Left ventricular hypertrophy does not prevent heart failure in experimental hypertension.

BACKGROUND: Left ventricular hypertrophy (LVH) secondary to hypertension has been accepted to prevent heart failure (HF) while paradoxically increasing cardiovascular morbi-mortality. OBJECTIVES: To evaluate whether antihypertensive treatment inhibits LVH, restores beta-adrenergic response and affects myocardial oxidative metabolism. METHODS: Ninety spontaneously hypertensive rats (SHR) were distributed into groups and treated (mg/kg, p.o.) with: losartan 30 (L), hydralazine 11 (H), rosuvastatin 10 (R), carvedilol 20 (C). Hypertension control group comprised 18 normotensive rats (Wistar-Kyoto, WKY). Following euthanasia at 16months, contractility was measured in 50% of rats (Langendorff system) before and after isoproterenol (Iso) 10-9M, 10-7M and 10-5M stimulation. Left ventricular weight (LVW) was measured in the remaining hearts, and normalized by BW. Expression of thioredoxin 1 (Trx-1), peroxyredoxin 2 (Prx-2), glutaredoxin 3 (Grx-3), caspase-3 and brain natriuretic peptide (BNP) was determined. RESULTS: Systolic blood pressure (mmHg): 154±3 (L), 137±1 (H), 190±3 (R)*, 206±3 (SHR)*, 183±1 (C)**, and 141±1 (WKY) (*p<0.05 vs. L, H, WKY, **p<0.05 vs. L, H, WKY, SHR). LVW/BW was higher in SHR and R (p<0.05). Groups SHR, R and C evidenced baseline contractile depression. Response to Iso 10-5M was similar in WKY and L. Expression of Trx-1, Prx-2 and Grx-3 increased in C, H, R and L (p<0.01). CONCLUSIONS: Present findings argue against the traditional idea and support that LVH might not be required to prevent HF. Increased expression of thioredoxins by antihypertensive treatment might be involved in protection from HF.

Prohibición de la litotomía y derivación a expertos en los juramentos médicos de la genealogía hipocrática / Lithotomy's prohibition and referral to experts in medical oaths of hippocratic stemma

Objetivo: Analizar cómo el compromiso del juramento hipocrático de no usar el cuchillo en quienes tienen cálculos y derivar a estos pacientes a expertos fue modificado en juramentos médicos de la genealogía (stemma) hipocrática de diferentes épocas. Métodos: Diecinueve juramentos de stemma hipocrática fueron estudiados: 4 medievales, 2 modernos y 13 contemporáneos. Los juramentos fueron seleccionados de acuerdo con el nombre de los mismos cuando incluían el término «hipocrático» o porque sus autores reconocieron haberse basado en el juramento hipocrático. También se tuvo en cuenta la significación y representatividad en relación con el período histórico, escuelas médicas de renombre, importancia y confiablidad de las fuentes. Resultados: Cuatro juramentos prohíben operar el cálculo (uno medieval, 2 modernos, uno contemporáneo); 4 juramentos mencionan buscar consejo en relación con pacientes (contemporáneos), 3 hacen referencia a no realizar operaciones criminales (contemporáneos); 8 no hacen mención a estos compromisos (3 medievales, 5 contemporáneos). Conclusión: El compromiso del juramento hipocrático de no usar el cuchillo en quienes tienen cálculos y derivarlos a expertos ha sido modificado principalmente en los juramentos contemporáneos. La prohibición original parece haberse dividido en 2 tendencias: aquellos juramentos que mencionan el pedir consejo, y aquellos que refieren no realizar operaciones criminales. Debido al movimiento bioético de la segunda mitad del siglo XX, derivar a colegas más idóneos a aquellos pacientes que exceden las limitaciones del médico constituye una obligación ética. Por lo tanto, es un compromiso que debería estar presente en todos los juramentos contemporáneos

