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BACKGROUND Circular RNAs (circRNAs) have recently been described as novel noncoding regulators of gene expression. They are detectable in the blood of patients with acute kidney injury. We tested whether circRNAs were present in urine and could serve as new predictors of outcome in renal transplant patients with acute rejection. METHODS A global circRNA expression analysis using RNA from urine of patients with acute T cell-mediated renal allograft rejection and control transplant patients was performed. Dysregulated circRNAs were confirmed in a cohort of 62 patients with acute rejection, 10 patients after successful antirejection therapy, 18 control transplant patients without rejection, and 13 stable transplant patients with urinary tract infection. RESULTS A global screen revealed several circRNAs to be altered in urine of patients with acute rejection. Concentrations of 2 circRNAs including hsa_circ_0001334 and hsa_circ_0071475 were significantly increased. These were validated in the whole cohort of patients. hsa_circ_0001334 was upregulated in patients with acute rejection compared with controls. Concentrations of hsa_circ_0001334 normalized in patients with acute rejection following successful antirejection therapy. hsa_circ_0001334 was associated with higher decline in glomerular filtration rate 1 year after transplantation. CONCLUSIONS CircRNA concentrations are significantly dysregulated in patients with acute rejection at subclinical time points. Urinary hsa_circ_0001334 is a novel biomarker of acute kidney rejection, identifying patients with acute rejection and predicting loss of kidney function.

Wertigkeit eines vereinfachten koronalen Ganzkorper-Magnetresonanztomographie(MRT)-Protokolls bei der Bestimmung der Todesursache. Insgesamt wurden 30 Verstorbene mit der postmortalen Ganzkorper-MRT untersucht. Die Radiologen erhielten keine Informationen uber die medizinische Vorgeschichte oder uber die Umstande des Todes. Die Untersuchung erfolgte mit einem koronalen Ganzkorperprotokoll ohne erganzende transversale Schnittfuhrung an einem 1,5 Tesla-Magnetresonanztomographen. Die verblindeten Ergebnisse der Bildgebung wurden mit dem Ergebnis der rechtsmedizinischen Untersuchung (Anamnese, Autopsie, Histopathologie) als Referenzstandard korreliert. Das mittlere Alter zum Zeitpunkt des Todes betrug 54 Jahre (ein Jahr bis 86 Jahre). Die haufigste Todesursache war eine kardiale Erkrankung in 15 Fallen, gefolgt von der Diagnose einer Lungenentzundung (3 Falle). In 3 Fallen blieb die Todesursache nach MRT und Autopsie ungeklart. Eine kardiale Todesursache wurde mit der MRT in 14 von 15 Fallen korrekt diagnostiziert und eine nichtkardiale Todesursache in 11 von 15 Fallen. Die Gesamtsensitivitat der MRT betrug 83 % bei einer Spezifitat von 98 %. Bei exakter Differenzierung zwischen akutem Myokardinfarkt und anderen kardialen Todesursachen reduzierte sich die Sensitivitat der MRT auf 60 % (Spezifitat 97 %). Trotz des vereinfachten koronalen Untersuchungsprotokolls sind Ubereinstimmungen mit der konventionellen Autopsie erreichbar, wie sie bisher nur fur aufwendigere Protokolle mit minimalinvasiven Methoden und Kombinationen aus Computertomographie (CT) und MRT beschrieben worden sind. Daher scheint eine vereinfachte MRT-Untersuchung wie in dieser Studie geeignet, um in die klinische Routine der postmortalen Diagnostik implementiert zu werden.

The mammalian cochlea contains two types of mechanosensory hair cell that have different and critical functions in hearing. Inner hair cells (IHCs), which have an elaborate presynaptic apparatus, signal to cochlear neurons and communicate sound information to the brain. Outer hair cells (OHCs) mechanically amplify sound-induced vibrations, providing enhanced sensitivity to sound and sharp tuning. Cochlear hair cells are solely generated during development, and hair cell death—most often of OHCs—is the most common cause of deafness. OHCs and IHCs, together with supporting cells, originate in embryos from the prosensory region of the otocyst, but how hair cells differentiate into two different types is unknown1–3. Here we show that Insm1, which encodes a zinc finger protein that is transiently expressed in nascent OHCs, consolidates their fate by preventing trans-differentiation into IHCs. In the absence of INSM1, many hair cells that are born as OHCs switch fates to become mature IHCs. To identify the genetic mechanisms by which Insm1 operates, we compared the transcriptomes of immature IHCs and OHCs, and of OHCs with and without INSM1. In OHCs that lack INSM1, a set of genes is upregulated, most of which are normally preferentially expressed by IHCs. The homeotic cell transformation of OHCs without INSM1 into IHCs reveals a mechanism by which these neighbouring mechanosensory cells begin to differ: INSM1 represses a core set of early IHC-enriched genes in embryonic OHCs and makes them unresponsive to an IHC-inducing gradient, so that they proceed to mature as OHCs. Without INSM1, some of the OHCs in which these few IHC-enriched transcripts are upregulated trans-differentiate into IHCs, identifying candidate genes for IHC-specific differentiation. Conditional deletion of Insm1 in mice demonstrates that INSM1 is the key switch that causes the maturation of outer hair cells in the cochlea, with its absence resulting in an increase in inner hair cells instead.

