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Positive selection at sites of multiple amino acid replacements since rat-mouse divergence.

New alleles become fixed owing to random drift of nearly neutral mutations or to positive selection of substantially advantageous mutations. After decades of debate, the fraction of fixations driven by selection remains uncertain. Within 9,390 genes, we analysed 28,196 codons at which rat and mouse differ from each other at two nucleotide sites and 1,982 codons with three differences. At codons where rat-mouse divergence involved two non-synonymous substitutions, both of them occurred in the same lineage, either rat or mouse, in 64% of cases; however, independent substitutions would occur in the same lineage with a probability of only 50%. All three non-synonymous substitutions occurred in the same lineage for 46% of codons, instead of the 25% expected. Furthermore, comparison of 12 pairs of prokaryotic genomes also shows clumping of multiple non-synonymous substitutions in the same lineage. This pattern cannot be explained by correlated mutation or episodes of relaxed negative selection, but instead indicates that positive selection acts at many sites of rapid, successive amino acid replacement.

Alleles↗

Sexual selection for size and symmetry in a diversifying secondary sexual character in Drosophila bipectinata Duda (Diptera: Drosophilidae).

Results of intrapopulation studies of sexual selection and genetic variation and covariation underlying elements of the sex comb of Drosophila bipectinata are presented. The magnitude of the sex comb, a sexual ornament, varies significantly among Australasian populations, motivating research into the evolutionary mechanisms responsible for its incipient diversification. The comb is composed of stout black teeth on the front legs of males arranged in three distinct segments: C1, C2, and C3. Significant sexual selection in field populations in northeastern Queensland, Australia, was detected for increasing C2 and body size, and simultaneously for reducing comb positional fluctuating asymmetry. In contrast, sexual selection was not detected for other comb segments, nor for sternopleural bristle number or symmetry. Selection intensities for C2 and comb positional fluctuating asymmetry were similar in magnitude, and although they were opposite in sign, values across twelve sampling dates, or selection episodes, were uncorrelated. Heritability estimates for C2 were high and significant across years, whereas heritability estimates for comb positional asymmetry were small, and generally nonsignificant. The major sex comb segments (C1 and C2) were significantly and positively correlated genetically, indicating the potential for correlated evolution of these components of the comb under sexual selection. The original finding of a significant positive genetic correlation between the magnitude of this sex trait and its positional asymmetry indicates that the counteracting and independent selection pressures detected could contribute to the maintenance of genetic variation sustaining sexual selection. The study documents the simultaneous presence of sexual selection in nature and of heritable genetic variation underlying expression of the sex comb, fundamental conditions necessary for its adaptive diversification. Drosophila bipectinata may be a valuable model for studies of adaptive diversification and incipient speciation by sexual selection.

Adaptation, Biological↗

Molecular evolution of prolactin in primates.

Pituitary prolactin, like growth hormone (GH) and several other protein hormones, shows an episodic pattern of molecular evolution in which sustained bursts of rapid change contrast with long periods of slow evolution. A period of rapid change occurred in the evolution of prolactin in primates, leading to marked sequence differences between human prolactin and that of nonprimate mammals. We have defined this burst more precisely by sequencing the coding regions of prolactin genes for a prosimian, the slow loris (Nycticebus pygmaeus), and a New World monkey, the marmoset (Callithrix jacchus). Slow loris prolactin is very similar in sequence to pig prolactin, so the episode of rapid change occurred during primate evolution, after the separation of lines leading to prosimians and higher primates. Marmoset prolactin is similar in sequence to human prolactin, so the accelerated evolution occurred before divergence of New World monkeys and Old World monkeys/apes. The burst of change was confined largely to coding sequence (nonsynonymous sites) for mature prolactin and is not marked in other components of the gene sequence. This and the observations that (1) there was no apparent loss of function during the episode of rapid evolution, (2) the rate of evolution slowed toward the basal rate after this burst, and (3) the distribution of substitutions in the prolactin molecule is very uneven support the idea that this episode of rapid change was due to positive adaptive selection. In the slow loris and marmoset there is no evidence for duplication of the prolactin gene, and evidence from another New World monkey (Cebus albifrons) and from the chimpanzee and human genome sequences, suggests that this is the general position in primates, contrasting with the situation for GH genes. The chimpanzee prolactin sequence differs from that of human at two residues and comparison of human and chimpanzee prolactin gene sequences suggests that noncoding regions associated with regulating expression may be evolving differently from other noncoding regions.

