Biomedical subjects

P R Williamson

Publications and source records attributed to P R Williamson.

At least 19 recordsLinked to original sources

PubMed2002

An auxotrophic pigmented Cryptococcus neoformans strain causing infection of the bone marrow.

Cryptococcosis, caused by an encapsulated fungus, Cryptococcus neoformans, has emerged as a life-threatening infection in HIV-positive individuals and other immunocompromised hosts. This report describes an unusual strain of C. neoformans isolated from an AIDS patient that developed pigment on Sabouraud's medium. The yeast was auxotrophic for adenine due to a deletion in the coding region of ADE2, and was complemented by introduction of a functional copy of the ADE2 gene from C. neoformans. The yeast had an unusual myelotropism that was clinically evident as a pancytopenia with displacement of bone marrow precursors by yeast cells, and it had an unusual spectrum of infection in the human host. This is the first description of a nutritional auxotroph of C. neoformans isolated from a patient.

AIDS-Related Opportunistic Infections↗

PubMed2001

Phenytoin versus valproate monotherapy for partial onset seizures and generalized onset tonic-clonic seizures.

BACKGROUND: Phenytoin and valproate are commonly used antiepileptic drugs. It is generally believed that phenytoin is more effective for partial onset (simple partial, complex partial and secondary generalized tonic-clonic seizures) seizures whilst valproate is more effective in generalized onset seizures (generalized tonic-clonic seizures, absence, myoclonus) although there is no evidence from randomized controlled trials to support this belief. The use of individual patient data meta-analysis enabled us to examine time to event outcomes which are important in epilepsy monotherapy trials, and also to examine treatment-covariate interactions. OBJECTIVES: To review the best evidence comparing phenytoin and valproate when used as monotherapy in subjects with partial onset seizures, or generalized onset tonic-clonic seizures with or without other generalized seizure types. SEARCH STRATEGY: Our search strategy included: (i) the Cochrane Epilepsy Group trial register, (ii) MEDLINE 1966-2000, (iii) hand-searching relevant journals, (iv) the pharmaceutical industry, and (v) researchers in the field. SELECTION CRITERIA: Randomized controlled trials in children or adults with partial onset seizures or generalized onset tonic-clonic seizures. Trials must have included a comparison of phenytoin monotherapy with valproate monotherapy. DATA COLLECTION AND ANALYSIS: This was an individual patient data review. Outcomes were time to (i) withdrawal of allocated treatment, (ii) 12 month remission, (iii) six month remission, and (iv) first seizure post randomization. Data were analysed using stratified logrank analysis with results expressed as hazard ratios (HR) and 95% confidence intervals (95% CI), where a HR>1 indicates an event is more likely on phenytoin. A test for interaction between treatment and seizure type (partial onset versus generalized onset) was also undertaken for each outcome. MAIN RESULTS: Data were available for 669 subjects from five trials, representing 60% of the subjects recruited into the eleven trials that met our inclusion criteria. One important limitation of these data is that in four of the five trials, for patients classified as having generalized onset seizures, tonic-clonic seizures were the only seizure types recorded at follow up, despite the fact that some patients will have been experiencing other generalized seizure types such as absence or myoclonus. Their results for the generalized seizures therefore relate only to generalized onset tonic-clonic seizures. The main overall results were as follows (HR(95% CI), HR>1 indicates a clinical advantage for phenytoin for both remission outcomes and a clinical advantage for valproate for the outcomes time to withdrawal and time to first seizure) (i) time to withdrawal of allocated treatment 1.10(0.79-1.54), (ii) time to 12 month remission 1.04(0.78-1.38), (iii) time to six month remission 0.89(0.71-1.11), and (iv) time to first seizure 0.92(0.74-1.14). The results suggest no overall difference between drugs for these outcomes. The test for an interaction between treatment and seizure type (generalized versus partial onset) was non significant for all outcomes. REVIEWER'S CONCLUSIONS: We have not found evidence that a significant difference exists between phenytoin and valproate for the outcomes examined in this review. As generalized seizures such as absence and myoclonus were counted in only one trial, results do not address the treatment of these seizure types. We found no unequivocal evidence to overthrow or support the policy of using valproate in generalized onset tonic-clonic seizures and phenytoin in partial onset seizures.

Anticonvulsants↗

PubMed2001

Phenobarbitone versus phenytoin monotherapy for partial onset seizures and generalized onset tonic-clonic seizures.

