The physician's decision to use tube feedings: the role of the family, the living will, and the Cruzan decision.

OBJECTIVE: To determine the relative importance of factors influencing physicians to use tube feedings in patients lacking decision-making capacity. DESIGN: Survey. SETTING AND PARTICIPANTS: Four hundred thirty-nine members of the Missouri Academy of Family Physicians. MEASUREMENTS: Using a mailed questionnaire, physicians were asked for a decision about feeding tube placement in an 89-year-old man who was unable to swallow or communicate after a stroke. Changing the conditions of the scenario, we then evaluated the influence of patient age, duration of disability, a living will, the Cruzan decision, and family preferences on the physician's decision. RESULTS: After reading the initial case history, 47% of physicians opposed tube feedings. Physicians who were told that the patient signed a living will specifically excluding tube feedings were more likely to oppose tube feedings than those who were told that he signed only a standard living will (53% vs 42%; P = 0.02). Forty-two percent of physicians who initially suggested a feeding tube changed their recommendation if the family opposed it. Sixty-six percent of physicians who initially opposed a feeding tube changed their recommendation if the family "pushed" for it. Thirty-three percent of physicians who initially opposed tube feedings under the living will scenario would favor tube feedings if the patient had not signed a living will. Twenty-two percent of physicians who initially opposed tube feedings would change to favor them if the issue had arisen before the Cruzan decision. CONCLUSIONS: Among this group of physicians, there was no consensus on whether tube feedings should be initiated. However, it was found that the family's opinion was the most influential factor affecting the physician's recommendation about tube feedings. Most physicians endorsed family preferences for tube feedings even when this intervention was specifically opposed in the patient's living will.     

Pulmonary artery aneurysms in Behçet's disease: contribution of imaging in 5 cases

Pulmonary involvement in Beh?et's disease is an uncommon condition (12%). Thromboembolism of the superior vena cava and/or other mediastinal veins, aneurysms of the aorta and pulmonary arteries are the main vascular manifestations in addition to pulmonary infarct and intrathoracic hemorrhage. Despite their scarcity, respiratory symptoms may be life-threatening. The aim of this study was to assess the contribution of thoracic imaging for one of the most serious aspects of the disease: pulmonary artery aneurysm. We report five patients with pulmonary artery aneurysms (mean age: 39.5 years). Hemoptysia revealed Beh?et's disease in three. Initially explored by conventional radiography, computed tomography and angiography, pulmonary artery aneurysms are currently investigated well with helicoidal computed tomography, digital angiography, magnetic resonance imaging (MRI) and angio-MRI. These imaging techniques provide helpful information for the diagnosis of Beh?et's disease.     

Laparoscopic-assisted one-stage resection of rectal cancer with synchronous liver metastasis utilizing a pfannenstiel incision

Laparoscopic approaches have been increasingly used in selected patients with either colorectal or liver cancer. However, simultaneous resection of colorectal carcinoma with synchronous liver metastases is still a subject of debate. The present case describes combined laparoscopic rectal and liver resections for a patient with primary rectal cancer and a synchronous liver metastasis utilizing a Pfannenstiel incision for specimen extraction. The operative time was 370 min and estimated blood loss was 400 mL. Postoperatively, the patient required parenteral analgesia for 48 h, resumed normal diet on day 3 and was discharged on day 7 after the operation. A laparoscopic approach utilizing a Pfannenstiel extraction incision may present an advantageous and attractive option for simultaneous laparoscopic rectal and liver resection in selected patients with the aim of improving short-term outcomes.     

Enhanced cellulose degradation by targeted integration of a cohesin-fused β-glucosidase into the Clostridium thermocellum cellulosome

The conversion of recalcitrant plant-derived cellulosic biomass into biofuels is dependent on highly efficient cellulase systems that produce near-quantitative levels of soluble saccharides. Similar to other fungal and bacterial cellulase systems, the multienzyme cellulosome system of the anaerobic, cellulolytic bacterium Clostridium thermocellum is strongly inhibited by the major end product cellobiose. Cellobiose-induced inhibition can be relieved via its cleavage to noninhibitory glucose by the addition of exogenous noncellulosomal enzyme β-glucosidase; however, because the cellulosome is adsorbed to the insoluble substrate only a fraction of β-glucosidase would be available to the cellulosome. Towards this end, we designed a chimeric cohesin-fused β-glucosidase (BglA-CohII) that binds directly to the cellulosome through an unoccupied dockerin module of its major scaffoldin subunit. The β-glucosidase activity is thus focused at the immediate site of cellobiose production by the cellulosomal enzymes. BglA-CohII was shown to retain cellobiase activity and was readily incorporated into the native cellulosome complex. Surprisingly, it was found that the native C. thermocellum cellulosome exists as a homooligomer and the high-affinity interaction of BglA-CohII with the scaffoldin moiety appears to dissociate the oligomeric state of the cellulosome. Complexation of the cellulosome and BglA-CohII resulted in higher overall degradation of microcrystalline cellulose and pretreated switchgrass compared to the native cellulosome alone or in combination with wild-type BglA in solution. These results demonstrate the effect of enzyme targeting and its potential for enhanced degradation of cellulosic biomass.     

