Laboratory exposure to Coccidioides: lessons learnt in a non-endemic country.

Coccidioides is a primary pathogenic fungus, which infects humans through highly infectious arthroconidia, causing substantial morbidity including life-threatening disseminated infections. Due to the low infectious dose, laboratory personnel might become infected during diagnostic procedures. Accordingly, coccidioidomycosis is reported as the most frequent laboratory-acquired systemic mycosis worldwide. This risk is aggravated in non-endemic countries, where the diagnosis may not be suspected. We report on an inadvertent exposure of 44 persons to Coccidioides posadasii in a clinical microbiology laboratory in Chile, the measures of containment after rapid diagnosis with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, and the lessons learnt in a non-endemic setting.

Hemorragia digestiva en neonato con uncinarias, Hospital Nacional San Bartolomé: Reporte de caso / Gastrointestinal bleeding in newborn with hookworm, National Hospital San Bartolome: Case report

Se presenta un caso de hemorragia digestiva por uncinariasis en una recién nacida de 27 días, procedente de la comunidad de Tangoshiri ubicada en la provincia de La Convención, en el departamento de Cuzco, quien ingresa al servicio de neonatología del Hospital Nacional Docente San Bartolomé de la ciudad de Lima, por anemia severa descompensada. Presentó, desde los 4 días de nacida, melena que se incrementa a la tercera semana de vida, con hematocrito de 12% por lo que se hospitaliza, recibiendo transfusión sanguínea y al persistir la hemorragia digestiva, se le realiza endoscopia digestiva alta evidenciándose múltiples larvas de Ancylostoma duodenal. Se le dio tratamiento con mebendazol a ella y a la madre con negativización de los exámenes de heces para la presencia del parásito.

We present the case of gastrointestinal bleeding uncinariasis in a newborn baby of 27 days old from anindigenous town of Tangoshiri, located in the province of La Convencion, department of Cuzco, who enters to the service of neonatology National Teaching Hospital San Bartolome in Lima, Peru, with decompensated severe anemia. The baby has melena since the fourth day of his birth, which increased in the third week of life, with hematocrit of 12%. She was hospitalized, receiving blood transfusion and she continue with gastrointestinal bleeding, so she underwent an upper endoscopy that showed multiple larvae Ancylostoma duodenale. She and her mother were treated with mebendazole. Afterwords they had stool examinations without the presence of the parasite.

Autores clásicos en psiquiatría: evaluación de un modelo de enseñanza de la psicopatología para residentes de psiquiatría / Classical authors in psychiatry: evaluation of a teaching model of psychopathology for psychiatry residents

Introducción: El aprendizaje de la psicopatología ha sido considerado una piedra angular en la formación de los residentes de psiquiatría. Objetivo: Evaluar el impacto de la enseñanza de un curso sobre autores clásicos de la psiquiatría y psicopatología en los residentes del programa de psiquiatría para determinar cambios en el nivel de conocimientos y valoración de la historia y fundamentos de la psicopatología. Método: Estudio de corte transversal pre post, con una encuesta anónima y voluntaria que se aplicó a todos los residentes con evaluación de las características socio demográficas, interés, utilidad y pertinencia de los contenidos, entre otros. Al inicio de cada seminario, evaluación de los conocimientos con una prueba escrita de desarrollo. Resultados: Participaron 24 residentes en total, 14 del programa adultos y 10 de infantojuvenil. La tasa de participación promedio fue de 87,5 por ciento. El 87,5 por ciento declaró tener conocimientos insuficientes o muy insuficientes. Entre las características de los residentes destacaron el interés por el deporte, la música y la literatura. Un 95,8 por ciento se proyecta como clínico y solo un 12,5 por ciento como docente. Al inicio del seminario solo hubo 29,16 por ciento de respuestas correctas en relación al origen y autor de los conceptos psicopatológicos revisados lo que aumentó a 65,4 por ciento al finalizar la serie de seminarios. Un 83 por ciento consideró los seminarios muy interesantes y el 75 por ciento muy útil para conocer la historia de la psiquiatría y mejorar su práctica clínica. Conclusión: La enseñanza de la psicopatología a partir de las descripciones clínicas de autores clásicos de la psiquiatría es altamente valorada por los residentes de psiquiatría en múltiples aspectos incluyendo el enriquecimiento de su práctica clínica.(AU)