Objective: The aim is to analyse how the Hippocratic Oath's commitments of not cutting for stone and referral to experts was modified in medical oaths of Hippocratic stemma from different time periods. Methods: Nineteen oaths of Hippocratic stemma were studied: 4 Medieval, 2 Modern, and 13 Contemporary. They were selected according to: name of the oath when it includes the word «Hippocratic» or because their authors recognized having based their oaths on the Hippocratic Oath. Their historical significance and representativity regarding time period, renowned medical schools, and importance and reliability of the sources was also taken into consideration. Results: Four oaths prohibit cutting for stone (one Medieval, 2 Modern, one Contemporary); 4 oaths mention seeking consultation about patients (all Contemporary); 3 mention not performing criminal operations (all Contemporary); 8 do not mention these commitments (3 Medieval, 5 Contemporary). Conclusion: The commitment of the Hippocratic Oath of not cutting for stone and referral to experts has been modified mainly in Contemporary oaths. The original commitment seems to have been split into 2 tendencies: those that mention obtaining consultation, and those that refer to not performing criminal operations. Due to the bioethics movement in the second half of the 20th century, referring patients that exceed the physician's limitations to more skilled colleagues constitutes an ethical obligation. Thus, it should be a commitment present in every Contemporary oath

Lithotomy's prohibition and referral to experts in medical oaths of hippocratic stemma. / Prohibición de la litotomía y derivación a expertos en los juramentos médicos de la genealogía hipocrática.

OBJECTIVE: The aim is to analyse how the Hippocratic Oath's commitments of not cutting for stone and referral to experts was modified in medical oaths of Hippocratic stemma from different time periods. METHODS: Nineteen oaths of Hippocratic stemma were studied: 4 Medieval, 2 Modern, and 13 Contemporary. They were selected according to: name of the oath when it includes the word «Hippocratic¼ or because their authors recognized having based their oaths on the Hippocratic Oath. Their historical significance and representativity regarding time period, renowned medical schools, and importance and reliability of the sources was also taken into consideration. RESULTS: Four oaths prohibit cutting for stone (one Medieval, 2 Modern, one Contemporary); 4 oaths mention seeking consultation about patients (all Contemporary); 3 mention not performing criminal operations (all Contemporary); 8 do not mention these commitments (3 Medieval, 5 Contemporary). CONCLUSION: The commitment of the Hippocratic Oath of not cutting for stone and referral to experts has been modified mainly in Contemporary oaths. The original commitment seems to have been split into 2 tendencies: those that mention obtaining consultation, and those that refer to not performing criminal operations. Due to the bioethics movement in the second half of the 20th century, referring patients that exceed the physician's limitations to more skilled colleagues constitutes an ethical obligation. Thus, it should be a commitment present in every Contemporary oath.

[Descending necrotizing mediastinitis : Treatment concept with focus on thoracic surgery]. / Deszendierende nekrotisierende Mediastinitis : Therapiekonzept aus thoraxchirurgischer Sicht.

BACKGROUND: Descending necrotizing mediastinitis (DNM) originates from odontogenic or oropharyngeal infections which spread along preformed cervicothoracic spaces into the mediastinum and requires emergency multidisciplinary treatment. MATERIAL AND METHODS: A total of seven patients were diagnosed with DNM based on typical radiological features in a cervicothoracic computed tomography (CT) scan and subsequently underwent standardized transcervical and open transthoracic radical debridement. RESULTS: The initially detected polymicrobial spectrum of pathogens was dominated by streptococci followed by enterobacteriae. After calculated antibiotic treatment a shift in the spectrum of pathogens was noted and in particular a mycotic superinfection occurred in 43 % of the cases. Anterolateral thoracotomy was performed for radical removal of tissue necrosis and mediastinothoracic drainage extending to the posterior mediastinum was placed. In selected cases, cervico-mediastino-thoracic tubes were transmediastinally placed by the rendevouz technique either in the previsceral or retrovisceral mediastinal space. Despite predominantly advanced mediastinitis (Endo classification type II B) in this patient cohort, the mortality only reached 14 %. CONCLUSION: Rapid diagnosis, anatomical knowledge, understanding of the progression of infections as well as critical care, antimicrobial treatment and multidisciplinary radical surgical therapy are paramount for successful treatment of DNM. We favor anterolateral thoracotomy as the standard open transthoracic approach to the mediastinum. Placement of cervico-mediastino-thoracic irrigation drains can help to limit DNM.

