Search

Platelets play a key role in hemostasis, inflammation, and cardiovascular diseases. Platelet reactivity is highly variable between individuals. The drivers of this variability in populations from Sub-Saharan Africa remain largely unknown.

Geographic variability in coagulation across populations and their determinants are poorly understood.

Background: Patients with hypertension may be vulnerable to vascular Chlamydia pneumoniae and/or cytomegalovirus (CMV) infection because of increased expression of adhesion molecules. Objective: To determine whether C pneumoniae or CMV is associated with the presence of atherosclerotic lesions in hypertensive patients. Methods: Ninety-six angiographic studies on 100 consecutive patients with of clinical signs or symptoms suggestive of renovascular hypertension were reviewed for the presence or absence of atherosclerotic lesions at the level of the renal arteries as well and abdominal aorta. Also, the presence of a hemodynamically notable renal artery stenosis and antibodies to C pneumoniae (IgG and IgA) and CMV (IgG and IgM) was determined, and all classic risk factors were recorded. Results: Atherosclerotic lesions were documented in 67 patients (70%), and in 49 patients (51%) such lesions were persent at the level of the renal artery. In the univariate analysis, significant associations between IgG (odds ratio, 3.8; 95% confidence interval, 1.2-11.7; P=.02) as well as IgA (odds ratio, 2.6; 95% confidence interval, 1.1-6.7; P=.03) antibodies to C pneumoniae and the presence of atherosclerosis were found for both the aorta and the renal arteries. Seroprevalence (IgG) to C pneumoniae in the 23 patients with a hemodynamically notable renal artery stenosis was 100% and differed (P=.01) from those without a notable renal artery stenosis (78%). In the multivariate analysis, IgG seropositivity to C pneumoniae was significantly associated with atherosclerosis (odds ratio, 6.0; 95% confidence interval, 1.33-27.5; P=.02), and age. There was no association between CMV seropositivity and atherosclerosis. Conclusion: The presence of antibodies to C pneumoniae was significantly associated with atherosclerosis and renovascular disease in hypertensive patients in whom a renal artery stenosis was strongly suspected.

Genetics play a significant role in coagulation phenotype and venous thromboembolism risk. Resistance to the anticoagulant activated protein C (APC) is an established risk for thrombosis. Herein, we explored the genetic determinants of thrombin generation (TG) and thrombomodulin (TM)‐modulated TG using plasma from the Human Functional Genomics Project.

Sub-Saharan Africa currently experiences an unprecedented wave of urbanization, which has important consequences for health and disease patterns. This study aimed to investigate and integrate the immune and metabolic consequences of rural or urban lifestyles and the role of nutritional changes associated with urban living. In a cohort of 323 healthy Tanzanians, urban as compared to rural living was associated with a pro-inflammatory immune phenotype, both at the transcript and protein levels. We identified different food-derived and endogenous circulating metabolites accounting for these differences. Serum from urban dwellers induced reprogramming of innate immune cells with higher tumor necrosis factor production upon microbial re-stimulation in an in vitro model of trained immunity. These data demonstrate important shifts toward an inflammatory phenotype associated with an urban lifestyle and provide new insights into the underlying dietary and metabolic factors, which may affect disease epidemiology in sub-Sahara African countries.

Supplemental Digital Content is available in the text

The intracellular proinflammatory mediator IL-32 is associated with tumor progression; however, the mechanisms remain unknown. We studied IL-32 mRNA expression as well as expression of other proinflammatory cytokines and mediators, including IL-1α, IL-1β, IL-6, IL-8, tumor necrosis factor (TNF)-α, the proangiogenic and antiapoptotic enzyme cyclooxygenase-2, the IL-8 receptor C-X-C chemokine receptor (CXCR) 1, and the intracellular kinase focal adhesion kinase-1. The interaction of IL-32 expression with expression of IL-6, TNF-α, IL-8, and cyclooxygenase-2 was also investigated. Biopsy specimens of 11 HIV-related, 7 non–HIV-related Kaposi sarcoma (KS), and 7 normal skin tissues (NSTs) of Dutch origin were analyzed. RNA was isolated from the paraffin material, and gene expression levels of IL-32 α, β, and γ isoforms, IL1a, IL1b, IL6, IL8, TNFA, PTGS2, CXCR1, and PTK2were determined using real-time quantitative PCR. Significantly higher expression of IL-32β and IL-32γ isoforms was observed in HIV-related KS biopsy specimens compared with non–HIV-related KS and NST. The splicing ratio of the IL-32 isoforms showed IL-32γ as the highest expressed isoform, followed by IL-32β, in HIV-related KS cases compared with non–HIV-related KS and NST. Our data suggest a possible survival mechanism by the splicing of IL-32γ to IL-32β and also IL-6, IL-8, and CXCR1 signaling pathways to reverse the proapoptotic effect of the IL-32γ isoform, leading to tumor cell survival and thus favoring tumor progression.

