Hypertrophic cardiomyopathy MYH7 mutation R723G alters mRNA secondary structure.

Point mutation R723G in the MYH7 gene causes hypertrophic cardiomyopathy (HCM). Heterozygous patients with this mutation exhibit a comparable allelic imbalance of the MYH7 gene. On average 67% of the total MYH7 mRNA are derived from the MYH7R723G-allele and 33% from the MYH7WT allele. Mechanisms underlying mRNA allelic imbalance are largely unknown. We suggest that a different mRNA lifetime of the alleles may cause the allelic drift in R723G patients. A potent regulator of mRNA lifetime is its secondary structure. To test for alterations in the MYH7R723G mRNA structure we used selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE) analysis. We show significantly different SHAPE reactivity of wild-type and MYH7R723G RNA, which is in accordance with bioinformatically predicted structures. Thus, we provide the first experimental evidence for mRNA secondary structure alterations by the HCM point mutation. We assume that this may result in a prolonged lifetime of MYH7R723G mRNA in vivo and subsequently in the determined allelic imbalance.

Cisplatin and 5-fluorouracil with or without epidermal growth factor receptor inhibition panitumumab for patients with non-resectable, advanced or metastatic oesophageal squamous cell cancer: a prospective, open-label, randomised phase III AIO/EORTC trial (POWER).

BACKGROUND: Palliative chemotherapy of advanced oesophageal squamous cell cancer (ESCC) consists of cisplatin/5-fluorouracil (CF) to target epidermal growth factor receptor (EGFR) with panitumumab (P); chemotherapy enhanced overall survival (OS) in advanced colorectal or squamous cell head and neck cancers. With prospective serum and tumour biomarkers, we tested if P added to CF (CFP) improved OS in advanced ESCC. PATIENTS AND METHODS: Eligible patients with confirmed ESCC that was not curatively resectable or did not qualify for definitive radiochemotherapy, were randomised 1 : 1 to receive CF [cisplatin (C) 100 mg/m2 i.v., day 1; 5-fluorouracil (F) 1000 mg/m2 i.v., days 1-4] or CF plus P (9 mg/kg, i.v., day 1, each q3-week cycle) until progressive disease or unacceptable toxicity. Safety was reviewed by the Data Safety Monitoring Board after 40, 70 and 100 patients who completed at least one cycle. After 53 enrolled patients, cisplatin was reduced from 100 mg/m2 to 80 mg/m2. RESULTS: The trial was stopped early based on interim efficacy results triggered by the third safety analysis: median OS (mOS) favoured CF over CFP, regardless of cisplatin dose [hazard ratio (HR) 1.77, 95% confidence interval (CI) 1.06-2.98; P = 0.028]. In the final analysis, mOS was 10.2 versus 9.4 months for CF versus CFP, respectively (HR 1.17, 95% CI 0.79-1.75; P = 0.43). One hundred (70.4%) of 142 patients in the safety population died, 51 (51.0%) with CFP. Most deaths were related to disease progression [44/49 (90%) deaths in CF versus 34/51 (67%) deaths in CFP]; objective responses [27/73 (37.0%)] were identical. The most common serious adverse events were kidney injury [3 (4.3%) versus 7 (9.7%)], general health deterioration [5 (7.1%) versus 5 (6.9%)] and dysphagia [4 (5.7%) versus 4 (5.6%)] in CF versus CFP, respectively. There were three (4.3%) and 17 (23.6%) common terminology criteria for adverse events (CTCAE) grade 5 events in CF versus CFP, respectively. Low soluble (s)EGFR levels were associated with better progression-free survival; sEGFR was induced under CFP. CONCLUSION: EGFR inhibition added to CF did not improve survival in unselected advanced ESCC patients. The results support further liquid biopsy studies. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01627379) and EudraCT (2010-020606-15).

[Exposure of Pupils to Recreational Noise from Portable Listening Devices and Possible Preventive Measures]. / Freizeitlärmbelastung durch tragbare Musikabspielgeräte bei Schülern und Präventionsmöglichkeiten.

