Recent changes in candidemia trends in a tertiary hospital (2011–2018)

BackgroundThe epidemiology of candidemia has changed over the last decades and varies widely among geographic areas.AimsWe examined in children (aged 0–14) with candidemia the trends in the incidence rate of this infection, as well as the clinical characteristics of the patients, in order to optimize the prognosis and the control measures of this serious disease.MethodsA retrospective cohort study of candidemia in the period 2011–2018 in the neonatal intensive care unit (NICU), pediatric ICU (PICU) and pediatric wards of a tertiary hospital, was conducted. The clinical course, Candida species isolated, antifungal susceptibility, outcome and incidence rates were analyzed and compared.ResultsWe diagnosed 68 episodes of candidemia in 62 children, 48% occurred in the NICU, 31% in the PICU and 21% in pediatric wards. Candida albicans was the most frequent species isolated in NICU infants (53%), and Candida parapsilosis predominated among PICU patients (59%) and pediatric wards (50%). One third of NICU infants had invasive candidiasis (IC), most of them having extremely low birth weight (ELBW) (35%). All isolates were susceptible to the antifungal administered. Over time, the incidence of candidemia decreased in the PICU (from 2.2 to 0.3 episodes/1000 patient-days, OR = 0.6; 95%CI 0.5–0.8), whereas in the NICU and in the wards remained stable. Mortality occurred mostly in NICU patients (26%), predominated in ELBW infants and did not change over time.ConclusionsThe higher incidence and mortality of candidemia and IC observed in preterm infants requires a continuous evaluation of practices and diagnostic methods which will allow improving the prognosis of this most vulnerable population.     

Adenovirus 36 improves glycemic control and markers of Alzheimer's disease pathogenesis

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder worldwide. While the causes of AD are unclear, several risk factors have been identified, including impaired glycemic control, which significantly increases the risk of cognitive decline and AD. In vitro and in vivo studies show that human adenovirus 36 (Ad36) improves glycemic control by increasing cellular glucose uptake in cells, experimental animal models and in humans who are naturally exposed to the virus. This study, tested improvement in glycemic control by Ad36 and delay in onset of cognitive decline in APPswe transgenic mice (Tg2576 line), a model of genetic predisposition to impaired glycemic control and AD. Three-month old APPswe mice were divided into Ad36 infected (Ad36) or mock infected (control) groups and baseline glycemic control measured by glucose tolerance test (GTT) prior to infection. Changes in glycemic control were determined 10- and 24-week post infection. Serum insulin was also measured during GTT. Cognition was determined by Y-maze test, while motor coordination and skill acquisition by rotarod test. Glycemic control as determined by GTT showed less deterioration in Ad36 infected mice over time, accompanied by a significant attenuation of cognitive decline. Analysis of brain tissue lysate showed significantly reduced levels of amyloid beta 42 in Ad36 mice relative to control mice. Golgi-Cox staining analysis also revealed reduced dendritic spines and synaptic gene expression in control mice compared to Ad36 infected mice. This proof of concept study shows that in a mouse model of AD, Ad36 improves glycemic control and ameliorates cognitive decline.     

A 12-year study of fungal infections in Rio Grande do Sul,Southern Brazil

BackgroundThe number of fungal infections has increased in recent years in Rio Grande do Sul (RS), Brazil. Epidemiological studies are important for proper control of infections.AimsTo evaluate the etiology of fungal infections in patients in RS, from 2003 to 2015.MethodsThis is a retrospective and longitudinal study carried out at Mycology Department of Central Laboratory of RS; 13,707 samples were evaluated. The variables sex, age, site of infection, and etiologic agent were analyzed. Susceptibility of Candida to fluconazole was tested in isolates from samples collected in 2015 from 51 outpatients.ResultsOf the 13,707 samples, 840 cases (6.12%) of fungal infections were found and included in the analyses; female gender accounted for the 55.9% of the cases. The main fungus was Candida albicans (450 cases, 53.38%; p < 0.001). Onychomycosis was the most frequent infection in superficial mycoses. Systemic mycoses accounted for 54.05% of the cases, from which 68.8% occurred in males, mainly HIV-positive (33.11%), and the main etiologic agent in these cases was Cryptococcus neoformans (73.13%). Among 51 samples tested for susceptibility to fluconazole, 78.43% of Candida isolates were susceptible; 5.88% were susceptible in a dose-dependent manner, and 15.69% were resistant.ConclusionsC. albicans is a common cause of fungal infections in RS, accounting for half of the cases; resistance to antifungals was found in non-hospitalized patients. In addition, women seem to be more susceptible to fungal infections than men, however men show more systemic mycoses than women. The nails are the most common site of infection.     

