Pharmacologic treatment of gastroparesis: What is (still) on the horizon?

Gastroparesis is a neuromuscular disorder of the upper gastrointestinal tract. Patients typically complain about early satiety, postprandial fullness, nausea and vomiting. Etiology is multifactorial. Treatment strategies include nutritional support, pharmacologic agents or surgery for refractory cases. Metoclopramide is the first and only FDA approved pharmacologic agent for (diabetic) Gastroparesis. A couple of compounds are currently in clinical testing. Some beacons of hope have failed recently, however. Here we present an update on possible future treatment options.

Real-time detection of neonatal seizures improves with on demand EEG interpretation.

OBJECTIVE: Under- and overtreatment of seizures may result in adverse outcomes; thus, early, reliable seizure identification is crucial. Continuous conventional ElectroEncephaloGram (cEEG) is the gold standard, but amplitude integrated EEG (aEEG) is most widely-used in the Neonatal Intensive Care Unit (NICU). We aimed to determine whether a novel pathway combining cEEG and aEEG for seizure detection would improve real-time seizure identification. METHODS: A single-center, prospective quality improvement project cohort. Patients at-risk of seizures were monitored by cEEG and aEEG concurrently, with the option for the neonatologist to contact a neurologist for real-time cEEG interpretation. The primary outcome was correct identification of seizures by the new combined pathway compared to aEEG alone. RESULTS: Seizure detection using aEEG had a sensitivity of 46.2%; specificity of 93.3%; PPV of 66.7%; and NPV of 85.7%. Utilizing the new on-demand, real-time cEEG interpretation by a neurologist, correct seizure identification increased by 27% (95%CI: 10-56%). Over-diagnosis of seizures was avoided in 33.3% (95% CI: 12.1-64.6%) and misuse of anti-seizure medication was prevented. CONCLUSIONS: Combining aEEG with on-demand cEEG interpretation improved accurate seizure detection in a high-risk NICU population, with the potential to avoid over-treatment. SIGNIFICANCE: We describe a novel combined EEG monitoring pathway to improve seizure detection, and prevent unnecessary treatment.

[Current possibilities and challenges in the diagnosis of laryngopharyngeal reflux]. / Aktuelle Möglichkeiten und Herausforderungen bei der Diagnostik des laryngopharyngealen Refluxes.

Laryngopharyngeal reflux (LPR) is defined as backflow of gastral or gastroduodenal content into the upper aerodigestive tract and characterized by a variety of unspecific symptoms such as chronic cough, globus sensation, or mucus hypersecretion. Due to the lack of a gold standard and the heterogeneity of studies, the diagnosis of LPR is still problematic and challenging. However, in patients with characteristic symptoms and endoscopic findings, with an increased reflux symptom index, a pathologic reflux finding score (RFS), pathologic 24 h esophageal or oropharyngeal pH monitoring, and without any other underlying condition, the diagnosis of LPR is probable. In the following review, we critically discuss the abovementioned methods as well as more recent tools such as measurements of pepsin concentrations in the saliva for diagnosis of LPR.

Stress in Parents of Children With Genetically Determined Leukoencephalopathies: A Pilot Study.

Genetically determined leukoencephalopathies comprise a group of rare inherited white matter disorders. The majority are progressive diseases resulting in early death. We performed a cross-sectional pilot study including 55 parents from 36 families to assess the level of stress experienced by parents of patients with genetically determined leukoencephalopathies, aged 1 month to 12 years. Thirty-four mothers and 21 fathers completed the Parenting Stress Index-4th Edition. One demographic questionnaire was completed per family. Detailed clinical data was gathered on all patients. Statistical analysis was performed with total stress percentile score as the primary outcome. Mothers and fathers had significantly higher stress levels compared with the normative sample; 20% of parents had high levels of stress whereas 11% had clinically significant levels of stress. Mothers and fathers had comparable total stress percentile scores. We identified pediatric behavioral difficulties and gross motor function to be factors influencing stress in mothers. Our study is the first to examine parental stress in this population and highlights the need for parental support early in the disease course. In this pilot study, we demonstrated that using the Parenting Stress Index-4th Edition to assess stress levels in parents of patients with genetically determined leukoencephalopathies is feasible, leads to valuable and actionable results, and should be used in larger, prospective studies.

Spectral field mapping in plasmonic nanostructures with nanometer resolution.

