Enzyme replacement therapy in mice lacking arylsulfatase B targets bone-remodeling cells, but not chondrocytes.

Mucopolysaccharidosis type VI (MPS-VI), caused by mutational inactivation of the glycosaminoglycan-degrading enzyme arylsulfatase B (Arsb), is a lysosomal storage disorder primarily affecting the skeleton. We have previously reported that Arsb-deficient mice display high trabecular bone mass and impaired skeletal growth. In the present study, we treated them by weekly injection of recombinant human ARSB (rhARSB) to analyze the impact of enzyme replacement therapy (ERT) on skeletal growth and bone remodeling. We found that all bone-remodeling abnormalities of Arsb-deficient mice were prevented by ERT, whereas chondrocyte defects were not. Likewise, histologic analysis of the surgically removed femoral head from an ERT-treated MPS-VI patient revealed that only chondrocytes were pathologically affected. Remarkably, a side-by-side comparison with other cell types demonstrated that chondrocytes have substantially reduced capacity to endocytose rhARSB, together with low expression of the mannose receptor. We finally took advantage of Arsb-deficient mice to establish quantification of chondroitin sulfation for treatment monitoring. Our data demonstrate that bone-remodeling cell types are accessible to systemically delivered rhARSB, whereas the uptake into chondrocytes is inefficient.

The gut hormone glucose-dependent insulinotropic polypeptide is downregulated in response to myocardial injury.

BACKGROUND: The gut incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic peptide) are secreted by enteroendocrine cells following food intake leading to insulin secretion and glucose lowering. Beyond its metabolic function GIP has been found to exhibit direct cardio- and atheroprotective effects in mice and to be associated with cardiovascular prognosis in patients with myocardial infarction. The aim of this study was to characterize endogenous GIP levels in patients with acute myocardial infarction. METHODS AND RESULTS: Serum concentrations of GIP were assessed in 731 patients who presented with clinical indication of coronary angiography. Circulating GIP levels were significantly lower in patients with STEMI (ST-elevation myocardial infarction; n=100) compared to clinically stable patients without myocardial infarction (n=631) (216.82 pg/mL [Q1-Q3: 52.37-443.07] vs. 271.54 pg/mL [Q1-Q3: 70.12-542.41], p = 0.0266). To characterize endogenous GIP levels in patients with acute myocardial injury we enrolled 18 patients scheduled for cardiac surgery with cardiopulmonary bypass and requirement of extracorporeal circulation as a reproducible condition of myocardial injury. Blood samples were drawn directly before surgery (baseline), upon arrival at the intensive care unit (ICU), 6 h post arrival to the ICU and at the morning of the first and second postoperative days. Mean circulating GIP concentrations decreased in response to surgery from 45.3 ± 22.6 pg/mL at baseline to a minimum of 31.9 ± 19.8 pg/mL at the first postoperative day (p = 0.0384) and rose again at the second postoperative day (52.1 ± 28.0 pg/mL). CONCLUSIONS: Circulating GIP levels are downregulated in patients with myocardial infarction and following cardiac surgery. These results might suggest nutrition-independent regulation of GIP secretion following myocardial injury in humans.

Safety and efficacy of transcatheter mitral valve repair in patients with COPD; results from real-world cohort.

OBJECTIVE: To evaluate the safety and efficacy of transcatheter mitral valve repair (TMVR) in patients with chronic obstructive pulmonary disease (COPD). BACKGROUND: Heart failure and COPD share many clinical features and commonly coexist. Data about the safety and efficacy of TMVR in patients with COPD is not conclusive. METHODS: Three hundred and forty consecutive patients undergoing TMVR were retrospectively included. COPD diagnosis was based on pulmonary function tests (PFTs). Intra-hospital, 30-day- and 1-year outcomes were compared between both groups. RESULTS: Eighty-two patients had COPD (24%). There was no difference in intra-hospital mortality between patients with and without COPD (both 5%, p = 0.95). Among patients who had a successful procedure and survived to discharge there was a trend toward more rehospitalization due to decompensated heart failure at 30-day follow-up in patients with COPD (12.9% vs. 6.8%, p = 0.08) with no difference in mortality. At median follow-up of 1 year, New York heart association (NYHA) category was comparable among both groups and there was no significant difference in rehospitalization (COPD: 29.9% vs. non-COPD: 34%, p = 0.5). There was a trend toward increased 1-year mortality in COPD patients (31.2% vs. 20.6%, p = 0.06). However, a composite endpoint of rehospitalization or death at 1 year did not differ between both groups (48% vs. 42.5%, p = 0.4). Regression analysis showed no correlation between COPD severity and worse TMVR outcomes. CONCLUSIONS: COPD is highly prevalent among patients undergoing TMVR. However, TMVR seems to be safe and effective in COPD patients. COPD severity and PFT impairment alone should not be considered as a contraindication for TMVR.

