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Purpose: Nowadays chronicity is one of the most frequent aspects of care doctors have to deal with. Students need to know and learn clinical, relational, social and managerial elements of chronicity and changes that disease causes in patients, families and doctors themselves. Methods: Students are supervised by a family doctor, in taking care of 'their' patient and of his/her family. They are asked to keep an updated diary, participate in the periodical revision of the medical history and write an end-report. Two focus groups were conducted, adopting a constructive qualitative approach in order to analyse results. Results: The focus groups and the SWOT analysis show common themes such as innovative learning and multidisciplinary approach. Clinical evolution of the disease, mental and body changes and the diagnostic and therapeutic future planning were also revealed. Conclusions: The main goal of this innovation was understanding the importance of a continuous clinical relationship and of the role of the doctor as 'therapy itself'. The project was demonstrated to be able to teach the future physicians how to practice more empathetic medicine and to improve the skills needed in a complex relational environment including that of chronic disease.

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AIMS: Glucagon-like peptide-1 (GLP-1) is an important modulator of insulin secretion by endocrine pancreas. In the present study, we investigated the effect of swim training on GLP-1 insulinotropic action in pancreatic islets from monosodium glutamate (MSG)-obese rats. METHODS: Obesity was induced by neonatal MSG administration. MSG-obese and control (CON) exercised rats swam for 30 min (3 times week(-1) ) for 10 weeks. Pancreatic islets were isolated by colagenase technique and incubated with low (5.6 mM) or high (16.7 mM) glucose concentrations in the presence or absence of GLP-1 (10 nM). In addition, GLP-1 gene expression in ileum was quantified in fasting and glucose conditions. RESULTS: Exercise reduced obesity and hyperinsulinemia in MSG-obese rats. Swim training also inhibited glucose-induced insulin secretion in islets from both groups. Islets from MSG-obese rats maintained GLP-1 insulinotropic response in low glucose concentration. In contrast, in the presence of high glucose concentration, GLP-1 insulinotropic action was absent in islets from MSG-obese rats. Islets from MSG-exercised rats showed reduced GLP-1 insulinotropic action in the presence of low glucose. However, in high glucose concentration swim training restored GLP-1 insulinotropic response in islets from MSG-obese rats. In all groups, glucose intake increased GLP-1 immunoreactivity and gene expression in ileum cells in relation to fasting conditions. Swim training reduced these parameters only in ileum cells from CON-exercised rats. Neither MSG treatment nor exercise affected GLP-1 expression in the ileum. CONCLUSIONS: Exercise avoids insulin hypersecretion restoring GLP-1's insulinotropic action in pancreatic islets from MSG-obese rats.

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Owing to its central role in DNA synthesis, human thymidylate synthase (hTS) is a well-established target for chemotherapeutic agents, such as fluoropyrimidines. The use of hTS inhibitors in cancer therapy is limited by their toxicity and the development of cellular drug resistance. Here, with the aim of shedding light on the structural role of the A-helix in fluoropyrimidine resistance, we have created a fluoropyrimidine-resistant mutant by making a single point mutation, Glu30Trp. We postulated that residue 30, which is located in the A-helix, close to but outside the enzyme active site, could have a long-range effect on inhibitor binding. The mutant shows 100 times lower specific activity with respect to the wild-type hTS and is resistant to the classical inhibitor, FdUMP, as shown by a 6-fold higher inhibition constant. Circular dichroism experiments show that the mutant is folded. The results of molecular modeling and simulation suggest that the Glu30Trp mutation gives rise to resistance by altering the hydrogen-bond network between residue 30 and the active site.

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Malignant melanoma is particularly resistant to conventional chemotherapy and radiotherapy. For this reason in the past years a huge variety of new compounds has been developed with potential chemotherapeutic activity which needs to be tested in vitro and in vivo. We investigated the in vitro action of three new experimental antifolate substances (MR7, MR21 and MR36) with a critical target for thymidylate synthase (TS), an essential enzyme for DNA synthesis. The response of two melanoma cell lines (SK-MEL-2 derived from malignant melanoma metastasis and SK-MEL-28 derived from primary malignant melanoma) was examined after treatment with these substances. The antifolate agents induced apoptosis in SK-MEL-2 and SK-MEL-28 cells as confirmed by the TUNEL technique and Comet Assay. Western-blot analysis showed a down-regulation of Bcl-2 protein level and PARP cleavage, otherwise p53 and Bax expressions were not modulated. Moreover, these antifolate-induced apoptosis was accompanied by both pro-caspase-9 and -8 activations. These results were supported by the use of the pan-caspases inhibitor Z-VAD-FMK that almost completely decreased the amount of apoptosis in both the melanoma cell lines treated with antifolate. In conclusion our results show that TS inhibitors are able to induce apoptosis through a caspase-mediated pathway, but without the involvement of the p53/Bax signalling.