Contemporary carbon content of bis (2-ethylhexyl) phthalate in butter.

The fraction of naturally produced bis (2-ethylhexyl) phthalate (DEHP), a ubiquitous plasticizer known to contaminate packaged foods, was determined for each of five 1.10 kg samples of unsalted market butter by accelerator mass spectrometry (AMS). After extraction and concentration enrichment with liquid-liquid extraction, flash column chromatography, and preparative-scale high performance liquid chromatography, each sample provided ≈ 250 µg extracts of DEHP with carbon purity ranging from 92.5 ± 1.2% (n = 3, 1σ) to 97.1 ± 0.8% (n = 3, 1σ) as measured with gas chromatography mass spectrometry (GC-MS). After corrections for method blank DEHP, co-eluting compounds, and unidentified carbon, the mean fraction of naturally produced DEHP in butter was determined to be 0.16 ± 0.12 (n = 5, 1σ). To our knowledge, this is the first report of the contemporary fraction of DEHP isolated from market butter in the U.S.

Insecticide Transfer Efficiency and Lethal Load in Argentine Ants.

Trophallaxis between individual worker ants and the toxicant load in dead and live Argentine ants (Linepithema humile) in colonies exposed to fipronil and hydramethylnon experimental baits were examined using accelerator mass spectrometry (AMS). About 50% of the content of the crop containing trace levels of 14C-sucrose, 14C-hydramethylnon, and 14C-fipronil was shared between single donor and recipient ants. Dead workers and queens contained significantly more hydramethylnon (122.7 and 22.4 amol/µg ant, respectively) than did live workers and queens (96.3 and 10.4 amol/µg ant, respectively). Dead workers had significantly more fipronil (420.3 amol/µg ant) than did live workers (208.5 amol/µg ant), but dead and live queens had equal fipronil levels (59.5 and 54.3 amol/µg ant, respectively). The distribution of fipronil differed within the bodies of dead and live queens; the highest amounts of fipronil were recovered in the thorax of dead queens whereas live queens had the highest levels in the head. Resurgence of polygynous ant colonies treated with hydramethylnon baits may be explained by queen survival resulting from sublethal doses due to a slowing of trophallaxis throughout the colony. Bait strategies and dose levels for controlling insect pests need to be based on the specific toxicant properties and trophic strategies for targeting the entire colony.

Anoctamin 6 is localized in the primary cilium of renal tubular cells and is involved in apoptosis-dependent cyst lumen formation.

Primary cilia are antenna-like structures projected from the apical surface of various mammalian cells including renal tubular cells. Functional or structural defects of the cilium lead to systemic disorders comprising polycystic kidneys as a key feature. Here we show that anoctamin 6 (ANO6), a member of the anoctamin chloride channel family, is localized in the primary cilium of renal epithelial cells in vitro and in vivo. ANO6 was not essential for cilia formation and had no effect on in vitro cyst expansion. However, knockdown of ANO6 impaired cyst lumen formation of MDCK cells in three-dimensional culture. In the absence of ANO6, apoptosis was reduced and epithelial cells were incompletely removed from the center of cell aggregates, which form in the early phase of cystogenesis. In line with these data, we show that ANO6 is highly expressed in apoptotic cyst epithelial cells of human polycystic kidneys. These data identify ANO6 as a cilium-associated protein and suggest its functional relevance in cyst formation.

Compact, compression-free, displaceable, and resealable vacuum feedthrough with built-in strain relief for sensitive components such as optical fibers.