Optimal bail-out and complication management strategies in protected high-risk percutaneous coronary intervention with the Impella.

Despite the routine use of percutaneous mechanical circulatory support (pMCS) with the Impella heart pump, vascular and bleeding complications may occur during removal with or without pre-closure. To safely close the large-bore access (LBA), post-hoc selection of the appropriate treatment of vascular complications is critical to patient recovery and survival. Femoral artery access is typically utilized for LBA, and percutaneous axillary artery access is a common alternative, especially in the instance of severe peripheral artery disease. Optimization of patient outcomes and efficiency of pMCS can be achieved with adequate arterial access using state-of-the-art techniques. Impella removal techniques with or without pre-closure will be addressed as well as the management of large-bore femoral access complications. In addition, treatment strategies to manage patient deterioration during a protected high-risk percutaneous coronary intervention will be provided.

Handling high-risk patients in the catheterization laboratory.

Protected percutaneous coronary intervention is considered a life-saving procedure for high-risk patients. Therefore it is important that the interventional cardiology team is prepared, the procedure is planned, and potential complications, as well as bail out strategies are considered. Throughout the procedure, it is critical to monitor the patient to identify any early signs of deterioration or changes in patient well-being to avoid any potential complications.

General Anesthesia Leads to Underestimation of Regurgitation Severity in Patients With Secondary Mitral Regurgitation Undergoing Transcatheter Mitral Valve Repair.

OBJECTIVES: To evaluate the effect of general anesthesia (GA) on severity of mitral regurgitation (MR) in patients undergoing transcatheter mitral valve repair (TMVR). DESIGN: Retrospective cohort study. SETTING: Tertiary care university hospital. PARTICIPANTS: Fifty consecutive patients with symptomatic severe MR and extremely high surgical risk. INTERVENTION: TMVR under GA. MEASUREMENTS AND RESULTS: Transesophageal echocardiography was performed during the preprocedural workup under conscious sedation and during TMVR under GA. After the parameters of MR were assessed, color-flow jet area (CJA), vena contracta (VC), effective regurgitant orifice area (EROA), regurgitant volume (RVOL), three-dimensional (3D) vena contracta area (VCA), and severity of MR were compared between the two examinations. In patients with primary MR (n = 11), there were no significant differences in CJA, VC, EROA, RVOL, or 3D-VCA between pre- and intraprocedural transesophageal echocardiography. In patients with secondary MR (n = 39), GA led to significant decreases of CJA (10 ± 7 v 7 ± 3 cm², p < 0.001), VC (5.5 ± 1.6 v 4.7 ± 1.5 mm, p = 0.002), EROA (30 ± 11 v 24 ± 10 mm², p < 0.001), and RVOL (47 ± 17 v 34 ± 13 mL/beat, p < 0.001). Consequently, GA led to a downgrade of regurgitation severity classification in 44% of patients when assessed by two-dimensional analysis. When evaluated by 3D analysis, GA also led to a significant but less extensive decrease of MR (3D-VCA: 66 ± 27 v 60 ± 29 mm², p = 0.002), and subsequent downgrade of MR classification in 20% of patients. CONCLUSIONS: GA underestimates regurgitation severity in patients with secondary, but not primary MR, undergoing TMVR. This effect must be considered when evaluating the immediate result of the procedure.

[Update on imaging in femoroacetabular impingement syndrome]. / Update Bildgebung beim Femoroazetabulären Impingement-Syndrom.

