Klinik und Poliklinik für Psychosomatik und Psychotherapie

The contribution of rare and low-frequency variants to human traits is largely unexplored. Here we describe insights from sequencing whole genomes (low read depth, 7×) or exomes (high read depth, 80×) of nearly 10,000 individuals from population-based and disease collections. In extensively phenotyped cohorts we characterize over 24 million novel sequence variants, generate a highly accurate imputation reference panel and identify novel alleles associated with levels of triglycerides (APOB), adiponectin (ADIPOQ) and low-density lipoprotein cholesterol (LDLR and RGAG1) from single-marker and rare variant aggregation tests. We describe population structure and functional annotation of rare and low-frequency variants, use the data to estimate the benefits of sequencing for association studies, and summarize lessons from disease-specific collections. Finally, we make available an extensive resource, including individual-level genetic and phenotypic data and web-based tools to facilitate the exploration of association results. Low read depth sequencing of whole genomes and high read depth exomes of nearly 10,000 extensively phenotyped individuals are combined to help characterize novel sequence variants, generate a highly accurate imputation reference panel and identify novel alleles associated with lipid-related traits; in addition to describing population structure and providing functional annotation of rare and low-frequency variants the authors use the data to estimate the benefits of sequencing for association studies. This paper, combining data and initial findings from the different arms of the UK10K project, describes insights from low-read-depth sequencing of whole genomes or high-read-depth exome sequencing of nearly 10,000 individuals sampled from a range of disease collections, as well as participants from healthy population based cohorts. The authors characterize novel sequence variants, generate a highly accurate imputation reference panel and identify novel alleles associated with lipid-related traits. In addition to describing population structure and providing functional annotation of rare and low frequency variants, they use the data to estimate the benefits of sequencing for association studies.

BACKGROUND: Osteoarthritis is the most common joint disease of adults worldwide. Its incidence rises with age. Both intrinsic and extrinsic risk factors promote its development. In men aged 60 to 64, the right knee is more commonly affected; in women, the right and left knees are affected with nearly equal frequency. METHODS: The PubMed, Medline, Embase and Cochrane Library databases were selectively searched for current studies (up to September 2009; case reports excluded) on the epidemiology, etiology, diagnosis, staging, and treatment of osteoarthritis of the knee. The search terms were "gonarthrosis," "prevention," "conservative treatment," "joint preservation," "physical activity," "arthroscopy," "osteotomy," "braces," "orthoses," and "osteoarthritis knee joint." RESULTS AND CONCLUSION: Osteoarthritis is not yet a curable disease, and its pathogenesis remains unclear. The best treatment for osteoarthritis of the knee is prevention. The goal of therapy is to alleviate clinical manifestations. The therapeutic spectrum ranges from physiotherapy and orthopedic aids to pharmacotherapy and surgery.

Imputing genotypes from reference panels created by whole-genome sequencing (WGS) provides a cost-effective strategy for augmenting the single-nucleotide polymorphism (SNP) content of genome-wide arrays. The UK10K Cohorts project has generated a data set of 3,781 whole genomes sequenced at low depth (average 7x), aiming to exhaustively characterize genetic variation down to 0.1% minor allele frequency in the British population. Here we demonstrate the value of this resource for improving imputation accuracy at rare and low-frequency variants in both a UK and an Italian population. We show that large increases in imputation accuracy can be achieved by re-phasing WGS reference panels after initial genotype calling. We also present a method for combining WGS panels to improve variant coverage and downstream imputation accuracy, which we illustrate by integrating 7,562 WGS haplotypes from the UK10K project with 2,184 haplotypes from the 1000 Genomes Project. Finally, we introduce a novel approximation that maintains speed without sacrificing imputation accuracy for rare variants.

Primary ciliary dyskinesia (PCD) is a hereditary disorder of mucociliary clearance causing chronic upper and lower airways disease. We determined the number of patients with diagnosed PCD across Europe, described age at diagnosis and determined risk factors for late diagnosis. Centres treating children with PCD in Europe answered questionnaires and provided anonymous patient lists. In total, 223 centres from 26 countries reported 1,009 patients aged < 20 yrs. Reported cases per million children (for 5-14 yr olds) were highest in Cyprus (111), Switzerland (47) and Denmark (46). Overall, 57% were males and 48% had situs inversus. Median age at diagnosis was 5.3 yrs, lower in children with situs inversus (3.5 versus 5.8 yrs; p < 0.001) and in children treated in large centres (4.1 versus 4.8 yrs; p = 0.002). Adjusted age at diagnosis was 5.0 yrs in Western Europe, 4.8 yrs in the British Isles, 5.5 yrs in Northern Europe, 6.8 yrs in Eastern Europe and 6.5 yrs in Southern Europe (p < 0.001). This strongly correlated with general government expenditures on health (p < 0.001). This European survey suggests that PCD in children is under-diagnosed and diagnosed late, particularly in countries with low health expenditures. Prospective studies should assess the impact this delay might have on patient prognosis and on health economic costs across Europe.

PURPOSE: The aim of the present study was to investigate the effects of a 6-wk multi-station proprioceptive exercise program that is easy to integrate in normal training programs. METHODS: Patients with chronic ankle instability were used, and results of three testing procedures before and afterward were compared: joint position sense, postural sway, and muscle reaction times to sudden inversion events on a tilting platform. A total of 30 subjects with 48 unstable feet were evaluated (exercise group: N = 31; control group: N = 17). RESULTS: In the exercise group, the results showed a significant improvement in joint position sense and postural sway as well as significant changes in muscle reaction times. CONCLUSION: Based on the present results, a multi-station proprioceptive exercise program can be recommended for prevention and rehabilitation of recurrent ankle inversion injuries.

AIMS: Dilated cardiomyopathy (DCM) is a major cause of heart failure with a high familial recurrence risk. So far, the genetics of DCM remains largely unresolved. We conducted the first genome-wide association study (GWAS) to identify loci contributing to sporadic DCM. METHODS AND RESULTS: One thousand one hundred and seventy-nine DCM patients and 1108 controls contributed to the discovery phase. Pools of DNA stratified on disease status, population, age, and gender were constituted and used for testing association of DCM with 517 382 single nucleotide polymorphisms (SNPs). Three DCM-associated SNPs were confirmed by individual genotyping (P < 5.0 10(-7)), and two of them, rs10927875 and rs2234962, were replicated in independent samples (1165 DCM patients and 1302 controls), with P-values of 0.002 and 0.009, respectively. rs10927875 maps to a region on chromosome 1p36.13 which encompasses several genes among which HSPB7 has been formerly suggested to be implicated in DCM. The second identified locus involves rs2234962, a non-synonymous SNP (c.T757C, p. C151R) located within the sequence of BAG3 on chromosome 10q26. To assess whether coding mutations of BAG3 might cause monogenic forms of the disease, we sequenced BAG3 exons in 168 independent index cases diagnosed with familial DCM and identified four truncating and two missense mutations. Each mutation was heterozygous, present in all genotyped relatives affected by the disease and absent in a control group of 347 healthy individuals, strongly suggesting that these mutations are causing the disease. CONCLUSION: This GWAS identified two loci involved in sporadic DCM, one of them probably implicates BAG3. Our results show that rare mutations in BAG3 contribute to monogenic forms of the disease, while common variant(s) in the same gene are implicated in sporadic DCM.

