Large changes in Pluto's atmosphere as revealed by recent stellar occultations.

Pluto's tenuous nitrogen atmosphere was first detected by the imprint left on the light curve of a star that was occulted by the planet in 1985 (ref. 1), and studied more extensively during a second occultation event in 1988 (refs 2-6). These events are, however, quite rare and Pluto's atmosphere remains poorly understood, as in particular the planet has not yet been visited by a spacecraft. Here we report data from the first occultations by Pluto since 1988. We find that, during the intervening 14 years, there seems to have been a doubling of the atmospheric pressure, a probable seasonal effect on Pluto.

A star in a 15.2-year orbit around the supermassive black hole at the centre of the Milky Way.

Many galaxies are thought to have supermassive black holes at their centres-more than a million times the mass of the Sun. Measurements of stellar velocities and the discovery of variable X-ray emission have provided strong evidence in favour of such a black hole at the centre of the Milky Way, but have hitherto been unable to rule out conclusively the presence of alternative concentrations of mass. Here we report ten years of high-resolution astrometric imaging that allows us to trace two-thirds of the orbit of the star currently closest to the compact radio source (and massive black-hole candidate) Sagittarius A*. The observations, which include both pericentre and apocentre passages, show that the star is on a bound, highly elliptical keplerian orbit around Sgr A*, with an orbital period of 15.2 years and a pericentre distance of only 17 light hours. The orbit with the best fit to the observations requires a central point mass of (3.7 +/- 1.5) x 10(6) solar masses (M(*)). The data no longer allow for a central mass composed of a dense cluster of dark stellar objects or a ball of massive, degenerate fermions.

Nasal nitric oxide is reduced in patients with HIV.

The gas nitric oxide (NO) is present in high concentrations in human nasal airways. Since NO is known to inhibit the growth of bacteria and viruses, it has been suggested that airborne NO represents the first line of defence against pathogens in the upper airways. Low nasal NO levels have been reported previously in patients susceptible to upper airway infection. Since HIV-positive patients are at risk for respiratory tract infections, including sinusitis, we studied the levels of NO in the upper and lower airways of these patients. A cross-sectional study with age-matched HIV patients and controls was carried out. Nasal and orally exhaled NO were measured in 31 HIV patients and 26 controls using a well-established chemiluminescence method developed for measurements of gaseous NO in the airways. Nasal NO was 21%, lower (p < 0.05, Student's t-test) in HIV patients than in controls, whereas orally exhaled NO did not differ between the two groups. We conclude that nasal NO is reduced in patients with HIV infection. The reduction in nasal NO may contribute to the decreased resistance to airway infections in these patients.

Identification of Pneumocystis carinii f. sp. hominis gene sequences in filtered air in hospital environments.

To evaluate the risk of a nosocomial spread of Pneumocystis carinii f. sp. hominis (P. carinii hominis), air filter samples from rooms of P. carinii pneumonia (PCP) patients, adjacent corridors, and other hospital environments have been investigated for the presence of P. carinii hominis. Amplified DNA from air filters and sputum or bronchoalveolar lavage samples from the PCP patients have been genotyped with the P. carinii hominis genes of the mitochondrial large-subunit (mtLSU) rRNA and the internal transcribed spacers (ITS1 and ITS2) of the rRNA. Genotypes of the two loci were identified by direct sequencing, and for site 85 of the mtLSU locus, three allele-specific PCR assays were used. P. carinii hominis DNA was identified in the air of five of seven PCP patient rooms and in the air of two of four air filtrations from the ward corridors. The P. carinii hominis genotypes were the same in four of the five room air samples as those in the corresponding patients, suggesting a risk of person-to-person transmission of P. carinii hominis from PCP patients. Three of 16 air samples collected in infectious disease wards without the presence of PCP patients and one sample from a cardiology unit in a separate hospital building were also positive, which further strengthens the possibility of acquisition of P. carinii hominis from the environment.

N-acetylcysteine treatment and the risk of toxic reactions to trimethoprim-sulphamethoxazole in primary Pneumocystis carinii prophylaxis in HIV-infected patients.

