Androgen Effects on Alcohol-induced Liver Fibrosis Are Controlled by a Notch-dependent Epigenetic Switch.

BACKGROUND & AIMS: Alcohol-associated liver disease (ALD) is a major cause of alcohol-related mortality. Sex is an important variable; however, the mechanism behind sex differences is not yet established. METHODS: Kdm5b flox/flox Kdm5c flox male mice were subjected to gonadectomy or sham surgery. Mice were fed a Western diet and 20% alcohol in the drinking water for 18 weeks. To induce knockout, mice received 2 × 1011 genome copies of AAV8-CMV-Cre or AAV8-control. To test the role of Notch, mice were treated with 10 mg/kg of avagacestat for 4 weeks. RESULTS: We found that Kdm5b/Kdm5c knockout promoted alcohol-induced liver disease, whereas gonadectomy abolished this effect, suggesting that male sex hormones promote liver disease in the absence of KDM5 demethylases. In contrast, in the thioacetamide-induced fibrosis model, male sex hormones showed a protective effect regardless of genotype. In human liver disease samples, we found that androgen receptor expression positively correlated with fibrosis levels when KDM5B levels were low and negatively when KDM5B was high, suggesting that a KDM5B-dependent epigenetic state defines the androgen receptor role in liver fibrosis. Using isolated cells, we found that this difference was due to the differential effect of testosterone on hepatic stellate cell activation in the absence or presence of KDM5B/KDM5C. Moreover, this effect was mediated by KDM5-dependent suppression of Notch signaling. In KDM5-deficient mice, Notch3 and Jag1 gene expression was induced, facilitating testosterone-mediated induction of Notch signaling and stellate cell activation. Inhibiting Notch with avagacestat greatly reduced liver fibrosis and abolished the effect of Kdm5b/Kdm5c loss. CONCLUSIONS: Male sex hormone signaling can promote or prevent alcohol-associated liver fibrosis depending on the KDM5-dependent epigenetic state.

Protective role of 17ß-estradiol in alcohol-associated liver fibrosis is mediated by suppression of integrin signaling.

BACKGROUND: Alcohol-associated liver disease is a complex disease regulated by genetic and environmental factors such as diet and sex. The combination of high-fat diet and alcohol consumption has synergistic effects on liver disease progression. Female sex hormones are known to protect females from liver disease induced by high-fat diet. In contrast, they promote alcohol-mediated liver injury. We aimed to define the role of female sex hormones on liver disease induced by a combination of high-fat diet and alcohol. METHODS: Wild-type and protein arginine methyltransferase (Prmt)6 knockout female mice were subjected to gonadectomy (ovariectomy, OVX) or sham surgeries and then fed western diet and alcohol in the drinking water. RESULTS: We found that female sex hormones protected mice from western diet/alcohol-induced weight gain, liver steatosis, injury, and fibrosis. Our data suggest that these changes are, in part, mediated by estrogen-mediated induction of arginine methyltransferase PRMT6. Liver proteome changes induced by OVX strongly correlated with changes induced by Prmt6 knockout. Using Prmt6 knockout mice, we confirmed that OVX-mediated weight gain, steatosis, and injury are PRMT6 dependent, while OVX-induced liver fibrosis is PRMT6 independent. Proteomic and gene expression analyses revealed that estrogen signaling suppressed the expression of several components of the integrin pathway, thus reducing integrin-mediated proinflammatory (Tnf, Il6) and profibrotic (Tgfb1, Col1a1) gene expression independent of PRMT6 levels. Integrin signaling inhibition using Arg-Gly-Asp peptides reduced proinflammatory and profibrotic gene expression in mice, suggesting that integrin suppression by estrogen is protective against fibrosis development. CONCLUSIONS: Taken together, estrogen signaling protects mice from liver disease induced by a combination of alcohol and high-fat diet through upregulation of Prmt6 and suppression of integrin signaling.

Male-Specific Activation of Lysine Demethylases 5B and 5C Mediates Alcohol-Induced Liver Injury and Hepatocyte Dedifferentiation.