AIMS: In patients with persistent atrial fibrillation (AF), the efficacy and safety of two anti-arrhythmic drugs in preventing the recurrence of AF after successful direct current (DC) cardioversion was prospectively assessed in a multi-centre double-blind, placebo-controlled, randomised trial using daily trans-telephonic monitoring. METHODS AND RESULTS: 1182 patients with persistent AF were prospectively enrolled, 848 patients were successfully cardioverted and then randomised to either sotalol (383 patients), quinidine plus verapamil (377 patients) or placebo (88 patients). The primary outcome parameter was AF recurrence or death. All patients received an event recorder (Tele-ECG) and had to record and transmit via telephone at least one ECG per day during follow-up. The mean follow-up period was 266 days. A total of 191,103 Tele-ECGs were recorded and transmitted. The primary outcome parameter (AF recurrence of any kind or death) was observed in 572 patients (67%) in whom at least one episode of AF recurrence was documented during follow-up, in 348 patients (41%) AF recurrence was persistent. The recurrence rates after one year for any AF were 83% for placebo, 67% for sotalol and 65% for quinidine plus verapamil, the latter being statistically superior to placebo but not different from sotalol. The recurrence rates for the secondary outcome parameter persistent AF were 77%, 49% and 38%, respectively. Quinidine plus verapamil was significantly superior to placebo and to sotalol. About 95% of all AF recurrences were initially detected in the daily Tele-ECG, about 70% of all AF recurrences occurred completely asymptomatic. Adverse events on sotalol and quinidine plus verapamil were comparable with the exception that all torsade de pointes tachycardias occurred on sotalol. CONCLUSION: Anti-arrhythmic treatment after DC cardioversion of persistent AF significantly decreases the recurrence rates of persistent AF compared to placebo with superiority of quinidine plus verapamil compared to sotalol. Symptoms were not reliable as clinical surrogates to detect episodes of AF.

Leptin and insulin have been identified as fuel sensors acting in part through their hypothalamic receptors to inhibit food intake and stimulate energy expenditure. As their intracellular signaling converges at the PI3K pathway, we directly addressed the role of phosphatidylinositol3,4,5-trisphosphate-mediated (PIP3-mediated) signals in hypothalamic proopiomelanocortin (POMC) neurons by inactivating the gene for the PIP3 phosphatase Pten specifically in this cell type. Here we show that POMC-specific disruption of Pten resulted in hyperphagia and sexually dimorphic diet-sensitive obesity. Although leptin potently stimulated Stat3 phosphorylation in POMC neurons of POMC cell-restricted Pten knockout (PPKO) mice, it failed to significantly inhibit food intake in vivo. POMC neurons of PPKO mice showed a marked hyperpolarization and a reduction in basal firing rate due to increased ATP-sensitive potassium (KATP) channel activity. Leptin was not able to elicit electrical activity in PPKO POMC neurons, but application of the PI3K inhibitor LY294002 and the KATP blocker tolbutamide restored electrical activity and leptin-evoked firing of POMC neurons in these mice. Moreover, icv administration of tolbutamide abolished hyperphagia in PPKO mice. These data indicate that PIP3-mediated signals are critical regulators of the melanocortin system via modulation of KATP channels.

Reference intervals are a vital part of the information supplied by clinical laboratories to support interpretation of numerical pathology results such as are produced in clinical chemistry and hematology laboratories. The traditional method for establishing reference intervals, known as the direct approach, is based on collecting samples from members of a preselected reference population, making the measurements and then determining the intervals. An alternative approach is to perform analysis of results generated as part of routine pathology testing and using appropriate statistical techniques to determine reference intervals. This is known as the indirect approach. This paper from a working group of the International Federation of Clinical Chemistry (IFCC) Committee on Reference Intervals and Decision Limits (C-RIDL) aims to summarize current thinking on indirect approaches to reference intervals. The indirect approach has some major potential advantages compared with direct methods. The processes are faster, cheaper and do not involve patient inconvenience, discomfort or the risks associated with generating new patient health information. Indirect methods also use the same preanalytical and analytical techniques used for patient management and can provide very large numbers for assessment. Limitations to the indirect methods include possible effects of diseased subpopulations on the derived interval. The IFCC C-RIDL aims to encourage the use of indirect methods to establish and verify reference intervals, to promote publication of such intervals with clear explanation of the process used and also to support the development of improved statistical techniques for these studies.

Unidirectional fluid flow plays an essential role in the breaking of left-right (L-R) symmetry in mouse embryos, but it has remained unclear how the flow is sensed by the embryo. We report that the Ca(2+) channel Polycystin-2 (Pkd2) is required specifically in the perinodal crown cells for sensing the nodal flow. Examination of mutant forms of Pkd2 shows that the ciliary localization of Pkd2 is essential for correct L-R patterning. Whereas Kif3a mutant embryos, which lack all cilia, failed to respond to an artificial flow, restoration of primary cilia in crown cells rescued the response to the flow. Our results thus suggest that nodal flow is sensed in a manner dependent on Pkd2 by the cilia of crown cells located at the edge of the node.

We sketch the semiclassical core of a proof of the so-called Bohigas-Giannoni-Schmit conjecture: A dynamical system with full classical chaos has a quantum energy spectrum with universal fluctuations on the scale of the mean level spacing. We show how in the semiclassical limit all system specific properties fade away, leaving only ergodicity, hyperbolicity, and combinatorics as agents determining the contributions of pairs of classical periodic orbits to the quantum spectral form factor. The small-time form factor is thus reproduced semiclassically. Bridges between classical orbits and (the nonlinear sigma model of) quantum field theory are built by revealing the contributing orbit pairs as topologically equivalent to Feynman diagrams.

