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Background: Oftentimes, obese dialysis patients develop a viable dialysis access but the access is too deep for cannulation and needs a superficialization procedure. Methods: We present our 14-patient cohort in whom we performed liposuction to superficialize viable but deep vascular accesses. Out of 14 patients, 12 had arteriovenous fistulas and 2 arteriovenous grafts. The primary end points were the ability to superficialize a completely unusable access and to remove the hemodialysis catheter (3patients), or to significantly extend the useful length of a deep access in which only a very short segment was used and to continue to use the access post-surgery without the need to place a dialysis catheter (11 patients). Results: The study goal was met in 13 out of 14 patients. In two of three patients, the catheters were removed and their access usable length was 14 and 13 cm, respectively. The accesses could be used immediately after liposuction in all patients in which this applied—11 patients. The usable access length increased from a mean of 5 to 12.7 cm. The access mean depth decreased from 10.8 mm pre-surgery to 7 mm post-surgery and 5.3 mm 4 weeks after surgery. The mean volume of fat removed was 43.8 cc. We had only one surgical complication: bleeding that was readily controlled with manual pressure. All patients were discharged to home the same day. Postoperative pain was mild. Conclusion: Liposuction is effective, safe, and seems to be the least invasive technique of superficialization.

Background This study aimed to investigate the implications of antinuclear antibodies (ANAs) in juvenile idiopathic arthritis (JIA), the association with uveitis and the favorable evolution of the disease. Methods We followed 45 pediatric patients suffering from JIA, according to the International League of Associations for Rheumatology (ILAR), for a period of 2 years. ANAs were followed through immunofluorescence methods using a high-performance immunofluorescence automatic Helios device. Results A total of 15 of the ANA-positive patients presented an oligoarticular form of the disease, eight of them presented a polyarticular form of the disease and two of them presented a systemic form. The most severe forms have associated iridocyclitis. ANA-positive patients presented an earlier onset of disease in comparison with ANA-negative ones. ANA-positive patients from different ILAR categories had similar characteristics of the disease such as onset age (earlier), higher prevalence in females and the presence of asymmetric arthritis or iridocyclitis. Conclusions ANA may be an important marker for JIA and association with iridocyclitis. Following ANA titer in evolution might be a criterion for assessing the evolution of the disease. The association between positive ANA, oligoarticular JIA, iridocyclitis and a 2- to 4-year-old onset is common.

TAAR1 is a neuroregulator with emerging evidence suggesting a role in immunomodulation. Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system. Here, we investigate TAAR1 expression in human primary monocytes, peripherally-derived macrophages, and MS brain tissue. RT-qPCR was used to assess TAAR1 levels in MS monocytes. Using a previously validated anti-human TAAR1 antibody and fluorescence microscopy, TAAR1 protein was visualized in lipopolysaccharide-stimulated or basal human macrophages, as well as macrophage/microglia populations surrounding, bordering, and within a mixed active/inactive MS lesion. In vivo, TAAR1 mRNA expression was significantly lower in MS monocytes compared to age- and sex-matched healthy controls. In vitro, TAAR1 protein showed a predominant nuclear localization in quiescent/control macrophages with a shift to a diffuse intracellular distribution following lipopolysaccharide-induced activation. In brain tissue, TAAR1 protein was predominantly expressed in macrophages/microglia within the border region of mixed active/inactive MS lesions. Considering that TAAR1-mediated anti-inflammatory effects have been previously reported, decreased mRNA in MS patients suggests possible pathophysiologic relevance. A shift in TAAR1 localization following pro-inflammatory activation suggests its function is altered in pro-inflammatory states, while TAAR1-expressing macrophages/microglia bordering an MS lesion supports TAAR1 as a novel pharmacological target in cells directly implicated in MS neuroinflammation.

BACKGROUND AND AIM: Portal vein thrombosis (PVT) is a common complication of cirrhosis. The exact pathophysiology remains largely unknown, and treatment with anticoagulants does not lead to recanalization of the portal vein in all patients. A better insight into the structure and composition of portal vein thrombi may assist in developing strategies for the prevention and treatment of PVT.APPROACH AND RESULTS: Sixteen prospectively and 63 retrospectively collected nonmalignant portal vein thrombi from patients with cirrhosis who underwent liver transplantation were included. Histology, immunohistochemistry, and scanning electron microscopy were used to assess structure and composition of the thrombi. Most recent CT scans were reanalyzed for thrombus characteristics. Clinical characteristics were related to histological and radiological findings. All samples showed a thickened, fibrotic tunica intima. Fibrin-rich thrombi were present on top of the fibrotic intima in 9/16 prospective cases and in 21/63 retrospective cases. A minority of the fibrotic areas stained focally positive for fibrin/fibrinogen (16% of cases), von Willebrand factor (VWF; 10%), and CD61 (platelets, 21%), while most of the fibrin-rich areas stained positive for those markers (fibrin/fibrinogen, 100%; VWF, 77%; CD61, 100%). No associations were found between clinical characteristics including estimated thrombus age and use of anticoagulants and presence of fibrin-rich thrombi.CONCLUSION: We demonstrate that PVT in patients with cirrhosis consists of intimal fibrosis with an additional fibrin-rich thrombus in only one-third of cases. We hypothesize that our observations may explain why not all portal vein thrombi in patients with cirrhosis recanalize by anticoagulant therapy.

Angelman syndrome (AS) is a neurodevelopmental disorder caused by the loss of maternal UBE3A, a ubiquitin protein ligase E3A. Here, we study neurons derived from patients with AS and neurotypical individuals, and reciprocally modulate UBE3A using antisense oligonucleotides. Unbiased proteomics reveal proteins that are regulated by UBE3A in a disease-specific manner, including PEG10, a retrotransposon-derived GAG protein. PEG10 protein increase, but not RNA, is dependent on UBE3A and proteasome function. PEG10 binds to both RNA and ataxia-associated proteins (ATXN2 and ATXN10), localizes to stress granules, and is secreted in extracellular vesicles, modulating vesicle content. Rescue of AS patient-derived neurons by UBE3A reinstatement or PEG10 reduction reveals similarity in transcriptome changes. Overexpression of PEG10 during mouse brain development alters neuronal migration, suggesting that it can affect brain development. These findings imply that PEG10 is a secreted human UBE3A target involved in AS pathophysiology.

Angelman syndrome (AS) is a severe neurodevelopmental disorder for which only symptomatic treatment with limited benefits is available. AS is caused by mutations affecting the maternally inherited ubiquitin protein ligase E3A (UBE3A) gene. Previous studies showed that the silenced paternal Ube3a gene can be activated by targeting the antisense Ube3a-ATS transcript. We investigated antisense oligonucleotide-induced (ASO-induced) Ube3a-ATS degradation and its ability to induce UBE3A reinstatement and rescue of AS phenotypes in an established Ube3a mouse model. We found that a single intracerebroventricular injection of ASOs at postnatal day 1 (P1) or P21 in AS mice resulted in potent and specific UBE3A reinstatement in the brain, with levels up to 74% of WT levels in the cortex and a full rescue of sensitivity to audiogenic seizures. AS mice treated with ASO at P1 also showed rescue of established AS phenotypes, such as open field and forced swim test behaviors, and significant improvement on the reversed rotarod. Hippocampal plasticity of treated AS mice was comparable to WT but not significantly different from PBS-treated AS mice. No rescue was observed for the marble burying and nest building phenotypes. Our findings highlight the promise of ASO-mediated reactivation of UBE3A as a disease-modifying treatment for AS.