Background: TGF-β is known as an important stress factor of podocytes in glomerular diseases. Apart from activation of direct pro-apoptotic pathways we wanted to analyze micro-RNA (miRs) driven regulation of components involved in the integrity of the glomerular filtration barrier induced by TGF-β. Since miR-143-3p (miR-143) is described as a TGF-β inducible miR in other cell types, we examined this specific miR and its ability to induce glomerular pathology. Methods: We analyzed miR-143 expression in cultured human podocytes after stimulation with TGF-β. We also microinjected zebrafish eggs with a miR-143 mimic or with morpholinos specific for its targets syndecan and versican and compared phenotype and proteinuria development. Results: We detected a time dependent, TGF-β inducible expression of miR-143 in human podocytes. Targets of miR-143 relevant in glomerular biology are syndecans and versican, which are known components of the glycocalyx. We found that syndecan 1 and 4 were predominantly expressed in podocytes while syndecan 3 was largely expressed in glomerular endothelial cells. Versican could be detected in both cell types. After injection of a miR-143 mimic in zebrafish larvae, syndecan 3, 4 and versican were significantly downregulated. Moreover, miR-143 overexpression or versican knockdown by morpholino caused loss of plasma proteins, edema, podocyte effacement and endothelial damage. In contrast, knockdown of syndecan 3 and syndecan 4 had no effects on glomerular filtration barrier. Conclusion: Expression of versican and syndecan isoforms is indispensable for proper barrier function. Podocyte-derived miR-143 is a mediator for paracrine and autocrine cross talk between podocytes and glomerular endothelial cells and can alter expression of glomerular glycocalyx proteins.

Hypertrophic cardiomyopathy (HCM) is a hereditary heart disease with a high risk for sudden cardiac death in young people. As a subtype, hypertrophic obstructive cardiomyopathy (HOCM) additionally has a left ventricular outflow gradient, showing stronger symptoms and requires a different treatment compared with hypertrophic nonobstructive cardiomyopathy (HNCM). In this study our aim was to investigate the regulation of mitochondrial and cardiac remodeling associated long noncoding RNAs (lncRNAs) in blood of patients affected with HOCM and HNCM. We included 28 HNCM, 57 HOCM, and 26 control inviduals. Already known mitochondrial and cardiac remodeling associated lncRNAs uc004cos.4, uc004coz.1, uc004cov.4, uc011mfi.2, uc022bqw.1, uc022bqs.1, and uc022bqu.1 were amplified in serum of these patients and correlated with clinical parameters. Long noncoding RNAs uc004cov.4 and uc022bqu.1 were significantly increased in patients with HOCM but not in patients with HNCM. With the use of receiver operator characteristic (ROC) curve analysis, lncRNAs uc004cov.4 and uc022bqu.1 were able to identify HOCM patients. In our study we evidenced that the specific mitochondrial long noncoding RNAs uc004cov.4 and uc022bqu.1 were upregulated in patients with HOCM and they were also able to identify HOCM and could be developed as useful clinical biomarkers in the future.