Alcohol-associated liver disease (ALD) is a major cause of alcohol-related mortality. Sex differences in sensitivity to ALD are well described, but these are often disregarded in studies of ALD development. We aimed to define sex-specific pathways in liver exposed to alcohol. Mice were fed the Lieber-DeCarli alcohol liquid diet or a combination of a high-fat diet with alcohol in water. Single-cell RNA sequencing (scRNA-Seq) was performed on liver cells from male and female mice. Mice were treated with adeno-associated virus (AAV)-short hairpin (sh)Control or AAV-sh lysine demethylase 5b (shKdm5b) and/or AAV-shKdm5c vectors. Changes after Kdm5b/5c knockdown were assessed by RNA-Seq and histone H3 lysine K4 (H3K4)me3 chromatin immunoprecipitation-Seq analysis. Using scRNA-Seq analysis, we found several sex-specific pathways induced by alcohol, including pathways related to lipid metabolism and hepatocyte differentiation. Bioinformatic analysis suggested that two epigenetic regulators, H3K4-specific lysine demethylases KDM5B and KDM5C, contribute to sex differences in alcohol effects. We found that in alcohol-fed male mice, KDM5B and KDM5C are involved in hepatocyte nuclear factor 4 alpha (Hnf4a) down-regulation, hepatocyte dedifferentiation, and an increase in fatty acid synthesis. This effect is mediated by alcohol-induced KDM5B and KDM5C recruitment to Hnf4a and other gene promoters in male but not in female mice. Kdm5b and Kdm5c knockdown or KDM5-inhibitor treatment prevented alcohol-induced lipid accumulation and restored levels of Hnf4a and other hepatocyte differentiation genes in male mice. In addition, Kdm5b knockdown prevented hepatocellular carcinoma development in male mice by up-regulating Hnf4a and decreasing tumor cell proliferation. Conclusion: Alcohol specifically activates KDM5 demethylases in male mice to promote alcohol-induced hepatocyte dedifferentiation and tumor development.

Risk Factors for Cerebral Aneurysm Rupture in Mongolia.

PURPOSE: Identification of country-specific demographic, medical, lifestyle, and geoenvironmental risk factors for cerebral aneurysm rupture in the developing Asian country of Mongolia. First-time estimation of the crude national incidence of aneurysmal subarachnoid hemorrhage (aSAH). METHODS: A retrospective analysis of all intracranial digital subtraction angiographies (DSA) acquired in Mongolia during the 2­year period 2016-2017 (1714 examinations) was performed. During this period, DSA was used as primary diagnostic imaging modality for acute severe neurological symptoms in the sole hospital nationwide dedicated to neurological patients. The catchment area of the hospital included the whole country. Patients with incidental and ruptured aneurysms were reviewed with respect to their medical history and living conditions. The data was used to install a Mongolian aneurysm registry. RESULTS: The estimated annual crude incidence of cerebral aneurysm rupture was 6.71 for the country of Mongolia and 14.53 per 100,000 persons for the capital region of Ulaanbaatar. Risk factors common in developed countries also applied for the Mongolian population: A medical history of hypertension, smoking or the presence of multiple aneurysms led to a higher relative risk of rupture. In contrast, female gender was not associated with a higher risk in this national cohort. Males pursuing a traditional nomadic living may exhibit a specifically high risk of rupture. CONCLUSION: Disease management of over 200 individuals/year with aSAH constitutes a socioeconomic burden in Mongolia. Efforts to raise awareness of the risk factors hypertension and smoking among the Mongolian population are desirable. Measures to improve the nationwide availability of modern neurovascular treatment options are currently under consideration.

Hepatocellular Protein Arginine Methyltransferase 1 Suppresses Alcohol-Induced Hepatocellular Carcinoma Formation by Inhibition of Inducible Nitric Oxide Synthase.

Alcohol is a well-established risk factor for hepatocellular carcinoma (HCC), but the mechanisms by which alcohol promotes liver cancer are not well understood. Studies suggest that ethanol may enhance tumor progression by increasing hepatocyte proliferation and through alcohol-induced liver inflammation. Protein arginine methyltransferase 1 (PRMT1) is the main enzyme responsible for cellular arginine methylation. Asymmetric dimethyl arginine, produced by PRMT1, is a potent inhibitor of nitric oxide synthases. PRMT1 is implicated in the development of several types of tumors and cardiovascular disease. Our previous work has shown that PRMT1 in the liver regulates hepatocyte proliferation and oxidative stress and protects from alcohol-induced liver injury. However, its role in HCC development remains controversial. In this study, we found that hepatocyte-specific PRMT1-knockout mice develop an increased number of tumors in an N-nitrosodiethylamine (DEN) alcohol model of liver tumorigenesis in mice. This effect was specific to the alcohol-related component because wild-type and knockout mice developed similar tumor numbers in the DEN model without the addition of alcohol. We found that in the presence of alcohol, the increase in tumor number was associated with increased proliferation in liver and tumor, increased WNT/ß-catenin signaling, and increased inflammation. We hypothesized that increased inflammation was due to increased oxidative and nitrosative stress in knockout mice. By blocking excess nitric oxide production using an inducible nitric oxide synthase inhibitor, we reduced hepatocyte death and inflammation in the liver and prevented the increase in WNT/ß-catenin signaling, proliferation, and tumor number in livers of knockout mice. Conclusion: PRMT1 is an important protection factor from alcohol-induced liver injury, inflammation, and HCC development.

