Bloodstream infections in haematological cancer patients colonized by multidrug-resistant bacteria.

Infections by multidrug-resistant (MDR) bacteria are a worrisome phenomenon in hematological patients. Data on the incidence of MDR colonization and related bloodstream infections (BSIs) in haematological patients are scarce. A multicentric prospective observational study was planned in 18 haematological institutions during a 6-month period. All patients showing MDR rectal colonization as well as occurrence of BSI at admission were recorded. One-hundred forty-four patients with MDR colonization were observed (6.5% of 2226 admissions). Extended spectrum beta-lactamase (ESBL)-producing (ESBL-P) enterobacteria were observed in 64/144 patients, carbapenem-resistant (CR) Gram-negative bacteria in 85/144 and vancomycin-resistant enterococci (VREs) in 9/144. Overall, 37 MDR-colonized patients (25.7%) developed at least one BSI; 23 of them (62.2%, 16% of the whole series) developed BSI by the same pathogen (MDRrel BSI), with a rate of 15.6% (10/64) for ESBL-P enterobacteria, 14.1% (12/85) for CR Gram-negative bacteria and 11.1% (1/9) for VRE. In 20/23 cases, MDRrel BSI occurred during neutropenia. After a median follow-up of 80 days, 18 patients died (12.5%). The 3-month overall survival was significantly lower for patients colonized with CR Gram-negative bacteria (83.6%) and VRE (77.8%) in comparison with those colonized with ESBL-P enterobacteria (96.8%). CR-rel BSI and the presence of a urinary catheter were independent predictors of mortality. MDR rectal colonization occurs in 6.5% of haematological inpatients and predicts a 16% probability of MDRrel BSI, particularly during neutropenia, as well as a higher probability of unfavourable outcomes in CR-rel BSIs. Tailored empiric antibiotic treatment should be decided on the basis of colonization.

Access to emergency care services: a transversal ecological study about Brazilian emergency health care network.

OBJECTIVES: Studies of health geography are important in the planning and allocation of emergency health services. The geographical distribution of health facilities is an important factor in timely and quality access to emergency services; therefore, the present study analyzed the emergency health care network in Brazil, focusing the analysis at the roles of small hospitals (SHs). STUDY DESIGN: Cross-sectional ecological study. METHODS: Data were collected from 9429 hospitals of which 3524 were SHs and 5905 were high-complexity centers (HCCs). For analytical purposes, we considered four specialties when examining the proxies of emergency care capability: adult, pediatrics, neonatal, and obstetric. We analyzed the spatial distribution of hospitals, identifying municipalities that rely exclusively on SHs and the distance of these cities from HCCs. RESULTS: More than 14 and 30 million people were at least 120 km away from HCCs with an adult intensive care unit (ICU) and pediatric ICU, respectively. For neonatal care distribution, 12% of the population was more than 120 km away from a health facility with a neonatal ICU. The maternities situation is different from other specialties, where 81% of the total Brazilian population was within 1 h or less from such health facilities. CONCLUSION: Our results highlighted a polarization in distribution of Brazilian health care facilities. There is a concentration of hospitals in urban areas more developed and access gaps in rural areas and the Amazon region. Our results demonstrate that the distribution of emergency services in Brazil is not facilitating access to the population due to geographical barriers associated with great distances.

A mathematical model for filtration and macromolecule transport across capillary walls.