Amino Acid Sequence↗

The Adaptive Evolution Database (TAED).

BACKGROUND: Developing an understanding of the molecular basis for the divergence of species lies at the heart of biology. The Adaptive Evolution Database (TAED) serves as a starting point to link events that occur at the same time in the evolutionary history (tree of life) of species, based upon coding sequence evolution analyzed with the Master Catalog. The Master Catalog is a collection of evolutionary models, including multiple sequence alignments, phylogenetic trees, and reconstructed ancestral sequences, for all independently evolving protein sequence modules encoded by genes in GenBank [1]. RESULTS: We have estimated from these models the ratio of nonsynonymous to synonymous nucleotide substitution (Ka/Ks), for each branch in their respective evolutionary trees of every subtree containing only chordata or only embryophyta proteins. Branches with high Ka/Ks values represent candidate episodes in the history of the family where the protein may have undergone positive selection, a phenomenon in molecular evolution where the mutant form of a gene must have conferred more fitness than the ancestral form. Such episodes are frequently associated with change in function. We have found that an unexpectedly large number of families (between 10 and 20% of those families examined) have at least one branch with a notably high Ka/Ks value (putative adaptive evolution). As a resource for biologists wishing to understand the interaction between protein sequences and the Darwinian processes that shape these sequences, we have collected these into The Adaptive Evolution Database (TAED). CONCLUSIONS: Placed in a phylogenetic perspective, candidate genes that are undergoing evolution at the same time in the same lineage can be viewed together. This framework based upon coding sequence evolution can be readily expanded to include other types of evolution. In its present form, TAED provides a resource for bioinformaticists interested in data mining and for experimental evolutionists seeking candidate examples of adaptive evolution for further experimental study.

Animals↗

Nitrate tolerance. A review of the evidence.

Organic nitrates are well established in the treatment of a wide variety of cardiovascular disorders, most notably angina pectoris and congestive heart failure. However, attenuation of, or tolerance to, haemodynamic and anti-ischaemic effects may occur with all long-acting nitrate formulations. In the majority of patients continuous administration of long acting nitrates tends to promote the development of attenuation, while intermittent administration avoids it. Likewise, higher-doses appear to induce attenuation to a greater degree than lower doses. Attenuation of haemodynamic effects and exercise tolerance in heart failure patients, and of clinical end-points in angina patients, appears to be less than attenuation of exercise testing end-points in angina patients. While the use of intermittent therapy avoids the development of attenuation, it may expose the patient to an as yet undefined risk of silent and/or symptomatic anginal episodes occurring during the nitrate-free interval. Likewise, the role of concomitant therapy in avoiding this potential risk remains to be defined. Means of avoiding attenuation may include the coadministration of sulfhydryl donors such as N-acetylcysteine. Alternatively, angiotension-converting enzyme (ACE) inhibitors such as captopril may block renin-angiotensin system-induced reflex sympathetic stimulation. Attenuation may occur to a greater or lesser degree in individual patients. The proportion of attenuators vs non-attenuators remains to be defined, as does a means of identifying such patients prospectively by clinical and/or laboratory parameters. Conflicting results among smaller studies may reflect variable proportions of attenuators vs non-attenuators. However, conflicting results among larger studies may reflect differences in patient selection criteria, such as selecting patients with positive and reproducible stress tests and little in the way of spontaneously occurring angina versus selecting patients with positive but variable stress tests and frequent episodes of spontaneously induced angina. The former group may reflect pure fixed coronary artery disease with little in the way of vasospasm, or change in vasomotor tone, while the latter group may reflect greater variability in vasomotor tone and/or more in the way of plaque instability. The clinical efficacy of long acting nitrates might therefore be expected to be greatest in those patients with larger numbers of spontaneously occurring angina episodes. Recent data suggest that nitrates may have important direct effects on coronary vessels including dilating eccentric coronary stenoses, dilating intercoronary collateral channels and having greater dilating effects on more diseased segments as opposed to less diseased coronary segments.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

Prevention of infections in the neutropenic patient.

