Abstract The expression intensities of cytokeratins and tight junction proteins were determined on re-epithelization. Experimental blister wound healing was studied in patients with diabetes mellitus and in patients with obstructive jaundice. Suction blisters were induced on healthy volunteers, and the healing blisters were biopsied at different time points. Cytokeratin expression and the tight junction proteins ZO-1 and occludin were studied immunohistochemically. Blisters were induced on 17 patients with diabetes and 11 control subjects, and the healing process was followed indirectly by measuring water evaporation and blood flow in the wounds. Microvascular reactivity in the diabetic patients was also studied by using non-immunologic contact irritants. Wound healing, skin collagen synthesis and serum levels of procollagen propeptides were studied in 24 patients with obstructive jaundice caused by neoplastic pancreaticobiliary obstruction and in 17 control patients with the corresponding condition without jaundice. Cytokeratin expression was altered in healing epidermis. In the suprabasal layer, K10 was replaced by K14 and, most likely, by K16. K18 keratin, which is not present in normal epidermis, was found in the basal and suprabasal layers. Thus, there was a shift towards lower molecular weight cytokeratins, which is a reflection of immaturity, and probably towards motility. The tight junction proteins ZO-1 and occludin were expressed in the migrating epidermal sheet, where they apparently form an early barrier. Enhanced expression was seen in the hyperproliferative zone of the wound edge. The diabetic patients showed slower restoration of the epidermal barrier and a weaker initial inflammatory response. Obstructive jaundice and its resolution had no effect on healing. Skin collagen synthesis was decreased in jaundiced patients, and it increased slightly after drainage. Serum type III collagen propeptide levels were elevated in patients with biliary obstruction and dropped after drainage. The elevated levels may be related to the increased synthesis due to fibrosis. As a conclusion, diabetes mellitus impairs epidermal wound healing, while obstructive jaundice does not.

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第13355号 / 論医博第2201号 / 新制||医||1044(附属図書館) / (主査)教授 妹尾 浩, 教授 羽賀 博典, 教授 武藤 学 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

JGH Open: An open access journal of gastroenterology and hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley and Sons Australia, Ltd. Background and Aim: The United Kingdom-primary biliary cholangitis (UK-PBC) and global primary biliary cholangitis group (GLOBE) prognostic models have been recently developed to predict long-term outcomes in primary biliary cholangitis (PBC). However, these predictive scores have not yet been well evaluated in the U.S. population. Methods: We retrospectively reviewed newly diagnosed PBC patients at the Cleveland Clinic between November 1998 and February 2017. Adverse events were defined as liver transplantation, liver-related mortality, and all-cause mortality. Transplant-free survival (TFS) was estimated using the Kaplan–Meier method. Predictive performances of all prognostic models were evaluated using the C-statistic. Results: We identified 352 patients who used ursodeoxycholic acid therapy. Of them, 311 (88.4%) only had PBC, while 41 (11.6%) were diagnosed with PBC-autoimmune hepatitis overlap. A total of 22 (6%), 47 (13%), and 55 (16%) patients had adverse events within 5, 10, and 15 years after diagnosis, respectively. In patients with PBC only, the C-statistic in predicting 15-year adverse events was 0.75 per GLOBE compared to 0.74 per UK-PBC (P = 0.94), 0.73 per Rotterdam (P = 0.44), 0.66 per Barcelona (P = 0.004), 0.65 per Paris 1 (P = 0.005), 0.62 per Paris 2 (P < 0.0001), 0.60 per Toronto (P < 0.0001), and 0.60 per Mayo (P < 0.0001) scores. Median follow-up was 9.2 years. Ten-year TFS for patients who had optimal versus suboptimal treatment response was 92 versus 74% per Paris 1 (P < 0.0001), 95 versus 79% per Paris 2 (P = 0.0002), 93 versus 65% per Barcelona (P < 0.0001), and 96 versus 68% per Rotterdam (P < 0.0001) risk scores, respectively. Conclusion: In our cohort of PBC patients, the UK-PBC and GLOBE scores were both accurate and reasonably valid prognostic models in the U.S. population.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23566号 / 医博第4780号 / 新制||医||1054(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 武藤 学, 教授 佐藤 俊哉, 教授 羽賀 博典 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.