BACKGROUND: Properly performed high-quality imaging is critical in the diagnosis of femoroacetabular impingement syndrome (FAIS). Currently, conventional imaging in the form of an anteroposterior view of the pelvis and at least a second view is still the first step in the diagnosis of FAIS. Here, by determining the various parameters, the acetabular configuration should also be accurately assessed with regard to a combination with dysplasia or acetabular retroversion. MRI: MRI should also be demanded as standard before joint-preserving surgery. It allows for more precise detection of morphology, secondary chondrolabral damage, and thus helps identify outcome-relevant risk factors and cases that are too advanced in terms of degenerative aspects. OTHER IMAGING METHODS: Depending on the problem, MRI can be supplemented by intravenous or intra-articular application of contrast agents (indirect or direct MRA), determination of torsion, and, if necessary, even with the performance of a traction MRA. While the importance of invasive MRA has decreased due to the improvements of 3­Tesla scanners in clinical practice, rotational analysis has gained in importance. Computed tomography (CT), although associated with increased radiation exposure, allows high-resolution imaging of bony structures and extremely illustrative 3D planning of complex corrections, and is an alternative to MRI for this purpose or in contraindications. PROSPECTS: 4D simulations appear useful and may make diagnostics and therapy planning safer and easier in the future. Thus, a broad portfolio of imaging techniques is available today, the advances of which have contributed significantly to the development of differentiated joint-preserving surgery of the hip joint.

Hemodynamic support with Impella ventricular assist device in patients undergoing TAVI: A single center experience.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) has become a well-established therapeutic option for patients with severe aortic stenosis (AS) at high to intermediate surgical risk. Although TAVI is associated with low mortality of 1.2-6.5%, cardiogenic shock (CS) as a peri-interventional complication remains a challenging problem with very high morbidity and mortality. AIM: This study evaluated the clinical outcome of the use of Impella ventricular assist device in patients undergoing TAVI. METHODS: Between 11/2015 and 08/2018, all patients undergoing TAVI requiring temporary circulatory during the same index hospitalization were included. Primary endpoint was 30-day all-cause mortality. Secondary endpoints were peri-interventional mortality and 30-day stroke rate. RESULTS: Of the 390 patients undergoing TAVI, 13 (3%) required hemodynamic support with an Impella device. Of these, 3 (23%) underwent protected high-risk PCI before TAVI and 10 patients (77%) needed emergency periprocedural hemodynamic support due to cardiogenic shock. Mortality at 30 days was 0% in Impella-protected PCI and 40% with Impella use for periprocedural CS. No stroke occurred in the cohort up to 30 days. Insertion of the Impella device in the setting of TAVI was fast with a mean insertion time of 10 min. Eight patients (80%) in the periprocedural CS group required cardiopulmonary resuscitation prior to Impella use. There was only one device-related complication. CONCLUSIONS: Temporary hemodynamic support with the Impella device in patients with severe aortic valve stenosis or in CS secondary to complicated TAVI was technically doable and allowed stabilization and treatment of salvageable patients.

Outcome predictors of patients with out of hospital cardiac arrest and immediate coronary angiography.

BACKGROUND: Out of hospital cardiac arrest (OHCA) is common and associated with low survival rates. Guidelines propose a fast work-up after OHCA including coronary angiography (CA) but little is known about the actual outcome of those patients who undergo immediate CA after OHCA with suspected cardiac origin. AIM: The aim of this retrospective single-center study was to evaluate the short-term outcomes and predictors of in-hospital mortality in patients who underwent immediate CA after OHCA with suspected cardiac origin. METHODS: We included all consecutive patients with OHCA who underwent immediate CA between January 2011 and December 2015. We defined immediate CA after OHCA as angiography within 2 hr after admission. RESULTS: Two hundred and nineteen consecutive patients with OHCA were included. Fifty six patients (26%) underwent CA without previous return of spontaneous circulation (ROSC) and with ongoing CPR using the LUCAS-device. One hundred and forty nine patients (67%) died in hospital. Of the 56 patients with CA with ongoing CPR, 55 died and only 1 patient survived to hospital discharge. In a multivariate analysis, older age (OR = 2.03, 95%CI 1.35-3.03; p = .001), initial shockable rhythm (OR = 0.28, 95%CI 0.07-1.13; p = .076), CA with ongoing CPR (OR = 11.63, 95%CI 1.20-122.55; p = .035), and initial arterial pH (OR = 0.008, 95%CI 0.00-0.228; p < .005) remained as independent predictors for in-hospital mortality. CONCLUSIONS: In this study older age, metabolic derangement on admission, initial nonshockable rhythm and failure to achieve ROSC before admission predicted in-hospital mortality. While CA with ongoing CPR with the LUCAS-device was feasible, mortality in patients without previous ROSC was extremely high, questioning whether this approach is medically useful.

