Paneth cell α-defensins HD-5 and HD-6 display differential degradation into active antimicrobial fragments.

Antimicrobial peptides, in particular α-defensins expressed by Paneth cells, control microbiota composition and play a key role in intestinal barrier function and homeostasis. Dynamic conditions in the local microenvironment, such as pH and redox potential, significantly affect the antimicrobial spectrum. In contrast to oxidized peptides, some reduced defensins exhibit increased vulnerability to proteolytic degradation. In this report, we investigated the susceptibility of Paneth-cell-specific human α-defensin 5 (HD-5) and -6 (HD-6) to intestinal proteases using natural human duodenal fluid. We systematically assessed proteolytic degradation using liquid chromatography-mass spectrometry and identified several active defensin fragments capable of impacting bacterial growth of both commensal and pathogenic origins. Of note, incubation of mucus with HD-5 resulted in 255-8,000 new antimicrobial combinations. In contrast, HD-6 remained stable with consistent preserved nanonet formation. In vivo studies demonstrated proof of concept that a HD-5 fragment shifted microbiota composition (e.g., increases of Akkermansia sp.) without decreasing diversity. Our data support the concept that secretion of host peptides results in an environmentally dependent increase of antimicrobial defense by clustering in active peptide fragments. This complex clustering mechanism dramatically increases the host's ability to control pathogens and commensals. These findings broaden our understanding of host modulation of the microbiome as well as the complexity of human mucosal defense mechanisms, thus providing promising avenues to explore for drug development.

[Clinical relevance of the new S3 guideline on hepatocellular carcinoma and biliary tract cancer for practitioners]. / Klinische Bedeutung der neuen S3-Leitlinie zum hepatozellulären und biliären Karzinom für die Praxis.

The update of the S3 German guideline for the management of the hepatocellular carcinoma and biliary tract cancer contains a comprehensive revision of the guideline for hepatocellular carcinoma and establishes a new guideline for biliary tract cancer. In recent years several studies have been conducted to improve diagnostic and therapeutic options for liver cancer. Magnetic resonance imaging (MRI) and biopsy are important for the diagnosis of hepatocellular carcinoma or cholangiocarcinoma. This guideline shows the progress in the treatment options for hepatocellular carcinoma, including advances in liver transplantation, bridging and downstaging. For cholangiocarcinoma there is a focus on interventional treatment and resection. This guideline also emphasizes the need of molecular diagnostics and the resulting treatment options in targeted therapy.

Winning hearts and minds: ECG reporting in the first seizure clinic.

BACKGROUND AND AIMS: An electrocardiogram (ECG) is a mandatory test for anyone presenting with loss of consciousness. Many referrals to the first seizure clinic (FSC) are caused by syncope. We assessed the sensitivity of neurologists' ECG reporting in detecting rhythm abnormalities including some potentially life-threatening cardiac conditions. METHODS: We audited patients referred to a FSC in Glasgow over 4 years. All ECGs were interpreted by the attending neurologist as standard practice. Subsequently, two cardiologists reviewed the ECGs independently. RESULTS: Of 160 consecutive patients, 92 patients (58%) were diagnosed as having seizures, 43 (27%) as syncope, and 25 (16%) were unclassified. Twenty eight ECGs thought to be normal by the neurologist were considered abnormal by the cardiologist, including three with long corrected QT interval. The proportion of abnormal ECGs and disparity in reporting between neurologists and cardiologists persisted independent of the underlying diagnosis. CONCLUSION: Reporting of ECGs by non-cardiologists may not be adequately sensitive in picking up potentially life threatening cardiac conditions. Cardiologist input into FSCs is recommended to enhance the diagnostic yield.

[Personalized treatment of cholangiocellular carcinoma (CCA)]. / Personalisierte Therapie des cholangiozellulären Karzinoms.

Cholangiocellular carcinoma (CCA) is one of the primary liver tumors and overall represents a rare malignancy; however, in recent years the incidence, particularly of intrahepatic CCA (iCCA) has increased worldwide. Due to the high mortality, CCAs cause a significant proportion of cancer-related deaths also in Germany. Because the diagnosis is often made in advanced stages of the disease, in many cases a surgical approach with curative intention is not possible. For locally advanced or metastatic CCA the combination of gemcitabine and cisplatin currently remains the only approved systemic treatment. As the average survival time is only approximately 12 months even under first-line treatment with gemcitabine/cisplatin, research is focused on developing new molecularly targeted and immunological treatment options. Various studies are currently being carried out to investigate approval options for targeted treatment, which could be considered for genetically altered tumors, e.g. in fibroblast growth factor receptor (FGFR) fusion and isocitrate dehydrogenase (IDH) mutations. Additionally, initial clinical data on immune checkpoint inhibitors are available for CCA. Due to the complex selection and partially limited applicability of current treatment options in patients with CCA, an early collaboration with a gastroenterology and oncology center with the possibility of supervision by a tumor board consisting of gastroenterological oncologists, surgeons, radiologists and radio-oncologists or in advanced stages by a molecular tumor board is essential.