INTRODUCTION: Infection of the spinal column is rare, and often recognized and treated too late. Spondylodiscitis is osteomyelitis of the spine and can cause severe symptoms. Hospital mortality is in the region of 2% to 17%. METHODS: Selective literature review and results of the authors' own research. RESULTS: The incidence of pyogenic spondylodiscitis is around 1 : 250 000, which represents around 3% to 5% of osteomyelitis as a whole. 10% to 15% of all vertebral infections can be ascribed to exogenous spondylodiscitis, with Staphylococcus aureus as the commonest pathogen, 2% to 16% of which are reported to be MRSA (methicillin-resistant S. aureus). Catheter-related, nosocomial infection with MRSA is a key cause for spondylodiscitis. 50% of all skeletal tuberculoses are found in the spine. DISCUSSION: Spondylodiscitis should be borne in mind in cases of diffuse back pain and non-specific symptoms. MRI is the diagnostic modality of choice for detecting spondylodiscitis. Thanks to precise monitoring of conservative treatments and primarily stable surgical techniques, prolonged immobilization of the patient is no longer necessary nowadays.

Received from the Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland.OPTIMAL postoperative pain relief may facilitate patients’ recovery. 1However, identification of the optimal perioperative treatment remains elusive, in part because the specific mechanisms leading to enhanced sensitivity to pain (allodynia and hyperalgesia) in postoperative patients is unclear. 1,2Recent studies using a rat model of postoperative pain 3indicate that pain and hyperalgesia after an incision has unique characteristics. 4For instance, ongoing input from the wound, not the afferent barrage during the injury, maintains sensitization of dorsal horn neurons and hyperalgesia after the incision. 5Hence, peripheral sensitization, for example, sensitization of Aδ- and C-fibers, 6might be necessary for mechanical hyperalgesia to occur after incision. The underlying molecular mechanisms involved in the sensitization processes after incision are, however, still unknown. Because transgenic mice lacking a single protein are potential instruments for further research, we created in the present study a mouse model of incision-induced pain behaviors.Adult male 20- to 30-g C3H/He mice (Harlan, Indianapolis, IN) were used in the experiments in accordance with the Ethical Guidelines for Investigations of Experimental Pain in Conscious Animals. 7Mice were maintained on a 12-h light–dark cycle with food and water available ad libitum . At the end of the experiments, all mice were euthanized with an overdose of pentobarbital. The Johns Hopkins Animal Care and Use Committee approved the protocols.Mice were anesthetized with 1.5% to 2% isoflurane delivered via a nose cone. After antiseptic preparation of the right hind paw with 10% povidone–iodine solution (Betadine Solution, Purdue Frederick, Norwalk, CT), a 5-mm longitudinal incision was made with a no. 11 blade through the skin and fascia of the plantar foot. The incision was started 2 mm from the proximal edge of the heel and extended toward the toes. The underlying muscle was elevated with a curved forceps, leaving the muscle origin and insertion intact. The skin was apposed with a single mattress suture of 8-0 nylon on a TG175-8 needle (ophthalmic, 1716G; Ethicon, Somerville, NJ), and the wound was covered with antibiotic ointment (Bacitracin Zinc Ointment USP, Fougera & Co., New York, NY). The suture was removed at the end of postoperative day 2.Control mice underwent a sham procedure that consisted of anesthesia, antiseptic preparation, and topical antibiotics without an incision.Individual mice were placed on an elevated plastic mesh floor and were covered with a clear Plexiglas chamber (5 × 5 × 8 cm). After acclimation for 20 to 30 min, withdrawal responses to punctate mechanical stimuli were determined using calibrated von Frey filaments (0.07-, 0.17-, 0.40-, 0.60-, 1.04-, 1.37-, and 2.0-g bending force; Stoelting, Wood Dale, IL). Each monofilament was applied five times to the plantar aspect of the right hind paw adjacent to the incision for approximately 1 s with a 10-s interval between stimulus presentations, starting with a force of 0.07 g and continuing in ascending order. A stimulus-related withdrawal of the tested paw was considered a withdrawal response. The paw withdrawal frequency (PWF) to each force was calculated from five applications (0–100%). The paw withdrawal threshold (PWT) was considered the force at which withdrawal occurred at least 3 times (response frequency ≥60%); 3.6 g was recorded as the PWT if less than 3 responses to all filaments occurred.Paw withdrawal latencies (PWL) to heat were determined in a manner similar to that described previously. 8Each mouse was placed on a preheated glass platform (28–29.8°C) within the plastic chamber. After acclimation for 20 to 30 min, a radiant heat source was focused from underneath the glass to the middle of the incision area. The time required to cause withdrawal of the hind paw from the thermal stimulus was measured to the nearest 0.1 s (cutoff time 20 s). The results of three trials 5 to 10 min apart provided the average PWL.For mechanical testing, 15 mice were habituated for 3 consecutive days by placing them on the mesh within the test chamber. On the second and third habituation days, mechanical stimuli were applied using the sequence described previously; withdrawal responses assessed on the third habituation day were used to calculate baseline PWF and PWTs before incision/sham procedure. On the day of the experiment, mice were randomly assigned to receive a plantar incision (incision group, n = 8) or sham procedure (control group, n = 7); withdrawal responses were tested 2, 4, and 6 h after the incision/sham procedure and once a day until postoperative day 8.To assess responses to radiant heat after the incision/sham procedure, 17 other mice were habituated on a heated platform for 3 days; pretesting 2 days and 1 day (pre) before a plantar incision (incision group, n = 8) or a sham procedure (control group, n = 9) was made. Thermal-evoked responses were tested 2 and 6 h after incision and once a day for the next 9 days.Twenty other mice were habituated similarly as described; to randomize the effects of previous testing, 10 mice were tested for their response to radiant heat and the other 10 were tested by applying mechanical stimuli first. On the day of the experiment, a plantar incision was made in the right hind paw. After a recovery period of 2 h, mechanical and heat testing were performed (time 0) in the order used to determine baseline in each mouse. At 3 h after the incision, the mice were randomly assigned to receive morphine (3 or 10 mg per kg body weight; Abbott Laboratories, Abbott Park, IL) or a saline vehicle subcutaneously. Responses to mechanical and heat stimuli were determined 30, 90, 150, 210, and 270 min after administration of morphine. The experimenter was blinded to the substance (vehicle, morphine) and dose that was injected.PWLs to heat were compared by a two-way analysis of variance (ANOVA). PWTs and PWFs to von Frey filaments were analyzed using nonparametric tests. We used Friedman's test for within-group analysis and the Kruskal-Wallis and Wilcoxon-Mann-Whitney tests for between-group comparisons. In addition, we used a two-tailed Dunnett's test to make multiple comparisons following Friedman's test and a two-tailed Dunn's test for these comparisons following the Kruskal-Wallis test. Data in the text are expressed as median or mean ± standard deviation when appropriate. P < 0.05 was considered statistically significant.Throughout the experimental period, all mice remained well-groomed and maintained normal food and water intake. Signs of spontaneous pain behaviors such as licking, biting, and flinching after plantar incision in mice were not obvious. Guarding behavior and impaired weight bearing of the incised hind limb occurred only initially in mice after incision.In control mice, PWFs to Frey filaments before and after the sham procedure were stable (fig. 1A). In the incision group, mean PWFs to the 0.4-g, 1.04-g, and 2.0-g filaments increased from 0 ± 0%, 10 ± 19%, and 38 ± 20% before to 43 ± 20%, 88 ± 19%, and 100 ± 0% 2 h after incision (P < 0.05 vs. pre and sham) and remained increased for 6 h (2.0 g) and throughout postincision day 1 (0.4 g, 1.04;fig. 1B).Median PWTs in control mice were 3.6 g before and after the sham procedure (fig. 1C). In the incision group, median PWTs decreased from 3.6 g before to ≤ 0.6 g 2 h to 1 day after incision (P < 0.05 vs. pre and sham;fig. 1D).Mean PWLs to radiant heat were stable before and after the sham procedure (fig. 2). Mean PWLs to radiant heat decreased from 11.1 ± 1.8 s before to 2.3 ± 0.5 s and 1.7 ± 0.5 s 2 and 6 h after incision and remained decreased for 7 days (P < 0.05 vs. pre and sham;fig. 2).In saline-treated mice, median PWTs to von Frey filaments decreased from 3.6 g before to 0.6 g 2 h after incision and remained decreased throughout the day of surgery (fig. 3A). Subcutaneous morphine attenuated the reduction in PWTs after incision in mice; after 10 mg morphine, median PWTs increased from 0.4 g 2 h after incision (time 0) to 3.6 g 30 min after injection (P < 0.05 vs. vehicle and time 0;fig. 3B and C). Morphine dose-dependently reversed the reduced PWLs to heat after plantar incision in mice. PWLs increased for 30 min after 3 mg morphine and for 90 min after 10 mg morphine (P < 0.05 vs. vehicle and time 0;fig. 3D).Plantar incision in mice enhances responsiveness to mechanical and thermal stimuli that are indicative of primary mechanical and thermal hyperalgesia. Alterations are characterized by increased PWFs and reduced PWTs to punctate mechanical stimuli for 2 days and by reduced PWLs to radiant heat for 7 days. Primary mechanical and heat hyperalgesia after incision in mice is blocked by systemic morphine, a common analgesic to manage postoperative pain. Our observations indicate that the mouse model of incision-induced pain could be a reliable, useful tool to investigate the mechanisms of postoperative pain in genetically modified mice.The mouse incision model described here was adapted from a well-established rat model of incisional pain developed by Brennan et al. 3Because mice are physiologically and behaviorally distinct from rats, 9,10some modifications were required to establish the model in mice. The length of the incision, for example, was 5 mm in the mouse versus 10 mm in the rat, and the incision was closed with one mattress suture (size 8-0) instead of the two used in the rats. Furthermore, the investigation of responses to punctate mechanical stimuli after incision in the mouse was modified from studies in rats after incision. In a preliminary experiment, we tested several different methods, including the one used in rats after incision 3,8and the Dixon up and down method modified for mice. 11However, a new sequence similar to one recently used by us and others in mice to study mechanical hyperalgesia was the most reliable and produced reproducible responses in mice after incision. 12–16As described in Materials and Methods, seven von Frey filaments were applied five times each in an ascending sequence after incision in mice. Testing was continued regardless of whether withdrawal occurred. This could limit reduced withdrawal thresholds as a result of rewarding and learning after repeated testing in mice. Because withdrawal to the monofilaments was not increased in mice after the sham procedure, increased response frequencies and threshold reduction in mice after plantar incision is most likely the result of the incision injury. This method also allowed us to calculate PWFs to each filament force and PWTs in mice after incision as two reliable ways to quantify primary mechanical hyperalgesia after incision in mice.The absolute PWTs before and after incision are considerably lower in mice as compared with rats. 3,8However, this corresponds with the substantially lower force needed to excite nociceptors in uninjured glabrous skin of mice (1 g for A-delta and 2.4 g for C-fiber nociceptors 17vs. rats (approximately 5 g for A-delta and 8 g for C-fiber nociceptors). 18In fact, the relative magnitude of primary mechanical hyperalgesia after plantar incision in mice and in rats is very similar; PWTs dropped well below the response threshold of nociceptors in glabrous skin of mice and rats. 17,18PWTs to punctate mechanical stimuli are reduced for 2 days in mice; this is similar to the primary punctate mechanical hyperalgesia after plantar incision in rats that usually lasts 3 days after plantar incision. 3,8Responses to heat stimulus in mice were assessed using methods similar to those described in rats. 8In mice, a marked reduction in PWLs to radiant heat (from 11.1 s before incision to 1.7 s at 6 h after incision) occurs, indicating the development of a profound primary heat hyperalgesia after incision. Primary hyperalgesia to heat lasts until postincision day 7 and, therefore, longer than primary hyperalgesia to mechanical stimuli after incision. In conclusion, the magnitude and time course of primary mechanical and heat hyperalgesia after plantar incision in mice and rats are similar 3,8but differ from that of other animal pain models, 10,11,19,20indicating either a quantitative or qualitative difference in the underlying mechanisms.Punctate mechanical hyperalgesia around a surgical incision in postoperative patients has been demonstrated. Furthermore, pain exacerbated by coughing or movement, which could reflect mechanical hyperalgesia, is very common in patients after surgery and could impair postoperative recovery. 1,2,21–23Therefore, mechanical evoked pain after surgery is important for postoperative pain, and the underlying mechanisms must be studied to improve postoperative analgesia and the outcome of patients after surgery.Only few studies have investigated changes in the responsiveness to heat around a surgical incision in postoperative patients. In one study, pain thresholds to a heat stimulus applied adjacent to the wound are reduced in patients after cholecystectomy and inguinal hernioplasty. 24Because cooling a surgical wound reduces spontaneous pain after surgery, 25changes in heat sensitivity after a surgical incision might be important for postoperative pain. However, the role and underlying mechanisms of thermal hyperalgesia for postoperative pain is not yet known.In conclusion, the mouse incision model could be a useful tool to study the neurobiologic mechanisms of pain after surgery, for example, the role of single proteins/receptors in postoperative pain using genetically modified mice.

