Reform follows failure: II. Pressure for change in the Lebanese health sector

This paper describes how, against a background of growing financial crisis, pressure for reform is building up in the Lebanese health care system. It describes the various agendas and influences that played a role. The Ministry of Health, backed by some international organizations, has started taking the lead in a reform that addresses both the way care is delivered and the way it is financed. The paper describes the interventions made to prepare reform. The experience in Lebanon shows that this preparation is a process of muddling through, experimentation and alliance building, rather than the marketing of an overall coherent blueprint.     

Pyloric Injection of Botulinum Toxin for the Treatment of Refractory GERD Accompanied with Gastroparesis: A Preliminary Report

Gastroesophageal reflux disease (GERD) refractory to conventional medical treatment is frequently associated with gastroparesis, a complex condition with no definitive treatment to date. We first developed a scoring system to assess the severity and frequency of both reflux- and gastroparesis-related symptoms. We then tested, for the first time, the hypothesis that endoscopic pyloric botulinum toxin injection alleviates both of these symptom types. Eleven patients (four males) with GERD (confirmed by esophageal pH monitoring) plus gastroparesis (confirmed by gastric emptying study) underwent toxin injection. Patients had no concomitant disease and were not allowed to use prokinetics before or after treatment. Injection significantly improved both gastroparesis- and reflux-related symptoms in the majority of patients but the duration of symptom relief was relatively short. Responders to treatment had significantly higher total reflux symptom scores (before injection) than nonresponders. All but one of the patients in whom gastroparesis symptoms improved also showed response in reflux symptoms, which supports our hypothesis. We believe that response to toxin injection is a reliable predictor of response to subsequent surgery following the recurrence of symptoms.     

Structural features of guinea pig aldehyde oxidase inhibitory activities of flavonoids explored using QSAR and molecular modeling studies

In this study, guinea pig aldehyde oxidase inhibitory activities of flavonoids were investigated using in silico, quantitative structure–activity relationships, molecular modeling, and experimental techniques, in order to understand more about their mode of interactions. The aldehyde oxidase inhibitory activity values determined experimentally in this work or collected from our previous report were used to derive mathematical models for the prediction purposes employing combined genetic algorithm and partial least square method, as well as multiple linear regression analysis. The statistical parameters for the developed models and the results of leave-one-out internal cross-validation were indicative of the validity of the models. To further investigate the mechanism of interaction between flavonoid inhibitors and guinea pig aldehyde oxidase enzyme, the structural model of the enzyme was built and the inhibitors were docked manually into the binding site. The model for quercetin-aldehyde oxidase complex was validated based on its appropriate stability during 10?ns molecular dynamics simulation, and hence the positioning procedure for the rest of flavonoids was guided based on the manually docked position of quercetin. The identified interactions were compared with those of flavonoids previously reported for rat aldehyde oxidase and the results showed a substantial commonality between the modes of interactions predicted for flavonoids positioned into the binding site of aldehyde oxidase from guinea pig and rat. This commonality is also reflected by the quantitative structure–activity relationships models. The results presented in this work may provide useful information where the structural requirements for aldehyde oxidase inhibition are sought, such as designing novel aldehyde oxidase inhibitors or investigating drug interaction involving aldehyde oxidase mediated biotransformation.     

Dynamic Graft-versus-Host Disease-Free,Relapse-Free Survival: Multistate Modeling of the Morbidity and Mortality of Allotransplantation

Graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) represents complete, ideal recovery after allogeneic hematopoietic cell transplantation (HCT). However, as originally proposed, this composite endpoint does not account for the possibility that HCT complications may improve after treatment. To more accurately estimate survival with response to GVHD and relapse after HCT, we developed a dynamic multistate GRFS (dGRFS) model with outcomes data from 949 patients undergoing their first allogeneic HCT for hematologic malignancy at the University of Minnesota. Because some patients were successfully treated for GVHD and relapse, dGRFS was higher than the originally defined time-to-event GRFS at 1 year (37.0 versus 27.6%) through 4 years (37.4% versus 22.2%). Mean survival without failure events was .52 years (95% confidence interval, .45 to .58 year) greater in dGRFS compared with the originally defined GRFS. Patient age (P< .001), disease risk (P < .001), conditioning intensity (P = .007), and donor type (P = .003) all significantly influenced dGRFS. The multistate model of dGRFS closely estimates the continuing and prevalent severe morbidity and mortality of allogeneic HCT. To serve the greater HCT community in more accurately modeling recovery from transplantation, we provide our R code for determination of dGRFS with annotations in Supplementary Materials.     