Objective: To evaluate the impact of learning psychopathology in seminars, focusing on clinical cases described by classic psychiatry authors. Methods: A specially designed questionnaire was administered to 24 residents of the psychiatry program at the beginning and end of a series of 12 seminars analyzing the life, work and selected clinical cases of classic psychiatry authors including S. Freud, K. Kraepelin, E. Bleuler and K. Schneider. Data were collected included respondents characteristics, how interesting and useful the seminars were perceived to be and respondents' knowledge of classic psychiatry authors. Results: Respondents were interested in sports, music and literature; 95.8 percent regarded themselves as clinicians and 12.5 percent regarded themselves as teachers. The seminars were rated very interesting by 83.0 percent and very useful by 58.3 percent; they were considered to contribute to knowledge of the history of psychiatry, professional development and clinical practice. Most respondents (87.5 percent ) stated that their knowledge of classic authors was inadequate or very inadequate. At the beginning of the seminar series only 29.2 percent of responses about the origin and author of the psychopathological concepts covered in the seminars were correct; increasing to 65.4 percent by the end of the course. Conclusion: Teaching psychopathology through the study of classical cases is valued by residents for various reasons, including its potential to enrich clinical practice.(AU)

APOE and Alzheimer disease: a major gene with semi-dominant inheritance.

Apolipoprotein E (APOE) dependent lifetime risks (LTRs) for Alzheimer Disease (AD) are currently not accurately known and odds ratios alone are insufficient to assess these risks. We calculated AD LTR in 7351 cases and 10 132 controls from Caucasian ancestry using Rochester (USA) incidence data. At the age of 85 the LTR of AD without reference to APOE genotype was 11% in males and 14% in females. At the same age, this risk ranged from 51% for APOE44 male carriers to 60% for APOE44 female carriers, and from 23% for APOE34 male carriers to 30% for APOE34 female carriers, consistent with semi-dominant inheritance of a moderately penetrant gene. Using PAQUID (France) incidence data, estimates were globally similar except that at age 85 the LTRs reached 68 and 35% for APOE 44 and APOE 34 female carriers, respectively. These risks are more similar to those of major genes in Mendelian diseases, such as BRCA1 in breast cancer, than those of low-risk common alleles identified by recent GWAS in complex diseases. In addition, stratification of our data by age groups clearly demonstrates that APOE4 is a risk factor not only for late-onset but for early-onset AD as well. Together, these results urge a reappraisal of the impact of APOE in Alzheimer disease.

[High prevalence of thyroid dysfunction among psychiatric inpatients]. / Alta prevalencia de disfunción tiroidea en pacientes psiquiátricos hospitalizados.

BACKGROUND: Thyroid dysfunction is frecuent in psychiatric outpatients and in the general Chilean population but there is no information about the prevalence of thyroid diseases in Chilean psychiatric inpatients. AIM: To retrospectively assess the frequency of thyroidal diseases in psychiatric inpatients. MATERIAL AND METHODS: Clinical charts and thyroid assessment of 241 psychiatric inpatients (147 women, mean age 33+/-16 years) attended in a University Psychiatric Clinic, were reviewed. Psychiatric diagnosis at discharge was made according to DSM IV criteria and endocrine diagnosis was made based on international criteria. RESULTS: Forty nine patients (20.7%) had thyroid abnormalities. Forty four patients had hypothyroidism (18.3%) and five had hyperthyroidism (2.35%). No specific associations were found between gender or psychiatric diagnosis and endocrine abnormalities. CONCLUSIONS: In this sample, the prevalence of thyroid abnormalities was similar to other reports in psychiatric inpatiens and higher than in the general population in Chile.

