Efficacy of piperacillin in combination with novel ß-lactamase inhibitor IID572 against ß-lactamase-producing strains of Enterobacteriaceae and Staphylococcus aureus in murine neutropenic thigh infection models.

OBJECTIVES: The neutropenic murine thigh infection model was used to assess the effectiveness of IID572, a novel ß-lactamase inhibitor, in rescuing piperacillin activity against bacterial strains expressing various ß-lactamase enzymes. METHODS: Mice (n = 4/group) were inoculated with Enterobacteriaceae or Staphylococcus aureus bacterial strains expressing a range of ß-lactamases via intramuscular injection. Two hours after bacterial inoculation, subcutaneous treatment with piperacillin/IID572 or piperacillin/tazobactam every 3 h was initiated. Animals were euthanized via CO2 24 h after the start of therapy and bacterial cfu (log10 cfu) per thigh was determined, and the static dose was calculated. RESULTS: In a dose-dependent manner, piperacillin/IID572 reduced the thigh bacterial burden in models established with Enterobacteriaceae producing class A, C and D ß-lactamases (e.g. ESBLs, KPC, CMY-2 and OXA-48). Piperacillin/IID572 was also efficacious against MSSA strains, including one producing ß-lactamase. Static doses of piperacillin/IID572 were calculable from animals infected with all strains tested and the calculated static doses ranged from 195 to 4612 mg/kg/day piperacillin, the active component in the combination. Of the 13 strains investigated, a 1 log10 bacterial reduction was achieved for 9 isolates and a 2 log10 reduction was achieved for 3 isolates; piperacillin/tazobactam was not efficacious against 6 of the 13 isolates tested. CONCLUSIONS: In contrast to tazobactam, IID572 was able to rescue piperacillin efficacy in murine thigh infection models established with ß-lactamase-producing strains of Enterobacteriaceae and S. aureus, including those expressing ESBLs or serine carbapenemases.

Pharmacokinetics and pharmacodynamics of the novel monobactam LYS228 in a neutropenic murine thigh model of infection.

Objectives: The neutropenic murine thigh infection model and a dose-fractionation approach were used to determine the pharmacokinetic/pharmacodynamic (PK/PD) relationship of LYS228, a novel monobactam antibiotic with activity against Enterobacteriaceae including carbapenem-resistant strains. Methods: Mice (n = 4 per group) were inoculated with Enterobacteriaceae strains via intramuscular injection. Two hours post-bacterial inoculation, treatment with LYS228 was initiated. Animals were euthanized with CO2 24 h after the start of therapy and bacterial counts (log10 cfu) per thigh were determined. PK parameters were calculated using free (f) plasma drug levels. Results: Following a dose-fractionation study, non-linear regression analysis determined that the predominant PK/PD parameter associated with antibacterial efficacy of LYS228 was the percentage of the dosing interval that free drug concentrations remained above the MIC (%fT>MIC). In a dose-dependent manner, LYS228 reduced the thigh bacterial burden in models established with Enterobacteriaceae producing ß-lactamase enzymes of all classes (e.g. ESBLs, NDM-1, KPC, CMY-2 and OXA-48). The range of the calculated static dose was 86-649 mg/kg/day for the isolates tested, and the magnitude of the driver of efficacy was 37-83 %fT>MIC. %fT>MIC was confirmed as the parameter predominantly driving efficacy as evidenced by a strong coefficient of determination (r2 = 0.68). Neutrophils had minimal impact on the effect of LYS228 in the murine thigh infection model. Conclusions: LYS228 is efficacious in murine thigh infection models using ß-lactamase-producing strains of Enterobacteriaceae, including those expressing metallo-ß-lactamases, ESBLs and serine carbapenemases, with the PK/PD driver of efficacy identified as %T>MIC.

Migraine and hypercoagulable states in ischemic stroke.