Metabolic substrates, such as oxygen and glucose, are rapidly delivered to the cells of large organisms through filtration across microvessels walls. Modelling this important process is complicated by the strong coupling between flow and transport equations, which are linked through the osmotic pressure induced by the colloidal plasma proteins. The microvessel wall is a composite media with the internal glycocalyx layer exerting a strong sieving effect on macromolecules, with respect to the external layer composed by the endothelial cells. The physiological structure of the microvessel is represented as the superimposition of two membranes with different properties; the inner membrane represents the glycocalyx, while the outer membrane represents the surrounding endothelial cells. Application of the mass conservation principle and thermodynamic considerations lead to a model composed of two coupled second-order ordinary differential equations for the hydrostatic and osmotic pressures, one, expressing volumetric mass conservation and the other, which is non-linear in the unknown osmotic pressure, expressing macromolecules mass conservation. Despite the complexity of the system, the assumption that the properties of the layers are piece-wise constant allows us to obtain analytical solutions for the two pressures. This solution is in agreement with experimental observations, which contrary to common belief, show that flow reversal cannot occur in steady-state conditions unless the hydrostatic pressure in the lumen drops below physiologically plausible values. The observed variations of the volumetric flux and the solute mass flux in case of a significant reduction of the hydrostatic pressure at the lumen are in qualitative agreement with observed variations during detailed experiments reported in the literature. On the other hand, homogenising the microvessel wall into a single-layer membrane with equivalent properties leads to a very different distribution of pressure across the microvessel walls, not consistent with observations.

'Real-life' report on the management of chronic GvHD in the Gruppo Italiano Trapianto Midollo Osseo (GITMO).

Several guidelines have been published about management of chronic GvHD (cGvHD), but the clinical practice still remains demanding. The Gruppo Italiano Trapianto di Midollo Osseo (GITMO) has planned a prospective observational study on cGvHD, supported by a dedicated software, including the updated recommendations. In view of this study, two surveys have been conducted, focusing the management of cGvHD and ancillary therapy in cGvHD, to address the current 'real life' situation. The two surveys were sent to all 57 GITMO centers, performing allografting in Italy; the response rate was 57% and 66% of the interviewed centers, respectively. The first survey showed a great disparity especially regarding steroid-refractory cGvHD, although extracorporeal photo-apheresis resulted as the most indicated treatment in this setting. Another challenging issue was the strategy for tapering steroid: our survey showed a great variance, and this disagreement could be a real bias in evaluating outcomes in prospective studies. As for the second survey, the results suggest that the ancillary treatments are not standardized in many centers. All responding centers reported a strong need to standardize management of cGvHD and to participate in prospective trials. Before starting observational and/or interventional studies, a detailed knowledge of current practice should be encouraged.

The Myc negative autoregulation mechanism requires Myc-Max association and involves the c-myc P2 minimal promoter.

Increasing evidence supports an important biological role for Myc in the downregulation of specific gene transcription. Recent studies suggest that c-Myc may suppress promoter activity through proteins of the basal transcription machinery. We have previously reported that Myc protein, in combination with additional cellular factors, suppresses transcription initiation from the c-myc promoter. To characterize the cis components of this Myc negative autoregulation pathway, fragments of the human c-myc promoter were inserted upstream of luciferase reporter genes and assayed for responsiveness to inducible MycER activation in Rat-1 fibroblasts. We found four- to fivefold suppression of a c-myc P2 minimal promoter fragment upon induction of wild-type MycER protein activity, while induction of a mutant MycER protein lacking amino acids 106 to 143 required for Myc autosuppression failed to elicit this response. This assay is physiologically significant, as it reflects Myc autosuppression of the endogenous c-myc gene with regard to kinetics, dose dependency, cell type specificity, and c-Myc functional domains. Analysis of mutations within the P2 minimal promoter indicated that the cis components of Myc autosuppression could not be ascribed to any known protein-binding motifs. In addition, to address the trans factors required for Myc negative autoregulation, we expressed MycEG and MaxEG leucine zipper dimerization mutants in Rat-1 cells and found that Myc-Max heterodimerization is obligatory for Myc autosuppression. Two models for the Myc autosuppression mechanism are discussed.

Myc is an essential negative regulator of platelet-derived growth factor beta receptor expression.

