Effectiveness of Biologics, Patient-Reported Outcomes, and Clinical Photography in a Subset of Patients with Moderate-to-Severe Psoriasis: Week 12 Results from the Psoriasis Study of Health Outcomes (PSoHO).

Purpose: Since skin is highly accessible, clinical photography is a useful tool to visually substantiate the real-world effectiveness outcomes of biologic-treated adults with moderate-to-severe psoriasis (PsO). We report the effectiveness and patient-reported outcomes at Week 12 between anti-interleukin (IL)-17A biologics and other biologics as well as ixekizumab and guselkumab in patients with available clinical photography at baseline and Week 12. Patients and Methods: The Psoriasis Study of Health Outcomes (PSoHO) is an international, non-interventional, cohort study investigating the effectiveness of biologics in adults with moderate-to-severe psoriasis at Week 12. Outcomes included the proportion of patients who achieved 90% improvement in Psoriasis Area and Severity Index (PASI90) and/or static Physician Global Assessment (sPGA) 0/1 (primary endpoint), PASI100, PASI90, Dermatology Life Quality Index (DLQI), and Itch Numeric Rating Scale (NRS) (secondary endpoints) at Week 12. Data are reported descriptively. Results: This analysis included 59 biologic-treated (23 anti-IL-17A; 36 other biologics) patients with available clinical photographs from the overall PSoHO study (n=1981). At baseline, the mean (standard deviation [SD]) age was 45.7 (11.1) years, 71.2% were male, 52.5% were bio-experienced and the median (interquartile range) duration of disease was 10.5 (12.4) years. Mean (SD) PASI was 16.9 (9.3) and sPGA was 3.5 (0.8). At Week 12, 65.2%/47.2% of the anti-IL-17A/other biologics cohort achieved the primary outcome. Response rates for PASI90/100 were numerically higher with anti-IL-17A than with other biologics. Patients receiving anti-IL-17A had numerically better outcomes for DLQI 0/1 and Itch NRS than those receiving other biologics at Week 12. Clinical photographs confirmed skin improvements in ixekizumab- and guselkumab-treated patients. Conclusion: This subgroup analysis showed that anti-IL-17A biologics are effective at rapidly improving signs and symptoms of PsO and improving quality of life. Additionally, serial photography provided visual evidence of biologic treatment response over time.

[Therapy of esophageal motility disorders]. / Therapieoptionen von primären Motilitätsstörungen des Ösophagus.

Esophageal motility disorders are diseases in which there are malfunctions of the act of swallowing due to a change in neuromuscular structures. The main symptom is therefore dysphagia for solid and/or liquid foods, often accompanied by symptoms such as chest pain, regurgitation, heartburn, and weight loss. Esophageal manometry is the gold standard in diagnostics. Endoscopy and radiology serve to exclude inflammatory or malignant changes. With the introduction of high-resolution esophageal manometry (HRM), the diagnosis of esophageal motility disorders has improved and led to a new classification with the Chicago Classification, which has been modified several times in the last decade, most recently in 2020 with the Chicago Classification v4.0. Compared to the previous version 3.0, there are some important changes that are presented based on the most important esophageal motility disorders in everyday clinical practice.

[Diagnosis of esophageal motility disorders - Significance of the new Chicago classification v4.0]. / Diagnostik von Motilitätsstörungen des Ösophagus ­ Bedeutung der neuen Chicago-Klassifikation v4.0.

Esophageal motility disorders are diseases in which there are malfunctions of the act of swallowing due to a change in neuromuscular structures. The main symptom is therefore dysphagia for solid and/or liquid foods, often accompanied by symptoms such as chest pain, regurgitation, heartburn, and weight loss. Esophageal manometry is the gold standard in diagnostics. Endoscopy and radiology serve to exclude inflammatory or malignant changes. With the introduction of high-resolution esophageal manometry (HRM), the diagnosis of esophageal motility disorders has improved and led to a new classification with the Chicago Classification, which has been modified several times in the last decade, most recently in 2021 with the Chicago Classification v4.0. Compared to the previous version 3.0, there are some important changes that are presented based on the most important esophageal motility disorders in everyday clinical practice.

