Vasoactive intestinal peptide, whose receptor-mediated signalling may be defective in alopecia areata, provides protection from hair follicle immune privilege collapse.

BACKGROUND: Alopecia areata (AA) is an autoimmune disorder whose pathogenesis involves the collapse of the relative immune privilege (IP) of the hair follicle (HF). Given that vasoactive intestinal peptide (VIP) is an immunoinhibitory neuropeptide released by perifollicular sensory nerve fibres, which play a role in IP maintenance, it may modulate human HF-IP and thus be therapeutically relevant for AA. OBJECTIVES: To answer the following questions: Do human HFs express VIP receptors, and does their stimulation protect from or restore experimentally induced HF-IP collapse? Is VIP signalling defective in AA HFs? METHODS: Firstly, VIP and VIP receptor (VPAC1, VPAC2) expression in human scalp HFs and AA skin was assessed. In HF organ culture, we then explored whether VIP treatment can restore and/or protect from interferon-γ-induced HF-IP collapse, assessing the expression of the key IP markers by quantitative (immuno-)histomorphometry. RESULTS: Here we provide the first evidence that VIP receptors are expressed in the epithelium of healthy human HFs at the gene and protein level. Furthermore, VIP receptor protein expression, but not VIP(+) nerve fibres, is significantly downregulated in lesional hair bulbs of patients with AA, suggesting defects in VIP receptor-mediated signalling. Moreover, we show that VIP protects the HF from experimentally induced IP collapse in vitro, but does not fully restore it once collapsed. CONCLUSIONS: These pilot data suggest that insufficient VIP receptor-mediated signalling may contribute to impairing HF-IP in patients with AA, and that VIP is a promising candidate 'HF-IP guardian' that may be therapeutically exploited to inhibit the progression of AA lesions.

Whole blood for the acutely haemorrhaging civilian trauma patient: a novel idea or rediscovery?

The concept of whole blood (WB) as a treatment modality for trauma patients requiring transfusion therapy is not new. Successfully employed in the early 20 century, WB was the product of choice for military trauma resuscitation until the advent of component therapy changed the landscape of transfusion medicine. However, the recognition of the success of WB in the military operational setting has provided some enthusiasm to explore its revival as a cold-stored option in the civilian trauma resuscitation sector. Concerns continue to exist over potential limitations for its application in regards to the efficacy of platelets after cold storage, the risk of haemolytic transfusion reactions following the transfusion of un-cross-matched WB and the logistical issues for civilian blood banks in providing WB. This review aims to reconcile these concerns with data available in the literature, with a view to establishing that there is in vitro evidence supporting the haemostatic effects of cold-stored WB as a potential therapeutic option in both the pre-hospital and in-hospital civilian trauma resuscitation settings.

[How safe is sedation in gastrointestinal endoscopy? A multicentre analysis of 388,404 endoscopies and analysis of data from prospective registries of complications managed by members of the Working Group of Leading Hospital Gastroenterologists (ALGK)]. / Wie sicher ist die Sedierung in der gastrointestinalen Endoskopie? Eine multizentrische Auswertung von 388 404 Endoskopien und Auswertung der Daten aus prospektiv geführten Komplikationsregistern von Mitgliedern der Arbeitsgemeinschaft leitender Gastroenterologen im Krankenhaus (ALGK).

BACKGROUND: Gastrointestinal endoscopies are increasingly being carried out with sedation. All of the drugs used for sedation are associated with a certain risk of complications. Data currently available on sedation-associated morbidity and mortality rates are limited and in most cases have substantial methodological limitations. The aim of this study was to record severe sedation-associated complications in a large number of gastrointestinal endoscopies. METHODS: Data on severe sedation-associated complications were collected on a multicentre basis from prospectively recorded registries of complications in the participating hospitals (median documentation period 27 months, range 9 - 129 months). RESULTS: Data for 388,404 endoscopies from 15 departments were included in the study. Severe sedation-associated complications occurred in 57 patients (0.01 %). Forty-one percent of the complications and 50 % of all complications with a fatal outcome (10/20 patients) occurred during emergency endoscopies. In addition, it was found that 95 % of the complications and 100 % of all fatal complications affected patients in ASA class ≥ 3. CONCLUSIONS: Including nearly 400,000 endoscopies, this study represents the largest prospective, multicenter record of the complications of sedation worldwide. The analysis shows that sedation is carried out safely in gastrointestinal endoscopy. The morbidity and mortality rates are much lower than previously reported in the literature in similar groups of patients. Risk factors for the occurrence of serious complications include emergency examinations and patients in ASA class ≥ 3.

