Rapid and extensive surface changes near Titan's equator: evidence of April showers.

Although there is evidence that liquids have flowed on the surface at Titan's equator in the past, to date, liquids have only been confirmed on the surface at polar latitudes, and the vast expanses of dunes that dominate Titan's equatorial regions require a predominantly arid climate. We report the detection by Cassini's Imaging Science Subsystem of a large low-latitude cloud system early in Titan's northern spring and extensive surface changes (spanning more than 500,000 square kilometers) in the wake of this storm. The changes are most consistent with widespread methane rainfall reaching the surface, which suggests that the dry channels observed at Titan's low latitudes are carved by seasonal precipitation.

Comparison of end-tidal and transcutaneous measures of carbon dioxide during general anaesthesia in severely obese adults.

BACKGROUND: Patients with severe obesity (body mass index (BMI) greater than 35 kg x m(-2)) present difficulties for end-tidal carbon dioxide (FE'(CO(2))) monitoring. Previous studies suggest that transcutaneous (TC) carbon dioxide measurements could be valuable, so we compared FE' and TC measures with Pa(CO(2)) in severely obese patients during anaesthesia. METHODS: We studied patients with severe obesity (BMI >or=40 kg x m(-2)) undergoing gastric bypass surgery. Carbon dioxide was measured with both FE' and TC devices. The difference between each measure (FE'(CO(2)) and TC-CO(2)) and the Pa(CO(2)) was averaged for each patient to provide one value, and data compared with a non-paired, two-way t-test, Fisher's exact test. RESULTS: We studied 30 adults (aged 18-54 yr, mean 41, SD 8.0 yr; weight: 115-267 kg, mean 162, SD 35 kg). The absolute difference between the TC-CO(2) and Pa(CO(2)) was 0.2 (0.2) (mean, SD) kPa while the absolute difference between the FE'(CO(2)) and Pa(CO(2)) was 0.7 (0.4) kPa (P<0.0001). The bias and precision were +0.1 (0.3) kPa for TC vs arterial carbon dioxide and -0.7 (0.4) kPa for FE' vs arterial carbon dioxide. CONCLUSIONS: Transcutaneous carbon dioxide monitoring provides a better estimate of Pa(CO(2)) than FE'(CO(2)) in patients with severe obesity.

Structure of secreted aspartic proteinases from Candida. Implications for the design of antifungal agents.

Pathogens of the genus Candida can cause life threatening infections in immuno-compromised patients. The three-dimensional structures of two closely related secreted aspartic proteinases from C. albicans complexed with a potent (Ki = 0.17 nM) inhibitor, and an analogous enzyme from C. tropicalis reveal variations on the classical aspartic proteinase theme that dramatically alter the specificity of this class of enzymes. The novel fungal proteases present: i) an 8 residue insertion near the first disulfide (Cys45-Cys50, pepsin numbering) that results in a broad flap extending towards the active site; ii) a seven residue deletion replacing helix hN2 (Ser110-Tyr114), which enlarges the S3 pocket; iii) a short polar connection between the two rigid body domains that alters their relative orientation and provides certain specificity; and i.v.) an ordered 12 residue addition at the carboxy terminus. The same inhibitor (A-70450) binds in an extended conformation in the two variants of C. albicans protease, and presents a branched structure at the P3 position. However, the conformation of the terminal methylpiperazine ring is different in the two crystals structures. The implications of these findings for the design of potent antifungal agents are discussed.

Structure of a secreted aspartic protease from C. albicans complexed with a potent inhibitor: implications for the design of antifungal agents.

The three-dimensional structure of a secreted aspartic protease from Candida albicans complexed with a potent inhibitor reveals variations on the classical aspartic protease theme that dramatically alter the specificity of this class of enzymes. The structure presents: (1) an 8-residue insertion near the first disulfide (Cys 45-Cys 50, pepsin numbering) that results in a broad flap extending toward the active site; (2) a 7-residue deletion replacing helix hN2 (Ser 110-Tyr 114), which enlarges the S3 pocket; (3) a short polar connection between the two rigid body domains that alters their relative orientation and provides certain specificity; and (4) an ordered 11-residue addition at the carboxy terminus. The inhibitor binds in an extended conformation and presents a branched structure at the P3 position. The implications of these findings for the design of potent antifungal agents are discussed.

Cholesterol sulfate protects Candida albicans from inhibition by sphingosine in vitro.