BACKGROUNDLong noncoding RNAs (lncRNAs) are novel intracellular noncoding ribonucleotides regulating the genome and proteome. They are detectable in the blood of patients with acute kidney injury. We tested whether lncRNAs are present in urine and may serve as new predictors of outcome in renal transplant patients with acute rejection.METHODSA global lncRNA expression analysis was performed with RNA from urine of patients with acute T cell–mediated renal allograft rejection and control transplant patients. Deregulated lncRNAs were confirmed in kidney biopsies and urine in a validation cohort of 62 patients with acute rejection, 10 of them after successful antirejection therapy, and 31 control transplant patients.RESULTSA global screen revealed several lncRNAs to be deregulated in urine of patients with acute rejection. Three intergenic lncRNAs, LNC-MYH13-3:1, RP11-395P13.3-001, and RP11-354P17.15-001, were most strongly altered. These were validated in the whole cohort of patients. RP11-395P13.3-001 and RP11-354P17.15-001 were upregulated in patients with acute rejection compared with controls. Only levels of RP11-354P17.15-001 normalized in patients with acute rejection after successful antirejection therapy. RP11-354P17.15-001 was associated with higher decline in glomerular filtration rate 1 year after transplantation. In vitro, in tubular epithelial cells, all lncRNAs were enriched by interleukin-6 treatment, but only RP11-395P13.3-001 and RP11-354P17.15-001 increased in cell culture supernatant, indicating that these lncRNAs might be secreted under inflammatory conditions.CONCLUSIONSlncRNAs are strongly altered in urine of patients with acute rejection. Urinary RP11-354P17.15-001 may serve as a novel biomarker of acute kidney rejection, identifying patients with acute rejection and predicting loss of kidney function.

INSM1 is a zinc-finger protein expressed throughout the developing nervous system in late neuronal progenitors and nascent neurons. In the embryonic cortex and olfactory epithelium, Insm1 may promote the transition of progenitors from apical, proliferative, and uncommitted to basal, terminally-dividing and neuron producing. In the otocyst, delaminating and delaminated progenitors express Insm1, whereas apically-dividing progenitors do not. This expression pattern is analogous to that in embryonic olfactory epithelium and cortex (basal/subventricular progenitors). Lineage analysis confirms that auditory and vestibular neurons originate from Insm1-expressing cells. In the absence of Insm1, otic ganglia are smaller, with 40% fewer neurons. Accounting for the decrease in neurons, delaminated progenitors undergo fewer mitoses, but there is no change in apoptosis. We conclude that in the embryonic inner ear, Insm1 promotes proliferation of delaminated neuronal progenitors and hence the production of neurons, a similar function to that in other embryonic neural epithelia. Unexpectedly, we also found that differentiating, but not mature, outer hair cells express Insm1, whereas inner hair cells do not. Insm1 is the earliest known gene expressed in outer versus inner hair cells, demonstrating that nascent outer hair cells initiate a unique differentiation program in the embryo, much earlier than previously believed.

Hypertrophic cardiomyopathy (HCM) is caused by mutations in different structural genes and induces pathological hypertrophy with sudden cardiac death as a possible consequence. HCM can be separated into hypertrophic non-obstructive and obstructive cardiomyopathy (HNCM/HOCM) with different clinical treatment approaches. We here distinguished between HNCM, HOCM, cardiac amyloidosis and aortic stenosis by using microRNA profiling and investigated potential interactions between circulating miRNA levels and the most common mutations in MYH7and MYBPC3 genes.Our study included 4 different groups: 23 patients with HNCM, 28 patients with HOCM, 47 patients with aortic stenosis and 22 healthy controls. Based on previous findings, 8 different cardiovascular known microRNAs (miR-1, miR-21, miR-29a, miR-29b, miR-29c, miR-133a, miR-155 and miR-499) were studied in serum of all patients and compared with clinically available patient data.We found miR-29a levels to be increased in patients with HOCM and correlating markers of cardiac hypertrophy. This was not the case in HNCM patients. In contrast, we identified miR-29c to be upregulated in aortic stenosis but not the other patient groups. ROC curve analysis of miR-29a/c distinguished between HOCM patients and aortic stenosis patients. MiR-29a and miR-155 levels discriminated HNCM patients from patients with senile cardiac amyloidosis. MiR-29a increased mainly in HOCM patients with a mutation in MYH7, whereas miR-155 was decreased in hypertrophic cardiomyopathy patients with a mutation in MYBPC3.We demonstrated that miR-29a and miR-29c show a specific signature to distinguish between aortic stenosis, hypertrophic non-obstructive and obstructive cardiomyopathies and thus could be developed into clinically useful biomarkers.

Ischaemia–reperfusion (I/R) injury of the kidney is a major cause of acute kidney injury. It may result in worsening or even loss of organ function. Transient occlusion of the renal vessel is followed by a reperfusion period, which induces further tissue damage by release of reactive oxygen and nitrogen species. Ischaemia–reperfusion injury of the kidney may be associated with surgical interventions in native kidneys and is also a common and unavoidable phenomenon in kidney transplantation. MicroRNAs are fascinating modulators of gene expression. They are capable of post-transcriptional silencing of genetic information by targeting the 3′-untranslated region of mRNAs, culminating in a suppression of protein synthesis or an increase in mRNA degradation. They might therefore be useful diagnostic and therapeutic entities during renal I/R injury; for instance, miR-21 has been shown to be enriched in kidney tissue in mice and humans with acute kidney injury. Interestingly, most recent literature suggests that modulation of vascular microRNAs might result in the amelioration of kidney function during renal I/R injury. To that end, miR-126 and miR-24, which have been demonstrated to be highly enriched in endothelial cells, were therapeutically modulated and shown to ameliorate renal I/R injury in mice. MicroRNAs in plasma, urine or enriched in microvesicles have been shown to serve as non-invasive tools for disease monitoring and to have potential impact on downstream mechanisms in recipient cells. This review highlights the latest developments regarding the role of microRNAs in renal I/R injury.