Infections are still a frequent cause of morbidity in patients with hematologic malignancies. Until 10 years ago the microorganisms most frequently encountered were aerobic gram-negative bacilli, which in many centers were responsible for, on average, one infection per neutropenic period. Many different approaches to the prevention of these infections have been designed. Patients have been kept in strict isolation and given broad-spectrum antibiotics prophylactically. This approach has led to a decrease in the incidence of infections in these patients, but compliance and emergence of resistance have been important limiting factors. The rationale of selective decontamination with trimethoprim-sulfamethoxazole or quinolones was that the elimination of potentially pathogenic aerobic gram-negative bacilli from the gastrointestinal tract would prevent colonization and subsequent infection. The use of these antibiotics has led to a shift in the spectrum of infections. Infections due to gram-negative bacilli have been virtually eliminated, but the number of infections caused by gram-positive bacteria is rapidly increasing; however, the latter infections are most often only minor. In some centers quinolones are now used together with agents active against these gram-positive bacteria. The approach of selective decontamination has not led to fewer febrile episodes or to a lower mortality in neutropenic patients. Future studies should be directed towards identifying the cause of febrile episodes and the epidemiology of gram-positive bacterial infections.

Acute Disease↗

The association between endogenous free testosterone and cognitive performance: a population-based study in 35 to 90 year-old men and women.

The relationship between testosterone (T) and cognition has yielded conflicting evidence, showing both positive and negative influences of T on cognitive performance. The association between free testosterone (FT) and cognition was revisited in a large population-based sample of 1276 women and 1107 men (35-90 years of age), assessed individually on visuospatial, verbal fluency, semantic, and episodic memory tasks. For men, higher FT levels were associated with better visuospatial abilities, semantic memory, and episodic memory, with greater positive influence with increasing age. Statistical covariates included age, education, and select medications. For women, FT was negatively associated with verbal fluency, semantic memory, and episodic memory, although only verbal fluency was significant at conventional alpha levels. These results support the claim that FT exerts sex-specific influences on cognitive performance.

Adult↗

Parenting and childhood behavior problems: mothers' and fathers' voices.

Through thematic analysis of interviews, we explored parents' perceptions of their child's behaviors and their own parenting. A purposive sample of four mothers and four fathers who reported behavior problems for their 7(1/2) year-old-child was selected from a larger study. Parents appraised their child positively despite episodic behavior problems, and described parenting in the context of financial difficulties, marital conflict, chronic illness, lack of support for parenting, and abuse in the parent's family of origin. Data suggest a need for timely mental health services to assist parents with managing their child's behaviors within the context of the family's situation.

Adult↗

The prion protein gene in humans revisited: lessons from a worldwide resequencing study.

Ample evidence has accumulated showing that different coding variants of the PRNP gene confer differential susceptibility for prion diseases. Here we evaluate the patterns of nucleotide variation in PRNP exon 2, which includes all the protein-coding sequence, by resequencing a worldwide sample of 174 humans for 2378 bp. In line with previous studies, we found two main haplotypes differentiated by nonsynonymous substitution in codon 129. Our analyses reveal the worldwide pattern of variation at the PRNP gene to be inconsistent with neutral expectations, indicating instead an excess of low-frequency variants, a footprint of the action of either positive or purifying selection. A comparison of neutrality test statistics for PRNP with other human genes indicates that the signal of positive selection on PRNP is stronger than expected from a possible confounding genome-wide background signal of population expansion. Two main conclusions arise from our analysis. First, the existence of an ancient, stable, balanced polymorphism that has been claimed in a previous study and related to cannibalism can be rejected and is shown to be due to ascertainment bias. Second, our results are consistent with a complex history of selection including mainly positive selection, even if short local periods of balancing selection (Kuru-like episodes), or even a weak purifying selection model, are consistent with our data.

Amino Acid Substitution↗

Episodic evolution of protein hormones in mammals.

Pituitary growth hormone (GH) and prolactin have been shown previously to display a pattern of evolution in which episodes of rapid change are imposed on a low underlying basal rate (near-stasis). This study was designed to explore whether a similar pattern is seen in the evolution of other protein hormones in mammals. Seven protein hormones were examined (with the common alpha-subunit of the glycoprotein hormones providing an additional polypeptide for analysis)--those for which sequences from at least four eutherian orders are available with a suitable non-eutherian outgroup. Six of these (GH, prolactin, insulin, parathyroid hormone, glycoprotein hormone alpha-subunit, and luteinizing hormone beta-subunit) showed markedly variable evolutionary rates in each case with a pattern of a slow basal rate and bursts of rapid change, the precise positions of the bursts varying from protein to protein. Two protein hormones (follicle-stimulating hormone beta-subunit and thyroid-stimulating hormone beta-subunit) showed no significant rate variation. Based on the sequences currently available, and pooling data from all eight proteins, the phase of slow basal change occupied about 85% of the sampled evolutionary time, but most evolutionary change (about 62% of the substitutions accepted) occurred during the episodes of rapid change. It is concluded that, in mammals at least, a pattern of prolonged periods of near-stasis with occasional episodes of rapid change provides a better model of evolutionary change for protein hormones than the one of constant evolutionary rates that is commonly favored. The mechanisms underlying this episodic evolution are not yet clear, and it may be that they vary from one group to another; in some cases, positive selection appears to underlie bursts of rapid change. Where gene duplication is associated with a period of accelerated evolution this often occurs at the end rather than the beginning of the episode. To what extent the type of pattern seen for protein hormones can be extended to other proteins remains to be established.

