Metabolic changes in the lower esophageal sphincter influencing the result of anti-reflux surgical interventions in chronic gastroesophageal reflux disease

AIM: With the availability of a minimally invasive approach, anti-reflux surgery has recently experienced a renaissance as a cost-effective alternative to life-long medical treatment in patients with gastroesophageal reflux disease (GERD). We are not aware of the fact whether reflux episodes causing complaints for a long time i.e., at least for one year are associated with metabolic changes in the lower esophageal sphincter, and if so, whether these may influence functional results achieved after anti-reflux surgery. METHODS: Between 1 January 2001 and 31 December 2002 we performed anti-reflux surgery on 79 patients. Muscle samples were taken from the lower esophageal sphincter (LES) in 33 patients during anti-reflux surgery. Inclusion criteria were: LES resting pressure below 10 mmHg and a marked, pH proven acid exposure to the esophagus of at least one year's duration, causing subjective complaints and requiring continuous proton pump inhibitor treatment. Control samples were obtained from muscle tissue in the gastroesophageal junction that had been removed from 17 patients undergoing gastric or esophageal resection. Metabolic and lysosomal enzyme activities and special protein concentrations 16 parameters in total were evaluated in tissue taken from control specimens and tissue taken from patients with GERD. The biochemical parameters of these intra-operative biopsies were used to correlate the results of anti-reflux operations (Visick Ⅰ and Ⅱ-Ⅲ). RESULTS: In the reflux-type muscle, we found a significant increase of the energy-enzyme activities e.g., creatine kinase, lactate dehydrogenase, β-hydroxybutyrate dehydrogenase, and aspartate aminotransaminase-. The concentration of the structural protein S-100 and the myofibrillar protein troponin Ⅰ were also significantly increased. Among lysosomal enzymes, we found that the activities of cathepsin B, tripeptidyl-peptidase Ⅰ, dipeptidyl-peptidase Ⅱ, β-hexosaminidase B, β-mannosidase and β-galactosidase were significantly decreased as compared to the control LES muscles. By analyzing the activity values of the 9 patients in Visick groups Ⅱ and Ⅲ at two months post-surgery, we found a significant increase in the activity of the so-called energy-enzyme values and in the concentration of structural and myofibrillar proteins as compared to the rest of the reflux patients. CONCLUSION: Our results call attention to the metabolic changes that occurred in the LES muscles of reflux patients. The developing hypertrophy-like changes of LES muscles may be a reason for complaints after anti-reflux surgery, which consisted mainly of reports of persisting dysphagia.     

An adult case of kawasaki disease with multiplex coronary aneurysms and0 myocardial infarction: The role of transesophageal echocardiography

Kawasaki disease (mucocutaneous lymph node syndrome) is an acute inflammatory disease that primarily affects infants and young children. in spite of proper therapy, coronary aneurysms develop in 10 to 25% of cases. Adult diagnosis of coronary aneurysm, presumably caused by Kawasaki disease, is rare. A 37-year-old male patient with previous inferior wall myocardial infarction (MI) was admitted with an acute anterior wall MI. Coronary angiography, performed 2 weeks after successful thrombolytic therapy, showed right coronary artery occlusion and multiplex (left main, left anterior descending, left circumflex, right coronary artery) giant coronary aneurysms. Transthoracic echocardiography was unable to detect the aneurysms. Transesophageal echocardiography (TEE) visualized a large left main coronary aneurysm with an occlusive thrombus and measured low flow velocity (0.2 m/s) in the proximal left anterior descending artery. At 4 weeks control, TEE showed marked regression of the thrombus, and it was not detectable after 6 months of oral anticoagulation with acenocumarol (International Normalized Ratio: 3-3.5) and standard postinfarction therapy. After 2 years of follow-up, the patient has no symptoms, and myocardial ischemia could not be provoked by stress tests [treadmill, dipyridamole single-photon emission computed tomography (SPECT)]. We conclude that, for diagnosis and follow-up of adult Kawasaki disease, transesophageal echocardiography is indicated. The importance and efficacy of long-term anticoagulant treatment should be emphasized in this disease.     

