Treatment of severe, nonfulminant acute hepatitis B with lamivudine vs placebo: a prospective randomized double-blinded multicentre trial.

Acute hepatitis B virus (aHBV) infection can lead to fulminant liver failure, which likely is prevented by early lamivudine therapy. Even nonfulminant but severe acute hepatitis B can lead to significant morbidity and impaired quality of life. Therefore, lamivudine was evaluated in patients with severe aHBV in a placebo-controlled trial. Patients with severe aHBV infection (ALT >10× ULN, bilirubin >85 µm, prothrombin time >50%) were prospectively treated with lamivudine 100 mg/day or with placebo within 8 days after the diagnosis. The primary end point was time to bilirubin <34.2 µm. Secondary end points were time to clear HBsAg and HBV-DNA, development of anti-HBs and normalization of ALT. Eighteen cases were randomized to lamivudine, 17 to placebo. 94% of patients were hospitalized. No individual progressed to hepatic failure; all but one patient achieved the primary end point. Due to smaller than expected patient numbers, all study end points did not become statistically significant between treatment arms. Median time end points [in days] were bilirubin <34.2 µm (26.5 vs 32), ALT normalization (35 vs 48) and HBsAg clearance (48 vs 67) referring to earlier recovery under lamivudine, in contrast to loss of HBV-DNA (62 vs 54) and development of anti-HBs (119 vs 109). In all but two patients (one in every group), HBsAg clearance was reached in the study. Adverse events occurred more frequently during lamivudine therapy, but did not reach statistical significance. Lamivudine may ameliorate severe aHBV infection, but limited patient numbers prevented definite conclusions.

Abnormal prefrontal activity subserving attentional control of emotion in remitted depressed patients during a working memory task with emotional distracters.

BACKGROUND: Patients with major depressive disorder (MDD) show deficits in processing of facial emotions that persist beyond recovery and cessation of treatment. Abnormalities in neural areas supporting attentional control and emotion processing in remitted depressed (rMDD) patients suggests that there may be enduring, trait-like abnormalities in key neural circuits at the interface of cognition and emotion, but this issue has not been studied systematically. METHOD: Nineteen euthymic, medication-free rMDD patients (mean age 33.6 years; mean duration of illness 34 months) and 20 age- and gender-matched healthy controls (HC; mean age 35.8 years) performed the Emotional Face N-Back (EFNBACK) task, a working memory task with emotional distracter stimuli. We used blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) to measure neural activity in the dorsolateral (DLPFC) and ventrolateral prefrontal cortex (VLPFC), orbitofrontal cortex (OFC), ventral striatum and amygdala, using a region of interest (ROI) approach in SPM2. RESULTS: rMDD patients exhibited significantly greater activity relative to HC in the left DLPFC [Brodmann area (BA) 9/46] in response to negative emotional distracters during high working memory load. By contrast, rMDD patients exhibited significantly lower activity in the right DLPFC and left VLPFC compared to HC in response to positive emotional distracters during high working memory load. These effects occurred during accurate task performance. CONCLUSIONS: Remitted depressed patients may continue to exhibit attentional biases toward negative emotional information, reflected by greater recruitment of prefrontal regions implicated in attentional control in the context of negative emotional information.

[Musculoskeletal infections in the era of multiresistant pathogens]. / Muskuloskelettale Infektionen im Zeitalter multiresistenter Erreger.

The burden of musculoskeletal infections is permanently growing. A probable explanation for this development could be the increasing number of elderly people undergoing extensive surgery using implants and prosthetic devices while having more significant comorbidities (e.g. cardiovascular, metabolic and malignant). However, a relative reduction of acute (hematogenous) osteomyelitis compared to the occurrence of much more complex situations, such as diabetic foot syndrome or chronic osteitis and prosthetic implant infections is being observed. This poses new challenges for the clinician in managing these patients. Furthermore, there is the evolving threat of antimicrobial resistance as well as the increasing amount of infections with Gram-negative pathogens. Several aspects have to be considered for successful management of musculoskeletal infections: the site of infection and feasibility of local surgical treatment, the effectiveness of antimicrobial treatment, the inclusion of comorbidities and their specific treatment in an advanced therapeutic concept as well as the interdisciplinary approach led by surgeons and infectious disease specialists.