The polymorphism rs975484 in the protein arginine methyltransferase 1 gene modulates expression of immune checkpoint genes in hepatocellular carcinoma.

Protein arginine methyltransferase 1 (PRMT1) is a key regulator of hepatic immune responses. Recently, we reported that PRMT1 regulates the tumor immune response in hepatocellular carcinoma (HCC). Here we found that PRMT1 expression in human HCC correlates with that of programmed cell death 1 ligand 1 (PD-L1), PD-L2, and other checkpoint genes. PRMT1 deletion in mice reduced PD-L1 and PD-L2 expression in tumors and reduced the efficiency of PD-1 antibody treatment in a diethylnitrosamine-induced HCC mouse model, suggesting that PRMT1 regulates the hepatic immune checkpoint. Mice had reduced PD-L1 and PD-L2 expression when PRMT1 was specifically deleted in tumor cells or macrophages, but PRMT1 deletion in dendritic cells did not alter PD-L1 and PD-L2 expression. rs975484 is a common polymorphism in the human PRMT1 gene promoter, and we found that it alters PRMT1 expression in blood monocytes and tumor-associated macrophages in human HCC. PRMT1 expression was higher in individuals with a GG genotype than in individuals with a CC genotype, and heterozygous carriers had intermediate expression. Luciferase reporter assays indicated that this differential expression is due to an extra C/EBPß-binding site in the PRMT1 promoter of individuals carrying the minor G allele. The rs975484 genotype also correlated with PRMT1 target expression in HCC. Individuals with the GG genotype had significantly higher levels of the PRMT1 targets PD-L1, PD-L2, and VISTA than those with the CC genotype. We conclude that PRMT1 critically controls immune checkpoints in mice and humans and that the PRMT1 polymorphism rs975484 affects checkpoint gene expression in HCC.

Inhibition of Endothelial PHD2 Suppresses Post-Ischemic Kidney Inflammation through Hypoxia-Inducible Factor-1.

BACKGROUND: Prolyl-4-hydroxylase domain-containing proteins 1-3 (PHD1 to PHD3) regulate the activity of the hypoxia-inducible factors (HIFs) HIF-1 and HIF-2, transcription factors that are key regulators of hypoxic vascular responses. We previously reported that deficiency of endothelial HIF-2 exacerbated renal ischemia-reperfusion injury, whereas inactivation of endothelial PHD2, the main oxygen sensor, provided renoprotection. Nevertheless, the molecular mechanisms by which endothelial PHD2 dictates AKI outcomes remain undefined. METHODS: To investigate the function of the endothelial PHD2/HIF axis in ischemic AKI, we examined the effects of endothelial-specific ablation of PHD2 in a mouse model of renal ischemia-reperfusion injury. We also interrogated the contribution of each HIF isoform by concurrent endothelial deletion of both PHD2 and HIF-1 or both PHD2 and HIF-2. RESULTS: Endothelial deletion of Phd2 preserved kidney function and limited transition to CKD. Mechanistically, we found that endothelial Phd2 ablation protected against renal ischemia-reperfusion injury by suppressing the expression of proinflammatory genes and recruitment of inflammatory cells in a manner that was dependent on HIF-1 but not HIF-2. Persistence of renoprotective responses after acute inducible endothelial-specific loss of Phd2 in adult mice ruled out a requirement for PHD2 signaling in hematopoietic cells. Although Phd2 inhibition was not sufficient to induce detectable HIF activity in the kidney endothelium, in vitro experiments implicated a humoral factor in the anti-inflammatory effects generated by endothelial PHD2/HIF-1 signaling. CONCLUSIONS: Our findings suggest that activation of endothelial HIF-1 signaling through PHD2 inhibition may offer a novel therapeutic approach against ischemic AKI.

