Pneumocystis carinii Research Papers - Academia.edu (original) (raw)

A library of 19 novel 4-(4-phenylpiperazine-1-yl)benzamidines has been synthesized and evaluated in vitro against Pneumocystis carinii. Among these compounds, N-ethyl- and N-hexyl-4-(4-phenylpiperazine-1-yl)benzamidines emerged as the... more

A library of 19 novel 4-(4-phenylpiperazine-1-yl)benzamidines has been synthesized and evaluated in vitro against Pneumocystis carinii. Among these compounds, N-ethyl- and N-hexyl-4-(4-phenylpiperazine-1-yl)benzamidines emerged as the most promising compounds, with inhibition percentages at 10.0 microg/mL of 87% and 96%, respectively. Those compounds remained active at 0.1 microg/mL.

By using mouse models, it has been shown that Pneumocystis carinii f. sp. muris can be transmitted to immunocompetent mice that are exposed to immunosuppressed mice with active P. carinii pneumonia. We sought to determine whether P.... more

By using mouse models, it has been shown that Pneumocystis carinii f. sp. muris can be transmitted to immunocompetent mice that are exposed to immunosuppressed mice with active P. carinii pneumonia. We sought to determine whether P. carinii f. sp. muris could be transmitted between normal mice. The rationale for these experiments was to demonstrate whether the normal host could serve as the reservoir of organisms that produce Pcp when the organism is acquired by the immunosuppressed host. Under the conditions of these experiments, normal mice are able to be infected by brief cohousing with P. carinii -infected SCID mice. There was active replication of organisms in the normal host such that the organism could be transmitted to other normal mice, again with active replication. Mice that had seroconverted after exposure to P. carinii -infected SCID mice were more resistant to infection when reexposed. Infection in normal mice was well tolerated with minimal effects on dynamic lung com...

Idiopathic lung lesions characterized by dense perivascular cuffs of lymphocytes and a lymphohistiocytic interstitial pneumonia have been noted in research rats since the 1990s. Although the etiology of this disease has remained elusive,... more

Idiopathic lung lesions characterized by dense perivascular cuffs of lymphocytes and a lymphohistiocytic interstitial pneumonia have been noted in research rats since the 1990s. Although the etiology of this disease has remained elusive, a putative viral etiology was suspected and the term 'rat respiratory virus' (RRV) has been used in reference to this disease agent. The purpose of this study was to determine whether Pneumocystis carinii infection in immunocompetent rats can cause idiopathic lung lesions previously attributed to RRV. In archived paraffin-embedded lungs (n = 43), a significant association was seen between idiopathic lung lesions and Pneumocystis DNA detected by PCR. In experimental studies, lung lesions of RRV developed in 9 of 10 CD rats 5 wk after intratracheal inoculation with P. carinii. No lung lesions developed in CD rats (n = 10) dosed with a 0.22-μm filtrate of the P. carinii inoculum, thus ruling out viral etiologies, or in sham-inoculated rats (n =...

Passive antibody immunoprophylaxis is one method used to protect patients against infection if they are unable to mount an adequate active immune response. Topical application of antibody may be effective against infections at mucosal... more

Passive antibody immunoprophylaxis is one method used to protect patients against infection if they are unable to mount an adequate active immune response. Topical application of antibody may be effective against infections at mucosal sites. Using a SCID mouse model of Pneumocystis carinii pneumonia, we were able to demonstrate protection against an airborne challenge with P. carinii by intranasal administration of antibody. Immunoglobulin M (IgM) monoclonal antibodies to an epitope shared by mouse and human P. carinii organisms reduced organism numbers by more than 99% under the conditions described. An IgG1 switch variant of one of the IgM monoclonal antibodies was also protective. These experiments provide a model for exploring the utility of this approach in protecting at-risk patients from infection with P. carinii.