The ob gene product leptin (OB) is a feedback signal from the adipocyte to the hypothalamus and is involved in regulation of food intake and energy expenditure in rodents. A major determinant of serum OB levels is fat mass. Several studies suggest that men have lower OB levels than women even after adjustment for percent body fat. We, therefore, investigated the influence of testosterone (T) substitution in hypogonadal men on serum OB levels. Hypogonadal men with T levels of 3.6 nmol/L or less and off substitution therapy for at least 3 months were assigned to two treatment groups: testosterone enanthate (TE; 250 mg, i.m., every 21 days; n = 10) or a single s.c. implantation of 1200 mg crystalline T (TPEL; n = 12). Blood samples for determination of T, 5 alpha-dihydrotestosterone (DHT), sex hormone-binding globulin, and 17 beta-estradiol were obtained before therapy and then every 21 days until day 189 and at follow-up visits on days 246 and 300. Serum OB levels were assessed on days 0, 42, 84, 126, 168, and 300. OB levels were referred to a normal range for men based on the analysis of OB levels in 393 adult men. Substitution with T led to a large rise in T and DHT in both groups compared to baseline values (average T, days 21-189: TE, 14.33 +/- 2.63 nmol/L; TPEL, 24.98 +/- 1.64; average DHT, days 21-189: TE, 4.20 +/- 0.57 nmol/L; TPEL, 5.11 +/- 0.56; P < or = 0.05). Concomitantly, 17 beta-estradiol increased in both groups, and sex hormone-binding globulin levels were significantly decreased. At baseline, serum OB levels in hypogonadal men were 3-fold elevated compared to those in normal men (12.39 +/- 2.93 micrograms/L vs. 4.28 +/- 0.52; P < 0.01) and not different between groups (TE, 13.7 +/- 5.6; TPEL, 11.3 +/- 2.9 micrograms/L). This elevation was retained after adjustment for body mass index in the normal control group [TE, 1.45 +/- 0.51 SD score (P < 0.0001); TPEL, 0.98 +/- 0.35 SD score (P < 0.0008)]. During T substitution serum OB was completely normalized (trough levels: TE, 4.6 +/- 1.0 micrograms/L; TPEL 4.3 +/- 0.9 micrograms/L). In multiple regression analysis, the androgen (T plus DHT)/estrogen ratio was the only significant determinant of OB levels (r = -0.32; P < 0.01). At baseline, OB levels did not correlate with body mass index, but during substitution, the correlation was considerably improved. We conclude that hypogonadal men exhibit elevated OB levels that are normalized by substitution with T. The only determinant of OB levels was the androgen/estrogen ratio, indicating a major influence of sex steroids on OB production. The interaction of T and OB might be part of a hypothalamic-pituitary-gonadal-adipose tissue axis that is involved in body weight maintenance and reproductive function.

In awake spontaneously breathing mice, inhaling gaseous hydrogen sulfide (H2S) produced a "suspended animation-like" metabolic status with hypothermia and reduced O2 demand, thus protecting from lethal hypoxia. Murine models may be questioned, however, because due to their large surface area/mass ratio, rodents can rapidly drop their core temperature. Therefore, we investigated whether intravenous H2S (Na2S, sodium sulfide) would induce a comparable metabolic response in anesthetized and mechanically ventilated pigs. Because H2S was reported to improve heart function after myocardial ischemia, we also investigated whether sulfide would influence the noradrenaline responsiveness during reperfusion after aortic occlusion. After 2 h of i.v. sulfide (0.2 mg.kg followed by 2 mg.kg.per h; n=8) or vehicle (n=8), animals underwent 30 minutes of aortic occlusion with nitroglycerine, esmolol, and adenosine-5'-triphosphate adjusted to maintain MAP at 80% to 120% of baseline. During reperfusion, noradrenaline was titrated to keep MAP greater than or equal to 80% of this level. Sulfide reduced heart rate and cardiac output without affecting stroke volume, markedly decreased the time and dose of noradrenaline required to maintain hemodynamic targets, and caused a drop in core temperature concomitant with lower O2 uptake and CO2 production. Although arterial PCO2 and acid-base status were comparable, arterial PO2 was lower in the sulfide group at the end of the experiment. Sulfide attenuated the reperfusion-related hyperlactatemia, although glycemia was higher at the end of the experiment. The parameters of inflammation and oxidative stress did not differ. Intravenous sulfide allowed reducing energy expenditure in an anesthetized large-animal model and improved the noradrenaline responsiveness during reperfusion after aortic occlusion. Investigations are warranted, hence, whether it may also protect other organs after I/R injury.

