Improving the finite element model accuracy of tissue engineering scaffolds produced by selective laser sintering.

In bone tissue engineering, both geometrical and mechanical properties of a scaffold play a major part in the success of the treatment. The mechanical stresses and strains that act on cells on a scaffold in a physiological environment are a determining factor on the subsequent tissue formation. Computational models are often used to simulate the effect of changes of internal architectures and external loads applied to the scaffold in order to optimise the scaffold geometry for the prospective implantation site. Finite element analysis (FEA) based on computer models of the scaffold is a common technique, but would not take into account actual inaccuracies due to the manufacturing process. Image based FEA using CT scans of fabricated scaffolds can provide a more accurate analysis of the scaffold, and was used in this work in order to accurately simulate and predict the mechanical performance of bone tissue engineering scaffolds, fabricated using selective laser sintering (SLS), with a view to generating a methodology that could be used to optimise scaffold design. The present work revealed that an approach that assumes isotropic properties of SLS fabricated scaffolds will lead to inaccurate predictions of the FE model. However, a dependency of the grey value of the CT scans and the mechanical properties was discovered, which may ultimately lead to accurate FE models without the need of experimental validation.

Optical Thomson scattering measurements of plasma parameters in the ablation stage of wire array Z pinches.

A Thomson scattering diagnostic has been used to measure the parameters of cylindrical wire array Z pinch plasmas during the ablation phase. The scattering operates in the collective regime (α>1) allowing spatially localized measurements of the ion or electron plasma temperatures and of the plasma bulk velocity. The ablation flow is found to accelerate towards the axis reaching peak velocities of 1.2-1.3×10(7) cm/s in aluminium and ∼1×10(7) cm/s in tungsten arrays. Precursor ion temperature measurements made shortly after formation are found to correspond to the kinetic energy of the converging ablation flow.

Late diagnosis of intraplacental choriocarcinoma co-existing with fetomaternal haemorrhage causing fetal demise: A case report.

Intraplacental choriocarcinoma (IC) is a rare disease, occurring in approximately 1 in 50,000 pregnancies. A 33-year-old woman, gravida 2 para 0, sustained an intrauterine fetal death due to fetomaternal haemorrhage (FMH) at 36 weeks of gestation after presenting with decreased fetal movements in the days prior. The placenta macroscopically appeared normal. However, histological examination revealed an intraplacental choriocarcinoma. Assessment of this woman's quantitative beta human chorionic gonadotropin (bHCG) level was negative and a computerized tomography scan of her chest, abdomen and pelvis revealed no metastatic disease yet a bulky uterus. After discussion at a multidisciplinary tumour board meeting, the patient had endometrial curettings to rule out any uterine pathology and serial bHCG tests until one year post-partum. Following this, the patient successfully carried and delivered a live female term infant. Although FMH is a rare clinical manifestation of IC it should always alert clinicians to investigate the cause further, through urgent and careful histopathological examination of the placenta. This will allow for appropriate management with chemotherapy if indicated and a reduction in maternal morbidity and mortality.

Observation of a velocity domain cooling instability in a radiative shock.

We report on experimental investigations into strong, laser-driven, radiative shocks in cluster media. Cylindrical shocks launched with several joules of deposited energy exhibit strong radiative effects including rapid deceleration, radiative preheat, and shell thinning. Using time-resolved propagation data from single-shot streaked Schlieren measurements, we have observed temporal modulations on the shock velocity, which we attribute to the thermal cooling instability, a process which is believed to occur in supernova remnants but until now has not been observed experimentally.

Candida chorioamnionitis associated with late stillbirth: A case report.

Vulvovaginal candidiasis during pregnancy is common, but serious complications, including chorioamnionitis, are infrequent. A 41-year-old woman presented at 37 weeks of gestation with reduced fetal movements, and fetal death in utero was subsequently confirmed on ultrasound. Histopathology of the cord and placenta revealed Candida infection and microabscesses on the umbilical cord. Overall, these features are suggestive of ascending infection, consistent with Candida as the causative organism. To the best of our knowledge, this is the first reported case of late stillbirth due to Candida chorioamnionitis. More research is needed to determine the mechanism whereby Candida becomes pathogenic in pregnancy. There is also no clear consensus on how to manage such patients in a subsequent pregnancy.