Cognitive dysfunction is a common presenting symptom in patients with HIV/AIDS. It is usually directly associated with HIV infection or due to opportunistic infection. Rapidly progressive dementia, however, is rarely observed in acute HIV... more

Cognitive dysfunction is a common presenting symptom in patients with HIV/AIDS. It is usually directly associated with HIV infection or due to opportunistic infection. Rapidly progressive dementia, however, is rarely observed in acute HIV infection or during immune reconstitution. Recently, a case of Creutzfeld-Jakob disease (CJD) has been reported in a patient with chronic HIV infection. The incidence of CJD is not known to be increased among immunocompromised patients. We here report the case of a 59-year-old male patient with a recent diagnosis of HIV/AIDS and Pneumocystis jiroveci pneumonia presenting with secondary behavioral changes and disorientation. Over the course of several weeks, progressive dementia developed characterized by apraxia, gait ataxia, and mutism. After the exclusion of common HIV-associated neurologic conditions, the clinical course as well as findings on electroencephalogram (EEG), magnetic resonance imaging (MRI), and a positive 14-3-3 assay converged int...

Mutations in the human-derived Pneumocystis carinii dihydropteroate synthase (DHPS) gene have been reported with increasing frequency and have been linked to prior sulfa prophylaxis and possible emergence of sulfa resistance. This study... more

Mutations in the human-derived Pneumocystis carinii dihydropteroate synthase (DHPS) gene have been reported with increasing frequency and have been linked to prior sulfa prophylaxis and possible emergence of sulfa resistance. This study was done to examine the prevalence and clinical significance of P. carinii DHPS mutations in Italian patients. A previously described singlestrand conformation polymorphism technique was used to identify P. carinii DHPS mutations in 107 patients with acquired immunodeficiency syndrome. Overall prevalence (8%) was low compared with that in other reports. Mutations were observed in 19% (6/31) of patients exposed to sulfa prophylaxis, compared with 4% (3/76) of patients not exposed to sulfa prophylaxis (P ¼ :017). No significant association was observed between the presence of DHPS mutations and mortality, CD4 cell count, or demographic factors. The study confirms the association between DHPS mutations and prior sulfa prophylaxis and shows that the prevalence of DHPS mutations in an Italian patient population is lower than that in other populations.

The Fifth European Conference on Infections in Leukaemia (ECIL-5) convened a meeting to establish evidence-based recommendations for using tests to diagnose Pneumocystis jirovecii pneumonia (PCP) in adult patients with haematological... more

The Fifth European Conference on Infections in Leukaemia (ECIL-5) convened a meeting to establish evidence-based recommendations for using tests to diagnose Pneumocystis jirovecii pneumonia (PCP) in adult patients with haematological malignancies. Immunofluorescence assays are recommended as the most sensitive microscopic method (recommendation A-II: ). Real-time PCR is recommended for the routine diagnosis of PCP ( A-II: ). Bronchoalveolar lavage (BAL) fluid is recommended as the best specimen as it yields good negative predictive value ( A-II: ). Non-invasive specimens can be suitable alternatives ( B-II: ), acknowledging that PCP cannot be ruled out in case of a negative PCR result ( A-II: ). Detecting β-d-glucan in serum can contribute to the diagnosis but not the follow-up of PCP ( A-II: ). A negative serum β-d-glucan result can exclude PCP in a patient at risk ( A-II: ), whereas a positive test result may indicate other fungal infections. Genotyping using multilocus sequence m...