Plasmonic nanostructures and -devices are rapidly transforming light manipulation technology by allowing to modify and enhance optical fields on sub-wavelength scales. Advances in this field rely heavily on the development of new characterization methods for the fundamental nanoscale interactions. However, the direct and quantitative mapping of transient electric and magnetic fields characterizing the plasmonic coupling has been proven elusive to date. Here we demonstrate how to directly measure the inelastic momentum transfer of surface plasmon modes via the energy-loss filtered deflection of a focused electron beam in a transmission electron microscope. By scanning the beam over the sample we obtain a spatially and spectrally resolved deflection map and we further show how this deflection is related quantitatively to the spectral component of the induced electric and magnetic fields pertaining to the mode. In some regards this technique is an extension to the established differential phase contrast into the dynamic regime.

Induction Mapping of the 3D-Modulated Spin Texture of Skyrmions in Thin Helimagnets.

Envisaged applications of Skyrmions in magnetic memory and logic devices crucially depend on the stability and mobility of these topologically nontrivial magnetic textures in thin films. We present for the first time quantitative maps of the magnetic induction that provide evidence for a 3D modulation of the Skyrmionic spin texture. The projected in-plane magnetic induction maps as determined from in-line and off-axis electron holography carry the clear signature of Bloch Skyrmions. However, the magnitude of this induction is much smaller than the values expected for homogeneous Bloch Skyrmions that extend throughout the thickness of the film. This finding can only be understood if the underlying spin textures are modulated along the out-of-plane z direction. The projection of (the in-plane magnetic induction of) helices is further found to exhibit thickness-dependent lateral shifts, which show that this z modulation is accompanied by an (in-plane) modulation along the x and y directions.

Higher prevalence of joint hypermobility in constipation predominant irritable bowel syndrome.

BACKGROUND: Joint hypermobility syndrome (JHS) is characterized by excessive connective tissue laxity manifest as joint hypermobility (JH) together with musculoskeletal symptoms. Previous studies have shown an association between JH/JHS and gastrointestinal symptoms, including irritable bowel syndrome (IBS), although its association with specific IBS subtypes is incompletely understood. We aimed to determine the prevalence of JH according to the subtypes of IBS, in particular IBS-C and IBS-D. METHODS: Data of 228 consecutive IBS patients were analyzed. IBS was subtyped into constipation and diarrhea predominant IBS (IBS-C and IBS-D), IBS with mixed bowel habits (IBS-M) and unsubtyped IBS (IBS-U). JH was defined as a Beighton Score ≥4/9 points and JHS diagnosed according to revised Brighton Criteria. Data of IBS patients were analyzed for psychological comorbidities assessed by Hospital Anxiety and Depression Scale (HADS) and Visceral Sensitivity Index (VSI). KEY RESULTS: Of 228 IBS patients, 64 (28.1%) suffered from IBS-C, 89 (39.0%) from IBS-D, 48 (21.1%) from IBS-M, and 27 (11.8%) from IBS-U. JH was diagnosed in 95 patients (41.7%). The prevalence of JH was significantly higher in IBS-C than IBS-D (57.8% vs 34.8%, P = .031). There was no significant difference in VSI and HADS according to JH or IBS subtype. CONCLUSIONS AND INTERFERENCES: The prevalence of JH was significantly higher in IBS-C compared to IBS-D. Abnormalities in the connective tissue biomechanics in those with JH may contribute to a degree of colonic inertia which could result in constipation in JH-positive IBS patients. Further work is needed to determine the colonic biomechanics in patients with JH.

Curriculum for neurogastroenterology and motility training: A report from the joint ANMS-ESNM task force.

Although neurogastroenterology and motility (NGM) disorders are some of the most frequent disorders encountered by practicing gastroenterologists, a structured competency-based training curriculum developed by NGM experts is lacking. The American Neurogastroenterology and Motility Society (ANMS) and the European Society of Neurogastroenterology and Motility (ESNM) jointly evaluated the components of NGM training in North America and Europe. Eleven training domains were identified within NGM, consisting of functional gastrointestinal disorders, visceral hypersensitivity and pain pathways, motor disorders within anatomic areas (esophagus, stomach, small bowel and colon, anorectum), mucosal disorders (gastro-esophageal reflux disease, other mucosal disorders), consequences of systemic disease, consequences of therapy (surgery, endoscopic intervention, medications, other therapy), and transition of pediatric patients into adult practice. A 3-tiered training curriculum covering these domains is proposed here and endorsed by all NGM societies. Tier 1 NGM knowledge and training is expected of all gastroenterology trainees and practicing gastroenterologists. Tier 2 knowledge and training is appropriate for trainees who anticipate NGM disorder management and NGM function test interpretation being an important part of their careers, which may require competency assessment and credentialing of test interpretation skills. Tier 3 knowledge and training is undertaken by trainees interested in a dedicated NGM career and may be restricted to specific domains within the broad NGM field. The joint ANMS and ESNM task force anticipates that the NGM curriculum will streamline NGM training in North America and Europe and will lead to better identification of centers of excellence where Tier 2 and Tier 3 training can be accomplished.