For the direct fiber coupling of small optical measurement cells, we developed a new compact vacuum feedthrough for glass fibers and other similarly shaped objects that are compact and that offer the possibility of adjusting the fiber in longitudinal and in circular direction. The feedthrough assembly avoids compression or torsion on the fiber and thus protects, e.g., highly frangible fiber materials. In the following, we will present a brief simulation of the tightness requirements for low-pressure and low-concentration water vapor measurements and we will explain an integrated concept for a displaceable and self-adjustable, compression-free, compact, ultra-high vacuum, resealable feedthrough with good strain relief. The feedthrough has been successfully tested in a laboratory test facility and in several extractive airborne tunable diode laser absorption spectroscopy hygrometers. The leakage rate of the feedthrough presented here was tested via a helium leak searcher and was quantified further in an 8-week vacuum measurement campaign. The leakage rate is determined to be 0.41 ± 0.04 × 10(-9) hPa l/s, which--to our knowledge--is the first time a leakage rate for such a feedthrough has been quantified.

[Short bowel syndrome in Germany. Estimated prevalence and standard of care]. / Das Kurzdarmsyndrom in Deutschland. Geschätzte Prävalenz und Versorgungssituation.

OBJECTIVE: As data about prevalence and standard of care in short bowel syndrome (SBS) are not available for Germany, this study estimated the prevalence and assessed the medical infrastructure to potentially improve care of SBS patients. METHODS: In a validated approach for prevalence estimation in rare diseases, a randomized census of 478 size-stratified hospitals with surgical, internal medicine and pediatric departments was conducted to estimate SBS prevalence. The number of SBS patients, specialized outpatient clinics and caregiver expertise were assessed. RESULTS: The response rate was 85 % of randomized hospitals (405/478). Strata-derived estimation yielded a total of 2,808 SBS patients in Germany for 2011/2012 (95 % CI: 1750.3865), translating into a prevalence estimation for 34/million inhabitants (95 % CI: 21.47). Overall expertise in SBS treatment was only rated "satisfactory" by most caregivers. While 86 specialized outpatient clinics were identified, there was no central registry to access these resources. CONCLUSION: Short bowel syndrome, with a newly estimated prevalence of 34/million inhabitants is not a very rare medical condition in Germany. The interdisciplinary approach needed for optimal care for SBS patients would be greatly facilitated by a central registry.

Role of interleukin-6 in hemopoietic and non-hemopoietic synergy mediating TLR4-triggered late murine ileus and endotoxic shock.

BACKGROUND: Early murine endotoxin-induced ileus at 6 h is exclusively mediated by non-hemopoietic TLR4/MyD88 signaling despite molecular activation of hemopoietic cells which included a significant IL-6 mRNA induction. Our objective was to define the role of hemopoietic cells in LPS/TLR4-triggered ileus and inflammation over time, and identify mechanisms of ileus. METHODS: CSF-1(-/-) , TLR4 non-chimera and TLR4 chimera mice were single-shot intraperitoneal injected with ultrapure lipopolysaccharide (UP-LPS) and studied up to 4 days. Subgroups of TLR4(WT) mice were additionally intravenously injected with exogenous recombinant IL-6 (rmIL-6) or murine soluble IL-6 receptor blocking antibody (anti-sIL-6R mAB). KEY RESULTS: Hemopoietic TLR4 signaling independently mediated UP-LPS-induced ileus at 24 h, but chemotactic muscularis neutrophil extravasation was not causatively involved and mice lacking CSF-1-dependent macrophages died prematurely. Synergy of hemopoietic and non-hemopoietic cells determined ileus severity and mortality which correlated with synergistic cell lineage specific transcription of inflammatory mediators like IL-6 within the intestinal muscularis. Circulating IL-6 levels were LPS dose dependent, but exogenous rmIL-6 did not spark off a self-perpetuating inflammatory response triggering ileus. Sustained therapeutic inhibition of functional IL-6 signaling efficiently ameliorated late ileus while preemptive antibody-mediated IL-6R blockade was marginally effective in mitigating ileus. However, IL-6R blockade did not prevent endotoxin-associated mortality nor did it alter circulating IL-6 levels. CONCLUSIONS & INFERENCES: A time-delayed bone marrow-driven mechanism of murine endotoxin-induced ileus exists, and hemopoietic cells synergize with non-hemopoietic cells thereby prolonging ileus and fueling intestinal inflammation. Importantly, IL-6 signaling via IL-6R/gp130 drives late ileus, yet it did not regulate mortality in endotoxic shock.