Rationale Many processes in endothelial cells including angiogenic responses are regulated by microRNAs. However, there is limited information available about their complex cross-talk in regulating certain endothelial functions. Aim The objective of this study is to identify endothelial functions of the pro-hypertrophic miR-212/132 cluster and its cross-talk with other microRNAs during development and disease. Methods and results We here show that anti-angiogenic stimulation by transforming growth factor-beta activates the microRNA-212/132 cluster by derepression of their transcriptional co-activator cAMP response element-binding protein (CREB)-binding protein (CBP) which is a novel target of a previously identified pro-angiogenic miRNA miR-30a-3p in endothelial cells. Surprisingly, despite having the same seed-sequence, miR-212 and miR-132 exerted differential effects on endothelial transcriptome regulation and cellular functions with stronger endothelial inhibitory effects caused by miR-212. These differences could be attributed to additional auxiliary binding of miR-212 to its targets. In vivo , deletion of the miR-212/132 cluster increased endothelial vasodilatory function, improved angiogenic responses during postnatal development and in adult mice. Conclusion Our results identify (i) a novel miRNA-cross-talk involving miR-30a-3p and miR-212, which led to suppression of important endothelial genes such as GAB1 and SIRT1 finally culminating in impaired endothelial function; and (ii) microRNAs may have different biological roles despite having the same seed sequence.

Purpose Changes in water diffusion can be quantified by diffusion-weighted MR imaging. However, there are only few reports about changes in post mortem brain. The aim of this study was to investigate the temporal pattern of the apparent diffusion coefficient (ADC) in the brain after death, to compare the values to in vivo brain and to assess the value of ex vivo DWI as a forensic tool. Material and methods The study was approved by the local Ethics Committee, and informed consent was obtained from all relatives and the control subjects. Twenty-one corpses, died of natural cause, were examined (13 males, 8 females; age: 70.5 ± 8.7 y, weight 74 ± 18 kg). Diffusion-Weighted Imaging (DWI) was performed with b -values of 0 and 1000 s/mm 2 at 1.5 T. Scans were repeated in intervals of 1 h. ADC-maps were calculated in thalamus, cerebrum and cerebellum. The obtained values were statistically compared to healthy volunteers ( n = 3) and to literature data. Results The ADC in the three regions decreased characteristically during the examination time. In the cerebrum there was a significant difference between ex vivo and in vivo ADC ( p p p = 0.045). Conclusion DWI of the postmortal brain can be added to the MRI methods for a post mortem imaging.

The anorexia that results from extended periods of cellular dehydration is an important physiological adaptation that limits the intake of osmolytes from food and helps maintain the integrity of fluid compartments. The ability to experimentally control both the development and reversal of anorexia, together with the understanding of underlying hormonal and neuropeptidergic signals, makes dehydration (DE)-anorexia a powerful model for exploring the interactions of neural networks that stimulate and inhibit food intake. However, it is not known which meal parameters are affected by cellular dehydration to generate anorexia. Here we use continuous and high temporal resolution recording of food and fluid intake, together with a drinking-explicit method of meal pattern analysis to explore which meal parameters are modified during DE-anorexia. We find that the most important factor responsible for DE-anorexia is the failure to maintain feeding behavior once a meal has started, rather than the ability to initiate a meal, which remains virtually intact. This outcome is consistent with increased sensitivity to satiation signals and post-prandial satiety mechanisms. We also find that DE-anorexia significantly disrupts the temporal distribution of meals across the day so that the number of nocturnal meals gradually decreases while diurnal meal number increases. Surprisingly, once DE-anorexia is reversed this temporal redistribution is maintained for at least 4 days after normal food intake has resumed, which may allow increased daily food intake even after normal satiety mechanisms are reinstated. Therefore, DE-anorexia apparently develops from a selective targeting of those neural networks that control meal termination, whereas meal initiation mechanisms remain viable.