Arthroscopic matrix-associated, injectable autologous chondrocyte transplantation of the hip: significant improvement in patient-related outcome and good transplant quality in MRI assessment.

PURPOSE: Acetabular chondral lesions are common in patients with FAI. For large full-thickness cartilage defects, arthroscopic matrix-associated autologous chondrocyte transplantation (MACT) using an injectable in situ crosslinking product is an option. Aim of the study was to evaluate clinical and MRI results 12 months after MACT of acetabular cartilage defects in FAI patients. METHODS: We report data on 21 patients with a focal cartilage defect of the hip [2.97 ± 1.44 cm2 (mean ± SD)] caused by FAI treated with an arthroscopically conducted MACT combined with FAI surgery. The results were assessed with patient-reported outcome measures (iHOT33, EQ-5D) pre- as well as post-operatively and by MRI using MOCART scoring system 6 and 12 months post-operatively. RESULTS: The iHOT33 score improved from 52.9 ± 21.14 (mean ± SD) pre-operative to 81.08 ± 22.04 (mean ± SD; p = 0.0012) 12 months post-operatively. The lower the pre-operative iHOT33 score and the larger the defect size, the greater the observed improvement compared to pre-operative scores at 12 months. Patients showed a significant improvement in EQ-5D-5L index value (p = 0.0015) and EQ-5D VAS (p = 0.0006). MRI analysis after 12 months revealed a complete integration of the transplant in 16 of 20 patients. CONCLUSIONS: Injectable MACT is a promising minimally invasive treatment option for full-thickness cartilage defects of the hip caused by FAI. A significant improvement in symptoms and function associated with an increase in quality of life was detected in patients treated with injectable MACT combined with FAI surgery. This is of considerable clinical relevance, since, in addition to the elimination of the mechanical cause, MACT allows the successful therapy of consequential cartilage damage. LEVEL OF EVIDENCE: Level 4, case series.

[Diagnostic algorithm "FAI and sports hernia" : Results of the consensus meeting for groin pain in athletes]. / Diagnostik-Algorithmus Grenzbereich "FAI und Sportlerleiste" : Ergebnisse des Konsensustreffens Leistenschmerz beim Sportler.

As a result of the complexity and diversity of diseases in the region of the groin, differentiation of the various soft-tissue and bone pathologies remains a challenge for differential diagnosis in routine clinical practice. In the case of athletes with pain localized in the area of the groin, femoroacetabular impingement (FAI) and athlete's groin must be considered as important causes of the groin pain, whereby the common occurrence of double pathologies further complicates diagnosis. Despite the importance of groin pain and its differential diagnoses in everyday clinical practice, there has been a lack of recognized recommendations for diagnostic procedure to date. To this end, a consensus meeting was held in February 2017, in which a group composed equally of groin and hip surgeons took part. With the formulation of recommendations and the establishment of a practicable diagnostic path, colleagues that are involved in treating such patients should be sensitized to this issue and the quality of the diagnosis of groin pain improved in routine clinical practice.

Single CpG hypermethylation, allele methylation errors, and decreased expression of multiple tumor suppressor genes in normal body cells of mutation-negative early-onset and high-risk breast cancer patients.

To evaluate the role of constitutive epigenetic changes in normal body cells of BRCA1/BRCA2-mutation negative patients, we have developed a deep bisulfite sequencing assay targeting the promoter regions of 8 tumor suppressor (TS) genes (BRCA1, BRCA2, RAD51C, ATM, PTEN, TP53, MLH1, RB1) and the estrogene receptor gene (ESR1), which plays a role in tumor progression. We analyzed blood samples of two breast cancer (BC) cohorts with early onset (EO) and high risk (HR) for a heterozygous mutation, respectively, along with age-matched controls. Methylation analysis of up to 50,000 individual DNA molecules per gene and sample allowed quantification of epimutations (alleles with >50% methylated CpGs), which are associated with epigenetic silencing. Compared to ESR1, which is representative for an average promoter, TS genes were characterized by a very low (< 1%) average methylation level and a very low mean epimutation rate (EMR; < 0.0001% to 0.1%). With exception of BRCA1, which showed an increased EMR in BC (0.31% vs. 0.06%), there was no significant difference between patients and controls. One of 36 HR BC patients exhibited a dramatically increased EMR (14.7%) in BRCA1, consistent with a disease-causing epimutation. Approximately one third (15 of 44) EO BC patients exhibited increased rates of single CpG methylation errors in multiple TS genes. Both EO and HR BC patients exhibited global underexpression of blood TS genes. We propose that epigenetic abnormalities in normal body cells are indicative of disturbed mechanisms for maintaining low methylation and appropriate expression levels and may be associated with an increased BC risk.