Background Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by either disruptions of the gene UBE3A or deletion of chromosome 15 at 15q11-q13, which encompasses UBE3A and several other genes, including GABRB3, GABRA5, GABRG3, encoding gamma-aminobutyric acid type A receptor subunits ( β 3, α 5, γ 3). Individuals with deletions are generally more impaired than those with other genotypes, but the underlying pathophysiology remains largely unknown. Here, we used electroencephalography (EEG) to test the hypothesis that genes other than UBE3A located on 15q11-q13 cause differences in pathophysiology between AS genotypes. Methods We compared spectral power of clinical EEG recordings from children (1–18 years of age) with a deletion genotype (n = 37) or a nondeletion genotype (n = 21) and typically developing children without Angelman syndrome (n = 48). Results We found elevated theta power (peak frequency: 5.3 Hz) and diminished beta power (peak frequency: 23 Hz) in the deletion genotype compared with the nondeletion genotype as well as excess broadband EEG power (1–32 Hz) peaking in the delta frequency range (peak frequency: 2.8 Hz), shared by both genotypes but stronger for the deletion genotype at younger ages. Conclusions Our results provide strong evidence for the contribution of non-UBE3A neuronal pathophysiology in deletion AS and suggest that hemizygosity of the GABRB3-GABRA5-GABRG3 gene cluster causes abnormal theta and beta EEG oscillations that may underlie the more severe clinical phenotype. Our work improves the understanding of AS pathophysiology and has direct implications for the development of AS treatments and biomarkers.

Trace amine-associated receptor 1 (TAAR1) is a G-protein coupled receptor with affinity for the trace amines. TAAR1 agonists have pro-cognitive, antidepressant-, and antipsychotic-like properties in both rodents and non-human primates (NHPs). TAAR1 agonism also increases wakefulness and suppresses rapid-eye movement (REM) sleep in mice and rats and reduces cataplexy in two mouse models of narcolepsy. We investigated the effects of TAAR1 agonism in Cynomolgus macaques, a diurnal species that exhibits consolidated night-time sleep, and evaluated the effects of TAAR1 agonists on cognition using a working memory (WM) paradigm in this species. Adult male Cynomolgus macaques (n = 6) were surgically implanted to record the electroencephalogram (EEG), electromyogram, and locomotor activity (LMA) and the efficacy of the TAAR1 partial agonist RO5263397 (0.1,1,10 mg/kg, p.o.) on sleep/wake, EEG spectra, and LMA was determined. In a second experiment, the acute effects of RO5263397 (0.1,1,10 mg/kg, p.o.) were assessed on a delayed-match-to-sample test of WM in adult male macaques (n = 7). RO5263397 (10 mg/kg) administered at lights off, when sleep pressure was high, promoted wakefulness and reduced both REM and non-REM sleep without inducing hyperlocomotion. RO5263397 (10 mg/kg) also increased delta/theta activity during all vigilance states. RO5263397 had no effect on WM at either short (2 sec) or long (10 sec) delay intervals. The wake-enhancing and REM-suppressing effects of R05263397 shown here in a diurnal primate are consistent with previous results in nocturnal rodents. These effects and the associated alterations in EEG spectra occurred without inducing hyperlocomotion or affecting WM, encouraging further study of TAAR1 agonists as potential narcolepsy therapeutics.

BackgroundThe mechanisms driving acute kidney injury (AKI) in critically ill COVID-19 patients are unclear. We collected kidney biopsies from COVID-19 AKI patients within 30 min after death in order to examine the histopathology and perform mRNA expression analysis of genes associated with renal injury.MethodsThis study involved histopathology and mRNA analyses of postmortem kidney biopsies collected from patients with COVID-19 (n = 6) and bacterial sepsis (n = 27). Normal control renal tissue was obtained from patients undergoing total nephrectomy (n = 12). The mean length of ICU admission-to-biopsy was 30 days for COVID-19 and 3–4 days for bacterial sepsis patients.ResultsWe did not detect SARS-CoV-2 RNA in kidney biopsies from COVID-19-AKI patients yet lung tissue from the same patients was PCR positive. Extensive acute tubular necrosis (ATN) and peritubular thrombi were distinct histopathology features of COVID-19-AKI compared to bacterial sepsis-AKI. ACE2 mRNA levels in both COVID-19 (fold change 0.42,p = 0.0002) and bacterial sepsis patients (fold change 0.24,p p = 0.0006, PV-1 fold change 1.5,p = 0.008). Angiopoietin-1 mRNA levels were downregulated in renal tissue from both COVID-19 (fold change 0.27,p p p = 0.037) and a disturbed VEGFR2/VEGFR3 ratio (fold change 0.09,p ConclusionsIn a small cohort of postmortem kidney biopsies from COVID-19 patients, we observed distinct histopathological and gene expression profiles between COVID-19-AKI and bacterial sepsis-AKI. COVID-19 was associated with more severe ATN and microvascular thrombosis coupled with decreased microvascular flow, yet minimal inflammation. Further studies are required to determine whether these observations are a result of true pathophysiological differences or related to the timing of biopsy after disease onset.

In kidney transplantation, microthrombi and fibrin deposition may lead to local perfusion disorders and subsequently poor initial graft function. Microthrombi are often regarded as donor-derived. However, the incidence, time of development, and potential difference between living donor kidneys (LDK) and deceased donor kidneys(DDK), remains unclear. Two open-needle biopsies, taken at preimplantation and after reperfusion, were obtained from 17 LDK and 28 DDK transplanted between 2005 and 2008. Paraffin-embedded sections were immunohistochemically stained with anti-fibrinogen antibody. Fibrin deposition intensity in peritubular capillaries(PTC) and glomeruli was categorized as negative, weak, moderate or strong and the number of microthrombi/mm2 was quantified. Reperfusion biopsies showed more fibrin deposition (20–100% moderate/strong, p 2 (0.97 ± 1.12 vs. 0.28 ± 0.53, p 2 (0.38 ± 0.61 vs. 0.09 ± 0.22, p = 0.02) and stronger fibrin intensity in glomeruli (28% vs. 0%, p 2 were comparable (p = 0.23) for LDK (0.09 ± 0.22 to 0.76 ± 0.49, p = 0.03) and DDK (0.38 ± 0.61 to 0.90 ± 1.11, p = 0.07). Upon reperfusion, there is an aggravation of microthrombus formation and fibrin deposition within the graft. The prominent increase of microthrombi in LDK indicates that they are not merely donor-derived.

Alpha-1 antitrypsin (AAT) deficiency, which is an under-recognised metabolic genetic disorder, is known to cause severe lung disease and liver cirrhosis in about 10%–15% of cases. Patients with AAT deficiency are at a higher risk for developing hepatocellular carcinoma, both in cirrhotic and in non-cirrhotic livers. In this case report, a 48-year-old woman with homozygous ZZ AAT deficiency presented with abdominal pain, and by imaging, an abnormal area in the liver was found. The initial differential diagnosis consisted of benign abnormalities but a malignancy could not be ruled out. Finally, this abnormality turned out to be an intrahepatic cholangiocarcinoma (iCCA) in a non-cirrhotic liver. Since this type of tumour has been very infrequently described to be associated with AAT deficiency, the question remains whether alpha-1 trypsin accumulation in the hepatocytes was responsible for the development of iCCA. However, other associated factors for developing an iCCA were ruled out.

There is paucity of literature on dietary treatment in glycogen storage disease (GSD) type IV and formal guidelines are not available. Traditionally, liver transplantation was considered the only treatment option for GSD IV. In light of the success of dietary treatment for the other hepatic forms of GSD, we have initiated this observational study to assess the outcomes of medical diets, which limit the accumulation of glycogen. Clinical, dietary, laboratory, and imaging data for 15 GSD IV patients from three centres are presented. Medical diets may have the potential to delay or prevent liver transplantation, improve growth and normalize serum aminotransferases. Individual care plans aim to avoid both hyperglycaemia, hypoglycaemia and/or hyperketosis, to minimize glycogen accumulation and catabolism, respectively. Multidisciplinary monitoring includes balancing between traditional markers of metabolic control (ie, growth, liver size, serum aminotransferases, glucose homeostasis, lactate, and ketones), liver function (ie, synthesis, bile flow and detoxification of protein), and symptoms and signs of portal hypertension.