Alta prevalencia de disfunción tiroidea en pacientes psiquiátricos hospitalizados / High prevalence of thyroid dysfunction among psychiatric inpatients

Background: Thyroid dysfunction is frecuent in psychiatric outpatients and in the general Chilean population but there is no information about the prevalence of thyroid diseases in Chilean psychiatric inpatients. Aim: To retrospectively assess the frequency of thyroidal diseases in psychiatric inpatients. Material and Methods: Clinical charts and thyroid assessment of 241 psychiatric inpatients (147 women, mean age 33±16 years) attended in a University Psychiatric Clinic, were reviewed. Psychiatric diagnosis at discharge was made according to DSM IV criteria and endocrine diagnosis was made based on international criteria. Results: Forty nine patients (20.7%) had thyroid abnormalities. Forty four patients had hypothyroidism (18.3%) and five had hyperthyroidism (2.35%). No specific associations were found between gender or psychiatric diagnosis and endocrine abnormalities. Conclusions: In this sample, the prevalence of thyroid abnormalities was similar to other reports in psychiatric inpatiens and higher than in the general population in Chile.

Trastornos del ánimo, psicofármacos y tiroides / Mood disorders, psychopharmacology and thyroid hormones

For more than 40 years thyroid hormones and mood disorders have been associated. Some psychiatric symptoms are produced by thyroid illnesses and there is a frequent association of thyroid dysfunction with mood disorders. Therefore, routine thyroid function assessment in patients with mood disorders and the treatment of sub-clinical thyroid dysfunctions is recommended. The usefulness of adding thyroid hormones to antidepressive treatment in euthyroid patients to obtain a potentiation effect has been probed repeatedly. The most common strategy is potentiation with T3, but high doses of T4 have been also used in patients with resistant depression. Thyroid hormones exert their action in the central nervous system through a variety of mechanisms: modulation of gene expression of several groups of proteins, some of them with known physiopathological implications in mood disorders and the influence over serotonin and noradrenergic neurotransmission, known to be one of the modes of action of antidepressants. Finally, it is also important to stress the complex relationship between psychiatric drugs, deiodinases and thyroid hormones, that can potentially help to understand the mechanisms of action of these drugs.

APOE genotype in cerebrovascular disease and vascular dementia.

BACKGROUND: The fact that the allele epsilon 4 of the Apolipoprotein E (APOE) gene could act like a risk factor not only in late-onset familial and sporadic Alzheimer's disease (AD) but also in cerebrovascular disease (CVD) and vascular dementia (VaD) is still controversial. METHODS: In order to study if epsilon 4 allele is overrepresented not only in AD but also in CVD and VaD, APOE genotyping was undertaken in a series of 247 patients: 26 cases with VaD, 41 cases with CVD but without cognitive impairment (CVD-C), 83 cases with AD and 97 aged-matched "healthy controls" (HC). RESULTS: Percentages of subjects bearing one or two copies of the epsilon 4 allele was much higher in AD patients (54%) than in either CVD-C (29%) (p<0.05), VaD (15%) (p<0.001) or HC (13%) (p<0.001). CONCLUSIONS: These results strengthen the hypothesis that involves the APOE epsilon 4 allele as a predisposing factor for AD, but not for CVD or VaD.

Contribution of APOE promoter polymorphisms to Alzheimer's disease risk.