The orphan transporter hORCTL3 (human organic cation transporter like 3; SLC22A13) is highly expressed in kidneys and to a weaker extent in brain, heart, and intestine. hORCTL3-expressing Xenopus laevis oocytes showed uptake of [3H]nicotinate, [3H]p-aminohippurate, and [14C]urate. Hence, hORCTL3 is an organic anion transporter, and we renamed it hOAT10. [3H]Nicotinate transport by hOAT10 into X. laevis oocytes and into Caco-2 cells was saturable with Michaelis constants (Km) of 22 and 44 μm, respectively, suggesting that hOAT10 may be the molecular equivalent of the postulated high affinity nicotinate transporter in kidneys and intestine. The pH dependence of hOAT10 suggests p-aminohippurate–/OH–, urate–/OH–, and nicotinate–/OH– exchange as possible transport modes. Urate inhibited [3H]nicotinate transport by hOAT10 with an IC50 value of 759 μm, assuming that hOAT10 represents a low affinity urate transporter. hOAT10-mediated [14C]urate uptake was elevated by an exchange with l -lactate, pyrazinoate, and nicotinate. Surprisingly, we have detected urate–/glutathione exchange by hOAT10, consistent with an involvement of hOAT10 in the renal glutathione cycle. Uricosurics, diuretics, and cyclosporine A showed substantial interactions with hOAT10, of which cyclosporine A enhanced [14C]urate uptake, providing the first molecular evidence for cyclosporine A-induced hyperuricemia. The orphan transporter hORCTL3 (human organic cation transporter like 3; SLC22A13) is highly expressed in kidneys and to a weaker extent in brain, heart, and intestine. hORCTL3-expressing Xenopus laevis oocytes showed uptake of [3H]nicotinate, [3H]p-aminohippurate, and [14C]urate. Hence, hORCTL3 is an organic anion transporter, and we renamed it hOAT10. [3H]Nicotinate transport by hOAT10 into X. laevis oocytes and into Caco-2 cells was saturable with Michaelis constants (Km) of 22 and 44 μm, respectively, suggesting that hOAT10 may be the molecular equivalent of the postulated high affinity nicotinate transporter in kidneys and intestine. The pH dependence of hOAT10 suggests p-aminohippurate–/OH–, urate–/OH–, and nicotinate–/OH– exchange as possible transport modes. Urate inhibited [3H]nicotinate transport by hOAT10 with an IC50 value of 759 μm, assuming that hOAT10 represents a low affinity urate transporter. hOAT10-mediated [14C]urate uptake was elevated by an exchange with l -lactate, pyrazinoate, and nicotinate. Surprisingly, we have detected urate–/glutathione exchange by hOAT10, consistent with an involvement of hOAT10 in the renal glutathione cycle. Uricosurics, diuretics, and cyclosporine A showed substantial interactions with hOAT10, of which cyclosporine A enhanced [14C]urate uptake, providing the first molecular evidence for cyclosporine A-induced hyperuricemia. The kidneys represent one avenue for the secretion of a large number of charged molecules. Among these are metabolites as well as exogenous substances such as drugs and environmental toxins, which are substrates for transporters of a family called solute carrier (SLC) 2The abbreviations used are: SLC, solute carrier; OAT, organic anion transporter; OCT, organic cation transporter; PAH, p-aminohippurate; CCD, cortical collecting duct; SMCT1, sodium-coupled monocarboxylate transporter; URAT1, urate transporter 1; PBS, phosphate-buffered saline; RT, reverse transcription; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; BBMV, brush border membrane vesicle; BLMV, basolateral membrane vesicle; HCTZ, hydrochlorothiazide; ES, estrone sulfate. family 22A. This transporter family consists of organic anion transporters (OATs), organic cation transporters (OCTs), and zwitterion transporters. In the last decade, many members of these three subfamilies were identified and functionally characterized (for review see Refs. 1Wright S.H. Dantzler W.H. Physiol. Rev. 2004; 84: 987-1049Crossref PubMed Scopus (349) Google Scholar, 2Rizwan A.N. Burckhardt G. Pharm. Res. 2007; 24: 450-470Crossref PubMed Scopus (220) Google Scholar, 3Anzai N. Kanai Y. Endou H. J. Pharmacol. Sci. 2006; 100: 411-426Crossref PubMed Scopus (194) Google Scholar). However, some proteins, which were classified under the SLC22 family, e.g. ORCTL3, ORCTL4, FLIPT1, or BOCT, have still not been characterized and are called orphan transporters (4Hediger M.A. Romero M.F. Peng J.B. Rolfs A. Takanaga H. Bruford E.A. Pfluegers Arch. Eur. J. Physiol. 2004; 447: 465-468Crossref PubMed Scopus (740) Google Scholar). 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Niwa T. Kanai Y. Endou H. Nature. 2002; 417: 447-452Crossref PubMed Scopus (1162) Google Scholar)). Most of these are highly expressed in the kidneys (OAT1-OAT4, Oat5, Oatv1, and URAT1), whereas Oat6 is only expressed in the olfactory bulb, and the recently identified human OAT7 is currently the only liver-specific OAT. The substrate panel of OATs includes important endogenous compounds like urate (15Enomoto A. Kimura H. Chairoungdua A. Shigeta Y. Jutabha P. Ho C.S. Hosoyamada M. Takeda M. Sekine T. Igarashi T. Matsuo H. Kikuchi Y. Oda T. Ichida K. Hosoya T. Shimokata K. Niwa T. Kanai Y. Endou H. Nature. 2002; 417: 447-452Crossref PubMed Scopus (1162) Google Scholar, 16Hagos Y. Stein D. Ugele B. Burckhardt G. Bahn A. J. Am. Soc. Nephrol. 2007; 18: 430-439Crossref PubMed Scopus (206) Google Scholar, 17Bakhiya N. Bahn A. Burckhardt G. Wolff N. Cell Physiol. Biochem. 2003; 13: 249-256Crossref PubMed Scopus (138) Google Scholar), prostaglandins (18Kimura H. Takeda M. Narikawa S. Enomoto A. Ichida K. Endou H. J. Pharmacol. Exp. Ther. 2002; 301: 293-298Crossref PubMed Scopus (156) Google Scholar), neurotransmitter and tryptophan metabolites (19Alebouyeh M. Takeda M. Onozato M.L. Tojo A. Noshiro R. Hasannejad H. Inatomi J. Narikawa S. Huang X.L. Khamdang S. Anzai N. Endou H. J. Pharmacol. Sci. 2003; 93: 430-436Crossref PubMed Scopus (88) Google Scholar, 20Bahn A. Ljubojevic M. Lorenz H. Schultz C. Ghebremedhin E. Ugele B. Sabolic I. Burckhardt G. Hagos Y. Am. J. Physiol. 2005; 289: C1075-C1084Crossref PubMed Scopus (76) Google Scholar), sulfated steroids, and a long list of drugs such as anti-viral drugs, antibiotics, antidotes (21Bahn A. Knabe M. Hagos Y. Rodiger M. Godehardt S. Graber-Neufeld D.S. Evans K.K. Burckhardt G. Wright S.H. Mol. Pharmacol. 2002; 62: 1128-1136Crossref PubMed Scopus (45) Google Scholar), or diuretics (22Hagos Y. Bahn A. Vormfelde S.V. Brockmoller J. Burckhardt G. J. Am. Soc. Nephrol. 2007; 18: 3101-3109Crossref PubMed Scopus (33) Google Scholar, 23Hasannejad H. Takeda M. Taki K. Shin H.J. Babu E. Jutabha P. Khamdang S. Aleboyeh M. Onozato M.L. Tojo A. Enomoto A. Anzai N. Narikawa S. Huang X.L. Niwa T. Endou H. J. Pharmacol. Exp. Ther. 2004; 308: 1021-1029Crossref PubMed Scopus (160) Google Scholar, 24Burckhardt B.C. Burckhardt G. Rev. Physiol. Biochem. Pharmacol. 2003; 146: 95-158Crossref PubMed Scopus (261) Google Scholar). hORCTL3 (human organic cation transporter like 3) was first described in 1998 together with hORCTL4 on chromosome 3p21.3 and noted to be ubiquitously expressed with some preference for kidneys, small intestine, and colon as detected by Northern blot analysis (25Nishiwaki T. Daigo Y. Tamari M. Fujii Y. Nakamura Y. Cytogenet. Cell Genet. 