Contains fulltext : 229604.pdf (Publisher’s version ) (Open Access) Glomerular endothelial cell (GEnC) dysfunction is important in the pathogenesis of glomerular sclerotic diseases, including Focal Segmental Glomerulosclerosis (FSGS) and overt diabetic nephropathy (DN). GEnCs form the first cellular barrier in direct contact with cells and factors circulating in the blood. Disturbances in these circulating factors can induce GEnC dysfunction. GEnC dysfunction occurs in early stages of FSGS and DN, and is characterized by a compromised endothelial glycocalyx, an inflammatory phenotype, mitochondrial damage and oxidative stress, aberrant cell signaling, and endothelial-to-mesenchymal transition (EndMT). GEnCs are in an interdependent relationship with podocytes and mesangial cells, which involves bidirectional cross-talk via intercellular signaling. Given that GEnC behavior directly influences podocyte function, it is conceivable that GEnC dysfunction may culminate in podocyte damage, proteinuria, subsequent mesangial activation, and ultimately glomerulosclerosis. Indeed, GEnC dysfunction is sufficient to cause podocyte injury, proteinuria and activation of mesangial cells. Aberrant gene expression patterns largely contribute to GEnC dysfunction and epigenetic changes seem to be involved in causing aberrant transcription. This review summarizes literature that uncovers the importance of cross-talk between GEnCs and podocytes, and GEnCs and mesangial cells in the context of the development of FSGS and DN, and the potential use of GEnCs as efficacious cellular target to pharmacologically halt development and progression of DN and FSGS.

Background and aim. Colorectal cancer is considered to be a major public health problem. It is the third most frequent cancer at a global level and also the fourth most frequent cause of death. Previous scientific findings have proved that a significant percentage of colorectal cancer deaths are due to the abscence of screening. The aim of this review is to present the evolution of the screening strategies by using the most recommended and recent colorectal cancer screening guidelines. Methods. A systematic literature search on the scientific databases was performed, identifying some of the most important colorectal cancer screening guidelines publications. Results. The most recent guidelines of American Cancer Society (2018) recommend that adults aged 45 years and older with an average risk of colorectal cancer should undergo regular screening. All the guidelines have considered fecal occult blood testing (annual or biennial), fecal immunochemical test (annual), flexible sigmoidoscopy (every 5 years) and colonoscopy (every 10 years) as the most preferred screening options. However, there are discrepancies with regards to which tests should be preferred for screening. Conclusion. Increased compliance with colorectal cancer screening recommendations has the potential to improve patients’ health and to reduce colorectal cancer morbidity and mortality rates. It is important for health care providers to have an understanding of the risk factors for colorectal cancer and various stages of disease development in order to recommend appropriate screening strategies.

Cartilage degeneration is one of the most common chronic age-related joint disorders leading to pain and reduced joint motion. The increasing prevalence of osteoarthritis requires accurate cartilage imaging, both clinically and in research. Detailed cartilage imaging is also necessary for traumatic cartilage lesions and for pre- and postoperative assessment of cartilage repair procedures. Although still widely used, conventional radiography bears significant limitations because it assesses cartilage indirectly by joint space width. Magnetic resonance imaging (MRI) enables direct visualization of cartilage damage along with other concomitantly affected joint tissues. Several semiquantitative grading systems and volumetric analysis methods exist to assess cartilage damage and cartilage repair on MRI. Quantification of hyaline and fibrocartilage biochemical composition is possible with novel MRI methods such as T2- and T1ρ-mapping, delayed gadolinium-enhanced MRI of cartilage, glycosaminoglycan chemical exchange saturation transfer, and sodium imaging, along with quantitative computed tomography arthrography. These techniques provide promising quantitative imaging biomarkers that can detect early cartilage changes before morphological alterations occur.

BACKGROUND: Pneumatic dilation and laparoscopic Heller's myotomy (LHM) are established treatments for idiopathic achalasia. Peroral endoscopic myotomy (POEM) is a less invasive therapy with promising early study results. METHODS: In a multicenter, randomized trial, we compared POEM with LHM plus Dor's fundoplication in patients with symptomatic achalasia. The primary end point was clinical success, defined as an Eckardt symptom score of 3 or less (range, 0 to 12, with higher scores indicating more severe symptoms of achalasia) without the use of additional treatments, at the 2-year follow-up; a noninferiority margin of -12.5 percentage points was used in the primary analysis. Secondary end points included adverse events, esophageal function, Gastrointestinal Quality of Life Index score (range, 0 to 144, with higher scores indicating better function), and gastroesophageal reflux. RESULTS: A total of 221 patients were randomly assigned to undergo either POEM (112 patients) or LHM plus Dor's fundoplication (109 patients). Clinical success at the 2-year follow-up was observed in 83.0% of patients in the POEM group and 81.7% of patients in the LHM group (difference, 1.4 percentage points; 95% confidence interval [CI], -8.7 to 11.4; P = 0.007 for noninferiority). Serious adverse events occurred in 2.7% of patients in the POEM group and 7.3% of patients in the LHM group. Improvement in esophageal function from baseline to 24 months, as assessed by measurement of the integrated relaxation pressure of the lower esophageal sphincter, did not differ significantly between the treatment groups (difference, -0.75 mm Hg; 95% CI, -2.26 to 0.76), nor did improvement in the score on the Gastrointestinal Quality of Life Index (difference, 0.14 points; 95% CI, -4.01 to 4.28). At 3 months, 57% of patients in the POEM group and 20% of patients in the LHM group had reflux esophagitis, as assessed by endoscopy; at 24 months, the corresponding percentages were 44% and 29%. CONCLUSIONS: In this randomized trial, POEM was noninferior to LHM plus Dor's fundoplication in controlling symptoms of achalasia at 2 years. Gastroesophageal reflux was more common among patients who underwent POEM than among those who underwent LHM. (Funded by the European Clinical Research Infrastructure Network and others; ClinicalTrials.gov number, NCT01601678.). ispartof: NEW ENGLAND JOURNAL OF MEDICINE vol:381 issue:23 pages:2219-2229 ispartof: location:United States status: published

Dopamine (DA) controls many vital physiological functions and is critically involved in several neuropsychiatric disorders such as schizophrenia and attention deficit hyperactivity disorder. The major function of the plasma membrane dopamine transporter (DAT) is the rapid uptake of released DA into presynaptic nerve terminals leading to control of both the extracellular levels of DA and the intracellular stores of DA. Here, we present a newly developed strain of rats in which the gene encoding DAT knockout Rats (DAT-KO) has been disrupted by using zinc finger nuclease technology. Male and female DAT-KO rats develop normally but weigh less than heterozygote and wild-type rats and demonstrate pronounced spontaneous locomotor hyperactivity. While striatal extracellular DA lifetime and concentrations are significantly increased, the total tissue content of DA is markedly decreased demonstrating the key role of DAT in the control of DA neurotransmission. Hyperactivity of DAT-KO rats can be counteracted by amphetamine, methylphenidate, the partial Trace Amine-Associated Receptor 1 (TAAR1) agonist RO5203648 ((S)-4-(3,4-Dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine) and haloperidol. DAT-KO rats also demonstrate a deficit in working memory and sensorimotor gating tests, less propensity to develop obsessive behaviors and show strong dysregulation in frontostriatal BDNF function. DAT-KO rats could provide a novel translational model for human diseases involving aberrant DA function and/or mutations affecting DAT or related regulatory mechanisms.SIGNIFICANCE STATEMENTHere, we present a newly developed strain of rats in which the gene encoding the dopamine transporter (DAT) has been disrupted (Dopamine Transporter Knockout rats [DAT-KO rats]). DAT-KO rats display functional hyperdopaminergia accompanied by pronounced spontaneous locomotor hyperactivity. Hyperactivity of DAT-KO rats can be counteracted by amphetamine, methylphenidate, and a few other compounds exerting inhibitory action on dopamine-dependent hyperactivity. DAT-KO rats also demonstrate cognitive deficits in working memory and sensorimotor gating tests, less propensity to develop compulsive behaviors, and strong dysregulation in frontostriatal BDNF function. These observations highlight the key role of DAT in the control of brain dopaminergic transmission. DAT-KO rats could provide a novel translational model for human diseases involving aberrant dopamine functions.

