Integrated molecular landscape of amyotrophic lateral sclerosis provides insights into disease etiology

Amyotrophic lateral sclerosis (ALS) is a severe, progressive and ultimately fatal motor neuron disease caused by a combination of genetic and environmental factors, but its underlying mechanisms are largely unknown. To gain insight into the etiology of ALS, we here conducted genetic network and literature analyses of the top‐ranked findings from six genome‐wide association studies of sporadic ALS (involving 3589 cases and 8577 controls) as well as genes implicated in ALS etiology through other evidence, including familial ALS candidate gene association studies. We integrated these findings into a molecular landscape of ALS that allowed the identification of three main processes that interact with each other and are crucial to maintain axonal functionality, especially of the long axons of motor neurons, i.e. (1) Rho‐GTPase signaling; (2) signaling involving the three regulatory molecules estradiol, folate, and methionine; and (3) ribonucleoprotein granule functioning and axonal transport. Interestingly, estradiol signaling is functionally involved in all three cascades and as such an important mediator of the molecular ALS landscape. Furthermore, epidemiological findings together with an analysis of possible gender effects in our own cohort of sporadic ALS patients indicated that estradiol may be a protective factor, especially for bulbar‐onset ALS. Taken together, our molecular landscape of ALS suggests that abnormalities within three interconnected molecular processes involved in the functioning and maintenance of motor neuron axons are important in the etiology of ALS. Moreover, estradiol appears to be an important modulator of the ALS landscape, providing important clues for the development of novel disease‐modifying treatments.     

Deviant neurophysiological responses to phonological regularities in speech in dyslexic children

Developmental dyslexia is strongly associated with a phonological deficit. Yet, implicit phonological processing (in)capacities in dyslexia remain relatively unexplored. Here we use a neurophysiological response sensitive to experience-dependent auditory memory traces, the mismatch negativity (MMN), to investigate implicit phonological processing of natural speech in dyslexic and normally reading children. In a modified passive oddball design that minimizes the contribution of acoustic processes, we presented non-words that differed by the degree of phonotactic probability, i.e. the distributional frequency of phoneme combinations in a given language. Overall morphology of ERP responses to the non-words indicated comparable processing of acoustic-phonetic stimulus differences in both children groups. Consistent with previous findings in adults, normally reading children showed a significantly stronger MMN response to the non-word with high phonotactic probability (notsel) as compared to the non-word with low phonotactic probability (notkel), suggesting auditory cortical tuning to statistical regularities of phoneme combinations. In contrast, dyslexic children did not show this sensitivity to phonotactic probability. These findings indicate that the phonological problems often reported in dyslexia relate to a subtle deficit in the implicit phonetic-phonological processing of natural speech.     

The yield of upper gastrointestinal endoscopy in patients with suspected reflux-related chronic ear, nose, and throat symptoms

OBJECTIVES: It is well established that various ENT disorders and symptoms may be a manifestation of gastroesophageal reflux disease (GERD). Erosive esophagitis is considered a rare finding in ENT patients and therefore upper gastrointestinal (GI) endoscopy is not recommended in the diagnostic work-up. However, large prospective studies underscoring this policy are lacking. The aim of the present study was to investigate the prevalence and severity of esophagitis in patients with suspected GERD-related chronic ENT symptoms. METHODS: Endoscopy was performed in 405 ENT patients with suspected GERD and 545 typical GERD patients. The presence of erosive esophagitis, Barrett's esophagus, hiatal hernia, peptic ulcer, and Helicobacter pylori infection on biopsies was determined and compared with the results of a symptom questionnaire. RESULTS: The prevalence of erosive esophagitis (52.3% vs 38.4%; p < 0.05), mainly grade 1 (31.9% vs 22.7%; p < 0.05), and of peptic ulcer (8.4% vs 4.3%; p < 0.05) was significantly higher in patients with GERD-related ENT symptoms compared to typical GERD. Barrett's mucosa occurred in, respectively, 4.9% and 4.5% of the patients (NS). Esophagitis prevalence was highest in patients with predominant cough and lowest in globus pharyngeus and throat symptoms. The presence of esophagitis was associated with significantly higher rates of symptom relief during the first 8 wk of proton pump inhibitor (PPI) therapy. CONCLUSIONS: Patients with suspected GERD-related ENT symptoms have a high prevalence of esophagitis and this is associated with better response to antisecretory therapy.     