1998; 83: 251-255Crossref PubMed Scopus (29) Google Scholar). It was speculated that hORCTL3 may function as a polyspecific organic cation transporter in several tissues. However, protein sequence alignments of all known OCTs and OATs, including the nonclassified orphan transporters listed in solute carrier family 22 (SLC22) revealed several highly conserved amino not the of these amino we that hORCTL3 is an organic anion transporter. In the we have the of the orphan transporter human have that hORCTL3 is highly expressed the of renal cells in a we evidence that hORCTL3 is a urate and the first identified high affinity nicotinate in kidneys and intestine. we renamed hORCTL3 hOAT10 (human organic anion transporter we the first molecular for a cyclosporine A-induced of urate by hOAT10. used and and substrates were by was by and were of the expressed sequence which we the into number an and the X. Google Scholar) revealed the of the hOAT10. of several were Caco-2 cells was with to the of was reverse in a of for of the was used in a with and as a (for hOAT10 (for hOAT10 in Caco-2 and (for for (for or (for for and for by a for were on a and and a of human and these were as described A. A. H. E. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). was and the to the and the sequence in the of the protein which is highly conserved the hOAT10 for for and for was in and the was border and basolateral membrane and rat kidneys were as described Wolff N.A. Burckhardt G. Pfluegers Arch. Eur. J. Physiol. 2000; PubMed Scopus Google Scholar, H. B. Burckhardt G. Am. J. Physiol. Google Scholar). protein was of the The protein was in of the and protein was to the Biochem. PubMed Scopus Google Scholar). of the for protein of was on a by an for and a blot to a membrane the membrane was for in in and in and which was by the for in a as a The was by the for three with PBS, the were the and Xenopus laevis laevis oocytes of and were and by with in pH were with of or which was in to the the oocytes were for in pH with of hOAT10 in X. laevis were for the in in the The oocytes were in uptake and in of X. laevis oocytes were or with of of pyrazinoate, l -lactate, cyclosporine or as a and the uptake of with was for Cell and human colon Caco-2 was in with in or in a transport the cells were a of were on in and pH The cells were with of and in [3H]nicotinate and the substances for In all of the the and were of the with of by and the of the urate that of [3H]nicotinate uptake the was used and by with is the of [3H]nicotinate uptake in the of the is the of [3H]nicotinate uptake in the of the to is the and is the the the substances and the transporter. The uptake of [3H]nicotinate transport in oocytes that in was a saturable function of substrate that was described by the for of and substrate C. A. J. Biol. PubMed Scopus Google Scholar), is the of [3H]nicotinate transport a of substrate to is the of [3H]nicotinate is the nicotinate that in transport Michaelis is the of nicotinate in the transport and is a that represents the of nicotinate uptake that is the of substrate and the of of the was used to analysis and were with and all of the an expressed sequence number was including the of the orphan transporter hORCTL3 which consists of for amino with a of to and were in the a of sequence or to the SLC22 family N. Kanai Y. Endou H. J. Pharmacol. Sci. 2006; 100: 411-426Crossref PubMed Scopus (194) Google Scholar), we hORCTL3 to hOAT10, of which are to be A of hOAT10 with all characterized members of the SLC22 family is in the that hOAT10 and only to the members of the SLC22 have the rat and the of the a panel of revealed a of the hOAT10 in the kidneys and weaker in brain, heart, and colon we detected several of hOAT10, which we by the cloning and of in and the hOAT10 in a of three and of a or all of not were detected in many a of hOAT10 and in of high of hOAT10 in and in cortical collecting whereas and of hOAT10 of hOAT10 in Caco-2 of a analysis of hOAT10 in Caco-2 cells is represents the molecular and the the of hOAT10. and 3) human and were used as and hOAT10 in rat or human we an a conserved an amino in to in the by not we is expressed in the or basolateral membrane of cells rat and blot analysis of protein of these showed a of a in BBMV, which was by the This molecular of hOAT10 well with the protein of was in BLMV, suggesting that renal hOAT10 is to the A of in and the with of protein showed a A of hOAT10 was in X. laevis oocytes substantial of for [14C]urate for and [3H]nicotinate for with of [3H]nicotinate was and for not was used for all of nicotinate hOAT10-mediated nicotinate uptake was saturable with a Michaelis of 22 that hOAT10 is a high affinity nicotinate transporter the affinity of hOAT10 for we an IC50 with nicotinate as a The urate of nicotinate transport was 759 μm, consistent with hOAT10 a low affinity urate transporter like in with the urate transporter Y. Stein D. Ugele B. Burckhardt G. Bahn A. J. Am. Soc. Nephrol. 2007; 18: 430-439Crossref PubMed Scopus (206) Google Scholar) analysis of nicotinate uptake by hOAT10. The of nicotinate on the uptake of [3H]nicotinate into X. laevis oocytes and into oocytes for and pH The are the of in three with oocytes The was a for urate nicotinate for hOAT10. The dependence of hOAT10-mediated uptake of [3H]nicotinate uptake in X. laevis oocytes of urate for is The represents the uptake of nicotinate by oocytes as a The are the of in three with oocytes The was a of hOAT10-mediated transport revealed a of uptake by urate and and highly for estrone and the of organic anion transport whereas and the substrate of organic cation not that hOAT10 is an the of uptake by ES, hOAT10 not transport not the pH dependence of hOAT10-mediated we as a substrate that not the pH of the uptake to pH to a in uptake with the uptake pH which was of the to pH in a of uptake to a pH dependence of hOAT10. on hOAT10-mediated [14C]urate uptake, of l -lactate, pyrazinoate, as a urate uptake by of these compounds is we of these substances in a of into oocytes and [14C]urate a of for all substances with the of suggesting that hOAT10 as well as exchange we the of hOAT10 with several diuretics, and the cyclosporine some of which are known to hyperuricemia. of the compounds [3H]nicotinate uptake by that may urate or nicotinate in of the of and cyclosporine A revealed enhanced urate uptake by oocytes for cyclosporine A not hOAT10-mediated urate uptake in with the of urate uptake by nicotinate we the of on hOAT10-mediated urate for the first that is by an OAT, hOAT10, urate uptake by a of it was that human as well as Caco-2 cells a high affinity nicotinate transporter M.L. 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Physiol. 2007; PubMed Scopus Google Scholar). hOAT10 an for glutathione not uptake it was the However, the revealed the first evidence that as a for urate into the we that hOAT10 is in the glutathione in the In we have identified a human organic anion transporter, hOAT10, that is a urate and the first known high affinity nicotinate transporter. we are to the first molecular evidence for cyclosporine A-induced of a hOAT10-mediated in urate the identified substrates of hOAT10 and and on function the for on transporter. G. and A. for and A. of for