The J4/5 loop of the group I intron in the mouse-derived fungal pathogen Pneumocystis carinii is the docking site for the first step of the RNA-catalyzed self-splicing reaction and thus is a model of a potential drug target. This... more

The J4/5 loop of the group I intron in the mouse-derived fungal pathogen Pneumocystis carinii is the docking site for the first step of the RNA-catalyzed self-splicing reaction and thus is a model of a potential drug target. This purine-rich asymmetric internal loop, 5′GGAAG/3′UAGU, is also thermodynamically more stable than other internal loops with two GU closing pairs and three nucleotides opposite two nucleotides. The results from optical melting, nuclear magnetic resonance spectroscopy, and functional group substitution experiments suggest that the GU closing pairs form and that sheared GA pairs form in the internal loop. The NMR spectra show evidence of conformational dynamics, and several GA pairings are possible. Thus, this dynamic loop presents several possible structures for potential binding of drugs that target group I self-splicing introns. The results also contribute to understanding the structural and dynamic basis for the function and thermodynamic stability of this loop. The J4/5 1 loop in group I introns (Figure 1) is the docking site for the first step of the self-splicing reaction required for processing of ribosomal RNA (1-6). The structure and function of the J4/5 loop in the Tetrahymena thermophila group I intron has been extensively studied (1, 3, 7-14); this asymmetric internal loop (Figure 1, C2) contains tandem sheared adenine pairs. The J4/5 loop in the mouse-derived fungal pathogen Pneumocystis carinii (Figure 1, C1) has potential GA pairs and GU closing pairs and is thermodynamically more stable than the T. thermophila and Candida albicans J4/5 loops (15) (Figure 1, C2 and C3). The free energy of a tertiary contact to a GU pair at the group I intron † This work supported by NIH Grant GM22939.

Two homosexual males with the 'gay bowel syndrome' experienced an acute unilateral loss of vision. Both patients had white intraretinal lesions, which became confluent. One of the cases had a depressed cell-mediated immunity; both... more

Two homosexual males with the 'gay bowel syndrome' experienced an acute unilateral loss of vision. Both patients had white intraretinal lesions, which became confluent. One of the cases had a depressed cell-mediated immunity; both patients ultimately died after a prolonged illness. In one patient cytomegalovirus was cultured from a vitreous biopsy. Autopsy revealed disseminated cytomegalovirus in both patients. Widespread retinal necrosis was evident, with typical nuclear and cytoplasmic inclusions of cytomegalovirus. Electron microscopy showed herpes virus, while immunoperoxidase techniques showed cytomegalovirus. The altered cell-mediated response present in homosexual patients may be responsible for the clinical syndromes of Kaposi's sarcoma and opportunistic infection by Pneumocystis carinii, herpes simplex, or cytomegalovirus. Retinal involvement in adult cytomegalic inclusion disease (CID) is usually associated with the concomitant presence of a neoplastic disorder of the haemopoietic and reticuloendothelial systems or treatment with immunosuppressive drugs following allotransplantation.1-3 While the diagnosis of CID can often be suggested by the ophthalmoscopic appearance,4 confirmation is made by demonstrating the inclusion bodies in urine, saliva, and biopsy specimens, rising serum titres, or positive cultures.6 Recently a syndrome has been described involving homosexual males comprising a severe, acquired immunodeficiency and characterised by weight loss, fever, and severe, unrelenting, often fatal infection with opportunistic microorganisms including cytomegalovirus, herpes simplex virus, Pneumocystis carinii, and Candida albicans.78 Other

Structural data from two independent crystal forms (P212121 and P21) of the folate (FA) binary complex and from the ternary complex with the oxidized coenzyme, NADP+, and recombinant Pneumocystis carinii dihydrofolate reductase (pcDHFR)... more

