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(Val)ganciclovir is used to treat cytomegalovirus (CMV) infection following solid organ (SOT) or hematopoietic stem cell (HSCT) transplantation. Treatment failures occur, but the contribution from 39 known ganciclovir‐related mutations (GRMs) in the CMV‐UL97 gene remains controversial. We propose a categorization of these GRMs potentially useful when interpreting sequence analyses in clinical settings. The UL97 gene was sequenced from first/recurrent CMV infections among consecutive SOT or HSCT recipients during 2004–2009. GRMs were categorized as: Signature GRM (sGRM) if in vitroganciclovir IC50ratio for mutated versus wild‐type virus >2 (n = 24); polymorphic GRM (pGRM) if ratio <2 (n = 15). (Val)ganciclovir treatment failure was defined as persistent viremia for 30 days or switch to foscarnet within this period. Of 99 (49 HSCT and 50 SOT) recipients with one CMV infection episode, 15 (13 HSCT and 2 SOT) experienced a total of 19 recurrent infection episodes. The prevalence of sGRM was 0% at start of first episode, whereas at start of recurrent episodes, prevalence was 37%. Only one sGRM was present at a time in individual patients. Patients with CMV containing an sGRM (vs. wild type)—but not with a pGRM—were at excess risk of treatment failure (odds ratio = 70.6 [95% CI:8.2–609.6]; p < 0.001). sGRMs emerged only following longer termed use of antiherpetic drugs and usually in recurrent CMV infection episodes. Risk of ganciclovir treatment failure was raised if an sGRM was detected.

Objective: This preliminary study examined nighttime eating behavior among patients with bulimia nervosa (BN). Method: The nighttime eating behavior of 31 females (age: 17–49 yr) enrolled in an outpatient cognitive-behavioral treatment study for BN was assessed with the Night Eating Questionnaire (NEQ); patient subgroups were compared on the NEQ, Beck Depression Inventory, and Eating Disorder Inventory, and effect sizes were derived. Results: Nighttime eating behavior was common. Sixteen patients (52%) reported evening hyperphagia, nocturnal ingestions of food, or both night eating behaviors. Clinically interesting patterns emerged on symptom assessments, although effect sizes were small. Discussion: The nighttime eating behavior of individuals with eating disorders should be examined further. These preliminary findings suggest that current conceptualizations of the night eating syndrome are limited by research which has often excluded patients with primary diagnoses of eating disorders.

The use of mechanical ventilation (MV) for AIDS-related Pneumocystis carinii pneumonia (PCP) has varied over time. The introduction of adjunctive corticosteroid therapy has changed the patophysiology of PCP. In the present study, we attempted to identify factors predictive of severe respiratory failure requiring MV amongst patients with PCP treated in the era of adjunctive corticosteroid therapy. Furthermore, we studied factors associated with survival in relation to MV. Of 170 consecutive patients with AIDS-related PCP, 18 (11%) required MV. Thirteen of 18 ventilated patients died (72%). In a logistic regression analysis, higher age, increased brnchooalveolar lavage (BAL) neutrophilia and a positive BAL cyto megalovirus CMV culture were associated with the need of MV. In multivariate analyses, only BAL neutrophilia remained independently predictive of mechanical ventilation. In conclusion, short-term mortality remained high after the introduction of adjunctive corticosteroid therapy. BAL neutrophilia may be a useful prognostic marker to identify patients at high risk of requiring mechanical ventilation. Copyright 2001 Harcourt Publishers Ltd.

Data were collected on 6578 patients diagnosed with AIDS at 52 clinical centres in 17 European countries during an 11-year period from 1979 to 1989. The centres were divided into four regions, North, Central, Southeast, and Southwest. Differences in the incidence of most AIDS-defining opportunistic infections and malignancies were found. After adjusting for known possible confounders, statistically significant differences between regions remained. Pneumocystis carinii pneumonia (PCP) was more common in Northern Europe, Kaposi's sarcoma and toxoplasmosis in Central Europe, cytomegalovirus retinitis in South-eastern Europe, and extrapulmonary tuberculosis in South-western Europe. These differences we attribute primarily to different degrees of exposure to the respective underlying pathogens. The prevalence of these and other micro-organisms will determine the clinical course of HIV infections in parts of Eastern Europe and elsewhere where the virus now is spreading.