Patients with low Alberta Stroke Program Early CT Score (ASPECTS) but good collaterals benefit from endovascular recanalization.

BACKGROUND: Benefit of thrombectomy in patients with a low initial Alberta Stroke Program Early CT Score (ASPECTS) is still uncertain. We hypothesized that, despite low ASPECTS, patients may benefit from endovascular recanalization if good collaterals are present. METHODS: Ischemic stroke patients with large vessel occlusion in the anterior circulation and an ASPECTS of ≤5 were analyzed. Collateral status (CS) was assessed using a 5-point-scoring system in CT angiography with poor CS defined as CS=0-1. Clinical outcome was determined using the modified Rankin Scale (mRS) score after 90 days. Edema formation was measured in admission and follow-up CT by net water uptake. RESULTS: 27/100 (27%) patients exhibited a CS of 2-4. 50 patients underwent successful vessel recanalization and 50 patients had a persistent vessel occlusion. In multivariable logistic regression analysis, collateral status (OR 3.0; p=0.003) and vessel recanalization (OR 12.2; p=0.009) significantly increased the likelihood of a good outcome (mRS 0-3). A 1-point increase in CS was associated with 1.9% (95% CI 0.2% to 3.7%) lowered lesion water uptake in follow-up CT . CONCLUSION: Endovascular recanalization in patients with ASPECTS of ≤5 but good collaterals was linked to improved clinical outcome and attenuated edema formation. Collateral status may serve as selection criterion for thrombectomy in low ASPECTS patients.

Clinical benefit of thrombectomy in stroke patients with low ASPECTS is mediated by oedema reduction.

The impact of endovascular vessel recanalization on patients with a low initial Alberta Stroke Program Early Computer Tomography Score (ASPECTS) is still uncertain. We hypothesized that vessel recanalization leads to an improvement in mortality and degree of disability by reducing brain oedema and malignant mass effect. In this multicentre observational study, patients with acute ischaemic stroke due to large vessel occlusion in the anterior circulation and an ASPECTS of ≤ 5 were analysed. Patients were assembled into two groups: successful vessel recanalization (thrombolysis in cerebral infarctions, TICI scale 2b/3) or persistent vessel occlusion (no endovascular procedure or TICI scale 0-2a). Observers were blinded to clinical data. Net water uptake within brain infarct, a quantitative biomarker based on CT densitometry, was used to quantify oedema in admission and follow-up CT and Δ-water uptake was calculated as difference between water uptake at both time points. Occurrence of malignant infarctions and secondary parenchymal haemorrhage was documented. Furthermore, modified Rankin scale score at 90 days was used for functional outcome. We included 117 patients admitted between March 2015 and August 2017 in three German stroke centres: 71 with persistent vessel occlusion and 46 with successful recanalization. The mean water uptake in the admission imaging was not different between both groups: 10.0% (±4.8) in patients with persistent vessel occlusion and 9.0% (±4.8) in patients with vessel recanalization (P = 0.4). After follow-up CT, the mean Δ-water uptake was 16.0% (±7.5) in patients with persistent vessel occlusion and 8.0% (±5.7) in patients with vessel recanalization (P < 0.001). Successful reperfusion was independently associated with a lowered Δ-water uptake of 8.0% (95% confidence interval, CI: -10.5 to -5.3%; P < 0.001) and lowered modifed Rankin scale score after 90 days of 1.5 (95% CI: -2.2 to -0.8; P < 0.001). The prevalence of malignant infarctions was 44.3% in patients with persistent vessel occlusion and 26.1% in patients with vessel recanalization. There was no significant difference for secondary haemorrhage in both groups (P = 0.7). In conclusion, successful recanalization in patients with low initial ASPECTS resulted in a significant reduction of oedema formation and was associated with a decreased prevalence of malignant infarctions and an improvement of clinical outcome.

Radiomics of Brain MRI: Utility in Prediction of Metastatic Tumor Type.