ARFI elastography of the spleen is inferior to liver elastography for the detection of portal hypertension.

PURPOSE: To date, the use of transient elastography has been limited to the liver. Acoustic radiation force impulse imaging (ARFI) is a new technology offering elastography of different tissues. Here, we present initial spleen elastography data and evaluate its influencing factors, especially portal hypertension. MATERIALS AND METHODS: Elastography of the spleen and liver using the ARFI method was performed in 30 patients with portal hypertension, 70 patients with chronic liver disease without portal hypertension and 25 healthy controls. RESULTS: ARFI elastography of the spleen was feasible in 99% of patients and valid in 78%. The mean propagation velocity inside the spleen was 2.95 ± 0.60 m/sec, thus much higher than in the normal liver (< 1.10 m/sec). Spleen stiffness was higher in the patients with portal hypertension (p < 0.008) but did not correlate to spleen size. Spleen stiffness increased with patient age and liver stiffness (both p < 0.0001) as confirmed by multivariate analysis (R2 = 0.19, p < 0.01). In ROC analysis, spleen elastography was inferior to liver elastography for the detection of portal hypertension (area under the curve 0.68 vs. 0.90). CONCLUSION: The new ARFI method allows accurate elastography of the spleen. The stiffness of the normal spleen is much higher than that of the normal liver and increases with age. However, spleen elastography is inferior to liver elastography for the detection of portal hypertension.

Extracellular Vesicles Derived from Neural Progenitor Cells--a Preclinical Evaluation for Stroke Treatment in Mice.

Stem cells such as mesenchymal stem cells (MSCs) enhance neurological recovery in preclinical stroke models by secreting extracellular vesicles (EVs). Since previous reports have focused on the application of MSC-EVs only, the role of the most suitable host cell for EV enrichment and preclinical stroke treatment remains elusive. The present study aimed to evaluate the therapeutic potential of EVs derived from neural progenitor cells (NPCs) following experimental stroke. Using the PEG technique, EVs were enriched and characterized by electron microscopy, proteomics, rt-PCR, nanosight tracking analysis, and Western blotting. Different dosages of NPC-EVs displaying a characteristic profile in size, shape, cargo protein, and non-coding RNA contents were incubated in the presence of cerebral organoids exposed to oxygen-glucose deprivation (OGD), significantly reducing cell injury when compared with control organoids. Systemic administration of NPC-EVs in male C57BL6 mice following experimental ischemia enhanced neurological recovery and neuroregeneration for as long as 3 months. Interestingly, the therapeutic impact of such NPC-EVs was found to be not inferior to MSC-EVs. Flow cytometric analyses of blood and brain samples 7 days post-stroke demonstrated increased blood concentrations of B and T lymphocytes after NPC-EV delivery, without affecting cerebral cell counts. Likewise, a biodistribution analysis after systemic delivery of NPC-EVs revealed the majority of NPC-EVs to be found in extracranial organs such as the liver and the lung. This proof-of-concept study supports the idea of EVs being a general concept of stem cell-induced neuroprotection under stroke conditions, where EVs contribute to reverting the peripheral post-stroke immunosuppression.

Of guinea pigs and men--an unusual case of jaundice.

A 21-year-old male presented at the emergency room with jaundice, itching, dry cough, malaise and weight loss of 10 kg during the preceding four weeks. Eighteen months earlier, the patient had suffered an automobile accident leading to polytrauma. Serological markers for viral or other causes of hepatitis were absent. For suspected secondary sclerosing cholangitis, ultrasound and ERCP were performed but failed to reveal pathological findings. A liver biopsy showed cholestatic liver disease without signs of portal field-associated hepatitis. Hepato-biliary scintigraphy demonstrated hepatocellular dysfunction. The patient finally mentioned his guinea pig farm with around 50 animals, 20 of which had recently died for unknown reasons. The patient and three of his guinea pigs were subsequently tested for serological evidence of leptospirosis. IgG and IgM antibodies reacting with Leptospira interrogans were detected in the patient's serum, and all 3 guinea pigs were serologically positive for serovar Bratislava. Bacterial culture was not successful, and also PCR tests remained negative. The clinical symptoms quickly resolved after the initiation of antibiotic therapy with amoxicillin.

Typical signs of acute appendicitis in ultrasonography mimicked by other diseases?