The polysaccharide fucoidin is a selectin blocker that inhibits leukocyte recruitment into the cerebrospinal fluid (CSF) during experimental pneumococcal meningitis. In the present study, the effect of fucoidin treatment on the release of the proinflammatory cytokines tumor necrosis factor alpha (TNF-alpha), interleukin-1 (IL-1), and IL-8 into the CSF was investigated. Rabbits (n = 7) were treated intravenously with 10 mg of fucoidin/kg of body weight every second hour starting 4 h after intracisternal inoculation of approximately 10(6) CFU of Streptococcus pneumoniae type 3 (untreated control group, n = 7). CSF samples were obtained every second hour during a 16-h study period. Treatment with fucoidin caused a consistent and significant decrease in CSF IL-1 levels (in picograms per milliliter) between 12 and 16 h (0 versus 170, 0 versus 526, and 60 versus 1,467, respectively; P < 0.02). A less consistent decrease in CSF TNF-alpha levels was observed in the fucoidin-treated group, but with no significant difference between the two groups (P > 0.05). In contrast, there was no attenuation in CSF IL-8 levels. Indeed, there was a significant increase in CSF IL-8 levels (in picograms per milliliter) in the fucoidin-treated group at 10 and 12 h (921 versus 574 and 1,397 versus 569, respectively; P < 0.09). In conclusion, our results suggest that blood-derived leukocytes mainly are responsible for the release of IL-1 and to some degree TNF-alpha into the CSF during pneumococcal meningitis, whereas IL-8 may be produced by local cells within the brain.

A possible immunomodulatory role of granulocyte colony-stimulating factor (G-CSF) was investigated in an experimental pneumococcal meningitis model in rabbits. Animals were pretreated with G-CSF (10 micrograms/kg subcutaneously twice a day) starting 48 h before in vivo and ex vivo experiments, causing a five- to six-fold increase in the peripheral leukocyte level. Meningitis was induced by intracisternal inoculation of approximately 4 x 10(5) CFU of Streptococcus pneumoniae type 3. Neutrophil pleocytosis and interleukin-8 (IL-8) levels were significantly attenuated in G-CSF-pretreated animals compared to untreated animals (P < 0.05). Furthermore, G-CSF pretreatment significantly delayed alterations in cerebrospinal fluid (CSF) tumor necrosis factor alpha and IL-1beta levels, as well as protein and glucose levels (P < 0.05). No difference in CSF bacterial concentrations was found, whereas the blood bacterial concentration was significantly decreased in G-CSF-pretreated animals (P < 0.05). Ex vivo chemotaxis of neutrophils isolated from G-CSF-pretreated animals was significantly decreased compared to that of neutrophils from untreated animals (P < 0.05). In conclusion, G-CSF pretreatment attenuates meningeal inflammation and enhances systemic bacterial killing. Further preclinical studies are required to investigate whether this may affect the clinical course of meningitis and thus whether G-CSF treatment may have a beneficial role in pneumococcal meningitis.

IgG and IgM antibodies to a purified humanPneumocystis carinii surface antigen (gp95) were measured in 694 serum specimens from two different population groups using an EIA technique. In a population of 441 patients with no evidence of immunosuppression, the percentage of persons positive for IgG antibodies to gp95 was significantly lower in the age group 1 to 9 years (30 %, 23/77) compared to persons 10 to 19 years old (56 %, 49/88). In the age group 1 to 14 years there was a significant correlation between the percentage of persons with IgG antibodies to gp95 and age. In 106 consecutive patients under evaluation due to atypical pneumonia, 76 patients showed no change in the titre of antibodies toLegionella spp. orMycoplasma pneumoniae in two consecutive serum samples. Three of these 76 patients (4 %) demonstrated an increase in the level of IgG antibodies to gp95 in the paired samples. One of these patients had a verifiedPneumocystis carinii pneumonia, and the two others were elderly men in whom no microbiological diagnosis of the pneumonia was established. Thus, it is concluded that IgG antibodies to gp95 develop in the majority of nonimmunosuppressed persons before the age of 13. Furthermore,Pneumocystis carinii pneumonia should be considered in the differential diagnosis in patients suspected of having atypical pneumonia.

