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Background and Aims: Bacterial cholangitis is a common complication in patients with ischemic type biliary lesions and/or anastomotic strictures after liver transplantation (LTX). Patients frequently need antibiotics and endoscopic retrograde cholangiography (ERC) to improve the bile flow. Antibiotic treatment is based on findings in standard microbiological cultivation (SMC) of bile. However, the cultivation techniques are limited to a subset of bacteria easy-to-cultivate. Therefore, the aim of our study was to evaluate the value of next generation sequencing as an additional diagnostic tool to SMC in ischemic type biliary lesions and/or anastomotic strictures., Methods: We sequenced the V1-V2 region of the 16S rRNA gene in 242 stored bile samples in patients after LTX and compared the results with findings of SMC. SMC was performed in n  = 135 (56%) fresh bile samples in addition to NGS. SMC was part of the clinical routine in these patients., Results: NGS detected bacterial genera in bile samples more often than SMC ( P  = 5.42 × 10 -74 ). SMC showed insufficient discovery of bacterial genera compared to NGS with better performance in patients receiving antibiotics prior to ERC. SMC missed many bacterial genera detected by NGS., Conclusions: NGS was more sensitive in detecting bacteria in bile than SMC, no clinical parameters could be used to improve discovery rates in SMC and many genera were missed by SMC. Therefore, NGS should be used in a combined approach with SMC for improved diagnostics to achieve more specific and targeted antibiotic treatments., (© 2023 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Potential indications for surgery frequently arise in patients awaiting liver transplantation. There is a risk of hepatic decompensation and death triggered by surgical trauma, but this has not been studied in detail in this unique population. We aimed to quantify the impact of surgical interventions in patients awaiting liver transplantation on hepatic function and identify risk factors for decompensation., Methods: All surgeries between 2000 and 2018 in patients awaiting liver transplantation in a highvolume German liver transplant center were analyzed retrospectively. Change in liver function measured as indicated by MELD score was assessed and complication rates recorded. The primary endpoint was a composite of an increase in MELD score by > 5 points or death. A logistic regression model was used for multivariate analysis to identify risk factors., Results: In total, 177 surgical procedures in 148 patients were analyzed. The primary endpoint was reached in 42 cases (23.7%). The overall in-hospital complication rate (including death) was 44.1%. Multivariate analysis identified elevated leukocyte count, perioperative blood transfusion, preoperative presence of ascites, and preoperative circulatory support as independent risk factors for a decline in liver function or death., Conclusion: Surgery in patients awaiting liver transplantation carries a relevant risk of hepatic decompensation and death that needs to be considered when deciding whether to perform elective surgery prior to or defer until after liver transplantation., (© 2021 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Patients with non ST-segment elevation myocardial infarction (NSTEMI) represent the largest fraction of patients with acute coronary syndrome in German Chest Pain units. Recent evidence on early vs. selective percutaneous coronary intervention (PCI) is ambiguous with respect to effects on mortality, myocardial infarction (MI) and recurrent angina. With the present study we sought to investigate the prognostic impact of PCI and its timing in German Chest Pain Unit (CPU) NSTEMI patients., Methods and Results: Data from 1549 patients whose leading diagnosis was NSTEMI were retrieved from the German CPU registry for the interval between 3/2010 and 3/2014. Follow-up was available at median of 167days after discharge. The patients were grouped into a higher (Group A) and lower risk group (Group B) according to GRACE score and additional criteria on admission. Group A had higher Killip classes, higher BNP levels, reduced EF and significant more triple vessel disease (p<0.001). Surprisingly, patients in group A less frequently received early diagnostic catheterization and PCI. While conservative management did not affect prognosis in Group B, higher-risk CPU-NSTEMI patients without PCI had a significantly worse survival., Conclusions: The present results reveal a substantial treatment gap in higher-risk NSTEMI patients in German Chest Pain Units. This treatment paradox may worsen prognosis in patients who could derive the largest benefit from early revascularization., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Direct transfer to the catheterization laboratory for primary percutaneous coronary intervention (PCI) is standard of care for patients with ST-segment elevation myocardial infarction (STEMI). Nevertheless, a significant number of STEMI-patients are initially treated in chest pain units (CPUs) of admitting hospitals. Thus, it is important to characterize these patients and to define why an important deviation from recommended clinical pathways occurs and in particular to quantify the impact of deviation on critical time intervals., Methods and Results: 1679 STEMI patients admitted to a CPU in the period from 2010 to 2015 were enrolled in the German CPU registry (8.5% of 19,666). 