Purpose To investigate the feasibility of tumor type prediction with MRI radiomic image features of different brain metastases in a multiclass machine learning approach for patients with unknown primary lesion at the time of diagnosis. Materials and methods This single-center retrospective analysis included radiomic features of 658 brain metastases from T1-weighted contrast material-enhanced, T1-weighted nonenhanced, and fluid-attenuated inversion recovery (FLAIR) images in 189 patients (101 women, 88 men; mean age, 61 years; age range, 32-85 years). Images were acquired over a 9-year period (from September 2007 through December 2016) with different MRI units, reflecting heterogeneous image data. Included metastases originated from breast cancer (n = 143), small cell lung cancer (n = 151), non-small cell lung cancer (n = 225), gastrointestinal cancer (n = 50), and melanoma (n = 89). A total of 1423 quantitative image features and basic clinical data were evaluated by using random forest machine learning algorithms. Validation was performed with model-external fivefold cross validation. Comparative analysis of 10 randomly drawn cross-validation sets verified the stability of the results. The classifier performance was compared with predictions from a respective conventional reading by two radiologists. Results Areas under the receiver operating characteristic curve of the five-class problem ranged between 0.64 (for non-small cell lung cancer) and 0.82 (for melanoma); all P values were less than .01. Prediction performance of the classifier was superior to the radiologists' readings. Highest differences were observed for melanoma, with a 17-percentage-point gain in sensitivity compared with the sensitivity of both readers; P values were less than .02. Conclusion Quantitative features of routine brain MR images used in a machine learning classifier provided high discriminatory accuracy in predicting the tumor type of brain metastases. © RSNA, 2018 Online supplemental material is available for this article.

Improved detectability of acute and subacute brainstem infarctions by combining standard axial and thin-sliced sagittal DWI.

BACKGROUND AND PURPOSE: Most false negative findings in DWI of ischemic stroke are in patients with minor deficits clinically localized to the brainstem. Our goal was to evaluate the benefit of a thin-sliced sagittal DWI in addition to conventional axial DWI at 1.5T for the detection of brainstem infarctions. METHODS: Data of patients with symptoms consistent with acute and subacute brainstem infarction and an MRI examination including standard axial DWI and thin-sliced sagittal DWI were retrospectively analyzed. Patients with the later diagnosis of a TIA, an inflammation or a tumor of the brainstem were excluded from analysis. Diffusion restrictions were identified by two independent raters blinded for the final clinical diagnosis in three separate reading steps: First, only axial DWI, secondly only sagittal DWI, and lastly both DWIs together. Presence and size of DWI-lesions were documented for each plane. Differences between the observers were settled in consensus in a separate joint reading. RESULTS: Of 73 included patients, 46 patients were clinically diagnosed with brainstem infarction. Inter-observer agreement was excellent for the detection of brainstem lesions in axial and sagittal DWI (kappa = 0.94 and 0.97). In 28/46 patients (60.9%) lesions were detected in the axial plane alone, whereas in 6 more patients (73.9%) lesions were detected in the review of both sequences together. All lesions undetectable in the axial plane were smaller than 5 mm in cranio-caudal direction. CONCLUSIONS: Thin-sliced sagittal DWI in addition to axial DWI improves the detection rate of brainstem infarction with little additional expenditure of time.

Dysfunction of intraflagellar transport-A causes hyperphagia-induced obesity and metabolic syndrome.

Primary cilia extend from the plasma membrane of most vertebrate cells and mediate signaling pathways. Ciliary dysfunction underlies ciliopathies, which are genetic syndromes that manifest multiple clinical features, including renal cystic disease and obesity. THM1 (also termed TTC21B or IFT139) encodes a component of the intraflagellar transport-A complex and mutations in THM1 have been identified in 5% of individuals with ciliopathies. Consistent with this, deletion of murine Thm1 during late embryonic development results in cystic kidney disease. Here, we report that deletion of murine Thm1 during adulthood results in obesity, diabetes, hypertension and fatty liver disease, with gender differences in susceptibility to weight gain and metabolic dysfunction. Pair-feeding of Thm1 conditional knock-out mice relative to control littermates prevented the obesity and related disorders, indicating that hyperphagia caused the obese phenotype. Thm1 ablation resulted in increased localization of adenylyl cyclase III in primary cilia that were shortened, with bulbous distal tips on neurons of the hypothalamic arcuate nucleus, an integrative center for signals that regulate feeding and activity. In pre-obese Thm1 conditional knock-out mice, expression of anorexogenic pro-opiomelanocortin (Pomc) was decreased by 50% in the arcuate nucleus, which likely caused the hyperphagia. Fasting of Thm1 conditional knock-out mice did not alter Pomc nor orexogenic agouti-related neuropeptide (Agrp) expression, suggesting impaired sensing of changes in peripheral signals. Together, these data indicate that the Thm1-mutant ciliary defect diminishes sensitivity to feeding signals, which alters appetite regulation and leads to hyperphagia, obesity and metabolic disease.

