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- DPPX potassium channel antibody: Frequency, clinical accompaniments, and outcomes in 20 patients. [JOURNAL ARTICLE]
- Neurology 2014 Oct 15.
To describe the detection frequency and clinical associations of immunoglobulin G (IgG) targeting dipeptidyl-peptidase-like protein-6 (DPPX), a regulatory subunit of neuronal Kv4.2 potassium channels.Specimens from 20 patients evaluated on a service basis by tissue-based immunofluorescence yielded a synaptic immunostaining pattern consistent with DPPX-IgG (serum, 20; CSF, all 7 available). Transfected HEK293 cell-based assay confirmed DPPX specificity in all specimens. Sixty-nine patients with stiff-person syndrome and related disorders were also evaluated by DPPX-IgG cell-based assay.Of 20 seropositive patients, 12 were men; median symptom onset age was 53 years (range, 13-75). Symptom onset was insidious in 15 and subacute in 5. Twelve patients reported prodromal weight loss. Neurologic disorders were multifocal. All had one or more brain or brainstem manifestations: amnesia (16), delirium (8), psychosis (4), depression (4), seizures (2), and brainstem disorders (15; eye movement disturbances , ataxia , dysphagia , dysarthria , respiratory failure ). Nine patients reported sleep disturbance. Manifestations of central hyperexcitability included myoclonus (8), exaggerated startle (6), diffuse rigidity (6), and hyperreflexia (6). Dysautonomia involved the gastrointestinal tract (9; diarrhea , gastroparesis, and constipation ), bladder (7), cardiac conduction system (3), and thermoregulation (1). Two patients had B-cell neoplasms: gastrointestinal lymphoma (1), and chronic lymphocytic leukemia (1). Substantial neurologic improvements followed immunotherapy in 7 of 11 patients with available treatment data. DPPX-IgG was not detected in any of the stiff-person syndrome patients.DPPX-IgG is a biomarker for an immunotherapy-responsive multifocal neurologic disorder of the central and autonomic nervous systems.
- Gastric vagal motoneuron function is maintained following experimental spinal cord injury. [JOURNAL ARTICLE]
- Neurogastroenterol Motil 2014 Oct 15.
Clinical reports indicate that spinal cord injury (SCI) initiates profound gastric dysfunction. Gastric reflexes involve stimulation of sensory vagal fibers, which engage brainstem circuits that modulate efferent output back to the stomach, thereby completing the vago-vagal reflex. Our recent studies in a rodent model of experimental high thoracic (T3-) SCI suggest that reduced vagal afferent sensitivity to gastrointestinal (GI) stimuli may be responsible for diminished gastric function. Nevertheless, derangements in efferent signals from the dorsal motor nucleus of the vagus (DMV) to the stomach may also account for reduced motility.We assessed the anatomical, neurophysiological, and functional integrity of gastric-projecting DMV neurons in T3-SCI rats using: (i) retrograde labeling of gastric-projecting DMV neurons; (ii) whole cell recordings from gastric-projecting neurons of the DMV; and, (iii) in vivo measurements of gastric contractions following unilateral microinjection of thyrotropin-releasing hormone (TRH) into the DMV.Immunohistochemical analysis of gastric-projecting DMV neurons demonstrated no difference between control and T3-SCI rats. Whole cell in vitro recordings showed no alteration in DMV membrane properties and the neuronal morphology of these same, neurobiotin-labeled, DMV neurons were unchanged after T3-SCI with regard to cell size and dendritic arborization. Central microinjection of TRH induced a significant facilitation of gastric contractions in both control and T3-SCI rats and there were no significant dose-dependent differences between groups.Our data suggest that the acute, 3 day to 1 week post-SCI, dysfunction of vagally mediated gastric reflexes do not include derangements in the efferent DMV motoneurons.
- Slow Wave Conduction Patterns in the Stomach: From Waller's Foundations to Current Challenges. [JOURNAL ARTICLE]
- Acta Physiol (Oxf) 2014 Oct 14.
This review provides an overview of our understanding of motility and slow wave propagation in the stomach. It begins by reviewing seminal studies conducted by Walter Cannon and Augustus Waller on in vivo motility and slow wave patterns. Then our current understanding of slow wave patterns in common laboratory animals and humans is presented. The implications of slow wave dysrhythmic patterns that have been recorded in animals and patients suffering from gastroparesis are discussed. Finally, current challenges in experimental methods and techniques, slow wave modulation and the use of mathematical models are discussed. This article is protected by copyright. All rights reserved.
- The dual role of domperidone in gastroparesis and lactation. [Journal Article]
- Int J Pharm Compd 2014 May-Jun; 18(3):203-7.
Domperidone is a prokinetic agent used as a second-line treatment option for gastroparesis in those unable to tolerate metoclopramide. Via inhibition of dopamine-2 receptors within the gastrointestinal tract and various parts of the central and peripheral nervous system, domperidone helps to facilitate peristalsis and gastric emptying. A major side effect of domperidone is prolactinemia, allowing it to be used off-label for the purpose of inducing lactation. In the U.S., domperidone is currently not U.S. Food and Drug Administration approved due to various case reports and literature associating the risks of sudden cardiac death and ventricular arrhythmia with the use of domperidone. Despite the evidence against the use of domperidone, it is still being widely used in Canada and Europe for both gastroparesis and to induce milk let-down. This article is a literature review intending to assess the risks associated with the use of domperidone in gastroparesis and lactation.
- Inside gastroparesis. Understanding and coping with a serious stomach disorder. [Journal Article]
- Johns Hopkins Med Lett Health After 50 2014 Aug; 26(7):3.
- [Motility and functional gastrointestinal disorders]. [English Abstract, Journal Article]
- Gastroenterol Hepatol 2014 Sep.:3-13.
