HIV-positive men who have sex with men are at high risk of development of significant liver fibrosis after an episode of acute hepatitis C.

Acute hepatitis C virus infection remains a major health concern in human immunodeficiency virus(HIV)-infected men who have sex with men (MSM). New direct-acting antiviral agent (DAA) combination therapy has not yet been approved for the treatment for acute hepatitis C virus(HCV), thereby potentially causing deferral of HCV treatment. Therefore, we aimed to study the course of liver disease after an episode of acute HCV. This study is a retrospective single-centre cohort of HIV-positive MSM with acute HCV infection. Liver fibrosis was estimated by Fibroscan® and Fibrotest® . Liver-related and non-liver-related outcomes were documented. Overall 213 episodes of acute HCV infection in 178 men were documented. Median follow-up for all included patients was 38.7 months. Spontaneous HCV clearance was found in 10.8% of patients, which was significantly associated with older age, lower HCV RNA levels, and higher ALT levels upon initial acute HCV diagnosis. Treatment with interferon-based therapy was initiated in 86.3% of cases, resulting in a sustained virological response(SVR) rate of 70.7%. After 3 years' follow-up, significant liver fibrosis of METAVIR F2 stage or higher was found in 39.4% of patients after first acute HCV diagnosis. Higher age, physician-declared alcoholism, and nonresponse to acute HCV therapy were independently associated with higher fibrosis stages. Ten patients died during the observation period (IR 1.4/100 patient-years) and four during interferon treatment. Significant liver fibrosis is a common finding in HIV-positive MSM following acute HCV infection despite high treatment uptake and cure rates, suggesting the need for close liver disease monitoring particularly if HCV treatment is deferred.

High rates of quinolone-resistant strains of Shigella sonnei in HIV-infected MSM.

PURPOSE: There is increasing evidence that shigellosis is a predominantly sexually transmitted disease among men who have sex with men (MSM) and that infection with the human immunodeficiency virus (HIV) is a risk factor for shigellosis. METHODS: Retrospective analysis of antibiotic resistance profiles of Shigella species isolated from stool specimens of patients presenting with diarrhea from January 2010 to July 2012 in three German outpatient clinics specialized in HIV care. RESULTS: Among 79 cases of Shigella sonnei, 56 occurred in HIV-infected MSM, while 23 were observed in HIV-negative MSM. High resistance rates (>90%) were found for doxycycline, tetracycline, aminoglycosides, all cephalosporins of first and second generations tested, and trimethoprim/sulfamethoxazole. In total, 54% of cases were resistant to ciprofloxacin. Compared to negative subjects, HIV-infected MSM had a significantly higher rate of quinolone resistance. For ciprofloxacin, the resistance rates were 66 versus 24%, respectively (p = 0.0016). Individual resistance patterns did not indicate that this was due to a limited outbreak. Rates of resistance to other antibiotics than quinolones showed no differences between HIV-infected and HIV-negative cases. No resistance was found for carbapenems or newer cephalosporins such as ceftriaxone. CONCLUSIONS: The high rates of S. sonnei isolates resistant to quinolones and other traditional antibiotics are of concern. Innovative prevention efforts are urgently needed. The empirical use of quinolones in HIV-infected patients presenting with S. sonnei infection is no longer recommended.

Routine immunizations in adult renal transplant recipients.

