Identification of a HTT-specific binding motif in DNAJB1 essential for suppression and disaggregation of HTT.

Huntington's disease is a neurodegenerative disease caused by an expanded polyQ stretch within Huntingtin (HTT) that renders the protein aggregation-prone, ultimately resulting in the formation of amyloid fibrils. A trimeric chaperone complex composed of Hsc70, DNAJB1 and Apg2 can suppress and reverse the aggregation of HTTExon1Q48. DNAJB1 is the rate-limiting chaperone and we have here identified and characterized the binding interface between DNAJB1 and HTTExon1Q48. DNAJB1 exhibits a HTT binding motif (HBM) in the hinge region between C-terminal domains (CTD) I and II and binds to the polyQ-adjacent proline rich domain (PRD) of soluble as well as aggregated HTT. The PRD of HTT represents an additional binding site for chaperones. Mutation of the highly conserved H244 of the HBM of DNAJB1 completely abrogates the suppression and disaggregation of HTT fibrils by the trimeric chaperone complex. Notably, this mutation does not affect the binding and remodeling of any other protein substrate, suggesting that the HBM of DNAJB1 is a specific interaction site for HTT. Overexpression of wt DNAJB1, but not of DNAJB1H244A can prevent the accumulation of HTTExon1Q97 aggregates in HEK293 cells, thus validating the biological significance of the HBM within DNAJB1.

Elastic compression stockings one year after DVT diagnosis: Who might discontinue?

BACKGROUND: Elastic compression stockings (ECS) are uncomfortable to wear but may prevent post-thrombotic syndrome (PTS). The ability to predict PTS may help clinical decision making regarding the optimal duration of ECS after deep vein thrombosis (DVT). AIMS: Predefined endpoint analysis of the Octavia study that randomized patients who compliantly used ECS up to one year after DVT to continue or discontinue ECS treatment. Primary aim was to identify predictors of PTS. METHODS: Patient characteristics were collected and ultrasonography was performed to assess reflux, residual thrombosis and persistent thrombus load 12 months after DVT. Multivariable analyses were performed to identify factors related to PTS. RESULTS: Thrombus score ≥ 3, BMI ≥ 26, duration of symptoms before DVT diagnosis ≥ 8 days and a Villalta score of 2-4 points were statistically significant predictors of PTS. The predictive value for PTS for the assessed variables was not different between the 2 treatment groups. In the stop ECS group, 3.2% (95%CI 0.08-18) of patients without any predictors for PTS were diagnosed with mild PTS during follow-up, and none with severe PTS, for a sensitivity of 98% (95% CI 89-100), a specificity of 14% (95% CI 10-20), a positive predictive value of 20% (95% CI 19-22), and a negative predictive value of 97% (95% CI 81-100). CONCLUSION: We identified 4 predictors of PTS occurring in the 2nd year after DVT. Our findings may be used to decide on whether to continue ECS treatment for an additional year, after one year of compliant ECS use, keeping in mind that patients with none of the predictors will have the lowest PTS incidence.

One versus two years of elastic compression stockings for prevention of post-thrombotic syndrome (OCTAVIA study): randomised controlled trial.