Structural data from two independent crystal forms (P212121 and P21) of the folate (FA) binary complex and from the ternary complex with the oxidized coenzyme, NADP+, and recombinant Pneumocystis carinii dihydrofolate reductase (pcDHFR) refined to an average of 2.15 A resolution, show the first evidence of ligand-induced conformational changes in the structure of pcDHFR. These data are also compared with the crystal structure of the ternary complex of methotrexate (MTX) with NADPH and pcDHFR in the monoclinic lattice with data to 2.5 A resolution. Comparison of the data for the FA binary complex of pcDHFR with those for the ternary structures reveals significant differences, with a >7 A movement of the loop region near residue 23 that results in a new "flap-open" position for the binary complex, and a "closed" position in the ternary complexes, similar to that reported for Escherichia coli (ec) DHFR complexes. In the orthorhombic lattice for the binary FA pcDHFR complex, there is also an unwinding of a short helical region near residue 47 that places hydrophobic residues Phe-46 and Phe-49 toward the outer surface, a conformation that is stabilized by intermolecular packing contacts. The pyrophosphate moiety of NADP+ in the ternary folate pcDHFR complexes shows significant differences in conformation compared with that observed in the MTX-NADPH-pcDHFR ternary complex. Additionally, comparison of the conformations among these four pcDHFR structures reveals evidence for subdomain movement that correlates with cofactor binding states. The larger binding site access in the new "flap-open" loop 23 conformation of the binary FA complex is consistent with the rapid release of cofactor from the product complex during catalysis as well as the more rapid release of substrate product from the binary complex as a result of the weaker contacts of the closed loop 23 conformation, compared to ecDHFR.

Las complicaciones pulmonares en los pacientes con infeccion por el virus de la inmunodeficiencia humana (VIH) son, actualmente, un problema de primer orden. En Espana son la primera causa de ingreso hospitalario de estos pacientes.... more

Las complicaciones pulmonares en los pacientes con infeccion por el virus de la inmunodeficiencia humana (VIH) son, actualmente, un problema de primer orden. En Espana son la primera causa de ingreso hospitalario de estos pacientes. Ademas, la mayoria experimenta alguna complicacion de este tipo durante su evolucion. La etiologia mas frecuente es la neumonia bacteriana, particularmente las producidas por neumococos; en segundo lugar, la neumonias por Pneumocystis jiroveci (anteriormente P. carinii), y en tercer lugar, las micobacterias, sobre todo la tuberculosis. Desde las primeras descripciones de complicaciones pulmonares, su epidemiologia ha experimentado cambios notables. Entre las causas principales se encuentra la introduccion de la profilaxis primaria frente a P. jiroveci, y mas recientemente, la generalizacion del tratamiento antirretroviral combinado de elevada eficacia. En esta revision se actualizan las principales causas en la actualidad de complicaciones pulmonares en ...

8-Aminoquinolines are an important class of antiparasitic agents, with broad utility and excellent efficacy, but also limitations due to hematological toxicities, primarily methemoglobinemia and hemolysis. One representative from this... more

8-Aminoquinolines are an important class of antiparasitic agents, with broad utility and excellent efficacy, but also limitations due to hematological toxicities, primarily methemoglobinemia and hemolysis. One representative from this class, (±)-8-[(4-amino-1-methylbutyl)amino]-6-methoxy-4-methyl-5-[3,4-dichlorophenoxy]quinoline succinate (NPC1161C), proved extremely efficacious in animal models of malaria and pneumocystis pneumonia. This racemic mixture was separated into its component enantiomers by chemical and chromatographic means. The enantiomers were evaluated for antiparasitic activity in murine models of Plasmodium berghei , Pneumocystis carinii , and Leishmania donovani infection, as well as the propensity to elicit hematotoxicity in dogs. The (−)-enantiomer NPC1161B was found to be more active (by severalfold, depending on the dosing regimen) than the (+)-enantiomer NPC1161A in all of these murine models. In addition, the (−) enantiomer showed markedly reduced general tox...