Background and Objectives: Exposure to recreational noise is becoming increasingly important due to a change in leisure behavior amongst children and adolescents. The aim of this pilot study was to assess exposure of 6th grade pupils to recreational noise from portable listening devices (PLD). Furthermore, preventive measures to reduce recreational noise exposure should be identified. Methods: In "Ohrkan Kids", 38 Bavarian pupils aged 11 to 14 were interviewed regarding their music listening behavior using a standardized questionnaire. In addition, measurements of commonly used volume settings on the children's portable listening devices were carried out. Furthermore, the German Social Accident Insurance (DGUV), health insurance companies as well as health and education ministries of the German federal states were surveyed regarding their activities in the prevention of recreational noise exposure. Results: Based on the questionnaire data for weekly usage, 10 out of 31 children (32.3%) exceeded the upper exposure value of 85 dB recommended by labor protection law. Taking actually measured values, 9 out of 31 children (29%) exceeded this level. The DGUV and some federal states carry out specific projects for the prevention of recreational noise exposure. Conclusion: The large number of children with hazardous music consumption indicates that measures for the prevention of noise-induced hearing loss are already required for 11 to 14 year olds. To maximize the number of children addressed, age-appropriate and target-group-specific preventive measures are needed. As there are only few studies which examined the effectiveness of awareness campaigns for the prevention of recreational noise, any future prevention projects should be evaluated with an increased focus on estimating their effectiveness.

Young patients and gastrointestinal (GI) tract malignancies - are we addressing the unmet needs?

BACKGROUND: Recent epidemiological studies indicate the rate of gastrointestinal (GI) malignancies among younger patients is increasing, mainly due to colorectal cancer. There is a paucity of data regarding the magnitude of treatment-related symptoms, psychosocial issues and potential unmet needs in this population. We aimed to characterize the needs of this population to evaluate whether unmet needs could be targeted by potential intervention. METHODS: Female and male patients diagnosed with cancer of the gastrointestinal tract <40y retrospectively completed a questionnaire to evaluate symptoms, daily function and unmet needs at pre-treatment, during and post-treatment. Comparisons were made by gender, disease stage and treatment modality. Multiple linear regression models evaluated effects of demographics, symptoms and needs on multiple domains of health-related-quality-of-life (using Short-Form Health Survey-12 and CARES). RESULTS: Fifty patients were enrolled (52 % female) to a pilot study. Median age at diagnosis was 35.5y (range, 21-40y). The symptoms that significantly increased from baseline to during and post-treatment were: diarrhea (37 %), sleeping disorder (32 %) and sexual dysfunction (40 %). Patients also reported significant deterioration in occupational activities and coping with children compared with baseline. Female patients reported significant unmet need for nutritional counseling and psychosocial support compared to male patients (p < 0.05). Patients treated with multimodality-treatment presented higher rates of unmet needs (p = 0.03). CONCLUSIONS: Young patients with GI cancers represent a group with unique characteristics and needs compared with published evidence on other young-onset malignancies. The distinctive symptoms and areas of treatment-related functional impairments indicate there are unmet needs, especially in the area of psychosocial support and nutritional counseling.

Is a reduction in albuminuria associated with renal and cardiovascular protection? A post hoc analysis of the ALTITUDE trial.

AIMS: To investigate whether the degree of albuminuria reduction observed in the ALTITUDE trial is associated with renal and cardiovascular protection, and secondly, whether the reduction in albuminuria was too small to afford clinical benefit. METHODS: In a post hoc analysis of the ALTITUDE trial in 8561 patients with type 2 diabetes and chronic kidney disease or cardiovascular disease we examined the effect of albuminuria changes at 6 months on renal and cardiovascular outcomes using Cox proportional hazard regression. RESULTS: The median change in albuminuria in the first 6 months in the aliskiren arm of the trial was -12% (25th to 75th percentile: -48.7_to_ +41.9%) and 0.0% (25th to 75th percentile: -40.2_to_55%) in the placebo arm. Changes in albuminuria in the first 6 months were linearly associated with renal and cardiovascular endpoints: a >30% reduction in albuminuria in the first 6 months was associated with a 62% reduction in renal risk and a 25% reduction in cardiovascular risk compared with an increase in albuminuria. The association between changes at 6 months in albuminuria and renal or cardiovascular endpoints was similar in the two treatment groups (p for interaction >0.1 for both endpoints). CONCLUSIONS: The addition of aliskiren to angiotensin-converting enzyme inhibitor/angiotensin receptor blocker therapy resulted in albuminuria changes that were associated with renal and cardiovascular risk changes. This did not translate into renal or cardiovascular protection because the overall reduction in albuminuria in the aliskiren arm was too small and nearly similar to that in the placebo arm.