Sphingosine is known to have potent biological activity, including pronounced anti-microbial action in vitro against Candida albicans and some bacteria. Several sphingosine bases are present in stratum corneum at concentrations several orders of magnitude above those in other tissues. Sphingosine forms an undissociated salt with organic sulfates, however, so that the free sphingosine in the epidermis may be inactivated by the cholesterol sulfate known to be present. To investigate this hypothesis, C. albicans was grown in cultures with graded concentrations of sphingosine added in ethanol. In 1% ethanol, 0.1-100 microgram/ml sphingosine completely prevented growth of the organism for 12 h. All cultures eventually entered log-phase growth and reached limiting density at a rate inversely proportional to sphingosine concentration. When sphingosine was added, together with an equimolar amount of cholesterol sulfate, there was no delay in the onset of growth of the yeast and the rate of growth and final density were similar to control cultures. These results demonstrate that natural ratios of cholesterol sulfate neutralize the anti-microbial activity of sphingosine in vitro. In the epidermis, endogenous cholesterol sulfate is hydrolyzed by sterol sulfatase at the skin surface, where the released sphingosine may resist microbial colonization of the stratum corneum. This mechanism for liberating anti-microbial sphingosine base only at the skin surface may protect the viable epidermis against known cytotoxic effects of free sphingosine.

Double-blind comparison of itraconazole and placebo in the treatment of tinea corporis and tinea cruris.

BACKGROUND: Tinea corporis and tinea cruris are usually treated with a topical antifungal agent unless the infection is unresponsive, involves an extensive area, is chronic, or is in a difficult-to-access area. In these cases oral antifungals are frequently used. OBJECTIVE: This double-blind study was undertaken to determine whether a 2-week course of oral itraconazole would produce statistically significant clinical and mycologic improvement in the treatment of tinea corporis, tinea cruris, or both, over the results obtained with placebo. A second objective was to determine the safety of itraconazole, through routine measurements of serum chemistry profiles. METHODS: Sixty-seven patients were entered into a double-blind, multicenter study to compare the clinical and mycologic effects of itraconazole, 100 mg daily (45 patients), and placebo (22 patients) on tinea corporis and/or tinea cruris. The duration of treatment was 2 weeks. The investigators assessed signs and symptoms and performed a potassium hydroxide examination and culture at baseline, at termination of therapy, and 2 weeks after completion of treatment. RESULTS: Twenty-two (96%) of 23 evaluable patients in the itraconazole group had healed or markedly improved lesions, as compared with 5 of 13 (39%) in the placebo group (p < or = 0.01). Similarly, the condition in 13 of 23 patients (57%) in the itraconazole group was mycologically cleared at the end of treatment whereas this result occurred in only 2 (17%) of 12 patients in the placebo group (p = 0.02). The prevalence of adverse side effects was lower for the itraconazole-treated group (20%) than for the placebo-treated group (36%). CONCLUSION: Itraconazole 100 mg once daily is an effective agent for the treatment of tinea cruris and tinea corporis.

Oral and perioral candidosis.

The following article has been assembled from the current literature and our clinical experience to provide a comprehensive review of oral and perioral candidal infections. A brief review of the epidemiology and pathogenesis is followed by a description of the various clinical signs and symptoms associated with oral candidosis. Methods useful in arriving at a diagnosis of candidal infection as well as a number of effective therapeutic modalities are discussed. In addition, special considerations relating to the treatment of patients with other concurrent mucosal diseases and long-term antifungal maintenance regimes are addressed.

Comparative production and rapid purification of Candida acid proteinase from protein-supplemented cultures.