INTRODUCTION: Dual hypothermic oxygenated machine perfusion (DHOPE) of the liver has been advocated as a method to reduce ischemia-reperfusion injury. This study aimed to determine whether DHOPE reduces IR injury of the bile ducts in DCD liver transplantation.MATERIALS AND METHODS: In a recently performed phase 1-trial, ten DCD livers were preserved with DHOPE after static cold storage (SCS) (www.trialregister.nl NTR4493). Bile duct biopsies were obtained at the end of SCS (before DHOPE; baseline) and after graft reperfusion in the recipient. Histological severity of biliary injury was graded according to an established semi-quantitative grading system. Twenty liver transplantations using DCD livers not preserved with DHOPE served as control.RESULTS: Baseline characteristics and the degree of bile duct injury at baseline (end of SCS) were similar between both groups. In controls, degree of stroma necrosis (P=0.002) and injury of the deep peribiliary glands (P=0.02) increased after reperfusion, compared to baseline. In contrast, in DHOPE preserved livers the degree of bile duct injury did not increase after reperfusion. Moreover, there was less injury of deep peribiliary glands (P=0.04) after reperfusion in the DHOPE group, compared to controls.CONCLUSION: This study suggests that DHOPE reduces ischemia-reperfusion injury of bile ducts after DCD liver transplantation. This article is protected by copyright. All rights reserved.

Background Narcolepsy, a disorder of rapid eye movement (REM) sleep, is characterized by excessive daytime sleepiness and cataplexy, a loss of muscle tone triggered by emotional stimulation. Current narcolepsy pharmacotherapeutics include controlled substances with abuse potential or drugs with undesirable side effects. As partial agonists at trace amine-associated receptor 1 (TAAR1) promote wakefulness in mice and rats, we evaluated whether TAAR1 agonism had beneficial effects in two mouse models of narcolepsy. Methods In the first experiment, male homozygous B6- Taar1 tm1(NLSLacZ)Blt ( Taar1 knockout) and wild-type mice were surgically implanted to record electroencephalogram, electromyogram, locomotor activity, and body temperature, and the efficacy of the TAAR1 agonist, RO5256390, on sleep/wake and physiological parameters was determined. In the second experiment, the effects of the TAAR1 full agonist RO5256390 and partial agonist RO5263397 on sleep/wake, locomotor activity, body temperature, and cataplexy were assessed in two mouse narcolepsy models. Results RO5256390 profoundly reduced rapid eye movement sleep in wild-type mice; these effects were eliminated in Taar1 knockout mice. The TAAR1 partial agonist RO5263397 also promoted wakefulness and suppressed nonrapid eye movement sleep. Both compounds reduced body temperature in the two narcolepsy models at the highest doses tested. Both TAAR1 compounds also mitigated cataplexy, the pathognomonic symptom of this disorder, in the narcolepsy models. The therapeutic benefit was mediated through a reduction in number of cataplexy episodes and time spent in cataplexy. Conclusions These results suggest TAAR1 agonism as a new therapeutic pathway for treatment of this orphan disease. The common underlying mechanism may be the suppression of rapid eye movement sleep.

Introduction: The liver is the main location for metastasization in stage IV colorectal cancers. Areas covered: This review intends to comprehensively present the most important studies conducted in the past few years concerning the role of miRNAs in colorectal cancer liver metastases, trying to clarify some aspects regarding tumor biology and favorite liver metastasization site. Expert commentary: Recent advances in tissue and serum RNA extraction has considerably improved the field of microRNAs studies. These molecules known to play a crucial role in the metastatic stage indicate a starting point in the development of clinical biomarkers with a possible role in the stratification of high-risk patients for adequate treatment.

Trace amine-associated receptors are G protein-coupled receptors of which TAAR1 is the most well-studied. Recently, Vattai et al. (J Cancer Res Clin Oncol 143:1637–1647 https://doi.org/10.1007/s00432-017-2420-8 , 2017) reported that expression of TAAR1 may be a marker of breast cancer (BC) survival, with a positive correlation also suggested between TAAR1 expression and HER2 positivity. Neither a role for TAAR1 in breast tissue, nor in cancer, had previously been suspected. We, therefore, sought to provide independent validation and to further examine these putative relationships. First, a bioinformatic analysis on 58 total samples including normal breast tissue, BC-related cell lines, and tumour samples representing different BC sub-types found no clear correlation between TAAR1 mRNA levels and any BC subtype, including HER2 + . We next confirmed the bioinformatics data correlated to protein expression using a well validated anti-human TAAR1 antibody. TAAR1 mRNA levels correlated with the relative intensity of immunofluorescence staining in six BC cell lines (MCF-7, T47D, MDA-MB-231, SKBR3, MDA-MB-468, BT-474), but not in the MCF-10A immortalized mammary gland line, which had high mRNA but low protein levels. As expected, TAAR1 protein was intracellular in all cell lines. Surprisingly MCF-7, SKBR3, and MDA-MB-468 showed pronounced nuclear localization. The relative protein expression in MCF-7, MDA-MB-231, and MCF-10A lines was further confirmed by semi-quantitative flow cytometry. Finally, we demonstrate that the commercially available anti-TAAR1 antibody has poor selectivity, which likely explains the lack of correlation with the previous study. Therefore, while we clearly demonstrate variable expression and sub-cellular localization of TAAR1 across BC cell lines, we find no evidence for association with BC subtype.

Cephalopelvic disproportion is common among Africans and is a major cause of maternal and perinatal mortality and morbidity. As the dimensions of the pelvis may vary between populations and according to stature and age, they need to be considered during childbirth and also in the planning and performance of pelvic and perineal procedures. The aim of this study was to assess the possible variations in the dimensions of the intact pelvic canal in South Africans and their implications. Eighty intact cadaver pelves, belonging to 40 white South Africans (20 males and 20 females) and 40 black South Africans (20 males and 20 females) were used for both metric and geometric morphometric analyses. Pelvic inlet shapes did not differ significantly between groups but pelvic inlet and midpelvic dimensions were the greatest in white South Africans and females. The pubic symphyseal length was the greatest in white males and the smallest in black females, resulting in a smaller pelvic cavity anteriorly than for white females. Pelvic outlet shapes varied significantly between sexes in white South Africans and between white and black males. Females presented with the greatest dimensions. Black South African females presented with an elongated anteroposterior outlet diameter. Certain transverse pelvic diameters correlated positively with age in white males and with height in females. In planning childbirth options, the smaller pelvic inlet of black females and stature-dependent diameters should be considered. Pelvic and perineal surgery may be technically more challenging because of smaller pelvic dimensions in black South Africans, especially in males.