[Taking Care of Asylum Seekers: Occupational Health Aspects with a Special Focus on Vaccination]. / Arbeitsmedizinische Aspekte und Impfschutz beim Umgang mit Asylbewerbern.

Employees and volunteers often feel insecure about the potential transmission of infectious diseases when taking care of asylum seekers. It could be shown that overall only a minor risk of infection emanates from asylum seekers. However, aspects of occupational health and vaccination should be kept in mind.Besides the standard vaccination the Standing Committee on Vaccination (STIKO) recommends for occupational indication, which is given for employees and volunteers in asylum facilities, vaccination against hepatitis A, hepatitis B, polio (if the last vaccination was more than 10 years before) as well as influenza (seasonal).According to the German Occupational Safety and Health Act taking care of the employer has to determine which exposures might occur at the workplace (risk assessment) and define necessary protection measures. Depending on task and exposure when taking care of asylum seekers different acts (e. g. biological agents regulation) and technical guidelines for the handling biological agents (e. g. TRBA 250 or TRBA 500) have to be applied.The Bavarian Health and Food Safety Authority (LGL) has published several information sheets regarding "asylum seekers and health management" for employees and volunteers from the non-medical as well as the medical area (www.lgl.bayern.de search term "Asylbewerber"). With theses publications insecurities in taking care of asylum seekers should be prevented. Furthermore the employer gets support in the implementation of legal obligations to ensure occupational safety for the employees.

HCRP1 expression status is a significant prognostic marker in oral and oropharyngeal cancer.

OBJECTIVE: The hepatocellular carcinoma-related protein 1 (HCRP1) is a key factor in the degradation of the epidermal growth factor receptor. In this study, we assessed the prognostic significance of HCRP1 expression in patients with oral and oropharyngeal squamous cell carcinoma (OOSCC). METHODS: HCRP1 expression was determined by immunohistochemistry on tissue biopsy sections of 111 patients with locally advanced OOSCC undergoing neoadjuvant chemoradiotherapy followed by surgery. The Kaplan-Meier method and Cox regression models were used for survival analyses. RESULTS: Low HCRP1 expression was associated with poor recurrence-free survival (P = 0.046) and overall survival (P = 0.03). Multivariate analysis revealed that low HCRP1 expression remained an independent risk factor for relapse (HR 2.98, 95% CI 1.19-7.49, P = 0.02) and death (HR 3.04, 95% CI 1.19-7.79, P = 0.02). CONCLUSION: Low HCRP1 expression was found to be of adverse prognostic significance in patients with OOSCC who received preoperative chemoradiotherapy.

Myeloma and thrombotic complications.

Multiple myeloma (MM) is a hematological malignancy with high risk for thrombosis. While venous thromboembolism is more common, myeloma patients can also present with arterial thrombosis. Risk factors responsible for this complication can be patient-related, myeloma- and treatment-related. Thromboprophylaxis is indicated along with specific therapeutic regimens employed in myeloma patients. This review will cover potential risk factors for thrombosis in patients with multiple myeloma, prevention recommendations and treatment strategies in this clinical setting.

The association between parental perception of neighborhood safety and asthma diagnosis in ethnic minority urban children.