BACKGROUND: Worldwide, phenytoin and phenobarbitone are commonly used antiepileptic drugs. They are more likely to be used in the developing world than the developed world, primarily because they are inexpensive. The aim of this review is to summarise data from existing trials comparing phenytoin and phenobarbitone. OBJECTIVES: To review the effects of phenobarbitone compared to phenytoin when used as monotherapy in patients with partial onset seizures or generalized tonic-clonic seizures with or without other generalized seizure types. SEARCH STRATEGY: Our search strategy has included: a) MEDLINE 1966 to 1998, b) the controlled trials register of the Cochrane Library, c) hand-searching relevant journals, d) the pharmaceutical industry, e) researchers in the field. SELECTION CRITERIA: Randomized controlled trials in children or adults with partial onset seizures or generalized onset tonic-clonic seizures. Trials must have included a comparison of phenobarbitone monotherapy with phenytoin monotherapy. DATA COLLECTION AND ANALYSIS: This was an individual patient data review. Outcomes were time to a) withdrawal of allocated treatment, b) 12 month remission, and c) first seizure post randomization. Data were analysed using a stratified logrank analysis with results expressed as hazard ratios (HR) and 95% confidence intervals (95% CI), where a HR>1 indicates an event is more likely to occur earlier on phenobarbitone than phenytoin. MAIN RESULTS: To date, data have been obtained for four of ten studies meeting the inclusion criteria, amounting to 599 patients, or approximately 65% of the potential data. The main overall results (HR, 95% CI) were: a) time to treatment withdrawal 1.62 (1.22 to 2.14), b) time to 12 month remission 0.93 (0.70 to 1.23), c) time to first seizure 0.84 (0.68 to 1.05). These results indicate a statistically significant clinical advantage for phenytoin in terms of treatment withdrawal and a non-significant advantage in terms of 12 month remission. Results for time to first seizure suggest a non-significant clinical advantage for phenobarbitone. REVIEWER'S CONCLUSIONS: The results of this review favour phenytoin over phenobarbitone, as phenobarbitone was significantly more likely to be withdrawn than phenytoin. Given that no significant differences for seizure outcomes were found, the higher withdrawal rate with phenobarbitone may be due to side effects.

Anticonvulsants↗

PubMed2001

Clinical, manometric, and EMG characteristics of patients with fecal incontinence.

Fecal incontinence occurs frequently in both men and women. Yet, few studies on fecal incontinence have separated the evaluation and interpretation of data by gender. This study was designed to identify differences in the clinical, anorectal manometry, and electromyography (EMG) characteristics between male and female patients with fecal incontinence. We compared 53 incontinent males (mean age, 64 years) with 72 incontinent females (mean age, 61 years). Each patient underwent computerized anorectal manometry, and invasive (pudendal nerve conduction studies and concentric needle EMG) and noninvasive EMG (anal sensor surface electrode). An anal incontinence score (AIS) ranging from 0 to 6 was used to categorize patients. Male patients had higher incontinence scores at presentation (AIS greater than 4, 70% vs. 54%). Female patients had significantly lower resting pressure (40 vs. 53 mmHg, p < 0.05) and more women had sphincter asymmetry (36% vs. 25%, p < 0.05). Both groups had similar PNTMLs (2.41 vs. 2.47 ms). Difference was seen in the net strength of the sphincter (women 4.0 microV vs. men 8.0 microV, p < 0.05), as measured by noninvasive EMG. In conclusion, it is well known that there are differences in anorectal physiologic function between male and female patients with normal continence. Comparing male and female patients with fecal incontinence suggests that female patients tend to have worse sphincter function that men. Both groups had similar EMG alterations, suggesting a common neurogenic injury as etiology. Future studies are needed to address the sexes separately.

Adult↗

PubMed2001

Time-related decay of the benefits of biofeedback therapy.