Compulsive, binge eating of highly palatable food constitutes a core feature of some forms of obesity and eating disorders, as well as of the recently proposed disorder of food addiction. Trace amine-associated receptor 1 (TAAR1) is a highly conserved G-protein-coupled receptor bound by endogenous trace amines. TAAR1 agonists have been shown to reduce multiple behavioral effects of drugs of abuse through their actions on the mesocorticolimbic system. In this study, we hypothesized that TAAR1 may have a role in compulsive, binge-like eating; we tested this hypothesis by assessing the effects of a TAAR1 agonist, RO5256390, in multiple excessive feeding-related behaviors induced by limiting access to a highly palatable diet in rats. Our results show that RO5256390 blocked binge-like eating in rats responding 1 h per day for a highly palatable sugary diet. Consistent with a palatability-selective effect, drug treatment selectively reduced the rate and regularity of palatable food responding, but it did not affect either baseline intake or food restriction-induced overeating of the standard chow diet. Furthermore, RO5256390 fully blocked compulsive-like eating when the palatable diet was offered in an aversive compartment of a light/dark conflict box, and blocked the conditioned rewarding properties of palatable food, as well as palatable food-seeking behavior in a second-order schedule of reinforcement. Drug treatment had no effect on either anxiety-like or depressive-like behavior, and it did not affect control performance in any of the tests. Importantly, rats exposed to palatable food showed decreased TAAR1 levels in the medial prefrontal cortex (mPFC), and RO5256390 microinfused into the infralimbic, but not prelimbic, subregion of the mPFC-reduced binge-like eating. Altogether, these results provide evidence for TAAR1 agonism as a novel pharmacological treatment for compulsive, binge eating.

Imaging modalities using tumor-directed monoclonal antibodies may be of value to improve the pre- and intraoperative detection and resection of lymph node (LN) metastatic disease in penile squamous cell carcinoma (PSCC). We investigated the expression of prostate-specific membrane antigen (PSMA), vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR) and epithelial cell adhesion molecule (EpCAM) to analyze their potency for diagnostic applications. Antigen expression was determined in primary tumors and LNs with and without metastases of 22 patients with PSCC. The total immunostaining score (TIS, 0–12) was determined as the product of a proportion score (PS, 0–4) and an intensity score (IS, 0–3). EGFR and VEGF expression were high in primary tumor (median TIS 8) and LN metastases (median TIS 6 and 8, respectively). No EGFR expression was seen in LNs without metastases. However, LNs without metastases did show VEGF expression (median TIS 6). No EpCAM or PSMA expression was seen in PSCC. This study shows that VEGF and EGFR expression is moderate to high in LN metastases of PSCC. Both VEGF and EGFR warrant further clinical evaluation to determine their value as a target for pre- and intraoperative imaging modalities in the detection of LN metastases in PSCC.

Objective In this study, we evaluated the toxicity and clinical efficacy of nivolumab, a programmed cell death protein 1 (PD-1) inhibitor, on patients with platinum resistant ovarian cancer. Methods Every second week, 18 patients with platinum resistance ovarian cancer received nivolumab until disease progression occurred. We assessed toxicity, disease control rate, progression free survival (PFS) and overall survival (OS). Radiological response evaluation according to irRECIST was performed every 12th week, while clinical evaluation was done every second week. Results The disease control rate was 44% (95% confidence interval [CI]=19-87) as 8 showed stable disease, 6 showed progressive disease and 4 died before the first radiological response evaluation. The median OS was 30 weeks (95% CI=14-42; range, 3-95), and PFS was 15 weeks (95% CI=13-17). The median follow-up time was 30 weeks (range, 3-123). The rate of grade 2-5 adverse events was 28% (5 out of 18). Two patients (11%) developed grade 2 and 3 adverse events, respectively, while no grade 4 events were observed. One patient died from intestinal perforation, believed to be caused by concomitant bevacizumab rather than nivolumab. Conclusion This study shows few adverse events, and promising clinical efficacy when using nivolumab for ovarian cancer.

Purpose The histopathology of sepsis-associated acute kidney injury (AKI) in critically ill patients remains an understudied area. Previous studies have identified that acute tubular necrosis (ATN) is not the only driver of sepsis-AKI. The focus of this study was to identify additional candidate processes that may drive sepsis-AKI. To do this we immunohistochemically characterized the histopathological and cellular features in various compartments of human septic kidneys. Methods We studied the following histopathological features: leukocyte subsets, fibroblast activation, cellular proliferation, apoptosis, and fibrin deposition in the glomerulus and the tubulointerstitium in human post-mortem kidney biopsy tissue. Biopsy tissue samples from 27 patients with sepsis-AKI were collected 33 min (range 24–150) after death in the ICU. The unaffected part of the kidneys from 12 patients undergoing total nephrectomy as a result of renal carcinoma served as controls. Results Immunohistochemical analysis revealed the presence of more neutrophils and macrophages in the glomeruli and more neutrophils in the tubulointerstitium of renal tissue from patients with sepsis compared to control renal tissue. Type II macrophages were predominant, with some macrophages expressing both type I and type II markers. In contrast, there were almost no macrophages found in control kidneys. The number of activated (myo)fibroblasts was low in the glomeruli of sepsis-AKI kidneys, yet this was not observed in the tubulointerstitium. Cell proliferation and fibrin deposition were more pronounced in the glomeruli and tubulointerstitium of sepsis-AKI than in control kidneys. Conclusions The extensive heterogeneity of observations among and within patients emphasizes the need to thoroughly characterize patients with sepsis-AKI in a large sample of renal biopsy tissue from patients with sepsis. Electronic supplementary material The online version of this article (10.1186/s13054-018-2287-3) contains supplementary material, which is available to authorized users.

Systemic capillary leak syndrome (SCLS) is a disorder characterized by increased vascular permeability with intermittent acute episodes of profound capillary leak that may result in hypotension or shock. A rarely described chronic form of SCLS (cSCLS) presents as refractory edema, with pleural and/or pericardial effusions and hypoalbuminemia. These entities are differentiated by massive and periodic episodes of capillary leak, which can result in shock in SCLS, and chronic refractory edema in cSCLS. The etiologies of these disorders are poorly understood, but both acute and chronic forms often present with an associated monoclonal gammopathy. Flares of the SCLS have been reduced by treatment with intravenous immune globulin (IVIG). Only six cases of cSCLS have been reported, and previous treatments have included steroids, terbutaline, and theophylline. Based upon the reported responses of SCLS to IVIG, we present the case of a 54-year-old man with cSCLS where ongoing treatment with IVIG resulted in a marked and sustained improvement in the signs and symptoms of the capillary leak syndrome. .

Sodium glucose cotransporter 2 inhibitors (SGLT2i) are the first antidiabetic compounds that effectively reduce heart failure hospitalization and cardiovascular death in type 2 diabetics. Being explicitly designed to inhibit SGLT2 in the kidney, SGLT2i have lately been investigated for their off-target cardiac actions. Here, we review the direct effects of SGLT2i Empagliflozin (Empa), Dapagliflozin (Dapa), and Canagliflozin (Cana) on various cardiac cell types and cardiac function, and how these may contribute to the cardiovascular benefits observed in large clinical trials. SGLT2i impaired the Na+/H+ exchanger 1 (NHE-1), reduced cytosolic [Ca2+] and [Na+] and increased mitochondrial [Ca2+] in healthy cardiomyocytes. Empa, one of the best studied SGLT2i, maintained cell viability and ATP content following hypoxia/reoxygenation in cardiomyocytes and endothelial cells. SGLT2i recovered vasoreactivity of hyperglycemic and TNF-α-stimulated aortic rings and of hyperglycemic endothelial cells. Anti-inflammatory actions of Cana in IL-1β-treated HUVEC and of Dapa in LPS-treated cardiofibroblast were mediated by AMPK activation. In isolated mouse hearts, Empa and Cana, but not Dapa, induced vasodilation. In ischemia-reperfusion studies of the isolated heart, Empa delayed contracture development during ischemia and increased mitochondrial respiration post-ischemia. Direct cardiac effects of SGLT2i target well-known drivers of diabetes and heart failure (elevated cardiac cytosolic [Ca2+] and [Na+], activated NHE-1, elevated inflammation, impaired vasorelaxation, and reduced AMPK activity). These cardiac effects may contribute to the large beneficial clinical effects of these antidiabetic drugs.