Prolonged early G1 arrest by selective CDK4/CDK6 inhibition sensitizes myeloma cells to cytotoxic killing through cell cycle-coupled loss of IRF4

Dysregulation of cyclin-dependent kinase 4 (CDK4) and CDK6 by gain of function or loss of inhibition is common in human cancer, including multiple myeloma, but success in targeting CDK with broad-spectrum inhibitors has been modest. By selective and reversible inhibition of CDK4/CDK6, we have developed a strategy to both inhibit proliferation and enhance cytotoxic killing of cancer cells. We show that induction of prolonged early-G(1) arrest (pG1) by CDK4/CDK6 inhibition halts gene expression in early-G(1) and prevents expression of genes programmed for other cell-cycle phases. Removal of the early-G(1) block leads to S-phase synchronization (pG1-S) but fails to completely restore scheduled gene expression. Consequently, the IRF4 protein required to protect myeloma cells from apoptosis is markedly reduced in pG1 and further in pG1-S in response to cytotoxic agents, such as the proteasome inhibitor bortezomib. The coordinated loss of IRF4 and gain of Bim sensitize myeloma tumor cells to bortezomib-induced apoptosis in pG1 in the absence of Noxa and more profoundly in pG1-S in cooperation with Noxa in vitro. Induction of pG1 and pG1-S by reversible CDK4/CDK6 inhibition further augments tumor-specific bortezomib killing in myeloma xenografts. Reversible inhibition of CDK4/CDK6 in sequential combination therapy thus represents a novel mechanism-based cancer therapy.     

Transient B-Cell Depletion Combined With Apoptotic Donor Splenocytes Induces Xeno-Specific T- and B-Cell Tolerance to Islet Xenografts

Peritransplant infusion of apoptotic donor splenocytes cross-linked with ethylene carbodiimide (ECDI-SPs) has been demonstrated to effectively induce allogeneic donor-specific tolerance. The objective of the current study is to determine the effectiveness and additional requirements for tolerance induction for xenogeneic islet transplantation using donor ECDI-SPs. In a rat-to-mouse xenogeneic islet transplant model, we show that rat ECDI-SPs alone significantly prolonged islet xenograft survival but failed to induce tolerance. In contrast to allogeneic donor ECDI-SPs, xenogeneic donor ECDI-SPs induced production of xenodonor-specific antibodies partially responsible for the eventual islet xenograft rejection. Consequently, depletion of B cells prior to infusions of rat ECDI-SPs effectively prevented such antibody production and led to the indefinite survival of rat islet xenografts. In addition to controlling antibody responses, transient B-cell depletion combined with ECDI-SPs synergistically suppressed xenodonor-specific T-cell priming as well as memory T-cell generation. Reciprocally, after initial depletion, the recovered B cells in long-term tolerized mice exhibited xenodonor-specific hyporesponsiveness. We conclude that transient B-cell depletion combined with donor ECDI-SPs is a robust strategy for induction of xenodonor-specific T- and B-cell tolerance. This combinatorial therapy may be a promising strategy for tolerance induction for clinical xenogeneic islet transplantation.Pancreatic islet transplantation is a promising treatment option for type 1 diabetes (1). However, a major limitation to its widespread clinical application is the shortage of human donor pancreata (2,3). Xenogeneic sources of islets are an attractive alternative. Currently, porcine islets are considered the best suitable substitute for human transplantation because of the unlimited donor source and their functional compatibility in humans (4). Moreover, they may be resistant to recurrent autoimmunity that is potentially present in recipients of islet transplantation (5,6). Unfortunately, the need for aggressive immunosuppression to control xenogeneic rejection is currently prohibitive for its application as a standard therapy for β-cell replacement in humans (7,8). Therefore, effective tolerance strategies for xenogeneic transplantation are urgently needed.Early studies in xenogeneic transplant models point to a critical role of T-cell–mediated processes in xenograft rejection (7–10). However, B cells are increasingly recognized for their role in xenogeneic immunity (11,12). In addition to mediating humoral responses by differentiating into antibody-producing plasma cells, B cells have also been shown to influence T-cell priming, expansion, and differentiation through a variety of mechanisms, including antigen presentation, costimulation, and cytokine production (13–16). Consequently, B-cell deficiency or depletion ameliorates autoimmune diseases, including type 1 diabetes, multiple sclerosis, and rheumatoid or collagen-induced arthritis (17–19). Likewise, B-cell depletion has been demonstrated to prolong allogeneic and xenogeneic graft survival in nonhuman primates (12,20).We have previously shown that intravenous infusion of donor splenocytes cross-linked with ethylene carbodiimide (ECDI-SPs) induces donor-specific tolerance to allogeneic islet and heart grafts (21–23), and the mechanisms of graft protection in these models involve deletion, anergy, and regulation of T cells of direct and indirect allo-specificities (24).In the current study, we tested donor ECDI-SPs in a concordant (rat-to-mouse) xenogeneic islet transplant model. We show that although ECDI-SPs alone significantly prolong islet xenograft survival, additional transient B-cell depletion is required to promote xenogeneic tolerance and indefinite islet xenograft survival. Furthermore, transient B-cell depletion significantly impairs xenogeneic T-cell priming and memory T-cell generation. Reciprocally, during B-cell reconstitution after transient B-cell depletion, the recovered B cells exhibit xenoantigen-specific unresponsiveness in the long-term tolerized hosts. Collectively, our findings establish a novel and effective tolerance therapy for xenogeneic islet transplantation and underscore the critical role of B-cell depletion in this process.