Lodderomyces elongisporus endocarditis in an intravenous drug user: a new entity in fungal endocarditis.

Lodderomyces elongisporus has been recently identified in the literature as an infrequent human bloodstream isolate, commonly mistaken for a non-albicans Candida. A case of Lodderomyces endocarditis in an intravenous drug user is described. To our knowledge, this report highlights the first documented case of Lodderomyces as a cause of endocarditis and summarizes the susceptibility patterns in the reported literature. All isolates reported so far have fluconazole MICs of ≤0.25 µg ml(-1).

Immune reconstitution inflammatory syndrome manifesting as development of multiple autoimmune disorders and skin cancer progression.

We report the case of a 56-year-old man with the rare autoimmune pathologies of alternating hypothyroidism and hyperthyroidism due to thyroid-stimulating hormone receptor antibodies, and rheumatoid arthritis as manifestations of a human immunodeficiency virus-related immune reconstitution inflammatory syndrome. The patient also developed overt progression of a pre-existing skin malignancy that may also be related. This case highlights immune reconstitution syndrome as an important differential diagnosis following antiretroviral therapy commencement, and that a high index of suspicion should be maintained for this rare but important cluster of conditions. Furthermore, the patient's genetic predisposition to autoimmunity provides helpful insights into the pathogenesis of these disorders.

Continuous and 4 h infusion of amphotericin B: a comparative study involving high-risk haematology patients.

OBJECTIVES: To assess whether a continuous infusion of amphotericin B (CI-AmB) is less nephrotoxic than a 4 h infusion in haematology patients with fever and neutropenia, including bone-marrow transplant recipients. Efficacy was assessed as a secondary end-point. PATIENTS AND METHODS: We conducted a retrospective cohort study over a 2 year period. A total of 1073 haematology admissions were reviewed (98.3% complete) and 81 admissions were eligible for study entry; 39 received CI-AmB and 42 a 4 h infusion of AmB. RESULTS: Renal impairment occurred significantly less frequently with CI-AmB compared with a 4 h infusion of AmB [10% versus 45%, respectively, odds ratio (OR) 0.14; 95% confidence interval (CI) 0.04-0.5, P < 0.001]. The difference was maintained among allogeneic transplant recipients (P = 0.007) and patients receiving concurrent nephrotoxic drugs (P < 0.001). An AmB infusion rate of <0.08 mg/kg/h was associated with a significant reduction in renal impairment (P < 0.001). A difference in survival was observed between the continuous and 4 h infusion of AmB (95% versus 79%, respectively, OR 5.1; 95% CI 1.02-25.1, P = 0.03). CONCLUSIONS: CI-AmB appears to be significantly less nephrotoxic than 4 h infusion AmB in haematology patients with fever and neutropenia--including high-risk bone-marrow transplant recipients--without increasing mortality. An AmB infusion rate of <0.08 mg/kg/h appears to be a safe threshold, associated with reduced renal impairment.

Coupling of the TCR to integrin activation by Slap-130/Fyb.

SLAP-130/Fyb (SLP-76-associated phosphoprotein or Fyn-binding protein; also known as Fyb/Slap) is a hematopoietic-specific adapter, which associates with and modulates function of SH2-containing leukocyte phosphoprotein of 76 kilodaltons (SLP-76). T cells from mice lacking SLAP-130/Fyb show markedly impaired proliferation following CD3 engagement. In addition, the T cell receptor (TCR) in SLAP-130/Fyb mutant cells fails to enhance integrin-dependent adhesion. Although TCR-induced actin polymerization is normal, TCR-stimulated clustering of the integrin LFA-1 is defective in SLAP-130/Fyb-deficient cells. These data indicate that SLAP-130/Fyb is important for coupling TCR-mediated actin cytoskeletal rearrangement with activation of integrin function, and for T cells to respond fully to activating signals.

Signaling networks regulating beta1 integrin-mediated adhesion of T lymphocytes to extracellular matrix.