Animals↗

Molecular evolution of ruminant lysozymes.

The evolution of a new digestive enzyme, stomach lysozyme, from an antibacterial host defense enzyme provides a link between molecular evolution and organismal evolution. Lysozymes have been recruited at least three times (twice from a conventional lysozyme c and once from a calcium-binding lysozyme c) in vertebrates for functioning in the stomach. The recruitment of lysozyme for its new biological function involved many molecular changes, beyond those required to adapt the protein to function in the stomach. The evolution of the stomach lysozyme gene has been extensively studied in ruminant artiodactyls. In ruminants, the lysozyme c gene has duplicated to yield a family of about ten genes. These duplications allowed: (1) specialization of gene function and (2) increased levels of expression. The ruminant stomach lysozyme genes have evolved in an episodic fashion - there was a period of rapid adaptive sequence evolution, driven by positive selection in the early ruminant, that was followed by an increase in purifying selection upon the well-adapted stomach lysozyme sequence among modern species. Recombination of small portions (exons) of the genes between members of the lysozyme gene family may have aided in adaptive evolution. Evolution to a stomach lysozyme is not irreversible; at least one member of the ruminant stomach lysozyme gene family appears to have reverted to a more ancestral function, yet retains hallmarks of its history as a stomach lysozyme.

Animals↗

Switch from depression to mania--a record study over decades between 1920 and 1982.

A representative sample of 908 hospital records covering admissions between 1920 and 1982 for depression was analyzed in order to assess the switch rate to hypomania/mania. The results are the following: (1) Over the decades of this century there has been a substantial increase in hospital admissions in Zurich for both depression and mania, but the ratio remained constant. (2) Due to this increase the clinicians can observe more spontaneous switches from depression to mania, which favors the assumption of a causal relationship when treatment is applied. (3) 64 of the 908 patients (7.0%) admitted for depression switched to hypomania or mania. Hypomania was observed in 48 cases (5.3%) and mania in 16 cases (1.7%). (4) The analysis of predisposing factors to a switch has resulted in a simple finding. Bipolar patients (including schizomanics) have an 8-fold higher switch rate (28.9%) than the unipolars (3.7%). The switchers are equally distributed over the two sexes and do not differ in the frequency of a family history of affective psychoses, schizophrenia, schizoaffective disorders, or suicide. (5) Bipolarity correlates positively with 'higher number of previous episodes', with 'readmitted' and with 'switch'. Therefore, studies selecting readmissions [Lewis and Winokur 1982] overrepresent switchers purposely. (6) A loglinear analysis together with some univariate strategies show that over the decades (from 1920 to 1982) there was no significant increase in switches of unipolar or bipolar patients. In conclusion, there is no evidence for a treatment-induced switch. This result is in line with Prien et al. [1973] and with Lewis and Winokur [1982].

Age Factors↗

Work retention and nonspecific low back pain.