Most patients with pancreatic cancer will present with metastatic or locally advanced disease. Unfortunately, most patients with localized disease will experience recurrence even after multimodality therapy. As such, pancreatic cancer patients arrive at a common endpoint where decisions pertaining to palliative care come to the forefront. This article summarizes surgical, endoscopic, and other palliative techniques for relief of obstructive jaundice, relief of duodenal or gastric outlet obstruction, and relief of pain due to invasion of the celiac plexus. It also introduces the utility of the palliative care triangle in clarifying a patient's and family's goals to guide decision making.

Introdução: A escolha da via de acesso para tratamento paliativo da obstrução biliar nos tumores da confluência biliopancreática (TCBP) permanece incerta para os pacientes com baixo risco anestésico-cirúrgico ou longa expectativa de vida. Objetivo: Estudar a influência da derivação biliar mediante abordagem laparotômica e endoscópica nos resultados assistenciais e nos custos do tratamento paliativo dos TCBP. Método: Estudo coorte retrospectivo de prontuários dos pacientes portadores de TCBP submetidos ao tratamento paliativo endoscópico ou cirúrgico no Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo (HCFMRP-USP), no período de 2002 a 2013, com análise de variáveis epidemiológicas, clínicas e assistenciais e dos custos. Resultados: Dentre os 150 pacientes com TCBP estudados, 92 (61,33%) foram submetidos à derivação das vias biliares por laparotomia (TL) e 58 (38,66%) por via endoscópica (TE), onde a prótese plástica foi utilizada na maioria dos casos (N = 38, 65,51%). Os grupos foram homogêneos para a maioria das variáveis epidemiológicas e clínicas antes dos procedimentos. As taxas de complicações precoces foram equivalentes na comparação dos grupos (55,17% para TE e 40,1% para TL), porém as complicações tardias foram mais frequentes no grupo TE (20,68% para TE e 10,34% para TL), o que se associou principalmente às recorrências das obstruções biliares. As curvas de sobrevida foram menores para TE. Não houve diferença significativa entre o custo mediano por procedimento no grupo TE (R$2.861,00) e TL (R$3.427,00) (p=0,3253). Por outro lado, o custo mediano total para o grupo TE (R$8.586,00) foi menor que o do grupo TL (R$12.810,00) (p=0,0001). Conclusão: a combinação das vantagens das duas modalidades de tratamento paliativo para os TCBP (maior sobrevida e eficácia na redução da colestase no grupo TL e menores tempo de internação e custo global no grupo TE) é uma meta a ser atingida e o acesso videolaparoscópico é uma alternativa a ser explorada. / Introduction: the advanced tumors of the biliopancreatic confluence (TCBP) often present with biliary obstruction, which can receive palliative treatment, through laparotomy, laparoscopic or endoscopic. Objective: to study the influence of laparotomy and endoscopic approaches in care results and costs of the palliative treatment of TCBP. Method: retrospective coorte study of medical records of patients with TCBP undergoing to the endoscopic and / or laparotomic palliation at the Hospital of Clinics of the Faculty of Medicine of Ribeirão Preto, University of São Paulo (HCFMRP-USP), from 2002 to 2013 with analysis of epidemiological variables, clinical, care and treatment costs. Results: among the 150 patients with TCBP studied, 92 (61.33%) underwent biliary bypass by laparotomy (TL) and 58 (38.66%) endoscopically (TE). The groups were homogeneous for most of the epidemiological and clinical variables before the procedures. The rates of early complications were similar between the groups (55.17% for TE and 40.1% for TL), but late complications were more frequent in the TE group (20.68% for TE and 10.34% for TL), which was mainly associated with the recurrence of biliary obstruction. The survival curves were lower for TE. The median cost of the procedure in the TE group (R$ 2,861.00) wasn´t different from TL (R$ 3,427.00) (p = 0,3253). On the other hand, the median total cost for the TE group (R$ 8,586.00) was lower than the TL group (R$ 12,810.00) (p = 0,0001). Conclusion: the combination of the advantages of the two methods of palliative treatment for TCBP (greater efficacy in reducing cholestasis in the TL group and lower length of stay and the overall costs in the TE group) is a goal to be achieved, and the laparoscopic access is an alternative to be explored.