Effects of lifestyle changes on adults with prediabetes: A systematic review and meta-analysis

Aims

To assess the efficacy, safety, and cost-effectiveness of lifestyle intervention, compared with treatment as usual in people with prediabetes as defined by the American Diabetes Association. For older studies, we used the 1985 World Health Organization definition.

T cell–derived interleukin (IL)-21 promotes brain injury following stroke in mice

T lymphocytes are key contributors to the acute phase of cerebral ischemia reperfusion injury, but the relevant T cell–derived mediators of tissue injury remain unknown. Using a mouse model of transient focal brain ischemia, we report that IL-21 is highly up-regulated in the injured mouse brain after cerebral ischemia. IL-21–deficient mice have smaller infarcts, improved neurological function, and reduced lymphocyte accumulation in the brain within 24 h of reperfusion. Intracellular cytokine staining and adoptive transfer experiments revealed that brain-infiltrating CD4⁺ T cells are the predominant IL-21 source. Mice treated with decoy IL-21 receptor Fc fusion protein are protected from reperfusion injury. In postmortem human brain tissue, IL-21 localized to perivascular CD4⁺ T cells in the area surrounding acute stroke lesions, suggesting that IL-21–mediated brain injury may be relevant to human stroke.Stroke is one of the leading causes of death and disability worldwide. Clinical and preclinical experimental studies highlight the importance of inflammation in both acute and delayed neuronal tissue damage after ischemic stroke; however, the mechanisms and cells involved in this neuroinflammation are not fully understood. There is currently no available treatment targeting the acute immune response that develops in the brain after transient focal ischemia. Therefore, we sought to identify novel T cell–derived cytokines that contribute to acute cerebral reperfusion using the mouse model of transient middle cerebral artery occlusion (tMCAO).During the reperfusion of infarcted brain tissue, leukocytes accumulate in the injured brain where, in addition to clearing cell debris, they promote secondary tissue injury (Yilmaz and Granger, 2010). Within the acute phase of ischemic reperfusion (I/R) injury there are multiple waves of cell infiltration of macrophages, neutrophils, and lymphocytes (Gelderblom et al., 2009). Brain-infiltrating T cells have also been widely reported in stroke and animal models of stroke and are thought to have acute detrimental and delayed protective effects (Magnus et al., 2012). Conventionally, the protective role of T cells has been attributed to the accumulation of regulatory T cells within the CNS in later stages of reperfusion injury. These T cells produce a variety of cytokines including TGFβ and IL-10, which are both antiinflammatory and neuroprotective. (Liesz et al., 2009; Stubbe et al., 2013). In addition to having an established role in delayed neuroprotection, Kleinschnitz et al. (2013) have recently shown that CD4⁺ CD25⁺ regulatory T cells also promote acute ischemic injury through interaction with the cerebral vasculature. The acute detrimental effects can be further divided into early (24 h) and late (72 h) phases, with IL-17 production by nonconventional γδ T cells (less common T cell subset associated with mucosal tissues) possibly accounting for the latter by promoting neutrophil accumulation (Gelderblom et al., 2012).The mechanisms of the early detrimental effects of T cells after cerebral ischemia are least understood. Several laboratories have reported reduced neurological deficit and infarct volumes at 24–48 h reperfusion in T cell–deficient mice after tMCAO (Yilmaz and Granger, 2010). After tMCAO, recombination activating gene 1–deficient (RAG1 KO) mice, which lack T and B lymphocytes, have significantly smaller brain injury compared with controls; whereas, adoptive transfer of WT CD4⁺ helper T cells or CD8⁺ cytotoxic T cells increases stroke infarct volumes within 24 h after ischemia in these mice (Kleinschnitz et al., 2010). Additionally, TCR-transgenic mice and mice lacking co-stimulatory TCR signaling molecules were fully susceptible to acute I/R injury, indicating that T cell involvement at early time points is antigen-independent (Kleinschnitz et al., 2010). These data demonstrate that conventional CD4⁺ or CD8⁺ αβ T cells exacerbate acute injury after cerebral ischemia independently of TCR ligation, and this effect seems to be concomitant with an early increase in T cell infiltration into the postischemic brain, which many have reported to be between 3 and 48 h (Yilmaz et al., 2006; Gelderblom et al., 2009).Recent findings suggest that, in the postischemic brain, within hours of reperfusion T cells accumulate in postcapillary segments of periinfarct inflamed cerebral microvasculature characterized by high endothelial expression of chemokines and adhesion molecules. These postcapillary venules have been postulated to allow accumulating immune cells to activate each other and promote platelet adhesion in a process termed thrombo-inflammation (Nieswandt et al., 2011). Much research has been devoted to identifying T cell factors that promote thrombo-inflammation (Barone et al., 1997; Hedtjärn et al., 2002; Yilmaz et al., 2006; Shichita et al., 2009; Gelderblom et al., 2012); however, to our knowledge no study has yet identified the T cell–derived factors responsible for the early increase in infarct volumes at 24 h reperfusion. Here, we present data that identify IL-21 as a key CD4⁺ T cell–derived inflammatory factor that contributes to increased early ischemic tissue injury.     

