[ISO 1999:2013 part 1 : Revised probability model for calculating noise-induced hearing loss]. / ISO 1999:2013 Teil 1 : Überarbeitetes Wahrscheinlichkeitsmodell zur Berechnung des lärmbedingten Hörverlusts.

The ISO 1999:2013 norm describes a method of calculating the statistically expected permanent threshold shift (PTS) due to noise. Input parameters are noise level LEX,8h related to an 8­hour working day, duration of noise exposure in years, gender, and age. The background is a formula based on four datasets of measured values from larger surveys. Within its defined scope, ISO 1999 provides audiometric hearing curves for the frequencies 0.5, 1, 2, 3, 4, and 6 kHz for probability percentiles 5 to 95. This international standard is a useful additional tool for estimating the most probable cause of hearing disability when compared to the hearing curve in a noise worker's threshold audiogram and thus for deciding whether an occupational noise-induced hearing loss is likely to be present or not. According to the formula given in ISO 1999, sets of curves were recalculated separately for women and men to make them easily accessible in a new, expanded, and modernized graphical representation in this publication. Thus, according to ISO 1999, the following applies for the assessment: The higher the age, the more likely a noise-induced hearing threshold shift is to recede behind an age-related hearing threshold shift.

In chronic spontaneous urticaria, IgE against staphylococcal enterotoxins is common and functional.

BACKGROUND: Chronic spontaneous urticaria (CSU) is a frequent disorder with recurrent itchy wheals and/or angioedema. Despite the known effectiveness of omalizumab therapy, the relevant IgE antigens are largely unknown. Recently, increased rates of elevated levels of IgE towards Staphylococcus aureus enterotoxins (SEs) were described in CSU. AIM: To assess the prevalence and functional relevance of IgE to SEs in CSU. METHOD: We investigated serum levels of IgE against SEs in 49 CSU patients and in 15 CSU patients additional specific IgE to SE components and basophil histamine release (BHR). Sera of 15 healthy controls (HCs) served as control group. RESULTS: Twenty-five (51%) of the CSU patients had detectable levels of SE-IgE as compared to 5 (33%) of HCs. Specific IgE to one of the SEs, Staphylococcus enterotoxin B (SEB), was present in 5 (33%) of 15 randomly selected CSU patients vs 3 (20%) of HC. Total IgE serum levels in CSU patients were significantly correlated with SE-IgE (r = .52, P < .001) and SEB-IgE (r = .54, P = .04) serum concentrations. Interestingly, SEB-IgE levels were strongly correlated with disease activity (UASday) in CSU patients (r = .657, P = .01). Furthermore, BHR in response to SEB was significantly higher in basophils loaded with the serum of CSU patients compared to HC (P < .05) and was clinically correlated with duration of disease (r > .51, P < .05). DISCUSSION: IgE against SEs may contribute to the pathogenesis of CSU in a subpopulation of patients. Its role and relevance in the pathophysiology of CSU need to be further analysed.

Clinical implications of gastrointestinal symptoms in systemic amyloidosis.

BACKGROUND: Gastrointestinal (GI) symptoms in systemic amyloidosis patients are poorly characterized. This purpose of this study is to define the epidemiology and clinical implications of such symptoms. METHODS: This was a retrospective cohort study of 583 amyloid patients seen at a tertiary referral center. Of 96 symptomatic patients, 82 received endoscopic biopsies, subsequently grouped into those with histologic evidence of GI amyloid (biopsy proven) vs without (biopsy absent). KEY RESULTS: 16.8% of patients had GI symptoms, and had more abnormal NT-proBNP, cardiac ejection fraction, serum albumin, and alkaline phosphatase (P < .01). Of those who received endoscopy, the sites of highest diagnostic yield were stomach, duodenum and colon. The most common symptom was abdominal pain, nausea, or vomiting (50.0%). Of the symptomatic patients, only 37 (45%) had biopsy proven GI amyloid. Biopsy proven patients more often had cardiac involvement (P < .005), and more often received hematologic therapy or transplant (P = .01). Biopsy absent patients had more frequent neurologic involvement (P = .17). Biopsy status had no significant correlation with other indicators of amyloid burden, GI symptoms or management. CONCLUSIONS & INFERENCES: Nearly one in six amyloid patients have GI symptoms, and half do not have GI amyloid. The type of symptom does not predict endoscopic findings. Most biopsy absent patients are not managed as a functional disorder despite no alternative etiology. Gastroenterologists may have an increased role to play in the care of systemic amyloidosis beyond performing endoscopies, such as evaluating cardiac amyloid patients for concurrent GI amyloid.

Efficacy and safety of midostaurin in patients with advanced systemic mastocytosis: 10-year median follow-up of a phase II trial.