BACKGROUND: The diagnosis of acute appendicitis in pediatric patients is difficult. There are patients with positive ultrasonography without clinical or histological confirmation of acute appendicitis. It is essential to recognise these patients to avoid unnecessary surgery. METHODS: During 1 year, we compared the patients with 'false-positive' ultrasonography with those with 'true-positive' and those with 'true-negative' ultrasonography. RESULTS: Eighty-two patients were admitted to our inpatient ward for suspected appendicitis. Ultrasonography was performed on 68 patients. In sixteen cases, the ultrasonography showed typical signs of acute appendicitis though the patients turned out to be negative for acute appendicitis either by an observation period (n = 13) or by negative histology (n = 3). We could not find any significant differences between the groups in terms of age, gender or laboratory inflammation markers, though the latter tended to be elevated in patients with confirmed appendicitis. CONCLUSIONS: There are patients with clearly visible typical signs of acute appendicitis that do not need surgery and cannot be distinguished from others by age, gender or laboratory values. In conclusion, the clinical presentation still is the determining indicator for need of surgery. The underlying cause of the visible changes of the appendiceal area remains unclear, but there are several presumptions.

Identifying Factors Predicting Response to Endoscopic Management of Chronic Pancreatitis Secondary to Pancreas Divisum.

INTRODUCTION: Appropriately selecting patients with chronic pancreatitis associated with pancreas divisum (PD) for endoscopic retrograde cholangiopancreatography (ERCP)-based therapy versus surgery remains difficult. The objective of this study was to identify factors that predict success or failure of ERCP for treatment of chronic pancreatitis in PD. METHODS: Patients undergoing ERCP for a diagnosis of PD and pancreatitis between 2008 and 2016 were identified and grouped according to whether they required one or two ERCPs or three or more ERCPs. Groups were compared along demographic, diagnostic, laboratory, ERCP-related, and outcome variables. RESULTS: Patients requiring 1-2 ERCPs were less likely to have back pain on initial presentation (4 vs. 24%, p = 0.02) and less likely to have a dilated bile duct on imaging prior to their first ERCP (8 vs. 30%, p = 0.04) than those requiring 3+ ERCPs. Patients requiring 1-2 ERCPs were also less likely to eventually require operative intervention for treatment of their chronic pancreatitis than those requiring 3+ ERCPs (24 vs. 44%, p = 0.047). On multivariable analysis, a dilated bile duct (odds ratio (OR) = 6.0, 95% confidence interval (CI) = 1.01-36.0, p = 0.048) was independently associated with requiring 3+ ERCPs. Back pain (OR = 6.3, 95% CI = 0.73-54.2, p = 0.09) trended toward but did not reach statistical significance for being independently associated with requiring 3+ ERCPs. CONCLUSIONS: The success of endoscopic treatment of chronic pancreatitis in patients with PD is dependent on proper patient selection. Patients with a dilated bile duct and back pain upon presentation may not respond well to endoscopic treatment alone and are more likely to eventually require operative intervention. Consideration should be given to early operative intervention in these patients.

The upregulation of GLAST-1 is an indirect antiapoptotic mechanism of GDNF and neurturin in the adult CNS.

Glial cell-line-derived neurotrophic factor (GDNF) and neurturin (NTN) protect retinal ganglion cells (RGCs) from axotomy-induced apoptosis. It is likely that neuroprotection by GDNF or NTN in the adult central nervous system (CNS) involves indirect mechanisms and independent signal transduction events. Extracellular glutamate is a trigger of apoptosis in injured RGCs, and glutamate transporter levels can be upregulated by GDNF. Therefore, GDNF may indirectly protect RGCs by enhancing glutamate uptake in the retina. We studied the upregulation of the glutamate transporters GLAST-1 and GLT-1 by GDNF and NTN, and the intracellular pathways required for GDNF/NTN neuroprotection. GDNF required phosphoinositide-3 kinase (PI3K) and Src activity to upregulate GLAST-1 and GLT-1. NTN required PI3K activity to upregulate GLAST-1 and did not affect GLT-1 levels. PI3K activity was also important for GDNF and NTN neuroprotection following optic nerve transection. However, GDNF also required Src and mitogen-activated protein kinase activity to prevent RGC apoptosis. RNA interference demonstrated that the upregulation of GLAST-1 by GDNF and NTN is required to rescue RGCs. Thus, additional independent signal transduction events, together with the upregulation of GLT-1 by GDNF, differentiate the biological activity of GDNF from NTN. Furthermore, the upregulation of the glial glutamate transporter GLAST-1 by both factors is an indirect neuroprotective mechanism in the CNS.