BACKGROUND: Whether migraine is associated with a higher prevalence of hypercoagulable states (HS) in ischemic stroke patients is unknown. METHODS: This was a prospective study of patients under 55 years of age with brain ischemia. A systematic questionnaire addressed the antecedent of migraine with aura (MA) or without aura (MO). We investigated the presence of HS by an extensive battery of haematological tests. The presence of patent foramen ovale (PFO) was assessed by trans-oesophageal echocardiography. RESULTS: A total of 154 patients (95 men; mean ± SD age, 44.12 ± 8.4 years) were included; 44 had migraine, 15 had MA. HS were more frequent in the migraine than non-migraine group (38.6% vs. 16.4%, p < 0.01). The multivariate analysis showed that MO was associated with a 2.88-fold (95% CI, 1.14 to 7.28) increased risk of HS diagnosis. However, in the group of patients with brain infarction under 50 years old, MA, but not MO, was independently associated with HS (OR 6.81; 95% CI, 1.01 to 45.79). CONCLUSION: In young patients with ischemic stroke, migraine may be associated with a higher frequency of HS.

Identification of GP2, the major zymogen granule membrane glycoprotein, as the autoantigen of pancreatic antibodies in Crohn's disease.

BACKGROUND AND AIMS: The aetiopathogenesis of Crohn's disease, an inflammatory bowel disease (IBD), is not yet fully understood. Autoimmune mechanisms are thought to play a role in the development of Crohn's disease, but the target antigens and the underlying pathways have not been sufficiently identified. METHODS: Based on data from immunoblotting and matrix-assisted laser desorption ionisation time-of-flight (MALDI-TOF) mass spectrometry, the major antigenic target of pancreatic autoantibodies (PABs), which are specific for Crohn's disease, was identified. Specificity of autoantibody reactivity was confirmed by enzyme-linked immunosorbent assay (ELISA) and indirect immunofluorescence (IIF) using purified rat and human recombinant GP2 synthesised in transiently transfected mammalian HEK 293 cells. Real-time polymerase chain reaction (rt-PCR) and IIF were used to detect mRNA and antigen localisation in human colon biopsies. RESULTS: The major zymogen granule membrane glycoprotein 2 (GP2) was identified as the autoantigen of PABs in Crohn's disease. PAB-positive sera from patients with Crohn's disease (n = 42) displayed significantly higher IgG reactivity to rat GP2 in ELISA than either PAB-negative sera (n = 31), or sera from patients with ulcerative colitis (n = 49), or sera from blood donors (n = 69) (p<0.0001, respectively). Twenty-eight (66%) and 18 (43%) of 42 PAB-positive sera demonstrated IgG and IgA reactivity to human recombinant GP2 in IIF, respectively. Patients with PAB-negative Crohn's disease (n = 31) were not reactive. GP2 mRNA transcription was significantly higher in colon biopsies from patients with Crohn's disease (n = 4) compared to patients with ulcerative colitis (n = 4) (p = 0.0286). Immunochemical staining confirmed GP2 expression in human colon biopsies from patients with Crohn's disease. CONCLUSION: Anti-GP2 autoantibodies constitute novel Crohn's disease-specific markers, the quantification of which could significantly improve the serological diagnosis of IBD. The expression of GP2 in human enterocytes suggests an important role for anti-GP2 response in the pathogenesis of Crohn's disease.

[Hepatitis C virus in populations at risk for infection. Venezuela]. / Virus de hepatitis C en poblaciones de riesgo a adquirir la infección. Venezuela.

OBJECTIVE: The aim of this study was to establish the prevalence of hepatitis C virus infection in different populations at risk for infection. METHODS: This was a descriptive, transversal study whose variables were evaluated by Pearson s correlation analysis. Different populations were selected: 100 drug users, 47 sex workers, and 50 hemodialysis patients for a total of 197 individuals. The only inclusion criterion was the apparent risk of acquiring this viral infection. The presence of antibodies against virus was examined by ELISA IV (Innotest HCV Ab IV). Reactive samples were then tested using a recombinant assay (INNO-LIA HCV Ab III), both from Innogenetics N. V. (Belgium). The presence of viral RNA was determined in all ELISA and immunoblot-reactive samples by a nested polymerase chain reaction method (HCV-fast of Pharma Gen). RESULTS: A prevalence of 1% was found in drug users, and absence of infection or previous contact with the virus in sex workers and hemodialysis patients. CONCLUSIONS: This study shows a very low prevalence of infection with hepatitis C virus in populations at risk for acquiring the infection, and considered that this infection is not a public health problem in these populations in Maracaibo, Venezuela.

Molecular karyotype of related clones of Entamoeba histolytica.