Brain and plasma levels of testosterone, dihydrotestosterone and estradiol in the one-day-old rat.

Current evidence indicates that the secretion of testosterone during perinatal life is essential in organizing the male brain which subsequently directs the male pattern of gonadotrophin (GTH) secretion and adult male sexual behavior in the rat. It has been hypothesized that testosterone is converted into estradiol enzymatically in the brain prior to its action. In the absence of testosterone and with the resultant low levels of estradiol, female patterns of gonadotrophin secretion and behavior result. In order to investigate this hypothesis further, the endogenous levels of gonadal steroids in the plasmas and brains of 24–48 hr old male and female rats were determined. Pooled samples were analyzed for testosterone, dihydrotestosterone and estradiol by radioimmunoassay. Testosterone levels in male brain and plasma samples were significantly (10-fold) higher than those in the female brain and plasma samples. Brain levels of estradiol were significantly higher in the male than in the female neonate, while plasma levels were identical. Whether the higher level of estradiol in the male brain is due to enzymatic conversion from testosterone within the brain differences in permeability or some other mechanism cannot be stated at this point. The significantly higher brain levels of both testosterone and estradiol in male neonates do fit the pattern predicted by the present concept of sexual differentiation. Dihydrotestosterone levels in brain and plasma of male rats were about 25% of those of testosterone. However in females the brain levels of dihydrotestosterone were significantly higher than testosterone even though the plasma levels of these hormones were identical. This may reflect a protective mechanism through which permeability of testosterone is lowered in the neonatal female brain during the critical period or simply a functional conversion of testosterone to dihydrotestosterone in the female during this period.     

The mechanism of inhibition and "reversal" of mitogen-induced lymphocyte activation in a model of purine-nucleoside phosphorylase deficiency

Purine-nucleoside phosphorylase (PNP) is a purine degradative enzyme that catalyzes the phosphorolysis of (deoxy) inosine or (deoxy) guanosine to their respective bases and (deoxy) ribose 1-phosphate. A severe T-cell immune deficiency syndrome with hypouricemia is associated with impaired PNP function. To study the biochemical basis for this syndrome we created an in vitro model of PNP deficiency in mitogen (phytohemagglutinin)-stimulated normal human peripheral blood lymphocytes using guanosine to competitively inhibit deoxyguanosine phosphorolysis. Guanosine-induced guanine toxicity was reversed by adenine. Under these conditions, deoxyguanosine (5-45 microM) diminished mitogen stimulation to 30% of control while increasing the deoxyguanosine triphosphate pool (dGTP) by over 20-fold. Deoxycytidine reversed deoxyguanosine toxicity with a diminution of dGTP accumulation, but no significant change in the deoxycytidine triphosphate pool. Thymidine reversed the deoxyguanosine toxicity, repleted the thymidine triphosphate (dTTP) pool, and caused an even further increase in the accumulation of dGTP. These data support a model of lymphotoxicity in PNP deficiency based on dGTP accumulation with inhibition of ribonucleotide reductase and depletion of the thymidine triphosphate pool. Thymidine triphosphate depletion is reversed by either deoxycytidine or thymidine; however, the former diminishes dGTP accumulation (probably by competition for phosphorylation) and the latter potentiates dGTP accumulation (probably through feedback augmentation of guanosine diphosphate (GDP) reduction by ribonucleotide reductase secondary to an increased dTTP pool).     

Mice: Pregnancy termination, lactation, and aggression

Hysterectomy on the 14th day of gestation in combination with the immediate and repetitive presentation of 1-day-old foster young produced lactation and fighting behavior toward adult males. The fighting behavior was comparable to that displayed by normally parturient mice. Hysterectomy alone or the presentation of pups alone initiated neither lactation nor fighting. Hysterectomy performed prior to the 12th day of gestation plus the presentation of foster young also did not initiate lactation or fighting. Ovariectomy performed in conjunction with hysterectomy on the 14th day of pregnancy together with the presentation of young produced lactation but not fighting behavior, thus suggesting that fighting and lactation are controlled by somewhat different hormonal mechanisms.     