[Therapy of esophageal motility disorders]. / Therapieoptionen von primären Motilitätsstörungen des Ösophagus.

Esophageal motility disorders are diseases in which there are malfunctions of the act of swallowing due to a change in neuromuscular structures. The main symptom is therefore dysphagia for solid and/or liquid foods, often accompanied by symptoms such as chest pain, regurgitation, heartburn, and weight loss. Esophageal manometry is the gold standard in diagnostics. Endoscopy and radiology serve to exclude inflammatory or malignant changes. With the introduction of high-resolution esophageal manometry (HRM), the diagnosis of esophageal motility disorders has improved and led to a new classification with the Chicago Classification, which has been modified several times in the last decade, most recently in 2020 with the Chicago Classification v4.0. Compared to the previous version 3.0, there are some important changes that are presented based on the most important esophageal motility disorders in everyday clinical practice.

[Diagnosis of esophageal motility disorders - Significance of the new Chicago classification v4.0]. / Diagnostik von Motilitätsstörungen des Ösophagus ­ Bedeutung der neuen Chicago-Klassifikation v4.0.

Esophageal motility disorders are diseases in which there are malfunctions of the act of swallowing due to a change in neuromuscular structures. The main symptom is therefore dysphagia for solid and/or liquid foods, often accompanied by symptoms such as chest pain, regurgitation, heartburn, and weight loss. Esophageal manometry is the gold standard in diagnostics. Endoscopy and radiology serve to exclude inflammatory or malignant changes. With the introduction of high-resolution esophageal manometry (HRM), the diagnosis of esophageal motility disorders has improved and led to a new classification with the Chicago Classification, which has been modified several times in the last decade, most recently in 2021 with the Chicago Classification v4.0. Compared to the previous version 3.0, there are some important changes that are presented based on the most important esophageal motility disorders in everyday clinical practice.

GWAS meta-analysis of 16 790 patients with Barrett's oesophagus and oesophageal adenocarcinoma identifies 16 novel genetic risk loci and provides insights into disease aetiology beyond the single marker level.

OBJECTIVE: Oesophageal cancer (EC) is the sixth leading cause of cancer-related deaths. Oesophageal adenocarcinoma (EA), with Barrett's oesophagus (BE) as a precursor lesion, is the most prevalent EC subtype in the Western world. This study aims to contribute to better understand the genetic causes of BE/EA by leveraging genome wide association studies (GWAS), genetic correlation analyses and polygenic risk modelling. DESIGN: We combined data from previous GWAS with new cohorts, increasing the sample size to 16 790 BE/EA cases and 32 476 controls. We also carried out a transcriptome wide association study (TWAS) using expression data from disease-relevant tissues to identify BE/EA candidate genes. To investigate the relationship with reported BE/EA risk factors, a linkage disequilibrium score regression (LDSR) analysis was performed. BE/EA risk models were developed combining clinical/lifestyle risk factors with polygenic risk scores (PRS) derived from the GWAS meta-analysis. RESULTS: The GWAS meta-analysis identified 27 BE and/or EA risk loci, 11 of which were novel. The TWAS identified promising BE/EA candidate genes at seven GWAS loci and at five additional risk loci. The LDSR analysis led to the identification of novel genetic correlations and pointed to differences in BE and EA aetiology. Gastro-oesophageal reflux disease appeared to contribute stronger to the metaplastic BE transformation than to EA development. Finally, combining PRS with BE/EA risk factors improved the performance of the risk models. CONCLUSION: Our findings provide further insights into BE/EA aetiology and its relationship to risk factors. The results lay the foundation for future follow-up studies to identify underlying disease mechanisms and improving risk prediction.

Clinical implementation of RNA sequencing for Mendelian disease diagnostics.