Cross-regulatory interactions among pair-rule genes in Drosophila.

The pair-rule genes of Drosophila are required for the subdivision of the developing embryo into a repeating series of homologous body segments. One of the pair-rule genes, even-skipped (eve), appears to be particularly important for the overall segmentation pattern since eve- embryos lack all segmental subdivisions in the middle body region. On the basis of homeo box cross-homology we have isolated a gene, S72, which probably corresponds to eve. In embryo tissue sections S72 transcripts show a periodic distribution pattern. The eve- phenotype appears to involve altered patterns of fushi tarazu and engrailed expression. These and other findings suggest that pair-rule gene expression might involve hierarchical cross-regulatory interactions.

Home-based crisis team in North Cork service description and patient-related outcomes.

OBJECTIVE: Home-based crisis team (HBCT) in North Cork was established in 2013 to provide short term, intensive home treatment to people who are experiencing acute mental health problems, with the aim of averting hospital admission wherever possible or supporting patients discharged from hospital. METHODS: A retrospective descriptive study design was adopted to describe the activities of the North Cork HBCT over a 1 year period. Data were analysed using R version 3.4.0 for Windows. RESULTS: A total of 388 patients were referred to the HBCT in 2015, of which 328 required assessments. General practitioners (GPs) made 56% of all referrals. The most common referral reason was low mood (40%). Stepped-up care to the psychiatric inpatient unit was required for 12.4% of patients, 62% were discharged to the outpatient clinic for routine follow-up. CONCLUSION: Many common psychiatric presentations can be managed at home with the support of the HBCT although hospital admission is required for significant numbers.

Gold nanoparticles and oxidative stress in Mytilus edulis.

Little is known about potential environmental impact of nanoparticles. Gold nanoparticles can cause unexpected biological responses. Here, Mytilus edulis were exposed (24h) to gold-citrate nanoparticles (GNP), menadione and both compounds simultaneously (GNP/menadione). Protein ubiquitination and carbonylation were determined in gill, mantle and digestive gland, along with traditional oxidative stress biomarkers; catalase activity and neutral red retention time assay (haemolymph). 2DE gels were performed on gill proteins (menadione; GNP/menadione). Our results reveal that GNP may induce oxidative stress.

Sex-dependent influences of morphine and its metabolites on pain sensitivity in the rat.

Preclinical studies report that the effective dose for morphine is approximately 2-fold higher in females than males. Following systemic administration, morphine is metabolized via Phase II glucuronidation in the liver and brain into two active metabolites: morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), each possessing distinct pharmacological profiles. M6G binds to µ opioid receptors and acts as a potent analgesic. In contrast, M3G binds to toll-like receptor 4 (TLR4), initiating a neuroinflammatory response that directly opposes the analgesic effects of morphine and M6G. M3G serum concentrations are 2-fold higher in females than males, however, sex-specific effects of morphine metabolites on analgesia and glial activation in vivo remain unknown. The present studies test the hypothesis that increased M3G, and subsequent TLR4-mediated activation of glia, is a primary mechanism driving the attenuated response to morphine in females. We demonstrate that intra-PAG M6G results in a greater analgesic response in females than morphine alone. M6G analgesia was reversed with co-administration of (-)-naloxone, but not (+)-naloxone, suggesting that this effect is µ opioid receptor mediated. In contrast, intra-PAG administration of M3G significantly attenuated the analgesic effects of systemic morphine in males only, increasing the 50% effective dose of morphine two-fold (5.0 vs 10.3mg/kg) and eliminating the previously observed sex difference. An increase in IL-1ß, IL-6 and TNF was observed in females following intra-PAG morphine or M6G. In males, only IL-1ß levels increased following morphine. Changes in cytokine levels following M3G were limited to TNF in females. Together, these data implicate sex differences in morphine metabolism, specifically M3G, as a contributing factor in the attenuated response to morphine observed in females.