Introdução: A escolha da via de acesso para tratamento paliativo da obstrução biliar nos tumores da confluência biliopancreática (TCBP) permanece incerta para os pacientes com baixo risco anestésico-cirúrgico ou longa expectativa de vida. Objetivo: Estudar a influência da derivação biliar mediante abordagem laparotômica e endoscópica nos resultados assistenciais e nos custos do tratamento paliativo dos TCBP. Método: Estudo coorte retrospectivo de prontuários dos pacientes portadores de TCBP submetidos ao tratamento paliativo endoscópico ou cirúrgico no Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo (HCFMRP-USP), no período de 2002 a 2013, com análise de variáveis epidemiológicas, clínicas e assistenciais e dos custos. Resultados: Dentre os 150 pacientes com TCBP estudados, 92 (61,33%) foram submetidos à derivação das vias biliares por laparotomia (TL) e 58 (38,66%) por via endoscópica (TE), onde a prótese plástica foi utilizada na maioria dos casos (N = 38, 65,51%). Os grupos foram homogêneos para a maioria das variáveis epidemiológicas e clínicas antes dos procedimentos. As taxas de complicações precoces foram equivalentes na comparação dos grupos (55,17% para TE e 40,1% para TL), porém as complicações tardias foram mais frequentes no grupo TE (20,68% para TE e 10,34% para TL), o que se associou principalmente às recorrências das obstruções biliares. As curvas de sobrevida foram menores para TE. Não houve diferença significativa entre o custo mediano por procedimento no grupo TE (R$2.861,00) e TL (R$3.427,00) (p=0,3253). Por outro lado, o custo mediano total para o grupo TE (R$8.586,00) foi menor que o do grupo TL (R$12.810,00) (p=0,0001). Conclusão: a combinação das vantagens das duas modalidades de tratamento paliativo para os TCBP (maior sobrevida e eficácia na redução da colestase no grupo TL e menores tempo de internação e custo global no grupo TE) é uma meta a ser atingida e o acesso videolaparoscópico é uma alternativa a ser explorada. / Introduction: the advanced tumors of the biliopancreatic confluence (TCBP) often present with biliary obstruction, which can receive palliative treatment, through laparotomy, laparoscopic or endoscopic. Objective: to study the influence of laparotomy and endoscopic approaches in care results and costs of the palliative treatment of TCBP. Method: retrospective coorte study of medical records of patients with TCBP undergoing to the endoscopic and / or laparotomic palliation at the Hospital of Clinics of the Faculty of Medicine of Ribeirão Preto, University of São Paulo (HCFMRP-USP), from 2002 to 2013 with analysis of epidemiological variables, clinical, care and treatment costs. Results: among the 150 patients with TCBP studied, 92 (61.33%) underwent biliary bypass by laparotomy (TL) and 58 (38.66%) endoscopically (TE). The groups were homogeneous for most of the epidemiological and clinical variables before the procedures. The rates of early complications were similar between the groups (55.17% for TE and 40.1% for TL), but late complications were more frequent in the TE group (20.68% for TE and 10.34% for TL), which was mainly associated with the recurrence of biliary obstruction. The survival curves were lower for TE. The median cost of the procedure in the TE group (R$ 2,861.00) wasn´t different from TL (R$ 3,427.00) (p = 0,3253). On the other hand, the median total cost for the TE group (R$ 8,586.00) was lower than the TL group (R$ 12,810.00) (p = 0,0001). Conclusion: the combination of the advantages of the two methods of palliative treatment for TCBP (greater efficacy in reducing cholestasis in the TL group and lower length of stay and the overall costs in the TE group) is a goal to be achieved, and the laparoscopic access is an alternative to be explored.