55.9% of the patients were delivered by an emergency medical system (EMS), 16.1% transferred from other hospitals and 15.2% referred by a general practitioner (GP). 12.7% were self-referrals. 55% did not get a pre-hospital ECG. Compared to the EMS, referral by GPs markedly delayed critical time intervals while a pre-hospital ECG demonstrating ST-segment elevation reduced door-to-balloon time. When compared to STEMI patients (n=21,674) enrolled in the ALKK-registry, CPU-STEMI patients had a lower risk profile, their treatment in the CPU was guideline-conform and in-hospital mortality was low (1.5%)., Conclusions: CPU-STEMI patients represent a numerically significant group because a pre-hospital ECG was not documented. Treatment in the CPU is guideline-conform and the intra-hospital mortality is low. The lack of a pre-hospital ECG and admission via the GP substantially delay critical time intervals suggesting that in patients with symptoms suggestive an ACS, the EMS should be contacted and not the GP., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: We investigated the current management of unstable angina pectoris (UAP) in certified chest pain units (CPUs) in Germany and focused on the European Society of Cardiology (ESC) guideline-adherence in the timing of invasive strategies or choice of conservative treatment options. More specifically, we analyzed differences in clinical outcome with respect to guideline-adherence., Method: Prospective data from 1400 UAP patients were collected. Analyses of high-risk criteria with indication for invasive management and 3-month clinical outcome data were performed. Guideline-adherence was tested for a primarily conservative strategy as well as for percutaneous coronary intervention (PCI) within <24 and <72h after admission., Results: Overall guideline-conforming management was performed in 38.2%. In UAP patients at risk, undertreatment caused by an insufficient consideration of risk criteria was obvious in 78%. Reciprocally, overtreatment in the absence of adequate risk markers was performed in 27%, whereas a guideline-conforming primarily conservative strategy was chosen in 73% of the low-risk patients. Together, the 3-month major adverse coronary and cerebrovascular events (MACCE) were low (3.6%). Nonetheless, guideline-conforming treatment was even associated with significantly lower MACCE rates (1.6% vs. 4.0%, p<0.05)., Conclusion: The data suggest an inadequate adherence to ESC guidelines in nearly two thirds of the patients, particularly in those patients at high to intermediate risk with secondary risk factors, emphasizing the need for further attention to consistent risk profiling in the CPU and its certification process., (Copyright © 2014 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Cholangiocarcinoma (CCA) is the second most common primary liver cancer. In clinical practice, the diagnosis remains challenging and often requires endoscopic approaches. Endoscopic retrograde and percutaneous transhepatic cholangiography are the first-line endoscopic procedures for the evaluation of indeterminate bile duct strictures. Tissue acquisition via brush cytology and forceps biopsies allows the cytological and/or histological confirmation of the disease. Due to the low sensitivity of these techniques, repetitive examinations and/or alternative approaches are required. Cholangioscopy, endoscopic and intraductal ultrasound and confocal laser endomicroscopy are additional methods which can be applied for the diagnosis of CCA. Particularly, new experimental approaches like bile and urine proteomic analyses show promising results which have to be evaluated prospectively for further integration in diagnostic algorithms., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: While dyspnea is a common symptom in patients admitted to Chest Pain Units (CPUs) little is known about the impact of dyspnea on their outcome. The purpose of this study was to evaluate the impact of dyspnea on the short-term outcome of CPU patients., Methods: We analyzed data from a total of 9169 patients admitted to one of the 38 participating CPUs in this registry between December 2008 and January 2013. Only patients who underwent coronary angiography for suspected ACS were included. 