KS is the most frequent malignancy in homo/bisexual male AIDS patients, affecting more than 30% of these patients. KS may present itself as a few innocent cutaneous lesions or may show progression resulting in severe morbidity and mortality. Approximately half of the patients may develop severe progressive disease. The prognosis of patients with progressive disease is poor, with a median survival of less than 6 months. There is no cure for AIDS-related KS, but several therapies are available for palliation. The treatment options may be applied locally or systemically. Radiotherapy is efficacious and safe, but only a few lesions may be treated at one time. For severe progressive KS, systemic therapy with various forms of chemotherapy is used. Three regimes in particular have been focused on, namely bleomycin/vincristine (BV), doxorubicin + BV (DBV), or liposomal daunorubicin (LD) administered every 2 weeks. The agents result in a clinically relevant response (in 50-80% of patients) 2-4 weeks after initiation, but few patients have complete remission of the KS (< 10%), and the tumour may relapse after 4-6 months despite continued therapy. BV is less effective but also less toxic compared with the other regimens. Time to response for DBV may be slightly better than for LD, but the overall efficacy of these 2 regimes is similar. LD treatment is associated with significantly fewer episodes of peripheral neuropathy and alopecia than treatment with DBV. Thus, the recommended order of use of chemotherapeutic agents is BV, LD and DBV. Alpha-interferon may have a role in the small percentage of patients with CD4 cell count > 200 mill/L. In conclusion, several therapeutic options are available for palliation of KS. All systemically applied therapies are associated with severe side-effects and the optimal choice of treatment is a careful balance between response and toxicity. The recent discovery of human herpes virus 8 as a putative causative agent for KS and new potent groups of anti-retroviral agents, may lead to the development of more effective treatments of KS.

The objective was to study changes in the occurrence of human immunodeficiency virus type 1-related Kaposi's sarcoma and the association with degree of immunodeficiency over time. Danish patients with acquired immunodeficiency syndrome (AIDS) diagnosed between 1979 and 1990 (n = 687) were followed clinically and with consecutive CD4 cell count measurement from time of AIDS-defining illness to date of death or censoring date, whichever came first. The proportion of homo-/bisexual men (n = 520) with Kaposi's sarcoma (n = 100) at AIDS diagnosis declined from 31% before 1985 to 13% in 1990, whereas the proportion of patients who died with Kaposi's sarcoma remained constant over time. Furthermore, the CD4 cell count at time of AIDS for patients diagnosed with Kaposi's sarcoma has declined in recent years. A CD4 cell count < 200 x 106/liter at the time of AIDS diagnosis predicted an increased risk of developing Kaposi's sarcoma after the AIDS diagnosis. Age, antiretroviral therapy, and primary Pneumocystis carinii pneumonia prophylaxis failed to influence the development of Kaposi's sarcoma. Thus, the occurrence of Kaposi's sarcoma remained constant over time but developed later in the course of AIDS and was associated with more severe immunosuppression in recent years.