BACKGROUND: Vaccination guidelines for transplant recipients include regular boosters of tetanus, diphtheria, and inactivated polio vaccine, but there are few published data on the efficacy of these vaccines in patients receiving immunosuppressive therapy. METHODS: Serum antibody values were evaluated before and 4 weeks after tetanus, diphtheria, and inactivated polio vaccination in 164 renal transplant recipients compared with healthy controls. Twelve months later, antibody levels were evaluated in 55 patients. RESULTS: Prebooster tetanus antitoxin values were lower in transplant recipients than in controls. All patients developed protective tetanus antibody levels (> or = 0.01 IU/ml) after vaccination. After 12 months, serum antibodies had decreased, but all patients maintained protective values. Diphtheria antitoxin titers before and after booster vaccination were lower in patients than in controls: 88.5% of patients and 96.2% of controls developed protective diphtheria antibody values. Twelve months after vaccination, diphtheria antitoxin values were below the protective level (0.1 IU/ml) in 38% of patients. Prebooster antibody values to poliovirus types 1 and 3 were comparable in patients and controls, whereas antibodies to poliovirus type 2 were lower in transplant recipients. Seroprotection rates and geometric mean antibody titers after vaccination were equivalent between the two groups for all three poliovirus types. No difference was observed in antibody levels between patients on different immunosuppressive drug regimens. Adverse reactions were significantly less often reported by transplant recipients. CONCLUSIONS: In transplant recipients, tetanus and inactivated polio vaccinations are well tolerated and induce protective antibody levels; diphtheria vaccination as currently recommended is less effective and protective antitoxin values decrease rapidly in these patients within 1 year after vaccination.

Upregulation of ICAM-I by Plasmodium falciparum: in vitro and in vivo studies.

AIMS: To monitor the expression of intercellular adhesion molecule I (ICAM-I) in vitro after stimulation of human macrophages with Plasmodium falciparum antigens, as well as the plasma concentrations of soluble ICAM-I (SICAM-I) in vivo in malarial patients. METHODS: Human mononuclear leucocytes were cultured and stimulated for four hours with 300 ng/ml exogenous P falciparum antigens. CD14 and CD54 (ICAM-I) expression was monitored using flow cytometry. Soluble ICAM-I (s ICAM-I) was also measured in the blood of 122 outpatients with malaria before and after treatment (Rio Branco, Acre, Brazil). RESULTS: ICAM-I expression increased from 15% to 375% after four hours of stimulation. When sICAM-I was analysed in the plasma of 122 patients with P falciparum or Plasmodium vivax malaria by enzyme immunoassay, significant increases were found. These were more pronounced in patients with P falciparum malaria, compared with healthy controls, and with the same patients four weeks after treatment. CONCLUSION: ICAM-I expression may also be upregulated in human macrophages by exogenous Plasmodium antigens as well as by cytokines during the acute phase of malaria. sICAM-I concentrations are downregulated after treatment, probably caused by the absence of circulating Plasmodium antigens.

Selective damage of hippocampal neurons in murine cerebral malaria prevented by pentoxifylline.

The effect of pentoxifylline, a phosphodiesterase inhibitor, was investigated on the development of cerebral malaria in Plasmodium berghei K 173 infected C57/B16 mice. No significant differences occurred in the course of parasitemia and survival time after infection between control mice and pentoxifylline treated mice. Moreover, no differences were observed between the groups with respect to the occurrence of cerebral malaria. The only striking difference was that pentoxifylline treatment selectively prevented neuronal cell damage in the sector CA1 of the hippocampus. These findings are in contrast to previous studies, where pentoxifylline prevented cerebral malaria in P. berghei ANKA infected CBA/Ca mice, another widely used model of cerebral malaria. Obvious differences exist between these models.

Prevalence and level of antibodies to the circumsporozoite proteins of human malaria parasites, including a variant of Plasmodium vivax, in the population of two epidemiologically distinct areas in the state of Acre, Brazil.

A seroepidemiological study of the prevalence of antibodies against the repeating epitopes of circumsporozoite (CS) proteins of human malaria parasites was conducted in 2 different areas in the state of Acre, Brazil in 1987 and 1990. In 1987 antibodies against the CS protein of the VK 247 variant Plasmodium vivax as well as antibodies against the CS proteins of P. falciparum and the classic P. vivax were found at relatively high rates in the 2 areas, but significant microepidemiological differences were observed. In 1990, when large scale migration in Amazonia had ceased and control measures were applied in the study areas, the malaria endemicity decreased, as determined by the declining prevalence of anti-sporozoite antibodies against all Plasmodium species, and the small number of individuals with positive blood smears. Antibodies against sporozoites of the variant P. vivax did not cross-react with the CS proteins of the classic P. vivax, nor with antibodies against sporozoites of P. falciparum and P. malariae. Sera containing antibodies against the CS protein of P. malariae were found at a very low frequency, and only in 1987. The anti-CS protein antibody response to all Plasmodium species was age-related.