Hoechst 33258 is a compound that binds nucleic acids. We report that Hoechst 33258 exhibits antimicrobial activity against Pneumocystis carinii f. sp. muris in a mouse model for P. carinii pneumonia and against Candida albicans and... more

Hoechst 33258 is a compound that binds nucleic acids. We report that Hoechst 33258 exhibits antimicrobial activity against Pneumocystis carinii f. sp. muris in a mouse model for P. carinii pneumonia and against Candida albicans and Candida dubliniensis in vitro. Relative to saline treatment, a 14-day, daily treatment of mice with 37.5 mg of Hoechst 33258/kg of body weight after inoculation with P. carinii reduced by about 100-fold the number of P. carinii organisms detected by either PCR or by microscopy after silver staining. For comparison, treatment based on a dose of 15 to 20 mg of the trimethoprim component in trimethoprim-sulfamethoxazole/kg reduced the number of P. carinii by about fourfold. In vitro inhibition of P. carinii group I intron splicing was observed with a 50% inhibitory concentration (IC50)of 30 μM in 2 or 4 mM Mg2+, suggesting RNA as a possible target. However, Hoechst 33258 inhibits growth of Candida strains with and without group I introns. IC50s ranged from 1...

The present review concentrates on the clinical, pathological and immunological aspects of pigs suffering from PMWS which strongly suggest that PCV2 may be, in particular conditions, a cause of secondary immunodeficiency in pigs. From a... more

The present review concentrates on the clinical, pathological and immunological aspects of pigs suffering from PMWS which strongly suggest that PCV2 may be, in particular conditions, a cause of secondary immunodeficiency in pigs. From a clinical point of view, the lack of antibiotic ...

The bamboo aphids, Pseudoregma spp., are the commonest insect pests found in ornamental bamboos throughout southeastern Asia. In this study, the mitochondrial genome of a representative of Pseudoregma bambucicola isolated from the bamboo... more

The bamboo aphids, Pseudoregma spp., are the commonest insect pests found in ornamental bamboos throughout southeastern Asia. In this study, the mitochondrial genome of a representative of Pseudoregma bambucicola isolated from the bamboo Bambusa multiplexcv in Guizhou of China was determined through Illumina MiSeq platform. The entire genome was 16,705 bp in length and encoded 13 protein-coding genes, 22 tRNA genes, and 2 rRNA genes. The phylogeneric analysis showed that the P. bambucicola (Guizhou isolate) clustered together with another two isolates from Sichuan and Fujian of China, respectively, and together formed a monophyletic relationship with Hormaphis betulae in Hormaphidinae. The mitochondrial DNA data presented here should contribute to future molecular identification, population genetic, and evolutionary biological studies of P. bambucicola.

Patients with pneumocystis pneumonia have a risk of progressing to acute respiratory failure necessitating admission to intensive care. The case described is of a patient with a newly diagnosed HIV infection presenting with pneumocystis... more

Patients with pneumocystis pneumonia have a risk of progressing to acute respiratory failure necessitating admission to intensive care. The case described is of a patient with a newly diagnosed HIV infection presenting with pneumocystis pneumonia. Despite initiating the appropriate pharmacological treatment the patient's clinical condition deteriorated, and required both rescue pharmacological therapy with echinocandins as well as respiratory support with extracorporeal membrane oxygenation therapy. The patient recovered well on ventilator and circulatory support despite a long weaning process complicated by sequelae common to pneumocystis pneumonia. Following initialisation of antiretroviral therapy and step-down from an intensive care setting, the patient required further prolonged hospital stay for rehabilitation and mental health support before being discharged. This case reviews the novel pharmacological therapies and respiratory support strategies used in cases of pneumocy...

The introduction of protease inhibitors (PIs) gave a dramatic drop in AIDS-related opportunistic events, mainly due to induced immune reconstitution. Discontinuation of prophylaxis against Pneumocystis carinii is considered safe when CD4... more