Patients with advanced systemic mastocytosis (SM) (e.g. aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN) and mast cell leukemia (MCL)) have limited treatment options and exhibit reduced survival. Midostaurin is an oral multikinase inhibitor that inhibits D816V-mutated KIT, a primary driver of SM pathogenesis. We conducted a phase II trial of midostaurin 100 mg twice daily, administered as 28-day cycles, in 26 patients (ASM, n=3; SM-AHN, n= 17; MCL, n=6) with at least one sign of organ damage. During the first 12 cycles, the overall response rate was 69% (major/partial response: 50/19%) with clinical benefit in all advanced SM variants. With ongoing therapy, 2 patients achieved a complete remission of their SM. Midostaurin produced a ⩾50% reduction in bone marrow mast cell burden and serum tryptase level in 68% and 46% of patients, respectively. Median overall survival for the entire cohort was 40 months, and 18.5 months for MCL patients. Low-grade gastrointestinal side effects were common and manageable with antiemetics. The most frequent grade 3/4 nonhematologic and hematologic toxicities were asymptomatic hyperlipasemia (15%) and anemia (12%). With median follow-up of 10 years, no unexpected toxicities emerged. These data establish the durable activity and tolerability of midostaurin in advanced SM.

HIV Pharmacist's Impact on Inpatient Antiretroviral Errors.

OBJECTIVES: Transitions in care between out-patient and in-patient settings provide ample opportunity for medication errors to occur in HIV-infected patients. The purpose of this study was to examine the effectiveness of an HIV pharmacist monitoring service in decreasing antiretroviral medication errors in a large south central teaching hospital in the USA. METHODS: A retrospective, observational study was conducted to examine the frequency of antiretroviral medication errors in HIV-seropositive patients with hospital admissions between 1 September 2011 and 30 September 2013 at a single tertiary care centre in Oklahoma. Patient assignment to the 12-month pre-intervention and intervention study periods was determined by admission date. Demographic, laboratory, and in-patient medication data were collected. Bivariate analyses were conducted using χ2 analysis with the Yates correction factor for continuity to examine frequencies in specific antiretroviral classes and error categories. A multivariable Poisson regression was employed to examine the frequency of medication errors before and after initiation of the pharmacist service. RESULTS: Medication errors were examined in a total of 330 patient admissions during the 2-year study period. A multivariable-adjusted decrease of 73.9% in the number of errors was observed between the pre-intervention and intervention periods (P < 0.001). Patients on protease inhibitor regimens or with impaired renal function had 2.6-fold and 2.8-fold higher numbers of errors, respectively (P < 0.001). CONCLUSIONS: HIV pharmacist monitoring can decrease medication errors in HIV-infected patients as they transition between out-patient and in-patient care. Patients receiving protease inhibitor-based therapy or with renal insufficiency are at higher risk for medication errors upon admission.

Outcomes after heart transplantation for amyloid cardiomyopathy in the modern era.

We conducted a review of patients undergoing heart transplantation (HT) at our institution for amyloid cardiomyopathy (ACM) between 2008 and 2013. Complete follow-up was available for all patients. Nineteen patients with ACM underwent HT during the study period, accounting for 9.4% of all HT performed at our institution during this period. Amyloid subtype was light chain (AL) in 9 patients and transthyretin (ATTR) in 10 (2 wild-type, 7 familial, 1 unknown). Eight of nine patients with AL amyloidosis began chemotherapy prior to HT, six have resumed chemotherapy since HT, and five have undergone autologous stem cell transplantation. Most recent free light chain levels in AL patients decreased by a median of 85% from peak values. Only one patient developed recurrent graft amyloidosis, occurring at 3.5 years post-HT and asymptomatic. After a median follow-up of 380 days, 17 (89.5%) patients are alive. To our knowledge, this is the largest single-center series reported of ACM patients undergoing HT in the modern era. Our results suggest that acceptable outcomes following HT can be achieved in the short-to-intermediate term and that this is a feasible option for end-stage ACM with careful patient selection and aggressive control of amyloidogenic light chains in AL patients.

Safety, efficacy and biological predictors of response to sequential azacitidine and lenalidomide for elderly patients with acute myeloid leukemia.

Acute myeloid leukemia (AML) is a disease of the elderly. Poor outcomes with standard therapies necessitate novel approaches. Outpatient regimens sufficiently potent and well tolerated to induce remissions and enable continuation therapy may be beneficial. In this phase-1 study, we determined the maximum tolerated dose (MTD) and the efficacy for sequential azacitidine and lenalidomide as remission induction and continuation therapy in elderly, previously untreated patients. We investigated the impact on global DNA methylation and bone marrow cytokines, and sought biological predictors of response. Eighteen patients were enrolled. The MTD was not reached. Median follow-up was 8.2 months (10.3 months for survivors). Common adverse events included fatigue, injection site reactions, constipation, nausea, pruritus and febrile neutropenia. Ten patients responded (56%), and the rate of complete remissions (CRs) or CRs with incomplete recovery of blood counts for evaluable patients was 44% (7/16). The median response duration was 6.2 months. DNA demethylation and changes in bone marrow cytokines were observed; responders had a unique cytokine profile and a trend towards lower methylation levels. Sequential azacitidine and lenalidomide was well tolerated with encouraging clinical and biological activity in previously untreated elderly AML patients. This trial is registered at ClinicalTrials.gov (NCT00890929).

