Immune thrombotic thrombocytopenic purpura in older patients: Results from the Spanish TTP Registry (REPTT).

Immune thrombotic thrombocytopenic purpura (iTTP) is an ultra-rare disease that seldom occurs in the elderly. Few reports have studied the clinical course of iTTP in older patients. In this study, we have analysed the clinical characteristics at presentation and response to therapy in a series of 44 patients with iTTP ≥60 years at diagnosis from the Spanish TTP Registry and compared them with 209 patients with <60 years at diagnosis from the same Registry. Similar symptoms and laboratory results were described in both groups, except for a higher incidence of renal dysfunction among older patients (23% vs. 43.1%; p = 0.008). Front-line treatment in patients ≥60 years was like that administered in younger patients. Also, no evidence of a difference in clinical response and overall survival was seen in both groups. Of note, 14 and 25 patients ≥60 years received treatment with caplacizumab and rituximab, respectively, showing a favourable safety and efficacy profile, like that observed in patients <60 years.

Compression, Rupture, and Puncture of Model Membranes at the Molecular Scale.

Elastic properties of biological membranes are involved in a large number of membrane functionalities and activities. Conventionally characterized in terms of Young's modulus, bending stiffness and stretching modulus, membrane mechanics can be assessed at high lateral resolution by means of atomic force microscopy (AFM). Here we show that the mechanical response of biomimetic model systems such as supported lipid bilayers (SLBs) is highly affected by the size of the AFM tip employed as a membrane indenter. Our study is focused on phase-separated fluid-gel lipid membranes at room temperature. In a small tip radius regime (≈ 2 nm) and in the case of fluid phase membranes, we show that the tip can penetrate through the membrane minimizing molecular vertical compression and in absence of molecular membrane rupture. In this case, AFM indentation experiments cannot assess the vertical membrane Young's modulus. In agreement with the data reported in the literature, in the case of larger indenters (>2 nm) SLBs can be compressed leading to an evaluation of Young's modulus and membrane maximal withstanding force before rupture. We show that such force increases with the indenter in agreement with the existing theoretical frame. Finally, we demonstrate that the latter has no influence on the number of molecules involved in the rupture process that is observed to be constant and rather dependent on the indenter chemical composition.

Analysis of mitochondrial DNA in Bolivian llama, alpaca and vicuna populations: a contribution to the phylogeny of the South American camelids.

The objectives of this work were to assess the mtDNA diversity of Bolivian South American camelid (SAC) populations and to shed light on the evolutionary relationships between the Bolivian camelids and other populations of SACs. We have analysed two different mtDNA regions: the complete coding region of the MT-CYB gene and 513 bp of the D-loop region. The populations sampled included Bolivian llamas, alpacas and vicunas, and Chilean guanacos. High levels of genetic diversity were observed in the studied populations. In general, MT-CYB was more variable than D-loop. On a species level, the vicunas showed the lowest genetic variability, followed by the guanacos, alpacas and llamas. Phylogenetic analyses performed by including additional available mtDNA sequences from the studied species confirmed the existence of the two monophyletic clades previously described by other authors for guanacos (G) and vicunas (V). Significant levels of mtDNA hybridization were found in the domestic species. Our sequence analyses revealed significant sequence divergence within clade G, and some of the Bolivian llamas grouped with the majority of the southern guanacos. This finding supports the existence of more than the one llama domestication centre in South America previously suggested on the basis of archaeozoological evidence. Additionally, analysis of D-loop sequences revealed two new matrilineal lineages that are distinct from the previously reported G and V clades. The results presented here represent the first report on the population structure and genetic variability of Bolivian camelids and may help to elucidate the complex and dynamic domestication process of SAC populations.

Analysis of genetic diversity in Bolivian llama populations using microsatellites.