Lack of evidence for systemic cytomegalovirus reactivation in maintenance hemodialysis patients.

The risk of cytomegalovirus (CMV) reactivation among hemodialysis (HD) patients is unknown. In 52 HD patients from a single center, CMV serology and quantitative PCR were performed. The detection limit of PCR was 20 copies/ml. Here, PCR ruled out CMV viremia, despite CMV-IgM seropositivity in 15.4% patients.

Reducing the burden of influenza-associated complications with antiviral therapy.

INTRODUCTION: Influenza imposes an annual burden on individuals, society, and healthcare systems. This burden is increased by the development of complications that are often more severe than the primary infection. Here, we examine the main complications associated with influenza and review the effectiveness of antiviral therapy in reducing the incidence of such events. MATERIAL AND METHODS: The content of this review is taken from the study of the authors' extensive collection of reference materials, examination of the bibliographical content of relevant papers, and the results of Medline searches. RESULTS: The most commonly encountered complications in adults are sinusitis, pharyngitis, bronchitis, and, particularly in the elderly, bacterial pneumonia. Such complications may exacerbate pulmonary complaints. Children are particularly prone to post-influenza croup and otitis media. Complications involving the central nervous system, heart, or skeletal muscle also occur in influenza patients. Influenza-associated complications impose sizeable healthcare costs in terms of outpatient contacts, hospitalizations, and antibiotic use. Vaccination is the primary prevention strategy for influenza and its complications, but has limitations. Neuraminidase inhibitors have demonstrated efficacy in reducing the incidence of influenza-associated complications in populations with different ages and risks. CONCLUSIONS: Influenza complications place a large burden on healthcare providers and society. Neuraminidase inhibitors can reduce the incidence of such complications, particularly in high-risk groups.

[Polyuria]. / Polyurie--Pathogenese, Diagnostik und Therapie.

Beyond polyuria following psychogenic polydipsia, in a more narrow sense, this condition may be classified into impaired water re-absorption (i) due to tubular injury or (ii) relative or absolute loss of function of antidiuretic hormone (ADH). Tubular injury may be caused by different toxins affecting the ascending Henle loop as hypercalciuria, drugs and antibiotics as tubular necrosis. ADH deficiency, either absolute or relative, occurs with central or peripheral diabetes insipidus, which is based on synthesis failure or loss of peripheral efficacy of ADH due to receptor malfunction. Diagnosis of polyuria rests upon a thirst challenge in conjunction with laboratory studies of osmolality in serum and urine, which discloses the non-function of the hypothalamic-renal axis. Administration of ADH may differentiate between central and peripheral diabetes insipidus.

A dose comparison study of didanosine in patients with very advanced HIV infection who are intolerant to or clinically deteriorate on zidovudine. German ddI Trial Group.

OBJECTIVE: Zidovudine (ZDV) is the only antiretroviral drug which has been shown to reduce mortality in patients with symptomatic HIV disease, but its use is restricted by intolerance in a significant proportion of patients. Additionally, the efficacy of ZDV therapy appears to decrease after prolonged treatment particularly in the advanced stage of HIV disease. Therefore, alternative antiretroviral regimens for patients are needed. In this study, didanosine (ddI; 2',3'-dideoxyinosine), another HIV reverse transcriptase inhibitor, was evaluated. DESIGN: A total of 426 patients with AIDS or AIDS-related complex (ARC) who were intolerant to or clinically progressing on ZDV therapy and who had CD4+ cell counts < or = 150 x 10(6)/l were randomized to receive either a high (750 mg for bodyweight > or = 60 kg or 500 mg for bodyweight < 60 kg) or a low (200 mg and 134 mg, respectively) dose of ddI daily. SETTING: The patients were recruited from 31 German and Austrian AIDS clinical primary-care centres. RESULTS: The study was stopped after the second interim analysis due to a statistically significant difference in the incidence of pancreatitis (nine versus 26; relative risk, 2.92; P = 0.003) and neuropathy (28 versus 43; relative risk, 1.55; P = 0.05) in favour of the low dose. There was no difference between the low and high dosage groups in survival rate at 6 (80 versus 80%) and 12 months (61 versus 65%), number of deaths [82 (43.6 per 100 patient-years) versus 84 (44.4 per 100 patient-years)], progression from ARC to AIDS or to AIDS or death, or average number of new/recurrent opportunistic infections (2.8 versus 3.0 per patient). CONCLUSIONS: This study cannot conclude on ddI efficacy but it shows that in patients with advanced HIV disease for whom no alternative antiretroviral therapy is available and ddI therapy is considered, daily doses < 750 mg should be administered.