It has been suggested that platelet activating factor (PAF) may participate in many aspects of bronchial asthma, including stimulation of mucus secretion. Feline tracheal and human bronchial explant production of respiratory glycoconjugates (RGC) in response to platelet activating factor (PAF) was investigatet, in order to differentiate the actions of this putative mediator on mucus secretion. PAF caused a dose-dependent increase in RGC release in concentrations ranging from 100–0.5 μM during a 1–2 hours incubation with either feline or human explants, and the effect was inhibited by the PAF receptor antagonists Ro 19-3704. Several lines of evidence suggest that PAF enhances RGC release indirectly through stimulation of the production of lipoxygenase metabolites of arachidonic acid. 1) Incubation of 10 μM PAF together with arachidonic acid (100 μg/ml) enhances PAF's stimulatory effect on RGC release in cats. 2) The cyclooxygenase inhibitor ibuprofen (65 and 420 μM) either failed to effect or slightly enhanced PAF induced RGC release in both species. 3) The combined cyclooxygenase and lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA) as well as the putatively specific 5-lipoxygenase inhibitor L-651, 392 (both at 50 μM) inhibited the response to PAF in both species. 4) The putative LTD4 receptor antagonists (L-660, 711, 100 μM) slightly reduced the PAF secretory response in human bronchi. We conclude that PAF causes specific receptor mediated RGC release. This response is indirectly mediated through the generation of lipoxygenase metabolite formation including 5-lipoxygenase pathway metabolites.

Pulsed field gel electrophoresis was used to identify the chromosome-size DNA of Pneumocystis carinii, a major pathogen of immunocompromised patients. Thirteen chromosomes of rodent Pneumocystis carinii, ranging in size from 300 to 700 kilobases (kb), were identified. The minimum genome size for P. carinii, estimated on the basis of the sizes of chromosomes, is 7,000 kb. Genetic heterogeneity among different P. carinii isolates was documented by demonstration of chromosomal size variability. By hybridization studies, the genes for topoisomerase I, dihydrofolate reductase, rRNA, actin, and thymidylate synthase were mapped to single chromosomes of approximately 650, 590, 550, 460, and 350 kb, respectively. Hybridization studies further confirmed the genetic heterogeneity of P. carinii.

Recent studies suggest that interleukin-8 (IL-8) and tumor necrosis factor alpha (TNF-alpha) may play a central role in host defense and pathogenesis during Pneumocystis carinii pneumonia. In order to investigate whether the major surface antigen (MSG) of human P. carinii is capable of eliciting the release of IL-8 and TNF-alpha, human monocytes were cultured in the presence of purified MSG. MSG-stimulated cells released significant amounts of IL-8 within 4 h, and at 20 h, cells stimulated with MSG released 45.5 +/- 9.3 ng of IL-8/ml versus 3.7 +/- 1.1 ng/ml for control cultures (P = 0.01). In a similar fashion, MSG elicited release of TNF-alpha. Initial increases were also seen at 4 h, and at 20 h, TNF-alpha levels reached 6.4 +/- 1.1 ng/ml, compared to 0.08 +/- 0.01 ng/ml for control cultures (P < 0.01). A concentration-dependent increase in IL-8 and TNF-alpha secretion was observed at 20 h with 0.2 to 5 microg of MSG/ml (P < 0.01). Secretion of IL-8 and TNF-alpha from MSG-stimulated monocytes at 20 h was inhibited by 60 and 86%, respectively, after coincubation with soluble yeast mannan (P = 0.01). With an RNase protection assay, increases in steady-state mRNA levels for IL-8 and TNF-alpha were detectable at 4 h. These data show that recognition of MSG by monocytes involves a mannose-mediated mechanism and results in the release of the proinflammatory cytokines IL-8 and TNF-alpha.

There are known to be wide differences in the prognosis of patients with a diagnosis of AIDS. In this study of 6578 patients with AIDS form 17 European centres, we develop a ranking of AIDS-defining illnesses, and determine how well this ranking holds after adjustment for potential confounding variables.

Rhodococcus equi is an aerobic, gram-positive, non-motile pleomorphic bacillus infecting immunocompromized patients. Forty-nine cases ofRhodococcus equi infection have been reported, mainly in patients infected with the human immunodeficiency virns (HIV). A case in whichRhodococcus equi eaused severe pulmonary infection, the most common presentation, is described. Clinically, patients have symptoms of pneumonia with hemoptysis as a prominent feature. X-ray will often show a cavitating upperlobe infiltrate, resembling infection with mycobacteria.Rhodococcus equi is easily cultured from blood or sputum on standard media, but is frequently regarded as a contaminant. Mortality fromRhodococcus equi pneumonia is high (25 %) and early surgical intervention has been recommended. Based on this review, the benefit of surgery seems dubious, whereas good results have been obtained using long-term antibiotic treatment with erythromycin plus rifampicin, or vancomycin in combination with either of these antibiotics.