Multicentre cohort study 'Rehabilitation of Occupational Skin Diseases - Optimization and Quality Assurance of Inpatient Management (ROQ)': results from a 3-year follow-up.

BACKGROUND: A tertiary individual prevention programme (TIP) is offered to patients with severe occupational skin disease (OSD) in Germany. Previously, it was shown that the burden of OSDs is considerably reduced in patients up to 1 year after the TIP. OBJECTIVES: To evaluate the long-term effects of the TIP. PATIENTS AND METHODS: In a prospective multicentre cohort study, the clinical and patient-reported outcome data 3 years after the TIP were evaluated. RESULTS: Of the 1788 patients initially included in the study, 1410 were available for the 3-year follow-up analysis. The severity of OSD, the use of topical corticosteroids and days of absence from work were significantly reduced 3 years after the TIP, and the quality of life and skin protective behaviour were significantly improved. Of the patients, 96.9% were able to resume work. One thousand one hundred and sixty-six patients (82.7%) were still working 3 years after the TIP, 874 of them (75.0%) in the same occupational field. Hairdressers had the lowest rate of remaining in their original profession (41.3%). CONCLUSIONS: The follow-up during 3 years of this unique cohort of patients with OSDs shows that the TIP is associated with sustained improvements in terms of disease severity, ability to work, quality of life, and prognosis.

The Endothelial Prolyl-4-Hydroxylase Domain 2/Hypoxia-Inducible Factor 2 Axis Regulates Pulmonary Artery Pressure in Mice.

Hypoxia-inducible factors 1 and 2 (HIF-1 and -2) control oxygen supply to tissues by regulating erythropoiesis, angiogenesis and vascular homeostasis. HIFs are regulated in response to oxygen availability by prolyl-4-hydroxylase domain (PHD) proteins, with PHD2 being the main oxygen sensor that controls HIF activity under normoxia. In this study, we used a genetic approach to investigate the endothelial PHD2/HIF axis in the regulation of vascular function. We found that inactivation of Phd2 in endothelial cells specifically resulted in severe pulmonary hypertension (∼118% increase in right ventricular systolic pressure) but not polycythemia and was associated with abnormal muscularization of peripheral pulmonary arteries and right ventricular hypertrophy. Concurrent inactivation of either Hif1a or Hif2a in endothelial cell-specific Phd2 mutants demonstrated that the development of pulmonary hypertension was dependent on HIF-2α but not HIF-1α. Furthermore, endothelial HIF-2α was required for the development of increased pulmonary artery pressures in a model of pulmonary hypertension induced by chronic hypoxia. We propose that these HIF-2-dependent effects are partially due to increased expression of vasoconstrictor molecule endothelin 1 and a concomitant decrease in vasodilatory apelin receptor signaling. Taken together, our data identify endothelial HIF-2 as a key transcription factor in the pathogenesis of pulmonary hypertension.

Evaluation of four different optimized magnetic-resonance-imaging sequences for visualization of dental and maxillo-mandibular structures at 3 T.

OBJECTIVES: The purpose of this study was to evaluate four in-house optimized, non-contrast enhanced sequences for MRI-investigation of maxillo-mandibular and dental structures by use of 3 T. METHODS: 12 volunteers with different dental status were examined by using a 3 T MRI with a 20-channel standard head-and-neck coil. All images performed were evaluated by using 3D-techniques, with different slice-thicknesses, in 3D T1- and T2-weighted sequences, as well as by using new techniques of image depictions. In addition phantom measurements were performed to estimate the extent of image artefacts caused by retainers and metal implants. RESULTS: Mean age of the participants was 33 years (range, 25.5-62.75 years), and the sex ratio was 5 females to 7 males. We identified different techniques to improve osseous and dental structures, despite problems caused by dental implants, tooth crowns or braces. CONCLUSION: The sequences evaluated offered excellent visualization in 2D and 3D of osseous and dental structures. Anatomical, osseous and dental structures were described at their ROI, in relation to patients with dental and head and neck pathologies. The ability to detect and distinguish pathological processes as soon as possible in 3D with excellent image quality avoiding ionizing radiation remains a challenging domain.

Downregulating hedgehog signaling reduces renal cystogenic potential of mouse models.