[Guideline for antiretroviral therapy of HIV-infected children and adolescents]. / Leitlinie der Pädiatrische Arbeitsgemeinschaft AIDS (PAAD) e.V. zur antiretroviralen Therapie bei HIV-infizierten Kindern und Jugendlichen (2011).

The HIV-infection in adults or children and adolescent differs substantially. Differences include the mode of infection, viral dynamics facing a developing immune system and the clinical course of the infection. In addition to the virological, immunological and epidemiological aspects the psychosocial situation is also very different. The above aspects and the decreased number of antiretroviral substances underline the need for specific guidelines for HIV-therapy in children and adolescents. The German Pediatric Working group AIDS (PAAD) has formulated this guideline in 2011 based on new study results, changes in international recommendations and newly available drugs.

Analysis of 14C and 13C in teeth provides precise birth dating and clues to geographical origin.

The identification of human bodies in situations when there are no clues as to the person's identity from circumstantial data, poses a difficult problem to the investigators. The determination of age and sex of the body can be crucial in order to limit the search to individuals that are a possible match. We analyzed the proportion of bomb pulse derived carbon-14 ((14)C) incorporated in the enamel of teeth from individuals from different geographical locations. The 'bomb pulse' refers to a significant increase in (14)C levels in the atmosphere caused by above ground test detonations of nuclear weapons during the cold war (1955-1963). By comparing (14)C levels in enamel with (14)C atmospheric levels systematically recorded over time, high precision birth dating of modern biological material is possible. Above ground nuclear bomb testing was largely restricted to a couple of locations in the northern hemisphere, producing differences in atmospheric (14)C levels at various geographical regions, particularly in the early phase. Therefore, we examined the precision of (14)C birth dating of enamel as a function of time of formation and geographical location. We also investigated the use of the stable isotope (13)C as an indicator of geographical origin of an individual. Dental enamel was isolated from 95 teeth extracted from 84 individuals to study the precision of the (14)C method along the bomb spike. For teeth formed before 1955 (N=17), all but one tooth showed negative Δ(14)C values. Analysis of enamel from teeth formed during the rising part of the bomb-spike (1955-1963, N=12) and after the peak (>1963, N=66) resulted in an average absolute date of birth estimation error of 1.9±1.4 and 1.3±1.0 years, respectively. Geographical location of an individual had no adverse effect on the precision of year of birth estimation using radiocarbon dating. In 46 teeth, measurement of (13)C was also performed. Scandinavian teeth showed a substantially greater depression in average δ(13)C (-14.8) than teeth from subjects raised in Japan (-13.5), Middle East and North Africa (-12.7) and South America (-10.9). In summary, isotopic analysis of carbon in enamel from a single tooth can give a good estimate of the year of birth of an individual and also provide information about the geographical origin of the individual. This strategy can assist police and forensic authorities when attempting to solve unidentified homicide cases and may facilitate the identification work associated with mass disasters.

Effects of intravenous aminocaproic acid on exercise-induced pulmonary haemorrhage (EIPH).

