-h area under the concentration-time curve was significantly higher than in the oral group. Despite this difference, there was no difference in early fungicidal activity between patients on intravenous compared with patients on oral flucytosine. The results suggest that either formulation can be used safely at this dosage in a developing country setting, without drug concentration monitoring. The bioavailability of the oral formulation may be reduced in late-stage HIV-infected patients in Thailand. Concentrations of flucytosine with intravenous formulation at 100 mg/kg/day may be in excess of those required for maximal fungicidal activity.

The pathophysiology of meningitis caused by Cryptococcus gattii in apparently immunocompetent individuals remains unclear. We measured multiple cytokines in CSF from a HIV-seronegative, apparently immunocompetent, Thai patient with C. gattii meningitis, over the first 2 weeks of antifungal therapy. Levels of proinflammatory IFN-gamma, TNF-alpha, and IL-6 were very low compared to patients with HIV-related Cryptococcus neoformans meningitis and of IL-10 very high. While patients with C. gattii meningitis may be a heterogeneous group, these data suggest in this case a maladapted immune response to cryptococcal exposure had allowed progression to clinical cryptococcal disease.

Reliable measures of antifungal drug susceptibility are needed. We tested the susceptibility of Cryptococcus neoformans from patients treated with amphotericin B. In vitro susceptibility employed a modified broth macrodilution method. We demonstrate a strong correlation between the quantitative measures of in vitro amphotericin B susceptibility and the quantitative response observed in patients.

Raised intracranial pressure in the absence of ventricular dilatation is common in cryptococcal meningitis and associated with increased mortality. We report the case of a patient with HIV-associated cryptococcal meningitis, who developed increasing CSF pressure and visual impairment on therapy despite serial lumbar punctures. Insertion of a temporary lumbar drain controlled the opening pressure and resulted in full visual recovery. The advantages and necessary precautions with this approach are reviewed, and alternative protocols for the use of lumbar drains discussed.

Pneumonia is a common manifestation of melioidosis, the disease caused by Burkholderia pseudomallei. In this study, we defined the prognostic significance of a positive sputum culture. A total of 712 patients presenting to Sappasithiprasong Hospital, Ubon Ratchathani, Thailand, with melioidosis between January 1992 and December 2002 had a sputum culture performed during admission, which was positive for B. pseudomallei in 444 patients (62%). The median duration of sputum positivity was 9 days (range, 1 to 49 days). Sputum cultures were negative in 32% of patients with radiologic changes suggestive of pulmonary involvement. Overall in-hospital mortality was 48%. A positive sputum culture was associated with mortality (adjusted OR 2.8, 95% CI: 1.9, 4.0; P < 0.001). This was independent of renal disease, a prior history of melioidosis, positive blood cultures, and other potential confounders. The presence of B. pseudomallei in the sputum of patients with melioidosis is associated with a poorer prognosis.

Cerebrospinal fluid (CSF) cryptococcal colony-forming unit counts and CSF cryptococcal antigen titers serve as alternative measures of organism load in cryptococcal meningitis. For these measures, we correlated baseline values and rates of decline during the first 2 weeks of therapy in 68 human immunodeficiency virus--seropositive patients with cryptococcal meningitis. At baseline, there was a strong correlation between CSF cryptococcal colony-forming unit counts and CSF cryptococcal antigen titers. During the first 2 weeks of therapy, CSF cryptococcal colony-forming unit counts decreased by >5 logs, and CSF cryptococcal antigen titers decreased by 1.5 dilutions. In individual patients, there was no correlation between the rate of decline in CSF cryptococcal colony-forming unit counts and that in CSF cryptococcal antigen titers.

In animal models, immunity to cryptococcal infection, as in many chronic fungal and bacterial infections, is associated with a granulomatous inflammatory response, intact cell-mediated immunity, and a Th1 pattern of cytokine release. To examine the correlates of human immunity to cryptococcal infection in vivo, we analyzed immune parameters at the site of infection over time and assessed the rate of clearance of infection by serial quantitative cerebrospinal fluid (CSF) fungal cultures in 62 patients in a trial of antifungal therapy for HIV-associated cryptococcal meningitis. CSF IL-6, IFN-gamma, TNF-alpha, and IL-8 were significantly higher in survivors compared with nonsurvivors. There were negative correlations between log TNF-alpha, IFN-gamma, and IL-6 levels and baseline cryptococcal CFU. Log IFN-gamma, G-CSF, TNF-alpha, and IL-6 were correlated positively with the rate of fall in log CFU/ml CSF/day. In a linear regression model including antifungal treatment group, baseline CFU, and these cytokines, only treatment group and log IFN-gamma remained independently associated with rate of clearance of infection. The results provide direct in vivo evidence for the importance of quantitative differences in IFN-gamma secretion in human immune control of granulomatous infections, and increase the rationale for adjunctive IFN-gamma in the treatment of refractory HIV-associated cryptococcosis.