Circulating microRNAs may have diagnostic potential in acute coronary syndrome (ACS). Previous studies, however, were based on low patient numbers and could not assess the relation of microRNAs to clinical characteristics and their potential prognostic value. We thus assessed the diagnostic and prognostic value of cardiomyocyte-enriched microRNAs in the context of clinical variables and a sensitive myonecrosis biomarker in a larger ACS cohort. MiR-1, miR-133a, miR-133b, miR-208a, miR-208b, and miR-499 concentrations were measured by quantitative reverse transcription PCR in plasma samples obtained on admission from 444 patients with ACS. High-sensitivity troponin T (hsTnT) was measured by immunoassay. Patients were followed for 6 months regarding all-cause mortality. In a multiple linear regression analysis that included clinical variables and hsTnT, miR-1, miR-133a, miR-133b, and miR-208b were independently associated with hsTnT levels (all P

Summary Introduction Salvage rates of free flaps have been reported to be inversely related to the time interval between the onset of ischaemia and its clinical recognition. Consecutively, monitoring of free flaps remains of major importance. The aim of this study was to analyse the correlation of postoperative free flap microcirculation and free flap skin temperature as a potential tool of postoperative flap monitoring. Hypothesis Free flap skin temperature correlates to free flap capillary microcirculation. Methods Fifty-four free flaps were prospectively monitored during the study. Postoperative flap monitoring was performed using a regular digital infrared surface thermometer (Medisana FTD, Germany) simultaneously to microcirculatory assessment using combined Laser-Doppler and photospectrometry (Oxygen-to-see, Lea Medizintechnik, Germany). Results Mean microcirculatory blood flow was 105 ± 35 arbitrary units (AU). Mean temperature was 34.9 ± 2.2 °C. We found a significant correlation between free flap temperature and free flap capillary blood flow (Pearson correlation r = 0.48; p r = −0.32; p = 0.021) in 54 free flaps. A 1 °C less free flap temperature was associated with a decrease of the mean microcirculatory capillary blood flow by 37 relative units. Conclusion Our study demonstrates free flap skin temperature related to capillary microcirculation. Our primary hypothesis was confirmed. We postulate an acute temperature drop of 3 °C at the centre of the skin island as indicative of arterial thrombosis, whereas a 1–2 °C uniform temperature drop of the flap is indicative of venous compromise. Consecutively, free flap skin temperature assessment might be a reliable and inexpensive adjunct monitoring method in plastic reconstructive surgery to improve patients' safety.

Osteopontin (OPN) is a pleiotropic cytokine that has been postulated to play a role in the pathogenesis of idiopathic pulmonary arterial hypertension (IPAH). OPN plasma levels may be related to disease severity and mortality in patients with PAH.OPN plasma levels obtained during right-sided heart catheterization were assessed by a commercially available enzyme-linked immunosorbent assay and related to hemodynamics, exercise capacity, N-terminal pro-brain natriuretic peptide (NT-pro-BNP) level, uric acid level, C-reactive protein level, and survival in two cohorts of patients with IPAH: a 4-year retrospective cohort (n = 70) and a prospective cohort (n = 25) followed for 3 months after initiation of therapy. Forty apparently healthy individuals served as control subjects.Baseline OPN levels were elevated in patients with IPAH compared with healthy control subjects (50.2 ± 35.9 vs 23.7 ± 2.8 ng/mL, P.0001). In the retrospective as well as in the prospective cohort, OPN levels correlated with mean right atrial pressure and NT-BNP. In the retrospective cohort, OPN levels also correlated with age (r = 0.3, P = .02), 6-min walking distance (r=-0.4, P = .05), and New York Heart Association class (r = 0.4, P = .001). Multivariate Cox analysis demonstrated that baseline OPN levels were independent predictors of mortality (P = .02). When patients were divided according to their baseline OPN values, being normal or elevated at baseline (below or above 34.5 ng/mL), proportional survival rates were 100% vs 80% after 1 year and 77% vs 51% after 3 years, respectively.Circulating OPN predicts survival in patients with IPAH and is associated with a higher New York Heart Association class. OPN, thus, may be useful as a biomarker in IPAH.

