Regression analyses of the data sets for the analysis of decomposition error in discrete-time open tandem queues.

The data sets and regression models presented here are related to the article "Point and interval estimation of decomposition error in discrete-time open tandem queues" [1]. The data sets are the first to analyze the approximation quality of the discrete-time decomposition approach and contain independent and dependent (explanatory) variables for the analysis of decomposition error, which were obtained using discrete-time queueing models and discrete-event simulation. Independent variables are the utilization parameters of the queues, and variability parameters of the service and arrival processes. Dependent variables are decomposition error with respect to the expected value and 95-percentile of the waiting time distribution at the downstream queue. This article presents multiple linear regression and quantile regression to explain the variance of the dependent variables for tandem queues with equal traffic intensity at both queues and for tandem queues with downstream bottlenecks, respectively.

Identification of Impaired Executive Functioning after Pediatric Liver Transplantation Using Two Short and Easily Applicable Tests: Cognitive Functioning Module PedsQL and Children's Color Trail Test.

We aimed to assess executive functioning in children after liver transplantation compared with healthy controls and in relation to real-life school performance using the PedsQLTM Cognitive Functioning Scale (CogPedsQL) and the Childrens' Color Trail Test (CCTT). One hundred and fifty five children (78f, median age 10.4 (1.2-18.3) years) underwent testing with CogPedsQL and/or CCTT 4.9 (0.1-17.0) years after transplantation. Results were compared to those of 296 healthy children (165f, median age 10.0 (2.0-18.0) years). Liver transplanted children displayed significantly reduced scores for cogPedsQL and CCTT1&2 compared to healthy controls. Overall, school performance was lower in patients compared to controls. In both patients and controls, results of CCTT2 and CogPedsQL correlated strongly with school performance. In contrast to controls, school performance in patients correlated with the level of maternal but not paternal primary education degree (r = -0.21, p = 0.03). None of the patient CCTT or CogPedsQL test results correlated with parental school education. Conclusion: CogPedsQL and CCTT 1&2 were easily applicable in children after OLT and revealed reduced executive functioning compared to controls. Results reflect real life school performance. The association of parental education with school performance is reduced in transplanted children, which possibly indicates the overriding impact of transplant-associated morbidity on cognitive outcomes.

"My Friend with HIV Remains a Friend": HIV/AIDS Stigma Reduction through Education in Secondary Schools-A Pilot Project in Buea, Cameroon.

The universal access to treatment and care for people living with HIV (PLWHIV) is still a major problem, especially in sub-Saharan Africa, where 70% of HIV-infected people live. Equally important is the fact that HIV/AIDS-related stigma is recognized to be a major obstacle to successfully control the spread of this disease. We devised a pilot project (titled "My friend with HIV remains a friend") to fight the HIV/AIDS stigmatization through educating secondary school students by openly HIV-positive teachers. In a first step, we have measured the amount and type of stigma felt by the PLWHIV in Buea/Cameroon using the "The people living with HIV Stigma Index" from Joint United Nations Programme on HIV/AIDS. Gossiping and verbal insults were experienced by 90% of the interviewees, while 9% have experienced physical assaults. Using these data and material from the "Toolkit for action" from the "International Centre for the Research on Women," the teachers educated the students on multiple aspects of HIV/AIDS and stigma. The teaching curriculum included role-plays, picture visualizations, drawing, and other forms of interactions like visits to HIV and AIDS treatment units. Before and after this intervention, the students undertook "True/False" examinations on HIV/AIDS and stigma. We compared these results with results from students from another school, who did not participate in this intervention. We were able to show that the students taking part in the intervention improved by almost 20% points in comparison to the other students. Their results did not change.

Impact of Immunosuppression on Executive Functioning After Pediatric Liver Transplantation: An Observational Cohort Study.