OBJECTIVE:  To study whether stopping elastic compression stockings (ECS) after 12 months is non-inferior to continuing them for 24 months after proximal deep venous thrombosis. DESIGN:  Multicentre single blind non-inferiority randomised controlled trial. SETTING:  Outpatient clinics in eight teaching hospitals in the Netherlands, including one university medical centre. PARTICIPANTS:  Patients compliant with compression therapy for 12 months after symptomatic, ultrasound proven proximal deep venous thrombosis of the leg. INTERVENTIONS:  Continuation or cessation of ECS 12 months after deep venous thrombosis. MAIN OUTCOME MEASURES:  The primary outcome was the incidence of post-thrombotic syndrome 24 months after diagnosis of deep venous thrombosis, as assessed by the standardised Villalta scale in an intention to treat analysis. The predefined non-inferiority margin was 10%. The main secondary outcome was quality of life (VEINES-QOL/Sym). RESULTS:  518 patients compliant with ECS and free of post-thrombotic syndrome were randomised one year after diagnosis of deep venous thrombosis to stop or continue ECS therapy for another year. In the stop-ECS group, 51 of 256 patients developed post-thrombotic syndrome, with an incidence of 19.9% (95% confidence interval 16% to 24%). In the continue-ECS group, 34 of 262 patients developed post-thrombotic syndrome (incidence 13.0%, 9.9% to 17%), of whom 85% used ECS six or seven days a week during the study period, for an absolute difference of 6.9% (95% confidence interval upper limit 12.3%). Because the upper limit of the 95% confidence interval exceeds the predefined margin of 10%, non-inferiority was not reached. The number needed to treat to prevent one case of post-thrombotic syndrome by continuing ECS was 14 (95% confidence interval lower limit 8). Quality of life did not differ between the two groups. CONCLUSION:  Stopping ECS after one year in compliant patients with proximal deep venous thrombosis seemed not to be non-inferior to continuing ECS therapy for two years in this non-inferiority trial. TRIAL REGISTRATION:  Netherlands Trial Register NTR1442.

[Prone positioning of patients during venovenous extracorporeal membrane oxygenation is safe and feasible]. / Bauchlagerung von Patienten an der venovenösen ECMO ist möglich und sicher.

BACKGROUND: Prone positioning of patients with acute respiratory distress syndrome (ARDS) has been shown to significantly improve survival rates. Prone positioning reduces collapse of dorsal lung segments with subsequent reduction of alveolar overdistension of ventral lung segments, optimizes lung recruitment and enhances drainage. Patients with ARDS treated by extracorporeal membrane oxygenation (ECMO) can also benefit from prone positioning; however, the procedure is associated with a possible higher risk of serious adverse events. OBJECTIVE: The aim of this study was to evaluate the safety and feasibility of prone positioning for patients with severe ARDS during ECMO therapy. MATERIAL AND METHODS: This study involved a retrospective analysis of all patients placed in a prone position while being treated by venovenous ECMO (vvECMO) for severe hypoxemia in ARDS as bridge to recovery in the interdisciplinary intensive care unit at the University Hospital Leipzig between January 2009 and August 2013. Baseline data, hospital mortality and serious adverse events were documented. Serious adverse events were defined as dislocation or obstruction of endotracheal tube or tracheal cannula, ECMO cannulas and cardiac arrest. Prone positioning was carried out by at least one doctor and three nurses according to a standardized protocol. Results are given as the median (1st and 3rd quartiles). RESULTS: A total of 26 patients were treated with vvECMO as bridge to recovery due to severe ARDS. Causes for ARDS were pneumonia (n = 20) and aspiration (n = 2) and four patients had different rare causes of ARDS. The median time on ECMO was 8 days (6;11) and during this period 134 turning events were documented. Patients were proned for a median of 5 (3;7) periods with a median duration of 12 h (8;12). No serious adverse events were recorded. The hospital mortality was 42% and mortality during the ECMO procedure was 35%. CONCLUSION: Prone positioning significantly reduces the mortality of patients with severe ARDS. In this series of 26 patients with severe ARDS during ECMO therapy no serious adverse events were found during the use of prone positioning.

Adsorption of small organic molecules on anatase and rutile surfaces: a theoretical study.