ABSTRACTIn patients with syphilis, central nervous system (CNS) involvement is often difficult to determine. In patients who also are infected with human immunodeficiency virus (HIV), this is even more challenging, as cerebrospinal fluid (CSF) pleocytosis can be attributed to HIV, syphilis, or both. Hence, this study investigated (i) CSF chemokine (C-X-C motif) ligand 13 (CXCL13) as a potential marker to diagnose neurosyphilis in HIV-infected individuals and (ii) the added value of CSF CXCL13 to conventional CSF biomarkers, such as the rapid plasma reagin test (RPR), in diagnosing neurosyphilis. We included 103 syphilis patients from two centers in The Netherlands: 47 non-HIV-infected patients and 56 HIV-infected patients. A positive CSF-RPR was regarded as the gold standard for neurosyphilis. CSF CXCL13 levels were significantly higher in neurosyphilis patients when neurosyphilis was diagnosed by CSF-RPR (P= 0.0002) than in the syphilis control group. The sensitivity and specificity of CSF CXCL13 (cutoff of 76.3 pg/ml) to diagnose neurosyphilis by using positive CSF-RPR as the gold standard were 50% and 90%, respectively. CSF CXCL13 had an added value to CSF-RPR positivity in 70% of HIV-positive patients and in 33% of HIV-negative patients. Our data show that CSF CXCL13 might be a potential additional marker in neurosyphilis when other markers are not conclusive. The added value of CSF CXCL13 measurement to the current neurosyphilis gold standard appears to benefit HIV-positive patients more than HIV-negative patients.

Opioid use may affect HIV infection through altered expression of HIV co-receptors. This was examined in Indonesia among antiretroviral therapy-naive HIV patients, many of whom use drugs. C-C chemokine receptor type 5 (CCR5) expression on CD4+cells was higher in heroin (P = 0.007), methadone (P = 0.024) and former opioid users (P = 0.003) compared to nonusers, whereas production of RANTES and other CCR5 ligands was similar or lower. This suggests that opioids can affect HIV susceptibility through up-regulation of CCR5 or down-regulation of its ligands.

Background To evaluate the effect of rifampicin-based tuberculosis (TB) treatment on the pharmacokinetics of efavirenz/tenofovir/emtricitabine in a fixed-dose combination tablet, and vice versa, in Tanzanian TB–HIV-coinfected patients.Methods This was a Phase II open-label multiple dose pharmacokinetic and safety study. This study was conducted in TB–HIV-coinfected Tanzanian patients who started TB treatment (rifampicin/isoniazid/pyrazinamide/ethambutol) at week 1 to week 8 and continued with rifampicin and isoniazid for another 16 weeks. Antiretroviral treatment (ART) of efavirenz/tenofovir/emtricitabine in a fixed-dose combination tablet was started at week 4 after initiation of TB treatment. A 24-h pharmacokinetic sampling curve was recorded at week 8 (with TB treatment) and week 28 (ART alone). For TB drugs, blood samples at 2 and 5 h post-dose were taken at week 3 (TB treatment alone) and week 8 (with ART).Results A total of 25 patients (56% male) completed the study; 21 had evaluable pharmacokinetic profiles. The area under the concentration–time curve 0–24 h post-dose of efavirenz, tenofovir and emtricitabine were slightly higher when these drugs were coadministered with TB drugs; geometric mean ratios (90% CI) were 1.08 (0.90, 1.30), 1.13 (0.93, 1.38) and 1.05 (0.85, 1.29), respectively. For TB drugs, equivalence was suggested for peak plasma concentrations when administered with and without efavirenz/tenofovir/emtricitabine. Adverse events were mostly mild and no serious adverse events or drug discontinuations were reported.Conclusions Coadministration of efavirenz, tenofovir and emtricitabine with a standard first-line TB treatment regimen did not significantly alter the pharmacokinetic parameters of these drugs and was tolerated well by Tanzanian TB patients who are coinfected with HIV.