Laboratory analogue of a supersonic accretion column in a binary star system.

Astrophysical flows exhibit rich behaviour resulting from the interplay of different forms of energy-gravitational, thermal, magnetic and radiative. For magnetic cataclysmic variable stars, material from a late, main sequence star is pulled onto a highly magnetized (B>10 MG) white dwarf. The magnetic field is sufficiently large to direct the flow as an accretion column onto the poles of the white dwarf, a star subclass known as AM Herculis. A stationary radiative shock is expected to form 100-1,000 km above the surface of the white dwarf, far too small to be resolved with current telescopes. Here we report the results of a laboratory experiment showing the evolution of a reverse shock when both ionization and radiative losses are important. We find that the stand-off position of the shock agrees with radiation hydrodynamic simulations and is consistent, when scaled to AM Herculis star systems, with theoretical predictions.

MIP-1 alpha contributes to the anticryptococcal delayed-type hypersensitivity reaction and protection against Cryptococcus neoformans.

Leukocyte infiltration into infected tissues is essential for the clearance of microorganisms. In animals with a cell-mediated immune (CMI) response to the infectious agent, as opposed to naive animals, leukocyte migration is greatly enhanced into sites of the organism or antigen. The role of the,chemotactic cytokine or chemokine, macrophage inflammatory protein-1 alpha (MIP-1 alpha), in the expression phase of the CMI response and in protection against Cryptococcus neoformans was assessed. With the use of a gelatin sponge model in mice as a means of detecting an anti-cryptococcal delayed-type hypersensitivity (DTH) reaction, we found that MIP-1 alpha levels in fluids from cryptococcal antigen (CneF)-injected sponges in immunized mice (DTH-reactive sponges) were significantly increased over levels of MIP-1 alpha in fluids from saline-injected control sponges at 12 and 24-30 h after injection. MIP-1 alpha levels peaked before increases in neutrophils and lymphocytes in the DTH-reactive sponges, suggesting that MIP-1 alpha was responsible, at least in part, for attracting these leukocyte types. Immunized mice treated with neutralizing antibody to MIP-1 alpha before sponge injection with CneF had reduced numbers of neutrophils and lymphocytes in the DTH-reactive sponges and showed reduced clearance of C. neoformans from the lungs, spleens, livers, and brains when compared with controls. Furthermore, injection of rmMIP-1 alpha into sponges in naive mice resulted in an increase in the influx of neutrophils and lymphocytes into the sponges compared with saline-injected sponges. Together our findings provide solid evidence that MIP-1 alpha is a component of the anticryptococcal DTH reaction. In addition, MIP-1 alpha influences neutrophil influx and attracts lymphocytes into the DTH reaction site. Finally, we showed that MIP-1 alpha plays a role in protection against C. neoformans.

Lupus autoantigens: their origins, forms, and presentation.

The immune system has developed a number of mechanisms by which to distinguish self from foreign proteins. These mechanisms are found throughout the ontogeny of B and T cell development and include the deletion of autoreactive cells in central lymphoid organs and the induction of self-tolerance in the periphery. However, any failure of these mechanisms for self-tolerance may result in autoimmune disease. Efforts in our laboratory have been directed at understanding how autoimmunity is initiated and maintained in both the B and T cell compartment, with particular interest in the autoimmunity of systemic lupus erythematosus (SLE). This review will focus on our studies on the forms of self-antigens that may be involved in the original "antigenic sin" of SLE and in the role of B lymphocytes as autoantigen presenting cells. We will also discuss whether costimulation is a formal requirement for the induction and maintenance of autoimmunity. Finally, we have provided a model for how all of these individual elements may contribute to the autoimmune processes leading to pathology.

Adult respiratory distress syndrome secondary to end-stage liver disease-successful outcome following liver transplantation.