Low-income populations, minorities, and children living in inner cities have high rates of asthma. Recent studies have emphasized the role of psychosocial stress in development of asthma. Residence in unsafe neighborhoods is one potential source of increased stress. The study objective was to examine the association between parental perception of neighborhood safety and asthma diagnosis among inner city, minority children. Cross-sectional data from a community-based study of 6-8-year-old New York City children were used. Asthma was defined as parental report of physician-diagnosed asthma and at least one asthma-related symptom. Parental perceptions of neighborhood safety were assessed with a questionnaire. Associations between perceived neighborhood safety and asthma were examined using chi-squared tests. Multivariate logistic regression analyses were then performed. Five hundred four children were included with 79% female, 26.5% non-Hispanic Black, and 73.5% Hispanic. Asthma was present in 23.8% of children. There was an inverse association between feeling safe walking in the neighborhood and asthma with 45.7% of parents of asthmatic children reporting they felt safe compared to 60.9% of parents of non-asthmatic children (p = 0.006). Fewer parents of asthmatic children than of non-asthmatic children reported that their neighborhood was safe from crime (21.7% versus 33.9%, p = 0.018). In multivariate analyses adjusting for race/ethnicity, age, gender, socioeconomic status, number of smokers in the home and breastfeeding history, parents reporting feeling unsafe walking in the neighborhood were more likely to have a child diagnosed with asthma (OR = 1.89, 95%CI 1.13-3.14). Psychosocial stressors such as living in unsafe neighborhoods may be associated with asthma diagnosis in urban ethnic minority children. Addressing the increased asthma burden in certain communities may require interventions to decrease urban stressors.

Increased serum potassium affects renal outcomes: a post hoc analysis of the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial.

AIMS/HYPOTHESIS: To assess the effect of an angiotensin receptor blocker (ARB) on serum potassium and the effect of a serum potassium change on renal outcomes in patients with type 2 diabetes and nephropathy. METHODS: We performed a post hoc analysis in patients with type 2 diabetes participating in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study. Renal outcomes were defined as a composite of doubling of serum creatinine or end-stage renal disease. RESULTS: At month 6, 259 (38.4%) and 73 (10.8%) patients in the losartan group and 151 (22.8%) and 34 (5.1%) patients in the placebo group had serum potassium ≥5.0 mmol/l and ≥5.5 mmol/l, (p < 0.001), respectively. Losartan was an independent predictor for serum potassium ≥5.0 mmol/l at month 6 (OR 2.8; 95% CI 2.0-3.9). Serum potassium at month 6 ≥ 5.0 mmol/l was in turn associated with increased risk for renal events (HR 1.22; 95% CI 1.00-1.50), independent of other risk factors. Adjustment of the overall treatment effects for serum potassium augmented losartan's renoprotective effect from 21% (6-34%) to 35% (20-48%), suggesting that the renoprotective effects of losartan are offset by its effect on serum potassium. CONCLUSIONS/INTERPRETATION: In this study, we found that treatment with the ARB losartan is associated with a high risk of increased serum potassium levels, which is in turn associated with an increased risk of renal outcomes in patients with diabetes and nephropathy. Whether additional management of high serum potassium would further increase the renal protective properties of losartan is an important clinical question.

Recommendations for the diagnosis and management of vaccine-induced immune thrombotic thrombocytopenia.

There have recently been safety concerns regarding an increased risk of vaccine-induced immune thrombotic thrombocytopenia (VITT) following administration of SARS-CoV-2 adenoviral vector vaccines. The Southern African Society of Thrombosis and Haemostasis reviewed the emerging literature on this idiosyncratic complication. A draft document was produced and revised by consensus agreement by a panel of professionals from various specialties. The recommendations were adjudicated by independent international experts to avoid local bias. We present concise, practical guidelines for the clinical management of VITT.

Psychological distress among male patients and male spouses: what do oncologists need to know?

BACKGROUND: The aim of the current study was to strengthen the knowledge of oncologists concerning psychological distress and social support among married and unmarried male cancer patients and healthy male spouses of female cancer patients. PATIENTS AND METHODS: Three groups of men were recruited from three major cancer centers in Israel: 185 married colon and rectal cancer patients, 54 single (unmarried) colon and rectal cancer patients, and 153 male spouses of female cancer patients. Participants were evaluated on four standardized instruments measuring psychological distress, coping, and social support. RESULTS: About 42.6% of the participants reported on a clinical level of psychological distress, with the highest rates (61.1%) among the single (unmarried) patients. Distress was negatively correlated to Karnofsky score and coping variables among all study groups. Distress was significantly and negatively correlated to social support variables among the spouses and married patients but not among the single patient groups. CONCLUSIONS: Social support received by male cancer patients from friends and family may be mediated by spouse support. As a result, single male patients are at higher risk for psychological distress. Male spouses were also found to have high rates of distress. These two groups need special attention by oncologists.