BACKGROUND: Lack of functional evidence hampers variant interpretation, leaving a large proportion of individuals with a suspected Mendelian disorder without genetic diagnosis after whole genome or whole exome sequencing (WES). Research studies advocate to further sequence transcriptomes to directly and systematically probe gene expression defects. However, collection of additional biopsies and establishment of lab workflows, analytical pipelines, and defined concepts in clinical interpretation of aberrant gene expression are still needed for adopting RNA sequencing (RNA-seq) in routine diagnostics. METHODS: We implemented an automated RNA-seq protocol and a computational workflow with which we analyzed skin fibroblasts of 303 individuals with a suspected mitochondrial disease that previously underwent WES. We also assessed through simulations how aberrant expression and mono-allelic expression tests depend on RNA-seq coverage. RESULTS: We detected on average 12,500 genes per sample including around 60% of all disease genes-a coverage substantially higher than with whole blood, supporting the use of skin biopsies. We prioritized genes demonstrating aberrant expression, aberrant splicing, or mono-allelic expression. The pipeline required less than 1 week from sample preparation to result reporting and provided a median of eight disease-associated genes per patient for inspection. A genetic diagnosis was established for 16% of the 205 WES-inconclusive cases. Detection of aberrant expression was a major contributor to diagnosis including instances of 50% reduction, which, together with mono-allelic expression, allowed for the diagnosis of dominant disorders caused by haploinsufficiency. Moreover, calling aberrant splicing and variants from RNA-seq data enabled detecting and validating splice-disrupting variants, of which the majority fell outside WES-covered regions. CONCLUSION: Together, these results show that streamlined experimental and computational processes can accelerate the implementation of RNA-seq in routine diagnostics.

Temporal hyper-precision of brainstem neurons alters spatial sensitivity of binaural auditory processing with cochlear implants.

The ability to localize a sound source in complex environments is essential for communication and navigation. Spatial hearing relies predominantly on the comparison of differences in the arrival time of sound between the two ears, the interaural time differences (ITDs). Hearing impairments are highly detrimental to sound localization. While cochlear implants (CIs) have been successful in restoring many crucial hearing capabilities, sound localization via ITD detection with bilateral CIs remains poor. The underlying reasons are not well understood. Neuronally, ITD sensitivity is generated by coincidence detection between excitatory and inhibitory inputs from the two ears performed by specialized brainstem neurons. Due to the lack of electrophysiological brainstem recordings during CI stimulation, it is unclear to what extent the apparent deficits are caused by the binaural comparator neurons or arise already on the input level. Here, we use a bottom-up approach to compare response features between electric and acoustic stimulation in an animal model of CI hearing. Conducting extracellular single neuron recordings in gerbils, we find severe hyper-precision and moderate hyper-entrainment of both the excitatory and inhibitory brainstem inputs to the binaural comparator neurons during electrical pulse-train stimulation. This finding establishes conclusively that the binaural processing stage must cope with highly altered input statistics during CI stimulation. To estimate the consequences of these effects on ITD sensitivity, we used a computational model of the auditory brainstem. After tuning the model parameters to match its response properties to our physiological data during either stimulation type, the model predicted that ITD sensitivity to electrical pulses is maintained even for the hyper-precise inputs. However, the model exhibits severely altered spatial sensitivity during electrical stimulation compared to acoustic: while resolution of ITDs near midline was increased, more lateralized adjacent source locations became inseparable. These results directly resemble recent findings in rodent and human CI listeners. Notably, decreasing the phase-locking precision of inputs during electrical stimulation recovered a wider range of separable ITDs. Together, our findings suggest that a central problem underlying the diminished ITD sensitivity in CI users might be the temporal hyper-precision of inputs to the binaural comparator stage induced by electrical stimulation.

Detection of aberrant gene expression events in RNA sequencing data.

RNA sequencing (RNA-seq) has emerged as a powerful approach to discover disease-causing gene regulatory defects in individuals affected by genetically undiagnosed rare disorders. Pioneering studies have shown that RNA-seq could increase the diagnosis rates over DNA sequencing alone by 8-36%, depending on the disease entity and tissue probed. To accelerate adoption of RNA-seq by human genetics centers, detailed analysis protocols are now needed. We present a step-by-step protocol that details how to robustly detect aberrant expression levels, aberrant splicing and mono-allelic expression in RNA-seq data using dedicated statistical methods. We describe how to generate and assess quality control plots and interpret the analysis results. The protocol is based on the detection of RNA outliers pipeline (DROP), a modular computational workflow that integrates all the analysis steps, can leverage parallel computing infrastructures and generates browsable web page reports.

