A comprehensive renal injury concept based on a validated finite element model of the human abdomen

BACKGROUND: The identification of abdominal injury mechanisms, development of effective countermeasures, and refinement of clinical approach to injury treatment are greatly facilitated by the employment of numerical models that can predict injuries resulting from complicated soft tissue interactions during blunt abdominal impact. METHODS: The present study introduces a detailed three-dimensional finite element model of the human abdomen that was developed specifically for the investigation of renal trauma. The model geometry and materials reflect the complex mechanical environment of the abdomen, and is validated against both published and novel experiments. RESULTS: It is shown that use of the proposed model, in combination with appropriate mechanical organ injury criteria, provides a significant step toward a comprehensive renal injury concept. Specifically, the abdominal model offers the possibility to investigate injury likelihood and identify injury mechanisms over a broad range of impact loading scenarios. CONCLUSIONS: A sophisticated numerical model of renal trauma has been developed that can be used to effectively predict renal injury outcome for lateral impact.     

How does blood glucose control with metformin influence intensive insulin protocols? Evidence for involvement of oxidative stress and inflammatory cytokines

INTRODUCTION: Recent investigations have revealed that control of hyperglycaemia with insulin improves outcomes. The cornerstone of hyperglycaemia in critically ill patients is insulin resistance and it remains refractory to intensive insulin protocols. We designed this study to evaluate the efficacy and safety of a new intensive insulin therapy (IIT) protocol combined with metformin. METHODS: Twenty-one patients with systemic inflammatory response syndrome and a blood glucose level of >120 mg/dl admitted to an intensive care unit (ICU) were randomised to receive either intravenous infusion of IIT alone (n=11) or combined with metformin (IIT+MET; n=10) to maintain a blood glucose level (BGL) of 80-120 mg/dl. Blood samples were obtained at baseline and at 48 hours, 96 hours and 7 days after initiation of the study. Samples were analysed for interleukin-6 (IL-6), tumour necrosis factor alpha (TNF-alpha) and nitric oxide (NO) as inflammatory mediators; plasminogen activation inhibitor-1 (PAI-1) as a coagulation mediator; and thiobarbituric reactive substances (TBARS), total antioxidant power (TAP) and total thiol molecules (TTM) as oxidative stress parameters. RESULTS: The addition of metformin to the IIT protocol decreased insulin requirement and concentration of insulin and C-peptide. With both treatments at most time points, the mean plasma levels of IL-6, TNF-alpha, NO, PAI-1 and TBARS were found to be significantly lower compared with baseline. Antioxidant activity was increased in both arms with increasing TAP and TTM (P<0.05). There was no significant difference between the two groups regarding reported beneficial effects on these parameters. Therapeutic Intervention Scoring System-28 (TISS-28) score, an index of nursing workload and number of therapeutic interventions, decreased in the IIT+MET group (P<0.01). We did not observe any occurrence of hyperlactataemia or acidosis in the IIT+MET group. CONCLUSION: Metformin plus insulin appears to lower the incidence of insulin resistance, lower insulin requirement while maintaining blood glucose level control, and consequently lower the incidence of adverse effects related to high-dose insulin therapy, particularly hypoglycaemia, and also declined nursing workload. Both treatment protocols showed improvements in inflammatory cytokine levels. Further studies with larger sample sizes are warranted to determine the undiscovered facts of insulin-sensitising agents in critically ill patients.     