The adsorption of several small organic molecules on rutile (110) and (100) as well as on anatase (101) surfaces was investigated by Car-Parrinello molecular dynamics in aqueous solution and a new approach to the calculation of adsorption energies is proposed, taking into account the potential energy fluctuation of larger systems. Acetylene and ethylene insert into twin oxygen vacancies in the surface and form polarized covalent Ti-C bonds. In one case spontaneous coupling of two acetylene molecules to a C(4)H(3) molecule with a structure similar to trans-butadiene was observed. Neutral catechol and the singly charged anion were not reactive on any titanium dioxide surface, but the twofold-charged anion attained stable mono- and bidentated geometries on anatase. Methanol, ethanol, formaldehyde and acetaldehyde adsorbed with their functional groups. Very stable geometries provide a Ti-O bond and have adsorption energies of 60-200 kJ/mol. The adsorbates compete with water molecules for similar adsorption sites in point defects as well as on perfect surfaces.

[Surprising findings in the colon 15 years after a holiday in Africa]. / Uberraschender Befund im Kolon 15 Jahre nach Afrika-Urlaub.

HISTORY AND ADMISSION FINDINGS: A 65-year-old woman was admitted to hospital with abdominal discomfort for several years. Travel history revealed two 4-week stays in Mwanza/Tanzania 15 and 17 years earlier. INVESTIGATIONS: Laboratory tests showed eosinophilia and an increase of IgE and antibodies against Schistosoma mansoni (IHA, EIA). Stool was negative for worm eggs. Colonoscopy revealed in several parts small nodules and increased vascularisation. Histology showed granulomas and eggs of Schistosoma mansoni. TREATMENT AND COURSE: Anthelmintic therapy with praziquantel was given. After that the patient was well. One year later, follow-up endoscopy and histology were the same as previously. Another course of Praziquantel was given. A year later the patient was still well. CONCLUSION: Even after several years the rare case of intestinal schistosomiasis should be considered in patients with a history of travel in endemic regions. In case of negative stool specimen biopsies of the colon and rectum should be taken.

Epidemiology of nasopharyngeal carriage of Neisseria meningitidis in healthy Dutch children.

We investigated the prevalence and determinants of nasopharyngeal carriage of Neisseria meningitidis in 3200 healthy children aged 1-19 years. The incidence of meningococcal carriage was, on average, 1.5%. Peak incidences were seen at age 1 year and after age 15 years. The independent determinants of meningococcal carriage included age, regular visits to youth clubs (odds ratio [OR], 2.2) and discotheques (OR, 4.3), and pneumococcal carriage (OR, 4.1).

[Gastrointestinal stromal tumours (GIST) of the jejunum in a patient with neurofibromatosis type 1 (von Recklingshausen's disease)]. / Gastrointestinale Stromatumoren (GIST) des Jejunums bei einer Patientin mit Neurofibromatose Typ 1 (Morbus von Recklinghausen).

CASE REPORT: A 72-year-old female patient with known neurofibromatosis type 1 was admitted to the hospital with symptomatic anaemia and a history of melaena. Upper and lower endoscopy did not show any signs of bleeding. Ultrasound and computed tomography revealed an abdominal mass. The histological analysis of a US-guided puncture showed a mesenchymal tumour with spindle-shaped appearance. Laparotomy revealed two jejunal tumours which could be classified as gastrointestinal stromal tumours (GIST) by immunohistochemistry. CONCLUSION: Patients with neurofibromatosis type 1 have an increased risk of developing gastrointestinal tumours including rare types such as GIST. Because the localisation in the small intestine by conventional endoscopy can be difficult, further diagnostic means such as ultrasound, computed tomography or possibly capsule endoscopy should be considered.

[Biliary ascariasis after cholecystectomy and papillotomy in a non-endemic area]. / Biliäre Askariasis nach Cholezystektomie und Papillotomie in einem Nicht-Endemiegebiet.

HISTORY AND ADMISSION FINDINGS: A 61-year-old woman was admitted to hospital with nausea and vomiting. Four years earlier she had undergone cholecystectomy and papillotomy. INVESTIGATIONS: Laboratory examination showed a slight increase of aspartate and alanine aminotransferase, glutamyl transpeptidase, and moderate eosinophilia. Ultrasound revealed an elongated echogenic structure within the common bile duct. At endoscopic cholangiopancreaticography (ERCP) a 23 cm-long Ascaris lumbricoides was found. TREATMENT AND COURSE: The worm was removed endoscopically with forceps. Antihelmintic therapy with mebendazole was given. After that the patient was well and laboratory findings were normal. CONCLUSION: Biliary ascariasis should also be considered in a non-endemic area. Previous cholecystectomy and papillotomy are predisposing factors. In our case ERCP was the diagnostic and therapeutic method of choice.