Six Candida spp. that were previously characterized for cutaneous pathogenicity were assessed for Candida acid proteinase (CAP) production in albumin-supplemented, nitrogen-restricted media. C. albicans CAP production was compared in media supplemented with albumin, casein, collagen, hemoglobin, or keratin and in TC medium 199. C. albicans, C. stellatoidea, and C. tropicalis, which are cutaneous pathogens in murine infections, produced 3.3 to 4.7 times more CAP than did the nonpathogens C. parapsilosis and C. guilliermondii. C. krusei, a nonpathogen, produced negligible amounts of enzyme. C. albicans CAP production was similar in each protein-supplemented medium, and only a single acid proteinase was recovered from each one. Rapid CAP purification from culture supernatants was achieved by hollow fiber and stirred cell ultrafiltration followed by Affi-Gel blue and Sephacryl column chromatographies. The highest yield, purity, and specific activity of CAP were obtained from keratin-supplemented medium supernatants, producing 2.86 mg of purified CAP from a 7-liter culture. CAP was characterized as a 41,500-dalton glycoprotein, with a pI of 4.5; a pH range of 2.5 to 5.5; and broad substrate specificity, including that for keratin, denatured collagen, hemoglobin, casein, and albumin. Isolation of CAP also isolated the keratinolytic proteinase of Candida spp. CAP was inhibited by pepstatin A, but not by EDTA or phenylmethylsulfonyl fluoride. Monospecific antibody to CAP was produced in mice and reacted only to the 41,500-dalton protein, as determined by immunoblot analysis. High CAP production by cutaneous pathogenic Candida spp. supports the fact that CAP is a potential virulence factor that may facilitate Candida colonization and invasion of skin. CAP production from keratin-supplemented medium was superior to that from the other media that were tested and yielded sufficient and suitable enzyme for use in immunoassays of CAP antigen and antibody.

Systemic candidiasis.

Systemic candidiasis is a disease of increasing incidence and proportions, which appears to be associated with the advances in modern medicine. It involves primarily patients with severe debilitating and malignant disease who are receiving immunosuppressive, cytotoxic, antimetabolite, and antibiotic therapy. Side effects of these otherwise major therapeutic agents predispose patients to opportunistic fungal infections, of which candidiasis is the most common. The high morbidity and mortality of disseminated candidiasis in neutropenic patients are difficult obstacles to obtaining the optimal, if not full, potential of modern chemotherapy for cancer. The inability to diagnose early invasive and systemic candidiasis is a major handicap that delays timely initiation of antifungal therapy. The paucity of highly efficacious antifungal agents with low toxicity severely limits the ability to successfully cure systemic fungal infections in cancer patients. Aggressive research into the basic biology of Candida spp. is necessary for directing the development of better diagnostic methods and improved antifungal drugs.

Scanning electron microscopy of epidermal adherence and cavitation in murine candidiasis: a role for Candida acid proteinase.

Adherence of blastoconidia to epidermal corneocytes is an early event in Candida colonization and infection of the skin. Pathogenic species adhere more avidly than nonpathogenic species, transform to hyphal growth, and invade the stratum corneum of the skin. Adherence was studied by scanning electron microscopy of experimental murine cutaneous Candida infections, using six species of Candida. Candida albicans and C. stellatoidea blastoconidia, applied to newborn mouse skin, adhered to the stratum corneum in greater numbers than other species tested, acquired fibrils and strands of amorphous mucinlike material ("cohesin") between spores and the corneocyte cell surface, formed cavitations in the corneocyte surface, and invaded the corneocyte envelope by hyphal growth at sites distant to the point of blastoconidia attachment. Other species showed little or no adherence, colonization, or cavitation of the corneocyte surface, except C. tropicalis, which showed intermediate results. Pepstatin, an inhibitor of Candida acid proteinase, did not alter adherence or cohesion formation, but inhibited formation of corneocyte cavitations about adherent blastoconidia, suggesting that this enzyme may facilitate adherence/invasion events on skin. Depletion of surface lipids did not alter the formation of cohesin material or the adherence process. Adherence and invasion of epithelium by pathogenic Candida species include the interaction of blastoconidia with an epithelial surface cohesin material that participates in the adherence process. Candida acid proteinase, a keratinolytic enzyme, may participate in the cavitation process of the corneocyte surface by C. albicans.

Oral candidiasis.

Oral candidiasis is one of the more common infections encountered by man. It manifests itself in a variety of forms, and can arise in any region of the mouth. A generally innocuous and treatable disorder in healthy individuals, it can be the herald of underlying disorders that affect the endocrine or immune systems. In the debilitated or seriously ill, the capacity for seemingly benign oral candidiasis to progress into fulminating fatal infections by hematogenous dissemination must not be ignored. Oral candidiasis in the otherwise healthy patient challenges the physician's ability to identify the contributing factors and associated diseases that predispose to the infection. In the cancer and transplant patient, oral candidiasis is a harbinger of systemic infection, and has become a significant obstacle to successful management of patients with life-threatening diseases. Although several efficacious agents are available for uncomplicated candidiasis, there remains a need for better prophylactic agents to prevent dissemination and better therapeutic agents to treat established infections in immunocompromised patients.

Intrauterine herpes simplex infection resembling mechanobullous disease in a newborn infant.