Although immediate results are good to excellent in great majority of patients who undergo biofeedback treatment (BFT) for chronic constipation and fecal incontinence, they tend to loose the benefit over a period of time. The purpose of this study was to evaluate the long-term sustainability of results after successful biofeedback treatment. Two groups of patients who successfully completed BFT at our institution from 1995 to 1997 were created based on the date of completion. The first had a mean follow-up of 35 months and the second group was followed for an average of 12 months. Both groups were questioned as to the presence of constipation and incontinence. The questioning was focused depending on the patient's diagnosis. This information was then compared with the initial BFT results. Overall, all patients were satisfied by the initial BFT results. All patients initially had an excellent or good response to BFT. However, after a mean of 35 months, in the first group, 19 of 22 patients had a near complete regression back to their pre-biofeedback status. In the 14 patients in the second group with mean follow-up of 12 months, 11 had a significant decay in benefits. Only time was a significant factor in the decay of BFT benefits. In conclusion, BFT is highly effective in the treatment of selected patients with complex defecation disorders. Although there is a high initial success rate, there is a clear loss of the immediate benefits over time. Other factors such as dietary habits, pelvic floor exercises, manometry, invasive EMG, and rectal sensation did not correlate with long-term outcomes. The comparison between the two groups reveals a linear model describing the time decay of the benefits of BFT. Based on the linear model, patients may need reevaluation after one year and may benefit from additional BFT.

Adult↗

PubMed2001

Multiple virulence factors of Cryptococcus neoformans are dependent on VPH1.

Acidification of vesicular compartments plays an important role in a number of cellular transport processes, including protein secretion, metal cofactor insertion, glycosylation and pH stability. In the present study, we identify and characterize a component of the vesicular proton pump, Vph1p, to determine its role in the virulence of the AIDS-related fungal pathogen Cryptococcus neoformans. Insertional mutagenesis and plasmid rescue were used to identify the VPH1 gene by screening for mutants defective in laccase activity. Disruption of VPH1 resulted in defects in three virulence factors (capsule production, laccase and urease expression), as well as a growth defect at 37 degrees C, but only a small growth reduction at 30 degrees C. These effects were duplicated by the vacuolar (H+)-ATPase inhibitor bafilomycin A1. Furthermore, the vph1 insertional mutant was also avirulent in a mouse meningo-encephalitis model. Complementation of the insertional mutant with wild-type VPH1 resulted in a recovery of virulence factor expression, normal growth at 37 degrees C and restoration of full virulence. These studies establish the importance of the VPH1 gene and vesicular acidification in the virulence of C. neoformans.

AIDS-Related Opportunistic Infections↗

PubMed2001

Laccase of Cryptococcus neoformans is a cell wall-associated virulence factor.

Virulence is the outcome of an interaction between the host and a microbe and is characterized by a large array of opposing reactions operating at the host-pathogen interface. Cryptococcus neoformans is an important opportunistic pathogen in immunocompromised patients, including those with human immunodeficiency virus, and expresses a virulence-associated laccase which is believed to oxidize brain catecholamines and iron as a defense against host immune cells. In the present report, we investigated the cellular location of laccase to understand more fully how it contributes to cryptococcal virulence. A monoclonal antibody to the C. neoformans laccase was generated and used to show localization in the cell walls of representative serotype A (H99) and serotype D (B-3501) strains by immunoelectron microscopy. In addition, confocal microscopy was used to show a peripheral location of green fluorescent protein-tagged laccase expressed in live H99 cells. Biochemical studies showed that laccase could be released from intact cells or cell wall fractions with glucanase enzymes but was retained in the cell wall after sequential extraction with 1 M NaCl, 6 M urea, and 1% sodium dodecyl sulfate. The presence of a hydrolyzable bond linking laccase to the cell wall was suggested by removal of laccase from cell wall preparations after they were boiled in 1% sodium dodecyl sulfate, as was the presence of a disulfide or thioester bond by removal with dithiothreitol or beta-mercaptoethanol. These data show that laccase is present as a tightly associated cell wall enzyme that is readily accessible for interactions with host immune cells.

Animals↗

PubMed2001

Evolutionary divergence of an elongation factor 3 from Cryptococcus neoformans.

Elongation factor 3 (EF3) is considered a promising drug target for the control of fungal diseases because of its requirement for protein synthesis and survival of fungi and a lack of EF3 in the mammalian host. However, EF3 has been characterized only in ascomycete yeast. In order to understand the role of EF3 in a basidiomycete yeast, we cloned the gene encoding EF3 from Cryptococcus neoformans (CnEF3), an important fungal pathogen in immunocompromised patients, including those infected with human immunodeficiency virus. CnEF3 was found to encode a 1,055-amino-acid protein and has 44% identity with EF3 from Saccharomyces cerevisiae (YEF3). Expressed CnEF3 exhibited ATPase activity that was only modestly stimulated by ribosomes from S. cerevisiae. In contrast, CnEF3 showed tight binding to cryptococcal ribosomes, as shown by an inability to be removed under conditions which successfully remove Saccharomyces EF3 from ribosomes (0.5 M KCl or 2 M LiCl). CnEF3 also poorly complemented a YEF3 defect in a diploid null mutant and two temperature-sensitive mutants which have been shown previously to be complemented well by EF3 from other ascomycetes, such as Candida albicans. These data clearly identify the presence of a functioning EF3 in the basidiomycete yeast C. neoformans, which demonstrates an evolutionary divergence from EF3 of ascomycete yeast.