Antinuclear antibodies (ANAs) are autoantibodies that attack self-proteins within cell nucleus structures; their presence in serum may indicate an autoimmune disease. Also, positive ANA test results have been obtained in chronic infectious diseases, cancers, medication-related adverse events, and even healthy individuals. As a result, a correct interpretation of the presence of ANAs is needed.Identification of ANAs subtypes is an important part of clinical immunology. The presence of ANAs in patient blood specimens is detected using a cell-line substrate from human laryngeal carcinoma (HEp-2 cells). On this substrate, ANAs will bind specific antigens, which will lead to a suggestive fluorescent emission. The fluorescence patterns visualized under the fluorescence microscope can be correlated with certain subtypes of ANA and certain autoimmune diseases.Depending on the subtype of ANA present in the serum and the targeted antigen, several staining patterns are reported, namely, nuclear patterns, nucleolar patterns, cell cycle patterns, or cytoplasmatic patterns. Identification of a certain pattern can lead to diagnosis of a certain autoimmune disease.

Objective Type 2 diabetes and obesity are emerging pandemics in the 21st century creating worldwide urgency for the development of novel and safe therapies. We investigated trace amine-associated receptor 1 (TAAR1) as a novel target contributing to the control of glucose homeostasis and body weight. Methods We investigated the peripheral human tissue distribution of TAAR1 by immunohistochemistry and tested the effect of a small molecule TAAR1 agonist on insulin secretion in vitro using INS1E cells and human islets and on glucose tolerance in C57Bl6, and db/db mice. Body weight effects were investigated in obese DIO mice. Results TAAR1 activation by a selective small molecule agonist increased glucose-dependent insulin secretion in INS1E cells and human islets and elevated plasma PYY and GLP-1 levels in mice. In diabetic db/db mice, the TAAR1 agonist normalized glucose excursion during an oral glucose tolerance test. Sub-chronic treatment of diet-induced obese (DIO) mice with the TAAR1 agonist resulted in reduced food intake and body weight. Furthermore insulin sensitivity was improved and plasma triglyceride levels and liver triglyceride content were lower than in controls. Conclusions We have identified TAAR1 as a novel integrator of metabolic control, which acts on gastrointestinal and pancreatic islet hormone secretion. Thus TAAR1 qualifies as a novel and promising target for the treatment of type 2 diabetes and obesity., Graphical abstract, Highlights • TAAR1 is a novel key player in metabolic control. • TAAR1 is expressed in β-cells and intestinal enteroendocrine cells in mice and humans. • TAAR1 agonist improved glucose tolerance and reduced body weight in mouse disease models.

Lower urinary tract symptoms (LUTS) refer to the symptom complex that is the common pathway for diseases affecting the lower urinary tract. It manifests as either irritative or obstructive symptoms. LUTS have long been recognised as a significant cause of morbidity in both sexes. The long term sequelae of the underlying cause are also a significant cause of mortality.LUTS have been noted to have a recognisable progression pattern that worsens with age. This is of particular concern in African countries that continue to evolve in terms of the population dynamics. This evolution has resulted in an increase in the geriatric population in both developed and developing countries. There has been a concordant increase in the recognition of the symptom complex with age. This results in a significant percentage of males presenting with LUTS and secondary complications.Several factors interact to produce LUTS. Complex pathophysiological pathways have been investigated to define the roles of individual and cumulativ...

In the majority of long-term survivors after PLTx, graft fibrosis has been identified. Recently, subtypes of graft fibrosis have been described based on their predominant acinar localization. We aimed to evaluate whether the development of portal, perisinusoidal, and centrilobular distribution of graft fibrosis is related to patient or transplantation-related parameters. We reviewed the histological features in protocol liver biopsies taken at 1 and 5 years after PLTx of 47 children on a tacrolimus-based immunosuppressive regimen. Fibrosis was assessed according to the LAFSc. The prevalence of portal fibrosis increased from 31% to 62%, sinusoidal from 68% to 79%, and centrilobular from 76% to 85%. The presence of portal fibrosis was associated with total bilirubin and γGT levels (each P

To prevent renal graft thrombosis in kidney transplantation, centres use different perioperative anticoagulant strategies, based on various risk factors. In our centre, patients transplanted preemptively are considered at increased risk of renal graft thrombosis compared to patients who are dialysis-dependent at time of transplantation. Therefore these patients are given a single dose of 5000 IU unfractionated heparin intraoperatively before clamping of the vessels. We questioned whether there is a difference in haemostatic state between preemptively and non-preemptively transplanted patients and whether the distinction in intraoperative heparin administration used in our center is justified. For this analysis, citrate samples of patients participating in the VAPOR-1 trial were used and several haemostatic and fibrinolytic parameters were measured in 29 preemptively and 28 non-preemptively transplanted patients and compared to 37 living kidney donors. Sample points were: induction anaesthesia (T1), 5 minutes after reperfusion (T2) and 2 hours postoperative (T3). At T1, recipient groups showed comparable elevated levels of platelet factor 4 (PF4, indicating platelet activation), prothrombin fragment F1+2 and D-dimer (indicating coagulation activation) and Von Willebrand Factor (indicating endothelial activation) compared to the donors. The Clot Lysis Time (CLT, a measure of fibrinolytic potential) was prolonged in both recipient groups compared to the donors. At T3, F1+2, PF4 and CLT were higher in non-preemptively transplanted recipients compared to preemptively transplanted recipients. Compared to donors, non-preemptive recipients showed a prolonged CLT, but comparable levels of PF4 and D-dimer. In conclusion pre-transplantation, preemptively and non-preemptively transplanted patients show a comparable enhanced haemostatic state. A distinction in intraoperative heparin administration between preemptive and non-preemptive transplantation does not seem justified.

Atherosclerosis is a chronic, multifactorial disease that starts in youth, manifests clinically later in life, and can lead to myocardial infarction, stroke, claudication, and death. Although inflammatory processes have long been known to be involved in atherogenesis, interest in this subject has grown in the past 30-40 years. Animal experiments and human analyses of early atherosclerotic lesions have shown that the first pathogenic event in atherogenesis is the intimal infiltration of T cells at arterial branching points. These T cells recognize heat shock protein (HSP)60, which is expressed together with adhesion molecules by endothelial cells in response to classic risk factors for atherosclerosis. Although these HSP60-reactive T cells initiate atherosclerosis, antibodies to HSP60 accelerate and perpetuate the disease. All healthy humans develop cellular and humoral immunity against microbial HSP60 by infection or vaccination. Given that prokaryotic (bacterial) and eukaryotic (for instance, human) HSP60 display substantial sequence homology, atherosclerosis might be the price we pay for this protective immunity, if risk factors stress the vascular endothelial cells beyond physiological conditions.