The molecular karyotype of 3 clones derived from strain HM1:IMSS of Entamoeba histolytica was studied by transverse alternating field electrophoresis. 11-20 bands ranging between 0.3 and over 3 Mb were resolved. Hybridization with total DNA detected highly repetitive sequences in the slow-migrating molecules, while non-repetitive sequences were located in the intermediate and fast-migrating molecules. rDNA, tubulin, actin, cysteine proteases DNA fragments, and a variable DNA sequence (EhVR1) located the respective genes mainly in the 1.3-1.5-Mb region, although they differed in the three clones. Two-dimensional transverse alternating field electrophoresis showed that more than one high-molecular weight molecule may comigrate in a single DNA band. rDNA, and EhVR1 hybridized with slow-migrating bands in a characteristic ladder pattern. Most of the bands recognized by EhVR1 seems to be linear molecules, although exonuclease III-resistant bands also hybridized with EhVR1, suggesting the presence of circles.

Renal artery stenosis and hypertension after abdominal irradiation for Hodgkin disease. Successful treatment with nephrectomy.

Hypertension secondary to stenosis of the left renal artery developed in a thirteen-year-old male six years after completion of inverted Y irradiation (3,600 rad) for abdominal Hodgkin disease. Surgical treatment with nephrectomy resulted in control of the hypertension without the use of antihypertensive agents. We review the literature for this unusual complication of abdominal irradiation, and recommend that a 99mTc-DMSA renal scan, selective renal vein sampling for renin determinations, and renal arteriography be performed on any patient in whom hypertension develops following abdominal irradiation in childhood.

Muscimol injections in the medial septum impair spatial learning.

These experiments examined the role of GABAergic systems in modulating septohippocampal cholinergic influences on learning. Microinjections of the GABA(A) agonist muscimol (0.5, 1.0 or 5.0 nmol) or physiological saline were administered (0.5 microliters) into the medial septum of rats via chronically implanted cannulae just prior to daily training in the Morris water maze spatial learning task. The animals received 3 training trials on each of 4 days. The escape latencies of rats trained with a submerged escape platform at a fixed location were significantly shorter than those trained with a randomly located platform. Rate of learning of the fixed location was significantly impaired in rats given pretraining muscimol injections in the medial septum at doses (1.0 and 5.0 nmol) that significantly reduced hippocampal high-affinity choline uptake (HACU). Analyses of responses on a probe trial with no pretraining injections and no platform revealed that, in comparison with controls, animals that had received muscimol prior to each training session were likely to swim in the region where the platform had been located. The finding that muscimol-injected rats were subsequently able to learn the task when trained without muscimol injections indicates that the acquisition impairment was not due to a lasting effect of the drug injections. Our results are consistent with the view that the septal GABAergic modulation of the septohippocampal cholinergic pathway is involved in regulating the acquisition of spatial information.

[In vivo evaluation of the effect of antacids and H2 receptor blockaders on the intragastric pH in gastric and duodenal ulcer]. / Evaluación in vivo del efecto de los antiácidos y bloqueadores H2 sobre el pH intragástrico en la ulcera gástrica y duodenal.

The aim of this work is to establish the best treatment for patients with gastric and duodenal ulcer, by measuring the effects of antiacids and H2-receptor antagonists on gastric pH. 16 patients were studied: 9 of them had a duodenal ulcer, 2 a gastric ulcer and 5 had both. All the patients remained fasting and receiving no drug for 24 hrs. During this 24 hrs., a nasogastric tube was inserted into the stomach and the gastric content was obtained by aspiration each hour from 8 A.M. to 8 P.M. Three days after, each patient received a daily dose of 1 g of Cimetidine, and the whole procedure was repeated. The same was done with 300 mg of Ranitidine daily, 150 ml of Al-Mg antiacids daily, and at last, the same procedure was performed with the association of Ranitidine and Al-Mg antiacids at the mentioned dosage. For the statistical analysis of the data, the mean ordinate of the pH was used as a representative value of each individual's pH. Individual differences (pH with treatment minus pH without treatment) were obtained. The mean effect of each treatment was obtained averaging that differences. For comparison among different drugs, the same procedure was used. Student's paired t tests were performed in a signification level. The buffering capacity was measured in the following way: The percentage of the gastric secretion samples with pH equal or higher than 4 in each treatment and in the total number of patients was confronted with the results obtained in the same patients with no treatment. All the drugs were useful for buffering the gastric acidity, but in different intensity. The association of Ranitidine and Al-Mg antiacids showed to be the most efficient statistically when compared with Cimetidine and Al-Mg antiacids; no statistical difference appeared in the comparison with Ranitidine.