Upregulation of ICAM-1, IL-1 and reactive oxygen intermediates (ROI) by exogenous antigens from Plasmodium falciparum parasites in vitro, and of sICAM-1 in the acute phase of malaria.

After 4 hours of stimulation of human mononuclear leukocytes in the presence of 300 ng/ml exogenous Plasmodium falciparum antigens, the ICAM-1 expression increased variably from 15% to 375%. Simultaneously, an increase of IL-1 mRNA production could be observed in Northern blot hybridizations with a specific cDNA gene probe for human IL-1 alpha labelled with digoxigenin. Furthermore, the reactive oxygen intermediates (ROI) production was also found to be enhanced in similar conditions. Additionally, when the levels of soluble ICAM-1 (sICAM-1) in plasma of 122 patients with P. falciparum or Plasmodium vivax malaria were analyzed in an enzyme immunoassay (EIA), significant sICAM-1 increases were found, more pronounced in patients with P. falciparum malaria, in comparison with healthy controls and with the same patients 4 weeks after chemotherapy. The presented results indicate that the expression of ICAM-1 may also be upregulated by exogenous Plasmodium antigens besides cytokines like IL-1 during the acute phase of malaria, with subsequently elevated sICAM-1 concentrations in blood.

Drug susceptibility of Plasmodium falciparum in the western Amazon region, State of Acre, Brazil.

Field studies in the western Amazon region (state of Acre, Brazil) indicate that the 4-aminoquinolines, as well as the combined regimen with sulfadoxine-pyrimethamine, can no longer be recommended for the treatment and prophylaxis of P. falciparum infections in this region. Quinine remains an effective drug when used correctly. However, compliance problems arise due to the often occurring side-effects during a ten day regimen. Prospects of overcoming these constraints by combining a short course of quinine with other drugs are limited, because of the lack of suitable partner compounds. For this reason quinine/clindamycin appears to be a more practical therapy of P. falciparum malaria. In vitro data from this study suggest that mefloquine is another effective alternative for the treatment of falciparum malaria in this Amazon region.

How much did cold shock and swimming failure contribute to drowning deaths in the fishing industry in British Columbia 1976-2002?

BACKGROUND: The Workers' Compensation Board of British Columbia requested a retrospective analysis of all fishermen's deaths from immersion in water in British Columbia. AIMS: To identify the underlying cause of drowning and make recommendations to improve safety in the fishing industry. METHOD: Eighty-nine inshore and offshore fishing accidents were analysed. Where possible, deaths were classified into the four stages of cold-water immersion: cold shock, swimming failure, hypothermia and post-rescue collapse. Other factors that led up to the drowning were also identified. RESULTS: One hundred and thirty fishermen died from immersion between 1976 and 2002. One hundred and twenty-eight drownings were certified by the coroner as drowning or drowning/hypothermia and two were certified as cardiac event after immersion. The underlying causes of drownings were reclassified as: cold shock (5.4%), swimming failure (5.4%), hypothermia (5.4%), post-rescue collapse (0.8%), cardiac event (0.8%) and drowning/other (10%). In the remaining 72.2% of deaths, there was insufficient information to determine an underlying cause. All deaths occurred in water below 17.5 degrees C but 95% were in water less than 15 degrees C. CONCLUSIONS: Immersion in water below 15 degrees C is dangerous and this should be emphasized on marine survival courses. Accident investigators, coroners and pathologists need a common checklist to record vital data. A recommended format is included as Supplementary data available at Occupational Medicine Online. Fishermen should be educated about the dangers of sudden, unexpected immersion in cold water. Consideration should be given to making marine survival courses mandatory for fishermen.