Glutamine-dependent carbamyl phosphate synthetase during fetal and neonatal life in the rat

The pyrimidine-synthesizing enzyme, carbamyl phosphate synthetase II (CP synthetase II) was examined in the rat during normal fetal development and in the fed and calorically deprived neonate. CP synthetase II in the placenta, liver, gut, carcass, and brain showed the following common properties; ability to utilize ammonia as well as l-glutamine as a substrate; negligible enhancement of activity by N-acetyl l-glutamate; inhibition of activity by the glutamine analog, 6-diazo-5-oxo-l-norleucine; and by the phosphorylated pyrimidine uridine 5′-triphosphate. Apparent K_m values for l-glutamine of CP synthetase II in placenta and extrahepatic fetal structures were found to vary from 1.1 to 2.3 × 10^?5M. In the brain and placenta, tissue concentrations of l-glutamine obtained at serial time points during gestation were at least 200-fold higher. Relative activities for the enzymes catalyzing the subsequent two steps in pyrimidine biosynthesis, aspartate transcarbamylase and dihydroorotase, were substantially greater than CP synthetase II at all times measured and therefore were consistent with the possibility that CP synthetase II may be one of the rate-limiting steps in the de novo biosynthesis of pyrimidines in the placenta and extrahepatic fetal tissues. Serial observations were obtained in placenta, brain, and neonatal muscle to see whether correlations could be demonstrated between concentrations of CP synthetase II per milligram of tissue DNA and daily increments in total tissue DNA. In all these structures, higher concentrations of enzyme were observed during periods of more rapid DNA accumulation. Certain exceptions were also demonstrable. Thus, manifest CP synthetase II activity persisted in the placenta beyond day 16 of gestation (when placental DNA no longer increases); and neonatal muscle exhibited CP synthetase II activity when all net increments in DNA were abolished by caloric deprivation. The latter observations have suggested that the enzyme may be operative (and of possible regulatory significance) even in the absence of cellular proliferation.     

Evidence suggesting direct oxidation of human erythrocyte membrane sulfhydryls by copper

Results are presented which suggest that cupric ion can directly oxidize the sulfhydryls of human erythrocyte membrane proteins leading to the formation of disulfide links. When packed ghosts were incubated in cupric sulfate (0.3 to 0.7 mM) at pH 8, and electrophoresed on sodium dodecyl sulfate polyacrylamide gels in the absence of dithiothreitol bands 1, 2 (spectrin); 4.2 and 5 (actin) diminished in intensity concomitant with the appearance of high molecular weight material. Band 3 moved to its dimeric position on the gel. Evidence that these crosslinks result from formation of new disulfide links due to direct copper binding includes: (a) reversal of crosslinking upon addition of dithiothreitol; (b) blockage of the effect by N-ethylmaleimide, EDTA and mercuric chloride. The effect of copper was observed under N₂, suggesting that it is not related to air oxidation. Furthermore, the crosslinking effect does not require high copper concentrations if the ghost concentration is low. The possible implication of these results with regard to copper induced hemolytic anemias is briefly discussed.     

Molecular characterization of Cryptococcus gattii genotype AFLP6/VGII isolated from woody debris of divi-divi (Caesalpinia coriaria), Bonaire,Dutch Caribbean

BackgroundThe basidiomycetous yeast Cryptococcus gattii is an emerging and primary pathogen. There is a lack of information about its environmental spread outside outbreak regions in Mediterranean Europe, North and South America. Environmental sampling for C. gattii and molecular characterization of the obtained isolates will provide an insight into the global spread of the various genotypes.MethodsWoody debris of native divi-divi (Caesalpinia coriaria) trees were sampled across Bonaire, Dutch Caribbean. Colonies suspected for Cryptococcus species were subjected to standard mycology investigations and identification by matrix-assisted laser desorption ionization-time of flight mass spectrometry. Isolates identified as C. gattii were subjected to amplified fragment length polymorphism genotyping, mating-type analysis and multi-locus sequence typing.ResultsTen colonies of C. gattii were cultured from different trunk hollows of the same divi-divi tree. Molecular characterization showed that all isolates were genotype AFLP6/VGII and mating-type α. Multi-locus sequence typing revealed that all isolates were genetically indistinguishable from each other.ConclusionsC. gattii is present in the environment of Bonaire, which suggests that this yeast is likely to be present in the environment of other Caribbean islands.     

Effects of glycol structure on the transesterification equilibria of oxo-osmium(VI) esters

We report equilibrium data on reactions between the N,N,N′,N′-tetramethylethylenediamine oxo-osmium(VI) ester of thymine with a variety of polyhydroxylated compounds including sugars, glycosides, sugar alcohols, and nucleosides. Some rate data are also included. The cis-furanosidic nucleosides showed the largest equilibrium constants; among the pyranosidic systems, the cis (ae) structure was preferred.