The adult respiratory distress syndrome (ARDS) complicating liver failure carries a 100% mortality. Two cases of ARDS that resolved following liver transplantation have been reported, one associated with acute allograft rejection, and the second due to sepsis. There is, however, a great reluctance to transplant these very-high-risk patients. We report the first series of patients with ARDS secondary to liver failure who successfully underwent OLTX. No patient had sepsis or pneumonia. Posttransplant mechanical ventilation was required for a median of 14 days (range 6-37 days). All patients in this series are alive and well, with a follow-up of 6-15 months. This demonstrates that ARDS associated with liver failure, an otherwise uniformly lethal complication, can respond dramatically to OLTX.

Early death or retransplantation in adults after orthotopic liver transplantation. Can outcome be predicted?

Early, reliable outcome prediction after a liver transplant would help improve organ use by minimizing unnecessary retransplantations. At the same time, early intervention in those cases destined to fail may ameliorate the high morbidity and mortality associated with retransplantation. The purpose of this study was to analyze several parameters that have been identified in the past as being associated with patient and graft outcome, and to try to develop a model that would allow us to make predictions based on data available in the early postoperative period. A total of 148 patients were followed in a prospective, observational study. Graft failure was defined as patient death or retransplantation within 3 months of surgery. Preoperative variables studied included patient demographics, need for life support, presence of ascites, serum bilirubin, serum albumin, prothrombin time, serum creatinine, and the results of the cytotoxic crossmatch. During the first 5 postoperative days, standard measurements included serum transaminases, serum bilirubin, ketone body ratio, prothrombin time, factor V, and serum lactate. Oxygen consumption was measured shortly after surgery, once the patients had rewarmed to 36 degrees C. There were 131 successful transplants (88.5%) and 17 failures (11.5%). Most of the variables studied were found to be associated with outcome (by univariate analysis) at different points in the early postoperative period. However, receiver operating characteristic curve analysis showed that the predictive ability of even the best parameter was not adequate to make decisions on individual patients. Multivariate analysis, using stepwise logistic regression, yielded a model with an overall accuracy of 92.7%. Again, receiver operating characteristic curve analysis suggested that this model did not achieve the discriminating power needed for routine clinical use. We are still not able to accurately predict outcome in the early posttransplant period. We must be very careful when evaluating parameters, or scoring systems, that are said to accomplish this. It is especially important in this era of cost containment, with its renewed pressures to guide therapy based on our perceived understanding of a patient's future clinical course.

Orthotopic liver transplantation in high-risk patients: risk factors associated with mortality and infectious morbidity.

BACKGROUND: One of the most controversial areas in patient selection and donor allocation is the high-risk patient. Risk factors for mortality and major infectious morbidity were prospectively analyzed in consecutive United States veterans undergoing liver transplantation under primary tacrolimus-based immunosuppression. METHODS: Twenty-eight pre-liver transplant, operative, and posttransplant risk factors were examined univariately and multivariately in 140 consecutive liver transplants in 130 veterans (98% male; mean age, 47.3 years). RESULTS: Eighty-two percent of the patients had postnecrotic cirrhosis due to viral hepatitis or ethanol (20% ethanol alone), and only 12% had cholestatic liver disease. Ninety-eight percent of the patients were hospitalized at the time of transplantation (66% United Network for Organ Sharing [UNOS] 2, 32% UNOS 1). Major bacterial infection, posttransplant dialysis, additional immunosuppression, readmission to intensive care unit (P=0.0001 for all), major fungal infection, posttransplant abdominal surgery, posttransplant intensive care unit stay length of stay (P<0.005 for all), donor age, pretransplant dialysis, and creatinine (P<0.05 for all) were significantly associated with mortality by univariate analysis. Underlying liver disease, cytomegalovirus infection and disease, portal vein thrombosis, UNOS status, Childs-Pugh score, patient age, pretransplant bilirubin, ischemia time, and operative blood loss were not significant predictors of mortality. Patients with hepatitis C (HCV) and recurrent HCV had a trend towards higher mortality (P=0.18). By multivariate analysis, donor age, any major infection, additional immunosuppression, posttransplant dialysis, and subsequent transplantation were significant independent predictors of mortality (P<0.05). Major infectious morbidity was associated with HCV recurrence (P=0.003), posttransplant dialysis (P=0.0001), pretransplant creatinine, donor age, median blood loss, intensive care unit length of stay, additional immunosuppression, and biopsy-proven rejection (P<0.05 for all). By multivariate analysis, intensive care unit length of stay and additional immunosuppression were significant independent predictors of infectious morbidity (P<0.03). HCV recurrence was of borderline significance (P=0.07). CONCLUSIONS: Biologic and physiologic parameters appear to be more powerful predictors of mortality and morbidity after liver transplantation. Both donor and recipient variables need to be considered for early and late outcome analysis and risk assessment modeling.