Long-term outcome of pigmented villonodular synovitis of the hip after joint preserving therapy.

INTRODUCTION: Pigmented villonodular synovitis (PVNS) is a rare, destructive synovial disease that affects the hip joint the second most common after the knee. However, in contrast, joint preserving surgery in the hip joint is considered to be significantly more difficult or even impossible due to earlier occurrence of osteochondral dissemination and surgical difficulties. Today, earlier diagnosis due to the generous use of MRI and modern surgical strategies raise hope for improved outcomes. METHODS: Since 2005, six patients with PVNS of the hip and a minimal follow-up of 2 years underwent joint preserving surgery in our institution (mean age 20.5 years, range 14-27). After PVNS was suspected in the MRI and confirmed by arthroscopic biopsy (four diffuse, two focal forms), synovectomy was carried out in 5 patients via surgical hip dislocation and in one focal case via arthroscopy. In diffuse forms, adjuvant radiosynoviorthesis (RSO) was conducted 6-8 week postoperatively. MRI and clinical examinations were performed during follow-up. RESULTS: After a mean follow-up of 8 years (range 35-141 months), five of six patients did not show recurrence or secondary osteoarthritis. Clinical outcome evaluation resulted in a mean modified Harris Hip Score of 91 points (range 67-100 points). A 21-year-old patient with a diffuse form and advanced osteochondral involvement at the time of diagnosis was eventually treated by total hip arthroplasty. CONCLUSION: In cases without osteochondral involvement, recurrence-free long-term results without progression of joint degeneration can be achieved by joint preserving therapy.

Arthroscopic treatment of femoroacetabular impingement shows persistent clinical improvement in the mid-term.

INTRODUCTION: The concept of femoroacetabular impingement (FAI) and the indication for surgical intervention have been established in the last decade. Despite promising short-term results and emerging arthroscopic techniques, it remains unclear whether patients benefit from surgical correction in the mid- to long-term and whether progressive joint degeneration can be prevented. MATERIALS AND METHODS: A retrospective study of our first 50 consecutive patients who underwent arthroscopic correction for FAI was conducted. The modified Harris hip score (mHHS) was assessed preoperatively and at final follow-up. In addition, the Western Ontario and McMaster Universities osteoarthritis index (WOMAC) and a subjective hip value (SHV) were added at final follow-up. Degenerative changes according to Kellgren and Lawrence scale and the α angle were analyzed preoperatively and on the most recent radiograph. RESULTS: Of a total of 50 patients, 44 (24 male, 20 female) with a mean age of 34.3 years (17-65) were available with complete follow-up. Of these 44 patients, 39 were treated with correction of the femoral offset for isolated cam deformity, 5 with additional focal pincer correction and partial labral resection. After a mean follow-up of 66.3 ± 14.5 months the mHHS had improved significantly from 67.2 ± 6.4 preoperatively to 86.4 ± 13.5 (p < 0.001). The WOMAC score (converted to 0 = best/100 = worst) resulted in mean indices for the subcategories pain, stiffness and function of 11.8 ± 16.5, 12.2 ± 17.8 and 9.1 ± 16.1. The SHV was reported with a mean of 77.7 ± 21.8 % at final follow-up. The α angle was reduced significantly from 57.2° ± 10.1° to 46.3° ± 7.4° (p < 0.001). The Kellgren and Lawrence score showed a non-significant trend from 2.0 ± 0.8 preoperatively to 2.2 ± 0.9 in the most recent radiograph (p = 0.46). 5 patients had been converted to a total hip arthroplasty a mean of 28 ± 7.1 months postoperatively. These patients were significantly (p < 0.01) older with a mean age of 49.8 ± 7.8 years and showed significantly higher present osteoarthritic changes with an average Kellgren and Lawrence score of 2.6 ± 2.5 before FAI correction (p < 0.01). CONCLUSIONS: Arthroscopic correction of femoroacetabular impingement results in a persistent clinical improvement without significant progression of degenerative changes in the majority of patients. The indication for surgery should be established cautiously when degenerative changes are present. LEVEL OF EVIDENCE: Level IV, Case series with no comparison group.