Background Atherosclerosis is an inflammatory process mediated by circulating immune cells, including monocytes. There is accumulating evidence for the involvement of Toll-like receptor 4 (TLR-4) as a mediator of atherogenesis. Methods We evaluated the association between CD14+/TLR-4+ monocytes in peripheral blood (flow cytometry) and future cardiovascular events (CVE), e.g. myocardial infarction, percutaneous transluminal coronary angioplasty (including stenting), aortocoronary bypass, stroke and angiographically verified stenosis of peripheral arteries and cardiovascular (CV) death, in 191 patients with chronic kidney disease Stage V receiving hemodialysis therapy. Results At baseline, CD14+/TLR-4+ monocytes correlated significantly with age (r = 0.2; P = 0.007), high-sensitivity C-reactive protein (r = 0.2; P = 0.008) and mean arterial pressure (r = -0.2; P = 0.02), but not with gender (P = 0.5), smoking (P = 0.6) and the presence of diabetes (P = 0.5). During a median follow-up period of 36 [1-54] months, 79 (41%) patients experienced a CVE. A total of 55 patients died during the follow-up period, 25 of those due to a confirmed CV cause. Log-rank test did not reveal statistical significance for TLR-4+ monocytes concerning incident CVE (P = 0.3), CV death (P = 0.85) and overall death (P = 0.8). In a multiple Cox-regression analysis, we identified age (P = 0.003) and smoking (P = 0.001) as the only independent variables associated with incident CVE. Conclusions Unexpectedly, we could not detect an association between CD14+/TLR-4+ monocytes and incident CVE as well as CV death in stable hemodialysis patients. Further studies have to clarify the potential role of this cell population for CV outcome in this population.

Eur J Clin Invest 2010; 40 (4): 294–300 Abstract Background The pleiotropic cytokine osteopontin (OPN) is thought to be involved in the pathogenesis of atherosclerosis. However, the relationship between OPN and renal function, a cardiovascular risk factor itself, is not known. Therefore, we assessed the relationship between OPN plasma levels and renal function in patients at different stages of chronic kidney disease (CKD). Methods We studied 49 non-diabetic and non-smoking patients with primary kidney disease at different CKD stages (K/DOQI 1-5). True glomerular filtration rate (GFR) in patients was assessed using the inulin-clearance technique. To examine the role of an abrupt change in GFR on circulating OPN, 15 living related kidney donors were studied before and after unilateral nephrectomy. Twenty matched non-smoking healthy subjects served as controls. Results OPN plasma levels in patients with CKD stage 1 (i.e. GFR above 90 mL min−1 1·73 m−2) were comparable with controls. OPN levels increase in a linear fashion with declining GFR (r = −0·9, P

An impairment in the local availability of nitric oxide (NO) may impair male erectile function. The activity of l-arginine-degrading arginase enzymes may attenuate the relaxation of cavernous smooth muscle by reducing local NO production. Arginase enzymes compete with the nitric oxide synthases for the common substrate, the amino acid l-arginine. Very little data are available regarding the significance of arginase enzymes in the control of human penile erectile tissue. The aim of the present study was to elucidate the effects of drugs known to inhibit arginase activity on the relaxation of isolated human corpus cavernosum (HCC) and the production of cyclic GMP. Using the organ bath technique, the effects of the arginase inhibitors DFMO, H-Orn-OH·HCl, H-lle-OH and nor-NOHA (10 nM–10 μM) on the tension induced by NE (1 μM) and the relaxation induced by electrical field stimulation (EFS) of HCC were investigated. HCC strips were also exposed to increasing concentrations of the compounds, and the production of cGMP was determined by means of a radioimmunoassay. Only marginal effects of the arginase inhibitors were registered on the tension induced by NE and the relaxation exerted by EFS. Mean reversion of tension ranged from 18 to 8%. Only DFMO and nor-NOHA amplified the EFS-induced relaxation by 11 and 29%, respectively. These effects were not paralleled by an increase in tissue levels of cGMP. Arginase inhibitors appeared to be ineffective in reversing the adrenergic tension and increasing the electrically induced relaxation of isolated HCC.

Several gene array studies have suggested that osteopontin (Opn) expression strongly correlates with albuminuria and glomerular disease. Urinary Opn concentration and kidney Opn immunoreactivity were found to be increased in patients with steroid-sensitive nephrotic syndrome. In addition, renal Opn mRNA was increased in the Ins2(Akita) mouse model of type 1 diabetic nephropathy, in the LPS-induced albuminuria model, and in glomeruli of puromycin aminonucleotide-induced nephrotic rats. Opn knockout mice did not develop albuminuria in response to LPS injection, and Opn knockout mice were protected from diabetes-induced albuminuria and mesangial expansion. In the glomerulus, Opn immunostaining was increased specifically in podocytes. Treatment of podocytes with recombinant Opn activated the NF-kappaB pathway, increased expression of urokinase plasminogen activator and matrix metalloproteinases 2 and 9, and increased podocyte motility. Taken together, these results indicate that Opn plays an important role in the development of albuminuria, possibly by modulating podocyte signaling and motility.