Diagnostic use of endoscopic full-thickness wall resection (eFTR)-a novel minimally invasive technique for colonic tissue sampling in patients with severe gastrointestinal motility disorders.

BACKGROUND: Complex gastrointestinal (GI) motility disorders such as chronic intestinal pseudo-obstruction (CIPO) or Hirschsprung's disease (HD) are challenging to diagnose and treat appropriately. Thorough assessment of patient history, radiographic exams, endoscopy, and motility measurements aid in diagnostic workup, yet underlying histology is the cornerstone to enable a more distinct diagnosis of neuromuscular GI disorders. Traditionally, surgical procedures have been performed to obtain specimen suitable for accurate histologic analysis. METHODS: We performed endoscopic full-thickness resection (eFTR) using a full-thickness-resection device (FTRD) under moderate propofol sedation in four patients with suspected severe neuromuscular gut disorders including CIPO. KEY RESULTS: The mean age of the four patients was 43 y (range 19-56 y). Technical and histological success providing large colonic full-thickness tissue samples of excellent quality was achieved in all four patients (success rate 100%). The mean procedure time was 12 min (range 5-20 min). The mean diameter of the resected specimen was 21 mm (range 20-22 mm). No adverse events connected to the procedure itself occurred. Histology ranged from aganglionosis such as Hirschsprung's disease (HD) to hypoganglionosis and eosinophilic leiomyositis combined with lymphocytic ganglionitis in a third patient. Histology was unspecific in one patient. CONCLUSION AND INFERENCES: EFTR allows safe and minimal invasive harvesting of ample full-thickness tissue samples for accurate histological analysis in patients with suspicion of neuromuscular gut disorders.

EMCD with an electron vortex filter: Limitations and possibilities.

We discuss the feasibility of detecting spin polarized electronic transitions with a vortex filter. This approach does not rely on the principal condition of the standard electron energy-loss magnetic chiral dichroism (EMCD) technique, the precise alignment of the crystal in order to use it as a beam splitter, and thus would pave the way for the application of EMCD to new classes of materials and problems, like amorphous magnetic alloys and interface magnetism. The dichroic signal strength at the L2, 3-edge of ferromagnetic Cobalt (Co) is estimated on theoretical grounds using a single atom scattering approach. To justify this approach, multi-slice simulations were carried out in order to confirm that orbital angular momentum (OAM) is conserved in amorphous materials over an extended range of sample thickness and also in very thin crystalline specimen, which is necessary for the detection of EMCD. Also artefact sources like spot size, mask tilt and astigmatism are discussed. In addition, the achievable SNR under typical experimental conditions is assessed.

MRI and clinicopathological correlation of childhood primary central nervous system angiitis.

AIM: To review the long-term clinical and imaging follow-up of eight children with histopathologically proven childhood primary central nervous system angiitis (cPACNS). MATERIALS AND METHODS: Eight children (5-17 years, five female and three male patients) with biopsy-proven cPACNS vasculitis were reviewed retrospectively. All children were followed at the Children's Hospital of Eastern Ontario. Magnetic resonance imaging (MRI) images of the brain parenchyma and vessel pattern of the arteries of the circle of Willis were reviewed at baseline and follow-up(s). All MRI images were correlated with clinical and histopathological findings. RESULTS: Seven (87.5%) children demonstrated parenchymal abnormalities: five of the seven (71.4%) presented with non-haemorrhagic lesions, one (14.3%) presented with a parenchymal bleed, and one (14.3%) showed diffuse oedema. One child remained negative for brain parenchymal abnormality at baseline and follow-up. Of the seven children with a parenchymal abnormality, parenchymal enhancement was seen in two (28.5%) and leptomeningeal enhancement was seen in one child. Only two children had positive diffusion-weighted imaging (DWI) restriction at baseline. Five of the seven children (71.4%) showed no magnetic resonance angiography (MRA) abnormalities at baseline. In one, MRA detected complete absence of flow. Follow-up MRA (24-74 months) demonstrated that five of the seven (71.4%) children had progressive paucity of the peripheral vascularity. Two children (28.5%) with shorter-term follow-up (7 and 13 months) did not demonstrate MRA changes. CONCLUSION: Long-term follow-up MRA demonstrated progressive paucity of peripheral vessels, which could be secondary to the inflammation affecting the peripheral vasculature causing reduction in vessel lumen size beyond the resolution of the maximum intensity projection (MIP) reconstruction.