Determinants of Long-Term Outcome of Patients with Reflux-Related Ear, Nose, and Throat Symptoms

Gastroesophageal reflux disease (GERD) is present in up to 75% of patients with chronic refractory ear, nose, and throat (ENT) symptoms, and proton pump inhibitor (PPI) therapy induces symptom relief in the majority of these patients. It has been suggested that endoscopic findings and quantification of esophageal acid exposure may help to predict the long-term outcome of medical therapy, but prospective studies that confirm this hypothesis are lacking. The aim of the present study was to investigate the relationship of endoscopic findings and quantification of reflux with long-term outcome in patients with reflux-related ENT symptoms. One hundred six consecutive patients with chronic refractory unexplained ENT symptoms underwent upper GI endoscopy, 24-hr dual-channel esophageal pH and Bilitec (n = 35) monitoring, and esophageal manometry. Subsequently, all were treated with omeprazole, 20 mg b.i.d., and patients were followed at 2-week intervals until symptom relief. Four weeks later, omeprazole therapy was gradually decreased and the lowest effective omeprazole maintenance dose, if any, was determined. Eighty-one patients (49 men; mean age, 50) experienced a clear or excellent therapeutic response after, on average, 4 weeks of omeprazole, 20 mg b.i.d. In 36 patients (44%; group A), PPI treatment could be stopped completely, 27 patients (33%; group B) required a maintenance dose of omeprazole, 20 mg/day, and 18 patients (22%; group C) required maintenance with omeprazole, 40 mg/day. The prevalence of reflux esophagitis was significantly lower in group A patients, who also had significantly lower distal esophageal acid exposure, proximal esophageal acid exposure, and esophageal duodenogastroesophageal reflux exposure compared to groups B and C. Multivariate analysis identified the presence of esophagitis and pathological distal esophageal acid exposure as risk factors for the need of maintenance therapy. In patients with reflux-related ENT symptoms, initial findings on upper GI endoscopy and 24-hr pH-metry help to predict the need for maintenance therapy.     

Frequency of a positive modified Allen's test in 1,000 consecutive patients undergoing cardiac catheterization

The modified Allen's test (A.T.) is used to prove the adequacy of the blood supply through the ulnar artery to the hand. The test is considered normal if, after compression of both the ulnar and radial arteries followed by repeated clenching of the fingers to squeeze out the blood, the normal or a slightly more pronounced red color of the palm of the hands returns within < 10 sec after release of only the ulnar artery. It is important to perform the test whenever intravascular access to the radial artery is planned. The objective of this study was to determine the percentage of patients presenting a clearly positive (< 5 sec), a moderately positive (between 5–9 sec), or a negative A.T. (10 sec and more). We performed an A.T. on 1,000 consecutive and different patients undergoing cardiac catheterization, on the right wrist, two times, each time by a different examinator trained in this test. An A.T. was performed on 1,000 patients: 640 men, 360 women, mean age 62,3 yr (range 28–90 yr). In our population of patients, the relative percentages of a clearly positive (< 5 sec), moderately positive (between 5–9 sec), or negative modified Allen's test (10 sec and more) is 49%, 24%, and 27%, respectively. © 1996 Wiley-Liss, Inc.     

