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- Gastric emptying and glycaemia in health and diabetes mellitus. [REVIEW]
- Nat Rev Endocrinol 2014 Nov 25.
The rate of gastric emptying is a critical determinant of postprandial glycaemia and, accordingly, is fundamental to maintaining blood glucose homeostasis. Disordered gastric emptying occurs frequently in patients with longstanding type 1 diabetes mellitus and type 2 diabetes mellitus (T2DM). A complex bidirectional relationship exists between gastric emptying and glycaemia-gastric emptying accounts for ∼35% of the variance in peak postprandial blood glucose concentrations in healthy individuals and in patients with diabetes mellitus, and the rate of emptying is itself modulated by acute changes in glycaemia. Clinical implementation of incretin-based therapies for the management of T2DM, which diminish postprandial glycaemia, in part by slowing gastric emptying, is widespread. Other therapies for patients with T2DM, which specifically target gastric emptying include pramlintide and dietary-based treatment approaches. A weak association exists between upper gastrointestinal symptoms and the rate of gastric emptying. In patients with severe diabetic gastroparesis, pathological changes are highly variable and are characterized by loss of interstitial cells of Cajal and an immune infiltrate. Management options for patients with symptomatic gastroparesis remain limited in their efficacy, which probably reflects the heterogeneous nature of the underlying pathophysiology.
- Microangiopathy is Common in Submucosal Vessels of the Colon in Patients With Diabetes Mellitus. [Journal Article]
- Rev Diabet Stud 2014; 11(2):175-80.
The pathophysiology behind gastrointestinal dysmotility in diabetes mellitus is unknown. Both esophageal dysmotility and gastroparesis have been shown to be associated with retinopathy, suggesting that microangiopathy is important in the common etiology. The aim of the present study was to examine whether patients with diabetes exhibit microangiopathy in the colon, and if present, to correlate microangiopathy with the clinical picture.Consecutive patients subjected to colon surgery were identified in the southernmost districts of Skåne between January 2011 and May 2013. Medical records were scrutinized, and patients with a history of diabetes were noted. Gender, age, type of diabetes, treatment, complications, and other concomitant diseases were registered. Histopathologic re-evaluation of surgical biopsies with morphometric analyses of submucosal vessels in the colon was performed. Morphometric examination and clinical data were compared with non-diabetic patients.Of 1135 identified patients during the time period studied, 95 patients with diabetes were recognized and included. Fifty-three non-diabetic, randomly chosen patients served as controls. The mean age was 71.8 ± 10.2 and 71.4 ± 9.5 years in diabetic and non-diabetic patients, respectively. Microangiopathy was found in 68.4% of diabetic patients and in 7.5% of non-diabetic patients (p < 0.001). The wall-to-lumen ratio was 0.31 (0.23-0.46) in patients with diabetes compared with 0.16 (0.12-0.21) in non-diabetic patients (p < 0.001). No clinical association with microangiopathy could be verified.Microangiopathy in the colon is more common in diabetic than in non-diabetic patients. The clinical significance of microangopathy has yet to be clarified.
- Effectiveness of gastric neurostimulation in patients with gastroparesis. [Journal Article]
- JSLS 2014 Jul; 18(3)
Patients with gastroparesis have significantly delayed gastric emptying because of impaired nerve function. Gastric neurostimulation from Enterra Therapy provides electrical pulses to the stomach tissue that promotes stimulation of stomach smooth muscle, thereby enhancing gastric emptying. This study evaluates the effectiveness of Enterra Therapy (Medtronic, Minneapolis, Minnesota) in reducing symptoms and improving the quality of life of patients with drug-refractory gastroparesis.In this study 25 patients underwent minimally invasive, laparoscopic placement of the Enterra Therapy device. Patients were asked to rank their severity of symptoms and quality of life retrospectively by completing the Gastrointestinal Symptoms Rating Scale and Short Form 36 Health Survey with respect to their condition before and 6 months after initiation of Enterra Therapy.Eighteen patients completed the surveys. Patients showed statistically significant improvement in their overall Gastrointestinal Symptoms Rating Scale scores and the mental health component of the Short Form 36 Health Survey.Currently, Enterra Therapy has Humanitarian Use Device status, which means that more clinical evidence is needed to prove its effectiveness in gastroparesis. By showing that Enterra Therapy reduces symptoms of gastroparesis and improves patient quality of life, this study contributes to the increasing amount of data supporting its use and potential Food and Drug Administration approval.
- Ventilator-associated respiratory infection following lung transplantation. [JOURNAL ARTICLE]
- Eur Respir J 2014 Oct 30.