OBJECTIVES: Children after liver transplantation show increased rates of impaired cognitive functioning. We aimed to assess the potential effects of immunosuppressive therapy on executive functioning measured by the Children's Color Trail Test and the cognitive functioning module of the PedsQL (cogPedsQL) in liver transplanted children to explore potential targets for intervention to improve executive functioning. METHODS: We performed a cross-sectional study in 155 children (78 girls) aged 10.4 (2-18) years at 5.0 (0.1-17) years after liver transplantation, with follow-up at 6 months in n = 114. Executive functioning was assessed by Children's Color Trail Test (ages 8-16) and by patients and parent-proxy cogPedsQL (ages 5-18/2-18, respectively). Results were correlated with clinical parameters. Stability of results over time was compared between n = 23 patients who for clinical reasons switched from twice daily calcineurin inhibitor (CNI) to once-daily slow-release tacrolimus (Tac) during the study period, and patients with unchanged CNI. RESULTS: Worse executive functioning was associated with longer stay in the intensive care unit and longer time elapsed since transplantation. No difference was found between users of cyclosporine and Tac. Children on once-daily slow-release Tac performed better than children on twice-daily Tac. In children who switched from twice-daily CNI to once-daily Tac, parent-proxy cogPedsQL improved significantly compared to stable results in the nonswitch group. CONCLUSIONS: In addition to a strong impact of disease burden around transplantation, executive functioning appears to deteriorate over time. Although there is no clear-cut advantage of any CNI, once-daily Tac appears to be advantageous compared to twice-daily Tac.

Renal phenotype of young and old telomerase-deficient mice.

Telomere shortening in the kidney explains the impaired regenerative capacity, but may not drive the ageing phenotype itself. We investigated kidneys from young and old Terc(+/+) and Terc(-/-) mice of early (G1) and late (G4, G5) generations. Functional parameters declined and age-related morphological changes increased in late generation Terc(-/-) mice and with further age. Podocyte loss was only seen in old G4 Terc(-/-). Whereas p21(CIP1/WAF1) was highest in old G1 and G4 Terc(-/-), telomere shortening and p16(INK4a) expression, also significantly associated with later generation young Terc(-/-), were not further induced in old Terc(-/-) mice. Both, young and old late generation Terc(-/-), showed increased pro-inflammatory cytokine levels. Young late generation Terc(-/-) animals show mild functional and histological abnormalities, the presence of cellular senescence explains their kidneys' limited regenerative capacity. While these aspects resemble the situation seen in aged human kidneys, the lack of telomere shortening and p16(INK4a) induction in older Terc(-/-) animals differs from observations in old human kidneys and may result from clearance of senescent cells. This animal model is well suited to investigate the mechanisms of impaired renal regeneration in aged human kidney, but may not fully explain the natural course of the human renal ageing phenotype.

In vivo and in vitro analysis of age-associated changes and somatic cellular senescence in renal epithelial cells.

Acute kidney injury is a major clinical problem and advanced age is associated with ineffective renal regeneration and poor functional outcome. Data from kidney injury models suggest that a loss of tubular epithelial proliferation contributes to a decrease in renal repair capacity with aging, but aging can also lead to a higher severity of inflammation and damage which may influence repair. In this study we tested intrinsic age-dependent changes in tubular epithelial proliferation in young and old mice, by injecting low-dose lead acetate as a non-injurious mitogen. In parallel, we explored in vitro techniques of studying cellular senescence in primary tubular epithelial cells (PTEC). Lead acetate induced tubular epithelial proliferation at a significantly higher rate in young as compared to old mice. Old kidneys showed significantly more senescence as demonstrated by increased p16 (INK4a), senescence associated ß-galactosidase, and γH2AX(+)/Ki-67(-) cells. This was paralleled in old kidneys by a higher number of Cyclin D1 positive tubular cells. This finding was corroborated by a positive correlation between Cyclin D1 positivity and age in human renal biopsies. When tubular cells were isolated from mouse kidneys they rapidly lost their age-associated differences under culture conditions. However, senescence was readily induced in PTEC by γ-irradiation representing a future model for study of cellular senescence in the renal epithelium. Together, our data indicate that the tubular epithelium of aged kidney has an intrinsically reduced proliferative capacity probably due to a higher load of senescent cells. Moreover, stress induced models of cellular senescence are preferable for study of the renal epithelium in vitro. Finally, the positive correlation of Cyclin D1 with age and cellular senescence in PTEC needs further evaluation as to a functional role of renal epithelial aging.