Childhood nephrotic syndrome (NS)3 is associated with an increase in the permeability across the glomerular filtration barrier due to processes that affect the dynamics and permselectivity of the glomerular filtration barrier. This increased permeability leads to an inability to restrict the loss of protein to 50 mg/kg per day), hypoalbuminemia (

High pressure X-ray diffraction studies have been performed in order to determine the linear and bulk compressibilities of two out of the four crystalline phases of poly(tetrafluoroethylene) (PTFE). It has been confirmed that two structures coexist in form III, orthorhombic and monoclinic. The bulk compressibility of crystalline PTFE decreases with increasing pressure. In form II it has a value of 1.57×10−4 1/MPa, in form III the values are 0.51×10−4 1/MPa (orthorhombic) and 0.38×10−4 1/MPa (monoclinic).

The study of phonon dispersion curves of materials under hydrostatic pressure provides important information such as the evolution of sound velocities, elastic constants, interatomic potentials, phase transition mechanisms, etc. Until very recently, coherent inelastic neutron scattering was the only spectroscopic technique, which allowed performing these types of studies up to typically 10 GPa. Today, inelastic X-ray scattering with meV energy resolution provides a complementary spectroscopic technique, where, using diamond anvil cell techniques, pressures beyond 100 GPa can be reached.

The magnetic properties of the Invar alloy Fe 72 Pt 28 have been investigated by X-ray emission spectroscopy as a function of temperature up to 900 K and pressure up to 25 GPa. With increasing temperature and pressure, the amplitude of the Fe local moment, deduced from the Fe K g line satellite intensity, is reduced. Both the temperature and pressure dependence are interpreted in terms of transitions from a high-spin state to a low-spin state. This behavior provides a microscopic picture of the Fe magnetism in Invar alloys in agreement with the 2 n state model.

The input power tolerance of a single-pump fiber-optic parametric amplifier (FOPA) is experimentally shown to be enhanced for return-to-zero differential phase-shift keying (RZ-DPSK) modulation compared to RZ ON–OFF keying modulation at 40 Gb/s. The improved nonlinear tolerance is exploited to demonstrate amplitude regeneration of a distorted RZ-DPSK signal in a gain-saturated FOPA. An optical signal-to-noise ratio penalty of 3.5 dB after amplitude distortion is shown to be reduced to 0.2 dB after the FOPA, thus clearly demonstrating the regenerative nature of saturated FOPAs for RZ-DPSK modulation.

A 55-year-old woman with systemic lupus erythematosus was admitted with fever of unknown origin. She had been on an immunosuppressive regimen for the past 8 years including steroids and Azathioprine. Laboratory parameters revealed a markedly elevated C-reactive protein of 189 mg/l, antinuclear antibodies of 1:2,560, a hemoglobin level of 9.0 g/dl, and a severe lymphopenia (total lymphocytes 49.4/microl, CD4(+) cells 2/microl, CD8(+) cells 7/microl). Neither blood culture samples nor computed tomography and magnetic resonance imaging of the chest and abdomen nor a trans-esophageal echocardiography revealed positive results. A bone marrow biopsy did not show signs of hematologic disease, but revealed a small granuloma rife with acid-fast bacilli, which were later confirmed to be Mycobacterium genavense by gene sequencing. To our knowledge, this is the first case involving M. genavense infection in a patient with systemic lupus erythematosus. In contrast to other reports regarding disseminated M. genavense infection, the patient is still alive and well.

Small-angle X-ray scattering using synchrotron radiation at pressures up to 700 MPa has been performed on triblock-copolymer gels, polystyrene-rubber-polystyrene with poly(ethylene/butylene) as the rubber mid-blocks. A 2-stage pressure behaviour could be verified by comparison of the experimental data with the Tait-equation and a model of pressure screening.

We present an experimental and theoretical investigation of the phonon dispersion relations in zinc blende (3C) SiC. The experimental data were obtained for the entire Brillouin zone by inelastic x-ray scattering (IXS) using a synchrotron radiation source. Eigenvector analysis is performed with the aid of state-of-the-art linear response first principles calculations based on density functional theory. The theoretical predictions reproduce the experimental phonon dispersion remarkably well. These results are compared with data obtained previously for the 〈111〉 direction by Raman spectroscopy using several SiC polytypes and the backfolding technique. IXS data for 4H modification along the c axis are also reported.

An increased gain in a fibre-optical parametric amplifier through suppression of stimulated Brillouin scattering is demonstrated by applying a temperature distribution along the fibre for a fixed phase modulation of the pump. The temperature distribution slightly impacts the gain spectrum.