Transcriptome-directed analysis for Mendelian disease diagnosis overcomes limitations of conventional genomic testing.

BACKGROUNDTranscriptome sequencing (RNA-seq) improves diagnostic rates in individuals with suspected Mendelian conditions to varying degrees, primarily by directing the prioritization of candidate DNA variants identified on exome or genome sequencing (ES/GS). Here we implemented an RNA-seq-guided method to diagnose individuals across a wide range of ages and clinical phenotypes.METHODSOne hundred fifteen undiagnosed adult and pediatric patients with diverse phenotypes and 67 family members (182 total individuals) underwent RNA-seq from whole blood and skin fibroblasts at the Baylor College of Medicine (BCM) Undiagnosed Diseases Network clinical site from 2014 to 2020. We implemented a workflow to detect outliers in gene expression and splicing for cases that remained undiagnosed despite standard genomic and transcriptomic analysis.RESULTSThe transcriptome-directed approach resulted in a diagnostic rate of 12% across the entire cohort, or 17% after excluding cases solved on ES/GS alone. Newly diagnosed conditions included Koolen-de Vries syndrome (KANSL1), Renpenning syndrome (PQBP1), TBCK-associated encephalopathy, NSD2- and CLTC-related intellectual disability, and others, all with negative conventional genomic testing, including ES and chromosomal microarray (CMA). Skin fibroblasts exhibited higher and more consistent expression of clinically relevant genes than whole blood. In solved cases with RNA-seq from both tissues, the causative defect was missed in blood in half the cases but none from fibroblasts.CONCLUSIONSFor our cohort of undiagnosed individuals with suspected Mendelian conditions, transcriptome-directed genomic analysis facilitated diagnoses, primarily through the identification of variants missed on ES and CMA.TRIAL REGISTRATIONNot applicable.FUNDINGNIH Common Fund, BCM Intellectual and Developmental Disabilities Research Center, Eunice Kennedy Shriver National Institute of Child Health & Human Development.

Lack of APP and APLP2 in GABAergic Forebrain Neurons Impairs Synaptic Plasticity and Cognition.

Amyloid-ß precursor protein (APP) is central to the pathogenesis of Alzheimer's disease, yet its physiological functions remain incompletely understood. Previous studies had indicated important synaptic functions of APP and the closely related homologue APLP2 in excitatory forebrain neurons for spine density, synaptic plasticity, and behavior. Here, we show that APP is also widely expressed in several interneuron subtypes, both in hippocampus and cortex. To address the functional role of APP in inhibitory neurons, we generated mice with a conditional APP/APLP2 double knockout (cDKO) in GABAergic forebrain neurons using DlxCre mice. These DlxCre cDKO mice exhibit cognitive deficits in hippocampus-dependent spatial learning and memory tasks, as well as impairments in species-typic nesting and burrowing behaviors. Deficits at the behavioral level were associated with altered neuronal morphology and synaptic plasticity Long-Term Potentiation (LTP). Impaired basal synaptic transmission at the Schafer collateral/CA1 pathway, which was associated with altered compound excitatory/inhibitory synaptic currents and reduced action potential firing of CA1 pyramidal cells, points to a disrupted excitation/inhibition balance in DlxCre cDKOs. Together, these impairments may lead to hippocampal dysfunction. Collectively, our data reveal a crucial role of APP family proteins in inhibitory interneurons to maintain functional network activity.

Maternal inflammation has a profound effect on cortical interneuron development in a stage and subtype-specific manner.