We present a case of transplacentally acquired intrauterine herpes simplex virus infection in a newborn delivered at 36 weeks' gestation by cesarean section because of intrauterine growth retardation and maternal preeclampsia. The mother experienced a single episode of serotype 2 herpes progenitalis at 14 weeks' gestation. At birth the infant manifested clinical findings of herpes simplex virus infection, which resembled epidermolysis bullosa and aplasia cutis congenita. Preexisting cutaneous lesions and intact fetal membranes at delivery strongly support a transplacentally acquired intrauterine herpes simplex virus infection. Repeated Tzanck smears, viral cultures, and immunohistochemical studies of the skin were required to confirm the diagnosis. Intrauterine herpes simplex virus infection is associated with significant morbidity and mortality but responds to antiviral therapy. Therefore this diagnosis must be considered in the neonate born with bullous or eroded skin lesions.

Adherence of Candida species to human epidermal corneocytes and buccal mucosal cells: correlation with cutaneous pathogenicity.

Adherence of microorganisms to epidermal corneocytes may be a prerequisite for cutaneous colonization and infection. Six species of Candida were assayed in vitro for adherence to human epidermal corneocytes and buccal mucosal cells, and compared to previous studies of pathogenicity in a rodent model of cutaneous candidiasis. C. albicans and C. stellatoidea exhibited marked adherence to both epithelial cell types over time, and were cutaneous pathogens in the rodent model. The remaining species showed little or no adherence, and were nonpathogenic to skin. Adherence to corneocytes was not inhibited by ethylenediamine tetraacetic acid, mannan polysaccharide, or concanavalin A lectin. Fresh human serum, but not heat-inactivated serum, inhibited C. albicans adherence by 50%, and was associated with the deposition of complement components, C3 and factor B on blastospores. Adherence to epithelial corneocytes and mucosal cells is a property of pathogenic species of Candida, and may participate in cutaneous colonization and infection mechanisms. Adherence was time-dependent, and did not require divalent cations. Cell wall mannan may participate in the "adhesin" complex. Mannan activation of serum complement and deposition of C3 and factor B on blastospores may provide a protective action by inhibiting Candida adherence to corneocytes.

A comparison of bone marrow transplantation with maintenance chemotherapy for patients with acute nonlymphoblastic leukemia in first complete remission.

Twenty patients treated with maintenance chemotherapy for acute nonlymphoblastic leukemia after achieving complete remission were compared with 13 patients who underwent bone marrow transplantation from an HLA-identical sibling. The median age was 27 years for both maintenance chemotherapy patients (range 17-42 years) and for patients undergoing bone marrow transplantation (range 16-42 years). The 1-year survival for maintenance chemotherapy was 80% vs. 54% with bone marrow transplantation (p = NS). Complete remission durability was 70% at 1 year for maintenance chemotherapy (34% projected for 5 years) compared with no relapses in the first year with bone marrow transplantation (p = 0.01). Patients on maintenance chemotherapy were hospitalized for an average of 22 days (range 0-171 days) during the first 12 months of treatment. Patients undergoing bone marrow transplantation were hospitalized for an average of 82 days (range 41-113 days) in the same time period. Severe hematologic toxicity was seen in 13/13 bone marrow transplantation patients and 6/20 maintenance chemotherapy patients. Chronic graft-vs.-host disease occurred in 3/7 surviving bone marrow transplantation patients. Maintenance chemotherapy had an average first year cost of +3,076.00 for patients who did not relapse and +48,827.00 for patients that relapsed. The first year costs for bone marrow transplantation averaged +84,102.00. Thus, maintenance chemotherapy was associated with a better early survival, less toxicity, and lower cost than bone marrow transplantation in the first year after initiating therapy. However, fewer relapses with bone marrow transplantation suggest that it will yield a higher long-term survival rate.

Acute graft-versus-host disease resulting from normal donor blood transfusions.

2 fatal cases of graft-versus-host disease (GvHD) occurred following blood product transfusions given to patients receiving standard chemotherapy for Hodgkin's disease. GvHD was established by HLA typing, clinical course, and compatible skin biopsy. 23 cases of GvHD following transfusion of blood products from normal donors are also reviewed. It should be suspected when fever or rash appear 1-2 weeks after transfusion of unirradiated blood products into a compromised host or when pancytopenia following chemotherapy is prolonged or unexpectedly severe. Prevention of GvHD by irradiation of granulocytes, platelets and packed red blood cells given to immunosuppressed patients is recommended to prevent this often fatal disease.