Adenosine Triphosphatases↗

PubMed2000

Assessing the potential for bias in meta-analysis due to selective reporting of subgroup analyses within studies.

Subgroup analysis is frequently used to investigate heterogeneity in meta-analysis. Subgroup data are not always available, and researchers should record what data were available for each trial. If data were not available, and it is known that the subgroup data were collected, the potential for selective reporting should be considered. Bias due to selective publishing of reports is widely recognized in meta-analysis. In contrast, selective reporting within studies is little discussed but potentially important. We explored this problem by evaluating the effect of potential bias in subgroup analysis due to within-study selective reporting with an existing meta-analysis. The review addressed malaria chemoprophylaxis in pregnancy. The conclusion in the original review, that benefit is limited to primigravidae, was based on subgroup analysis using the three trials out of five which reported on subgroups. We developed a method of sensitivity analysis that imputes data for the missing subgroups to assess the robustness of the results and the conclusions drawn. In this particular example, our analysis indicates that the estimate of effect reported in the review is most likely to overestimate the true effect and the conclusion that benefit is limited to primigravidae may be false.

Bias↗

PubMed2000

Temperature measured at the axilla compared with rectum in children and young people: systematic review.

OBJECTIVE: To evaluate the agreement between temperature measured at the axilla and rectum in children and young people. DESIGN: A systematic review of studies comparing temperature measured at the axilla (test site) with temperature measured at the rectum (reference site) using the same type of measuring device at both sites in each patient. Devices were mercury or electronic thermometers or indwelling thermocouple probes. STUDIES REVIEWED: 40 studies including 5528 children and young people from birth to 18 years. DATA EXTRACTION: Difference in temperature readings at the axilla and rectum. RESULTS: 20 studies (n=3201 (58%) participants) had sufficient data to be included in a meta-analysis. There was significant residual heterogeneity in both mean differences and sample standard deviations within the groups using different devices and within age groups. The pooled (random effects) mean temperature difference (rectal minus axillary temperature) for mercury thermometers was 0.25 degrees C (95% limits of agreement -0.15 degrees C to 0.65 degrees C) and for electronic thermometers was 0. 85 degrees C (-0.19 degrees C to 1.90 degrees C). The pooled (random effects) mean temperature difference (rectal minus axillary temperature) for neonates was 0.17 degrees C (-0.15 degrees C to 0. 50 degrees C) and for older children and young people was 0.92 degrees C (-0.15 degrees C to 1.98 degrees C). CONCLUSIONS: The difference between temperature readings at the axilla and rectum using either mercury or electronic thermometers showed wide variation across studies. This has implications for clinical situations where temperature needs to be measured with precision.

Adolescent↗

PubMed2000

Carbamazepine versus valproate monotherapy for epilepsy.

BACKGROUND: Carbamazepine and valproate are drugs of first choice for epilepsy. Despite the lack of hard evidence from individual randomized controlled trials, there is strong clinical belief that valproate is the drug of choice for generalized epilepsies and carbamazepine for partial epilepsies. OBJECTIVES: To overview the best evidence comparing carbamazepine and valproate monotherapy SEARCH STRATEGY: Our search strategy included: (a) MEDLINE 1966-99, (b) The Cochrane Library 1999 issue 4, (c) The trial register of the Cochrane Epilepsy Group (d) the pharmaceutical industry. SELECTION CRITERIA: Randomized controlled trials comparing carbamazepine and valproate monotherapy for epilepsy. DATA COLLECTION AND ANALYSIS: This was an individual patient data review. Outcome measures were time to withdrawal of allocated treatment, time to 12 month remission, and time to first seizure post randomization. Data were analysed using the stratified Logrank test with results expressed as hazard ratios (HR) (95% CI), where HR>1 indicates an event is more likely on valproate. A test for an interaction between treatment and epilepsy type (partial versus generalized) was also undertaken. MAIN RESULTS: Results Data were available for 1265 patients from five trials, representing 85% of the patients recruited into the eight trials that met our inclusion criteria. The main overall results (HR 95% CI) were: Time to treatment withdrawal 0.97 (0.79-1.18), 12 month remission 0.87 (0.74-1.02), first seizure 1.09 (0.96-1.25) suggesting no overall difference for these outcomes. The test for an interaction between treatment and epilepsy type was non significant for time to treatment withdrawal and 12 month remission, but significant for time to first seizure. The age distribution of adults classified as having a generalized epilepsy indicate that significant numbers of patients may have had their epilepsy misclassified. REVIEWER'S CONCLUSIONS: We have found some evidence to support the policy of using carbamazepine as the first treatment of choice in partial epilepsies, but no evidence to support the choice of valproate in generalized epilepsies, but confidence intervals are too wide to confirm equivalence. Misclassification of patients may have confounded our results, and has important implications for the design and conduct of future trials.