OBJECTIVE: To determine whether the effects of APOE promoter polymorphisms on AD are independent of the APOE-epsilon4 allele. BACKGROUND: Recently, the -491 A-->T and -219 G-->T polymorphisms located in the APOE promoter have been suggested to be risk factors for AD. However, the effects of these polymorphisms have not always been reproduced in case-control studies, possibly because of the strong linkage disequilibrium existing at this locus or the characteristics of the populations studied. METHODS: Data collection was performed from six independent samples (1,732 patients with AD and 1,926 control subjects) genotyped for APOE exon 4 and the two APOE promoter polymorphisms. The risks associated with the APOE polymorphisms for developing AD were estimated using logistic regression procedures and calculation of odds ratios with 95% CI adjusted by age, sex, and collection center. Independence of the APOE promoter polymorphisms was tested by stratification for APOE-epsilon4 and tertile design was used for age stratification. RESULTS: The independence of the -491 AA genotype was observed in the whole sample whereas the independence of the -219 TT genotype was observed only in the oldest population. CONCLUSION: The -491 and -219 APOE promoter polymorphisms incur risk for AD in addition to risk associated with the APOE-epsilon4 allele, with age accentuating the effect of the -219 TT genotype. Because these polymorphisms appear to influence apoE levels, these results suggest that APOE expression is an important determinant of AD pathogenesis.

Interaction of alpha-2-macroglobulin and HSV-1 during infection of neuronal cells.

We describe the effect of pretreatment with alpha-2-macroglobulin (A2M) on the susceptibility of the human neuroblastoma SKNMC cell line to infection by herpes virus type 1 (HSV-1). ELISA and co-immunoprecipitation experiments confirmed the A2M-HSV-1 interaction in vitro. Indirect immunofluorescence shows that A2M exacerbated the cytopathic effect induced after HSV-1 infection. However, A2M-pretreated SKNMC cells notably produced fewer HSV-1 particles than did the untreated cells, suggesting that A2M could induce a restrictive infection. Furthermore, high levels of HSV-1 and A2M induced the production of nitric oxide (NO) in SKNMC. Preliminary results suggest that A2M might induce apoptosis in HSV-1-infected cells. These findings affirm the conclusion that A2M may interact directly with HSV-1 and modulate the course of the infection in SKNMC human neuroblastoma cells.

Identification of amino acid residues of transcription factor AP-2 involved in DNA binding.

AP-2 is a cell-type specific, developmentally regulated transcription factor which has been described as a critical regulator of gene expression during vertebrate development and embryogenesis. Although the overall domains of this factor necessary for their activity have been identified, the exact identity of AP-2 amino acid residues responsible for its interaction with the DNA structure has not yet been described. Here, we describe the identification of a region of AP-2 which was protected by an oligonucleotide probe containing its binding site from trypsin digestion, monitored by peptide mapping by MALDI-TOF mass spectrometry. Furthermore, we analyzed the relative in vitro DNA-binding activity, the stimulatory potency on the AP-2-dependent APOE promoter, as well as the ability to inhibit the effect of the wild-type protein of each one of a set of single-site substitution AP-2 mutants spanning the identified region. Taken together, our data clearly demonstrate that the region between amino acid residues 252-260 of AP-2 is essential for its DNA-binding activity. Particularly, the individual substitution in any of the residues 253, 254, 255, 257 or 260 is sufficient for completely abolishing the interaction with DNA and the stimulation of APOE promoter activity. These results indicate a crucial role of this region in the formation of an active DNA-binding domain and strongly suggest that these residues provide direct contacts with the DNA structure at the AP-2 binding site.

Alzheimer's risk associated with human apolipoprotein E, alpha-2 macroglobulin and lipoprotein receptor related protein polymorphisms: absence of genetic interactions, and modulation by gender.

Apolipoprotein E (apoE), the lipoprotein receptor related protein (LRP) and alpha-2 macroglobulin (alpha2M) have been proposed as a functional complex involved in amyloid clearance, a crucial event for Alzheimer's disease development. In this work, we present an epidemiological approach aimed to study the interactions among these genes, age and gender. This approach did not reveal significant associations between the genes; however, the present study indicated that the risk associated with APOE promoter and LRP gene polymorphisms is modulated by gender.

Apolipoprotein E gene promoter polymorphisms in Alzheimer's disease.