HIV/AIDS-related stigma felt by people living with HIV from Buea, Cameroon.

The universal access to treatment and care for people living with HIV (PLWHIV) is a major problem especially in Sub-Saharan Africa, where the majority of HIV infected people live. However, equally important is the fact that HIV/AIDS-related stigma is recognized to be a major obstacle to successfully control the spread of this disease. In this study we measured the HIV/AIDS-related stigma felt by PLWHIV in Cameroon using "The people living with HIV stigma index" questionnaire developed by UNAIDS, International Planned Parenthood Federation and Global Network of PLWHIV/AIDS among others. A total of 200 questionnaires were anonymously administered to PLWHIV in the HIV/AIDS treatment center of the Regional Hospital Annex Buea in the South West Region of Cameroon by trained academics who were themselves PLWHIV. In this setting the major problems faced by the PLWHIV with regard to stigmatization and discrimination were gossiping and verbal insults, which was felt by about half of the interviewees. Equally important was internal stigma, half of the PLWHIV felt ashamed and guilty to be HIV infected. This is the first report of this kind in Cameroon. These results will help to better understand HIV/AIDS-related stigma in this setting and in turn will improve the quality of life of PLWHIV by promoting their acceptance by the community.

Quorum sensing in the probiotic bacterium Escherichia coli Nissle 1917 (Mutaflor) - evidence that furanosyl borate diester (AI-2) is influencing the cytokine expression in the DSS colitis mouse model.

BACKGROUND: "Quorum sensing" (QS) is the phenomenon which allows single bacterial cells to measure the concentration of bacterial signal molecules. Two principle different QS systems are known, the Autoinducer 1 system (AI-1) for the intraspecies communication using different Acyl-homoserine lactones (AHL) and AI-2 for the interspecies communication. Aim of this study was to investigate QS of Escherichia coli Nissle 1917 (Mutaflor). RESULTS: While E. coli Nissle is producing AI-2 in a density dependent manner, no AI-1 was produced. To study the effect of AI-2 in the DSS (dextran sulphate sodium) induced mouse model of acute colitis, we silenced the corresponding gene luxS by intron insertion. The mutant bacterium E. coli Nissle::luxS was equally effective in colonizing the colon and the mutation turned out to be 100% stable during the course of the experiment. Isolating RNA from the colon mucosa and performing semiquantitative RT PCR, we were able to show that the expression of the pro-inflammatory cytokine IFN-y was suppressed in mice being infected with the E. coli Nissle wild type. Mice infected with the E. coli Nissle::luxS mutant showed a suppressed expression of IL-10 compared to uninfected mice, while the expression of the pro-inflammatory cytokines IL-6 and TNF-α was higher in these mice. The expression of mBD-1 was suppressed in mice being infected with the mutant in comparison to the mice not infected or infected with the wild type. No differences were seen in the histological examination of the colon sections in the different groups of mice. CONCLUSIONS: E. coli Nissle is producing AI-2 molecules, which are influencing the expression of cytokines in the mucosa of the colon in the DSS mice. However, if QS has a direct influence on the probiotic properties of E. coli Nissle remains to be elucidated.

Escherichia coli Nissle 1917 (Mutaflor): new insights into an old probiotic bacterium.

Probiotic bacteria are live microorganisms which contribute health benefits to their host. The numerous mechanisms of the probiotic-acting microorganisms include the induction of expression of certain cytokines and increasing the secretion of IgA and mucin. They activate lymphocytes and macrophages and inhibit the adhesion and invasion of epithelial cells. Escherichia coli Nissle 1917 (Mutaflor) is one of the most investigated probiotic bacteria. While the number of reports discussing the underlying mechanisms of Mutaflor has increased rapidly in recent years, novel clinical studies are missing. Here we provide an overview of the mechanisms of action and clinical studies related to Mutaflor. While most of the studies had positive outcomes, there are also a few in which Mutaflor did not perform to its expectations.

Validating a new oscillometric device for aortic pulse wave velocity measurements in children and adolescents.