Reduced-Intensity Conditioning Followed by Related and Unrelated Allografts for Hematologic Malignancies: Expanded Analysis and Long-Term Follow-Up

Reduced-intensity conditioning (RIC) extends the curative potential of allogeneic hematopoietic cell transplantation (HCT) to patients with hematologic malignancies unable to withstand myeloablative conditioning. We prospectively analyzed the outcomes of 292 consecutive patients, median age 58 years (range, 19 to 75) with hematologic malignancies treated with a uniform RIC regimen of cyclophosphamide, fludarabine, and total body irradiation (200 cGy) with or without antithymocyte globulin and cyclosporine and mycophenolate mofetil graft-versus-host disease (GVHD) prophylaxis followed by allogeneic HCT at the University of Minnesota from 2002 to 6. Probability of 5-year overall survival was 78% for patients with indolent non-Hodgkin lymphoma, 53% for chronic myelogenous leukemia, 55% for Hodgkin lymphoma, 40% for acute myelogenous leukemia, 37% for myelodysplastic syndrome, 29% for myeloma, and 14% for myeloproliferative neoplasms. Corresponding outcomes for relapse were 0%, 13%, 53%, 37%, 39%, 75%, and 29%, respectively. Disease risk index (DRI) predicted both survival and relapse with superior survival (64%) and lowest relapse (16%) in those with low risk score compared with 24% survival and 57% relapse in those with high/very-high risk scores. Recipient cytomegalovirus (CMV)-positive serostatus was protective from relapse with the lowest rates in those also receiving a CMV-positive donor graft (29%). The cumulative incidence of 2-year nonrelapse mortality was 26% and was lowest in those receiving a matched sibling graft at 21%, with low (21%) or intermediate (18%) HCT-specific comorbidity index, and was similar across age groups. The incidence of grades II to IV acute GVHD was 43% and grades III to IV 27%; the highest rates were found in those receiving an unrelated donor (URD) peripheral blood stem cell (PBSC) graft, at 50%. Chronic GVHD at 1 year was 36%.Future approaches incorporating alternative GVHD prophylaxis, particularly for URD PBSC grafts, and targeted post-transplant antineoplastic therapies for those with high DRI are indicated to improve these outcomes.     

An orthotopic mouse model of remetastasis of human colon cancer liver metastasis.

Whether liver metastases from colon cancer are capable of metastasizing to other sites is an important question in surgical oncology. To answer this question, we have developed a highly metastatic orthotopic transplant model of a liver metastasis from a human colon cancer patient in nude mice that targets the liver and lymph nodes. The metastatic human tumor was transplanted in athymic nude mice by surgical orthotopic implantation (SOI) of a liver metastasis from a colon cancer patient. The human colon tumor was then subsequently implanted in the colon by SOI or, in an additional series of nude mice, in the liver by surgical hepatic implantation (SHI). The mice were then explored over time for lymph node involvement beginning 10 days after implantation. After SOI, 100% of the animals had liver metastasis within 10 days, and subsequently, 19 days after SOI, all lymph nodes draining the liver were involved with metastasis without any retroperitoneal or lung tissue involvement. After SHI, all sites of lymphatic drainage of the liver, including portal, celiac, and mediastinal lymph nodes, were massively involved by metastasis in 100% of the animals as early as 10 days after tumor implantation on the liver. The results of this study demonstrate that liver metastases from colon cancer are capable of remetastasizing to other sites. This study thus suggests that in colon cancer patients with liver metastasis, mediastinal, celiac, and portal lymph node metastases originate from the liver metastasis and not, as previously thought, from primary colon cancer.     

Oxidative Stress-Induced Apoptosis in Chronic Myelogenous Leukemia K562 Cells by an Active Compound from the Dithio- Carbamate Family

Previous studies suggested that dithio-carbamates are potent apoptosis and anti-apoptosis inducing agents in various cancer cells. Here, the anti-proliferative and apoptosis inducing effects of a new derivative (2-NDC) from the dithio-carbamate family was examined in human leukemia K562 cells. We use thiazolyl blue tetrazolium bromide (MTT) to measure viability and cell growth inhibition. The 2-NDC showed effects on viability in a dose and time-dependent manner, inhibiting proliferation at concentrations of 10-30 M after 24-48 hours of treatment and increasing values after 72 hours at 40-120 M. The cytotoxic effect of the compound was calculated with an IC50 of 30 M after 24-hour. Apoptosis induction was confirmed by acridine orange-ethidium bromide (AO/EtBr) staining, DNA fragmentation assay, flow cytometric assessment and also caspase-3 activation assay. Furthermore, enzymes level such as superoxide dismutase (SOD) and catalase (CAT) involved in oxidative stress were evaluated. The results of this study demonstrated insignificant increase of intracellular ROS levels for 24 hours and reduction after 48-72 hours. In addition to reduction of intracellular thiol, caspase-3 like activity was also decreased in a time-dependent manner in cells treated with 2-NDC. Thus 2-NDC can be considered as a good candidate for further pharmaceutical evaluations.