There are limited data regarding endovascular treatment of arteriovenous graft (AVG) pseudoaneurysms using stent grafts. We performed a comprehensive literature review on the use of stent grafts in the treatment of AVG pseudoaneurysms. We included 10 studies (121 patients). The mean AVG age was 3.1 years (95% confidence interval [CI]: 2.2-4) and pseudoaneurysm mean diameter was 34 mm (95% CI: 23-46). The majority (71%) of the pseudoaneurysms were located on the arterial limb of the AVG and 77% presented with venous anastomosis stenosis requiring angioplasty. The mean number of stents used to treat one lesion was 1.4 (95% CI: 1.3-1.5). The technical success rate of pseudoaneurysm isolation was 100% in all studies and 100% of patients received hemodialysis using the AVG after pseudoaneurysm treatment without the need for catheter placement. The primary patency rates for 1, 3, and 6 months were 81%, 73%, and 24%. Secondary patency was 80%, 77%, and 74% at 1, 3, and 6 months. Arteriovenous graft thrombosis occurred in 12% of patients. Arteriovenous graft infection developed in 35% of cases. Arteriovenous graft pseudoaneurysm treatment using stent grafts is effective in managing even large pseudoaneurysms and has acceptable primary and secondary patency rates. Graft infection was a relatively frequent complication.

Knee osteoarthritis (OA) in the elderly is one of the most common degenerative age-related joint diseases leading to typical degradation of articular cartilage with severe pain and limitation of joint motion. Its increasing prevalence due to the demographic development of the society has major implications for individual and public healthcare with the increasing necessity for clinical imaging assessment in a high number of individuals. Although conventional X-ray radiographs are widely considered as gold standard for the assessment of knee OA, in clinical and scientific settings they increasingly bare significant limitations in situations when high resolution and detailed assessment of cartilage is demanded. New imaging modalities are broadening the possibilities in knee OA clinical practice and are offering new insights to help for a better understanding of the disease. X-ray analysis in OA of the knee is associated with many technical limitations and increasingly is replaced by high-quality assessment using magnetic resonance imaging or ultrasonography both in clinical routine and scientific situations. These novel imaging modalities enable an in vivo visualization of the quality of the cartilaginous structure and bone as well as all articular and periarticular tissues. Therefore, the limitations of radiographs in knee OA assessment could be overcome by these techniques. This review article should provide an insight into the most important radiological features of knee OA and their systematic visualization with different imaging approaches that can be used in clinical routine.

During the last decade, many educational efforts and technological improvements have been made to protect skiing athletes from injuries. Whether these efforts have changed the pattern of acute injuries from skiing casualties has not yet been shown on a medical basis, which this longitudinal study examines. All patients transferred to the Department of Radiology of our level I trauma center for acute emergency computed tomography (CT) after alpine skiing accidents from 2000 to 2011 were included. We hypothesized that only patients with clinical suspicion for injuries were admitted for acute CT. Of all acute patients after skiing accidents, 2,252 could be included. From 2000 to 2011, all cerebral injuries and vascular arterial injuries statistically significantly decreased (p

Introduction: Renal disease, designated as lupus nephritis (LN), is one of the severe manifestations of Systemic Lupus Erythematosus (SLE). The proliferative forms require aggressive treatment with corticosteroids and cytotoxic drugs. In a substantial number of patients, renal disease relapses after treatment. Case report: In this case report, we present a 27-year old woman, who had been treated for a membranoproliferative LN in the past. Seventeen years later she presented with chest pain and nephrotic-range proteinuria and severe hypoalbuminemia. The diagnosis of pulmonary embolism was made. Renal biopsy revealed only minimal abnormalities, confined to the mesangium. There was no glomerulonephritis. Based on this finding and the nephrotic-range proteinuria, the diagnosis of minimal-change disease was made. The patient was treated with prednisolone, after which the proteinuria diminished, but did not disappear. After the addition of azathioprine, the proteinuria resolved completely. Conclusion: This case illustrates that, although the diagnosis of LN has been made in the past, this does not exclude the occurrence of renal pathology caused by other diseases than SLE. Therefore, a renal biopsy is mandatory in every SLE patient with occurrence of renal abnormality es, even when a history of LN is present.

Purpose Computed tomography (CT) examinations, often using high-radiation dosages, are increasingly used in the acute management of polytrauma patients. This study compares a low-dose polytrauma multi-phase whole-body CT (WBCT) protocol on a latest generation of 16-cm detector 258-slice multi-detector CT (MDCT) scanner with advanced dose reduction techniques to a single-phase polytrauma WBCT protocol on a 64-slice MDCT scanner. Methods Between March and September 2015, 109 polytrauma patients (group A) underwent acute WBCT with a low-dose multi-phase WBCT protocol on a 258-slice MDCT whereas 110 polytrauma patients (group B) underwent single-phase trauma CT on a 64-slice MDCT. The diagnostic accuracy to trauma-related injuries, radiation dose, quantitative and semiquantitative image quality parameters, subjective image quality scorings, and workflow time parameters were compared. Results In group A, statistically significantly more arterial injuries (p = 0.04) and arterial dissections (p = 0.002) were detected. In group A, the mean (±SD) dose length product value was 1681 ± 183 mGy*cm and markedly lower when compared to group B (p

This article presents the recommendations of the European Society of Musculoskeletal Radiology Arthritis Subcommittee on the use of ultrasonography (US) in rheumatic disease, focused on the examination of joints in the adult population. The recommended examination technique and protocols used in a radiologic work-up are discussed. The main US features that can lead to a final diagnosis in the most common rheumatic diseases are addressed. The differential diagnosis that should be considered at image interpretation is presented. The role of US in interventional procedures and clinically important recent developments is also discussed.

IntroductionChronic pain and the pattern of opioid use after skeletal fractures has been a neglected topic in pain medicine. Pelvic and in particular acetabular fractures represent some of the most troublesome injuries for patients with a high incidence of chronic pain after fracture. We examined the long-term opioid analgesic use among patients with acetabular fractures and analysed if potential risk factors would predict a prolonged opioid therapy.Patients and methodsData were extracted from medical databases such as the Swedish National Hospital Discharge Register and the National Pharmacy Register. The study period was 2005–2008. Kaplan–Meier analysis constructed the cumulative opioid consumption with 95% confidence intervals (CI). Cox multiple-regression model was used to study risk factors for a prolonged opioid prescription after admission for fracture. An age- and sex-matched control group was included for comparisons.ResultsWe identified 1017 patients with isolated acetabular fractures. The proportion of dispensing opioids for these patients was 39%, which was 7 times higher than in the age- and sex-matched non-fracture controls (n=5077). The median follow-up time was 14 (interquartile range [IQR] 5–24) months. Most patients with opioid use after fracture were male (60%) and the median age was 76 (IQR 61–85) years. The leading mechanism of injury was fall on the same level (52%). At 6 and 12 months after fracture, 41% (95% CI 36–47) and 33% (28–39) were still treated with opioids. The multiple Cox regression-analysis (adjusted for age, sex, type of treatment, and mechanism of injury) revealed that younger patients (age

To assess the value of sonographic criteria, based on measurements of joint capsule distension and synovial hyperemia, during the course of repeated ultrasound (US)-guided intra-articular injections of hyaluronic acid (HA) in hand osteoarthritis (OA).Thirty-three patients (28 females/5 males), with hand OA in 78 joints, were included in this study. Patients underwent sonographic evaluation at baseline and consecutively for 4 weeks at weekly US-guided intra-articular injections of HA (Hyalgan(®)). Measurements of joint thickening and joint inflammation were performed with Grey-scale and semi-quantitative Power-Doppler US (PDUS). Sonographic values were correlated with weekly patients self-assessment of pain for each treated joint.The mean (SD) patients self-assessment of pain statistically significantly (p0.0001) decreased from the first [68.3(22.3)] to the last week [37.3(30.34)]. A steady pain relief could be noticed in 67 (86%) of all treated joints. Over the whole observation period, the mean (SD) joint thickening of all joints markedly decreased from 15.6mm (5.3) to 13.1mm (6.4) (p0.0001). The PDUS-score before initiation of HA treatment was statistically significantly higher than at the end of therapy (p0.0001). The decrease in pain statistically significantly correlated with the decrease of joint thickening and PDUS-score between baseline and the end of therapy (p0.001).In this study, we demonstrate the meaningfulness of sonographic evaluation criteria including measurements of joint capsule distension and PDUS vascularization, both significantly correlating with the decrease of pain, during the therapy follow-up of US-guided intra-articular HA-injections in patients with hand OA.