The introduction of protease inhibitors (PIs) gave a dramatic drop in AIDS-related opportunistic events, mainly due to induced immune reconstitution. Discontinuation of prophylaxis against Pneumocystis carinii is considered safe when CD4 > 200 cells/mm 3. Ideally, we should have specific functional tests for HIV-1related decisions. We examined viro-immunological profiles, clinical outcome and lymphocyte proliferation (LP) to P. carinii and other antigens in 108 subjects: 28 AIDS presenters with P. carinii pneumonia (PCP) (CD4 < 200 cells/mm 3), 22 untreated asymptomatic HIV-1-infected patients (CD4 > 200 cells/mm 3), 44 HIV-1infected patients immune-reconstituted on antiretroviral regimens and 14 HIV-1-uninfected healthy controls. As regards viral load, there was no significant difference in therapy duration, nadir, or actual CD4, CD8, natural killer or B cell counts in immune-reconstituted patients receiving protease inhibitor (PI)-based versus those receiving PI-sparing antiretroviral regimens. Among subjects showing abnormally low P. carinii-specific LP, three patients receiving a non-nucleoside reverse transcriptase inhibitor (nNRTI) developed PCP despite having CD4 > 250 cells/mm 3. P. carinii-specific LP could be considered for doubtful situations, i.e. for a safer clinical decision of discontinuing or restarting prophylaxis in patients with a low CD4 nadir or experiencing a sudden CD4 decrease under highly active antiretroviral therapy (HAART). HIV-1 PIs, having in vitro aspecific effects against Pneumocystis, could play a clinically significant anti-opportunistic role, thus offering a further benefit in heavily immunosuppressed patients during early stages of antiretroviral therapy.

From 1994 to date we have been using the internal transcribed spacers (ITSs) nested polymerase chain reaction (PCR) to investigate the possibility of diagnosing Pneumocystis carinii pneumonia on non-invasive samples collected from... more

From 1994 to date we have been using the internal transcribed spacers (ITSs) nested polymerase chain reaction (PCR) to investigate the possibility of diagnosing Pneumocystis carinii pneumonia on non-invasive samples collected from HIV-positive patients with pulmonary involvement. The objectives were: (1) to test the sensitivity, specificity and prognostic value of PCR in diagnosis and follow up of PCP; (2) to investigate the eventual occurrence and role of asymptomatic carriers of P. carinii; (3) to evaluate the prognostic significance of blood PCR positivity versus respiratory samples; (4) to verify the occurrence of exogenous infections or endogenous reactivations in cases of recurrent P. carinii pneumonia; and (5) to study the possible correlation between P. carinii genotype identified and capability of blood dissemination, prior prophylactic treatments, clinical parameters and outcome of the patients.

Since 1996, the introduction of protease inhibitors (PIs) has led to a dramatic decrease of human immunodeficiency virus-related Pneumocystis carinii pneumonia. This effect is clearly due, in large part, to the induction of immune... more

Since 1996, the introduction of protease inhibitors (PIs) has led to a dramatic decrease of human immunodeficiency virus-related Pneumocystis carinii pneumonia. This effect is clearly due, in large part, to the induction of immune reconstitution by highly active antiretroviral therapy (HAART). However, it is conceivable that PIs had other beneficial effects, including direct activity against Pneumocystis. In this study, the occurrence of specific aspartyl proteases in Pneumocystis is described. These protease targets seemed to be affected in vitro by antiretroviral PIs. These data suggest intriguing implications for the possible antipneumocystis benefit of receiving indinavir, ritonavir, nelfinavir, or saquinavir during HAART. Pneumocystis carinii is a major cause of pneumonia in patients with AIDS and in other immunocompromised patients [1]. Since the introduction of human immunodeficiency virus (HIV) protease inhibitors (PIs), dramatic declines in all opportunistic infections, including P. carinii pneumonia (PCP), have been observed [2, 3]. This favorable outcome and the decline in PCP incidence is clearly due, in large part, to T cell clonal reconstitution induced by highly active antiretroviral therapy (HAART), mainly because of the potent effect of PIs added to classic antiretroviral therapy [4, 5]. The PIs currently used for HIV are aspartyl proteases. However, protease targets exist in a variety of eukaryotes (e.g., Toxoplasma) and fungi (e.g., Candida) [6-9]. In 1991, we used zymograms for a preliminary detection of P. carinii serine-cysteine proteases [10], and our data have been confirmed by recent biomolecular and immunological studies [11-16]. Microorganisms that are related to Pneumocystis in terms of drug susceptibility (e.g., Plasmodium species) [17-19] possess both acid and alkaline proteases [20]. We performed acid zymograms to detect Pneumocystis acid proteases, screened the aspartyl PI activity of pepstatin A, and performed repeated in vitro studies to determine whether HIV