Cephalic tetanus presenting with bilateral facial palsy.

We discuss the case and differential diagnoses of an elderly man who presented with bilateral facial palsy. He had injured his forehead in the garden during a fall on his face and the open wound was contaminated by soil. He then presented to the emergency department with facial weakness causing difficulty speaking. The penny dropped when he started developing muscle spasms affecting his lower jaw a day after admission. It also became clear that he could not open his mouth wide (lock jaw). The combination of muscle spasms and lock jaw (trismus) made tetanus the most likely possibility, and this was proven when he had samples taken from his wound and analysed under the microscope, which showed Clostridium tetani bacilli. C. tetani spores are widespread in the environment, including in the soil, and can survive hostile conditions for long periods of time. Transmission occurs when spores are introduced into the body, often through contaminated wounds. Tetanus in the United Kingdom is rare, but can prove fatal if there is a delay in recognition and treatment.

Bacterial Periplasmic Oxidoreductases Control the Activity of Oxidized Human Antimicrobial ß-Defensin 1.

The antimicrobial peptide human ß-defensin 1 (hBD1) is continuously produced by epithelial cells in many tissues. Compared to other defensins, hBD1 has only minor antibiotic activity in its native state. After reduction of its disulfide bridges, however, it becomes a potent antimicrobial agent against bacteria, while the oxidized native form (hBD1ox) shows specific activity against Gram-negative bacteria. We show that the killing mechanism of hBD1ox depends on aerobic growth conditions and bacterial enzymes. We analyzed the different activities of hBD1 using mutants of Escherichia coli lacking one or more specific proteins of their outer membrane, cytosol, or redox systems. We discovered that DsbA and DsbB are essential for the antimicrobial activity of hBD1ox but not for that of reduced hBD1 (hBD1red). Furthermore, our results strongly suggest that hBD1ox uses outer membrane protein FepA to penetrate the bacterial periplasm space. In contrast, other bacterial proteins in the outer membrane and cytosol did not modify the antimicrobial activity. Using immunogold labeling, we identified the localization of hBD1ox in the periplasmic space and partly in the outer membrane of E. coli However, in resistant mutants lacking DsbA and DsbB, hBD1ox was detected mainly in the bacterial cytosol. In summary, we discovered that hBD1ox could use FepA to enter the periplasmic space, where its activity depends on presence of DsbA and DsbB. HBD1ox concentrates in the periplasm in Gram-negative bacteria, which finally leads to bleb formation and death of the bacteria. Thus, the bacterial redox system plays an essential role in mechanisms of resistance against host-derived peptides such as hBD1.

Heart rate variability for rapid risk stratification of emergency patients with malignant disease.

INTRODUCTION: Neoplasms are the second most common diseases in western countries. Many patients with malignant diseases repeatedly present themselves in the emergency department (ED). Due to limited capacities, appropriate risk stratification strategies for cancer patients have to be developed. This study assesses if deceleration capacity (DC) of heart rate as a parameter of heart rate variability predicts mortality in emergency patients with malignant diseases. METHODS: Prospectively, 140 adults with different entities of malignant diseases who presented in the medical ED were included. Primary and secondary endpoints were intrahospital mortality and mortality within 180 days, respectively. We calculated DC from short-term ECG readings of the surveillance monitors. Additionally, the Modified Early Warning Score (MEWS) and laboratory parameters such as white blood cells (WBC), lactate dehydrogenase, serum hemoglobin, and serum creatinine were determined. RESULTS: The median age of the patients was 65 ± 14 years. 19.3% of the patients died within the hospital stay and 57.9% died within 180 days. DC and WBC were independent predictors of intrahospital death reaching a hazard ratio (HR) of 0.79 (95% confidence interval (CI) 0.63-0.993, p = 0.043) and of 1.00 (95% CI 1.00-1.00, p = 0.003), respectively. DC and serum creatinine independently predicted death within 180 days (HR 0.90, 95% CI 0.82-0.98, p = 0.023 and HR 1.41, 95% CI 1.05-1.90, p = 0.018, respectively). CONCLUSION: Deceleration capacity of heart rate is suitable for rapid risk assessment of emergency patients with malignant diseases.