[The importance of HLA antigens in alcoholic cirrhosis]. / HLA y cirrosis. La importancia de los antígenos de histocompatibilidad en el desarrollo de una cirrosis alcoholica.

The existence of a relationship between HLA and the possibility of the development of an alcoholic cirrhosis is researched in this paper. This work was done from 1982 to 1984, by the staff of four clinics of the Medicine School of the University of Uruguay. We studied 47 alcoholics with portal cirrhosis, 19 non-cirrhotic alcoholics and 250 healthy nonalcoholic controls. We confirmed with liver biopsy the cirrhosis in the first group and in the second, liver biopsy was performed in order to assure that they had no cirrhosis. Table I shows the histocompatibility antigens which were tested in the 3 groups. Levels of significance were obtained from exact Fisher test with Yates correction for discontinuity; Pc (corrected P) and RR (relative risk) were also determined. In the alcoholics with portal cirrhosis, the HLABW40 showed a Pc less than 0,005 (RR = 3,93). In the non-cirrhotic alcoholics no significative association was found. We conclude that the carrier of the genetic marker HLABW40, has almost 4 times more chances to develop a cirrhosis as consequence of chronic alcoholic abuse. The presence of this marker, in our patients, has no association with the possibility that an individual becomes an alcoholic abuser. We think that if this data are confirmed in a wider study, some guidelines for the prevention of alcoholic cirrhosis may be established.

A comparative clinical trial of Norinyl 1 + 35 versus Norinyl 1 + 50 in Merida, Yucatan, Mexico.

A comparative clinical trial of two combined oral contraceptives differing only in estrogen type and dosage was conducted at the Centro de Investigaciones Hideyo Noguchi in Merida, Yucatan, Mexico. The trial was designed to determine the differences between Norinyl 1 + 50 (Syntex) and Norinyl 1 + 35 (Syntex) in rates of discontinuation and frequency of selected side-effects which might contribute to method discontinuation. Three hundred women were randomly assigned to either the Norinyl 1 + 35 group or to the Norinyl 1 + 50 group and follow-up visits were scheduled at 1, 4, 8 and 12 months after admission. In the Norinyl 1 + 35 group, more women experienced an increase in intermenstrual bleeding (primarily staining and spotting) (p less than 0.05), breast discomfort (p less than 0.05) and nausea than in the Norinyl 1 + 50 group. There was a significantly higher discontinuation rate for personal reasons, such as desired change of method and method not needed, among the women taking Norinyl 1 + 35 (p less than 0.05). The largest number of discontinuations comprised women discontinuing for menstrual problems in both groups. The life-table total discontinuation rate at 12 months was 52.0 for the Norinyl 1 + 35 group and 50.7 for the Norinyl 1 + 50 group. The lost-to-follow-up rates at 12 months were 17.8 for the Norinyl 1 + 35 group and 22.8 for the Norinyl 1 + 50 group.

[Lactation and amenorrhea in women from the rural and urban areas of Yucatan]. / Lactancia y amenorrea en mujeres de las áreas rural y urbana de Yucatán.

Influence of environment and lactation patterns on amenorrhea duration and frequency of ovulation before the first menstrual bleeding postpartum are studied on a group of 100 women (half rural, half from urban areas). All subjects studied were highly motivated to breastfeed for prolonged periods. Results show a more prolonged amenorrhea, although not statistically significant, in those women from the rural zone. Ovulation frequency before the first vaginal bleeding was 14% none ovulated before six months.

PIP: 100 women in Yucatan, Mexico, participated in a longitudinal and prospective study of the influence of lactation patterns and rural or urban residence on the duration of amenorrhea and the frequency of ovulation before the first postpartum menstrual period. 50 women from the city of Merida and 50 from nearby villages were followed until their first postpartum menstruation. The women were of lower socioeconomic status and aged 20-31 years. All had breast fed at least two older children and none used contraception before the first postpartum menstruation. 25 women in each residence group practiced exclusive breast feeding in the first months and 25 mixed bottle and breast feeding. The women kept records of the number of nursing episodes or bottles given, and collected 24-hour urine samples weekly beginning in the fourth postpartum month for urinary pregnanediol determination. Monthly blood samples were obtained before and after nursing to measure prolactin levels. Ten of the 100 women withdrew before completion of the study. The women in all four subgroups were very similar in age, education, and family size. The average duration of amenorrhea was 10.58 months for the 49 rural women and 8.02 months for the 44 urban women, but the difference was not statistically significant. The 11.02 month duration of amenorrhea of the exclusively breast feeding mothers was significantly longer than the 7.34 months of the partially breast feeding group. At six months postpartum, nine exclusively breast feeding and 22 partially breast feeding mothers had resumed menstruation. 75 of the women (88.3%) resumed menstruation within one year. 13 women (14.4%) ovulated before the first menstruation, with an average duration of amenorrhea of 9.8 months. None of the women became pregnant before the first menstruation. Prolactin levels were significantly lower in the women who ovulated before the first menstruation.