Identification of new kinase clusters required for neurite outgrowth and retraction by a loss-of-function RNA interference screen.

Disruption of synaptic integrity, loss of connectivity and axodendritic degeneration are early and essential components of neurodegeneration. Although neuronal cell death mechanisms have been thoroughly investigated, less is known about the signals involved in axodendritic damage and the processes involved in regeneration. Here we conducted a genome-wide RNA interference-based forward genetic screen, using small interfering RNA targeting all human kinases, and identified clusters of kinases families essential for growth cone collapse, neurite retraction and neurite outgrowth. Of 59 kinases identified as positive regulators of neurite outgrowth, almost 50% were in the tyrosine kinase/tyrosine kinase-like (TK/TKL) receptor subgroups, underlining the importance of extracellular ligands in this process. Neurite outgrowth was inhibited by 66 other kinases, none of which were TK/TKL members, whereas 79 kinases inhibited lysophosphatidic acid-induced neurite retraction. Twenty kinases were involved in both inhibitory processes suggesting shared mechanisms. Within this group of 20 kinases, some (ULK1, PDK1, MAP4K4) have been implicated previously in axonal events, but others (MAST2, FASTK, CKM and DGUOK) have not. For a subset of kinases, the effect on neurite outgrowth was validated in rat primary cerebellar cultures. The ability to affect regeneration was further tested in a model of axodendritic lesion using primary rat midbrain cultures. Finally, we demonstrated that haploinsufficiency of two members of the AGC kinase subgroup, ROCK1 and PKN1, was able to suppress retinal degeneration in Drosophila model of class III Autosomal Dominant Retinitis Pigmentosa.

Mutant SOD1 detoxification mechanisms in intact single cells.

Mutant superoxide dismutase 1 (mtSOD1) causes dominantly inherited amyotrophic lateral sclerosis (ALS). The mechanism for mtSOD1 toxicity remains unknown. Two main hypotheses are the impairment of proteasomal function and chaperone depletion by misfolded mtSOD1. Here, we employed FRET/FLIM and biosensor imaging to quantitatively localize ubiquitination, as well as chaperone binding of mtSOD1, and to assess their effect on proteasomal and protein folding activities. We found large differences in ubiquitination and chaperone interaction levels for wild-type (wt) SOD1 versus mtSOD1 in intact single cells. Moreover, SOD1 ubiquitination levels differ between proteasomal structures and cytoplasmic material. Hsp70 binding and ubiquitination of wt and mtSOD1 species are highly correlated, demonstrating the coupled upregulation of both cellular detoxification mechanisms upon mtSOD1 expression. Biosensor imaging in single cells revealed that mtSOD1 expression alters cellular protein folding activity but not proteasomal function in the neuronal cell line examined. Our results provide the first cell-by-cell-analysis of SOD1 ubiquitination and chaperone interaction. Moreover, our study opens new methodological avenues for cell biological research on ALS.

Proinflammatory cell stress in sporadic inclusion body myositis muscle: overexpression of alphaB-crystallin is associated with amyloid precursor protein and accumulation of beta-amyloid.

BACKGROUND: In the pathology of sporadic inclusion body myositis (sIBM), the relevance of cell stress molecules such as the heat shock protein alphaB-crystallin, particularly in healthy appearing muscle fibres, has remained elusive. METHODS: 10 muscle biopsies from sIBM patients were serially stained for haematoxylin-eosin, trichrome and multi-immunohistochemistry for neural cell adhesion molecule (NCAM), alphaB-crystallin, amyloid precursor protein (APP), desmin, major histocompatibility complex I, beta-amyloid and ubiquitin. Corresponding areas of all biopsies were quantitatively analysed for all markers. Primary myotube cultures were exposed to the proinflammatory cytokines interleukin (IL)-1beta and interferon (IFN)-gamma. RESULTS: In human myotubes exposed to IL-1beta+IFN-gamma, overexpression of APP was accompanied by upregulation of alphaB-crystallin. In sIBM muscle biopsies, over 20% of all fibres displayed accumulation of beta-amyloid or vacuoles/inclusions. A clearly larger fraction of the fibres were positive for alphaB-crystallin or APP. In contrast with the accumulation of beta-amyloid in atrophic fibres, a major part of fibres positive for APP or alphaB-crystallin showed no morphological abnormalities. Expression of APP and alphaB-crystallin significantly correlated with each other and most double positive fibres displayed accumulation of beta-amyloid, vacuoles or an atrophic morphology. In almost all of these fibres, other markers of degeneration/regeneration such as NCAM and desmin were evident as additional indicators of a cell stress response. Some fibres double positive for APP and alphaB-crystallin displayed infiltration by inflammatory cells. CONCLUSION: Our results suggest that alphaB-crystallin is associated with overexpression of APP in sIBM muscle and that upregulation of alphaB-crystallin precedes accumulation of beta-amyloid. The data help to better understand early pathological changes and underscore the fact that a network of cell stress, inflammation and degeneration is relevant to sIBM.