South American camelids (SACs) have a major role in the maintenance and potential future of rural Andean human populations. More than 60% of the 3.7 million llamas living worldwide are found in Bolivia. Due to the lack of studies focusing on genetic diversity in Bolivian llamas, this analysis investigates both the genetic diversity and structure of 12 regional groups of llamas that span the greater part of the range of distribution for this species in Bolivia. The analysis of 42 microsatellite markers in the considered regional groups showed that, in general, there were high levels of polymorphism (a total of 506 detected alleles; average PIC across per marker: 0.66), which are comparable with those reported for other populations of domestic SACs. The estimated diversity parameters indicated that there was high intrapopulational genetic variation (average number of alleles and average expected heterozygosity per marker: 12.04 and 0.68, respectively) and weak genetic differentiation among populations (FST range: 0.003-0.052). In agreement with these estimates, Bolivian llamas showed a weak genetic structure and an intense gene flow between all the studied regional groups, which is due to the exchange of reproductive males between the different flocks. Interestingly, the groups for which the largest pairwise FST estimates were observed, Sud Lípez and Nor Lípez, showed a certain level of genetic differentiation that is probably due to the pattern of geographic isolation and limited communication infrastructures of these southern localities. Overall, the population parameters reported here may serve as a reference when establishing conservation policies that address Bolivian llama populations.

Web-enabled registry of inherited bleeding disorders in Portugal: conditions and perception of the patients.

Local and national haemophilia registries are powerful instruments to support the healthcare and researchers and improve the communication between Comprehensive Haemophilia Diagnostic and Treatment Centres (HTCs) and patients. Hemo@care is an example of a Local Haemophilia Registry Systems (LHR_Sys) based on the Web, developed in collaboration with a HTC located in Portugal, to support the haemophilia treatments registry, collect and manage the clinical information and provide mechanisms to control the clotting factor concentrates (CFC) stock. To extend this solution (the hemo@care) to other Portuguese HTCs and consequently to meet the preconditions to create a National Haemophilia Registry Systems (NHR_Sys), a study based on a questionnaire was carried out at nationwide. This study aims to assess the conditions and motivations of people with haemophilia (PWH) geographically scattered throughout the country, to use a potential Web-enabled registry with the purpose of replacing the traditional paper-diaries, to understand their judgment about a potential NHR_Sys currently non-existent in Portugal, and at the same time, to characterize demographically and pathologically those people at the nationwide. The results based on the analysis of 168 responses (response rate of 31%) confirmed the high prevalence of the disease in haemophilia A (75%) compared with haemophilia B (11.3%) and a large incidence in the severe levels, or the existence of people with mild severity without diagnosis and treatment. Furthermore, the results also revealed the need, conditions and motivation for using a registry system by PWH; thus it is deemed to justify the extension of the hemo@care to other HTCs in Portugal and consequently to create the NHR_Sys.

Evaluation of Spatial Pattern of Altered Flow Regimes on a River Network Using a Distributed Hydrological Model.

Alteration of the spatial variability of natural flow regimes has been less studied than that of the temporal variability, despite its ecological importance for river ecosystems. Here, we aimed to quantify the spatial patterns of flow regime alterations along a river network in the Sagami River, Japan, by estimating river discharge under natural and altered flow conditions. We used a distributed hydrological model, which simulates hydrological processes spatiotemporally, to estimate 20-year daily river discharge along the river network. Then, 33 hydrologic indices (i.e., Indicators of Hydrologic Alteration) were calculated from the simulated discharge to estimate the spatial patterns of their alterations. Some hydrologic indices were relatively well estimated such as the magnitude and timing of maximum flows, monthly median flows, and the frequency of low and high flow pulses. The accuracy was evaluated with correlation analysis (r > 0.4) and the Kolmogorov-Smirnov test (α = 0.05) by comparing these indices calculated from both observed and simulated discharge. The spatial patterns of the flow regime alterations varied depending on the hydrologic indices. For example, both the median flow in August and the frequency of high flow pulses were reduced by the maximum of approximately 70%, but these strongest alterations were detected at different locations (i.e., on the mainstream and the tributary, respectively). These results are likely caused by different operational purposes of multiple water control facilities. The results imply that the evaluation only at discharge gauges is insufficient to capture the alteration of the flow regime. Our findings clearly emphasize the importance of evaluating the spatial pattern of flow regime alteration on a river network where its discharge is affected by multiple water control facilities.

Neuroendocrine carcinomas of the stomach: a clinicopathologic evaluation.