Address reprint requests to: Cary Peterson, M.D., Department of Internal Medicine, University of Nebraska Medical Center, 42nd and Dewey Avenue, Omaha, NB 68105, USA treated at different times with chemotherapy, readiation therapy for retroperitoneal adenopathy and splenectomy. The patient had been asymptomatic for the past year. The medical history was otherwise negative. Physical examination demonstrated mild tenderness over the left greater trochanter and pain when the hip was rotated. Examination of the right hip showed no abnormality. The remainder of the physical examination was unremarkable. Roentgenograms of the pelvis showed a mot

Pancreatic polypeptide (PP) has been considered to be predominantly under cholinergic-vagal control and may therefore serve as an indicator of vagal tone. We found similar basal plasma concentrations of PP in athletes with bradycardia and in untrained subjects. We further observed that physical exercise--an adrenergic situation--induces a several-fold rise in PP plasma concentration. Maximal plasma PP levels correlated positively with maximal blood pressure. The exercise-induced rise of PP was completely abolished by propranolol. These findings suggest that stimulation of the adrenergic system releases PP and that therefore plasma PP concentrations cannot be used to determine cholinergic-vagal activity.

Background Dosing of antibiotics in critically ill patients is challenging. It becomes even more difficult if renal or hepatic impairment ensue. Modern means of renal replacement therapy are capable of removing antibiotics to a higher rate than decades ago, leaving clinicians with a high degree of uncertainty concerning the dose of antibiotics in this patient population. Cotrimoxazole, a combination of trimethoprim (TMP) and sulfamethoxazole (SMX) is frequently used in the treatment of several infections including Pneumocystis jirovecii pneumonia (PCP). Case presentation Here we describe a patient with acute kidney injury in which we investigated the TMP and SMX levels during the course of an ICU stay. Cotrimoxazole was administered every six hours i.v. in a dose of TMP/SMX 15/75 mg/kg/day. Extended dialysis was performed with a high-flux dialyzer. Blood samples, as well as pre- and postdialyzer samples and aliquots of the collected spent dialysate were collected. Observed peak concentrations (Cmax) were 7.51 mg/l for TMP and 80.80 mg/l for SMX. Decline of blood levels during extended dialysis (TMP 64%; SMX 84%) was mainly due to removal by the dialysis procedure, illustrated by the high dialyzer clearances (median of 4 extended dialysis sessions: TMP 94.0 / SMX 51.0 ml/min), as well as by the absolute amount of both substances in the collected spent dialysate (median of 6 extended dialysis sessions: TMP 556 mg / SMX 130 mg). Within the limitation of a case report our data from 4 consecutive extended dialysis sessions suggest that this procedure substantially removes both TMP and SMX. Conclusions Dose reduction, which is usually advocated in patients with acute kidney injury under renal replacement therapy, might lead to significant under-dosing. Pharmacokinetic studies for TMP/SMX dosing in this patient population are necessary to allow adequate dosing.

Background Lithium intoxication has potentially fatal neurologic and cardiac side effects. Extracorporeal removal can therefore be lifesaving. The dialysance of lithium is high as it is a small molecule. Comparable to its neighbor in the periodic table, sodium, its intracellular accumulation hampers its removal by renal replacement therapy, despite its favorable size. For this reason the combination of short intermittent and prolonged dialysis may be a beneficial approach in acute lithium intoxication, yet only a report of such a combination has been published and actual removed lithium has not been quantified. Case presentation We describe the first measurement of lithium in the spent total dialysate treating an acute lithium overdose of a 44 year old Caucasian patient on chronic lithium therapy, undergoing extended dialysis. Extracorporeal therapy was initiated at a lithium serum concentration of 3.24 mmol/l. With blood/dialysate flow of 350 ml/min the 1.3 m2 polysulfone dialyzer exhibited a maximum lithium clearance of 177 ml/min. After 4.1 hours of treatment the lithium level was lowered to 1.25 mmol/l. In the total spent dialysate 250 mg lithium, i.e. ~ 40% of the ingested amount were found. The subsequent extended dialysis over 9.5 hours further decreased serum levels to 0.79 mmol/l. Neurological symptoms improved within the first 60 min of treatment. The patient could be transferred to a psychiatric hospital on the morning after admission. Conclusion Standard intermittent hemodialysis with subsequent extended dialysis can efficiently be employed in severe lithium intoxication by combining prompt a fast decrease of lithium blood levels and preventing rebound/assuring removal of redistributed lithium.