STUDY DESIGN: A cohort study of patients with nonspecific low back pain (LBP) participated in a 4-week multidisciplinary rehabilitation program. OBJECTIVE: To identify factors that predict work retention 24 months after treatment in patients with nonspecific LBP. SUMMARY OF BACKGROUND DATA: There is evidence that select physical, psychologic, and psychosocial factors are related to positive outcome for work-related nonspecific LBP. However, there is very little information related to work retention following an episode of nonspecific LBP. This is an exploratory study to identify select physical and psychosocial factors related to work retention. METHODS: Patients who returned to work after treatment (n = 67) were followed for 2 years. Physical baseline measures included tests of flexibility, strength, and functional capacity. Psychosocial baseline measures were The Symptoms Checklist 90-R, The Pain Beliefs and Perceptions Inventory, The Oswestry Scale of perceived disability, The Work Stress Inventory, and The Quality of Life Scale. All physical parameters, perceived disability, and quality of life were tested before and after treatment. The dependent variable, work retention, was defined as the number of days that the subject worked during the 2-year follow-up period. Survival analysis was used to establish the predictive model. RESULT: The average time out of work before treatment was 9 months (standard deviation 12.8) for 67 subjects (mean age 40 years [standard deviation 9.6]), including 18 females and 49 males. There were 18 participants (25%) that had interruption of work retention at follow-up. Average work retention was 362 days (range 47-682). Variables that reached a P value of <0.10 in the bivariate analysis were included in the multivariate analysis. They were trunk flexion (hazard ratio [HR = 2.4], 95% confidence interval [CI] 1.24-4.38; P = 0.01), trunk extension (HR = 2.1, 95% CI 1.02-4.16; P = 0.04), the somatization scale from the Symptom Checklist 90 revised (HR = 2.0, 95% CI 1.03-4.05; P = 0.04), and the obsessive-compulsiveness scale from the Symptom Checklist 90 revised (HR = 0.4, 95% CI 0.12-1.15; P = 0.09). Results showed that post-test trunk flexion, somatization, and obsessive compulsiveness predicted work retention (final trunk flexion HR = 2.5 [95% CI 1.26-4.79; P = 0.01], somatization scale HR = 2.5 [95% CI 1.25-4.93; P = 0.01], and obsessive compulsion HR = 0.2 [95% CI 0.07-0.77; P = 0.02]). CONCLUSION: Psychosocial and physical factors are associated with work retention for patients with nonspecific LBP. The predictive value of certain constructs may vary with the time when they are assessed and how outcome is operationalized. Further studies are needed to confirm these findings.

Absenteeism↗

Selective dysfunction of ventricular electrode-endocardial junction following DC cardioversion in a patient with a dual chamber pacemaker.

A patient with a dual chamber pacemaker received two transthoracic (anterior-anterior paddle position) shocks for VF. Subsequent analysis of stimulation thresholds revealed a marked rise in the ventricular threshold only. Later, she received three additional shocks (anterior-posterior paddle position) during electrophysiological study to terminate episodes of induced VT. Following these, the ventricular stimulation threshold was > 10 V at 2.0 ms. The selective damage at the ventricular site in this patient led us to carry out in vitro studies that revealed a preferential shunting of high electrical energy into the ventricular lead, as compared to the atrial lead, following a DC shock. These observations may explain the selective pacing malfunction observed in out patient.

Burns, Electric↗

Phenotypic diversity of enterotoxigenic Escherichia coli strains from a community-based study of pediatric diarrhea in periurban Egypt.

No past studies of diarrhea in children of the Middle East have examined in detail the phenotypes of enterotoxigenic Escherichia coli (ETEC) strains, which are important pathogens in this setting. During a prospective study conducted from November 1993 to September 1995 with 242 children under 3 years of age with diarrhea living near Alexandria, Egypt, 125 episodes of diarrhea were positive for ETEC. ETEC strains were available for 98 of these episodes, from which 100 ETEC strains were selected and characterized on the basis of enterotoxins, colonization factors (CFs), and O:H serotypes. Of these representative isolates, 57 produced heat-stable toxin (ST) only, 34 produced heat-labile toxin (LT) only, and 9 produced both LT and ST. Twenty-three ETEC strains expressed a CF, with the specific factors being CF antigen IV (CFA/IV; 10 of 23; 43%), CFA/II (5 of 23; 22%), CFA/I (3 of 23; 13%), PCFO166 (3 of 23; 13%), and CS7 (2 of 23; 9%). No ETEC strains appeared to express CFA/III, CS17, or PCFO159. Among the 100 ETEC strains, 47 O groups and 20 H groups were represented, with 59 O:H serotypes. The most common O serogroups were O159 (13 strains) and O43 (10 strains). O148 and O21 were each detected in five individual strains, O7 and O56 were each detected in four individual strains, O73, O20, O86, and O114 were each detected in three individual strains, and O23, O78, O91, O103, O128, and O132 were each detected in two individual strains. The most common H serogroups were H4 (16 strains), 12 of which were of serogroup O159; H2 (9 strains), all of which were O43; H18 (6 strains); H30 (6 strains); and H28 (5 strains); strains of the last three H serogroups were all O148. Cumulatively, our results suggest a high degree of clonal diversity of disease-associated ETEC strains in this region. As a low percentage of these strains expressed a CF, it remains possible that other adhesins for which we either did not assay or that are as yet undiscovered are prevalent in this region. Our findings point out some potential barriers to effective immunization against ETEC diarrhea in this population and emphasize the need to identify additional protective antigens commonly expressed by ETEC for inclusion in future vaccine candidates.