Colorectal cancer in young patients in Israel: a distinct clinicopathological entity?

PURPOSE: This study was designed to characterize the entity of colorectal cancer (CRC) in young patients and to evaluate whether it has any unique epidemiological or clinicopathological features. METHODS: The study population consisted of all consecutive young (≤50 years old at diagnosis) patients with CRC who were diagnosed during the years 1997-2007 and were treated at our institution, and a matching group of patients (>50 years at diagnosis). The medical files of these patients were reviewed, and the epidemiological, clinical, and pathological features of both groups were compared. RESULTS: There were 406 patients: 203 in each group. The features of the older group were typical for patients with CRC, but the younger group showed female predominance, different ethnic composition, prevalence of family history of cancer and hereditary CRC syndromes, and lower incidence of polyps. The incidence of left-sided tumors and advanced stages (III-IV) at diagnosis was higher in the younger patients. Mucinous/signet ring histology, grade, stage, lymphatic and vascular invasion were all predictive of survival, whereas age was not. CONCLUSIONS: Colorectal cancer in young patients was found to display a cluster of unique characteristics but fewer than previously reported and young age by itself was not found to impact patient outcome.

Force-generating cross-bridges during ramp-shaped releases: evidence for a new structural state.

Mechanical and two-dimensional (2D) x-ray diffraction studies suggest that during isometric steady-state contraction, strongly bound cross-bridges mostly occupy early states in the power stroke, whereas rigor or rigor-like cross-bridges could not be detected. However, it remained unclear whether cross-bridges accumulate, at least transiently, in rigor or rigor-like states in response to rapid-length releases. We addressed this question using time-resolved recording of 2D x-ray diffraction patterns of permeabilized fibers from rabbit psoas muscles during isometric contraction and when small, ramp-shaped length-releases were applied to these fibers. This maneuver allows a transient accumulation of cross-bridges in states near the end of their power stroke. By lowering the temperature to 5 degrees C, force transients were slowed sufficiently to record diffraction patterns in several 2-4-ms time frames before and during such releases, using the RAPID detector (Refined ADC Per Input Detector) at beam line ID02 of the European Synchrotron Radiation Facility (Grenoble, France). The same sequence of frames was recorded in relaxation and rigor. Comparisons of 2D patterns recorded during isometric contraction, with patterns recorded at different [MgATPgammaS] and at 1 degrees C, showed that changes in intensity profiles along the first and sixth actin layer lines (ALL1 and ALL6, respectively) allowed for discernment of the formation of rigor or rigor-like cross-bridges. During ramp-shaped releases of activated fibers, intensity profiles along ALL1 and ALL6 did not reveal evidence for the accumulation of rigor-like cross-bridges. Instead, changes in the ALL6-profile suggest that during ramp-shaped releases, cross-bridges transiently accumulate in a structural state that, to our knowledge, was not previously seen, but that could well be a strongly bound state with the light-chain binding domain in a conformation between a near prepower-stroke (isometric) orientation and the orientation in rigor.

Cardiomyopathy mutations reveal variable region of myosin converter as major element of cross-bridge compliance.