Background Lopinavir/ritonavir-containing antiretro-viral therapy can cause hyperlipidaemia. However, most statins are contraindicated due to drug-drug interactions. Rosuvastatin undergoes minimal metabolism by CYP450, so no CYP450-based interaction with lopinavir/ritonavir is expected. This study explored the lipid-lowering effect of rosuvastatin and assessed the effect of lopinavir/ritonavir on the pharmacokinetics of rosuvastatin and vice versa.Methods HIV-infected patients on lopinavir/ritonavir (viral load <400 copies/ml) with total cholesterol (TC) >6.2 mmol/l were treated with rosuvastatin for 12 weeks, starting on 10 mg once daily. If fasting target values (TC<5.0 mmol/l, high-density lipoprotein-cholesterol >1.0 mmol/l, low-density lipoprotein-cholesterol [LDL-c] <2.6 mmol/l and triglycerides <2.0 mmol/l) were not reached, rosuvastatin was escalated to 20 mg or 40 mg at week 4 and 8, respectively. Plasma lopinavir/ritonavir trough levels (Cmin) were determined at week 0, 4, 8 and 12 and rosuvastatin Cmin, at week 4, 8 and 12.Results Twenty-two patients completed the study. Mean reductions in TC and LDL-c from baseline to week 4 (on rosuvastatin 10 mg once a day) were 27.6% and 31.8%, respectively. Lopinavir/ritonavir concentrations were not influenced by rosuvastatin (P=0.44 and 0.26, repeated-measures analysis). Median (interquartile range) rosuvastatin Cminfor 10 mg, 20 mg and 40 mg once daily were 0.97 (0.70–1.5), 2.5 (1.3–3.3) and 5.5 (3.3–8.8) ng/ml, respectively.Conclusions Rosuvastatin appeared to be an effective statin in hyperlipidaemic HIV-infected patients. Lopinavir/ritonavir levels were not affected by rosuvastatin, but rosuvastatin levels unexpectedly appeared to be increased 1.6-fold compared with data from healthy volunteers. Until safety and efficacy have been confirmed in larger studies, the combination of rosuvastatin and lopinavir/ritonavir should be used with caution.

OBJECTIVE: To report serious psychiatric symptoms after standard chloroquine treatment following human malaria infection induced for research.CASE SUMMARY: A 34-year-old healthy woman volunteered to participate in a study of malaria treatment. She was infected on day 0 with a chloroquine-susceptible strain of Plasmodium falciparumand was treated with a standard 3-day course of chloroquine from day 9 onward, following a positive blood smear (parasitemia 0.001%). On day 10, the blood smear became negative. On day 11, she developed a psychotic disorder not otherwise specified, most probably caused by chloroquine use, with symptoms of depersonalization and anxiety. The diagnosis of delirium was considered but ruled out because of clear consciousness with lack of diurnal fluctuations. She refused to take antipsychotic medication. Three weeks later, the woman still encountered serious concentration problems. All complaints gradually subsided over the next 4 months, after which she felt completely recovered. Plasma chloroquine concentrations were within the therapeutic range.DISCUSSION: Chloroquine may achieve high concentrations in the brain and has a long half-life. As quinolines, the antimalarials may have the same pathologic activity as the fluoroquinolone antibiotics in acting as N-methyl-D-aspartate agonists and γ-aminobutyric acid antagonists. Application of the Naranjo probability scale indicated that, in this patient, chloroquine was the probable cause of the serious psychiatric symptoms.CONCLUSIONS: Our unique observation demonstrates that serious psychiatric symptoms can emerge as a rare occurrence during standard chloroquine therapy. This adverse effect may persist for several months.

Efavirenz is currently regarded as an effective first-line treatment for HIV infection. It is therefore important that possible side effects are well investigated.

ABSTRACTWe report on a case of phaeohyphomycosis caused by Alternaria infectoriain a renal transplant recipient with pulmonary infiltrates and multiple skin lesions. Diagnosis was based on microscopy and culture of the skin lesions. Treatment consisted of a combination of surgical excision and systemic antifungal therapy, first with itraconazole and subsequently with liposomal amphotericin B, for 39 days. At a 20-month follow-up visit, no recurrence of the skin lesions or the pulmonary infiltrates had occurred.

Influenza-associated pulmonary aspergillosis (IAPA) has been reported increasingly since the advent of use of neuraminidase (NA) inhibitors following the 2009 influenza pandemic. We hypothesize that blocking host NA modulates the immune response against Aspergillus fumigatus. We demonstrate that NA influences the host response against A. fumigatus in vitroand that oseltamivir increases the susceptibility of mice to pulmonary aspergillosis. Oseltamivir impairs the mouse splenocyte and human peripheral blood mononuclear cell (PBMC) killing capacity of A. fumigatus, and adding NA restores this defect in PBMCs. Furthermore, the sialic acid-binding receptor SIGLEC15is upregulated in PBMCs stimulated with A. fumigatus. Silencing of SIGLEC15decrease PBMC killing of A. fumigatus. We provide evidence that host NA activity and sialic acid recognition are important for anti-Aspergillusdefense. NA inhibitors might predispose individuals with severe influenza to invasive aspergillosis. These data shed light on the pathogenesis of invasive fungal infections and may identify potential therapeutic targets.

