Pathophysiology of Gastroparesis Syndromes Includes Anatomic and Physiologic Abnormalities.

BACKGROUND: Factors underlying gastroparesis are not well defined. AIMS: We hypothesized that multiple systems may be involved in patients with gastroparesis symptoms and performed a comparative physiologic study. METHODS: We studied 43 consecutive eligible patients with gastroparetic symptoms categorized by GI symptoms, metabolic status, illness quantification, and gastric physiology. Patients were evaluated by two methods in each of five core areas: inflammatory, autonomic, enteric, electrophysiologic, and hormonal with abnormalities examined by correlations. RESULTS: Patients had similar GI symptoms regardless of baseline gastric emptying or diabetic/idiopathic status, and all patients demonstrated abnormalities in each of the 5 areas studied. Nearly all patients presented with elevated markers of serum TNFα (88%) and serum IL-6 (91%); elevated cutaneous electrogastrogram frequency (95%); and interstitial cells of Cajal count abnormalities (inner: 97%, outer: 100%). Measures of inflammation correlated with a number of autonomic, enteric anatomy, electrophysiologic and hormonal abnormalities. CONCLUSIONS: We conclude that patients with the symptoms of gastroparesis have multiple abnormalities, when studied by traditional, as well as newer, diagnostic assessments. Inflammation appears to be a fundamental abnormality that affects other organ systems in symptomatic patients. Future work on gastroparetic syndromes and their treatment may benefit from a focus on the diffuse nature of their illness, diverse pathophysiologic mechanisms involved, especially the possible causes of underlying inflammation and disordered hormonal status. TRAIL REGISTRY: This study is registered with Clinicaltrials.gov under study # NCT03178370 https://clinicaltrials.gov/ct2/show/NCT03178370 .

Gastroparesis syndromes: Response to electrical stimulation.

BACKGROUND AND AIMS: Factors underlying gastroparesis are not well defined, nor is the mechanism of action of gastric electrical stimulation (GES). We hypothesized that GES acts via several mechanisms related to underlying disordered pathophysiology. METHODS: We studied 43 consecutive eligible patients with gastroparetic symptoms, previously evaluated by two methods in each of five core areas: inflammatory, autonomic, enteric, electrophysiologic, and hormonal; and also categorized by GI symptoms, metabolic status, illness quantification, and gastric physiology. We then studied 41 patients who underwent temporary GES for 5-7 days. Thirty-six of those patients were implanted and 30 were followed up at 6 months after permanent GES. RESULTS: In previous but separately reported work, patients had similar GI symptoms regardless of baseline gastric emptying or diabetic/idiopathic status and all patients demonstrated abnormalities in each of the five areas studied. After GES, patients showed early and late effects of electrical stimulation with changes noted in multiple areas, categorized by improvement status. CONCLUSION: Patients with symptoms of gastroparesis have multiple abnormalities, including systemic inflammation and disordered hormonal status. GES affects many of these abnormalities. We conclude electrical stimulation improves symptoms and physiology with (a) an early and sustained anti-emetic effect; (b) an early and durable gastric prokinetic effect in delayed emptying patients; (c) an early anti-arrhythmic effect that continues over time; (d) a late autonomic effect; (e) a late hormonal effect; (f) an early anti-inflammatory effect that persists; and (g) an early and sustained improvement in health-related quality of life. This study is registered with Clinicaltrials.gov under study # NCT03178370 (https://clinicaltrials.gov/ct2/show/NCT03178370).

Clinical Efficacy of Serum-Derived Bovine Immunoglobulin in Patients With Refractory Inflammatory Bowel Disease.