Hereditary chorea - what else to consider when the Huntington's disease genetics test is negative?

Chorea, cognitive, behavioural and psychiatric disturbance occur in varying combinations in Huntington's disease (HD). This is often easy to recognise particularly in the presence of an autosomal dominant history. Whilst HD may be the most common aetiology of such a presentation, several HD phenocopies should be considered if genetic testing for HD is negative. We searched PubMed and the Cochrane Database from January 1, 1946 up to January 1, 2016, combining the search terms: 'chorea', 'Huntington's disease', 'HDL' and 'phenocopies'. HD phenocopies frequently display additional movement disorders such as myoclonus, dystonia, parkinsonism and tics. Here, we discuss the phenotypes, and investigations of HD-like disorders where the combination of progressive chorea and cognitive impairment is obvious, but HD gene test result is negative. Conditions presenting with sudden onset chorea such as vascular, infectious and autoimmune causes are not the primary focus of our discussion, but we will make a passing reference to these as some of these conditions are potentially treatable. Hereditary forms of chorea are a heterogeneous group of conditions and this number is increasing. While most of these conditions are not curable, molecular genetic testing has enabled many of these disorders to be distinguished from HD. Getting a precise diagnosis may enable patients and their families to better understand the nature of their condition.

A review of medication adherence in people with epilepsy.

People with epilepsy (PWE) have a higher risk of mortality in comparison with the general population. This in part reflects intrinsic factors or associated comorbidities, but poor adherence to anti-epileptic drugs (AED) has also been shown to contribute to increased risk of death and increased utilization of unscheduled care. The aim of this review was to determine the prevalence of non-adherence to AED in PWE, evaluate whether specific clinical and demographic features can allow clinicians to identify those at highest risk and identify the methods and techniques that can be used to improve adherence in clinical settings. We identified relevant studies for the prevalence of medication non-adherence in PWE by searching MEDLINE (1946-7 Dec 2015), EMBASE (1947-7 Dec 2015) and Cochrane Library (1946-7 Dec 2015) as per predefined inclusion and exclusion criteria. We included 17 research studies from our review of the medical literature to determine the prevalence of medication non-adherence in epilepsy. The prevalence of significant medication non-adherence in epilepsy has been reported to vary between 26% and 79%. This variation partly reflects the differences in defining what clinically significant medication adherence is, the methods used to estimate the scale of the problem and the underlying population heterogeneity. A number of clinical and demographic features have been associated with poor adherence allowing clinicians to identify those at greatest risk. Educating patients and their carers about the risks associated with poor adherence, certain behavioural interventions and simplifying their drug regimens have been shown to improve adherence.

Electroencephalographic markers in dementia.

Dementia is a global health problem with a huge impact on the lives of those afflicted. There are several distinct diseases that are classified under the umbrella term "dementia" ranging from neurodegenerative disorders such as Alzheimer's disease to chronic infections of the central nervous system such as subacute sclerosing panencephalitis (SSPE), a rare complication of measles virus infection in childhood. Clinical features, neuropsychological profiles and imaging characteristics of the various dementia syndromes can be sufficiently distinct to distinguish them from one another. However, in some cases, the cognitive, psychiatric and behavioural features can sufficiently overlap such that neurophysiologic testing may be of help. While it is recognized the electroencephalogram (EEG) may have a special role to play in the diagnosis of certain dementing illnesses such as SSPE and Creutzfeldt-Jakob disease (CJD) that have characteristic EEG changes, current research focusses on the potential utility of quantitative EEG as one more tool in the armamentarium of clinicians dealing with patients who suffer from a dementing illness. We searched PubMed and the Cochrane Database from 1 January 1946 up to 1 January 2016, combining the search terms "EEG," "electroencephalography," "dementia" and "status epilepticus"; identified papers from these searches were then read in detail and summarized. Here, we discuss both the qualitative and quantitative EEG findings in the various types of dementia.

Relationship between [123 I]-FP-CIT SPECT and clinical progression in Parkinson's disease.