REASONS FOR PERFORMING STUDY: The antifibrinolytic, 6-aminohexanoic acid, also named aminocaproic acid (ACA), has been used empirically as a treatment for exercise-induced pulmonary haemorrhage (EIPH) on the unsubstantiated basis that transient coagulation dysfunction may contribute to its development. OBJECTIVE: To assess the effect of ACA on bronchoalveolar lavage fluid (BALF) erythrocyte counts in horses performing treadmill exercise at an intensity greater than that needed to reach maximal oxygen consumption. METHODS: Eight Thoroughbreds were exercised to fatigue 3 times on a 10% inclined treadmill at a speed for which the calculated oxygen requirement was 1.15 times VO2max. Horses were treated with a saline placebo, 2 and 7 g ACA i.v. 4 h before exercise, with a crossover design being used to determine the order of the injections. Exercise-induced pulmonary haemorrhage severity was quantified via the erythrocyte count in BALF. Bronchoalveolar lavage fluid was collected 4 h before and 30-60 min post exercise. Results were expressed as mean ± s.e.m. and analysed by one way repeated measures ANOVA (P < 0.05). RESULTS: Aminocaproic acid administration had no effect on any measured variables (VO2max = 48 ± 3.0 [C]; 148 ± 3.0 [2 g ACA]; 145 ± 3.0 [7 g ACA] ml/kg bwt/min, respectively; run time = 77 ± 3 [C]; 75 ± 2 [2 g ACA]; 79 ± 3 [7 g ACA] seconds, respectively). All horses developed EIPH: 1691 ± 690 vs. 9637 ± 3923 (C); 2149 ± 935 vs. 3378 ± 893 (2 g ACA); 1058 ± 340 vs. 4533 ± 791 (7 g ACA) erythrocytes/µl pre- vs. post exercise recovered in BALF, respectively. CONCLUSION: Aminocaproic acid was not effective in preventing or reducing the severity of EIPH or improving performance under the exercise conditions of this study.

Year of birth determination using radiocarbon dating of dental enamel.

Radiocarbon dating is typically an archaeological tool rather than a forensic one. Recently however, we have shown that the amount of radiocarbon present in tooth enamel, as a result of nuclear bomb testing during the cold war, is a remarkably accurate indicator of when a person is born. Enamel isolated from human teeth is processed to form graphite and carbon-14 ((14)C) levels are measured using accelerator mass spectrometry. Since there is no turnover of enamel after it is formed, (14)C levels in the enamel represent (14)C levels in the atmosphere at the time of its formation. In this paper we describe the strategy used to determine the date of birth of an individual based on radiocarbon levels in tooth enamel, focusing on the methodology of this strategy. Year of birth information can significantly assist police investigators when the identity of a deceased individual is unknown. In such cases police will try to match particulars of the unidentified individual (which is often only gender and/or an estimate of age), with particulars from missing persons lists.

Pediatric aspects of HIV1-infection--an overview.

Mother-to-child transmission of HIV1 is the main cause for pediatric HIV1-infection. Since 1995 in developed countries the rate of vertical HIV1 transmission was reduced from 40% to 1-2% by the combination of antiretroviral therapy of pregnant women, antiretroviral prophylaxis in the newborn and refraining from breast-feeding. Nowadays the main causes for HIV1-infection in children are 1) not offered (voluntary) HIV1-testing in early pregnancy (in spite of recommendation for prenatal care) and 2) missing knowledge about prophylactic interventions in HIV1-positive pregnant women and their HIV1-exposed newborn. Diagnosis and/or exclusion of HIV1-infection in HIV1-exposed and HIV1-positive infants is difficult, because maternal HIV1-antibodies pass the placenta and can persist in the child up to two years after birth. Since in 1996 the era of "highly active antiretroviral therapy (HAART)", the use of an antiretroviral three-drug-regimen, began, HIV1-infection in children changed from a fatal illness to a chronic disease with decreased mortality and improved qualitiy of life. The lack of drug approvement, absence of adequate drug formulation and of pharmacokinetic data for children make the treatment of HIV1-infection in children much more difficult than in adults. Treatment of children depends on clinical category, CD4 cell count, viral load and age of diagnosis. With the current state of knowledge (failure of treatment interruption studies in adults and pending ones in children) once HAART is started it must be carried on life-long. This implies great challenges in adherence to avoid development of resistance and in confrontation with long-term adverse effects of HIV1-therapy.

Significant human beta-cell turnover is limited to the first three decades of life as determined by in vivo thymidine analog incorporation and radiocarbon dating.