Severe infections during pregnancy are one of the major risk factors for cognitive impairment in the offspring. It has been suggested that maternal inflammation leads to dysfunction of cortical GABAergic interneurons that in turn underlies cognitive impairment of the affected offspring. However, the evidence comes largely from studies of adult or mature brains and how the impairment of inhibitory circuits arises upon maternal inflammation is unknown. Here we show that maternal inflammation affects multiple steps of cortical GABAergic interneuron development, i.e., proliferation of precursor cells, migration and positioning of neuroblasts, as well as neuronal maturation. Importantly, the development of distinct subtypes of cortical GABAergic interneurons was discretely impaired as a result of maternal inflammation. This translated into a reduction in cell numbers, redistribution across cortical regions and layers, and changes in morphology and cellular properties. Furthermore, selective vulnerability of GABAergic interneuron subtypes was associated with the stage of brain development. Thus, we propose that maternally derived insults have developmental stage-dependent effects, which contribute to the complex etiology of cognitive impairment in the affected offspring.

Influence of oral premedication and prewarming on core temperature of cardiac surgical patients: a prospective, randomized, controlled trial.

BACKGROUND: Perioperative hypothermia is still very common and associated with numerous adverse effects. The effects of benzodiazepines, administered as premedication, on thermoregulation have been studied with conflicting results. We investigated the hypotheses that premedication with flunitrazepam would lower the preoperative core temperature and that prewarming could attenuate this effect. METHODS: After approval by the local research ethics committee 50 adult cardiac surgical patients were included in this prospective, randomized, controlled, single-centre study with two parallel groups in a university hospital setting. Core temperature was measured using a continuous, non-invasive zero-heat flux thermometer from 30 min before administration of the oral premedication until beginning of surgery. An equal number of patients was randomly allocated via a computer-generated list assigning them to either prewarming or control group using the sealed envelope method for blinding. The intervention itself could not be blinded. In the prewarming group patients received active prewarming using an underbody forced-air warming blanket. The data were analysed using Student's t-test, Mann-Whitney U-test and Fisher's exact test. RESULTS: Of the randomized 25 patients per group 24 patients per group could be analysed. Initial core temperature was 36.7 ± 0.2 °C and dropped significantly after oral premedication to 36.5 ± 0.3 °C when the patients were leaving the ward and to 36.4 ± 0.3 °C before induction of anaesthesia. The patients of the prewarming group had a significantly higher core temperature at the beginning of surgery (35.8 ± 0.4 °C vs. 35.5 ± 0.5 °C, p = 0.027), although core temperature at induction of anaesthesia was comparable. Despite prewarming, core temperature did not reach baseline level prior to premedication (36.7 ± 0.2 °C). CONCLUSIONS: Oral premedication with benzodiazepines on the ward lowered core temperature significantly at arrival in the operating room. This drop in core temperature cannot be offset by a short period of active prewarming. TRIAL REGISTRATION: This trial was prospectively registered with the German registry of clinical trials under the trial number DRKS00005790 on 20th February 2014.

NMDA receptors mediate synaptic depression, but not spine loss in the dentate gyrus of adult amyloid Beta (Aß) overexpressing mice.

Amyloid beta (Aß)-mediated synapse dysfunction and spine loss are considered to be early events in Alzheimer's disease (AD) pathogenesis. N-methyl-D-aspartate receptors (NMDARs) have previously been suggested to play a role for Amyloid beta (Aß) toxicity. Pharmacological block of NMDAR subunits in cultured neurons and mice suggested that NMDARs containing the GluN2B subunit are necessary for Aß-mediated changes in synapse number and function in hippocampal neurons. Interestingly, NMDARs undergo a developmental switch from GluN2B- to GluN2A-containing receptors. This indicates different functional roles of NMDARs in young mice compared to older animals. In addition, the lack of pharmacological tools to efficiently dissect the role of NMDARs containing the different subunits complicates the interpretation of their specific role. In order to address this problem and to investigate the specific role for Aß toxicity of the distinct NMDAR subunits in dentate gyrus granule cells of adult mice, we used conditional knockout mouse lines for the subunits GluN1, GluN2A and GluN2B. Aß-mediated changes in synaptic function and neuronal anatomy were investigated in several-months old mice with virus-mediated overproduction of Aß and in 1-year old 5xFAD mice. We found that all three NMDAR subunits contribute to the Aß-mediated decrease in the number of functional synapses. However, NMDARs are not required for the spine number reduction in dentate gyrus granule cells after chronic Aß-overproduction in 5xFAD mice. Furthermore, the amplitude of synaptic and extrasynaptic NMDAR-mediated currents was reduced in dentate gyrus granule of 5xFAD mice without changes in current kinetics, suggesting that a redistribution or change in subunit composition of NMDARs does not play a role in mediating Amyloid beta (Aß) toxicity. Our study indicates that NMDARs are involved in AD pathogenesis by compromising synapse function but not by affecting neuron morphology.