BACKGROUND: The purpose of this study was to determine by immunocytochemistry the relative incidence and clinicopathologic characteristics of neuroendocrine carcinomas of the stomach. METHODS: Sections from paraffin blocks from 81 patients who had undergone resection of carcinomas of the stomach were immunostained with a battery of neuroendocrine differentiation markers and with A-80, a marker of exocrine differentiation. The clinical and pathologic data of the 12 patients diagnosed with neuroendocrine carcinomas of the stomach were analyzed. RESULTS: The 10 men and two women ranged from 53 to 81 years of age (median, 69 years). Procedures performed included distal subtotal gastrectomy in eight patients and total gastrectomy in four patients. Pathologic stages were stage I, one patient; stage III, four patients; and stage IV, seven patients. Metastatic sites included regional nodes, 11 patients; liver, four patients; and bone, one patient. Adjunct treatment included multiagent chemotherapy plus radiotherapy, four patients; and only radiotherapy, one patient. Eleven patients died of disease 1 to 27 months after diagnosis with an overall median survival of 15 months. Three groups of neuroendocrine carcinomas were identified based on immunostaining patterns. These included pure neuroendocrine carcinomas, two patients; neuroendocrine carcinomas with occasional exocrine cells, three patients; and mixed neuroendocrine-exocrine carcinomas, seven patients. CONCLUSIONS: (1) The relative incidence of neuroendocrine differentiation in carcinomas of the stomach is higher than is generally recognized. (2) Neuroendocrine gastric carcinomas behave aggressively and display numerous structural and functional similarities with their colonic, extrahepatic biliary tract, and pulmonary counterparts.

Spontaneous murine lung adenocarcinoma (P07): A new experimental model to study paraneoplastic syndromes of lung cancer.

We report the histological and biological behavior characteristics of a lung tumor (P07) that arose spontaneously in a Balb/c mouse. P07 is a moderately to poorly differentiated adenocarcinoma that secretes granulocyte-macrophage colony stimulating factor (GM-CSF) in culture supernatants. This tumor presents some paraneoplastic syndromes, such as leukocytosis, hypercalcemia and cachexia. taken together with the peripheral blood leukocyte (PBL) counts and serum calcium levels during s.c. tumor growth and after surgery, this study suggests that P07 may be a useful experimental model to study the biology of lung cancer and paraneoplastic syndromes.

[Chronic myeloproliferative syndromes and tuberculosis: apropos of 3 cases]. / Síndromes mieloproliferativos crónicos y tuberculosis: a propósito de 3 casos.

We report 3 patients with chronic myeloproliferative syndromes and active tuberculous infection. The first patient had chronic myelocytic leukemia. In this patient, primary tuberculosis was localized in the lung. In spite of tuberculostatic treatment, he developed laterocervical lymphadenopathy and a tuberculous abscess in right lower limb. The second patient had agnogenic myeloid metaplasia. In this patient splenic tuberculosis (TBC) with subsequent pulmonary involvement were diagnosed. The third patient had idiopathic thrombocytopenia with pulmonary tuberculous infection. In two patients, tuberculosis was diagnosed some time after the diagnosis of hematologic disease, while in the third one both conditions were simultaneously identified. One of the patients died of complications of alkylating therapy, and the other two are still alive. In none of the three patients there has been evidence of active tuberculous infection after therapy, although their course has been slow and two have required associated surgery to eradicate the infection. We review the hematologic conditions which can develop during tuberculosis, the incidence of this infection during chronic myeloproliferative syndromes, the possible pathogenetic relation between both conditions, and the clinical presentation of tuberculosis in these patients, which usually is disseminated in character.

[Reproducibility of nuclear grade in breast neoplasm. A multicenter experience]. / Reproducibilidad del grado nuclear en el cáncer de mama. Una experiencia multicéntrica.

Nuclear grade is considered a valuable prognostic factor in mammary carcinomas. Since the histological diagnosis of most of these tumors is made by "non expert" pathologists, it was considered interesting to find out the reproducibility of general pathologists to define the nuclear grade. In order to do this, a series of 15 mammary carcinomas, 10 of them randomly selected and 5 because they were considered difficult to classify for nuclear grade, were examined separately by 10 general pathologists. In a first round of observation, each one of them graded the cases according to their own criteria as used routinely, and for a second round they followed a written guide. An analysis of variance was applied to the data and no significant differences were found between observers, neither in the randomly selected cases nor in the total series. The written guide, surprisingly, instead of lowering the differences, increased them. Analysis of the individual performance of observers showed two of them having a great variation between both rounds of observation, and this was considered to influence the results of the whole group. Interobserver performance to discriminate high grade tumors (G3) from the rest, showed a good correlation in all the participants. These results allow us to conclude that in this series, examined by general pathologists, an acceptable reproducibility was observed, specially when high risk tumors were being identified.