Alzheimer's disease, the most frequent form of senile dementia, presents in the vast majority of cases as a multifactorial trait, where a series of genetic and environmental risk factors converge. The increasing body of data, both epidemiological and functional, is strengthening the evidence that apolipoprotein E (APOE, gene; apoE, protein) is a true susceptibility factor for the onset of the common form of Alzheimer's disease. The E4 isoform of apoE remains to date as the main genetic risk factor for the disease, although the mechanisms responsible for this association are not well understood. It is also clear that apoE4 is not necessary or sufficient to cause the disease, indicating that other risk and protecting factors exist. ApoE is upregulated in response to nervous system injury, suggesting that it could have a neuroprotective role; on the other hand, there is evidence indicating that apoE is neurotoxic when present at high levels. Thus, apoE levels seem to be relevant for the functionality of the protein. The APOE proximal promoter hosts numerous regulatory elements, raising the possibility that polymorphisms in this region could produce variation in apoE levels by altering APOE transcriptional activity, which could finally result in AD susceptibility. We will review here the current evidence on the relationship between APOE proximal promoter polymorphisms, APOE gene transcriptional activity and apoE protein levels, and risk for AD.

A polymorphism in the tau gene associated with risk for Alzheimer's disease.

Searching for tau genetic variations which could be associated with risk for Alzheimer's disease (AD), we have performed a mutational analysis of a region containing the whole exon 11 of the tau gene, which encodes a microtubule binding region critical for tau self-assembly, and we have found a biallelic polymorphism at position +34 of intron 11 (IVS11 + 34G/A). We have analyzed the allelic frequencies of this polymorphism in a case-control sample (167 clinically diagnosed AD and 194 controls) and found that the presence of any G allele (genotypes AG + GG) is associated with a five-fold AD risk in individuals carrying the apolipoprotein E4 allele, strongly suggesting that the combined effect of tau and apoE is relevant in relation with AD pathogenesis.

DGGE method for the mutational analysis of the coding and proximal promoter regions of the Alzheimer's disease presenilin-1 gene: two novel mutations.

Many different mutations that cause Alzheimer's disease (AD) have been found in the presenilin-1 gene (PSEN1) and are associated with the most aggressive forms of the disease. With the aim of screening for PSEN1 genetic variations, we developed a method based on denaturing gradient gel electrophoresis (DGGE) that allows the mutational analysis of all the coding exons and the proximal promoter of PSEN1 using only four DGGE gels. The analysis by this methodology of a sample of 58 early-onset AD (EOAD) patients nonselected for family history resulted in finding four genetic variants within the PSEN1 coding region, two of which are novel mutations (M233L and A409T), whereas the other two have been reported previously (L282R and E318G). We also found a novel mutation within the PSEN1 proximal promoter (-280 C-->G) that, interestingly, provokes significant changes in the transcriptional activity of the gene in cell lines of neuronal and astrocytic, but not hepatic origin. These data strongly suggest that the region around -280 of PSEN1 promoter contains a regulatory element that controls its transcription specifically in neural cells.

Apolipoprotein E promoter and alpha2-macroglobulin polymorphisms are not genetically associated with Chinese late onset Alzheimer's disease.

In this study, we investigated two newly reported polymorphisms in association with late onset Alzheimer's disease (AD) in Chinese. They were a -491 A/T polymorphism in the Apolipoprotein E (APOE) promoter region and a five base pair deletion at exon 18 of alpha2-Macroglobin (A2M). There were 196 AD and 180 normal controls (N), which were age- and sex-matched. APOE epsilon4 alleles were significantly increased in AD vs. N (chi2 = 33.3, P < 0.000001). However, neither the -491 A/T (chi2 = 1.13, P = 0.29) nor A2M (chi2 = 0.18, P = 0.67) polymorphism was associated with AD risk, suggesting that these polymorphisms do not represent risk factors for AD in the Chinese population.

Transcription factor AP-2 activity is modulated by protein kinase A-mediated phosphorylation.