The ability of myosin to generate motile forces is based on elastic distortion of a structural element of the actomyosin complex (cross-bridge) that allows strain to develop before filament sliding. Addressing the question, which part of the actomyosin complex experiences main elastic distortion, we suggested previously that the converter domain might be the most compliant region of the myosin head domain. Here we test this proposal by studying functional effects of naturally occurring missense mutations in the beta-myosin heavy chain, 723Arg --> Gly (R723G) and 736Ile --> Thr (I736T), in comparison to 719Arg --> Trp (R719W). All three mutations are associated with hypertrophic cardiomyopathy and are located in the converter region of the myosin head domain. We determined several mechanical parameters of single skinned slow fibers isolated from Musculus soleus biopsies of hypertrophic cardiomyopathy patients and healthy controls. Major findings of this study for mutation R723G were i), a >40% increase in fiber stiffness in rigor with a 2.9-fold increase in stiffness per myosin head (S( *)(rigor R723G) = 0.84 pN/nm S( *)(rigor WT) = 0.29 pN/nm); and ii), a significant increase in force per head (F( *)(10 degrees C), 1.99 pN vs. 1.49 pN = 1.3-fold increase; F( *)(20 degrees C), 2.56 pN vs. 1.92 pN = 1.3-fold increase) as well as stiffness per head during isometric steady-state contraction (S( *)(active10 degrees C), 0.52 pN/nm vs. 0.28 pN/nm = 1.9-fold increase). Similar changes were found for mutation R719W (2.6-fold increase in S( *)(rigor); 1.8-fold increase in F( *)(10 degrees C), 1.6-fold in F( *)(20 degrees C); twofold increase in S( *)(active10 degrees C)). Changes in active cross-bridge cycling kinetics could not account for the increase in force and active stiffness. For the above estimates the previously determined fraction of mutated myosin in the biopsies was taken into account. Data for wild-type myosin of slow soleus muscle fibers support previous findings that for the slow myosin isoform S( *) and F( *) are significantly lower than for fast myosin e.g., of rabbit psoas muscle. The data indicate that two mutations, R723G and R719W, are associated with an increase in resistance to elastic distortion of the individual mutated myosin heads whereas mutation I736T has essentially no effect. The data strongly support the notion that major elastic distortion occurs within the converter itself. Apparently, the compliance depends on specific residues, e.g., R719 and R723, presumably located at strategic positions near the long alpha-helix of the light chain binding domain. Because amino acids 719 and 723 are nonconserved residues, cross-bridge stiffness may well be specifically tuned for different myosins.

Renal risk scores: progress and prospects.

Worldwide adoption of the Kidney Disease Outcomes Quality Initiative classification for chronic kidney disease (CKD) and widespread use of the estimated glomerular filtration rate to assess renal function have identified large numbers of patients with previously undiagnosed CKD. It is clear, however, that this is a heterogeneous group and that only a small minority of such patients ever progress to end-stage renal disease. There is thus an urgent need for a simple method of risk assessment that can be applied to all patients with CKD to identify those few at greatest risk. The magnitude of baseline proteinuria has long been recognized as an important predictor of renal prognosis. Furthermore, several studies have found that change in proteinuria after initiation of antihypertensive treatment as well as achieved level of proteinuria correlate with prognosis. Thus, proteinuria has emerged as the single most important marker of renal risk. Many other factors have been identified as risk factors for CKD progression. Several attempts have been made to combine a relatively small number of risk factors into a risk score to predict renal outcomes in specific groups of patients. Validation of these risk scores as well as further studies are now required to develop a renal risk score applicable to a more general population of patients with CKD. Similar methodology could be applied to assess the important issue of the cardiovascular risk associated with CKD.

High incidence of non-upper aerodigestive primary tumors in patients with esophageal cancer.

Earlier reports have described an association between esophageal cancer (EC) and high incidence of other primary tumors (OPTs) of the upper aerodigestive tract and breast cancer. We evaluated the incidence of non-upper aerodigestive OPTs among Israeli EC patients; 2328 EC patients were retrieved from the Israeli National Cancer Registry between 1980 and 2004. The relative risk of OPTs for EC patients was measured using standardized incidence ratio (SIR). Two cohorts, Israeli National Cancer Registry registered colorectal cancer (CRC) patients and the general Israeli population, were used for reference; 297 EC patients (12.7%) had OPTs, including breast (18.9%), CRC (16.2%), prostate (8.8%), and bladder (8.4%) cancers. Upper aerodigestive OPTs were less common. Most OPTs were identified before (74.4%) or simultaneously with (13.8%) EC diagnosis. The median time interval between OPTs diagnoses and EC development was 6.0 years. The incidence of OPTs was significantly higher among EC patients compared with CRC patients (SIR: 2.05, P < 0.01) or the general Israeli population (SIR: 3.90, 95% CI: 3.46-4.34, P < 0.01) regardless of gender or tumor histology. Patients with EC have high incidence of non-upper aerodigestive malignancies. Unlike previous reports, the distribution of OPTs in EC seems to represent the relative incidences of these cancers in the western populations.

Administration off label of recombinant factor-VIIa (rFVIIa) to patients with blunt or penetrating brain injury without coagulopathy.