Bacterial Proteins↗

Adaptive evolution in the photosensory domain of phytochrome A in early angiosperms.

Flowering plant diversity now far exceeds the combined diversity of all other plant groups. Recently identified extant remnants of the earliest-diverging lines suggest that the first angiosperms may have lived in shady, disturbed, and moist understory habitats, and that the aquatic habit also arose early. This would have required the capacity to begin life in dimly lit environments. If so, evolution in light-sensing mechanisms may have been crucial to their success. The photoreceptor phytochrome A is unique among angiosperm phytochromes in its capacity to serve a transient role under conditions where an extremely high sensitivity is required. We present evidence of altered functional constraints between phytochrome A (PHYA) and its paralog, PHYC. Tests for selection suggest that an elevation in nonsynonymous rates resulted from an episode of selection along the branch leading to all angiosperm PHYA sequences. Most nucleotide sites (95%) are selectively constrained, and the ratio of nonsynonymous to synonymous substitutions on branches within the PHYA clade does not differ from the ratio on the branches in the PHYC clade. Thus, positive selection at a handful of sites, rather than relaxation of selective constraints, apparently has played a major role in the evolution of the photosensory domain of phytochrome A. The episode of selection occurred very early in the history of flowering plants, suggesting that innovation in phyA may have given the first angiosperms some adaptive advantage.

Evolution, Molecular↗

[Clinical evaluation of endoscopic variceal ligation (EVL)].

From August 1992 through February 1993, we treated 21 patients with endoscopic variceal ligation (EVL). Two patients had a history of the esophageal variceal bleeding, but 19 patients did not have bleeding episodes. To evaluate preventive effect of bleeding, we selected the patients who had grade F2 or red color sign positive varices. We repeated EVL until varices improved into grade F0 or F1 and red color sign negative. The therapeutic goal was sometimes changed according to patient's general condition. No additional therapy was performed to eradicate varices, such as endoscopic injection sclerotherapy. As a result of our therapy, eradication rate was 73.7% and period of hospitalization were 25 +/- 11 days. No major complications were found during and after EVL. EVL affected neither liver function test nor size of gastric varices. Recurrent varices with red color sign were found in 4 patients, but easily controlled by retreatment with EVL. EVL seems to be convenient and effective therapy in our short-term study, and useful for preventive therapy of the esophageal variceal bleeding.

Aged↗

Persistent fungemia--risk factors and outcome in 40 episodes.

The aim of this multicenter survey was to assess risk factors and mortality in patients with persistent fungemia (PF). Cases of persistent fungemia, defined as positive blood culture for at least 3 causative days of antifungal therapy were selected. Forty cases of persistent fungemia (lasting more than 3 days) were compared with 270 non-persistent fungemias appearing within the same period, and analyzed by univariate and multivariate analysis for risk factors and outcome. The median number of days of positive culture was 4.4 (3 - 20): 22 episodes were due to Candida albicans, 1 due to non-albicans Candida spp., 6 episodes due to non-Candida spp. Yeasts: 15 were catheter related, 16 patients had yeast-infected surgical wounds, 12 were neutropenic, 4 cases were caused by species resistant in vitro, 2 to amphotericin B (Trichosporon spp.) and 2 to fluconazole (C. laurentii, C. glabrata). Fifteen patients (37.5%) died, 7 of whom due to fungemia. Nineteen cases had one known risk factor (10 had infected wound, 4 infected vascular catheter, 3 were neutropenic and 2 had inappropriate therapy). Fourteen cases had two known risk factors (4 had wound and infected catheter, 4 neutropenia and infected catheter, 2 neutropenia and resistant organism, 4 other combinations. Two cases had 3 known risk factors and one had 4 risk factors for persistent fungemia. Artificial ventilation, C. glabrata etiology, non-Candida spp. yeasts such as Trichosporon spp. and Cryptococcus spp. and prior surgery were significantly associated with persistent fungemia in univariate, whereas only C. glabrata etiology in multivariate analysis. Breakthrough fungemia during empiric therapy with fluconazole was also observed more frequently in patients with persistent fungemia. However, there was no difference in both attributable and overall mortality between both groups.

Aged↗