BACKGROUND: Pulse wave velocity (PWV) is an indicator of aortic stiffness and a predictor of cardiovascular risk. Applanation tonometry (e.g., SphygmoCor) is a well-established method to measure aortic PWV (aPWV). The Vicorder, a new oscillometric device, has not been validated in children and adolescents. METHODS: We performed intra- and interobserver repeatability studies in 14 individuals using the Vicorder. Vicorder and SphygmoCor measurements were compared in 156 healthy children (6-18 years) using two different path length measurements. RESULTS: Intra- and interobserver repeatabilities of the Vicorder were excellent with coefficients of variation of 5.6% and 5.8% and intraclass correlation coefficients (ICCs) of 0.8 and 1.0. aPWV calculated using the distances (suprasternal notch-to-femoral recording point) - (suprasternal notch-to-carotid artery), the path length most commonly used in adults, revealed a mean of 4.8 ± 0.7 m/s for SphygmoCor and 4.9 ± 0.6 m/s for Vicorder. The percentage deviation between both devices was 13.0% and the limit of agreement (LoA) ranged from -1.0 to 1.7 m/s reflecting a good concordance. Using a path length that measured the distance from suprasternal notch to femoral recording point via the umbilicus (Umb), an even better agreement was found (percentage deviation: 11.8%, LoA: -1.0 to 1.6 m/s). CONCLUSIONS: Vicorder aPWV values are similar to those obtained by SphygmoCor applanation tonometry. The best agreement between devices was obtained with the path length that most accurately describes the aortic tree. Excellent intra- and interobserver repeatability and ease of measurements make Vicorder appropriate for large multicentre studies in children and adolescents.

Hypoxia-induced down-regulation of microRNA-449a/b impairs control over targeted SERPINE1 (PAI-1) mRNA - a mechanism involved in SERPINE1 (PAI-1) overexpression.

After publication of our article 1, we realized the need for posting a correction note in order to prevent i) overinterpretation of some results by the readers and ii) concerns about potentially unintended misguidance by the authors.

Treating critically ill patients with probiotics: Beneficial or dangerous?

Probiotic bacteria are live microorganisms which confer to health benefits of the host. They help to maintain the integrity of the intestinal barrier function by modulating the mucosal and systemic immune response of the host. These bacteria have proven their beneficial effect in several conditions of ulcerative colitis. More recently probiotics/synbiotics have been included in the treatment of critically ill patients. However to date it remains uncertain whether probiotics/synbiotics are beneficial or even dangerous to the clinical outcome of this patient group. This article reviews the current evidence of the use of bacteria in critically ill patients in intensive care settings.

Is cellular senescence important in pediatric kidney disease?

Somatic cellular senescence (SCS) describes the limited ability of cells to divide. Normally, SCS is associated with physiological aging, but evidence suggests that it may play a role in disease progression, even in young patients. Stressors such as acute injury or chronic inflammation may induce SCS, which in turn exhausts organ regenerative potential. This review summarizes what is known about SCS in the kidney with aging and disease. As most patients with chronic kidney disease (CKD) also develop cardiovascular complications, a second focus of this review deals with the role of SCS in cardiovascular disease. Also, as SCS seems to accelerate CKD and cardiovascular disease progression, developing strategies for new treatment options that overcome SCS or protect a patient from it represents an exciting challenge.

"Hypoxia-induced down-regulation of microRNA-449a/b impairs control over targeted SERPINE1 (PAI-1) mRNA - a mechanism involved in SERPINE1 (PAI-1) overexpression".