Effects of high-dose oral acyclovir on herpesvirus disease and survival in patients with advanced HIV disease: a double-blind, placebo-controlled study. European-Australian Acyclovir Study Group.

OBJECTIVE: To determine the efficacy of high-dose oral acyclovir in preventing cytomegalovirus (CMV) and other herpesvirus disease in patients with advanced HIV disease and to evaluate its effect on patient survival. DESIGN: Double-blind, placebo-controlled randomized trial of up to 1 year's therapy. SETTING: Outpatient clinics in 16 hospitals in Europe and Australia. PARTICIPANTS: A total of 302 patients with Centers for Disease Control and Prevention stage IV HIV disease, seropositive for CMV and with CD4+ lymphocyte counts < or = 150 x 10(6)/l. INTERVENTIONS: Oral acyclovir (800 mg, four times daily) or matching placebo for 48 weeks. MAIN OUTCOME MEASURES: Time to development of CMV and other herpesvirus disease. Following the results of another study, the protocol was amended to make survival a second major endpoint. RESULTS: Acyclovir failed to reduce the incidence of CMV disease: the probability of developing CMV disease at 1 year was 0.24 and 0.23 in the placebo and acyclovir groups, respectively (P = 0.53). However, acyclovir significantly reduced the probability of dying at 1 year of follow-up (from 0.39 to 0.23; P = 0.018). As expected, acyclovir significantly reduced the incidence and frequency of herpes simplex virus disease. There were no notable differences between treatment groups in clinically adverse experiences and no changes in haematological parameters to indicate clinically significant drug-induced toxicity. CONCLUSIONS: High-dose acyclovir failed to reduce the incidence of CMV disease, but significantly reduced the probability of dying at 1 year of follow-up.

Spectral power and coherence analysis of sleep EEG in AIDS patients: decrease in interhemispheric coherence.

Fifteen patients aged between 26 and 55 years with the acquired immunodeficiency syndrome (AIDS) and various cerebral manifestations of the disease underwent an all-night sleep electroencephalogram (EEG) registration. The recordings of 15 age-matched volunteers were examined as controls. Sleep stages were determined visually and the following spectral analysis was based on corresponding artifact-free 40-second periods. The sampling rate was 64 second-1, the spectral resolution was 0.25 Hz and the frequency ranged from 0.25-24 Hz. The power density spectra of eight EEG derivations (left and right frontopolar, frontal, central and occipital; reference montage to the ipsilateral Cb electrodes) and the coherence spectra of interhemispheric (interfrontal, interoccipital) and intrahemispheric (frontooccipital, left and right) channel pairs were computed. The power density of the patients in the 11.5-13-Hz frequency range of nonrapid eye movement (NREM) sleep was considerably lower than that of the controls (p < 0.05 and p < 0.01 at left and right frontal derivations, two-tailed Mann-Whitney U test). The power density of rapid eye movement (REM) sleep showed no consistent differences between the two groups. The interfrontal coherence of the whole frequency range below 12 Hz was markedly lower in the patient group. This applied to NREM sleep and also to REM sleep (p < 0.01 and p < 0.001 for different frequency bands between 1 and 12 Hz in NREM and REM sleep). Possible relations to clinical features are discussed.