[Retrospective evaluation of western blot for detection of early HIV infections]. / Retrospektive Bewertung des Western Blot zur Erfassung früher HIV-Infektionen.

The purpose of HIV diagnosis is to establish safely whether there is an infection or not. The enzyme-linked immunosorbent assay (ELISA) as screening test, and the western blot assay for confirmation is the most widely used serologic test system to get this information. Diagnostic problems occur if the two tests yield different results. In our 1993 study 491 (4.4%) of 11,127 tested sera were reactive by ELISA. 39 (7.9%) of these samples could not be confirmed by western blot, giving negative or indeterminate results. In addition, 370 ELISA-negative samples were tested by HIV-1 western blot to detect the infection in the early stage. 115 (31%) of these sera showed indeterminate western blot patterns, the other samples were negative. Results of follow-up investigations of 26 (Table 1) or 11 (Table 2) persons with indefinite serodiagnosis were analysed. HIV infection was not detected in any of these cases. In the literature, persons whose sera were reactive according to ELISA and were indeterminate in western blot, had a 3-5% probability of an aisting HIV infection. In contrast, indeterminate western blot patterns in ELISA-negative sere were without significance for the prognosis as to whether a person was or was not HIV-infected.

Characterization of erythrocytic glucose-6-phosphate dehydrogenase in a mouse strain with reduced G6PD activity.

Erythrocytic glucose-6-phosphate dehydrogenase (G6PD) of a mutant mouse strain with X-linked G6PD-deficiency was purified and compared with the wildtype G6PD by biochemical and physiological characteristics. The red cell G6PD activity of the mutant was 20% of the wildtype. The Michaelis constant (Km) of the substrate glucose-6-phosphate (G6P) was higher (90 microM) for the mutant than for the wildtype (56 microM). The isoelectric focusing with a pH range from 3 to 10 showed one more enzymatically active band for the wildtype G6PD compared to the mutant enzyme. Other enzyme characteristics, however, such as Km for nicotinamide adenine dinucleotide phosphate (NADP), utilisation of 2-deoxy-glucose-6-phosphate (2dG6P) and deamino-NADP, heat stability, pH optimum, molecular weight, and glucose metabolisation via the pentosephosphate pathway were similar in mutant and wildtype enzyme.

[Evaluation of an enzyme immunoassay for the determination of the status of immunity against diphtheria before and after vaccination]. / Validierung eines Enzymimmunoassays zur Bestimmung des Diphtherieimmunstatus vor und nach Impfung.

PURPOSE: Assessment of an Easy-to-Perform Immunoenzymatic Assay for Detecting Diphtheria Immunity in the Population. Can an immunoassay replace or support the toxin neutralisation test? SERA AND METHODS: Sera of 75 adults were collected before and after vaccination and tested in the vero cell neutralisation test and the immunoassay. RESULTS: The sensitivity of the EIA was 73 and 94%, specificity was 74 and 67% before and after vaccination, respectively. Positive or negative predictive value was 70 and 96% or 78 and 49% before and after vaccination, respectively. The correlation coefficient changed from 0.43 to 0.77 after vaccination. A comparison of the quantitative results of the test showed differences up to 19 times in individual cases. CONCLUSIONS: Only cases with relatively high antibody titres (e.g. after booster vaccination) show EIA high sensitivity. Linear correlation is also high in such cases. If you expect low antitoxin levels as is the case before booster vaccination, EIA will then often be false positive or negative. Such studies should be limited to the neutralisation method.

Interference by antimalarial drugs with the in-vitro production of reactive nitrogen intermediates by murine macrophages.