BACKGROUND: The demonstration of presynaptic dopaminergic deficiency on [123 I]-FP-CIT SPECT imaging is a useful ancillary tool in the diagnosis of Parkinson's disease (PD). Whilst there is evidence of a cross-sectional relationship between the degree of dopaminergic deficiency and severity of bradykinesia and rigidity, longitudinal studies are rare. Moreover, the relationship between motor subtypes and their dopaminergic deficient state is not well characterized. AIM: Our primary aim was to assess the correlations between dopaminergic deficiency on baseline [123 I]-FP-CIT SPECT imaging with the progression of motor severity in patients classified by motor subtype, and the development of motor complications. Our secondary aim was to assess the correlation between UPDRS-III subscores and the time to onset of motor complications. METHODS: 42 PD patients with abnormal baseline [123 I]-FP-CIT SPECT scans and at least 3 years of clinical follow-up were classified by motor subtype: akinetic-rigid, tremor-dominant or mixed. UPDRS-III scores at baseline and at 3-year follow-up, and time to onset of motor complications were recorded. RESULTS: [123 I]-FP-CIT uptake ratios were inversely correlated with UPDRS-III scores at 3 years only in akinetic-rigid patients (r=-.51, P=.04). Time to onset of motor complications was inversely correlated with UPDRS-III subscores for bradykinesia and rigidity at baseline (r=-.52, P=.02) and at 3 years (r=-.54, P=.01). CONCLUSION: The degree of dopaminergic deficiency on baseline [123 I]-FP-CIT SPECT inversely correlates with motor severity at 3-year follow-up in akinetic-rigid patients only. Furthermore, UPDRS-III subscores for bradykinesia and rigidity at baseline show an inverse correlation with time to onset of motor complications across all PD subtypes.

Common toxidromes in movement disorder neurology.

BACKGROUND: Physicians can come across patients who are exposed to certain prescription drugs or toxins that can result in adverse effects and complications which have high rates of morbidity and mortality. OBJECTIVE: To summarise the key clinical features and management of the common movement disorder toxidromes relevant to physicians (with an interest in neurology). METHODS: We searched PUBMED from 1946 to 2016 for papers relating to movement toxidromes and their treatment. The findings from those studies were then summarised and are presented here. RESULTS: The key features of 6 of the common movement disorder toxidromes and their treatment are tabulated and highlighted. The management of toxidromes with the highest mortality like neuroleptic malignant syndrome and serotonin syndrome are discussed in detail. CONCLUSION: There are several toxidromes that have the potential to become a serious life-threatening emergency if there is a delay in recognition of key clinical features and instituting the appropriate treatment at the earliest is crucial.

[Personalization in the medicine of the future : Opportunities and risks]. / Personalisierung in der Medizin der Zukunft : Chancen und Risiken.

Personalized medicine is not a new concept. The renaissance of the term is due to the enormous progress in gene sequencing technology and functional imaging, as well as the development of targeted therapies. Application of these technologies in clinical medicine will necessitate infrastructural as well as organizational and educational changes in the healthcare system. An important change required already in the short-term is the introduction of centralized structures, preferably in university clinics, which adopt these innovations and incorporate them into clinical care. Simultaneously, the collation and use of large quantities of relevant data from highly variable sources must be successfully mastered, in order to pave the way for disruptive technologies such as artificial intelligence.

[Varicella gastritis under immunosuppression : Case report of a woman after lung transplantation due to granulomatosis with polyangiitis]. / Varizella-Gastritis unter Immunsuppression : Kasuistik einer Patientin nach Lungentransplantation bei Granulomatose mit Polyangiitis.

A 35-year-old woman who had previously undergone a lung transplantation presented with severe abdominal pain and vomiting. The gastroscopy showed diffuse ulcerative gastric lesions. Tests for varicella zoster virus and Epstein-Barr virus via polymerase chain reactions (PCR) on endoscopically obtained gastric biopsies were found to be positive and confirmed varicella gastritis. Intravenous antiviral therapy with acyclovir was administered resulting in a normalization of all clinical symptoms, especially of abdominal pain and inflammation parameters.

Olfaction in Parkin single and compound heterozygotes in a cohort of young onset Parkinson's disease patients.