Antiviral treatment and prophylaxis of influenza in primary care: German recommendations.

Antiviral drugs are a valuable supplementation to vaccines for the control and prevention of influenza. In Germany, for treating influenza amantadine, oseltamivir and zanamivir are approved. Amantadine and oseltamivir are also licensed for prophylactic use. On behalf of the Paul-Ehrlich-Society of Germany and the German Association for the Control of Virus Diseases, as two independent scientific societies, the first consensus Conference on the Antiviral Treatment and Prophylaxis of Influenza was held in June 2002. Based on the available data of clinical studies an expert group developed the following recommendations for the appropriate clinical use of the antiviral drugs: (1) since oseltamivir (orally administered) and zanamivir (administered by inhalation) have apparently similar clinical efficacy both drugs can be used alternatively for treatment. (2) Amantadine is not an alternative to the neuraminidase (NA) inhibitors because it is not effective against influenza B viruses, it frequently selects resistant virus mutants and it can cause adverse events. (3) When influenza is prevalent in the community patients with the clinical diagnosis of influenza should be treated with neuraminidase inhibitors if the symptoms are lasting not longer than 48 h. (4) Immunocompetent patients with a non-febrile illness and patients with a symptom history of more than 2 days should not be treated with antiviral drugs. (5) Although there are no data from clinical trials immunocompromised patients should also be treated when influenza has been diagnosed. (6) The prophylactic use of antiviral drugs can be recommended for persons with close contact to acutely ill persons and no recent vaccination against influenza. (7) The use of anti-influenza drugs have to be considered for prophylaxis in pandemics. A precondition for the adequate use of anti-influenza drugs in the primary medical care is the timely information on the local influenza situation delivered by surveillance systems.

Immunoglobulin G subclass preference of intrathecally produced HIV-specific oligoclonal antibodies.

Cerebrospinal fluid (CSF) and serum samples from 16 HIV-seropositive subjects were examined by ELISA and isoelectric focusing for the presence of HIV-specific immunoglobulin G (IgG) subclass antibodies. Autochthonous synthesis of IgG in the CSF was demonstrated in 11 patients. Intrathecally synthesized antibodies specific for individual HIV structural proteins were largely restricted to IgG1 (10 of 11 patients). One patient revealed additional local synthesis of IgG2 antibodies related to HIV-p15. In another patient locally produced antibodies specific for HIV consisted entirely of IgG4. In this patient amounts of locally produced antibodies were too low to be detected by routine procedures (calculation from an evaluation graph). No local synthesis of HIV-related IgG3 was demonstrated in any patient. Further studies will be needed to show whether determination of IgG-subclass-restricted antibodies to HIV is of prognostic value.

Meningovascular neurosyphilis in human immunodeficiency virus infection as a differential diagnosis of focal CNS lesions: a clinicopathological study.

The acquired immunodeficiency syndrome (AIDS) appears to alter the course of syphilis and particularly neurosyphilis. We report the case of an HIV-positive patient with two CNS lesions due to vascular complications of neurosyphilis of the meningovascular type, 18 months after he had developed a penile chancre. On admission, CT scans were inconsistent with cerebral toxoplasmosis or CNS lymphoma. At necropsy, histopathological examination showed typical Heubner's endarteritis of the basilar and posterior cerebral arteries. In AIDS patients, superadded meningovascular syphilis must be suspected, especially when CT scanning reveals the presence of multi-focal, low density lesions with the particular characteristics of infarction.

Acute and long-term efficacy of antituberculous treatment in HIV-seropositive patients with tuberculosis: a study of 36 cases.