Platelets are increasingly recognized to play a role in the complications of Streptococcus pneumoniaeinfections. S. pneumoniaeexpresses neuraminidases, which may alter glycans on the platelet surface.

ABSTRACTTo improve our understanding about the severity of invasive pneumococcal disease (IPD), we investigated the association between the genotype of Streptococcus pneumoniaeand disease outcomes for 349 bacteremic patients. A pneumococcal genome-wide association study (GWAS) demonstrated a strong correlation between 30-day mortality and the presence of the phage-derived gene pblB, encoding a platelet-binding protein whose effects on platelet activation were previously unknown. Platelets are increasingly recognized as key players of the innate immune system, and in sepsis, excessive platelet activation contributes to microvascular obstruction, tissue hypoperfusion, and finally multiorgan failure, leading to mortality. Our in vitrostudies revealed that pblBexpression was induced by fluoroquinolones but not by the beta-lactam antibiotic penicillin G. Subsequently, we determined pblBinduction and platelet activation by incubating whole blood with the wild type or a pblBknockout mutant in the presence or absence of antibiotics commonly administered to our patient cohort. pblB-dependent enhancement of platelet activation, as measured by increased expression of the α-granule protein P-selectin, the binding of fibrinogen to the activated αIIbβ3 receptor, and the formation of platelet-monocyte complex occurred irrespective of antibiotic exposure. In conclusion, the presence of pblBon the pneumococcal chromosome potentially leads to increased mortality in patients with an invasive S. pneumoniaeinfection, which may be explained by enhanced platelet activation. This study highlights the clinical utility of a bacterial GWAS, followed by functional characterization, to identify bacterial factors involved in disease severity.IMPORTANCEThe exact mechanisms causing mortality in invasive pneumococcal disease (IPD) patients are not completely understood. We examined 349 patients with IPD and found in a bacterial genome-wide association study (GWAS) that the presence of the phage-derived gene pblBwas associated with mortality in the first 30 days after hospitalization. Although pblBhas been extensively studied in Streptococcus mitis, its consequence for the interaction between platelets and Streptococcus pneumoniaeis largely unknown. Platelets are important in immunity and inflammation, and excessive platelet activation contributes to microvascular obstruction and multiorgan failure, leading to mortality. We therefore developed this study to assess whether the expression of pblBmight increase the risk of death for IPD patients through its effect on enhanced platelet activation. This study also shows the value of integrating extensive bacterial genomics and clinical data in predicting and understanding pathogen virulence, which in turn will help to improve prognosis and therapy.

We studied the relation between the occurrence of adverse reactions to trimethoprim-sulfamethoxazole (TMP-SMZ) prophylaxis and the subsequent course of human immunodeficiency virus (HIV) infection in a cohort of homosexual men. Adverse reactions to TMP-SMZ were associated with a more rapid progression to AIDS (P < .001) and death (P < .001) and with a more rapid decline in CD4+ cell counts (P = .001). The median time to progression to AIDS was 14.9 months in subjects with adverse reactions to TMP-SMZ and 32.5 months in those without adverse reactions. After exclusion of Pneumocystis carinii pneumonia (PCP) and toxoplasmosis from the case definition of AIDS, the differences in the rate of progression to AIDS between subjects with and without adverse reactions to TMP-SMZ were still highly significant (P = .004). A low CD4+ cell count at baseline and the use of antiretroviral agents before the start of prophylaxis were predictors of adverse reactions to TMP-SMZ but did not account for the difference in progression to AIDS between subjects with and without adverse reactions to TMP-SMZ. In a univariate analysis, the relative hazard of adverse reactions to TMP-SMZ for progression to AIDS was 2.54 (95% confidence interval [CI], 1.50–4.28); in a multivariate analysis, it was 2.21 (95% CI, 1.29–3.81). The relative hazards of adverse reactions to TMP-SMZ for progression to AIDS with the exclusion of PCP and toxoplasmosis, CD4+ cell counts of <50/mm3, and death were 2.16 (95% CI, 1.25–3.72), 2.37 (95% CI, 1.36–34.12), and 3.21 (95% CI, 1.80–5.72), respectively. It is unclear whether adverse reactions to TMP-SMZ induce or merely predict progression of HIV disease.