Phenotyping of subjects for large scale studies on patients with IBS.

BACKGROUND: Irritable bowel syndrome (IBS) is a complex condition with multiple factors contributing to its aetiology and pathophysiology. Aetiologically these include genetics, life-time events and environment, and physiologically, changes in motility, central processing, visceral sensitivity, immunity, epithelial permeability and gastrointestinal microflora. Such complexity means there is currently no specific reliable biomarker for IBS, and thus IBS continues to be diagnosed and classified according to symptom based criteria, the Rome Criteria. Carefully phenotyping and characterisation of a 'large' pool of IBS patients across Europe and even the world however, might help identify sub-populations with accuracy and consistency. This will not only aid future research but improve tailoring of treatment and health care of IBS patients. PURPOSE: The aim of this position paper is to discuss the requirements necessary to standardize the process of selecting and phenotyping IBS patients and how to organise the collection and storage of patient information/samples in such a large multi-centre pan European/global study. We include information on general demographics, gastrointestinal symptom assessment, psychological factors, quality of life, physiological evaluation, genetic/epigenetic and microbiota analysis, biopsy/blood sampling, together with discussion on the organisational, ethical and language issues associated with implementing such a study. The proposed approach and documents selected to be used in such a study was the result of a thoughtful and thorough four-year dialogue amongst experts associated with the European COST action BM1106 GENIEUR (www.GENIEUR.eu).

Determinants and effects of sinus worm Skrjabingylus nasicola (Nematoda: Metastrongyloidae) infestation in invasive American mink Neovison vison in Germany.

Skrjabingylus nasicola (Leuckart, 1842) are geographically widespread nematodes that parasitize the nasal and frontal sinus cavities of smaller mustelids. As most prior work was solely based on the analysis of bone injuries of museum skull, little is known about the determinants and effects of infestation in the host species. Working on fresh skulls, we aimed to analyze infestation patterns in American mink (Neovison vison Schreber, 1777) from nine study areas in northern Germany and to identify factors that explained infestation prevalence and intensity in the host species. The prevalence (46.7-62.9 %) and infestation intensity values (4.5-10.89 nematodes) reported here were relatively large, especially compared to other American mink populations in Europe. Considering mink diet, our study sites probably harbored a larger number of infested paratenic hosts and climate did not have a substantial negative influence on survival of S. nasicola larvae. We did not observe any significant sex-age differences in either prevalence or intensity of S. nasicola infestation. We did not find a negative impact of an infestation on the host animals' body weight, confirming prior results that the parasite is not a significant mortality factor in mustelids. Our study suggests that this holds even outside the native distributional range where the host's defenses might not be optimally adapted to an autochthonous parasite.

TEM investigations on the local microstructure of electrodeposited galfenol nanowires.

The local microstructure of Fe-Ga nanowires is investigated considering dependence on the deposition technique. Using a complexed electrolyte, smooth and homogeneous Fe80Ga20 nanowires are deposited into anodic aluminum oxide templates by either applying pulse potential or potentiostatic deposition technique. At optimized deposition conditions the wires show the desired composition of Fe80±2Ga20±2 without a gradient along the growth direction. Composition distribution, structure and microstructure are examined in detail and reveal only minor differences. Line EELS and crystal lattice measurements reveal a negligible oxygen content for both preparation routines. Neither Fe/Ga oxides nor hydroxides were found. Both potentiostatically deposited as well as pulse deposited nanowires exhibit a preferred 〈110〉orientation, the latter with slightly larger crystals. Different contrast patterns were found by TEM that appear more pronounced in the case of pulse deposited wires. High resolution transmission electron microscopy analysis and comparison of differently prepared focused ion beam lamellas reveal that these contrasts are caused by defects in the alternating potential deposition itself and are not induced during the TEM preparation process. The alternating potential mode causes periodic growth thereby inducing different layers with reduced wire thickness/defects at the layer interfaces.