No epidemiological evidence for infant vaccinations to cause allergic disease.

CONTEXT: The prevalence of allergic diseases has increased considerably over the last decades. The hygiene hypothesis has emerged, linking reduced microbial exposure and infections early in life with the development of allergic diseases. Especially some of currently available non-replicating infant vaccines are unlikely to mimic a natural infection-mediated immune response that protects against the development of allergic diseases. Moreover, several studies suggested infant vaccinations to increase the risk of allergic diseases. OBJECTIVE: To determine whether infant vaccinations increase the risk of developing allergic disease. DATA SOURCES: We searched MEDLINE from 1966 to March 2003 and bibliography lists from retrieved articles, and consulted experts in the field to identify all articles relating vaccination to allergy. STUDY SELECTION AND DATA EXTRACTION: We selected epidemiological studies with original data on the correlation between vaccination with diphtheria, pertussis, tetanus (DPT), measles, mumps, rubella (MMR) and Bacillus Calmette-Guérin (BCG) vaccine in infancy and the development of allergic diseases, and assessed their quality and validity. DATA SYNTHESIS: Methodological design and quality varied considerably between the studies we reviewed. Many studies did not address possible confounders, such as the presence of lifestyle factors, leaving them prone to bias. The studies that offer the stronger evidence, including the only randomized controlled trial at issue published to date, indicate that the infant vaccinations we investigated do not increase the risk of developing allergic disease. Furthermore, BCG does not seem to reduce the risk of allergies. CONCLUSIONS: The reviewed epidemiological evidence indicates that, although possibly not contributing to optimal stimulation of the immune system in infancy, current infant vaccines do not cause allergic diseases.

[Anaphylactic shock caused by rupture of an echinococcal cyst in a 25-year-old asylum seeker from Georgia]. / Anaphylaktischer Schock bei einem 25-jährigen Asylbewerber aus Georgien.

HISTORY AND ADMISSION FINDINGS: A 25-year-old asylum seeker from Georgia was admitted to hospital with acute right upper quadrant abdominal pain, vertigo, dyspnea, generalized urticaria and positive shock index (blood pressure 80/40 mmHg, pulse 120/min) several minutes after eating an instant soup. INVESTIGATIONS: Laboratory investigations showed a slight increase of the eosinophilic cell count and GOT and GPT activities. Abdominal ultrasound scan (USS) and computed tomography (CT) revealed a multivesicular septated cystic space-occupying lesion of the right liver lobe (segment VII, 13 x 9 x 8 cm) and perihepatic fluid. TREATMENT AND COURSE: Intravenous steroids, H 1 and H 2 antagonists and fluid were given. Emergency laparatomy with endocystectomy was performed. A 3-month course of antihelmintic therapy with albendazole was applied. During follow-up up to one year after surgery the patient did well. Ultrasonography and computed tomography showed only a small residual defect in the right liver lobe where the cyst had been removed. CONCLUSION: In patients from echinococcosis-endemic regions who develop an anaphylactic reaction, a ruptured Echinococcus granulosus cyst should be considered in the differential diagnosis. Abdominal ultrasonography and serology (to be noted: substantial rate of false negative results!) should be performed.

Neonatal pulmonary arteriovenous malformation in hereditary haemorrhagic telangiectasia.

A 3 week old infant presented with persistent hypoxaemia and was diagnosed with pulmonary arteriovenous malformations. Her family history was positive for hereditary haemorrhagic telangiectasia. She was treated successfully with coil embolotherapy at the age of 4 months. Transcatheter embolisation may be considered the primary treatment for pulmonary arteriovenous malformations in infancy.