In a randomized double blind placebo controlled trial, HIV sero-positive patients with CD4+ cell count less than 200 x 10(6)/l or an AIDS diagnosis were evaluated for drug reactions to trimethoprim-sulphamethoxazole (TMP-SMX) during treatment, including pretreatment, with N-acetylcysteine (NAC) 800 mg daily or placebo. TMP-SMX (one double-strength tablet containing 160 mg of trimethoprim and 800 mg of sulphamethoxazole) was given three times weekly as primary Pneumocystis carinii (PCP) prophylaxis. Thirty percent (n = 15) of the patients experienced adverse reactions 8-20 (mean 12.7) days after starting with TMP-SMX. At entry, low cysteine and glutathione levels in plasma were found in the HIV-positive patients. Age, sex, CD4+ count, plasma cysteine and glutathione levels were not risk factors for adverse reactions to TMP-SMX. However, concomitant therapy with nucleoside analogues was associated with increased risk for TMP-SMX reactions. Oral NAC 800 mg daily was well tolerated, but replenished neither cysteine nor glutathione levels in plasma. NAC 800 mg/day did not significantly decrease the risk of adverse reactions to TMP-SMX in this study, and could thus not be recommended for this purpose. A prolonged pretreatment period and/or higher dose of NAC may be necessary for clinical effect.

Longer survival after HIV infection for injecting drug users than for homosexual men: implications for immunology.

BACKGROUND: Comparisons of progression in HIV-1 infection between injecting drug users (IDU) and homosexual men have been inconclusive due to the short follow-up periods, often with less well-defined starting points and endpoints. In addition, comparisons of survival after injection have been to some extent obscured by higher non-AIDS mortality in IDU. METHOD: In a retrospective cohort study, homo-/bisexual men and IDU were followed, with dates of seroconversion defined within +/- 1 year by a previously negative HIV antibody test. Endpoints were CD4 cell count below 200 x 10(6)/l, AIDS and death from AIDS. RESULTS: Sixty-three homo-/bisexual men and 125 IDU fulfilled the entry criteria, with no significant differences in age at or date for seroconversion. Mean follow-up times were 6.7 and 7.0 years, respectively. The homo-/bisexual group had a significantly accelerated progression rate to all three endpoints: time to CD4 cell count below 200 x 10(6)/l (P = 0.002), to AIDS (P = 0.0003), and to death from AIDS (P < 0.0001). Adjusting for age and sex only made marginal alterations. Ten years after infection, 54% of homosexual men had developed an AIDS-defining condition and 51% had died from AIDS, whereas the corresponding precentages in the IDU group were 26 and 15, respectively. There was, however, no difference in overall mortality due to almost constant, non HIV-related, yearly mortality of some 4% in IDU. CONCLUSIONS: In our cohort there was a highly significant difference in disease progression and death from AIDS between homo-/bisexual men and IDU. This difference was proposed to be due to the transmission route determining the initial immune response and suggested that this route may have played a more important role than virus variability of the subsequent prognosis.

Transmission of Pneumocystis carinii from patients to hospital staff.

BACKGROUND: An extrahuman reservoir of human pathogenic Pneumocystis carinii remains unknown. Host to host transmission has been described in animal studies and in cluster cases among immunodeficient patients. P carinii DNA has recently been detected in air filters from inpatient and outpatient rooms in departments of infectious diseases managing patients with P carinii pneumonia (PCP), suggesting the airborne route of transmission. Exposure of staff to P carinii may occur in hospital departments treating patients with PCP. METHODS: Exposure to P carinii was detected by serological responses to human P carinii by ELISA, Western blotting, and indirect immunofluorescence in 64 hospital staff with and 79 staff without exposure to patients with PCP from Denmark and Sweden. DNA amplification of oropharyngeal washings was performed on 20 Danish staff with and 20 staff without exposure to patients with PCP. RESULTS: There was no significant difference in the frequency or level of antibodies to P carinii between staff exposed and those unexposed to patients with PCP. None of the hospital staff had detectable P carinii DNA in oropharyngeal washings. CONCLUSIONS: There is no difference in antibodies and no detectable P carinii DNA in oropharyngeal washings, which suggests that immunocompetent staff treating patients with PCP are not a potentially infectious source of P carinii for immunocompromised patients.

No evidence of nosocomial Pneumocystis carinii infection via health care personnel.

Clusters of Pneumocystis carinii pneumonia (PCP) in immunocompromised settings suggest person-to-person transmission. We examined whether personnel in a ward for HIV-infected patients were carriers of P. carinii. None of 29 sputum samples from 19 personnel caring for HIV-infected patients had detectable amounts of P. carinii DNA, as determined by the two PCR methods used. Two of 26 personnel were found, by an immunofluorescence assay, to have serum antibodies for P. carinii. The results do not support the hypothesis that personnel represent major vectors or transient reservoirs for spreading P. carinii infection to immunocompromised hosts.

A rapid and simple nested PCR assay for the detection of Pneumocystis carinii in sputum samples.