Background: Although Cryptococcus neoformans is a fungal pathogen that causes human disease predominantly in the immunocompromised host, severe cryptococcal infections are occasionally encountered in apparently immunocompetent individuals. Activation of cellular immunity by proinflammatory cytokines plays a central role in anticryptococcal defense., Methods: We describe 2 patients with severe cryptococcal meningitis who appeared to have idiopathic CD4 lymphopenia. For these patients and for 4 healthy volunteers, ex vivo stimulation of whole blood with microbial stimuli was used to investigate putative defects in cytokine production capacity., Results: Assessment of the cytokine released from the 2 patients with CD4 lymphopenia revealed a defective production of the proinflammatory cytokines interferon (IFN)- gamma and tumor necrosis factor (TNF) but not of the anti-inflammatory cytokine interleukin-10 (IL-10). One patient with disease progression despite receipt of antifungal treatment was administered immunotherapy with recombinant IFN- gamma . Administration of recombinant IFN- gamma resulted in both restoration of immunological parameters and a sustained clinical recovery., Conclusions: Refractory meningitis may be due to defective TNF and IFN- gamma production, and IFN- gamma treatment may be useful in patients with an impaired cellular immune response and refractory cryptococcal meningitis.

Background: Patients with cryptococcal meningitis (CM) show elevated intracranial pressure (ICP) and blood-brain barrier (BBB) disruption in most cases. Elevated ICP is an important contributor to mortality. Vascular endothelial growth factor (VEGF) might be the mediator of BBB disruption during CM., Methods: We measured VEGF levels in serum, plasma, and cerebrospinal fluid (CSF) of 95 patients and 63 control subjects, and we analyzed the required trigger and cellular source of VEGF secretion in vitro., Results: Cryptococcus neoformans and its capsular antigens dose-dependently induced VEGF secretion by polymorphonuclear neutrophils, monocytes, and peripheral blood mononuclear cells (PBMCs). VEGF production by PBMCs induced by antigens strongly exceeded production by monocytes (P<.001). The addition of major histocompatibility complex class II antibody inhibited this production of VEGF (P=.005). Confirming the in vitro data, patients with CM showed significantly elevated VEGF levels in CSF (P<.001), plasma (P=.028), and serum (P<.001), compared with healthy control subjects. Calculated VEGF indices demonstrated that VEGF was produced intrathecally., Conclusions: Our findings suggest that VEGF plays a role in the pathophysiology of CM. We propose that CD4(+) T lymphocytes--stimulated by monocytes acting as antigen-presenting cells--are the cells that produce VEGF in response to cryptococcal antigens.

Leucine is known to enhance insulin secretion from islets of Langerhans, and insulin promotes leucine uptake in peripheral tissues. The present studies were designed to elucidate the effects of leucine on glucose responsiveness and stimulus secretion coupling in mouse islets of Langerhans. The effects of 20 mM leucine on insulin secretion and membrane potential were studied over a range of glucose concentrations (0-27.7 mM). Microdissected, perifused pancreatic islets from normal adult mice were used for both studies of insulin secretion and electrophysiology in order to make a close comparison between these measurements. Leucine enhanced the insulin secretion in the presence of 5.6, 11.1, and 22.2 mM glucose. In the presence of leucine, 27 mM glucose inhibited insulin secretion. In the absence of glucose-leucine did not induce electrical activity of the beta cell membrane, whereas in the presence of 5.6, 11.1, and 22.2 mM glucose leucine increased spike frequency. Thus, leucine shifts both the glucose-dependent insulin secretion and electrical activity toward lower glucose concentrations. It is concluded that leucine and glucose share a common metabolic pathway (citric acid cycle) for stimulatory effects. Leucine is deaminated to form 2-ketoisocaproic acid (KIC) and produce NH4+. We propose that in the absence of glucose this increases cytosolic pH, which in turn increases K+ permeability, and inhibits electrical activity and insulin secretion.