The medical records of 170 adult patients who underwent lung transplantation between January 2010 and December 2012 were reviewed to assess the incidence, causative organisms, risk factors and outcomes of post-operative pneumonia and tracheobronchitis. 20 (12%) patients suffered 24 episodes of ventilator-associated pneumonia. The condition was associated with mean increases of 43 days in mechanical ventilation and of 35 days in hospital stay, and significantly higher hospital mortality (OR 9.0, 95% CI 3.2-25.1). Pseudomonas aeruginosa (eight out of 12 patients were multidrug-resistant) was the most common pathogen, followed by Enterobacteriaceae (one out of five patients produced extended-spectrum β-lactamases). Gastroparesis occurred in 55 (32%) patients and was significantly associated with pneumonia (OR 6.2, 95% CI 2.2-17.2). Ventilator-associated tracheobronchitis was associated with a mean increase of 28 days in mechanical ventilation and 30.5 days in hospital stay, but was not associated with higher mortality (OR 1.2, 95% CI 0.4-3.2). Pseudomonas aeruginosa (six out of 16 patients were multidrug resistant) was the most common pathogen, followed by Enterobacteriaceae (three out of 14 patients produced extended-spectrum β-lactamase). Patients with gastroparesis also had more episodes of ventilator-associated tracheobronchitis (40% versus 12%, p<0.001). In conclusion, ventilator-associated pneumonia following lung transplantation increased mortality. Preventing gastroparesis probably decreases the risk of pneumonia and tracheobronchitis. Multidrug-resistant bacteria frequently cause post-lung-transplantation pneumonia and tracheobronchitis.
- The investigational drug camicinal for the treatment of gastroparesis. [JOURNAL ARTICLE]
- Expert Opin Investig Drugs 2014 Oct 24.:1-8.
Introduction: Gastroparesis is a syndrome of delayed gastric emptying in the absence of mechanical obstruction that presents with upper gastrointestinal symptoms. Despite its growing prevalence, there remains an unmet clinical need for more efficacious prokinetic treatment options. The current market includes prokinetic agents that reduce gastroparesis symptoms. However, adverse drug effects and tachyphylaxis with repeated dosing are among the factors that limit their use. Camicinal (GSK962040) is the most advanced, small-molecule, selective motilin receptor agonist with therapeutic potential to date. Areas covered: This article reviews the literature on the limitations of current prokinetic agents used in the treatment of gastroparesis. It also summarizes the current evidence and influential clinical trial results involving the investigational drug camicinal, and shares its preliminary findings from the literature. Expert opinion: Camicinal represents a new opportunity as a treatment in a clinical area in need of new agents. There is emerging literature to support how the drug addresses both gastroparesis symptoms and dysmotility with no significant adverse effects or tachyphylaxis reported to date. Challenges remain in getting a new compound approved for gastroparesis. However, careful design of future trials will help to continue the record of success camicinal trials have had thus far.
- Dynamic carbon 13 breath tests for the study of liver function and gastric emptying. [REVIEW]
- Gastroenterol Rep (Oxf) 2014 Oct 21.
In gastroenterological practice, breath tests (BTs) are diagnostic tools used for indirect, non-invasive assessment of several pathophysiological metabolic processes, by monitoring the appearance in breath of a metabolite of a specific substrate. Labelled substrates originally employed radioactive carbon 14 ((14)C) and, more recently, the stable carbon 13 isotope ((13)C) has been introduced to label specific substrates. The ingested (13)C-substrate is metabolized, and exhaled (13)CO2 is measured by mass spectrometry or infrared spectroscopy. Some (13)C-BTs evaluate specific (microsomal, cytosolic, and mitochondrial) hepatic metabolic pathways and can be employed in liver diseases (i.e. simple liver steatosis, non-alcoholic steato-hepatitis, liver fibrosis, cirrhosis, hepatocellular carcinoma, drug and alcohol effects). Another field of clinical application for (13)C-BTs is the assessment of gastric emptying kinetics in response to liquids ((13)C-acetate) or solids ((13)C-octanoic acid in egg yolk or in a pre-packed muffin or the (13)C-Spirulina platensis given with a meal or a biscuit). Studies have shown that (13)C-BTs, used for gastric emptying studies, yield results that are comparable to scintigraphy and can be useful in detecting either delayed- (gastroparesis) or accelerated gastric emptying or changes of gastric kinetics due to pharmacological effects. Thus, (13)C-BTs represent an indirect, cost-effective and easy method of evaluating dynamic liver function and gastric kinetics in health and disease, and several other potential applications are being studied.
- DPPX potassium channel antibody: Frequency, clinical accompaniments, and outcomes in 20 patients. [Journal Article]
- Neurology 2014 Nov 11; 83(20):1797-803.
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 arrhythmic 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.
- The dual role of domperidone in gastroparesis and lactation. [Journal Article, Review]
- 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.