Hepatic Retransplantation--an analysis of risk factors associated with outcome.

Hepatic retransplantation is controversial because the results are inferior to primary transplants and organs are so scarce. To determine the factors that are associated with poor outcome within the first year following retransplantation, we performed a multivariate analysis, using stepwise logistic regression, of 418 hepatic retransplantations performed at a single institution from November 1987 to December 1993. The minimum follow-up was 1 year. Seven variables were found to be independently associated with subsequent graft failure (defined as either patient death or retransplantation): donor age (odds ratio 2.2 for each 10-year increase over age 45, 95% CI 1.3 to 3.7), female donor sex (odds ratio 1.7, 95% CI 1.05 to 2.7), recipient age (odds ratio 1.6 for each 10-year increase over age 45,95% CI 1.2 to 2.8), need for preoperative mechanical ventilation (odds ratio 1.8, 95% CI 1.1 to 2.9), pretransplant serum creatinine (odds ratio 1.24 for each increase of 1 mg/dl, 95% CI 1.1 to 1.4), pretransplant total serum bilirubin (odds ratio 1.4 for each 10-mg/dl increase over 15 mg/dl, 95% CI 1.1 to 1.8), and the primary immunosuppressant, using tacrolimus as the reference category (odds ratio for cyclosporine-based immunosuppression 3.9, 95% CI 2.3 to 6.8). Although not part of the logistic regression model, the timing of retransplantation was also found to be important, with the overall probability of failure increasing from 0.58 on day 0 to a peak of 0.8 on day 38 and decreasing slowly after that. The implications of these results regarding the appropriateness of retransplantation are discussed.

Orthotopic liver transplantation for life-threatening veno-occlusive disease of the liver after allogeneic bone marrow transplant.

Veno-occlusive disease (VOD) of the liver is a serious and often lethal sequela to bone marrow transplantation. Although a history of prior hepatitis moderately increases the risk of VOD, reliable screening methods for identifying high risk patients are not available. New approaches to managing patients who develop serious VOD are needed. One approach may be the use of orthotopic liver transplantation in selected patients who are likely to die of the disease. In this report we describe a patient who underwent liver transplantation for life-threatening VOD following allogeneic transplantation for CML. Although this patient died early from interstitial pneumonitis, the orthotopic liver functioned well up to her death. Other reports describing successful liver transplants in patients with advanced VOD or graft-versus-host disease of the liver are discussed and the possible indications for liver transplantation for VOD after marrow transplantation are considered. Taken together, these reports suggest that orthotopic liver transplantation may be a feasible and potentially effective approach to managing select patients with life-threatening liver dysfunction after marrow transplantation.

Distribution of neurotensin in the canine gastrointestinal tract.

The distribution of immunoreactive neurotensin in the canine gastrointestinal tract from the esophagus to the rectum, as well as in the pancreas, was determined by a specific neurotensin radioimmunoassay. Immunoreactive neurotensin was found throughout the gastrointestinal tract and in the pancreas. The highest concentrations of immunoreactive neurotensin were found in the mucosal extracts of the jejunum (422 +/- 68 ng/gm) and ileum (3025 +/- 289 ng/gm). Small but substantial amounts of immunoreactive neurotensin were found in the esophagus, fundus (includes fundus and corpus), antrum, duodenum, colon, and pancreas. The concentrations of neurotensin in the mucosal extracts of the jejunum and ileum increased in a graded fashion from the proximal jejunum to the distal ileum. The neurotensin concentration in extracts of the seromuscular layers of jejunum (73 +/- 14 ng/gm) and ileum (187 +/- 38 ng/gm) were statistically higher in comparison with other gut loci.