The production of reactive oxygen intermediates (ROI) by host macrophages has long been recognized as an important defense mechanism against microorganisms. More recently, reactive nitrogen intermediates (RNI), also produced by activated macrophages, have been shown to be part of the host's first line of defense against malaria. In the present in-vitro study we have investigated the effects of antimalarial drugs on RNI production by murine macrophages stimulated by interferon-gamma (IFN-gamma) and/or malaria antigen, and on ROI production induced by phorbol myristate acetate. At concentrations exceeding the peak serum levels achieved with therapeutic dosages, chloroquine, in a dose-dependent manner, inhibited IFN-gamma- and malaria antigen-induced RNI production. Quinine, at a concentration of 10 mg/L also caused a significant reduction in IFN-gamma and malaria antigen-induced RNI synthesis; this concentration was well within the therapeutic range. High concentrations of artelinate significantly inhibited IFN-gamma-induced RNI production but clindamycin had no effect on RNI synthesis. In contrast, halofantrine, in concentrations attainable with therapeutic dosages, significantly enhanced IFN-gamma-induced RNI production. ROI production by murine macrophages was unaffected by the antimalarial drugs over the same concentration ranges. It remains to be determined whether these in-vitro effects of antimalarial drugs on RNI production also influence the clinical and parasitological response in patients with malaria.

Determinants of the immune response in visceral leishmaniasis: evidence for predominance of endogenous interleukin 4 over interferon-gamma production.

Accumulating evidence points toward an antagonism between TH1 and TH2 focused immune responses decisive for the outcome of parasitic infections with leishmaniae. Interferon-gamma (IFN-gamma) and interleukin 4 (IL4), the principal cytokines involved in these pathways, as well as IgE and the IgG subclasses differentially modulated by these cytokines, were therefore assessed in 18 Brazilian patients with visceral leishmaniasis. The results are compared to those of a local control group. IL4 was detected in all patient sera but in only one control. Low concentrations of IFN-gamma where detectable in 50% of the Brazilian controls but in only two patients. While group medians of mitogen-induced in vitro synthesis of IL4 and IFN-gamma were similar, release of these lymphokines correlated inversely in patients (Spearman's rho = -0.84). Elevations of serum IgE complement the lymphokine data to indicate prominent TH2 type responses in clinical infections with Leishmania donovani.

Antibody response in Plasmodium vinckei malaria after treatment with chloroquine and adjuvant interferon-gamma.

The antibody response of mice infected with Plasmodium vinckei after treatment with chloroquine either alone or in combination with interferon-gamma (IFN-gamma) was determined. Sequential serum samples were drawn from BALB/c mice receiving either 240 micrograms chloroquine on the day of infection or 120 micrograms chloroquine plus 10(4) units IFN-gamma daily for 11 days beginning on day 3 prior to infection. Mice treated with additional IFN-gamma showed an early induction of IgG2a response and a reduction in IgG1 antibodies as detected by the immunofluorescence technique at between 10 and 16 days after infection as compared with mice treated with chloroquine alone. Thus, IFN-gamma may partly exert its antimalarial activity via the induction of IgG2a antibody formation. At 4-6 weeks after infection, when mice from both groups resisted homologous re-infection, the predominant antibody isotypes found in both groups were IgG1 and IgG2a. Serum samples obtained from mice in both treatment groups at 6 weeks after infection were used for serum transfer experiments. When parasitised erythrocytes were preincubated with such immune serum, a retardation of the course of parasitaemia by 2 days was observed.

Interferon-gamma induced lethality in the late phase of Plasmodium vinckei malaria despite effective parasite clearance by chloroquine.