T-cell recognition of foreign antigen and migration to specific anatomic sites in vivo involves transient adhesive contacts between beta1 integrins expressed on T cells and cell surface proteins or extracellular-matrix components. Engagement of the CD3-T-cell receptor (CD3-TCR) complex initiates a complex signaling cascade involving coordinated regulation and recruitment of tyrosine and lipid kinases to specific regions or microdomains in the plasma membrane. Although considerable attention has been focused on the signaling events by which the CD3-TCR complex regulates transcriptional events in the nucleus, CD3-TCR signaling also rapidly enhances integrin-mediated adhesion without increasing surface expression of integrins. Recent studies suggest that CD3-TCR signaling to beta1 integrins involves coordinated recruitment and activation of the Tec family tyrosine kinase Itk by src family tyrosine kinases and phosphatidylinositol 3-kinase. These signaling events that regulate integrin-mediated T-cell adhesion share both common and distinct features with the signaling pathways regulating interleukin-2 gene transcription.

A novel function for the Tec family tyrosine kinase Itk in activation of beta 1 integrins by the T-cell receptor.

Stimulation of T cells via the CD3--T-cell receptor (TCR) complex results in rapid increases in beta 1 integrin-mediated adhesion via poorly defined intracellular signaling events. We demonstrate that TCR-mediated activation of beta 1 integrins requires activation of the Tec family tyrosine kinase Itk and phosphatidylinositol 3-kinase (PI 3-K)-dependent recruitment of Itk to detergent-insoluble glycosphingolipid-enriched microdomains (DIGs) via binding of the pleckstrin homology domain of Itk to the PI 3-K product PI(3,4,5)-P(3). Activation of PI 3-K and the src family kinase Lck, via stimulation of the CD4 co-receptor, can initiate beta 1 integrin activation that is dependent on Itk function. Targeting of Itk specifically to DIGs, coupled with CD4 stimulation, can also activate beta 1 integrin function independently of TCR stimulation. Changes in beta 1 integrin function mediated by TCR activation of Itk are also accompanied by Itk-dependent modulation of the actin cytoskeleton. Thus, TCR-mediated activation of beta 1 integrins involves membrane relocalization and activation of Itk via coordinate action of PI 3-K and a src family tyrosine kinase.

Candida tropicalis vertebral osteomyelitis complicating epidural catheterisation with disease paralleled by elevated D-arabinitol/L-arabinitol ratios.

Deep-seated Candida infections are challenging to diagnose by noninvasive means, and new modalities are needed to improve the yield of such investigations. Reported here is a case of Candida tropicalis vertebral osteomyelitis complicating epidural catheterisation in a diabetic patient with complicated abdominal sepsis. The diagnosis was supported by detection of increased D-arabinitol/L-arabinitol ratios in urine samples, and failure of medical management was indicated by elevated D-arabinitol/L-arabinitol ratios, which later decreased to baseline with successful surgical debridement and prolonged antifungal therapy.

Activation-dependent changes in soluble fibronectin binding and expression of beta1 integrin activation epitopes in T cells: relationship to T cell adhesion and migration.

The relationship between activation-dependent changes in beta1 integrin conformation, T cell adhesion to immobilized fibronectin, and T cell migration in vitro was analyzed in this study. Stimulation of Jurkat T cells and peripheral T cells with Mn(2+), the activating beta1 integrin-specific monoclonal antibody (mAb) TS2 /16, CD2, or CD28 stimulation led to increased adhesion, soluble fibronectin (FN) binding and expression of the activation epitope defined by the beta1 integrin mAb HUTS-21. Phorbol 12-myristate 13-acetate treatment increased adhesion, but not soluble FN binding or HUTS-21 epitope expression. In peripheral T cells, CD3 or CD7 stimulation also led to increased adhesion, soluble FN binding and HUTS-21 epitope expression. Soluble FN blocked peripheral T cell adhesion induced by Mn(2+) or TS2/16, but had no effect on adhesion induced by the other integrin-activating signals. In contrast, migration induced by TS2/16, CD2, CD3, CD7 or CD28 stimulation was blocked by excess soluble FN. Phosphoinositide 3-OH kinase (PI 3-K) inhibitors blocked receptor-mediated increases in cell adhesion, but not soluble FN binding or HUTS-21 expression. Migration was similarly unaffected by PI 3-K inhibitors, with the exception of CD7- and CD28-induced migration, which was specifically blocked by LY294,002. These results suggest that activation-dependent changes in beta1 integrin conformation are PI 3-K-independent and are involved in T cell migration but not adhesion.

Protein meals reduce nausea and gastric slow wave dysrhythmic activity in first trimester pregnancy.