Outcomes of pneumatic dilation in achalasia: Extended follow-up of more than 25 years with a focus on manometric subtypes.

BACKGROUND AND AIM: Pneumatic dilation (PD) is the most popular nonsurgical treatment for achalasia. This study investigated predicting factors, including manometric subtypes for symptom recurrence in the long term, in patients with achalasia treated with a single PD. METHODS: Between 1983 and 2013, a total of 107 patients were treated initially with a single PD and included in this longitudinal cohort study. Outcomes were correlated with demographics, symptoms (Eckardt score), and esophagographic and manometric features. Manometric tracings were retrospectively classified according to the three subtypes of the Chicago classification. RESULTS: Ninety-one (85%) patients were successfully treated after the first PD. The median follow-up was 13.8 years (interquartile range 7-20). During follow-up, 54% of the patients experienced a clinical relapse. The overall cumulative success rates at 2, 5, 10, 15, 20, and 25 years were 64%, 53%, 49%, 42%, 36%, and 36%, respectively. Age < 40 years, lower esophageal sphincter pressure > 15 mmHg, a cardia width < 5 mm, and an esophageal barium column height > 1 cm 4 to 12 weeks post-dilation significantly correlated with symptom recurrence, whereas achalasia subtypes did not significantly correlate with the treatment results. CONCLUSION: Pneumatic dilation in achalasia is an effective therapy in the short term, but its effect wanes in the very long term. Young age at presentation, a high lower esophageal sphincter pressure, a narrow cardia, and an esophageal barium column of > 1 cm after PD are predictive factors for the need of repeated treatment.

Functional Characterization of Rare RAB12 Variants and Their Role in Musician's and Other Dystonias.

Mutations in RAB (member of the Ras superfamily) genes are increasingly recognized as cause of a variety of disorders including neurological conditions. While musician's dystonia (MD) and writer's dystonia (WD) are task-specific movement disorders, other dystonias persistently affect postures as in cervical dystonia. Little is known about the underlying etiology. Next-generation sequencing revealed a rare missense variant (c.586A>G; p.Ile196Val) in RAB12 in two of three MD/WD families. Next, we tested 916 additional dystonia patients; 512 Parkinson's disease patients; and 461 healthy controls for RAB12 variants and identified 10 additional carriers of rare missense changes among dystonia patients (1.1%) but only one carrier in non-dystonic individuals (0.1%; p = 0.005). The detected variants among index patients comprised p.Ile196Val (n = 6); p.Ala174Thr (n = 3); p.Gly13Asp; p.Ala148Thr; and p.Arg181Gln in patients with MD; cervical dystonia; or WD. Two relatives of MD patients with WD also carried p.Ile196Val. The two variants identified in MD patients (p.Ile196Val; p.Gly13Asp) were characterized on endogenous levels in patient-derived fibroblasts and in two RAB12-overexpressing cell models. The ability to hydrolyze guanosine triphosphate (GTP), so called GTPase activity, was increased in mutants compared to wildtype. Furthermore, subcellular distribution of RAB12 in mutants was altered in fibroblasts. Soluble Transferrin receptor 1 levels were reduced in the blood of all three tested p.Ile196Val carriers. In conclusion, we demonstrate an enrichment of missense changes among dystonia patients. Functional characterization revealed altered enzyme activity and lysosomal distribution in mutants suggesting a contribution of RAB12 variants to MD and other dystonias.