Pneumocystis pneumonia (PCP) is a major cause of morbidity and mortality among immunocompromised persons, and it remains a leading acquired immune deficiency syndrome (AIDS)-defining opportunistic infection in human immunodeficiency virus... more

Pneumocystis pneumonia (PCP) is a major cause of morbidity and mortality among immunocompromised persons, and it remains a leading acquired immune deficiency syndrome (AIDS)-defining opportunistic infection in human immunodeficiency virus (HIV)- ...

BACKGROUND: Pulmonary alveolar proteinosis is a rare lung disorder, which was first reported as idiopathic condition in 1958. The prevalence of acquired pulmonary alveolar proteinosis has been estimated to be 0.37 per 100,000 population.... more

BACKGROUND: Pulmonary alveolar proteinosis is a rare lung disorder, which was first reported as idiopathic condition in 1958. The prevalence of acquired pulmonary alveolar proteinosis has been estimated to be 0.37 per 100,000 population. The cause of this condition is not entirely clear. We present alveolar proteinosis in a case recently treated for pulmonary Pneumocystis carinii infection. CASE PRESENTATION: A

Background: The fungal pathogen Pneumocystis carinii causes a pneumonia which is an opportunistic infection of AIDS patients. Current therapy includes the dihydrofolate reductase (DHFR) inhibitor trimethoprim which is selective but only a... more

Background: The fungal pathogen Pneumocystis carinii causes a pneumonia which is an opportunistic infection of AIDS patients. Current therapy includes the dihydrofolate reductase (DHFR) inhibitor trimethoprim which is selective but only a relatively weak inhibitor of the enzyme for P. carinii. Determination of the three-dimensional structure of the enzyme should form the basis for design of more potent and selective therapeutic agents for treatment of the disease. Results: The structure of P. carinii DHFR in complex with reduced nicotinamide adenine dinucleotide phosphate and trimethoprim has accordingly been solved by X-ray crystallography. The structure of the ternary complex has been refined at 1.86 A resolution (R=0.181). A similar ternary complex with piritrexim (which is a tighter binding, but less selective inhibitor) has also been solved, as has the binary complex holoenzyme, both at 2.5 A resolution. Conclusions: These structures show how two drugs interact with a fungal DHFR. A comparison of the threedimensional structure of this relatively large DHFR with bacterial or mammalian enzyme-inhibitor complexes determined previously highlights some additional secondary structure elements in this particular enzyme species. These comparisons provide further insight into the principles governing DHFR-inhibitor interaction, in which the volume of the active site appears to determine the strength of inhibitor binding.

The following experimental techniques were used to determine the structure: X-RAY DIFFRACTION The reported resolution of this entry is 2.30 Å. Percentile scores (ranging between 0-100) for global validation metrics of the entry are shown... more

The following experimental techniques were used to determine the structure: X-RAY DIFFRACTION The reported resolution of this entry is 2.30 Å. Percentile scores (ranging between 0-100) for global validation metrics of the entry are shown in the following graphic. The table shows the number of entries on which the scores are based. Metric Whole archive (#Entries) Similar resolution (#Entries, resolution range(Å)) Clashscore 141614 5643 (2.30-2.30) Ramachandran outliers 138981 5575 (2.30-2.30) Sidechain outliers 138945 5575 (2.30-2.30) The table below summarises the geometric issues observed across the polymeric chains and their t to the electron density. The red, orange, yellow and green segments on the lower bar indicate the fraction of residues that contain outliers for >=3, 2, 1 and 0 types of geometric quality criteria respectively. A grey segment represents the fraction of residues that are not modelled. The numeric value for each fraction is indicated below the corresponding segment, with a dot representing fractions <=5% Note EDS was not executed. Mol Chain Length Quality of chain 1 A 206 Full wwPDB X-ray Structure Validation Report 1DAJ 2 Entry composition i