Liver transplantation without the use of blood products.

OBJECTIVES: To examine the techniques and the outcome of liver transplantation with maximal conservation of blood products and to analyze the potential benefits or drawbacks of blood conservation and salvage techniques. DESIGN: Case series survey. SETTING: Tertiary care, major university teaching hospital. PATIENTS AND METHODS: Four patients with religious objections to blood transfusions who were selected on the basis of restrictive criteria that would lower their risk for fatal hemorrhage, including coagulopathy, a thrombosed splanchnic venous system requiring extensive reconstruction, active bleeding and associated medical complications. All patients were pretreated with erythropoietin to increase production of red blood cells. All operations were performed at the same institution, with a 36-month follow-up. INTERVENTIONS: Orthotopic liver transplantation that used blood salvage, plateletpheresis, and autotransfusion and the withholding of the use of human blood products with the exception of albumin. MAIN OUTCOME MEASURES: Survival and postoperative complications, with the effectiveness of erythropoietin and plateletpheresis as secondary measures. RESULTS: All patients are alive at 36 months after orthotopic liver transplantation. One patient, a minor (13 years of age), was transfused per a state court ruling. Erythropoietin increased the production of red blood cells as shown by a mean increase in hematocrit levels of 0.08. Platelet-pheresis allowed autologous, platelet-rich plasma to be available for use after allograft reperfusion. Three major complications were resolved or corrected without sequelae. Only one patient developed postoperative hemorrhage, which was corrected surgically. The mean charge for bloodless surgery was $174,000 for the three patients with United Network for Organ Sharing (UNOS) status 3 priority for transplantation. This result was statistically significant when these patients were compared with all the patients with UNOS status 3 priority during the same period who met the same restrictive guidelines (P < .05). Only 19 of 1009 orthotopic liver transplantations performed at our institution were similar according to the UNOS status and the fulfillment of the guidelines. The mean charge for these comparison patients was $327,000, 3.8% of which was related to transfusions. CONCLUSIONS: Orthotopic liver transplantation without the use of blood products is possible. Blood conservation techniques do not increase morbidity or mortality and can result in fewer transfusion-related, in-hospital charges.

An intelligent and cost-effective computer dosing system for individualizing FK506 therapy in transplantation and autoimmune disorders.

The accuracy and precision of an intelligent dosing system (IDS) for FK506 in predicting doses to achieve target drug levels has been prospectively evaluated in transplant and autoimmune patients. For dose individualization, the knowledge base is updated with patient-specific feedback including the current dose, drug level, and the new target level. The study population of 147 patients consisted of 97 transplant patients (liver and kidney) and 50 patients with autoimmune disorders. Patients in the transplant study group were entered sequentially and followed as a cohort. Patients in the autoimmune study group were randomly assigned to one of three predefined FK506 concentration windows (low, 0.1-.3; medium, 0.4-.7; and high, 0.8-1.3 ng/mL) as part of a concentration controlled clinical trial. Predictions of steady-state plasma drug levels were made throughout the clinical course of autoimmune patients and during the first 6 weeks post-transplant in liver and kidney recipients. FK506 concentration in plasma was measured by a monoclonal antibody based ELISA assay. Accuracy was computed as the mean prediction error (mpe). Precision was computed as the root mean squared prediction error (rmspe). The accuracy of the IDS in each study group was as follows: 0.016 ng/mL (liver), -0.034 ng/mL (kidney), and -0.022 ng/mL (autoimmune). Because the 95% confidence interval included zero in each case, the IDS showed no bias. The precision of the IDS in each study group was as follows: 0.133 ng mL (liver), 0.1903 ng/mL (kidney), and 0.1188 ng/mL (autoimmune). These results indicate that the FK506 IDS is both accurate and very precise (reproducible) in transplant and autoimmune patients.(ABSTRACT TRUNCATED AT 250 WORDS)