A combination therapy was tested consisting of chloroquine and interferon-gamma (IFN-gamma) in the late phase of blood-stage Plasmodium vinckei malaria in BALB/c mice. When mice were treated with three times 300 micrograms chloroquine at 24-h intervals starting at a parasitemia of 30%-50%, only 5 of 14 mice (36%) died 2-4 days after initiation of therapy. However, when infected mice received chloroquine plus 1 microgram IFN-gamma at the same time, 14 of 18 mice (78%) died 0.5-3 days after start of therapy (p < 0.05) despite clearance of parasitemia. The histopathology from mice dying after combination therapy revealed interstitial leukocyte infiltration of lung tissue, severe liver cell necrosis and kidney tubular necrosis. Pretreatment of P. vinckei-infected mice with pentoxifylline, a phosphodiesterase inhibitor, led to a significant decrease of IFN-gamma-induced lethality (p < 0.05). In contrast, pretreatment with neutralizing antibodies to tumor necrosis factor or with L-N-monomethyl arginine, the latter an inhibitor of the nitric oxide synthase, significantly increased lethality (p < 0.05).

Interferon-gamma enhances the effect of antimalarial chemotherapy in murine Plasmodium vinckei malaria.

Most nonimmune patients with Plasmodium falciparum infection are no longer cured by such standard antimalarial drugs as chloroquine. Thus, alternative treatment regimens are necessary. A combination therapy was tested consisting of a subcurative dose of chloroquine and interferon-gamma (IFN-gamma) in BALB/c mice with lethal Plasmodium vinckei malaria. Treatment with either agent alone prolonged median survival by 1-2 days compared with placebo-treated mice. However, a combination of 80 micrograms of chloroquine given at the time of infection plus 1 x 10(4) units of IFN-gamma/day for 11 days (starting 3 days before infection) cured 83% of infected mice. Moreover, these mice showed solid immunity when challenged with the homologous strain of P. vinckei. However, when these mice were infected with the heterologous strain of Plasmodium berghei, the same degree of parasitemia developed as did in P. berghei-infected control mice. Thus, the combination of chemotherapy with the cytokine IFN-gamma leads to substantial improvement of antimalarial treatment and to a rapid development of strain-specific immunity in murine P. vinckei malaria.

[High percentage of isolated anti-HBc-positive persons among prisoners]. / Hoher Prozentsatz isoliert anti-HBc-positiver Personen unter Strafgefangenen.

PURPOSE: Is the result "isolated Anti-HBc" higher among prisoners than in the normal population and can testing for HBV-DNA clarify the results? PATIENTS AND METHODS: In Berlin, 519 prisoners were serologically tested in 1994 for hepatitis-B and -C because of intravenous drug abuse and alcohol disease or signs of hepatitis. Beside virus antigen and antibodies, HBV-DNA was also measured by hybridisation technique or PCR. RESULTS: 50.3% of all individuals showed markers of hepatitis-B and 36.8% of hepatitis-C. 19.2% of persons with hepatitis B markers were positive for anti HBc only, i.e. more than twice as many than in the normal population. 90% of the isolated anti-HBc-positive Persons were also anti-HCV positive, which is nearly double the number of individuals with other patterns of HBV markers. Half of them were tested for HBV-DNA. Whereas the hybridisation technique failed to detect HBV-DNA, 36% of sera were found positive by HBV-PCR. CONCLUSION: This study shows again that the result "anti-HBc alone" is relatively frequent especially among prisoners. This pattern often seems associated with concurrent HCV-infection and in one third of the cases correlated with a chronic hepatitis-B. The result of an isolated anti-HBc should therefore always lead to further testing of anti-HCV and HBV-DNA by PCR.

Splenic interleukin 1 gene expression is associated with accumulation of macrophages and oxygen radical production in Plasmodium vinckei malaria.

High levels of interleukin 1 alpha (IL-1 alpha) were detected in vitro, in murine peritoneal macrophages stimulated with Plasmodium vinckei exogenous antigens, and in vivo, in sera of P. vinckei-parasitized mice. Moreover, high production of IL-1 alpha mRNA could be detected by in situ hybridization analysis in spleen sections of mice during the course of P. vinckei malaria. The observed IL-1 alpha gene expression in the spleen was associated with the accumulation of F4/80+ macrophages in the red pulp and in the marginal zone of follicles, as well as with the relative proportions of Mac-1+ cells in the spleen and the capacity of spleen cells to produce reactive oxygen intermediates during murine malaria.