Two homosexual males with the 'gay bowel syndrome' experienced an acute unilateral loss of vision. Both patients had white intraretinal lesions, which became confluent. One of the cases had a depressed cell-mediated immunity; both... more

Two homosexual males with the 'gay bowel syndrome' experienced an acute unilateral loss of vision. Both patients had white intraretinal lesions, which became confluent. One of the cases had a depressed cell-mediated immunity; both patients ultimately died after a prolonged illness. In one patient cytomegalovirus was cultured from a vitreous biopsy. Autopsy revealed disseminated cytomegalovirus in both patients. Widespread retinal necrosis was evident, with typical nuclear and cytoplasmic inclusions of cytomegalovirus. Electron microscopy showed herpes virus, while immunoperoxidase techniques showed cytomegalovirus. The altered cell-mediated response present in homosexual patients may be responsible for the clinical syndromes of Kaposi's sarcoma and opportunistic infection by Pneumocystis carinii, herpes simplex, or cytomegalovirus. Retinal involvement in adult cytomegalic inclusion disease (CID) is usually associated with the concomitant presence of a neoplastic disorder of the haemopoietic and reticuloendothelial systems or treatment with immunosuppressive drugs following allotransplantation.1-3 While the diagnosis of CID can often be suggested by the ophthalmoscopic appearance,4 confirmation is made by demonstrating the inclusion bodies in urine, saliva, and biopsy specimens, rising serum titres, or positive cultures.6 Recently a syndrome has been described involving homosexual males comprising a severe, acquired immunodeficiency and characterised by weight loss, fever, and severe, unrelenting, often fatal infection with opportunistic microorganisms including cytomegalovirus, herpes simplex virus, Pneumocystis carinii, and Candida albicans.78 Other

RESUME L'objectif de cette ~.tude ouverte prospective ~tait d'~valuer l'int~r~t des a~.rosols d'is6thionate de pentamidine t~ la dose quotidienne de 300 mg dans le traitement de relais de 13 ~pisodes de pneumocystose survenus chez des... more

RESUME L'objectif de cette ~.tude ouverte prospective ~tait d'~valuer l'int~r~t des a~.rosols d'is6thionate de pentamidine t~ la dose quotidienne de 300 mg dans le traitement de relais de 13 ~pisodes de pneumocystose survenus chez des patients atteints de syndrome d'immunod~ficience acquise. Les a~rosols de pentamidine ont 6t~ administr~s dans 11 cas apr~s un traitement d'une dur~e moyenne de 10 jours par rassociation trim~thoprime-sulfam~thoxazole, et dans 2 cas apr~s 6 jours de traitement par la pentamidine intraveineuse. Apr~s une dur~e totale du traltement anti-Pneurnocystis de 21 jours, tous les patients ont ~t~ consid~r~s gu~ris sur les crit~res cliniques. Une aggravation des anomalies radiologiques et gazom~triques a ~t~ constat~e chez deux patients pr~.sentant une pathologie pulmonaire associ~e (tuberculose et sarcome de Kaposi). La tol6rance des a6rosols de pentamidine a 6t6 bonne. Deux patients ont d6velopp~ des signes de surinfection bronchique. Au total, cette ~tude montre l'int~r~t du traitement s~quentieltraitement par vote g~n~rale puis locale-des pneumocystoses non s(~v~res li~es au SIDA. Mots-ch~s : SIDA-Pneumocystose-A~rosols de pentamidine.