Clearance of chronic HCV infection during acute delta hepatitis.

The course of chronic hepatitis C in acute HDV/HBV superinfection is unknown. Here, we report a patient with chronic hepatitis C who cleared HCV during acute self-limited hepatitis B/D superinfection. Recovery from HCV was associated with the appearance of a strong and multispecific HDV-specific memory CD4+ and CD8+ T cell response - but only weak HCV-specific CD4+ T cell responses. These data suggest that HCV can be cleared by bystander mechanisms during acute infections with other pathogens which may be considered in the development of immunotherapies for hepatitis C.

The Dead Sea needs salt water massively bleeding patients need whole blood: The evolution of blood product resuscitation.

Whole blood, that is blood that is not manufactured into its component red blood cells (RBC) plasma, and platelets (PLT) units, was the mainstay of transfusion for many years until it was discovered that the component parts of a blood donation could be stored under different conditions thereby optimizing the storage length of each product. The use of low anti-A and -B titer group O whole blood (LTOWB) has recently been rediscovered for use in massively bleeding trauma patients. Whole blood has several advantages over conventional component therapy for these patients, including simplifying the logistics of the resuscitation, being more concentrated than whole blood that is reconstituted from conventional components, and providing cold-stored PLTs, amongst other benefits. While randomized controlled trials to determine the efficacy of using LTOWB in the resuscitation of massively bleeding trauma patients are currently underway, retrospective data has shown that massively bleeding recipients of LTOWB with traumatic injury do not have worse outcomes compared to patients who received conventional components and, in some cases, recipients of LTOWB have more favourable outcomes. This paper will describe some of the advantages of using LTOWB and will discuss the emerging evidence for its use in massively bleeding patients.

The problem of strict image-based inclusion criteria for mechanical thrombectomy - an analysis of stroke patients with an initial low CBV-ASPECTS score.

INTRODUCTION: Endovascular treatment for acute ischaemic stroke with large artery occlusion has become the standard of care. However, the question if a subgroup of patients, with a low cerebral blood volume Alberta Stroke Program Early CT score (CBV-ASPECTS) ≤ 7 should be excluded from endovascular treatment remains open. Therefore; we investigated the difference of outcome between patients who were treated by endovascular treatment vs patients who did not receive endovascular treatment. METHODS: We retrospectively analysed our stroke database for all patients who presented within six hours of onset with unfavourable imaging findings and who received endovascular treatment or best medical treatment alone. Unfavourable imaging was defined as a CBV-ASPECTS ≤ 7, which was an exclusion criterion for endovascular treatment at our institution before 2015. RESULTS: From 60 patients with an initial CBV-ASPECTS ≤ 7, 40 received best medical treatment and 20 were treated with endovascular treatment. Arterial hypertension and atrial fibrillation was more present in patients without endovascular treatment, the other baseline characteristics and percentage of patients treated with intravenous recombinant tissue plasminogen activator were not significantly different in both groups. At discharge, 40% of the interventional treated patients had a favourable outcome (eight of 20 (40%) vs six of 40 (15%; p = 0.031). The median values of the National Institute of Health Stroke Score and modified Rankin Scale at discharge were significantly lower in the treated cohort (6.5 (2.5-10.5) vs 16 (9.5-22.5); p = 0.006; 3 (0-5.5) vs 5 (4.5-5.5); p = 0.003). CONCLUSION: Patients with a CBV-ASPECTS ≤ 7 are likely to benefit from therapy and therefore may not be excluded from endovascular treatment. Further randomised trials are warranted to validate the data.

Appearance of target-specific guidance information for regenerating axons after CNS lesions.