To assess whether a recently developed indirect immunofluorescent stain using monoclonal antibodies was more sensitive in detectingPneumocystis carinii than the combination of Giemsa and methenamine silver nitrate stains which has routinely been used in the laboratory, 88 lavage fluid specimens and 34 induced sputum specimens were examined. All specimens were stained by five techniques: immunofluorescence using a combination of three monoclonal antibodies (from the National Institutes of Health, USA), immunofluorescence using a single monoclonal antibody (from Dakopatts), Giemsa, methenamine silver nitrate and toluidine blue O. Immunofluorescence using the monoclonal antibodies from the NIH was significantly more sensitive than any other single staining method and than the combination of Giemsa and methenamine silver nitrate staining. The study also showed that the cytospin centrifuge was very suitable for the preparation of slides with lavage fluid and processed induced sputum. Finally, the sensitivity of examination of induced sputum to detectPneumocystis carinii was found to be 50 % when compared with bronchoalveolar lavage fluid. However, this sensitivity may increase through practice.

OBJECTIVE: To study epidemiology and possible risk factors associated with the development of cryptosporidiosis among European patients with AIDS. METHODS: An inception cohort of 6548 patients with AIDS, consecutively diagnosed from 1979 to 1989, from 52 centres in 17 European countries was studied. Data on all AIDS defining events were collected retrospectively from patients' clinical records. Kaplan-Meier estimates, log rank tests and Cox proportional hazard models were used to examine for possible risk factors associated with cryptosporidiosis. RESULTS: Cryptosporidiosis was diagnosed in 432 (6.6%) patients, 216 at time of the AIDS diagnosis and 216 during follow-up. The probability of being diagnosed with cryptosporidiosis at AIDS diagnosis was significantly lower for intravenous drug users (1.3%) than for homosexual men (4.1%) and for patients belonging to other transmission categories (4.0%) (p < 0.001). The probability was also higher for patients from Central Europe compared with patients from South Europe (4.1% versus 2.5%, p = 0.005). The rate of developing cryptosporidiosis after the diagnosis of AIDS was 3 per 100 patient years of follow-up. The rate was significantly lower for intravenous drug users than for homosexual men (relative risk 0.34, 95% confidence limits 0.22-0.54) and for women compared with men (RR 0.43 (0.21-0.87)). The risk was higher in North Europe than in South and Central Europe. In a multivariate analysis only transmission category remained a significant predictor for the development of cryptosporidiosis. CONCLUSION: The development of cryptosporidiosis in AIDS patients may be associated with sexual risk behaviour. [ABSTRACT FROM PUBLISHER]

This study examined the factors associated with the development of a first episode of Pneumocystis carinii pneumonia (PCP) in 5,025 patients with AIDS, including 1,976 patients with primary PCP at the time of AIDS diagnosis and 635 with primary PCP occurring subsequently. Compared with untreated patients, patients treated with zidovudine were at similar risk of developing PCP during the first year of therapy but were at greater risk after longer intervals of treatment. The following factors were associated with an increased risk of PCP (either at the time of AIDS diagnosis or thereafter): lack of primary PCP prophylaxis, male homosexualitylbisexuality, diagnosis of AIDS in northern Europe, and CD4 cell count below 200 × 106/L at the time of AIDS diagnosis. Patients with severe weight loss had a 60% higher risk of developing PCP during follow-up than those without such weight loss. Thus, the occurrence of PCP depended on geographic location, mode of acquisition of human immunodeficiency virus and AIDS, degree of immunodeficiency, and use of various treatment regimens.