Platelet-derived growth factor BB (PDGF BB) is a potent mitogen for fibroblasts as well as many other cell types. Interaction of PDGF BB with the PDGF beta receptor (PDGF-betaR) activates numerous signaling pathways and leads to a decrease in receptor expression on the cell surface. PDGF-betaR downregulation is effected at two levels, the immediate internalization of ligand-receptor complexes and the reduction in pdgf-betar mRNA expression. Our studies show that pdgf-betar mRNA suppression is regulated by the c-myc proto-oncogene. Both constitutive and inducible ectopic Myc protein can suppress pdgf-betar mRNA and protein. Suppression of pdgf-betar mRNA in response to Myc is specific, since expression of the related receptor pdgf-alphar is not affected. We further show that Myc suppresses pdgf-betar mRNA expression by a mechanism which is distinguishable from Myc autosuppression. Analysis of c-Myc-null fibroblasts demonstrates that Myc is required for the repression of pdgf-betar mRNA expression in quiescent fibroblasts following mitogen stimulation. In addition, it is evident that the Myc-mediated repression of pdgf-betar mRNA levels plays an important role in the regulation of basal pdgf-betar expression in proliferating cells. Thus, our studies suggest an essential role for Myc in a negative-feedback loop regulating the expression of the PDGF-betaR.

Pathophysiology of bleeding in surgery.

Bleeding is a major surgical complication. Although mortality rates of 0.1% are observed for surgical procedures, it may be 5% to 8% for elective vascular surgery, and increase to 20% in the presence of severe bleeding. In major surgery for liver diseases, as well as in cardiac surgery, excessive blood loss is associated with increased mortality, morbidity, and intensive care stay. Approximately 75% to 90% of intraoperative and early postoperative bleeding is due to technical factors. However, in some cases either acquired or congenital coagulopathies may favor, if not directly cause, surgical hemorrhage. Uncontrolled bleeding leads to a combination of hemodilution, hypothermia, consumption of clotting factors, and acidosis, which in turn worsen the clotting process, further exacerbating the problem in a vicious bloody circle. At present, the standard treatment for surgical bleeding is the rapid control of the source of bleeding by either surgical or radiological techniques. Blood-derived products as well as hemostatic agents, such as aprotinin, tranexamic acid, and DDAVP, are widely used to improve hemostatic balance in bleeding patients. Recombinant activated factor VII (rFVIIa) has been reported to be effective for the treatment of surgical or traumatic massive bleeding unresponsive to conventional therapy. Although most reports are anecdotal, and therefore exposed to a "positive" selection bias, the number of cases is impressive, strongly suggesting that in such patients rFVIIa may afford a hemostatic advantage beyond that of conventional replacement therapy.

Thiotepa-based high-dose therapy for autologous stem cell transplantation in lymphoma: a retrospective study from the EBMT.

Clinical information about thiotepa-based autologous stem cell transplantation (auto-SCT) outside the primary central nervous system lymphoma (PCNSL) field is sparse. In this registry-based retrospective study, we evaluated potential risks and benefits of thiotepa-based preparative regimens compared with BEAM (carmustine, etoposide, cytarabine, melphalan) in auto-SCT for diffuse large B-cell lymphoma (DLBCL, excluding PCNSL), follicular lymphoma (FL) or Hodgkin lymphoma (HL). A total of 14 544 patients (589 thiotepa and 13 955 BEAM) met the eligibility criteria, and 535 thiotepa- and 1031 BEAM-treated patients were matched in a 1:2 ratio for final comparison. No significant differences between thiotepa and BEAM groups for any survival end point were identified in the whole sample or disease entity subsets. For a more detailed analysis, 47 TEAM (thiotepa, etoposide, cytarabine, melphalan)-treated patients were compared with 75 matched BEAM patients with additional collection of toxicity data. Again, there were no significant differences between the two groups for any survival end point. In addition, the frequency of common infectious and non-infectious complications including secondary malignancies was comparable between TEAM and BEAM. These results indicate that thiotepa-based high-dose therapy might be a valuable alternative to BEAM in DLBCL, HL and FL. Further evaluation by prospective clinical trials is warranted.

Myc induces cyclin D1 expression in the absence of de novo protein synthesis and links mitogen-stimulated signal transduction to the cell cycle.