[Prevention of HIV infection in adolescents and young adults]. / La prevención de la infección por el VIH en adolescentes y adultos jóvenes.

The prevention of HIV infection in school and university communities acquires great importance in adolescents and young adults where the risk of HIV infection is caused by age, occupation, location, and also adjoining relations with other groups of high incidence of infection, such as teachers and administrative employees. Adequate strategies for specific groups are needed. This paper focuses on the strategies developed at the National Autonomous University of Mexico. An interdisciplinary health commission for the prevention and control of AIDS was established to inform the student body. Other activities performed by this commission include providing medical and psychological attention for AIDS victims, as well as detecting and carrying out follow-up studies of infected students. Efforts in health education have also been made by training professors to include preventive measures against this disease as part of their subject matter. Specific, organized, and immediate action must be taken by health personnel and community organizations in order to prevent HIV infection in adolescents and young adults.

Virus de hepatitis C en poblaciones de riesgo a adquirir la infección. Venezuela / Hepatitis C virus in populations at risk for infection. Venezuela

Objetivo: conocer la prevalencia del virus de hepatitis C en diferentes poblaciones de riesgo a adquirir la infección de la ciudad de Maracaibo, Venezuela. Método: la presente investigación comprendió un estudio de tipo descriptivo y transversal, cuyas variables fueron evaluadas por el análisis de correlación de Pearson. Se seleccionaron 100 drogadictos, 47 trabajadoras sexuales y 50 hemodializados, para un total de 197 individuos. Como único criterio de inclusión se tomó el hecho de presentar riesgo de contraer la infección por el virus de hepatitis C. Para la detección de anticuerpos contra el virus se utilizó la técnica de inmunoensayo enzimático de cuarta generación (Innotest HCV Ab IV). Toda muestra reactiva se confirmó por el método de inmunoblot recombinante de tercera generación (INNO-LIA HCV Ab III ), ambos de Innogenetics Lab (Bélgica). La detección del genoma viral (ARN) se realizó en aquellas muestras reactivas por ELISA e INNO-LIA por la técnica de reacción en cadena de la polimerasa, HCV-fast de Pharma Gen. Resultados: se encontró uno por ciento de prevalencia de hepatitis C en la población de drogadictos y ausencia de infección o contacto previo con el virus en trabajadoras sexuales y pacientes en hemodiálisis. Conclusiones: en el presente estudio se señala la baja prevalencia de la infección por el virus de hepatitis C en poblaciones de riesgo a adquirir la infección, por lo que se considera que esta infección no representa un problema de salud en estas poblaciones de la ciudad de Maracaibo, Venezuela

Objective: the aim of this study was to establish the prevalence of hepatitis C virus infection in different populations at risk for infection. Method: this was a descriptive, transversal study whose variables were evaluated by Pearson’s correlation analysis. Different populations were selected: 100 drug users, 47 sex workers, and 50 hemodialysis patients for a total of 197 individuals. The only inclusion criterion was the apparent risk of acquiring this viral infection. The presence of antibodies against virus was examined by ELISA IV (Innotest HCV Ab IV). Reactive samples were then tested using a recombinant assay (INNO-LIA HCV Ab III), both from Innogenetics N. V. (Belgium). The presence of viral RNA was determined in all ELISA and immunoblot-reactive samples by a nested polymerase chain reaction method (HCV-fast of Pharma Gen). Results: a prevalence of 1% was found in drug users, and absence of infection or previous contact with the virus in sex workers and hemodialysis patients. Conclusions: this study shows a very low prevalence of infection with hepatitis C virus in populations at risk for acquiring the infection, and considered that this infection is not a public health problem in these populations in Maracaibo, Venezuela