Clinical value of the Integrated Pulmonary Index® during sedation for interventional upper GI-endoscopy: A randomized, prospective tri-center study.

BACKGROUND AND STUDY AIMS: The Integrated Pulmonary Index® (IPI) is a mathematically-determined factor based on parameters of capnography and pulse oximetry, which should enable sensitive detection of impaired respiratory function. Aim was to investigate whether an additional measurement of the IPI during sedation for interventional endoscopy, compared to standard monitoring alone, allows a reduction of sedation-related respiratory depression. PATIENTS AND METHODS: 170 patients with standard monitoring randomly underwent either a blinded recording of capnography (control group, n=87) or capnography, including automated IPI calculation (IPI group, n=83), during deep sedation with midazolam and propofol. The primary endpoint was the maximum decrease of oxygen saturation from the baseline level before sedation. Secondary endpoints: incidence of hypoxemia (SaO2<90%), other sedation-related complications (apnea rate, bradycardia, hypotension), patient cooperation and satisfaction (VAS). RESULTS: Mean propofol dose in the IPI group (245±61mg) was comparable to the control group (225±47mg). The average drop of the oxygen saturation in the IPI group (6.5±4.1%) was nearly identical to that of the control group (7.1±4.6%, p=0.44). Apnea episodes >15s was found in 46 patients of the control and 31 of the IPI group (p<0.05). Frequency of occurrence of a drop in pO2-saturation <90%, bradycardia <50/min or a drop of systolic pressure <90mmHg were not significantly different in both groups. Mechanical ventilation was not required in any case. Patient cooperation and satisfaction were assessed similar in both groups. CONCLUSION: A clinically appealing advantage of IPI-assessment during deep sedation with midazolam and propofol for interventional endoscopy could not be documented. However, IPI registration was more effective in reducing the incidence of apnea episodes.

Esophagus-Related Symptoms in First-Degree Relatives of Patients with Achalasia: Is Screening Necessary?

BACKGROUND: Despite an increasing understanding of the pathophysiology of achalasia, the etiology of this esophageal motility disorder remains largely unknown. However, the occurrence of familial achalasia, its association with well-defined genetic syndromes, the candidate gene approach, and recent presentation of the first systematic genome-wide association study on achalasia suggest the involvement of genetic factors. METHODS: In this study we analyzed the frequency with which symptoms associated with esophageal function (swallowing difficulties, regurgitations, retrosternal cramps/pain, heartburn) occur in first-degree relatives of patients with achalasia to determine if screening is useful and justified against the background of early diagnosis in a genetically predisposed population. The survey of data was carried out in 759 relatives of the 359 achalasia patients included in this study by means of structured interviews. RESULTS: Swallowing difficulties as the principal symptom of achalasia were found to occur at least occasionally in 11.2% of first-degree relatives. In comparison with the prevalence of dysphagia in the general population of 7-10% up to 22%, as described in the literature, the frequency of swallowing difficulties does not seem to be increased in our population of relatives. CONCLUSION: Screening measures do not appear to be justified in spite of the potential genetic background of achalasia.

Reconstitution of the membrane protein OmpF into biomimetic block copolymer-phospholipid hybrid membranes.

Structure and function of many transmembrane proteins are affected by their environment. In this respect, reconstitution of a membrane protein into a biomimetic polymer membrane can alter its function. To overcome this problem we used membranes formed by poly(1,4-isoprene-block-ethylene oxide) block copolymers blended with 1,2-diphytanoyl-sn-glycero-3-phosphocholine. By reconstituting the outer membrane protein OmpF from Escherichia coli into these membranes, we demonstrate functionality of this protein in biomimetic lipopolymer membranes, independent of the molecular weight of the block copolymers. At low voltages, the channel conductance of OmpF in 1 M KCl was around 2.3 nS. In line with these experiments, integration of OmpF was also revealed by impedance spectroscopy. Our results indicate that blending synthetic polymer membranes with phospholipids allows for the reconstitution of transmembrane proteins under preservation of protein function, independent of the membrane thickness.