Mitogen-activated signal transduction frequently leads to the induction of the c-myc proto-oncogene, but the subsequent molecular events downstream of Myc protein expression which promote cell cycle progression remain unclear. To study Myc-specific effects, without the complexity of the broader proliferative response evoked by serum, we employed the MycER-inducible system in the non-transformed Rat-1 cell line. We demonstrate that activation of wild-type, but not mutant, MycER is sufficient to transiently induce cyclin D1 RNA as well as protein expression to physiological levels, and promote G0/G1 to S phase transition of the cell cycle. Stimulation of endogenous cyclin D1 RNA is rapid and clearly evident within 30 min of MycER-activation, reaching a peak at 3 h. Nuclear run-on analysis demonstrates that this induction occurs at the transcriptional level with a fivefold increase in the rate of transcription. Moreover, MycER induces cyclin D1 transcription with equal efficacy in the presence or absence of de novo protein synthesis. Our work shows that Myc and cyclin D1 lie consecutively in a major proliferation-control pathway, and together create a pivotal connection between signal transduction and cell cycle control.

Myc represses the growth arrest gene gadd45.

The c-Myc protein strongly stimulates cellular proliferation, inducing cells to exit G0/G1 and enter the cell cycle. At a molecular level, Myc prevents growth arrest and drives cell cycle progression through the transcriptional regulation of Myc-target genes. Expression of the growth arrest and DNA damage inducible gene 45 (gadd45) is elevated in response to DNA damaging agents, such as ionizing radiation via a p53-dependent mechanism, upon nutrient deprivation, or during differentiation. Gadd45 holds a vital role in growth arrest as ectopic expression confers a strong block to proliferation. Exposure of quiescent cells to mitogen stimulates a rapid increase in c-Myc expression which is followed by the subsequent reduction in gadd45 expression. The kinetics of these two regulatory events suggest that Myc suppresses the expression of gadd45, contributing to G0/G1 phase exit of the cell cycle. Indeed, ectopic Myc expression in primary and immortalized fibroblasts results in the suppression of gadd45 mRNA levels, by a mechanism which is independent of cell cycle progression. Using an inducible MycER system, rapid suppression of gadd45 mRNA is first evident approximately 0.5 h following Myc activation. The reduction in gadd45 mRNA expression occurs at the transcriptional level and is mediated by a p53-independent pathway. Moreover, Myc suppression and p53 induction of gadd45 following exposure to ionizing radiation are non-competitive co-regulatory events. Myc suppression of gadd45 defines a novel pathway through which Myc promotes cell cycle entry and prevents growth arrest of transformed cells.

Hydrophilic interaction liquid chromatography-electrospray ionization-tandem mass spectrometry of a complex mixture of native and oxidized phospholipids.

A mixture of native and oxidized phospholipids (PLs), generated by the soybean lipoxygenase type V-catalyzed partial oxidation of a lipid extract obtained from human platelets, was analyzed by Hydrophilic Interaction Liquid Chromatography-ElectroSpray Ionization-Tandem Mass Spectrometry (HILIC-ESI-MS/MS). The complexity of the resulting mixture was remarkable, considering that the starting lipid extract, containing (as demonstrated in a previous study) about 130 native PLs, was enriched with enzymatically generated hydroperoxylated derivatives and chemically generated hydroxylated forms of PLs bearing polyunsaturated side chains. Nonetheless, the described analytical approach proved to be very powerful; indeed, focusing on phosphatidylcolines (PCs), the most abundant PL class in human platelets, about fifty different native/oxidized species could be identified in a single HILIC-ESI-MS/MS run. Low-energy collision induced dissociation tandem MS (CID-MS/MS) experiments on chromatographically separated species showed single neutral losses of H2O2 and H2O to be typical fragmentation pathways of hydroperoxylated PCs, whereas a single H2O loss was observed for hydroxylated ones. Moreover, diagnostic losses of n-hexanal or n-pentanol were exploited to recognize PCs hydroperoxylated on the last but five carbon atom of a É·-6 polyunsaturated side chain. Despite the low resolution of the 3D ion trap mass analyzer used, the described HILIC-ESI-MS/MS approach appears very promising for the identification of oxidized lipids in oxidatively stressed complex biological systems.