Antihypertensive effect of Nigella sativa seed extract in patients with mild hypertension

Hypertension (HT) is a lifestyle-related disease and dietary modifications are effective for its management and prevention. We conducted a randomized, double-blind, placebo-controlled trial to evaluate the efficacy of treatment with an oral Nigella sativa (NS) seed extract supplement in patients with mild HT. Subjects were randomized into three groups: a placebo and two test groups that received 100 and 200 mg of NS extract twice a day. After 8 weeks, systolic blood pressure (SBP) values in both case groups were found to be significantly reduced when compared with the baseline values for each group. In addition, the decrease in SBP in the two case groups was statistically significant relative to the placebo group ( P  < 0.05–0.01). Meanwhile, diastolic blood pressure (DBP) values in the case groups were found to be significantly reduced from the baseline and a significant reduction was also observed in these groups ( P  < 0.01) when compared with the placebo group. In addition, extract administration reduced both SBP and DBP in a dose-dependent manner. Meanwhile, NS extract caused a significant decline in the level of total and low-density-lipoprotein (LDL)-cholesterol relative to baseline data. No complications caused by NS were observed. The results suggest that the daily use of NS seed extract for 2 months may have a blood pressure-lowering effect in patients with mild HT.     

Hesperidin inhibits cyclophosphamide-induced tumor growth delay in mice

Hesperidin is a natural compound that has chemoprotective effects in tumor cell lines and protective effects against hematotoxicity induced by cyclophosphamide. The aim of this study was to evaluate the effect of hesperidin on the antitumor effect of cyclophosphamide in tumor-bearing mice. Administration of hesperidin reduced the leukopenia induced by cyclophosphamide in normal mice. White blood cell counts were increased in mice treated with hesperidin at a dose 200 mg/kg prior to cyclophosphamide injection. This significant protective effect was observed at 4 and 7 days after cyclophosphamide injection. Coadministration of hesperidin with cyclophosphamide in colon carcinoma (CT-26)-bearing mice was found to significantly inhibit cyclophosphamide-induced tumor growth delay. Tumor-bearing mice treated with hesperidin had increased tumor development compared with control animals that did not receive any treatment. These results show that hesperidin interacts with cyclophosphamide to inhibit its antitumor effect. In this study, estrogen receptor was negative for the development of CT-26 tumor. These results imply that fruits containing hesperidin, such as citrus, might have side effects on the efficacy of cyclophosphamide in the treatment of patients with colon cancer.     

Local Expression of Indoleamine 2,3 Dioxygenase in Syngeneic Fibroblasts Significantly Prolongs Survival of an Engineered Three-Dimensional Islet Allograft

OBJECTIVE

The requirement of systemic immunosuppression after islet transplantation is of significant concern and a major drawback to clinical islet transplantation. Here, we introduce a novel composite three-dimensional islet graft equipped with a local immunosuppressive system that prevents islet allograft rejection without systemic antirejection agents. In this composite graft, expression of indoleamine 2,3 dioxygenase (IDO), a tryptophan-degrading enzyme, in syngeneic fibroblasts provides a low-tryptophan microenvironment within which T-cells cannot proliferate and infiltrate islets.

RESEARCH DESIGN AND METHODS

Composite three-dimensional islet grafts were engineered by embedding allogeneic mouse islets and adenoviral-transduced IDO–expressing syngeneic fibroblasts within collagen gel matrix. These grafts were then transplanted into renal subcapsular space of streptozotocin diabetic immunocompetent mice. The viability, function, and criteria for graft take were then determined in the graft recipient mice.

RESULTS

IDO-expressing grafts survived significantly longer than controls (41.2 ± 1.64 vs. 12.9 ± 0.73 days; P < 0.001) without administration of systemic immunesuppressive agents. Local expression of IDO suppressed effector T-cells at the graft site, induced a Th2 immune response shift, generated an anti-inflammatory cytokine profile, delayed alloantibody production, and increased number of regulatory T-cells in draining lymph nodes, which resulted in antigen-specific impairment of T-cell priming.