Adult↗

PubMed2000

Individual patient data meta-analysis of randomized anti-epileptic drug monotherapy trials.

Meta-analysis may be based on either aggregate data or individual patient data (IPD). Three reasons why IPD are desirable for the meta-analysis of anti-epileptic drug (AED) monotherapy trials are: (1) to undertake a more complete analysis of time-to-event outcomes; (2) to investigate the interaction between AED and type of epilepsy; and (3) to undertake re-analysis of the trial to obtain results for all relevant outcomes. We demonstrate that IPD meta-analysis is possible in AED research. Problems arose from missing data at four levels: (1) unknown trials; (2) known trials but no IPD supplied; (3) known trials but missing outcome data for some individuals within trials; and (4) known trials but missing covariate data for some individuals within trials. Empirical evidence of the reliability of meta-analyses based on aggregate rather than individual patient data is still lacking. Examples of other benefits such projects may bring include improvements to the design of a new trial in the area, in terms of the sample size considerations, the definition of outcomes and data collection.

Anticonvulsants↗

PubMed1999

The yeast Cryptococcus neoformans uses 'mammalian' enhancer sites in the regulation of the virulence gene, CNLAC1.

Transcriptional regulation in mammalian and plant cells is distinguished from fungi by the presence of blocks of multiple interacting DNA binding sites distributed over a relatively large upstream region of genes and the ability to use glutamine-rich enhancers such as Sp1. We offer evidence that the haploid yeast Cryptococcus neoformans contains a virulence gene, CNLAC1, having regulatory properties more similar to mammalian systems than to that of yeast. We used a novel promoter plasmid, pVEW, and electromobility shift assay techniques adapted for the fungus for the first systematic structural and functional study of a 5'-enhancer region of a basidiomycete fungus using the upstream region of CNLAC1. Two groups of interactive enhancer regions, located over a range of 1.5kb from the mRNA start site are involved in CNLAC1 regulation (region 2: -1721 to -1615 and region 7) in addition to a TATA promoter at position -539. Region 2 contains a consensus Sp1 site and region 7 contains a consensus E2F site, each of which shows significant binding to nuclear proteins under derepressed conditions; cooperative binding was also suggested between DNA-binding protein of these sites and those binding nearby CCAAT sequences in each region. Two regions of repression were also evident under derepressed conditions (region 5: -1351 to -1207 and region 8: -991 to -971). Identification of functional Sp1 binding sites and the presence of multiple interactive enhancer sites over a fairly large upstream range suggests that cryptococcal transcriptional regulation contains features often associated with higher eukaryotic regulation. C. neoformans thus may provide a unique system for the study of certain aspects of higher eukaryotic transcription, using yeast genetic approaches. In addition, properties of basidiomycete yeast such as Cryptococcus exemplified in the present study suggest an evolutionary progression in gene regulation within fungi toward properties exhibited in the kingdoms Animalia and Plantae.

Animals↗

PubMed1999

Small-cell carcinoma of the rectum: report of two cases.

Small-cell carcinoma of the rectum is an infrequent pathologic finding, and its precise incidence is unknown. Its incidence is less than 0.2 percent among all colorectal cancers. This tumor manifests highly aggressive behavior. The treatment of choice is combination chemotherapy similar to that used for small-cell carcinoma of the lung, but in small localized tumors surgery plus chemotherapy is an alternative. We present two cases of small-cell carcinoma of the lower rectum and a review of the literature.

Aged↗

PubMed1999

Catecholamine oxidative products, but not melanin, are produced by Cryptococcus neoformans during neuropathogenesis in mice.