Thirty-six consecutively observed HIV-seropositive patients with tuberculosis, including 31 patients with AIDS, who received antituberculous treatment, were followed up to evaluate its efficacy. Treatment with standard antituberculous regimens was intended except when an individual's condition required a modified therapeutic approach. Therapeutic failure occurred in five patients (14%) while on treatment, one also had a post-treatment relapse. Treatment failure was associated with drug resistance and non-compliance in three patients and in another two, both of whom died early in the course of their disease, with HIV-related conditions other than tuberculosis. The median relapse-free post-treatment follow-up time in 24 patients in whom treatment did not fail was 13 months (range 4-67). Standard antituberculous treatment is highly effective in the immediate and long-term treatment of HIV-related tuberculosis provided that drug susceptibility and treatment compliance are confirmed.

Isolation of atypical mycobacteria from tap water in hospitals and homes: is this a possible source of disseminated MAC infection in AIDS patients?

Infections caused by mycobacteria other than tuberculosis (MOTT), especially Mycobacterium avium complex (MAC), are common in AIDS patients, but rare in immunocompetent persons. The route of transmission is unknown, but tap water could provide a possible source of infection: MAC was isolated from tap water in the U.S.A. but this has not been reported in Germany. We therefore investigated tap water in Berlin for the presence of mycobacteria and compared radiometric (Bactec) and standard plate culture methods processing large volumes of water samples. The Bactec method yielded equal results compared to standard methods but had the advantage of easy handling. Mycobacteria were isolated from 50/118 (42.4%) samples and from 21/30 (70%) sites. The most frequently isolated species was Mycobacterium gordonae (from 28% samples and from 53.3% sites); MAC was isolated from two samples only (1.7%).

Twice-weekly pyrimethamine-sulfadoxine effectively prevents Pneumocystis carinii pneumonia relapse and toxoplasmic encephalitis in patients with AIDS.

OBJECTIVE: To evaluate the safety and efficacy of a fixed 25mg pyrimethamine--500mg sulfadoxine combination plus 15mg folinic acid given twice weekly for the prevention of relapses of Pneumocystis carinii pneumonia (PCP) and primary episodes of toxoplasmic encephalitis. METHODS: Ninety-five HIV-infected patients with successfully treated PCP and without history of toxoplasmic encephalitis were enrolled between January 1990 and October 1995 in a single-arm open-label prospective study. No patient was receiving highly active antiretroviral treatment, including protease inhibitors or non-nucleoside reverse transcriptase inhibitors, while on study medication. Efficacy was analysed on an "as-treated" basis. RESULTS: Five patients (5.3%) suffered a PCP relapse while on study medication, three of whom had been non-compliant. No relapse occurred in the first year. Probabilities of freedom from relapse were 0.96 after 24 months and 0.90 after 36 months. Of 69 patients positive for anti-toxoplasma IgG antibodies, one (1.5%) developed cerebral lesions compatible with toxoplasmic encephalitis after 50 months. Cutaneous allergic reactions were observed in 16 patients (16.8%) resulting in permanent discontinuation in six patients (6.3%). Two patients (2.1%) developed serious adverse reactions (Stevens-Johnson syndrome), both of whom had continued prophylaxis despite progressive hypersensitivity reactions. CONCLUSIONS: The prophylactic regimen used is effective in preventing PCP relapses and toxoplasmic encephalitis. The regimen appears to be safe. Severe adverse events can likely be prevented by discontinuation of prophylaxis at the time allergic reactions are noted. Rechallenge frequently results in tolerance of the regimen. Efficacy and safety compare favourably with previously studied regimens. This simple prophylactic regimen may provide a convenient alternative for patients unable to tolerate approved regimens.

Extracerebral toxoplasmosis in AIDS. Histological and immunohistological findings based on 80 autopsy cases.

Despite the great amount of literature concerning toxoplasmic encephalitis in AIDS patients, little is known about extracerebral toxoplasmosis. Therefore we conducted a study of 80 autopsy cases to estimate the frequency of extracerebral toxoplasmosis. A control group of 50 cases was completely negative for all markers applied. In 35 of the 80 AIDS-cases (43.7%), organisms could be detected. In 13 cases (16.2%) there was an extracerebral toxoplasmosis; 4 cases (5%) showed only extracerebral involvement and in 9 cases (11.2%), extracerebral toxoplasmosis occurred in combination with cerebral manifestations. In 22 cases (27.5%), only cerebral toxoplasmosis was found. The following organs were involved: cardiac muscle (15%), lungs (6.2%), liver (5%), pancreas (5%), gastrointestinal tract (6.2%), adrenal glands (5%), lymph nodes (5%) and testis (3.7%). In individual cases further organs, not mentioned above, were involved. Pseudocysts could be demonstrated within necroses and inflammatory foci by conventional staining, whereas trophozoites became apparent only immunohistologically.