2601 patients (28.4%) presented with dyspnea., Results: Patients with dyspnea at admission were older and frequently had a wide range of comorbidities compared to patients without dyspnea. Heart failure symptoms in particular were more common in patients with dyspnea (21.0% vs. 5.3%, p<0.05) at admission. Importantly, in patients presenting with dyspnea the 3month mortality was fourfold higher compared to patients without dyspnea (8.6% vs. 2.1%, p<0.05, OR death: 4.40 95% CI 3.14-6.03). Interestingly, the mortality estimated from the GRACE risk score was below the actual mortality assessed after the 3month follow-up. After adjustment for the GRACE risk score or for heart failure, dyspnea remained highly predictive of death and myocardial infarction within 3months (OR death adjusted for heart failure: 2.99 95% CI 1.99-4.47 and OR death adjusted for GRACE risk score: 3.37 95% CI 2.27-4.99)., Conclusion: Dyspnea is a common symptom in CPU patients. Our data show that dyspnea is associated with a fourfold higher 3month mortality which is underestimated by the established ACS risk scores. To improve their predictive value we therefore propose to add dyspnea as an item to common risk scores., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objectives: Usually, the course of paraneoplastic cerebellar degeneration(PCD) is stable or progresses only slowly. Sudden marked progression after several years, as in the following case, has not been reported., Case Report: After a 57 year old female had developed diplopia, cerebellar signs, upper-limb weakness, and bilateral stocking-type hypoesthesia, and Yo-antibodies were positive, PCD and sensory polyneuropathy were diagnosed. Upon further diagnostic work-up ovarian cancer FIGO-IIC was detected and treated with ovarectomy, hysterectomy, omentectomy, and chemotherapy. Within the following years she experienced several relapses and developed multifocal metastasis requiring surgery, various chemotherapies, thermocoagulations, and radiotherapy. During the first years, PCD showed only minor progression. After 5 years, however, asymmetric ataxia and dysarthria acutely deteriorated such that she became severely handicapped and dependent on the help of others. Several cycles of immunoglobulines were ineffective and she died at age 64 years in a severely disabled state without recovery of the PCD., Conclusions: PCD, which usually progresses only slowly, can acutely deteriorate without recovery., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objectives: If Refsum disease (RD) is not considered as a differential at onset of the initial manifestations the diagnosis of RD remains unrecognized for a long time as in the following case., Case Report: A 55-y old Caucasian female with hyperextensible joints developed progressive visual impairment due to retinitis pigmentosa and sensorimotor polyneuropathy of the lower limbs since age 32 y. Screening for causes of polyneuropathy at age 40 y revealed markedly elevated serum phytanic acid (PA) with a maximum value of 293.6 microg/ml (n:<6 microg/ml) why RD was diagnosed. Since age 48 y slowly progressive hypacusis was noted. RD was caused by the known transition A135G in exon 3 of the PHYH gene. Additionally, the polymorphism T153C in exon 3 of the PHYH gene was detected. Upon strict adherence to the Chelsea diet PA levels slightly decreased since onset of this therapy., Conclusion: This case confirms that RD remains unrecognized for a long time if RD is not considered as a differential of retinitis pigmentosa as the initial manifestation of the disease. Early recognition of RD is important since there is the therapeutic option of starting a diet.

Objectives: To report the elevation of the 14-3-3 protein and the complete denervation of hand muscles in idiopathic acute transverse myelitis (IATM) of the cervical cord., Case Description: In a 29-year-old woman with a 2-week history of neck pain and repeated attenuated flus, subacute quadriplegia, hypaesthesia of both arms, a T3 sensory level, and urinary dysfunction occurred. Based upon the clinical findings, the cervical MRIs, and an elevated 14-3-3 protein in the CSF, IATM C4-C7 was diagnosed. Ten, 17, 28 and 61 days after onset, nerve conduction studies revealed complete denervation of the right abductor pollicis brevis and abductor digiti minimi muscles but gradual improvement of the compound muscle action potential of the left abductor pollicis brevis muscle. F-waves of the right median nerve were absent. Tibial somatosensory evoked potentials showed a prolonged central conduction time. Transcranial magnetic stimulation evoked a response in the left but not the right abductor digiti minimi muscle., Conclusion: IATM may cause elevation of the 14-3-3 protein and loss of motor axons originating from affected anterior horn cells.