Renal cystic diseases are a leading cause of renal failure. Mutations associated with renal cystic diseases reside in genes encoding proteins that localize to primary cilia. These cystoproteins can disrupt ciliary structure or cilia-mediated signaling, although molecular mechanisms connecting cilia function to renal cystogenesis remain unclear. The ciliary gene, Thm1(Ttc21b), negatively regulates Hedgehog signaling and is most commonly mutated in ciliopathies. We report that loss of murine Thm1 causes cystic kidney disease, with persistent proliferation of renal cells, elevated cAMP levels, and enhanced expression of Hedgehog signaling genes. Notably, the cAMP-mediated cystogenic potential of Thm1-null kidney explants was reduced by genetically deleting Gli2, a major transcriptional activator of the Hedgehog pathway, or by culturing with small molecule Hedgehog inhibitors. These Hedgehog inhibitors acted independently of protein kinase A and Wnt inhibitors. Furthermore, simultaneous deletion of Gli2 attenuated the renal cystic disease associated with deletion of Thm1. Finally, transcripts of Hedgehog target genes increased in cystic kidneys of two other orthologous mouse mutants, jck and Pkd1, and Hedgehog inhibitors reduced cystogenesis in jck and Pkd1 cultured kidneys. Thus, enhanced Hedgehog activity may have a general role in renal cystogenesis and thereby present a novel therapeutic target.

Multicentre study 'rehabilitation of occupational skin diseases -optimization and quality assurance of inpatient management (ROQ)'-results from 12-month follow-up.

BACKGROUND: Occupational skin disease (OSD) is common, and imposes a considerable personal and public burden. To tackle OSD, the German stepwise procedure of handling OSD was set up. It contains an interdisciplinary, integrated inpatient rehabilitation measure [tertiary individual prevention (TIP)] [dermatological treatment and diagnostic procedures, and patient education (health and psychological)]. The primary aims of the TIP are reduction of the severity of OSD, reduction in the use of corticosteroids, facilitation of return to work, decreased absence from work, and enhanced quality of life (QoL). It was positively evaluated for a period of 4 weeks after return to work. OBJECTIVES: To investigate whether the observed short-term effects remain significant and meaningful over a period of 12 months after discharge from the TIP. METHODS: A prospective design was used to compare clinical and patient-reported outcome data between admission to a 3-week inpatient TIP and 12 months after discharge (12-month follow-up). RESULTS: Of 1788 individuals admitted to the TIP, data from 1617 individuals were available for analysis. We observed a significant reduction in the severity of OSD, the use of topical corticosteroids, and days of absence from work because of OSD. QoL was significantly improved, and 87.4% were able to return to work and remain in the workforce. CONCLUSIONS: A randomized controlled trial would have been desirable, but was not possible, for legal and other reasons. However, the long-term 12-month follow-up shows that the TIP is associated with sustained improvements in terms of ability to work, QoL, and prognosis, and reductions in days of absence from work because of skin conditions and topical corticosteroid application. These results indicate that the TIP provided a reduction in the personal and public burden of OSD.

First results from the multicentre study rehabilitation of occupational skin diseases--optimization and quality assurance of inpatient management (ROQ).

UNLABELLED: BACKGROUND AND OBJECTIVES. The German stepwise procedure of handling occupational skin diseases (OSDs) offers interdisciplinary integrated (inpatient/outpatient) rehabilitation measures [tertiary individual prevention (TIP)] for severe OSD. In 2005, a prospective cohort multicentre study was started in order to evaluate TIP. METHODS: One thousand seven hundred and eighty-eight patients with severe OSD were treated and educated in five clinics with follow-up before and 4 weeks after return to work. RESULTS: During the inpatient phase, there was a significant improvement in the severity of OSD (Osnabrueck Hand Eczema Severity Index, p < 0.001) and in the quality of life (Dermatology Life Quality Index, p < 0.001). These effects were largely sustained during the outpatient follow-up phase and in the 4 weeks after return to work. Among all patients, 89.4% used topical steroids before TIP, including 52.5% using high-grade topical steroids; 93.2% of the patients were able to refrain from using topical steroids before returning to work. As a result of TIP, return to work was possible for 1587 patients (88.8%). CONCLUSIONS: The primary objectives of TIP (return to work, improvement of OSD, enhancement of quality of life, and reduction in the use of topical steroids) were successfully met. The long-term follow-up (1 and 3 years after TIP) will examine whether these favourable outcomes can be sustained.