Traumatic brain contusions may increase in size over time or may develop at a delay after injury. This may lead to neurological deterioration, long term morbidity or even death. Coagulation disorders after injury can contribute to progression of haemorrhage. Recombinant activated factor VII (rFVIIa) was used in 12 patients with a severe head injury who had no systemic coagulopathy but who were considered to be at risk of progression of their intracranial lesion. Twelve consecutive patients suffering from life-threatening acute head injuries from blunt (3 cases) and penetrating mechanisms were given with rFVIIa, either to prevent the expected development of brain contusion or to assist in bleeding control during surgery. In 11 patients, rFVIIa was given by the attending neurosurgeon. Two of the patients died of their severe penetrating injuries one of whom had severe vasospasm 2 days after administration of rFVIIa. The other 11 patients did not appear to suffer any treatment-related adverse effects. When the drug was given prophylactically to prevent brain resection (6 cases) or to limit the need for widening resection (5 cases), marked control was achieved in seven cases, and a lesser effect was observed in the other 4 cases. We conclude that, in a small and highly individually selected series of patients with severe head injury, the administration of rFVIIa did not lead to adverse effects. Although the majority of patients were considered to be at high risk of progression of their lesions, this occurred in only one. The early use of rFVIIa in head injured patients without systemic coagulopathy may reduce the occurrence of enlargement of contusions, the requirement of further operation, and adverse outcome. Prospective randomised controlled studies are required to investigate this.

Do we need a cancer screening in patients with idiopathic deep vein thrombosis?

AIM: To review the literature concerning the need for a cancer screening battery to diagnose a hidden cancer in patients presenting with idiopathic venous thromboembolism (VTE). MATERIALS AND METHODS: Data from computerized database programs (Medline, Ovid) was retrieved. A review of the literature regarding studies on cancer screening in patients with idiopathic VTE was performed and our own policy included. RESULTS: Patients with VTE have a higher rate of malignancy which may still be undiagnosed. During follow-up of patients with idiopathic VTE, the incidence of cancer increases and is more likely associated with a worse prognosis. Limited diagnostic work-up in patients with idiopathic VTE allows the diagnosis of a hidden malignancy in about half of the cases with a sensitivity of 48 %. Extensive screening of cancer with idiopathic VTE allows less of a delay and earlier stage at diagnosis with a 93 % sensitivity. However, reduced cancer-related mortality is not statistically significant. A two-fold fatal PE and more than 3-fold fatal bleeding are registered in VTE patients with hidden cancer compared to patients without cancer. The major risk factors for hidden cancer are old age, anemia, idiopathic and bilateral deep vein thrombosis. CONCLUSION: There is no consensus regarding the benefit of extensive screening in patients presenting with idiopathic VTE. Clear diagnostic work-up guidelines are not yet available. A cost-effective diagnostic algorithm for cancer screening in patients with idiopathic VTE is needed.

Successful knock-in of Hypertrophic Cardiomyopathy-mutation R723G into the MYH7 gene mimics HCM pathology in pigs.

Familial Hypertrophic Cardiomyopathy (HCM) is the most common inherited cardiac disease. About 30% of the patients are heterozygous for mutations in the MYH7 gene encoding the ß-myosin heavy chain (MyHC). Hallmarks of HCM are cardiomyocyte disarray and hypertrophy of the left ventricle, the symptoms range from slight arrhythmias to sudden cardiac death or heart failure. To gain insight into the underlying mechanisms of the diseases' etiology we aimed to generate genome edited pigs with an HCM-mutation. We used TALEN-mediated genome editing and successfully introduced the HCM-point mutation R723G into the MYH7 gene of porcine fibroblasts and subsequently cloned pigs that were heterozygous for the HCM-mutation R723G. No off-target effects were determined in the R723G-pigs. Surprisingly, the animals died within 24 h post partem, probably due to heart failure as indicated by a shift in the a/ß-MyHC ratio in the left ventricle. Most interestingly, the neonatal pigs displayed features of HCM, including mild myocyte disarray, malformed nuclei, and MYH7-overexpression. The finding of HCM-specific pathology in neonatal R723G-piglets suggests a very early onset of the disease and highlights the importance of novel large animal models for studying causative mechanisms and long-term progression of human cardiac diseases.