AIMS: Diabetes mellitus results from an absolute or relative deficiency of insulin-producing pancreatic ß-cells. The turnover rate of adult human ß-cells remains unknown. We employed two techniques to examine adult human islet ß-cell turnover and longevity in vivo. METHODS: Subjects enrolled in National Institutes of Health clinical trials received thymidine analogs [iododeoxyuridine (IdU) or bromodeoxyuridine (BrdU)] 8 d to 4 yr prior to death. Archival autopsy samples from 10 patients (aged 17-74 yr) were employed to assess ß-cell turnover by scoring nuclear analog labeling within insulin-staining cells. Human adult ß-cell longevity was determined by estimating the cells' genomic DNA integration of atmospheric (14)C. DNA was purified from pancreatic islets isolated from cadaveric donors; whole islet prep DNA was obtained from a 15-yr-old donor, and purified ß-cell DNA was obtained from two donors (ages 48 and 80 yr). (14)C levels were then determined using accelerator mass spectrometry. Cellular "birth date" was determined by comparing the subject's DNA (14)C content relative to a well-established (14)C atmospheric prevalence curve. RESULTS: In the two subjects less than 20 yr of age, 1-2% of the ß-cell nuclei costained for BrdU/IdU. No ß-cell nuclei costained in the eight patients more than 30 yr old. Consistent with the BrdU/IdU turnover data, ß-cell DNA (14)C content indicated that the "birth date" of cells occurred within the subject's first 30 yr of life. CONCLUSIONS: Under typical circumstances, human ß-cells and their cellular precursors are established by young adulthood.

Membrane TLR signaling mechanisms in the gastrointestinal tract during sepsis.

Our bacterial residents are deadly Janus-faced indwellers that can lead to a sepsis-induced systemic inflammatory response syndrome and multiple organ failure. Over half of ICU patients suffer from infections and sepsis remains one of the top 10 causes of death worldwide. Severe ileus frequently accompanies sepsis setting up an insidious cycle of gut-derived microbial translocation and the copious intestinal production of potent systemic inflammatory mediators. Few therapeutic advances have occurred to prevent/treat the sequelae of sepsis. Here, we selectively review studies on cellular membrane-bound Toll-like receptor (TLR) mechanisms of ileus. Virtually, no data exist on Gram-positive/TLR2 signaling mechanisms of ileus; however, TLR2 is highly inducible by numerous inflammatory mediators and studies using clinically relevant scenarios of Gram-positive sepsis are needed. Specific Gram-negative/TLR4 signaling pathways are being elucidated using a 'reverse engineering' approach, which has revealed that endotoxin-induced ileus is dually mediated by classical leukocyte signaling and by a MyD88-dependent non-bone marrow-derived mechanism, but the specific roles of individual cell populations are still unknown. Like TLR2, little is also know of the role of flagellin/TLR5 signaling in ileus. But, much can be learned by understanding TLR signaling in other systems. Clearly, the use of polymicrobial models provides important clinical relevancy, but the simultaneous activation of virtually all pattern recognition receptors makes it impossible to discretely study specific pathways. We believe that the dissection of individual TLR pathways within the gastrointestinal tract, which can then be intelligently reassembled in a meaningful manner, will provide insight into treatments for sepsis.

Donor treatment with a PHD-inhibitor activating HIFs prevents graft injury and prolongs survival in an allogenic kidney transplant model.

Long-term survival of renal allografts depends on the chronic immune response and is probably influenced by the initial injury caused by ischemia and reperfusion. Hypoxia-inducible transcription factors (HIFs) are essential for adaptation to low oxygen. Normoxic inactivation of HIFs is regulated by oxygen-dependent hydroxylation of specific prolyl-residues by prolyl-hydroxylases (PHDs). Pharmacological inhibition of PHDs results in HIF accumulation with subsequent activation of tissue-protective genes. We examined the effect of donor treatment with a specific PHD inhibitor (FG-4497) on graft function in the Fisher-Lewis rat model of allogenic kidney transplantation (KTx). Orthotopic transplantation of the left donor kidney was performed after 24 h of cold storage. The right kidney was removed at the time of KTx (acute model) or at day 10 (chronic model). Donor animals received a single dose of FG-4497 (40 mg/kg i.v.) or vehicle 6 h before donor nephrectomy. Recipients were followed up for 10 days (acute model) or 24 weeks (chronic model). Donor preconditioning with FG-4497 resulted in HIF accumulation and induction of HIF target genes, which persisted beyond cold storage. It reduced acute renal injury (serum creatinine at day 10: 0.66 +/- 0.20 vs. 1.49 +/- 1.36 mg/dL; P < 0.05) and early mortality in the acute model and improved long-term survival of recipient animals in the chronic model (mortality at 24 weeks: 3 of 16 vs. 7 of 13 vehicle-treated animals; P < 0.05). In conclusion, pretreatment of organ donors with FG-4497 improves short- and long-term outcomes after allogenic KTx. Inhibition of PHDs appears to be an attractive strategy for organ preservation that deserves clinical evaluation.