Autoantibodies in dilated cardiomyopathy induce vascular endothelial growth factor expression in cardiomyocytes.

BACKGROUND: Autoantibodies have been identified as major predisposing factors for dilated cardiomyopathy (DCM). Patients with DCM show elevated serum levels of vascular endothelial growth factor (VEGF) whose source is unknown. Besides its well-investigated effects on angiogenesis, evidence is present that VEGF signaling is additionally involved in fibroblast proliferation and cardiomyocyte hypertrophy, hence in cardiac remodeling. Whether autoimmune effects in DCM impact cardiac VEGF signaling needs to be elucidated. METHODS: Five DCM patients were treated by the immunoadsorption (IA) therapy on five consecutive days. The eluents from the IA columns were collected and prepared for cell culture. Cardiomyocytes from neonatal rats (NRCM) were incubated with increasing DCM-immunoglobulin-G (IgG) concentrations for 48 h. Polyclonal IgG (Venimmun N), which was used to restore IgG plasma levels in DCM patients after the IA therapy was additionally used for control cell culture purposes. RESULTS: Elevated serum levels of VEGF decreased significantly after IA (Serum VEGF (ng/ml); DCM pre-IA: 45 ± 9.1 vs. DCM post-IA: 29 ± 6.7; P < 0.05). In cell culture, pretreatment of NRCM by DCM-IgG induced VEGF expression in a time and dose dependent manner. Biologically active VEGF that was secreted by NRCM significantly increased BNP mRNA levels in control cardiomyocytes and induced cell-proliferation of cultured cardiac fibroblast (Fibroblast proliferation; NRCM medium/HC-IgG: 1 ± 0.0 vs. NRCM medium/DCM-IgG 100 ng/ml: 5.6 ± 0.9; P < 0.05). CONCLUSION: The present study extends the knowledge about the possible link between autoimmune signaling in DCM and VEGF induction. Whether this observation plays a considerable role in cardiac remodeling during DCM development needs to be further elucidated.

Degarelix therapy for prostate cancer in a real-world setting: experience from the German IQUO (Association for Uro-Oncological Quality Assurance) Firmagon® registry.

BACKGROUND: We investigated the use of the gonadotropin-releasing hormone (GnRH) antagonist degarelix in everyday clinical practice using registry data from uro-oncology practices in Germany. METHODS: Data were analysed retrospectively from the IQUO (Association for uro-oncological quality assurance) patient registry. Data were prospectively collected from all consecutive PCa patients treated with degarelix (n = 1010) in 138 uro-oncology practices in Germany between May 2009 and December 2013. RESULTS: Median overall survival had not yet been reached in the all-patient group or in subgroups who had or had not received prior hormonal therapy (HT). Cox regression analysis showed that patients who had received prior HT (n = 542) had a 58 % increased mortality risk (hazard ratio 1.58, 95 % CI 1.20-2.09) versus patients who had not (n = 468) (p = 0.001). Also, in patients who had received prior luteinizing hormone-releasing hormone (LHRH) analogue therapy (LHRH agonists or GnRH antagonists), median time to PSA progression was shorter (209 weeks) than in those who had not received prior LHRH analogues (n = 555; median PSA progression-free survival not yet reached). Degarelix was generally well tolerated. CONCLUSIONS: Degarelix was effective and well tolerated in everyday clinical practice, confirming observations from clinical studies. Patients who received prior HT appeared to have a significantly higher mortality risk.

Targeted next-generation sequencing of deafness genes in hearing-impaired individuals uncovers informative mutations.