Evidence for genetic regulation of susceptibility to toxoplasmic encephalitis in AIDS patients.

The frequency of HLA-DQ antigens in AIDS patients with toxoplasmic encephalitis (TE) were examined. HLA-DQ3 was significantly more frequent in white North American AIDS patients with TE (85.0%) than in the general white population (51.8%; P = .007, corrected P = .028) or randomly selected control AIDS patients who had not developed TE (40.0%; P = .016). In contrast, the frequency of HLA-DQ1 was lower in TE patients than in healthy controls (40.0% vs. 66.5%, P = .027), but this difference did not reach statistical significance when corrected for the number of variables tested (corrected P = .108 for the general white population). HLA-DQ3 thus appears to be a genetic marker of susceptibility to development of TE in AIDS patients, and DQ1 may be a resistance marker. These HLA associations with disease indicate that development of TE in AIDS patients is affected by a gene or genes in the HLA complex and that HLA-DQ typing may help in decisions regarding TE prophylaxis.

Prevention of Pneumocystis carinii pneumonia and toxoplasmic encephalitis in human immunodeficiency virus infected patients: a clinical approach comparing aerosolized pentamidine and pyrimethamine/sulfadoxine.

The incidence of Pneumocystis carinii pneumonia (PCP) and toxoplasmic encephalitis (TE) was analyzed in 83 human immunodeficiency virus (HIV)-infected patients who inhaled aerosolized pentamidine (AP) either for primary prophylaxis (group Ia) or secondary prophylaxis (group IIa) of PCP. These cohorts were compared with two historical groups of patients who took Fansidar (pyrimethamine/sulfadoxine) for primary prophylaxis (group Ib) or secondary prophylaxis (group IIb) of PCP. The follow-up was 3-41 months (median 8 months). PCP did not occur in group Ia but was seen in 1 patient of group Ib (5%). TE was observed in 3 patients of group Ia (7.3%) and in 1 patient of group Ib (5%). PCP relapses were seen in 5 patients of group IIa (11.9%) and in 3 patients of group IIb (6.9%), whereas TE occurred in 13 patients of group IIa (30.9%) and in 1 patient of group IIb (2.3%). 20.3% of patients with CD4+ counts less than or equal to 100/microliters and only 7.7% of those with CD4+ counts greater than 100/microliters developed toxoplasmosis. In conclusion, Fansidar rather than AP prophylaxis should be recommended for patients with a history of PCP or toxoplasmosis and for all HIV-infected patients with CD4+ counts less than or equal to 100/microliters. In patients with CD4+ lymphocyte counts between 100 and 200/microliters, AP prophylaxis appears appropriate.

Upper lobe relapse of Pneumocystis carinii pneumonia during aerosolized pentamidine prophylaxis.

A patient with a history of Pneumocystis carinii pneumonia (PCP) inhaled aerosolized pentamidine (AP) for secondary prophylaxis of PCP. Nine months after the first PCP episode he presented with pulmonary upper-lobe infiltrations demonstrated by chest x-ray, and bronchoalveolar lavage confirmed the diagnosis of PCP. The clinical course and possible explanations for this unusual form of PCP are presented. The case emphasizes the importance of clinical controls for early diagnosis of relapse of PCP in patients inhaling aerosolized pentamidine. Monitoring of serum lactate dehydrogenase levels appeared to be important in the follow-up of the patient described.

Structuring and articulation of Rorschach inkblots in relation to alcohol consumption: a co-twin control study.

20 male, alcohol-discordant twin pairs, aged 45 to 65 yr. were compared for ability to structure and articulate Rorschach inkblots. The Rorschach responses were evaluated by a new rating scale technique. Data were analyzed by means of one-sample t and multivariate Td2 tests. No relationship between alcohol consumption and tendency to articulate and structure could be established.