First trimester nausea is associated with gastric slow wave dysrhythmias (tachygastria, bradygastria). We tested the roles of meal composition and caloric content on nausea and slow wave rhythm in 14 nauseated pregnant women. Electrogastrography quantified dysrhythmic activity and signal power responses to meals. Symptomatic women reported mild to moderate nausea and exhibited increased dysrhythmias during fasting (P < 0.05). Protein-predominant meals reduced nausea and dysrhythmic activity to greater degrees than equicaloric carbohydrate and fat meals and noncaloric meals (P < 0.05). Meal consistency did not affect symptom responses, although liquid meals decreased dysrhythmias more than solids (P < 0.05). Carbohydrates and fats increased electrogastrographic power to similar degrees as proteins, whereas responses to noncaloric meals were less. In conclusion, protein meals selectively reduce nausea and gastric slow wave dysrhythmias in first trimester pregnancy. Meal consistency is a limited factor in the favorable effects of protein. Electrogastrographic power changes do not explain the symptom response to protein. Thus dietary modulation of gastric myoelectric rhythm with protein supplementation may provide symptomatic benefit in nausea of pregnancy.

Investigation of an outbreak of vancomycin-resistant Enterococcus faecium in a low prevalence university hospital.

BACKGROUND: Until 1995, there were no cases of vancomycin resistant enterococcus (VRE) identified at our university hospital. From May 1995 to August 1996, we investigated a cluster of 10 cases of phenotypic class Van B Enterococcus faecium. METHODS: Patients were matched with controls who were on the same unit for at least 7 days prior to the case developing VRE. Control patients were age and sex matched if possible, and had duration of hospitalization at least as long as the number of days it took the patient to become VRE positive. We analyzed 16 independent risk factors using Epi-info version 6. Environmental cultures were obtained in the MICU where 5 of the patients were located. All 10 patient isolates and environmental isolates were analyzed by pulsed field gel electrophoresis (PFGE). RESULTS: PFGE confirmed the genetic relatedness of all 10 patient isolates and environmental isolates. The VRE-positive group was more likely to be immunosuppressed and to have exposure to 3 physicians. In the MICU, significant, P < 0.05) risk factors for VRE were higher Apache scores, location adjacent to a VRE case, duration of vancomycin and amino-glycoside use, duration of invasive catheter use, and diarrhea. Among the VRE-positive environmental cultures was a blood pressure cuff wash that was used on several patients. CONCLUSION: We hypothesize that a VRE strain was introduced into our hospital environment and was spread by personnel or contaminated equipment. As a consequence of this study, a hospital-wide VRE policy was implemented.

HIV combination therapy: partial immune restitution unmasking latent cryptococcal infection.

OBJECTIVE: To describe two cases of cryptococcal meningitis and one re-exacerbation of Cryptococcus-associated meningitis occurring in temporal association with commencement of highly active antiretroviral therapy (HAART) in patients with advanced HIV infection (CD4 cells < 50 x 10(6)/l), which suggests that partial immune restitution can facilitate development of clinically apparent meningitis in response to Cryptococcus or its antigen. DESIGN: All HIV-infected patients with culture-proven cryptococcal meningitis diagnosed at a tertiary referral centre specialist infectious diseases unit from 1 January 1996 to 31 December 1996 were reviewed to examine the clinical and immunological parameters prior to and after commencing antiretroviral therapy. RESULTS: Three patients were diagnosed with clinically apparent meningitis within 7-39 days of changing or altering antiretroviral combination therapy consisting of zidovudine or stavudine, in combination with lamivudine and saquinavir. All patients had CD4 cell counts below 50 x 10(6)/l at initiation of therapy. Following institution of HAART, evidence of immune restitution was suggested by the following: (i) significant increases (3.7-14-fold) in numbers of CD4 cells (all three patients), (ii) significantly reduced (> 2-4 log10 reduction) HIV viral loads (two out of three patients), and (iii) prominent inflammatory changes in cerebrospinal fluid (white blood cells > 10 x 10(6)/l) at diagnosis (two out of three patients). CONCLUSIONS: Our report suggests that in patients with advanced HIV infection, partial immune restitution induced by HAART can precipitate onset of clinically apparent meningitis in those patients with latent cryptococcal central nervous system infection or with residual cryptococcal antigen present in the cerebrospinal fluid.