Objective Production of anti–citrullinated protein antibodies (ACPAs) is an important biomarker for rheumatoid arthritis (RA). We undertook this study to determine whether genetic factors (HLA—DRB1 alleles) are associated with extreme ACPA levels in individuals with ACPA-positive RA, and to ascertain whether there are any phenotypic characteristics associated with these subgroups of RA. Methods HLA–DRB1 allelic groups were genotyped in 1,073 ACPA-positive RA patients from the Swedish Epidemiological Investigation of Rheumatoid Arthritis study. We found that 283 patients (26.4%) had high ACPA levels (defined as >1,500 units/ml using the Euro-Diagnostica anti-CCP2 test), while the rest of the patients had moderate ACPA levels and served as the comparison group. A replication group consisted of 235 RA patients. Results No significant differences in baseline disease activity were observed between patients with high and those with moderate ACPA levels. However, the HLA–DRB1*15 allele was associated with high ACPA levels (P = 0.0002). A similar trend was detected in HLA–DRB1*15–positive patients in the replication cohort, with meta-analysis of the discovery and replication cohorts demonstrating an overall effect of HLA–DRB1*15 on development of high ACPA levels in both the discovery and replication cohorts (P < 0.0001 by Mantel-Haenszel test with a fixed-effects model). Conclusion Our data indicate that HLA–DRB1*15 may promote the production of high ACPA levels. Due to the high value of ACPA level scores in the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for RA, the presence of HLA–DRB1*15 may, at least in part, contribute to fulfilling the criteria for RA. This illustrates the complex nature of the genetic regulation of ACPA levels. Additional mechanistic studies of the regulation of ACPAs and ACPA-positive RA are pending.

Klinisches/methodisches Problem Eine fruhe Diagnosestellung bei rheumatoider Arthritis (RA) stellt eine grose klinische Herausforderung dar, da sich daraus unmittelbare therapeutische Konsequenzen ableiten. Es gibt keinen epidemiologischen, genetischen, klinischen, serologischen oder radiologischen Test, mit dessen alleiniger Anwendung die Diagnose der RA definitiv gestellt werden kann.

Obesity and its associated complications, which can lead to the development of metabolic syndrome, are a worldwide major public health concern especially in developed countries where they have a very high prevalence. RIP140 is a nuclear coregulator with a pivotal role in controlling lipid and glucose metabolism. Genetically manipulated mice devoid of RIP140 are lean with increased oxygen consumption and are resistant to high-fat diet-induced obesity and hepatic steatosis with improved insulin sensitivity. Moreover, white adipocytes with targeted disruption of RIP140 express genes characteristic of brown fat including CIDEA and UCP1 while skeletal muscles show a shift in fibre type composition enriched in more oxidative fibres. Thus, RIP140 is a potential therapeutic target in metabolic disorders. In this article we will review the role of RIP140 in tissues relevant to the appearance and progression of the metabolic syndrome and discuss how the manipulation of RIP140 levels or activity might represent a therapeutic approach to combat obesity and associated metabolic disorders. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease., Research Highlights ► RIP140 regulates energy expenditure and storage in adipose tissue. ► RIP140 modulates muscle fiber type. ► RIP140 affects inflammatory responses. ► RIP140 is a promising target for treatment of metabolic disorders.

Diagnostic tests in patients complaining of carpal tunnel syndrome (CTS) are based on physical examination, electrodiagnostic tests (EDTs), and diagnostic imaging. Timely diagnosis helps prevent permanent nerve damage and its sequelae in terms of functional impairment. Imaging provides additional information to that obtained from clinical tests and EDTs. By allowing direct visualization of the compressed median nerve (MN), ultrasound (US) and magnetic resonance imaging can depict the causes for secondary CTS and describe anatomical variants, such as a bifid MN or a persistent median artery of the forearm, as well as space-occupying lesions including tenosynovitis and ganglion cysts. In addition, diagnostic imaging is of value for postoperative patients presenting with persistent symptoms. Finally, US is able to add information for EDT-negative symptomatic patients. Over time, US has increased in its sensitivity and specificity so it can be used as the initial test in patients presenting with clinical symptoms of CTS because it is now equivalent to EDT. The use of US as a screening test may reduce the number of EDT examinations in patients with suspected CTS, providing additional valuable anatomical information.

Iron is suggested to play a detrimental role in the progression of chronic kidney disease (CKD). The kidney recycles iron back into the circulation. However, the localization of proteins relevant for physiological tubular iron handling and their potential role in CKD remain unclear. We examined associations between iron deposition, expression of iron handling proteins and tubular injury in kidney biopsies from CKD patients and healthy controls using immunohistochemistry. Iron was deposited in proximal (PT) and distal tubules (DT) in 33% of CKD biopsies, predominantly in pathologies with glomerular dysfunction, but absent in controls. In healthy kidney, PT contained proteins required for iron recycling including putative iron importers ZIP8, ZIP14, DMT1, iron storage proteins L- and H-ferritin and iron exporter ferroportin, while DT only contained ZIP8, ZIP14, and DMT1. In CKD, iron deposition associated with increased intensity of iron importers (ZIP14, ZIP8), storage proteins (L-, H-ferritin), and/or decreased ferroportin abundance. This demonstrates that tubular iron accumulation may result from increased iron uptake and/or inadequate iron export. Iron deposition associated with oxidative injury as indicated by heme oxygenase-1 abundance. In conclusion, iron deposition is relatively common in CKD, and may result from altered molecular iron handling and may contribute to renal injury.

Background The antiangiogenic drug sorafenib has been shown to be an effective treatment for hepatocellular carcinoma (HCC) in patients with liver cirrhosis. It might also be effective in noncirrhotic HCC provided that the angiogenic properties of both tumor types are comparable. The aim of this study is to compare endothelial cell dynamics, microvessel density (MVD), and vessel maturation as indirect markers of angiogenesis in human HCC in cirrhotic and noncirrhotic livers. Materials and Methods In a tertiary care setting, 70 consecutive HCC tumors were analyzed for endothelial cell dynamics. CD34 was applied to identify tumor microvessels, double immunolabeling Ki67/CD34 and activated caspase-3/CD34 to assess endothelial cell proliferation and apoptosis, and α-smooth muscle actin/CD34 for pericyte coverage. These characteristics were compared in cirrhotic (n = 33) and noncirrhotic HCCs (n = 37). Microvessel density was correlated with radiological signs of hypervascularity as obtained with dynamic four-phase CT scans during the arterial and portal phase of contrast enhancement. Results Microvessels in cirrhotic and noncirrhotic HCC were mainly mature. In both groups endothelial cell turnover was low and MVD was not different. There was no correlation between MVD and venous invasion, tumor size, and turnover of tumor cells or endothelial cells. MVD was negatively correlated with contrast washout in the portal venous phase of CT scanning. In transplanted patients, MVD was not correlated with survival, whereas in patients after liver resection a high MVD was associated with a better prognosis. Conclusion Angiogenic characteristics of HCC in cirrhotic and noncirrhotic livers have a remarkable similarity.