CONCLUSIONS

Local IDO expression prevents cellular and humoral alloimmune responses against islets and significantly prolongs islet allograft survival without systemic antirejection treatments. This promising finding proves the potent local immunosuppressive activity of IDO in islet allografts and sets the stage for development of a long-lasting nonrejectable islet allograft using stable IDO induction in bystander fibroblasts.Endocrine replacement therapy by islet transplantation represents a feasible and attractive alternative therapeutic approach for treating type 1 diabetes (1,2). Despite improvement of allogeneic islet engraftment using systemic immunosuppression, islet transplantation is still limited by high rates of rejection. Furthermore, some immunosuppressive agents are prodiabetogenic and associated with adverse side effects (3–6). Finding more efficient and less harmful strategies to protect islet graft is therefore required for improving islet transplantation outcome.Localized expression of immunoregulatory factors using gene transfer to graft is a feasible method to provide an immunoprivileged microenvironment and consequently improves graft survival. Such an on-site delivery system results in more potent local immunosuppression with less systemic side effects (7–9).IDO is a cytosolic enzyme that catalyzes essential amino acid l-tryptophan to kynurenine (10) and has profound effects on T-cell proliferation, differentiation, effector functions, and viability (11). Both the reduction in local tryptophan concentration and the production of immunomodulatory tryptophan metabolites contribute to immunosuppressive effects of IDO (12,13). Broad evidence implicates IDO and the tryptophan catabolic pathway in generation of immune tolerance to antigens in tissue microenvironments. In particular, the role of IDO in fetal tolerance in mammalian pregnancy (14,15), immunologic tolerance to tumors (16,17), and self-tolerance has been documented (18,19). The unique immunoregulatory function of IDO substantiates the application of this enzyme as a strategy to suppress alloimmune responses in transplantation.Our research group has shown that overexpression of IDO in fibroblasts suppresses immune response and improves outcome of skin grafts (20–25) and that bystander IDO-expressing fibroblasts suppress immune response to allogeneic mouse islets in vitro (26). Furthermore, in a recent study we showed that mouse islets and fibroblasts are selectively resistant to IDO-mediated activation of nutrient deficiency stress (27). Here, we engineered a three-dimensional composite islet allograft equipped with IDO-expressing fibroblasts and examined whether local expression of IDO, conferred by adenoviral-mediated gene transfer to bystander syngeniec fibroblasts, prevents the rejection of islet allograft. Our approach here is novel compared with other studies that examined the suppressive effect of IDO in islet transplantation (28,29) because 1) bystander syngeneic fibroblasts were used as the target of gene transfer instead of islets to avoid deleterious effects of adenovirus infection on islets (30–32), 2) islets were embedded within an extracellular matrix that by itself improves islet function and viability (33,34), and 3) cotransplanted fibroblasts are more than just a source of IDO and can enhance islet physiological competence (35,36).     

Psychological adjustment of survivors of localised prostate cancer: investigating the role of dyadic adjustment, cognitive appraisal and coping style

OBJECTIVES: The aim of this study was to identify the factors that contribute to psychological adjustment in prostate cancer patients two or more years post-treatment. METHOD: One hundred and sixty-seven men who had undergone treatment for localised prostate cancer participated in this study. In the sample 63 participants had undergone external beam radiotherapy (EBRT), 55 radical prostatectomy (RP), 27 EBRT plus hormone therapy (EBRT/HT), and the remainder a combination of treatments. Patients completed the UCLA-PCI, the POMS, CISS, DAS and a threat appraisal questionnaire. RESULTS: The majority of patients reported relatively positive adjustment in most domains except sexual functioning. For those who reported ongoing psychological difficulty mood disturbance was associated with sexual bother, dyadic adjustment, threat appraisal, self-efficacy appraisal and emotion-focussed coping. Lower levels of urinary bother were associated with the use of more task-focussed coping. Emotion-focussed coping and threat appraisal mediated the relationship between sexual bother and mood disturbance. Emotion-focussed coping moderated the influence of dyadic adjustment on mood disturbance. CONCLUSIONS: Dyadic adjustment, threat appraisal and coping style play a significant role in the long-term psychological adjustment of prostate cancer patients. The results of the current study indicate that the use of emotion-focussed coping to manage sexual bother appears to result in poor psychological adjustment, which indicates the need for further education or intervention to manage sexual dysfunction. ETHICS CLEARANCE: Human ethics approval was granted from Southern Health, Peter MacCallum Cancer Centre and the Monash University Ethics Committee before commencement of data collection.