[Comparative morbidity study 1984-1989 in the internal medicine department of a second-level general hospital]. / Estudio comparativo 1984-1989 de la morbilidad en el Servicio de Medicina Interna de un hospital general de segundo nivel.

In order to determine the changes in the clinico-pathological pattern of admitted patients in an internal medicine department, 240 patients/year were compared during the years 1984 and 1989. A predominant proportion of males was registered (3:2); which did not vary by the year. An increased tendency of the median age (55.78 vs 58.48 years) was also established. The medium time of admission (8.98 vs 9.5 days) and mortality rate (6.3% vs 7.1%) did not change. A high rate (greater than 50%) of cardiovascular and respiratory disease was found on analyzing the cause of admission; in 1989 infection caused by HIV was detected and admissions to optimize the treatment of patients with diabetes mellitus were observed which did not exist in 1984. A slight but surprising decrease in admissions due to acute ischemic cardiopathy and significant decrease of admissions owing to respiratory disease were also noted. The majority of the patients admitted had a baseline disease (85% in 1984 and 87.1% in 1989). The knowledge of these data and their variations in every hospital department will, undoubtedly, assist in achieving a better use of technical and human health resources.

Cell competition may function either as tumour-suppressing or as tumour-stimulating factor in Drosophila.

Drosophila endocytosis-defective cells develop tumour overgrowths in the imaginal discs. We have analysed the tumorigenic potential of cells mutant for Rab5, a gene involved in endocytosis. We found that while a compartment entirely made by Rab5 mutant cells can grow indefinitely, clones of Rab5 cells surrounded by normal cells are eliminated by cell competition. However, when a group of about 400 cells are simultaneously made mutant for Rab5, they form an overgrowing tumour: mutant cells in the periphery are eliminated, but those inside survive and continue proliferating because they are beyond the range of cell competition. These results identify group protection as a mechanism to evade the tumour-suppressing function of cell competition in Drosophila. Furthermore, we find that the growth of the tumour depends to a large extent on the presence of apoptosis inside the tumour: cells doubly mutant for Rab5 and the proapoptotic gene dronc do not form overgrowing tumours. These results suggest that the apoptosis caused by cell competition acts as a tumour-stimulating factor, bringing about high levels of Jun N-terminal kinase and subsequently Wg/Dpp signalling and high proliferation levels in the growing tumour. We conclude that under these circumstances cell competition facilitates the progression of the tumour, thus reversing its normal antitumour role.

Adsorptive endocytosis of lysosomal enzymes by human fibroblasts: presence of two different functional systems that deliver an acid hydrolase to lysosomes.

Endocytosis of human spleen beta-glucuronidase by human fibroblasts can be completely impaired by the competitive inhibitor mannose 6-phosphate or by pretreatment with acid phosphatase or endoglycosidases H or F. However, endocytosis of bovine spleen and liver beta-glucuronidase is partially impaired by the same treatments, suggesting that the bovine enzyme contains two endocytosis recognition markers located in separate enzyme domains. The mannose 6-phosphate recognition marker seems to be responsible for approximately 23% of the bovine enzyme endocytosis. The existence of two lysosomal endocytosis systems in human fibroblasts is supported by the following facts: (a) the rate of endocytosis of mannose 6-phosphate-containing human beta-glucuronidase was not affected by the presence of high levels of the bovine enzyme (which has only the other marker). (b) Anti-215K mannose 6-phosphate receptor antibodies selectively impair the endocytosis of the beta-glucuronidase containing mannose 6-phosphate. (c) Weak bases exert a differential effect on human and bovine endocytosis. beta-Glucuronidase internalized by either system is targeted to secondary lysosomes of human beta-glucuronidase-deficient fibroblasts, where it is able to degrade accumulated glycosaminoglycans. These results suggest that human fibroblasts have two different and independent endocytic systems for targeting of acid hydrolases to lysosomes.

[Granulocytic sarcoma of the base of the skull in chronic myeloid leukemia]. / Sarcoma granulocítico de base de cráneo en el curso de una leucemia mieloide crónica.