We recently reported that APOE promoter activity is stimulated by cAMP, this effect being mediated by factor AP-2 [Garcia et al. (1996) J. Neurosci. 16, 7550-7556]. Here, we study whether cAMP-induced phosphorylation modulates the activity of AP-2. Recombinant AP-2 was phosphorylated in vitro by protein kinase A (PKA) at Ser239. Mutation of Ser239 to Ala abolished in vitro phosphorylation of AP-2 by PKA, but not the DNA binding activity of AP-2. Cotransfection studies showed that PKA stimulated the effect of AP-2 on the APOE promoter, but not that of the S239A mutant. Therefore, cAMP may modulate AP-2 activity by PKA-induced phosphorylation of this factor.

[Emergence of resistance to macrolides in Streptococcus pyogenes]. / Emergencia de resistencia a macrólidos en Streptococcus pyogenes.

BACKGROUND: Diseases produced by Streptoccocus pyogenes are still a problem in Chile, as in the rest of the world. It exhibits in vitro susceptibility to different antimicrobials, but penicillin continues to be the treatment of choice. Alternative drugs have been developed for allergic patients, such as erythromycin, new macrolides and cephalosporins. Nevertheless, resistant strains are appearing due to the indiscriminate use of macrolides. AIM: To assess present antimicrobial susceptibility of S Pyogenes strains isolated from chilean patients. MATERIAL AND METHODS: The susceptibility to penicillin, macrolides, clindamycin, cephalotin and vancomycin of 153 S Pyogenes strains, obtained from different health centers of the Metropolitan Region and isolated between 1996 and 1998, was assessed using the Kirby-Bauer method. Agar dilution minimal inhibitory concentration was then determined to macrolide resistant strains. RESULTS: All strains were susceptible to penicillin. There was a 7.2% cross-resistance to macrolides. CONCLUSIONS: These results confirm that S Pyogenes resistance to macrolides has increased considerably in the Metropolitan Region of Chile during the last years.

[Antimicrobial resistance of agents causing urinary tract infections in 11 Chilean hospitals. PRONARES project]. / Resistencia a los antimicrobianos en agentes causantes de infección del tracto urinario en 11 hospitales chilenos. Proyecto PRONARES.

BACKGROUND: The computer program WHONET generates a common database to analyze local or general antimicrobial resistance of bacteria. A surveillance of agents causing urinary tract infections in Chile has been performed using this program. AIM: To report the results after 12 months of urinary tract infection agent surveillance. MATERIAL AND METHODS: Since November, 1997, a surveillance of in vitro antimicrobial resistance, using agar diffusion techniques, has been performed in 20 to 40 bacterial strains per month, isolated from 11 hospitals in the country. Results have been analyzed using WHONET program. RESULTS: In first 12 months, 3144 strains, 1625 coming from outpatients, have been studied. Seventy four percent of isolated strains were E coli, 19% were other enterobacteria, 4.1% were non fermenting bacilli and 2.1% were Gram (+) cocci. Sixty five percent of E coli strains were resistant to ampicillin, 11% to cefazolin, 2.5% to cefuroxime, 19% to ceftriaxone, 9% to ceftazidime, 4.2% to gentamicin 1.3% to amikacin, 5.6% to ciprofloxacin, 8.4% to grepafloxacin, 4.3% to nitrofurantoin and 43% to trimeproprim/sulphamethoxazole. Eighty two percent of other enterobacteria strains were resistant to ampicillin, 45.5% to cefazolin, 33.5% to cefuroxime, 26.6% to ceftriaxone, 21.5% to ceftazidime, 30.3% to gentamicin 17.2% to amikacin, 21% to ciprofloxacin, 16.3% to grepafloxacin, 48.2% to nitrofurantoin and 44.6% to trimeproprim/sulphamethoxazole. There were differences in betalactamic resistance among hospitals. CONCLUSIONS: Noteworthy is the high resistance rates to third generation cephalosporins, evidenced when the new cutoff values for E coli and Klebsiella spp are used. This national surveillance provides updated information on antimicrobial resistance of agents causing urinary tract infections.