[Histopathologically verified cerebral CT findings in AIDS]. / Histopathologisch verifizierte zerebrale CT-Befunde bei AIDS.

Computer tomographic and histopathological findings in 55 patients who died of the complications of acquired immunodeficiency syndrome, were reviewed retrospectively. In 23 patients (42%) an increased space of the internal or external cerebral spinal fluid was diagnosed. 20 patients (36%) had focal lesions. We differentiated between single, multiple and ring-shaped lesions with contrast enhancement and hypodense lesions. In 12 cases (22%) no CT abnormalities were found. Focal lesions proved to be secondary to toxoplasmosis in 85%. Single lesions were never caused by toxoplasmosis.

[Cerebral and meningeal manifestations of AIDS: sensitivity of CT and T2-weighted MRT (129 patients)]. / Zerebrale und meningeale Manifestation des AIDS: Sensitivität von CT und T2-gewichteter MRT (129 Patienten).

We studied 129 AIDS patients with suspected or proved intracranial manifestations of the disease. The purpose of this study was to compare the diagnostic sensitivity of unenhanced and contrast enhanced CT and unenhanced T2-weighted MR. In 35/129 patients CT and MR findings were normal. In 37/129 patients equivalent findings were obtained with both methods. Although CT and MR demonstrated intracranial pathology in 25 cases, MR was clearly superior. Six of these cases had solitary lesions in CT, while MR demonstrated multiple lesions. MR detected more foci than CT. In 24 patients with normal CT, MR detected intracranial manifestations of AIDS, namely solitary lesions in 8, multiple lesions in 12 and meningeal alterations in 4 patients. In only 8 patients with normal MR findings, CT revealed pathological contrast enhancement in 2 and parenchymal calcifications in 6 patients. Thus, in 20% of our patients MR but not CT was diagnostic. In another 20% MR provided additional diagnostic information. In conclusion, MR is recommended as the imaging modality of choice in AIDS patients with non-conclusive cranial CT.

Self-organization of spiking neurons using action potential timing.

We propose a mechanism for unsupervised learning in networks of spiking neurons which is based on the timing of single firing events. Our results show that a topology preserving behavior quite similar to that of Kohonen's self-organizing map can be achieved using temporal coding. In contrast to previous approaches, which use rate coding, the winner among competing neurons can be determined fast and locally. Our model is a further step toward a more realistic description of unsupervised learning in biological neural systems. Furthermore, it may provide a basis for fast implementations in pulsed VLSI (very large scale integration).

3D numerical simulations of negative hydrogen ion extraction using realistic plasma parameters, geometry of the extraction aperture and full 3D magnetic field map.

Decreasing the co-extracted electron current while simultaneously keeping negative ion (NI) current sufficiently high is a crucial issue on the development plasma source system for ITER Neutral Beam Injector. To support finding the best extraction conditions the 3D Particle-in-Cell Monte Carlo Collision electrostatic code ONIX (Orsay Negative Ion eXtraction) has been developed. Close collaboration with experiments and other numerical models allows performing realistic simulations with relevant input parameters: plasma properties, geometry of the extraction aperture, full 3D magnetic field map, etc. For the first time ONIX has been benchmarked with commercial positive ions tracing code KOBRA3D. A very good agreement in terms of the meniscus position and depth has been found. Simulation of NI extraction with different e/NI ratio in bulk plasma shows high relevance of the direct negative ion extraction from the surface produced NI in order to obtain extracted NI current as in the experimental results from BATMAN testbed.