BACKGROUND: Inflammatory bowel disease (IBD) can have autoimmunity and/or intestinal barrier dysfunction as part of pathophysiology and may be refractory to all available treatment options. Serum-derived bovine immunoglobulin (SBI) binds microbial components with postulated downstream effects of normalized gut immune and barrier function, which may be useful for managing IBD. The purpose of our study was to evaluate the effectiveness of SBI in the management of refractory IBD, particularly symptoms of chronic diarrhea and loose stools. METHODS: We retrospectively analyzed charts for patients diagnosed with IBD (n = 40) who were refractory to standard treatment. Patients received oral SBI 5 g daily for a period of at least 6 weeks. Twelve patients with IBD fulfilled study inclusion criteria. Each patient graded the severity and frequency of gastrointestinal symptoms before starting SBI and at 6 weeks of treatment using a standardized patient assessment form. Means and standard deviations for all symptom scores at baseline and week 6 of treatment were analyzed. RESULTS: Mean symptom scores decreased significantly for nausea (P = 0.02 for severity and P = 0.03 for mean symptom score) and diarrhea (P = 0.0006, P = 0.0001 and P = 0.0001 for severity, frequency and mean symptom score, respectively). CONCLUSIONS: Therapy with SBI alleviated some refractory gastrointestinal symptoms in patients with IBD, including nausea and diarrhea. Increased duration, dosage and/or frequency of SBI might provide additional symptom improvement and could be tested through controlled clinical trials with larger sample sizes and longer follow-up.

Twenty-five years of advocacy for patients with gastroparesis: support group therapy and patient reported outcome tool development.

BACKGROUND: Gastroparesis (Gp) is a poorly understood chronic gastrointestinal medical condition for which patient reported outcomes (PRO) are lacking. Previously developed symptoms scoring has been used for several decades. Using symptoms scores as a basis for documentation, 12 years of support/focus group patient feedback from the nearly 1000 attendees were integrated with medical care and recommendations for treatment were developed. Early attenders of the support group were compared with non-attendees for illness acuity, disability, and duration and number of office phone calls. METHODS: Patients cared for in an academic medical practice were assessed for patient-derived PRO symptoms, coupled with standardized Health Related Quality of Life (HRQOL) measures. Based on factors identified by the patients via support/focus groups, a diagnostic and prognostic tool was developed. RESULTS: The new tool utilized PRO symptoms and included provider assessments of medical illnesses as well as resource utilization. This 'post PRO' tool has been applied in a variety of settings for patients with the symptoms of Gp over the last two decades. The 'pre-PRO' factors from the support/focus groups were compared to the PRO measures as well as the 'post-PRO' scale to assess their usefulness. Using methods that combine chart data, including electronic medical records (EMR), with PRO symptoms may have design implications for PRO assessment. The resultant scales, as part of a new tool, can allow for sharing of PRO derived scores in a chronic gastrointestinal (GI), illness with different practitioners. CONCLUSIONS: These newly-derived scales offer a potentially useful tool for clinical decision-making, tailoring treatment to patient subgroups and engaging both patients and their families and caregivers in more active partnerships with providers to improve health outcomes.

A pilot study to evaluate the safety and efficacy of an oral dose of (-)-epigallocatechin-3-gallate-rich polyphenon E in patients with mild to moderate ulcerative colitis.

BACKGROUND: Green tea and its main polyphenolic component, (-)-epigallocatechin-3-gallate (EGCG), exert powerful anti-inflammatory effects that are protective against both inflammatory diseases and cancer. Research with animal and human cell lines provide plausible support for these claims. Poor absorption results in low systemic bioavailability of EGCG after oral administration but high colonic mucosal exposure. METHODS: Patients with mild to moderate ulcerative colitis (UC) were randomized to daily doses of oral Polyphenon E (400 mg or 800 mg of total EGCG daily, administered in split doses) or placebo in a double-blinded, placebo-controlled pilot study. Response was measured by the UC disease activity index and the inflammatory bowel disease questionnaire on day 56. RESULTS: Twenty patients were randomized to active therapy or placebo in a 4:1 ratio. Nineteen subjects received >1 dose of study medication (15 Polyphenon E, 4 placebo). The mean UC disease activity index score at study entry was 6.5 ± 1.9 in the treatment group and 7.3 ± 1.7 in the placebo group. After 56 days of therapy, the response rate was 66.7% (10 of 15) in the Polyphenon E group and 0% (0 of 4) in the placebo group (P = 0.03). The active treatment remission rate was 53.3% (8 of 15) compared with 0% (0 of 4) for placebo (P = 0.10). Polyphenon E treatment resulted in only minor side effects. CONCLUSIONS: Administration of Polyphenon E resulted in a therapeutic benefit for patients who were refractory to 5-aminosalicylic and/or azathioprine. This agent holds promise as a novel option for the treatment of patients with UC with mild to moderately active disease.