BACKGROUND: In damaged organs tissue repair and replacement of cells by connective tissue provokes a response of fibroblasts to cellular stress factors such as hypoxia.MicroRNAs (miRNA) are small non-coding RNA molecules which bind to their mRNA targets which eventually lead to repression of translation. Whether the response of fibroblasts to stress factors also involves the miRNA system is largely unknown. RESULTS: By miRNA profiling we identified down-regulation of miRNA-449a/b expression in hypoxic fibroblasts. Specific miRNA inhibitors and mimics showed direct evidence for targeting the serine protease inhibitor (serpin) protein (SERPINE1; plasminogen activator inhibitor-1, PAI-1) by miRNA-449a/b leading to SERPINE1 mRNA and protein up- and down-regulation, respectively. SERPINE1 expression in vivo could be located predominantly in areas of fibrosis and remodeling. CONCLUSIONS: Our study offers serious lines of evidence for a novel hypoxia-dependent mechanism involving hypoxia-induced decrease of clustered miRNA-449a/b, hypoxia-induced amplification of concomitant increase of targeted SERPINE1 (PAI-1) and its overexpression in tissues showing a hypoxic environment.

Telomere shortening reduces regenerative capacity after acute kidney injury.

Telomeres of most somatic cells progressively shorten, compromising the regenerative capacity of human tissues during aging and chronic diseases and after acute injury. Whether telomere shortening reduces renal regeneration after acute injury is unknown. Here, renal ischemia-reperfusion injury led to greater impairment of renal function and increased acute and chronic histopathologic damage in fourth-generation telomerase-deficient mice compared with both wild-type and first-generation telomerase-deficient mice. Critically short telomeres, increased expression of the cell-cycle inhibitor p21, and more apoptotic renal cells accompanied the pronounced damage in fourth-generation telomerase-deficient mice. These mice also demonstrated significantly reduced proliferative capacity in tubular, glomerular, and interstitial cells. These data suggest that critical telomere shortening in the kidney leads to increased senescence and apoptosis, thereby limiting regenerative capacity in response to injury.

Ageing mouse kidney--not always the SAME old story.

BACKGROUND: As interest in the ageing kidney grows rapidly, more experimental ageing studies are conducted in the field. One of the main obstacles that researchers have to face is that studies in old animals are often less reproducible than in young animals. We have observed that the aged animal's provenance can be an overlooked factor accounting for such experimental heterogeneity. METHODS: Male C57BL/6J mice aged 19-22 months were purchased from four different suppliers. Baseline renal parameters were evaluated by measuring serum urea, serum creatinine and proteinuria. Renal morphology was analysed by quantifying glomerulosclerosis, interstitial fibrosis and amyloid deposits on paraffin sections stained with PAS, Masson trichrome, Sirius red and Congo red. RESULTS: We found normal renal ageing in mice from three sources, but an unexpected renal pathology in mice from one major European supplier. Mice from this supplier had significantly elevated serum urea, creatinine values and an increased urinary protein excretion. Corresponding kidneys displayed massive glomerulosclerosis with evidence of amyloid deposits and increased interstitial fibrosis. CONCLUSIONS: Supplier-dependent differences, such as observed here, can explain irreproducibility of experimental results in renal ageing research. This can be avoided by careful baseline analysis prior to in vivo experiments.

Effects of bacterial N-acyl homoserine lactones on human Jurkat T lymphocytes-OdDHL induces apoptosis via the mitochondrial pathway.

Diverse Gram-negative bacteria communicate with each other by using diffusible N-acyl-homoserine lactone (AHL) signaling molecules to coordinate gene expression with cell population density. This mechanism termed 'quorum sensing' is involved in the regulation of physiological functions as well as multiple virulence determinants. It becomes more and more evident, that bacteria communicate not only with each other but also with their host. Up to now, little is known about this interkingdom communication. The AHL quorum sensing molecule N-3-(oxododecanoyl)-L-homoserine lactone (OdDHL) from Pseudomonas aeruginosa has been shown to influence the immune system of the host. The role and potential influence of other AHL molecules from other bacteria have so far not been determined. In this paper, we investigated the role of 7 different AHLs on apoptosis of human Jurkat T lymphocytes. We found, that among all homoserine lactones tested, only OdDHL rapidly induced apoptosis which was accompanied by the breakdown of the mitochondrial transmembrane potential (DeltaPsi(m)). Since overexpression of anti-apoptotic Bcl-2 completely abrogated the apoptotic effect, we presume that OdDHL induces apoptosis by activation of the intrinsic mitochondrial apoptosis pathway. The reason that bacteria induce apoptosis is largely unknown. We suspect that through apoptosis an anti-inflammatory response is triggered.