Detection of Pneumocystis carinii by the polymerase chain reaction (PCR), based on the thymidylate synthase (TS) gene of rat P. carinii, is a specific and sensitive method for the detection of the parasite in respiratory samples. However, the use of the method is limited by a laborious phenol-chloroform DNA extraction method and an expensive and time-consuming hybridization procedure. For routine clinical samples, DNA preparation can be simplified and hybridization substituted by a nested PCR technique. Such a modified PCR procedure, based on the TS gene of P. carinii, was evaluated on 190 induced sputum samples from 50 immunosuppressed patients, infected with human immunodeficiency virus (HIV), with and without symptoms of P. carinii pneumonia (PCP). The PCR assay, preceded by a rapid DNA preparation (Wizard DNA Clean-up), detected P. carinii-DNA in 13/15 sputa containing parasites as seen by microscopy using immunocytochemical (IFL) staining, and in 10 additional sputum samples lacking demonstrable parasites by microscopy. These samples are to be considered as 'true' positives, since all but 2 were from patients, who developed a PCP within 1 year. We conclude that the nested PCR assay is more sensitive than IFL for the detection of P. carinii in AIDS patients, prior to the debut of PCP symptoms.

Aerosolized pentamidine as primary prophylaxis for Pneumocystis carinii pneumonia: efficacy, mortality and morbidity.

OBJECTIVE: Primary prophylaxis against Pneumocystis carinii pneumonia (PCP) for patients with HIV infection has been recommended by the Centers for Disease Control and Prevention. We evaluated alternatives to routine primary PCP prophylaxis with aerosolized pentamidine. METHODS: A total of 121 HIV-infected patients with CD4+ cell counts < or = 200 x 10(6)/l or an AIDS diagnosis were enrolled in a controlled study of aerosolized pentamidine as primary PCP prophylaxis. Patients were randomly assigned to treatment (n = 61) with aerosolized pentamidine once every month or to no treatment (n = 60). Patients were evaluated for PCP, mortality, morbidity and progression of HIV disease. Morbidity was estimated from the number of days patients were unable to work due to illness, number of days hospitalized and AIDS events. RESULTS: Baseline characteristics were similar in the treatment and control groups and mean CD4+ cell counts were 116 and 107 x 10(6)/l, respectively. Eight incidents of PCP and 19 deaths were observed in the treatment group during a median follow-up of 16.4 months (range, 2.3-32.4 months). Nineteen incidents of PCP and 13 deaths, of which one was related to an acute episode of PCP, were noted in the control group. Median follow-up of controls was 18.5 months (range, 3.1-32.9 months). Patients in the treatment group were unable to work 19% of the observation time and were hospitalized for 4.3% of that time. Corresponding figures were 20 and 3.0%, respectively, in the control group. CONCLUSIONS: Aerosolized pentamidine had significant prophylactic efficacy, but we could not detect any major effect on mortality and morbidity. The overall mortality and morbidity were not markedly influenced by PCP. Clinical check-ups and treatment of acute PCP could be a justifiable alternative to drug prophylaxis with aerosolized pentamidine in selected patients.

Plasma pentamidine concentrations vary between individuals with Pneumocystis carinii pneumonia and the drug is actively secreted by the kidney.

The multiple-dose pharmacokinetics of pentamidine were studied in six AIDS patients with acute Pneumocystis carinii pneumonia given infusions of pentamidine isethionate 3.7-4 mg/kg/day i.v. Plasma and urine concentrations of pentamidine of repeated samples taken on days 1, 4 and 7 of treatment were assayed by HPLC. Creatinine clearance Clcr was also determined. On day 7, the area under the plasma concentration versus time curve (AUC) varied fourfold (3263 to 12776 nmol.h/L) between individuals. It was lowest in a patient receiving concomitant treatment with carbamazepine, suggesting that this drug may induce the metabolism of pentamidine. On day 7, a mean of 12% of the dose was excreted unchanged in the urine. Clcr was decreased significantly on day 7 compared with day 1 (mean decrease 31%, range 11-63%). Renal clearance of pentamidine (Clr) decreased over time but always exceeded the Clcr, indicating tubular secretion. The decrease of Clr may be explained by capacity-limited secretion and/or a tubulotoxic effect of the drug. The variation of the AUC values is consistent with interindividual differences in rates of metabolism, which supports individual dosing strategies for pentamidine.

Natural history of asymptomatic and symptomatic pneumocystis carinii infection in HIV infected patients.