[Acute hearing impairment by extremely high sound pressure levels]. / Akute Gehörschäden durch extrem hohe Schalldruckpegel.

The bulletin for occupational disease no. 2301 in the annex of the Occupational Disease Act, noise-induced hearing impairment, ("Merkblatt zu der Berufskrankheit Nr. 2301 der Anlage zur Berufskrankheiten-Verordnung: Lärmschwerhörigkeit") states that sound events with an intensity exceeding 137 dB (C) may cause immediate mechanical damage to the inner ear. Up to now a distinction has been made between prevention and actual damage potential for the risks caused by sounds with extremely high peak levels. In the field of prevention the unweighted sound pressure peak level of 140 dB, which is now 137 dB(C,peak) according to the LärmVibrationsArbSchV, was applied as the trigger threshold for measures; in contrast actual hearing impairment was not found until 150-160 dB. This article compiles the current state of knowledge and demonstrates that in the area of the reasons mentioned here for acute hearing impairment, no scientifically based new findings exist especially with reference to publications listed in the bulletin.

Quality of life in 1000 patients with early relapsing-remitting multiple sclerosis.

BACKGROUND AND PURPOSE: To examine the quality of life (QoL) in a large cohort of untreated patients with relapsing-remitting multiple sclerosis (RRMS) and to investigate the impact of intramuscular (IM) interferon beta-1a (IFNbeta-1a) treatment. METHODS: Prospective, observational, open-label, multicentre study conducted in Germany. Untreated patients with RRMS who initiated treatment with IM IFNbeta-1a were included and followed for 12 months. QoL was measured using the EQ-5D questionnaire. Clinical response was assessed by relapse rate and disability (Expanded Disability Status Scale; EDSS). RESULTS: A total of 1157 patients were included [mean age 37.6 years, median disease duration 13 months, mean relapse rate 1.7 (95%CI: 1.58-1.73), median EDSS score 2.0]. Relapse rate was reduced to 0.6 at 12 months (95%CI: 0.51-0.69, P < 0.0001). EDSS did not change significantly. At baseline, QoL was considerably lower in MS patients compared with the general German population, but was improved after treatment initiation [utilities of EQ-5D: 0.77 (95%CI: 0.75-0.78) vs. 0.75 (95%CI: 0.74-0.76) at baseline, 95%CI for difference: 0.01-0.03, P = 0.0046]. Higher disease activity and inability to work were negative predictors of QoL. 14.7% of patients were incapable of working for MS-related reasons. CONCLUSIONS: Quality of life is considerably impaired in early stages of MS. Treatment initiation with IM IFNbeta attenuates MS disease activity and improves QoL. Inability to work early during the disease is a major challenge for the social security systems.

Surveillance imaging during remission identifies a group of patients with more favorable aggressive NHL at time of relapse: a retrospective analysis of a uniformly-treated patient population.

BACKGROUND: Approximately one-third of the patients with relapsed aggressive non-Hodgkin's lymphoma (NHL) are cured by second-line chemotherapy followed by high-dose consolidation. The age-adjusted international prognostic index determined at the time of relapse (sAAIPI) predicts outcome in relapsed diffuse large B-cell lymphoma, suggesting that the success of salvage therapy could be enhanced by early relapse detection. This study evaluated the role of surveillance imaging in detection of relapsed disease and its impact on outcome of salvage treatment. PATIENTS AND METHODS: One hundred and eight patients with relapsed aggressive NHL were treated with ICE-based second-line chemotherapy. Relapses were categorized as detected by imaging, examination, or patient-reported symptoms. RESULTS: Twenty per cent of relapses were detected by routine imaging while 80% were identified by reported symptoms or abnormalities on exam. Patients were 4.1 times (95% CI: 1.7-10.2) more likely to have low risk disease if relapse was diagnosed by routine imaging (group 1) compared with those diagnosed by reported symptoms or physical findings (group 2). Median overall 5-year survival for group 1 versus group 2 was 54% and 43% respectively (P = 0.13). CONCLUSION: These results suggest that routine surveillance imaging can identify a population of patients with a more favorable outcome based on the sAAIPI.

Risk by use of hearing protectors--expert programme supports SMEs in appropriate selection and use.