Melanin has been proposed as a virulence factor in Cryptococcus neoformans, but its presence has not been shown unambiguously in vivo. Validated methods used previously to show production of cryptococcal eumelanin pigment in vitro (P. R. Williamson, K. Wakamatsu, and S. Ito, J. Bacteriol. 180:1570-1572, 1998) were used to assess for production of laccase-derived products in mouse brain of the Lacc+ strains, 2E-TUC, H99 (serotype A), and ATCC 34873 (serotype D), and the Lacc- strain, 2E-TU. Pyrrole-2,3, 5-tricarboxylic and pyrrole-2,3-dicarboxylic acid, specific degradation products of catecholamine derivatives such as melanin, were found in all Lacc+ strains, but not in the Lacc- strain, 2E-TU. However, the presence of melanin pigment itself could not be demonstrated in the same cells. Lack of the specific degradation products aminohydroxyphenylalanine and aminohydroxyphenylethylamine in Lacc+ strains upon hydriodic acid hydrolysis showed that pheomelanin was also not produced by the fungus in vivo. These are the first data to support the generation of catecholamine oxidation products by C. neoformans in vivo, but they do not support postenzymatic polymerization of these products to form typical eumelanin, as previously proposed.

Animals↗

PubMed1999

Laccase protects Cryptococcus neoformans from antifungal activity of alveolar macrophages.

While laccase of Cryptococcus neoformans is implicated in the virulence of the organism, our recent studies showing absence of melanin in the infected mouse brain has led us to a search for alternative roles for laccase in cryptococcosis. We investigated the role of laccase in protection of C. neoformans against murine alveolar macrophage (AM)-mediated antifungal activity by using a pair of congenic laccase-positive (2E-TUC) and laccase-deficient (2E-TU) strains. The laccase-positive cells with laccase derepression were more resistant to the antifungal activity of AM than a laccase-deficient strain ([28.9 +/- 1.2]% versus [40.2 +/- 2.6]% killing). Addition of L-dopa to Cryptococcus to produce melanin in a laccase-positive strain resulted in a slight increase in protection of C. neoformans from the antifungal activity of macrophages ([25.4 +/- 3.4]% versus [28.9 +/- 1.2]% killing). Recombinant cryptococcal laccase exhibited iron oxidase activity in converting Fe(II) to Fe(III). Moreover, recombinant laccase inhibited killing of C. neoformans by hydroxyl radicals catalyzed by iron in a cell-free system. Addition of the hydroxyl radical scavenger mannitol or dimethyl sulfoxide to AMs prior to the introduction of cryptococcal cells decreased killing of both strains and reduced the difference in susceptibility between the laccase-positive and laccase-deficient strains. Furthermore, laccase-mediated protection from AM killing was inhibited by the addition of Fe(II), presumably by overcoming the effects of the iron oxidase activity of cryptococcal laccase. These results suggest that the iron oxidase activity of laccase may protect C. neoformans from macrophages by oxidation of phagosomal iron to Fe(III) with a resultant decrease in hydroxyl radical formation.

Animals↗

PubMed1998

Melanin biosynthesis in Cryptococcus neoformans.

Pigment production by Cryptococcus neoformans is virulence associated. Dopamine- and 3,4-dihydroxyphenylalanine-melanin products were identified after acidic permanganate oxidation, alkaline hydrogen peroxide oxidation, or hydrolysis with hydriodic acid. These data provide direct chemical evidence for the formation of eumelanin polymers by catecholamine oxidation by laccase alone followed by oxidative coupling of dihydroxyindole.

Acids↗

PubMed1998

Cryptococcus neoformans: virulence and host defences.

Cryptococcus neoformans represents a model organism for the study of virulence and the host response. In this discussion, there is a focus on the genetic, molecular, and biochemical aspects of C. neoformans as it interacts with the host. Investigations into direct and indirect virulence phenotypes are now possible. The molecular aspects of two major virulence factors, capsule and melanin, are characterized. Yeast polyol metabolism through mannitol is examined as a potential biochemical pathway for virulence. The concept of C. neoformans differentially expressed genes within the host or in response to certain environmental cues can be used indirectly to identify potential virulence genes. However, despite significant progress in molecular pathogenesis with C. neoformans, the future of research in this area will require a certain critical mass of investigators to help share in the developmental costs which continue to occur.

Cryptococcosis↗