PURPOSE: Targeted next-generation sequencing provides a remarkable opportunity to identify variants in known disease genes, particularly in extremely heterogeneous disorders such as nonsyndromic hearing loss. The present study attempts to shed light on the complexity of hearing impairment. METHODS: Using one of two next-generation sequencing panels containing either 80 or 129 deafness genes, we screened 30 individuals with nonsyndromic hearing loss (from 23 unrelated families) and analyzed 9 normal-hearing controls. RESULTS: Overall, we found an average of 3.7 variants (in 80 genes) with deleterious prediction outcome, including a number of novel variants, in individuals with nonsyndromic hearing loss and 1.4 in controls. By next-generation sequencing alone, 12 of 23 (52%) probands were diagnosed with monogenic forms of nonsyndromic hearing loss; one individual displayed a DNA sequence mutation together with a microdeletion. Two (9%) probands have Usher syndrome. In the undiagnosed individuals (10/23; 43%) we detected a significant enrichment of potentially pathogenic variants as compared to controls. CONCLUSION: Next-generation sequencing combined with microarrays provides the diagnosis for approximately half of the GJB2 mutation-negative individuals. Usher syndrome was found to be more frequent in the study cohort than anticipated. The conditions in a proportion of individuals with nonsyndromic hearing loss, particularly in the undiagnosed group, may have been caused or modified by an accumulation of unfavorable variants across multiple genes.

Terminal chromosome 4q deletion syndrome in an infant with hearing impairment and moderate syndromic features: review of literature.

BACKGROUND: Terminal deletions of chromosome 4q are associated with a broad spectrum of phenotypes including cardiac, craniofacial, digital, and cognitive impairment. The rarity of this syndrome renders genotype-phenotype correlation difficult, which is further complicated by the widely different phenotypes observed in patients sharing similar deletion intervals. CASE PRESENTATION: Herein, we describe a boy with congenital hearing impairment and a variety of moderate syndromic features that prompted SNP array analysis disclosing a heterozygous 6.9 Mb deletion in the 4q35.1q35.2 region, which emerged de novo in the maternal germ line. CONCLUSION: In addition to the index patient, we review 35 cases from the literature and DECIPHER database to attempt genotype-phenotype correlations for a syndrome with great phenotypic variability. We delineate intervals with recurrent phenotypic overlap, particularly for cleft palate, congenital heart defect, intellectual disability, and autism spectrum disorder. Broad phenotypic presentation of the terminal 4q deletion syndrome is consistent with incomplete penetrance of the individual symptoms.

Paclitaxel-eluting balloon versus everolimus-eluting stent for treatment of drug-eluting stent restenosis.

OBJECTIVE: Drug-eluting stent (DES) implantation is a very effective treatment of bare-metal stent-in-stent restenosis (BMS-ISR). Therapeutic options for drug-eluting stent-in-stent restenosis (DES-ISR) are less well defined, as there are only few data on safety and effectiveness of interventional modalities. This study compared the 1-year clinical outcome after the use of drug-eluting balloon (DEB) to second-generation everolimus-eluting stent (EES) for treatment of DES-ISR. METHODS: This observational study included 86 patients with 86 DES-ISR. Forty patients were treated by repeat percutaneous coronary intervention (PCI) using an EES. Forty-six patients were treated by repeat PCI using a DEB. Follow-up periods were 22 ± 11 and 25 ± 19 months, respectively. The primary endpoint of the study was survival free of major adverse cardiac events (MACEs) at 1 year. Secondary endpoints were needed for target lesion revascularization (TLR), definite stent thrombosis (ST) at 1 year, and MACE rate during total follow-up period. RESULTS: Baseline clinical and angiographic parameters were comparable between the two groups. EES were associated with a higher MACE rate at 1 year compared to DEB (27.5 vs. 8.6%, respectively; P = 0.046). TLR rates for EES and DEB were 22.5% versus 4.3%, respectively, P = 0.029, while rates of definite ST at 1 year follow-up were comparable (2.5% vs. 0%, respectively; P = 0.945). There were no differences in myocardial infarction rates between the two groups (5% vs. 2%, respectively; P = 0.595) and in mortality. Considering the complete follow-up periods, DEB were associated with significantly less MACE compared to EES (log-rank test, P = 0.045). Furthermore, comparison of TLR rates showed a strong trend in favor of DEB compared to EES (P = 0.074). CONCLUSIONS: Treatment of DES-ISR using a DEB is associated with favorable rates of MACE and TLR at 1-year follow-up compared to the implantation of an EES.