The natural appearance of Pneumocystis carinii in induced sputum samples was studied in 60 HIV-infected patients with severe immunodeficiency and without a history of P. carinii pneumonia (PCP). The patients were prospectively evaluated for occurrence of P. carinii in induced sputum samples, PCP diagnosis and CD4+ cell counts during observation periods of 2 to 31 months. P. carinii was detected in 16 patients all of whom developed clinical PCP. In 5 patients P. carinii was detected 3 weeks to 8 months prior to clinical symptoms. Immunofluorescence using monoclonal antibody 3F6 was more sensitive than toluidine in detecting P. carinii in sputum samples (p < 0.05). In the patients who developed PCP a drop of the mean CD4 count to 40-50 x 10(6)/l was observed 200 days before diagnosis. However, out of 13 patients with CD4 counts of 0-20 x 10(6)/l only 7 developed PCP during 200 days of observation. The results do not support the suggested reactivation of a latent infection present in the vast majority of adults. PCP may instead result from exposure to the organism or presence of an unknown cofactor. We conclude that P. carinii is present in some asymptomatic HIV patients and that the detection of the organism in sputum should be regarded as pathological and prophylaxis or treatment inserted. The risk of transmission of P. carinii to patients with severe immunodeficiency should be seriously considered.

Aerosolized pentamidine versus i.v. pentamidine for secondary prophylaxis of Pneumocystis carinii pneumonia.

The efficacy and toxicity of aerosolized pentamidine was evaluated in 78 AIDS patients given 60 mg biweekly as secondary prophylaxis against Pneumocystis carinii pneumonia (PCP). Patients were monitored for clinical progression and mortality and were compared to 42 historical controls given 200-300 mg i.v. pentamidine biweekly. The relapse rates did not differ markedly between the two groups, and the PCP-free rates in survivors were at 12 months 0.83 and 0.77, respectively. Seventy-one new AIDS-defining events and 25 deaths were recorded in patients on aerosolized pentamidine compared to 29 AIDS events and two deaths in patients on intravenous pentamidine. Recurrent PCP contributed to death in only one case of the aerosolized pentamidine group. PCP is not a serious clinical problem in immunodeficient patients taking pentamidine prophylaxis by either route compared to the progression of clinical HIV disease and death.

Interferon alpha-2b treatment in an HIV-infected patient with hepatitis B virus induced nephrotic syndrome.

A 31-year-old male patient with an asymptomatic HIV infection but with a hepatitis B (HBV) related membraneous glomerulonephritis with nephrotic syndrome was given interferon alpha-2b subcutaneously 3 times weekly for 7.5 months. Zidovudine was added at the 10th week due to low CD4+ cell counts. Before the 6th week of treatment the patient reported a reduced need for diuretics to keep his lower limb edemas at a minimum. This response was partially sustained even after the 7.5 months interferon treatment course. The titers of HBV-DNA decreased markedly during the treatment with interferon but rose to pretreatment levels after discontinuation of the interferon treatment. The serum albumin increased but the proteinuria and hematuria were unaffected. Adverse reactions like fever, myalgias and anemia were tolerable and did not require dose reduction of either interferon or zidovudine. This treatment regimen, at least temporarily, improved the situation for the patient and can be worthwhile to try in HIV-infected patients with HBV related nephritis with nephrotic syndrome.

CD4+ cells and CD4+ percent as risk markers for Pneumocystis carinii pneumonia (PCP): implications for primary PCP prophylaxis.

The incidence of Pneumocystis carinii pneumonia (PCP) during 2 years in HIV-infected patients with less than or equal to 100 x 10(6)/l CD4+ cells, less than or equal to 200 x 10(6)/l CD4+ cells and less than 20% CD4+ cells of total T lymphocytes were compared. The relative PCP risk in 57 patients with less than or equal to 100 CD4+ cells was more than twice higher than in 120 patients with less than or equal to 200 CD4+ cells. The latter had almost twice higher relative PCP risk than 271 patients with less than or equal to 20% CD4+ cells. Only 3/56 patients who acquired PCP had greater than 200 CD4+ cells and 15/56 patients had greater than 100 CD4+ cells. Centers for Disease Control (CDC) recommends primary PCP prophylaxis in HIV-infected patients when the number of CD4+ cells is less than 200 x 10(6)/l or when the CD4+ is less than 20. On the basis of the presented data we suggest that primary prophylaxis is considered only when CD4+ cells fall below 200 x 10(6)/l.

Aetiology of pulmonary diseases in immunocompromised patients.