Hydroxyl groups in bone mineral.

The question of whether the apatite crystals of bone contain hydroxyl groups was explored using magic angle spinning, proton nuclear magnetic resonance spectroscopy, and resolution enhanced Fourier transform infrared spectroscopy. The powdered bone samples were heated at 300 degrees C in air, in CO2 at 4 bar atmosphere, and at 300 degrees C in air and subsequently at 300 degrees C in CO2, to eliminate the effects of water tightly bound to the crystals and to prevent the degradation of carbonate groups and the elimination of potentially present OH groups. Results confirm earlier findings that bone apatite crystals do not contain detectable amounts of hydroxyl ions.

Child labor and health: problems and perspectives.

Child labor remains a widespread problem. Although it can have positive effects, in some situations it has negative effects on health and development of the children. Although mainly a problem in developing countries, it is also possible to find child workers, some working in hazardous activities, in developed countries. The authors describe the child labor profiles in developed and developing countries, the principal occupations of children, and their concomitant hazards. They summarize the epidemiologic evidence for a greater impact of some occupational exposures on the health of children as compared with adults, and the theoretical concerns about the impact of child labor on health, and suggest policies that can be used to combat harmful child labor.

[The rural labor process and health in the Southern Brazilian mountains: a descriptive study]. / Processo de produção rural e saúde na serra gaúcha: um estudo descritivo.

This cross-sectional study among rural workers in the mountainous region of the southernmost Brazilian State of Rio Grande do Sul was designed to identify the characteristics of work performed on family farms. The research focused on the socio-demographic profiles of rural workers, identifying the characteristics of rural labor and describing the prevalence of some disease entities in such populations. Some 1479 rural workers from 495 farms were interviewed. In this sample, 87% of the individuals were members of the farm-owning family, mean age was 41 years, 56% were males, and mean schooling was 5 years. Farms had a mean area of 37 hectares, 50% had at least one type of farm machinery, and fruits constituted the main crop. About 75% of workers handled several types of pesticides, while 12% reported at least one lifetime episode of pesticide poisoning. Prevalence of minor psychiatric disorders was 36%, and annual frequency of occupational injuries was 10%. There was a wide variety of activities and occupational risks. The high prevalence of health problems identified in the study calls attention to the need for measures to promote and protect rural workers' health.

The Brazilian cohort of pulp and paper workers: the logistic of a cancer mortality study.

The International Agency for Research on Cancer (IARC) proposed this international historical cohort study trying to solve the controversy about the increased risk of cancer in the workers of the Pulp and Paper Industry. One of the most important aspects presented by this study in Brazil was the strategies used to overcome the methodological challenges, such as: data access, data accuracy, data availability, multiple data sources, and the large follow-up period. Through multiple strategies it was possible to build a Brazilian cohort of 3,622 workers, to follow them with a 93 percent success rate and to identify in 99 percent of the cases the cause of death. This paper, has evaluated the data access, data accuracy and the effectiveness of the strategies used and the different sources of data.

[Measuring the impact of promoting breastfeeding in primary health care services in Pelotas, Rio Grande do Sul, Brazil]. / Medindo o impacto da promoção do aleitamento materno em serviços de atenção primária à Saúde em Pelotas, Rio Grande do Sul, Brasil.