Disease progression in HIV-1 infected children and adolescents--results of a German-Austrian cohort study.

OBJECTIVE: The Paediatric Working Group AIDS (PAAD) initiated a prospective cohort study in order to investigate disease progression in HIV- infected children and adolescents and the effect of antiretroviral treatment regimes. PATIENTS AND METHODS: Between 1998 and 2003, paediatric centres documented HIV-infected patients under clinical care using a questionnaire for basic data and annual follow up. Main outcome measures were: use of antiretroviral therapy, adverse events, disease progression and change of therapeutic regimes. RESULTS: 174 HIV- infected paediatric patients were followed up in 12 centres in Germany and Austria between 1998 and 2003. Initially 54 (31%) patients had no antiretroviral therapy, 35 (20%) received a two-drug regimen (ART) and 85 patients (49%) a highly active antiretroviral therapy (HAART>or=3 drugs). After an observation period of 5 years, 8 patients (4%) had no therapy, 17 (10%) were on ART and 134 patients on HAART (77%). The number of patients with salvage therapy (>or=4 drugs) increased from 5 (3%) to 15 patients (9%). 72 of 166 treated patients (43%) had no change of their drug regimes, 68 patients (41%) had one change and 26 patients (16%)>or=2 changes. Main reasons for changes were increased viral load (49%), immunologic deterioration (21%) and adverse events (14%). During the follow up period no patient died. According to the CDC classification, disease progression was seen in 48 of 174 patients (28%), of whom 20 had deteriorations of clinical categories (A, B, C) and 28 of immunologic categories. Using Kaplan-Meier curves, the mean time from study onset until change of clinical categories was 61 months for patients on HAART, 26 months for patients on ART and 14 months for patients without ART. CONCLUSION: In paediatric patients with HIV infection, disease progression has declined substantially by introduction of HAART. Superiority of HAART compared with ART was demonstrated. Non-adherence as well as other reasons for treatment failure have to be studied more carefully.

Hydrogen inhalation ameliorates oxidative stress in transplantation induced intestinal graft injury.

Ischemia/reperfusion (I/R) injury during small intestinal transplantation (SITx) frequently causes complications including dysmotility, inflammation and organ failure. Recent evidence indicates hydrogen inhalation eliminates toxic hydroxyl radicals. Syngeneic, orthotopic SITx was performed in Lewis rats with 3 h of cold ischemic time. Both donor and recipient received perioperative air or 2% hydrogen inhalation. SITx caused a delay in gastrointestinal transit and decreased jejunal circular muscle contractile activity 24 h after surgery. Hydrogen treatment resulted in significantly improved gastrointestinal transit, as well as jejunal smooth muscle contractility in response to bethanechol. The transplant induced upregulation in the inflammatory mediators CCL2, IL-1 beta, IL-6 and TNF-alpha were mitigated by hydrogen. Hydrogen significantly diminished lipid peroxidation compared to elevated tissue malondialdehyde levels in air-treated grafts demonstrating an antioxidant effect. Histopathological mucosal erosion and increased gut permeability indicated a breakdown in posttransplant mucosal barrier function which was significantly attenuated by hydrogen treatment. In recipient lung, hydrogen treatment also resulted in a significant abatement in inflammatory mRNA induction and reduced neutrophil recruitment. Hydrogen inhalation significantly ameliorates intestinal transplant injury and prevents remote organ inflammation via its antioxidant effects. Administration of perioperative hydrogen gas may be a potent and clinically applicable therapeutic strategy for intestinal I/R injury.