Fibreoptic bronchoscopy with bronchoalveolar lavage (BAL), transbronchial lung biopsy (TBB) and brushing was performed, in 134 episodes of pulmonary disease in 118 compromised patients. Sixty eight of the patients were infected with immunodeficiency virus type 1 (HIV-1), 18 were renal and pancreas transplant recipients, 7 were liver and 15 were bone marrow transplant recipients, and 10 patients were undergoing immunosuppressive and/or cytotoxic drug therapy. Pneumocystis carinii (PC) was the predominant pathogen in HIV-1 infected patients. It was considered to be the aetiological cause of pneumonia in 54/82 (66%) episodes of lung complications noted in these patients. Cytomegalovirus (CMV) was the most common micro-organism in transplant recipients. CMV pneumonia was diagnosed in 22/42 episodes of pulmonary disease in these patients. CMV was detected by bronchoscopy procedures at a relatively high frequency of 36/82 (44%) episodes in HIV-1 infected patients. However, after analysis of clinical information, cultures from leucocytes and autopsy findings, CMV seemed to be involved in the pathogenicity of pneumonia in only two out of the 36 patients. Bacterial aetiology, including mycobacterial agents, was unusual, but was the major cause of pulmonary infections in 6/10 episodes in patients undergoing extensive immunosuppressive and/or cytotoxic drug therapy. Bronchoscopy was helpful in establishing correct aetiology in 98/134 (73%) episodes of pulmonary disease. Growth of Candida albicans and bacteria should always be viewed sceptically because of the possibility of contamination from colonization in the upper respiratory tract.

Fiberoptic bronchoscopy and sputum examination for diagnosis of pulmonary disease in AIDS patients in Stockholm.

For diagnosing pulmonary disease on 82 occasions in 68 patients (64 males) aged 39 (23-73) years infected with HIV-1 we used flexible fiberoptic bronchoscopy (FFB) with bronchoalveolar lavage (BAL) or washing with or without transbronchial lung biopsy (TBB) and brushing. A clinical diagnosis of lower respiratory tract disease was obtained in 68/82 episodes (83%). An etiological diagnosis was reached by FFB in 59/82 episodes (72%). Pneumocystis carinii (PC), the dominating pathogen causing pneumonia in 54/82 episodes (66%), was detected by FFB in 51/54 (94%). In spite of being isolated in bronchoscopy material in 36/82 episodes (44%) cytomegalovirus (CMV) seemed to be the cause of pneumonia only in 2/36 (5%) episodes. Except PC and CMV, only bacteria (including mycobacteria) were found as infectious etiological agents. Kaposi's sarcoma and pulmonary edema were diagnosed in one patient each. For detection of PC in 37 episodes we compared staining of BAL fluid with indirect immunofluorescence (IF) using monoclonal antibodies (MoAB) with staining of BAL material by silver methenamine (Grocott). Staining with IF MoAB alone of BAL fluid only seemed to be even more sensitive than silver methenamine staining of BAL, TBB and brushing material. When using IF MoAB staining of BAL fluid, TBB and brushing added nothing to the result, except in the patient with Kaposi's sarcoma, diagnosed by TBB. Sputum investigation using IF MoAB for detection was increasingly adopted during the study time. It was very useful (sensitivity approximately 74%) and reduced the number of required FFBs.

Pneumocystis carinii pneumonia in Stockholm, Sweden: treatment, outcome, one-year-follow-up and pyrimethamine prophylaxis.

In 33 consecutive AIDS patients with a first episode of Pneumocystis carinii pneumonia (PCP) we evaluated treatment, outcome, recurrence rate and pyrimethamine as chemoprophylaxis in a 1-year follow-up. Only 2 patients had a CD4 lymphocyte cell count greater than 0.2 X 10(9)/l. Trimethoprim-sulfamethoxazole (TMP-SMX) was initially given to 32 patients but in 20 of these patients severe adverse reactions caused us to discontinue treatment. Of these 20 patients 11 were started on i.v./i.m. pentamidine but in 6 adverse reactions forced us to withdraw pentamidine. Patients were retrospectively divided with regard to duration of therapy into 2 groups. We could not find any difference between patients in Group 1 treated for less than or equal to 14 days and patients in Group 2 treated for greater than 14 days when comparing outcome, number of recurrences and mean time until recurrence. In 16/21 patients given only TMP-SMX initially in a high dose (means = 16 mg trimethoprim/kg/day), dose reduction was performed to means = 10.5 mg trimethoprim/kg/day after a mean time of 6.9 days. The case-fatality rate for these patients was 10% (2/21) and the overall case-fatality rate was 15% (5/33). We chose pyrimethamine (50-175 mg/week) as secondary prophylaxis for PCP. At 1-year follow-up another 16 patients had died (21/32) and 9/27 (33%) discharged patients had had one recurrence each of PCP. All recurrences occurred among patients treated with only TMP-SMX for the acute episode of PCP. Of these 27 discharged patients 23 had been given pyrimethamine and 8 (36%) of these had experienced a recurrence.(ABSTRACT TRUNCATED AT 250 WORDS)