Taurolidine reduces the tumor stimulating cytokine interleukin-1beta in patients with resectable gastrointestinal cancer: a multicentre prospective randomized trial.

BACKGROUND: The effect of additional treatment strategies with antineoplastic agents on intraperitoneal tumor stimulating interleukin levels are unclear. Taurolidine and Povidone-iodine have been mainly used for abdominal lavage in Germany and Europe. METHODS: In the settings of a multicentre (three University Hospitals) prospective randomized controlled trial 120 patients were randomly allocated to receive either 0.5% taurolidine/2,500 IU heparin (TRD) or 0.25% povidone-iodine (control) intraperitoneally for resectable colorectal, gastric or pancreatic cancers. Due to the fact that IL-1beta (produced by macrophages) is preoperatively indifferent in various gastrointestinal cancer types our major outcome criterion was the perioperative (overall) level of IL-1beta in peritoneal fluid. RESULTS: Cytokine values were significantly lower after TRD lavage for IL-1beta, IL-6, and IL-10. Perioperative complications did not differ. The median follow-up was 50.0 months. The overall mortality rate (28 vs. 25, p = 0.36), the cancer-related death rate (17 vs. 19, p = .2), the local recurrence rate (7 vs. 12, p = .16), the distant metastasis rate (13 vs. 18, p = 0.2) as well as the time to relapse were not statistically significant different. CONCLUSION: Reduced cytokine levels might explain a short term antitumorigenic intraperitoneal effect of TRD. But, this study analyzed different types of cancer. Therefore, we set up a multicentre randomized trial in patients undergoing curative colorectal cancer resection. TRIAL REGISTRATION: ISRCTN66478538.

Application of a solid tumor model to evaluate tumor recurrence after an open or laparoscopic rectal resection in rats.

PURPOSE: We used a solid tumor model to evaluate the influence of laparotomy versus laparoscopy on tumor growth after curative resection for rectal cancer in rats. METHODS: Colon tumor cells (DHD/K12/TRb) were administered intraperitoneally in 15 rats, which were used as solid tumor donors. Twenty-one days later, a 20-mg piece was then implanted in the rectal submucosa of the study rats (n=45). Animals were randomized into 3 groups for rectal resection either open or laparoscopic using either carbon dioxide (CO2) or helium for pneumoperitoneum. Autopsy took place 21 days after resection and tumor recurrence was evaluated. RESULTS: Port-site metastasis was observed after laparoscopy with CO2 (1 animal) and helium (1), whereas intraperitoneal tumor growth was detected in 2 and 3 animals of these groups. No tumor recurrence was observed after open surgery. CONCLUSIONS: Our solid tumor model is a novel neoplastic model that might simulate the clinical situation of an upper rectal carcinoma. It might be helpful to develop new protocols in studying solid tumor biology and different surgical procedures for cancer to address problematic issues in oncologic research.

Robotic-assisted laparoscopic and thoracoscopic surgery with the da Vinci system: a 4-year experience in a single institution.

PURPOSE: We set up a pilot study to evaluate the efficacy of telerobotic surgery using the da Vinci system for several procedures for which traditional laparoscopy (or thoracoscopy) is a standard approach in a single institution. METHODS: We performed fundoplications (hiatal hernia repair and antireflux surgery, n=112), upside-down stomach (14), cholecystectomy (16), gastric banding (3), colectomy (5), esophagectomy (4), sub/total gastrectomy (2), gastrojejunostomy (2), along with thymectomy (100), thoracic symatectomy (11), lobectomy (5), mediastinal parathyroidectomy (5), and left pancreatic resection (1). RESULTS: The median set up time for all procedures was reduced from 25.0 to 10.4 minutes. Conversion to traditional laparoscopy or thoracoscopy occurred in 12 cases and in open surgery in 11 cases. There was no morbidity related to the telerobotic system. CONCLUSIONS: Robotically assisted laparoscopic and thoracoscopic surgery is feasible and safe for a variety of procedures in general, visceral, and thoracic surgery.