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Recent methodologies applied to the drug discovery process, such as genomics and proteomics, have greatly implemented our basic understanding of drug action and are giving more input to medicinal chemists, in finding genuinely new targets and opportunities for the development of drugs with original mechanisms of action. In this paper, an example of the successful application of some new techniques to the target enzymes with the Thymidylate Synthase (TS) function is given. The improved knowledge of the complex mechanism of the biological pathways in which thymidylate synthase is involved represents a unique chance to find new mechanism-based inhibitors, aimed to treat not only cancerous diseases, but also infectious pathologies. Thymidylate synthase (TS or ThyA) has long been considered as one of the best-known drug targets in the anti-cancer area, after which old and new drugs, such as 5-fluoro uracil and the anti-folate ZD1694, have been introduced into chemotherapy to treat solid tumours. Only a few attempts have been made to find non-classical anti-folate inhibitors that are dissimilar to the folate co-factor, with the aim of finding unshared protein target domains on the enzyme structure, in order to specifically inhibit TS enzymes from pathogens. Only recently from omic studies, a new Thymidylate Synthase Complementing Protein (TSCP or ThyX) has been identified in a number of pathogens, showing a different structure with respect to human TS, thus opening new avenues to specific inhibitions. A depiction of the most recent progress in the study of Thymidylate Synthase enzymes is presented in the following sections.

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A case of malignant esophageal schwannoma is reported. A 54-year-old man consulted for a 1-year history of dysphagia. Investigations revealed a tumor of the distal esophagus, with involvement of the cardia, and were suspicious for metastatic mediastinal nodes. Ivor-Lewis esophagectomy with gastric-tube reconstruction was performed, with favorable outcome. Histological examination revealed esophageal sarcoma in a Barrett's esophagus. Periesophageal nodes had metastatic involvement. Immunohistochemical study was positive for S100 and vimentin and was negative for CD117, compatible with a diagnosis of esophageal schwannoma. We discuss this rare disease and its characteristics. This is the second reported case of malignant schwannoma with lymph node metastasis.

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El hígado graso es una entidad patológica que se caracteriza por acumulación de glóbulos de grasa dentro de los hepatocitos. Es una patología que en ultrasonido se diagnostica cada vez más, sin embargo es necesario usar algunos criterios para su diagnóstico. Nuestro objetivo fue estandarizar criterios ultrasonográficos, correlacionándolos con anatomía patológica, para diagnóstico de esteatosis y su cuantificación en grados de severidad (leve, moderado, severo). Este estudio mostró una concordancia moderada entre el ultrasonido y biopsia.

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The purpose of this study was to investigate the impact of a modified surgical protocol and the survival of implants placed in the posterior maxilla. Forty-two implants were placed in the maxillary posterior area of 29 partially edentulous patients (17 men, 12 women; mean age 50 years; range 38 to 62 years) according to the modified surgical protocol. Twenty-nine of these implants had been placed into the maxillary tuberosity. All implants were checked radiologically every 12 months with a customized film holder. The restorations were fixed partial prostheses. Only 1 of the 42 implants was lost at stage 2 surgery. Results suggest that considerable benefits may be obtained by modifying a standard surgical protocol to maximize the results for a particular anatomic site.

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The inhibitory effect of one of the major proteins secreted by the rat seminal vesicles (SV-IV) on platelet-activating factor (PAF)-induced biological activities was investigated in vivo. SV-IV was found to prevent dose dependently both hypotension and acute bronchospasm caused by PAF administration in guinea-pigs. In addition, SV-IV inhibited both PAF- and ethanol-induced gastric mucosal injury in a dose-dependent manner.

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We report our experience with 19 patients with early gastric cancer in Valdivia, a southern province of Chile. All patients had symptoms and 15 had a preoperative biopsy. A mean of 39 days elapsed between biopsy and surgery. An emergency operation was performed in 3 patients. The mean lesion size was 10 cm2. An intramucous location was present in 9 patients and a submucous one in 10. Infiltration of the first lymph node barrier was observed in only 1 patient. A type P.1 resection was performed in 68% of patients, a type 2 resection in 11% and a type 3 in 5%. Recurrences were observed in 3 patients and 2 of them died. 5 year survival rate was 100% and 7 year survival was 68%.

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Dose-response studies to tetragastrin were performed in patients with duodenal ulcer before and after highly selective vagotomy, hemigastrectomy and truncal vagotomy plus antrectomy. The calculated maximal response and the dose necessary to elicit 50 percent of that response (D50) were calculated by linear transformation of the results. Both highly selective vagotomy and hemigastrectomy were followed by a significant decrease in the stimulated acid output, characterized by a decrease in the calculated maximal response, but no change in the sensitivity of the parietal cells (D50) was observed. This indicates a noncompetitive reduction in the acid output. The calculated maximal response could not be restored to preoperative values by increasing the dose of stimulant. Truncal vagotomy plus antrectomy was followed by severe alteration in gastric physiology, and no linear transformation of the acid output could be made. This investigation shows that maximal acid output was obtained by the same dose of stimulant before and after all three operations studied. Therefore it is not necessary to increase the dose in postvagotomy acid studies.

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