Differential symptomatic and electrogastrographic effects of distal and proximal human gastric distension.

Nausea and gastric dysrhythmias occur in conditions associated with gastric distension. The roles of distal and proximal gastric mechanoreceptors in these responses are unexplored. Because antral distension induces vomiting in animals and antral and fundic vagal afferent discharges differ, we hypothesized that distal gastric distension in humans leads to greater symptomatic and dysrhythmic responses than proximal distension. Symptoms and electrogastrograms were recorded in healthy humans during distal and proximal gastric distension with a barostat. Distal but not proximal distension induced nausea and a 747 +/- 250% increase in dysrhythmic power (P < 0.05), responses not affected by granisetron, indomethacin, or atropine, agents that block dysrhythmias in other settings. In the distal stomach, bloating and pain developed at lower pressures (P < 0.05) not modified by granisetron, and compliance was significantly lower (P < 0.05). In conclusion, gastric mechanoreceptor activation in the less-compliant distal stomach produces nausea and dysrhythmias via non-5-hydroxytryptamine3 (5-HT3), non-prostaglandin-dependent, and noncholinergic pathways. Distal mechanoreceptor activation induces greater bloating and pain than proximal mechanoreceptor activation via 5-HT3-independent pathways.

Differential 5-HT3 mediation of human gastrocolonic response and colonic peristaltic reflex.

Colonic motor function is modulated by extended and local neural reflexes involving unknown mediators. To test the role of serotonin (5-HT3) pathways, increases in colonic tone during antral distension and duodenal lipid perfusion (gastrocolonic responses) and changes in orad and caudad colonic tone in response to local colonic distension (peristaltic reflex) were measured after double-blind granisetron (10 microg/kg) or placebo infusion in healthy human volunteers. Antral distension evoked increases in colonic tone, which were blunted by granisetron (P < 0.05) without effects on antral compliance. Intraduodenal lipid perfusion also evoked increased colonic tone, which was reduced by granisetron (P < 0.05). In contrast, orad colonic contractions and caudad relaxations and contractions during colonic distension were unaffected by granisetron. In conclusion, 5-HT3 receptor antagonism blunts both the mechano- and chemoreceptor components of the human gastrocolonic response without altering antral compliance. In contrast, 5-HT3 pathways play no role in the ascending or descending components of the colonic peristaltic reflex. These findings demonstrate different roles for 5-HT3 receptors in the control of colonic motor function by the proximal gastrointestinal tract and by local neural reflexes.

Disseminated mycobacterium avium complex infection presenting as osteomyelitis in a normal host.

Disseminated Mycobacterium avium complex (MAC) infection presenting as a painful lytic femur lesion with associated fever, night sweats and weight loss occurred in a 45-y-old woman with apparent normal immune function. Surgical drainage and 24 months of medical therapy resulted in a cure.

Chlamydia species infect human vascular endothelial cells and induce procoagulant activity.

BACKGROUND: Chlamydia pneumoniae infections have been linked with myocardial infarction, stroke, and the development of atherosclerosis by epidemiologic studies, immunohistochemical studies, and electron microscopic studies. The mechanisms underlying this association are unknown. METHODS: Using cultured human venous endothelial cells, we investigated whether C pneumoniae, C trachomatis (types H and L2/434/BU) could infect these cells. The ability of infected cells to express procoagulant (tissue factor) activity was also measured using clotting and chromogenic substrate assays. Adhesion of platelets to chlamydia-infected cells was also quantitated. RESULTS: We found that C pneumoniae, C trachomatis type H, and C trachomatis L2/434/BU could infect cultured human umbilical vein endothelial cells and stimulate a 4-fold increase in expression of tissue factor, which reached a peak 18 hours postinfection. Tissue factor expression was enhanced even in the presence of tetracycline, suggesting that the chlamydial factor responsible for stimulating synthesis of endothelial cell tissue factor was preformed. Platelet adhesion was significantly enhanced when endothelial cells were infected by chlamydia species. CONCLUSIONS: These in vitro studies suggest possible pathogenic mechanisms that may explain the association of thrombotic events with C pneumoniae infection, including pathologically enhanced production of tissue factor by human endothelial cells and enhanced focal platelet deposition.