Evaluation of impaired fingertip texture discrimination and wrist position sense in patients affected by stroke: comparison of clinical and new quantitative measures.

Discriminative sensory loss is common following stroke but may not be adequately detected by routine clinical measures. Quantitative tests of texture discrimination and limb position sense have been recently developed. These tests provide reliable estimates of discrimination, differentiate impaired performance following stroke, and have standardized criteria of abnormality. The purpose of this study was to compare predictions of impairment based on current clinical measures with predictions based on these quantitative, standardized measures. Thirty-five patients who had strokes were tested on the new quantitative measures and clinical measures of texture discrimination and limb position sense. The findings indicated poor agreement between impairment defined using current clinical measures and statistically abnormal performance on the new quantitative, norm-referenced measures. The findings suggest that the quantitative tests may provide additional assessment information to supplement that of the existing clinical measures of texture discrimination and limb position sense. Further development of these new quantitative measures is indicated.     

The Loss of Pacing-induced Preconditioning in Atherosclerotic Rabbits: Role of Hypercholesterolaemia

A brief rapid pacing has been shown to protect rabbit heart against global myocardial ischaemia induced by subsequent longer pacing. We studied whether pacing-induced preconditioning was reproducible in experimental hypercholesterolaemia. In conscious rabbits with an implanted right ventricular electrode and left ventricular polyethylene catheters, pacing of 500 bpm over 20 min induced an intracavitary ST-segment elevation of 3.2±0.41 mV, shortened ventricular effective refractory period and increased left ventricular end-diastolic pressure from prepacing 105±3.9 ms and 4.0±0.93 mmHg to post-pacing 62±6.4 ms and 27.9±7.2 mmHg, respectively. A 10-min preconditioning pacing followed by a 5-min interval markedly attenuated these test pacing-induced ischaemic changes. Rabbits were fed a cholesterol-enriched diet over 4, 8 and 12 weeks, responded to a 5- or 10-min pacing with ischaemic changes of the same degree as did controls to a 10- or 20-min pacing, respectively. A 4-week diet elevated total serum cholesterol from 1.7±0.4 to 24.1±2.9 mmol/l without apparent atherosclerotic lesions in the thoracic aorta assessed by Oil-Red O staining and planimetry, but it abolished protection induced by a 5-min preconditioning pacing. A 12-week diet increased serum cholesterol and lesion surface area to 26.9±3.2 mmol/l and 89.6±6.4%, respectively, and continued to block preconditioning. When these animals were refed normal chow over additional 6 weeks, serum cholesterol level dropped to 2.6±0.80 mmol/l with no change in atherosclerotic lesions, the preconditioning effect, however, recovered. We conclude that hypercholesterolaemia blocks preconditioning irrespective of the development of atherosclerosis.     

Stable T wave effects during improvement of heart rate control with biofeedback.

Under audiovisual heart rate feedback the differences between attempts to accelerate and decelerate improved with practice. Simultaneously, T wave amplitude was reduced during acceleratory trials and remained constant during deceleratory trials. The T wave difference between acceleratory and deceleratory trials, unlike the heart rate differences, did not improve with trial repetition. It was concluded that the improvement in heart rate control was parasympathetically mediated.