) and cannabis dependence (International Classification of Diseases [ICD]-10). Several lines of evidence from animal and human studies indicate that cessation from long-term and regular cannabis use precipitates a specific withdrawal syndrome with mainly mood and behavioral symptoms of light to moderate intensity, which can usually be treated in an outpatient setting. Regular cannabis intake is related to a desensitization and downregulation of human brain cannabinoid 1 (CB1) receptors. This starts to reverse within the first 2 days of abstinence and the receptors return to normal functioning within 4 weeks of abstinence, which could constitute a neurobiological time frame for the duration of CWS, not taking into account cellular and synaptic long-term neuroplasticity elicited by long-term cannabis use before cessation, for example, being possibly responsible for cannabis craving. The CWS severity is dependent on the amount of cannabis used pre-cessation, gender, and heritable and several environmental factors. Therefore, naturalistic severity of CWS highly varies. Women reported a stronger CWS than men including physical symptoms, such as nausea and stomach pain. Comorbidity with mental or somatic disorders, severe CUD, and low social functioning may require an inpatient treatment (preferably qualified detox) and post-acute rehabilitation. There are promising results with gabapentin and delta-9-tetrahydrocannabinol analogs in the treatment of CWS. Mirtazapine can be beneficial to treat CWS insomnia. According to small studies, venlafaxine can worsen the CWS, whereas other antidepressants, atomoxetine, lithium, buspirone, and divalproex had no relevant effect. Certainly, further research is required with respect to the impact of the CWS treatment setting on long-term CUD prognosis and with respect to psychopharmacological or behavioral approaches, such as aerobic exercise therapy or psychoeducation, in the treatment of CWS. The up-to-date ICD-11 Beta Draft is recommended to be expanded by physical CWS symptoms, the specification of CWS intensity and duration as well as gender effects.