From soft to hard magnetic Fe-Co-B by spontaneous strain: a combined first principles and thin film study.

In order to convert the well-known Fe-Co-B alloy from a soft to a hard magnet, we propose tetragonal strain by interstitial boron. Density functional theory reveals that when B atoms occupy octahedral interstitial sites, the bcc Fe-Co lattice is strained spontaneously. Such highly distorted Fe-Co is predicted to reach a strong magnetocrystalline anisotropy which may compete with shape anisotropy. To probe this theoretical suggestion experimentally, epitaxial films are examined. A spontaneous strain up to 5% lattice distortion is obtained for B content up to 4 at%, which leads to uniaxial anisotropy constants exceeding 0.5 MJ m(-3). However, a further addition of B results in a partial amorphisation, which degrades both anisotropy and magnetisation.

Self-reported lactose intolerance in clinic patients with functional gastrointestinal symptoms: prevalence, risk factors, and impact on food choices.

BACKGROUND: Many patients complain of abdominal symptoms with dairy products; however, clinical and psychosocial factors associated with self-reported lactose intolerance (SLI) have not been assessed in large studies. In particular, data are lacking from lactase deficient populations. This prospective cohort study assessed the prevalence of, and risk factors for, SLI in Chinese patients attending a gastroenterology clinic. METHODS: Consecutive patients completed questionnaires to assess digestive health (Rome III), psychological state (HADS), life event stress (LES), food intake, and quality-of-life (SF-8). A representative sample completed genetic studies and hydrogen breath testing (HBT) at the clinically relevant dose of 20 g lactose. KEY RESULTS: SLI was present in 411/910 (45%) clinic patients with functional abdominal symptoms. The genotype in all subjects was C/C-13910. A small number of novel SNPs in lactase promoter region were identified, including C/T-13908 which appeared to confer lactase persistence. Over half of the patients (54%) completed the 20 g lactose HBT with 58% (285/492) reporting typical symptoms. Positive and negative predictive values of SLI for abdominal symptoms during HBT were 60% and 44%, respectively. Psychological state and stress were not associated with SLI in clinic patients. SLI impacted on physical quality-of-life and was associated with reduced ingestion of dairy products, legumes, and dried fruit (p ≤ 0.05). CONCLUSIONS & INFERENCES: In a lactase deficient population, approximately half of patients attending clinic with functional gastrointestinal symptoms reported intolerance to dairy products; however, SLI did not predict findings on 20 g lactose HBT. Independent of psychosocial factors, SLI impacted on quality-of-life and impacted on food choices with restrictions not limited to dairy products.

On the stability of AuFe alloy nanoparticles.

AuFe nanoparticles with mean diameters d p  = 13.2 nm have been prepared by inert-gas condensation. Conventional and high-resolution transmission electron microscopy and energy-dispersive x-ray spectroscopy investigations show that the particles are mostly icosahedra. Scanning transmission electron microscopy-energy-dispersive x-ray spectroscopy and scanning transmission electron microscopy-electron energy-loss spectroscopy show that the as-grown particles exhibit a core-shell structure. The shell is mainly composed of an amorphous FeO layer. Although Fe and Au are immiscible in the bulk, the particle cores are found to be homogeneously mixed at the atomic level with a local composition of around Au84Fe16 (at.%). AuFe nanoparticles exhibit a complex magnetic structure in which the core behaves as a spin glass with a freezing temperature of 35 K, whereas the amorphous FeO shell behaves as a ferro-ferrimagnetic system. On annealing above 300 °C, the AuFe icosahedra phases separate into their elemental constituents. Hence the as-grown AuFe icosahedra are metastable, thereby implying that the bulk phase diagram also applies for nanoscopic materials.

Atomic surface diffusion on Pt nanoparticles quantified by high-resolution transmission electron microscopy.

Aberration-corrected high-resolution transmission electron microscopy allows for the delocalization-free observation of atomic motions on metallic surfaces and thus enables measurements of the diffusion of single atoms on the surfaces of nanoscopic objects such as nanoparticles. Using this recently introduced method, the diffusion coefficient for surface self-diffusion of Pt nanoparticles is determined through the fluctuating occupation of the particle's atomic columns. This diffusion coefficient is determined to lie in the range D∼(10(-17)…10(-16)) cm(2)/s.