During development of the vertebrate visual system, an orderly projection of ganglion cells from the retina onto the superior colliculus (SC) is established. Mechanisms that might govern this process include the coordinated action of guidance and corresponding receptor molecules that are specifically distributed on the axons and their targets. In birds and mammals, information for axonal guidance and targeting appears to be confined to the time when the retinocollicular projection is being formed. Here we show that putative guidance activities for temporal and nasal retinal axons, which are not detectable in the normal adult SC, appear after optic nerve transection in adult rats. Both embryonic and adult retinal axons are able to respond to these guiding cues, although the guidance activities detectable in the deafferented adult rat SC might be different from those found during development. These findings imply that it might be possible to reestablish an ordered projection after lesions in the adult mammalian visual system.

Cyclin-dependent kinase 5 is an upstream regulator of mitochondrial fission during neuronal apoptosis.

Under physiological conditions, mitochondrial morphology dynamically shifts between a punctuate appearance and tubular networks. However, little is known about upstream signal transduction pathways that regulate mitochondrial morphology. We show that mitochondrial fission is a very early and kinetically invariant event during neuronal cell death, which causally contributes to cytochrome c release and neuronal apoptosis. Using a small molecule CDK5 inhibitor, as well as a dominant-negative CDK5 mutant and RNAi knockdown experiments, we identified CDK5 as an upstream signalling kinase that regulates mitochondrial fission during apoptosis of neurons. Vice versa, our study shows that mitochondrial fission is a modulator contributing to CDK5-mediated neurotoxicity. Thereby, we provide a link that allows integration of CDK5 into established neuronal apoptosis pathways.

Neuron-specific overexpression of the co-chaperone Bcl-2-associated athanogene-1 in superoxide dismutase 1(G93A)-transgenic mice.

Bcl-2-associated athanogene-1 (BAG1) binds heat-shock protein 70 (Hsp70)/Hsc70, increases intracellular chaperone activity in neurons and proved to be protective in several models for neurodegeneration. Mutations in the superoxide dismutase 1 (SOD1) gene account for approximately 20% of familial amyotrophic lateral sclerosis (ALS) cases. A common property shared by all mutant SOD1 (mtSOD1) species is abnormal protein folding and the propensity to form aggregates. Toxicity and aggregate formation of mutant SOD1 can be overcome by enhanced chaperone function in vitro. Moreover, expression of mtSOD1 decreases BAG1 levels in a motoneuronal cell line. Thus, several lines of evidence suggested a protective role of BAG1 in mtSOD1-mediated motoneuron degeneration. To explore the therapeutic potential of BAG1 in a model for ALS, we generated SOD1G93A/BAG1 double transgenic mice expressing BAG1 in a neuron-specific pattern. Surprisingly, substantially increased BAG1 protein levels in spinal cord neurons did not significantly alter the phenotype of SOD1G93A-transgenic mice. Hence, expression of BAG1 is not sufficient to protect against mtSOD1-induced motor dysfunction in vivo. Our work shows that, in contrast to the in vitro situation, modulation of multiple cellular functions in addition to enhanced expression of a single chaperone is required to protect against SOD1 toxicity, highlighting the necessity of combined treatment strategies for ALS.

Detection of a significant association between mutations in the ACVRL1 gene and hepatic involvement in German patients with hereditary haemorrhagic telangiectasia.

Hereditary haemorrhagic telangiectasia (HHT) is a heterogeneous multisystemic dysplasia of the vascular tissue. This autosomal dominant inherited disorder shows a wide variation in its phenotypic expression. Between 8 and 78% of the HHT patients show arteriovenous malformations of the liver. The molecular basis for hepatic manifestation is still unknown. Two genes are known to play a major role in the development of HHT: activin A receptor type II-like 1 gene (ACVRL1) and ENG. Previously, we and others showed that hepatic involvement is associated with mutations in the ACVRL1 gene, but rarely caused by ENG mutations. Here, we report about the sequencing analysis of a new cohort of 18 adult HHT patients. In these patients, we identified eight novel (four in ACVRL1 and four in ENG) and eight already known mutations. Statistical analysis of our entire data revealed significant differences in the distribution of ACVRL1 and ENG mutations among HHT patients with and without liver involvement (p = 0.0016). The positive predictive value for type 2 HHT (ACVRL1 positive) patients to develop liver disease until the age of 52 years is 68.4%. We conclude that molecular genetic testing of HHT patients is important for prognosis with respect to liver disease.