Monoclonal antibody MIB-1 is a reliable tool for determining proliferating cells in human tissues, but does not react with the homologous mouse antigen and is therefore useless in experimental pathology using mice as model systems. Standard method for assessment of cellular proliferation in formalin-fixed, paraffin-embedded murine tissues is immunohistochemical detection of DNA synthesis using antibodies against exogenously injected 5-bromodeoxyuridine (BrdU), which is a tedious procedure and not useful for routine investigations. We tested monoclonal antibody MIB-5 and monoclonal and polyclonal anti-MCM3 antibodies as immunohistochemical proliferation markers for paraffin-embedded nonneoplastic and neoplastic tissues of wild-type and transgenic mice, compared to anti-BrdU immunostaining. Percentage of proliferating cells was determined with continuously decreasing antibody dilutions. Percentages of MIB-5 and anti-BrdU immunostained cells correlated strongly, as well as percentage of MIB-5-decorated cells and frequency of mitotic figures. Anti-MCM3 antibodies labeled significantly higher percentages of cells than anti-BrdU or MIB-5, and showed a linear decrease with increasing antibody dilutions. We conclude that MIB-5 detects reliably the cell growth fraction in formalin fixed, paraffin-embedded murine tissues, bypassing methodological drawbacks of BrdU. Anti-MCM3 antibodies are less useful for determination of proliferating cells although they might detect the fraction of cells remaining competent for proliferation.

Human transmissible spongiform encephalopathies (TSEs) or prion diseases are neurodegenerative disorders of infectious, inherited or sporadic origin and include Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker disease (GSS), kuru and fatal familial insomnia (FFI). Clinicopathologic features of FFI differ markedly from other human TSEs. Previous studies demonstrated selective neuronal vulnerability of parvalbumin positive (PV+) GABAergic inhibitory interneurons in sporadic CJD and experimental TSEs. In this report we show uniform severe loss of PV+ neurons also in other TSEs such as GSS, kuru, new variant and familial CJD. In contrast, these neurons are mostly well preserved, or only moderately reduced, in FFI. Only PV+ neurons surrounded by isolectin-B4 positive perineuronal nets were severely affected in TSEs, suggesting a factor residing in this type of extracellular matrix around PV+ neurons as modulator for the selective neuronal vulnerability.

Agenesis of the cerebellar vermis (paleocerebellar agenesis) with fusion of the cerebellar hemispheres (rhombencephalosynapsis) is a rare malformation of the central nervous system (CNS). Its combination with synencephaly (telencephalosynapsis), telencephalic ventricular aplasia, aqueductal atresia and cystic fourth ventricle has not yet been described, as far as we know. Here, we report this combination in a 23-weeks' gestation male fetus who was aborted to a 24-year-old diabetic mother. In this fetus with cerebral and cerebellar hemispheric fusion, vermian agenesis was associated with a Dandy-Walker-like posterior fossa cyst, in spite of the fusion of the hypoplastic cerebellar hemispheres. The CNS malformations were further accompanied by dysmorphic facial stigmata such as unilateral atresia of the external ear, ocular hypertelorism and a broad nasal bridge. Preaxial polydactyly and contractures of the upper limbs were the only associated non-cranial abnormalities. Cytogenetic studies revealed a numerically and structurally normal male (46, XY). The malformation complex described in this fetus of a mother with antedating pregnancy diabetes appears to represent a previously undescribed aberrant syngenetic CNS phenotype, some basic teratogenetic aspects of which will be discussed in this paper.

We report on two patients in whom the anomalous left main coronary artery arising from the right sinus of Valsalva with a septal course could be visualized by transthoracic echocardiography. It appeared as a small echo-free space, anterior to the aorta in the short parasternal axis. If the left main coronary artery arises anomalously from the right sinus of Valsalva, it can take four different courses until it branches into the left anterior descending and the circumflex coronary artery. The course between aorta and pulmonary trunk can be differentiated into an interarterial and a septal course using angiographic criteria. The interarterial course is a potentially life-threatening anomaly due to a high rate of myocardial infarction and sudden cardiac death. Echocardiography alone seems not to be able to distinguish between the potentially life-threatening interarterial and the benign septal course, as in our patients.