All mothers with children enrolled in the Program for Child Growth and Development at primary care units belonging to the Federal University of Pelotas (UFPel) in the state of Rio Grande do Sul, Brazil, were interviewed with a standardized questionnaire. This research aimed to assess the impact of the "Groups of Expecting Mothers" in the promotion of breastfeeding. The family income of almost half of the 347 children studied was two times the minimum wage. About 1/4 of the children's mothers had spent less than four years in school, and these were the mothers who attended the Groups most frequently. Most of the mothers received prenatal care and nearly half of then participated in the Groups. In contrast, 1/3 of the children were weaned at the age of three months and almost 80% received tea in the early months of life. The results show that the Groups of Expecting Mothers suffer serious limitations in promoting breastfeeding and in postponing the introduction of foods other than breast milk in the children's diet. Data obtained in this study are intended to help strengthen action under current programs and to show that with minimum resources and a rather simple methodology it is possible to assess the quality of health services available to the population.

Drug usage in southern Brazilian hospitals.

A drug usage survey was carried out in 14 hospitals in the southernmost region of Brazil in the year 1979. The average number of drugs prescribed per patient was 8.6, and antimicrobials, followed by analgesics, vitamins and sedatives-tranquilizers were the most often employed drug categories. Among the antimicrobials, ampicillin was the first, followed by chloramphenicol, but the overall leading drug was an analgesic-antipyretic, dipyrone. Some possible distortions in drug usage are discussed.

[The worker model and perception of occupational and environmental risks: the optimal use of a descriptive study]. / Modelo operário e percepção de riscos ocupacionais e ambientais: uso exemplar de estudo descritivo.

An attempt was made to identify the risks resulting from exposure to the chemicals to which workers are exposed as well as from the poor working conditions to which they are subject in a chemical and pharmaceutical factory. A descriptive study based on the "workers model"--a methodological approach developed in Italy in the 60's, was carried out. Such a study requires direct contact with the workers and has the advantage of overcoming the difficulty of gaining access to their work-place. The activities of the different departments of the plant were reconstructed and the main chemicals used, the main physical complaints, the potential harms and the main environmental risks identified. The report on the harmful working conditions produced was used by the workers as a means of pressing the authorities into carrying out an inspection of the plant concerned to verify its accuracy. The report's findings have been confirmed and demonstrate the usefulness of the methodological approach adopted. The workers' publicizing of the study's findings through the means of mass communication have helped to build up greater public awareness of the occupational and environmental risks of that particular industrial activity.

[Use of outpatient services in an urban area of Southern Brazil: place and frequency]. / Utilização de serviços ambulatoriais em Pelotas: onde a população consulta e com que freqüência.

OBJECTIVE: The objective was determine the use of health services by the adult population in Pelotas, RS, Brazil. METHODS: A cross-sectional study was made on the basis of a population sample. One thousand six hundred and fifty-seven persons we interviewed during the months of March and June, 1992. A percentage of 9.7 of the sample was lost. RESULTS: Two dependents variables. One the type of service as determined by type of payment. The other the number of medical visits made during the previous year. The type of service was seen to be associated with the following social variables: social class, level of schooling and place of residence. The frequency of medical visits was associated with sex, risk factors and reasons for the visit. CONCLUSION: It was concluded that choice of the type of service depends more heavily in social class than other variables associated with the severity of the disease in question.

[A cross-sectional study about mental health of farm-workers from Serra Gaucha (Brazil)]. / Estudo transversal sobre saúde mental de agricultores da Serra Gaúcha (Brasil).

OBJECTIVE: In view of the shortage of population-based rural studies, this research project evaluated the associations between the characteristics of rural work and the occurrence of minor psychiatric disorders (MPD). METHODS: A cross sectional study was carried out on the 1,282 farm workers of 446 farms. Information about the farms (land extension, agricultural activities, technology and pesticide use) was collected. Demographic and socioeconomic data, characteristics of the work process and mental health indicators were obtained from the workers. RESULTS: MPD were found in 37.5% of the farm workers. The risk was higher on farms with a land extension of from 26 to 50 hectares, and lower where there was an increased level of job technology and schooling. The prevalence of MPD was higher among bean producers and lower among apple producers. Despite the impossibility of defining the direction of the causal link, pesticide poisoning was strongly associated with MPD. CONCLUSION: The results call attention to the dimension of the problem and to the importance of adopting new policies for the protection of farm workers' mental health.