Articular cartilage changes in patients with osteoarthritis after osteotomy.

BACKGROUND: High tibial osteotomy (HTO) is a method used to treat medial compartmental osteoarthritis in the knee. The realignment of the knee changes the loading patterns within the joint and may allow for regeneration of articular cartilage. Magnetic resonance imaging methods can be used to assess the quality of the regenerated cartilage. HYPOTHESIS: Altering mechanical alignment through HTO will have predictable effects on articular cartilage, allowing cartilage preservation and possible regeneration. Quality of regenerated cartilage will be inferior to normal articular cartilage. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Ten patients undergoing medial opening wedge HTO were evaluated using dGEMRIC methods (ie, delayed gadolinium-enhanced magnetic resonance imaging of cartilage) preoperatively and at 6 months, 1 year, and 2 years after HTO. Magnetic resonance images were evaluated by hand segmentation, and T1(Gd) relaxation times reflective of glycosaminoglycan content were determined for these regions of interest using magnetic resonance imaging analysis software. RESULTS: The lateral compartment displayed higher T1(Gd) values than the medial compartment at baseline. Initially, a decrease in T1(Gd) values on the medial side were observed for all patients at 6 months and remained reduced for all but 2 participants at 1 year and 2 years after HTO. However, on the medial side after 6 months, the rate of change for T1(Gd) values shifted from being negative (-9.6 milliseconds per month) to being positive (1.7 milliseconds per month). A positive change in the T1(Gd) of the medial tibial plateau was responsible for the positive overall change in the medial compartment. There was no significant difference in the rate of change on the lateral side (P = .141), with the average over the 2-year period being a decrease of 2.28 milliseconds per month. CONCLUSION: Medial opening wedge HTO provides subjective improvements in pain and quality of life, but the potential benefit of allowing articular cartilage preservation and possible regeneration is not well established. Results showed that after a nonweightbearing period, the rate of change in the medial compartment changes from negative to positive, indicating the potential for articular cartilage recovery secondary to an improved mechanical environment.

Gait dynamics on an inclined walkway.

OBJECTIVE: This paper documents research that quantifies and describes the biomechanics of normal gait on inclined surfaces. DESIGN: Experimental, investigative. BACKGROUND: It is necessary to walk on inclined surfaces to negotiate the natural and built environments. Little research has been conducted on the biomechanics of normal gait on inclined surfaces. METHODS: The gait of 11 healthy male volunteers was measured using a Vicon system 370 on an inclinable walkway. Gait was measured at 0 degrees , 5 degrees , 8 degrees and 10 degrees of incline. Passive optical markers were placed on each subject and they walked at a self-selected speed up and down the walkway. Ground reaction forces and EMG were measured. Gait data were analysed in Vicon Clinical Manager. RESULTS: Changes in the dynamics of the lower limbs with respect to incline angles are described. Between subject and between condition differences in biomechanical parameters were significant. Hip flexion increased at heel strike with inclines from -10 degrees to +10 degrees . Knee flexion and ankle dorsiflexion at heel strike increased with increasing angle walking up, but not down. Changes in joint moments and powers due to change in the angle of incline or direction of walking were observed. CONCLUSIONS: The mechanisms by which the body enables walking up and downhill, specifically raising and lowering the centre of mass, and preventing slipping, can be seen in the alteration in the dynamics of the lower limbs. Increases in range of motion and muscle strength requirements need to be considered in the design of lower limb prostheses and in orthopaedic and neurological rehabilitation. RELEVANCE: Gait, prosthetics, rehabilitation, balance and falls.