Hemispheric Asymmetry of Auditory Steady-State Responses to Monaural and Diotic Stimulation

Amplitude modulations in the speech envelope are crucial elements for speech perception. These modulations comprise the processing rate at which syllabic (∼3–7 Hz), and phonemic transitions occur in speech. Theories about speech perception hypothesize that each hemisphere in the auditory cortex is specialized in analyzing modulations at different timescales, and that phonemic-rate modulations of the speech envelope lateralize to the left hemisphere, whereas right lateralization occurs for slow, syllabic-rate modulations. In the present study, neural processing of phonemic- and syllabic-rate modulations was investigated with auditory steady-state responses (ASSRs). ASSRs to speech-weighted noise stimuli, amplitude modulated at 4, 20, and 80 Hz, were recorded in 30 normal-hearing adults. The 80 Hz ASSR is primarily generated by the brainstem, whereas 20 and 4 Hz ASSRs are mainly cortically evoked and relate to speech perception. Stimuli were presented diotically (same signal to both ears) and monaurally (one signal to the left or right ear). For 80 Hz, diotic ASSRs were larger than monaural responses. This binaural advantage decreased with decreasing modulation frequency. For 20 Hz, diotic ASSRs were equal to monaural responses, while for 4 Hz, diotic responses were smaller than monaural responses. Comparison of left and right ear stimulation demonstrated that, with decreasing modulation rate, a gradual change from ipsilateral to right lateralization occurred. Together, these results (1) suggest that ASSR enhancement to binaural stimulation decreases in the ascending auditory system and (2) indicate that right lateralization is more prominent for low-frequency ASSRs. These findings may have important consequences for electrode placement in clinical settings, as well as for the understanding of low-frequency ASSR generation.     

Paroxysmal Laryngospasm: A Typical but Underrecognized Supraesophageal Manifestation of Gastroesophageal Reflux?

Thirty-five consecutive adult patients with paroxysmal laryngospasm (LS) and with unimpaired vocal fold mobility were prospectively studied for coexisting gastroesophageal reflux disease (GERD). Nineteen patients reported frequent (>3 episodes a week) LS episodes (FLS patients) and 16 patients reported occasional LS episodes (OLS patients). All patients underwent an extensive otorhinolaryngological (ORL) examination, upper gastrointestinal (GI) endoscopy, ambulatory 24-hr dual-channel esophageal pH monitoring, and esophageal manometry. In addition, a subset of LS patients also underwent ambulatory duodenogastroesophageal reflux (DGER) monitoring. Patients with daily LS used the symptom marker during pH monitoring indicating separate LS episodes. All FLS patients and 14 OLS patients (87%) had a diagnosis of GERD. Only 10 patients (29%) experienced heartburn and/or regurgitation. Compared to OLS patients, FLS patients generally had more severe GERD as indicated by a higher prevalence of a hiatus hernia, higher distal and proximal esophageal acid exposure times, and higher values of DGER. In six FLS patients, 21 LS episodes (91%) occurred simultaneously with acid reflux, indicating a causal association between LS and GER. On antireflux therapy consisting of omeprazole, 20 mg bid, or lansoprazole, 30 mg oid, and lifestyle measures, LS ceased completely in all patients within 6 weeks. The present study not only demonstrates the role of GER in the pathogenesis of LS and the effectiveness of antireflux therapy, but also suggests that LS in adult patients with unimpaired vocal fold mobility might be considered a typical, although most frequently unrecognized, supraesophageal manifestation of GER.     

Abdominal wound dehiscence in gastroenterological surgery.

The occurrence of complete wound dehiscence is analyzed in a group of 4538 patients treated with abdominal surgery. All possible measures for the prevention of wound dehiscence should be taken at the time of operation, especially when two or more of the following predisposing factors are present: male, more than 64-years-old, complicated neoplastic and inflammatory diseases, as well as bleeding and noncomplicated inflammatory diseases (except appendicitis), as well as emergency interventions. The use of Ventrofil plates for the prevention of wound dehiscence is recommended in these cases. It is demonstrated that the incidence of complete wound dehiscence in cases with predisposing factors in significantly decreased when extrapreventive measures are taken at the time of wound closure, what results in a decrease of the frequency by which wound dehiscence after gastrointestinal operations occurs.