Abstract Learning Objectives After completing this course, the reader will be able to: Describe major enchondroma distribution patterns that were identified in this study.Identify variables that are predictive for the secondary transformation of enchondroma over the lifetime of individuals with Ollier disease or Maffucci syndrome. CME This article is available for continuing medical education credit at CME.TheOncologist.com Background. Enchondromatosis is characterized by the presence of multiple benign cartilage lesions in bone. While Ollier disease is typified by multiple enchondromas, in Maffucci syndrome these are associated with hemangiomas. Studies evaluating the predictive value of clinical symptoms for development of secondary chondrosarcoma and prognosis are lacking. This multi-institute study evaluates the clinical characteristics of patients, to get better insight on behavior and prognosis of these diseases. Method. A retrospective study was conducted using clinical data of 144 Ollier and 17 Maffucci patients from 13 European centers and one national databank supplied by members of the European Musculoskeletal Oncology Society. Results. Patients had multiple enchondromas in the hands and feet only (group I, 18%), in long bones including scapula and pelvis only (group II, 39%), and in both small and long/flat bones (group III, 43%), respectively. The overall incidence of chondrosarcoma thus far is 40%. In group I, only 4 patients (15%) developed chondrosarcoma, in contrast to 27 patients (43%) in group II and 26 patients (46%) in group III, respectively. The risk of developing chondrosarcoma is increased when enchondromas are located in the pelvis (odds ratio, 3.8; p = 0.00l). Conclusions. Overall incidence of development of chondrosarcoma is 40%, but may, due to age-dependency, increase when considered as a lifelong risk. Patients with enchondromas located in long bones or axial skeleton, especially the pelvis, have a seriously increased risk of developing chondrosarcoma, and are identified as the population that needs regular screening on early detection of malignant transformation.

We performed a multicentre retrospective cohort study including 606,649 acute inpatient episodes at 10 European hospitals in 2010 and 2011 to estimate the impact of antimicrobial resistance on hospital mortality, excess length of stay (LOS) and cost. Bloodstream infections (BSI) caused by third-generation cephalosporin-resistant Enterobacteriaceae (3GCRE), meticillin-susceptible (MSSA) and -resistant Staphylococcus aureus (MRSA) increased the daily risk of hospital death (adjusted hazard ratio (HR) = 1.80; 95% confidence interval (CI): 1.34-2.42, HR = 1.81; 95% CI: 1.49-2.20 and HR = 2.42; 95% CI: 1.66-3.51, respectively) and prolonged LOS (9.3 days; 95% CI: 9.2-9.4, 11.5 days; 95% CI: 11.5-11.6 and 13.3 days; 95% CI: 13.2-13.4, respectively). BSI with third-generation cephalosporin-susceptible Enterobacteriaceae (3GCSE) significantly increased LOS (5.9 days; 95% CI: 5.8-5.9) but not hazard of death (1.16; 95% CI: 0.98-1.36). 3GCRE significantly increased the hazard of death (1.63; 95% CI: 1.13-2.35), excess LOS (4.9 days; 95% CI: 1.1-8.7) and cost compared with susceptible strains, whereas meticillin resistance did not. The annual cost of 3GCRE BSI was higher than of MRSA BSI. While BSI with S. aureus had greater impact on mortality, excess LOS and cost than Enterobacteriaceae per infection, the impact of antimicrobial resistance was greater for Enterobacteriaceae.

OBJECTIVE: Reduction in red blood cell mass, as well as structural and functional alterations of erythrocytes, occurs in critical illness. This review discusses these changes in red blood cell physiology, emphasizing the pathogenesis of anemia in intensive care unit patients. DATA SOURCE: Studies published in biomedical journals. DATA SYNTHESIS AND CONCLUSION: Anemia in intensive care unit patients resembles the anemia of chronic disease, being characterized by diminished erythropoietin production relative to decreased hematocrit, altered iron metabolism, and impaired proliferation and differentiation of erythroid progenitors in the bone marrow. Inflammatory mediators play a major role in the development of insufficient erythropoiesis and altered iron metabolism. Furthermore, a proinflammatory milieu promotes structural and functional alterations of erythrocytes, impairing their deformability and possibly impairing microvascular perfusion. Collectively, these changes in red blood cell physiology can impair oxygen transport to tissues and, thereby, might contribute to the development of multiple organ failure in critical illness.