The differentiation, in an infant with cholestasis, between extrahepatic biliary atresia (EHBA) and the neonatal hepatitis syndrome (NHS) is important in that laparotomy is always indicated in EHBA but is undesirable in NHS. This differentiation is particularly difficult in those infants with complete cholestasis. Hepatobiliary scintigraphy is a commonly used investigation in infants with obstructive jaundice. The scintigraphic demonstration of excretion into the gut excludes extrahepatic obstruction, however, absence of excretion may be due to EHBA, severe cholestasis with patent extrahepatic bile ducts or poor uptake of the agent, and is therefore not diagnostic. This study has examined the quantitative measurement of the hepatic uptake of p-butyl IDA and Sn colloid, and an estimation of liver shape, in a group of patients with complete cholestasis in whom conventional scan interpretation, based on excretion into the-gut, would not be useful. The scans were recorded as dynamic studies and the resultant time-activity curves were subjected to curve fitting to calculate a rate constant for uptake of radiopharmaceutical. Liver shape was determined from the anterior static image of the colloid scan. The results show a significant difference between the EHBA and the NHS patients in the rate of uptake of p-butyl IDA, in the ratio of the rate of uptake of p-butyl IDA/the rate of uptake of colloid and in the measurements used to express liver shape. Using this method of scan interpretation, a diagnostic accuracy of 85% was achieved in this study of patients who clinically, and on scan, had no evidence of bile flow. Hepatic scintigraphy is therefore a useful investigation in the diagnostic work-up of infants presenting with obstructive jaundice even when bile flow is completely absent.

Enteric fever remains the most common febrile illness in urban Nepal. Some individuals may have recurrent infection and some may even progress to become long term chronic carriers. The aim of this thesis was to investigate the rate and factors leading to relapse with typhoid fever in patients who were enrolled in clinical treatment trials for acute enteric fever. The results show that relapses in enteric fever is a common complication and is more likely to be associated with the treatment antimicrobial, cefixime. Gallbladder carriage of invasive Salmonella is considered fundamental in sustaining enteric fever transmission as humans are the only known natural host. This thesis, therefore, also aimed to investigate the prevalence, characteristics, immunological responses, and mechanism of carriage of invasive Salmonella in the gallbladder by examining bile and tissue obtained from individuals who underwent cholecystectomy in Kathmandu. Data presented here demonstrate that S. Paratyphi A is almost as prevalent as S. Typhi in the gallbladder and that carriage may not be driven by antimicrobial resistance. Gallbladders that contained Salmonella were more likely to show evidence of acute inflammation with extensive neutrophil infiltrate. Chronic carriers were found to have dramatically elevated levels of IgG to O:2 and Vi antigens with high bactericidal activity yet low pro-inflammatory cytokine levels suggesting that Salmonella are stimulating a constant immunological response, in the form of antibody. S. Typhi may be controlling the inflammatory process through the expression of the Vi capsule in the gallbladder. Genome sequencing of S. Typhi isolated from chronic carriers were different from those S. Typhi causing acute disease. These data question the current dogmas surrounding the carriage of S. Typhi in gallbladder and predict a pivotal role of Vi capsule and gallstones in maintaining carriage. Therefore, prospectively identifying these individuals is paramount for rapid local and regional elimination. Furthermore, combining cytokine profiles and antibody levels may be a method of prospectively detecting carriers in the general population.