This article discusses the studies on functional and motor gastrointestinal disorders presented at the 2014 Digestive Diseases Week conference that are of greatest interest to us. New data have been provided on the clinical importance of functional gastrointestinal disorders, with recent prevalence data for irritable bowel syndrome and fecal incontinence. We know more about the pathophysiological mechanisms of the various functional disorders, especially irritable bowel syndrome, which has had the largest number of studies. Thus, we have gained new data on microinflammation, genetics, microbiota, psychological aspects, etc. Symptoms such as abdominal distension have gained interest in the scientific community, both in terms of patients with irritable bowel syndrome and those with constipation. From the diagnostic point of view, the search continues for a biomarker for functional gastrointestinal disorders, especially for irritable bowel syndrome. In the therapeutic area, the importance of diet for these patients (FODMAP, fructans, etc.) is once again confirmed, and data is provided that backs the efficacy of already marketed drugs such as linaclotide, which rule out the use of other drugs such as mesalazine for patients with irritable bowel syndrome. This year, new forms of drug administration have been presented, including metoclopramide nasal sprays and granisetron transdermal patches for patients with gastroparesis. Lastly, a curiosity that caught our attention was the use of a vibrating capsule to stimulate gastrointestinal transit in patients with constipation.
- Gastric dysregulation induced by microinjection of 6-OHDA in the substantia nigra pars compacta of rats is determined by alterations in the brain-gut axis. [JOURNAL ARTICLE]
- Am J Physiol Gastrointest Liver Physiol 2014 Oct 2.
Idiopathic Parkinson's disease (PD) is a late-onset, chronic and progressive motor dysfunction due to loss of nigrostriatal dopamine neurons. PD patients experience significant gastrointestinal (GI) issues, including gastroparesis. We aimed to evaluate whether 6-OHDA induced degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) induces gastric dysmotility via dysfunctions of the brain-gut axis. 6-OHDA microinjection into the SNpc induced a >90% decrease in TH-immunoreactivity (IR) on the injection site. The [(13)C]-octanoic acid breath test showed a delayed gastric emptying four weeks after the 6-OHDA treatment. In control rats, microinjection of the indirect sympathomimetic, tyramine, in the dorsal vagal complex (DVC) decreased gastric tone and motility; this inhibition was prevented by 4(th) ventricular application of either a combination of α1 and α2 or a combination of D1 and D2 receptor antagonists. Conversely, in 6-OHDA treated rats, while DVC microinjection of tyramine had reduced effects upon gastric tone or motility, DVC microinjection of TRH induced a similar increase in tone and motility as in control rats. In 6-OHDA treated rats there was a decreased expression of ChAT- and nNOS-IR in DVC neurons but an increase in DβH-IR in the A2 area. Within the myenteric plexus of the esophagus, stomach and duodenum, there were no changes in the total number of neurons, however the percentage of NOS-IR neurons increased while that of ChAT-IR decreased. Our data suggest that the delayed gastric emptying in a 6-OHDA rat model of PD may be caused by neurochemical and neurophysiological alterations in the brain-gut axis.
- Gastroparesis: separate entity or just a part of dyspepsia? [REVIEW]
- Gut 2014 Sep 26.
Gastroparesis is defined by the presence of delayed gastric emptying (GE) in the absence of mechanical obstruction. Symptoms that have been attributed to gastroparesis include postprandial fullness, early satiation nausea and vomiting. Gastroprokinetic drugs are the preferred treatment option. A number of problems with the concept of gastroparesis have been identified recently. Major overlap exists with the symptom complex of the functional dyspepsia subtype of postprandial distress syndrome. The distinguishing feature of gastroparesis is delayed GE, but the correlation between delayed emptying and symptom pattern or severity in gastroparesis is modest and the stability of delayed emptying over time is poor. Other pathophysiological mechanisms such as hypersensitivity or impaired accommodation may also underlie symptoms in patients with gastroparesis. Moreover, symptomatic response to prokinetic therapy is variable and cannot be predicted based on the degree of enhancing GE. A number of approaches have been proposed to increase clinical usefulness of a diagnosis of gastroparesis, including a higher threshold of abnormal emptying and selection of patients with a specific symptom pattern more likely to be associated with delayed emptying.
- Time Trends in Gastroparesis Treatment. [JOURNAL ARTICLE]
- Dig Dis Sci 2014 Sep 26.
While delayed emptying is the defining criterion for gastroparesis, prokinetics often only have a limited impact on symptoms and have been associated with potentially serious adverse effects. The goal of this study was to determine how this information and regulatory changes affected gastroparesis management.The electronic medical records of patients seen between 2003 and 2012 in the outpatient clinic of a large tertiary center were retrieved based on the billing diagnosis of gastroparesis. Demographic, clinical, and survival data were abstracted.A total of 709 patients were identified, with diabetes (21.2 %) and prior surgery (9.8 %) being the most common identifiable causes. The majority of patients (56 %) had idiopathic gastroparesis. The cohort was female predominant (79.5 %) with an average age of 45.4 ± 0.6 years. At the index encounter, 61.8 % received prokinetics. About one-third (37.7 %) used antiemetics at least intermittently. Between 2003 and 2012, prokinetic use dropped from 81 to 43 %, while the use of antiemetics increased from 14 to 41 %. Similarly, there was a significant increase in prescribed opioids and antidepressants. During the period of the study, 44 patients (6.2 %) died. Increasing age, a higher comorbidity burden, anxiety, and medication use were associated with higher mortality risks.This large outpatient cohort suggests that treatment trends move away from prokinetics and focus on symptom-oriented therapy and/or confounding mood disorders.