A 54 years old patient with Ph' negative chronic granulocytic leukaemia is reported, who presented rapidly progressive multiple cranial nerve palsies. A cerebral CT scan showed an invasive tumoral disease on the base of skull. Histologic examination of this mass was diagnostic for granulocytic sarcoma, which was the presentation form of an extramedullary blastic crisis. The general characteristics of granulocytic sarcoma are commented, special attention being paid to its appearance in the course of chronic granulocytic leukaemia.

Protection conferred against Junin virus infection in rats.

2-day-old Wistar rats intracerebrally infected with the XJC13 strain of virus exhibited a 5% survival rate which rose to 71% after immune serum treatment. Brain viral titers were relatively unaffected by this treatment. Histologic studies showed necrosis in the cerebellum and brain cortex with mononuclear cell infiltration in both treated and nontreated groups. Beginning on day 16 postinfection, however, intracerebral perivascular gliosis foci and mild meningeal congestion were minimal in the treated animals. These findings imply that passively transferred humoral immunity leads to prompt recovery in this experimental model.

Childhood injury prevention practices by parents in Mexico.

OBJECTIVE: Scientifically based injury prevention efforts have not been widely implemented in Latin America. This study was undertaken to evaluate the baseline knowledge and practices of childhood safety on the part of parents in Monterrey, Mexico and in so doing provide information on which to base subsequent injury prevention efforts. METHODS: Interviews were carried out with parents from three socioeconomic strata (upper, middle, lower). Questionnaires were based on Spanish language materials developed by The Injury Prevention Program (TIPP) of the American Academy of Pediatrics. RESULTS: Data were obtained from parents of 1123 children. Overall safety scores (percent safe responses) increased with increasing socioeconomic status. The differences among the socioeconomic groups were most pronounced for transportation and less pronounced for household and recreational safety. The differences were most notable for activities that required a safety related device such as a car seat, seat belt, helmet, or smoke detector. Appropriate use of such devices declined from 47% (upper socioeconomic group) to 25% (middle) to 15% (lower). CONCLUSIONS: Considerable differences in the knowledge and especially the practice of childhood safety exist among parents in different socioeconomic levels in Mexico. Future injury prevention efforts need to address these and especially the availability, cost, and utilization of specific highly effective safety devices.

Contaminación Enterobacteriana del Guarapo de una Fábrica de Cochabamba, en Fermentación Normal y Fermentación Flemosa / Guarapo Enterobacteriana Pollution in the Normal and Fermentation Fermentation Phlegmy of a Factory Cochabamba

El guarapo es una bebida alcohólica que sigue la vía de fermentación y un desvío del mismo resulta en guarapo de consistencia flemosa. La presencia de enterobacterias (entéricas fecales y la E. coli) son indicadores de contaminación y tienen relación con los grupos tifoide-paratifoide. El objetivo de la investigación fue determinar la contaminación enterobacteriana presente en el guarapo en fermentación normal y en fermentación de consistencia flemosa en muestras recolectadas en una fábrica de la provincia Cercado-Cochabamba. Se realizó un estudio de tipo transversal y descriptivo tomando en cuenta 9 muestras de guarapo de consistencia flemosa y una muestra de guarapo en fermentación normal tomada al azar, durante el tiempo de estudio establecido. Se encontró 100% de coliformes fecales en las muestras dos, tres y cinco, existiendo contaminación de gravedad entre 20.000 a 2.640.000 UFC/ml sobrepasando el parámetro normal < 10 UFC/ml, causado posiblemente por el escaso control de calidad y saneamiento.

The cane juice is an alcoholic beverage that follows the route of fermentation and diverted the same results in consistency guarapo phlegmy. The presence of Enterobacteriaceae (enteric coliforms and E. coli) are indicators of pollution and are linked to the typhoid groups - paratyphoid.The research objective was to determine the contamination present in the juice enterobacteriana in normal fermentation and fermentation phlegmy consistency in samples collected from a factory in the province Cercado - Cochabamba.A study of cross-sectional and descriptive sample taking into account 9 phlegmy consistency of juice and a sample of juice in normal fermentation chosen at random during the study period established. We found 100% of fecal coliform in the samples two, three and five, there contamination of gravity between 20,000 to 2,640,000 CFU / ml exceeding the normal parameter < 10 CFU / ml, possibly caused by the low quality control and sanitation.