BACKGROUND: Parkin related Parkinson's disease (PD) is differentiated from idiopathic PD by absent or sparse Lewy bodies, and preserved olfaction. The significance of single Parkin mutations in the pathogenesis of PD is debated. OBJECTIVES: To assess olfaction results according to Parkin mutation status. To compare the prevalence of Parkin single heterozygous mutations in patients diagnosed with PD to the rate in healthy controls in order to establish whether these single mutations could be a risk factor for developing PD. METHODS: Parkin gene mutation testing was performed in young onset PD (diagnosed <50 years old) to identify three groups: Parkin homozygous or compound heterozygote mutation carriers, Parkin single heterozygote mutation carriers, and non-carriers of Parkin mutations. Olfaction was tested using the 40-item British version of the University of Pennsylvania smell identification test (UPSIT). RESULTS: Of 344 young onset PD cases tested, 8 (2.3%) were Parkin compound heterozygotes and 13 (3.8%) were Parkin single heterozygotes. Olfaction results were available in 282 cases (eight compound heterozygotes, nine single heterozygotes, and 265 non-carriers). In Parkin compound heterozygotes, the median UPSIT score was 33, interquartile range (IQR) 28.5-36.5, which was significantly better than in single Parkin heterozygotes (median 19, IQR 18-28) and non-carriers (median score 22, IQR 16-28) (ANOVA P < 0.001). These differences persisted after adjusting for age, disease duration, gender, and smoking (P < 0.001). There was no significant difference in UPSIT scores between single heterozygotes and non-carriers (P = 0.90). CONCLUSIONS: Patients with Parkin compound heterozygous mutations have relatively preserved olfaction compared to Parkin single heterozygotes and non-carriers. The prevalence of Parkin single heterozygosity is similar to the 3.7% rate reported in healthy controls.

AFP-producing adenocarcinoma of the esophagogastric junction: report of a case with atypical immunohistochemical findings responding to palliative chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT regime).

AFP-producing adenocarcinoma of the esophagus and esophagogastric junction are rare tumor diseases. These tumors show an aggressive behavior characterized by early occurrence of liver metastases and mimic hepatocellular carcinoma (HCC). A general recommendation for palliative therapy is not established for these special tumors.Here we report about a 61-year-old man with multiple liver metastases and high serum alpha-fetoprotein (AFP) level. First, HCC was suspected, but further evaluation showed an AFP-producing adenocarcinoma of the esophagogastric junction with unusual findings on further immunohistochemical analysis. Palliative chemotherapy with FLOT (5-fluorouracil, leucovorin, oxaliplatin, and docetaxel) regime showed a 9 month duration of partial response.

[Diagnostics and treatment of cholangiocellular carcinoma]. / Diagnostik und Therapie des cholangiozellulären Karzinoms.

Cholangiocellular carcinoma (CCA) is the second most frequent primary liver carcinoma and is an aggressive tumor, which is mostly diagnosed in advanced stages. The overall survival is poor. Histpathological analysis of tumor biopsies or cytological analysis of biliary brushings can be used to confirm the diagnosis. A differentiation is made between distal, perihilar and intrahepatic CCA. The anatomical position determines the diagnostic and therapeutic strategy. Before diagnostic or therapeutic measures are undertaken it is essential to resolve biliary obstruction via endoscopic stenting or percutaneous biliary drainage. Depending on the tumor stage curative treatment options comprise radical surgical resection with hepaticojejunostomy or in selected cases liver transplantation. For intrahepatic or distal CCA liver transplantation is not indicated. In the palliative setting systemic chemotherapy with gemcitabine and cisplatin leads to a significant improvement in survival time.

Recurrent pyogenic cholangitis as a differential diagnosis in biliary tract diseases.

Recurrent Pyogenic Cholangitis (RPC) or Primary Hepatolithiasis is a common disease of the biliary tract in Asia, whereas it is usually not seen in Europeans. With increasing global mobility, the disease will be encountered in Europe more frequently, too. It should therefore be considered as a differential diagnosis in patients from endemic countries with recurrent symptoms of cholestasis/cholangitis and bile duct dilations, strictures and hepatolithiasis. In this case report, we present the history of a 37-year old patient from Sri Lanka and describe typical aspects of RPC. The patient presented at our hospital with scleral jaundice and pruritus. In the past she had been treated for septic cholangitis. Diagnosis in our patient was made after laboratory tests, MRT/MRCP and ERC. She was treated interventionally by ERC and is now monitored on a regular basis.

[Primary perivascular epitheloid cell tumour (PEComa) of the liver - is a new entity of the liver tumors?]. / Das PECom der Leber - eine neue Entität der Lebertumoren?

Perivascular epitheloid cell tumor (PEComa) is a rare tumor, characterized by dual Expression of smooth muscle and melanocytic markers. Due to the development of diagnostic procedures, we now diagnose PEComa more often. We report about a case of PEComa of the liver as an accidental finding. We analyze the clinical and morphological characteristics of this tumor and compare it with the data of the literature. Management of patients with PEComa is not yet standardized; therefore biopsy with immunhistochemical staining is necessary for the diagnosis. In case of liver tumors which cannot be classified by their morphology on imaging modalities, it is important to think about this rare entity.