Comprehensive protection by use of PPE against the hazards at work requires more than proper selection based on the protection level needed: The PPE user directive (Council Directive 89/656/EEC, Official Journal of the European Communities L 393, 30/12/1989 p.0018 - 0028) requires an assessment of personal protective equipment itself, which has to consider the risks which may be introduced by use of PPE or use of combinations of PPE. As an example risks which may be introduced by use of hearing protectors are described. Assistance in the assessment required by PPE user directive (Council Directive 89/656/EEC, Official Journal of the European Communities L 393, 30/12/1989 p. 0018 - 0028) and in selection and use of hearing protectors with regard to this assessment is presented.

Regulation of Bcr-Abl-induced SAP kinase activity and transformation by the SHPTP1 protein tyrosine phosphatase.

The oncogenic Bcr-Abl variant of the c-Abl tyrosine kinase transforms cells by a mechanism dependent on activation of the stress-activated protein kinase (SAPK). Other work has shown that c-Abl interacts with the SHPTP1 protein tyrosine phosphatase in induction of SAPK activity by genotoxic stress. The present studies demonstrate that Bcr-Abl binds constitutively to SHPTP1. We show that Bcr-Abl phosphorylates SHPTP1 on C-terminal Y536 and Y564 sites. The functional significance of the Bcr-Abl/SHPTP1 interaction is supported by the finding that SHPTP1 regulates Bcr-Abl-induced SAPK activity. Importantly, SHPTP1 also decreases Bcr-Abl-dependent transformation of fibroblasts. These findings indicate that SHPTP1 functions as a tumor suppressor in cells transformed by Bcr-Abl.

[Charles Bonnet syndrome]. / Charles-Bonnet-Syndrom.

An 80-year old previously healthy woman with recent onset of binocular macular degeneration presented for clinical psychiatric evaluation of elaborate complex visual hallucinations. In the absence of other organic or psychiatric findings the patient maintained insight into the unreal nature of her visions. As neuroleptic drugs showed no effect, low dose treatment with carbamazepin resulted in disappearance of hallucinations. The phenomenon of Charles-Bonnet-syndrome is discussed as an example of a neuro-psychiatric hallucinosis.

A site-directed mutagenesis study to identify amino acid residues involved in the catalytic function of the restriction endonuclease EcoRV.

We have used site-directed mutagenesis of the EcoRV restriction endonuclease to change amino acid side chains that have been shown crystallographically to be in close proximity to the scissile phosphodiester bond of the DNA substrate. DNA cleavage assays of the resulting mutant proteins indicate that the largest effects on nucleolytic activity result from substitution of Asp74, Asp90, and Lys92. We suggest on the basis of structural information, mutagenesis data, and analogies with other nucleases that Asp74 and Asp90 might be involved in Mg2+ binding and/or catalysis and that Lys92 probably stabilizes the pentacovalent phosphorus in the transition state. These amino acids are part of a sequence motif, Pro-Asp...Asp/Glu-X-Lys, which is also present in EcoRI. In both enzymes, it is located in a structurally similar context near the scissile phosphodiester bond. A preliminary mutational analysis with EcoRI indicates that this sequence motif is of similar functional importance for EcoRI and EcoRV. On the basis of these results, a proposal is made for the mechanism of DNA cleavage by EcoRV and EcoRI.

[Eye diseases and control of labor. Studies of changes in the eye in labor exemplified by subconjunctival hemorrhage (hyposphagmas)]. / Augenerkrankungen und Geburtsleitung. Untersuchungen über Vorgänge am Auge unter der Geburt am Beispiel von subkonjunktivalen Blutungen (Hyposphagmen).

The possible significance of subconjunctival bleedings (hyposphagmas) as a symptom for other pathological changes of the eye was studied in a group of 354 postpartum patients. They were found in 10.5% of the cases. A relatively higher frequency occurred in primiparas. No other maternal factors than parity were detected as of statistically significant influence. A slightly higher percentage in mothers with large newborn (above average cranial circumference) indicates a relationship to the necessary bearing-down effort. In a second study, 49 postpartum women with subconjunctival bleeding were examined by an ophthalmologist. Neither any intraocular or retrobulbar bleeding nor any other grievous damage to the eye were found. In accordance with the literature we recommend, that highly myopic pregnant women (even with a previous history of retinal detachment, but ophthalmologically sufficiently treated) should undergo induced delivery. However, the approach to pregnant women with retinal detachment occurring and treated during pregnancy, or to glaucoma-patients with risk to a small remaining visual field, should be more careful. In those cases, a vaginal operative delivery procedure (forceps, vacuum-extraction) is recommended. Nevertheless, one should consider individual wishes of the mother, when striving to diminish the risk to the foetus. The same applies to irrational fears related to previously damaged (and possibly only functional) eye.