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To (1) describe the prevalence of cardiometabolic disease (CMD) at spinal cord injury (SCI) rehabilitation discharge; (2) compare this with controls without SCI; and (3) identify factors associated with increased CMD.Multicenter, prospective observational study.Five National Institute on Disability, Independent Living, and Rehabilitation Research Model SCI Rehabilitation Centers.SCI (n=95): patients aged 18-70 years, with SCI (neurologic levels of injury C2-L2, American Spinal Injury Association Impairment Scale grades A-D), and enrolled within 2 months of initial rehabilitation discharge. Control group (n=1609): age/sex/body mass index-matched entries in the National Health and Nutrition Examination Education Survey (2016-2019) (N=1704).None MAIN OUTCOME MEASURES: Percentage of participants with SCI with CMD diagnosis, prevalence of CMD determinants within 2 months of rehabilitation discharge, and other significant early risk associations were analyzed using age, sex, body mass index, insulin resistance (IR) by fasting glucose and Homeostasis Model Assessment (v.2), fasting triglycerides, high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol, total cholesterol, and resting blood pressure (systolic and diastolic).Participants with SCI had significantly higher diastolic blood pressure and triglycerides than those without SCI, with lower fasting glucose and HDL-C. A total of 74.0% of participants with SCI vs 38.5% of those without SCI were obese when applying population-specific criteria (P.05). Low HDL-C was measured in 54.2% of participants with SCI vs 15.4% of those without (P.05). IR was not significantly different between groups. A total of 31.6% of participants with SCI had ≥3 CMD determinants, which was 40.7% higher than those without SCI (P.05). Interplay of lipids and lipoproteins (ie, total cholesterol:HDL-C ratio and triglyceride:HDL-C ratio) were associated with elevated risk in participants with SCI for myocardial infarction and stroke. The only significant variable associated with CMD was age (P.05).Individuals with SCI have an increased CMD risk compared with the general population; obesity, IR, and low HDL-C are the most common CMD risk determinants; age is significantly associated with early CMD.

Genetic analysis of an adult patient with an unusual course of Ketosis-Prone Diabetes (KPD) and lacking islet autoantibodies demonstrated a nucleotide variant in the 5’-UTR of PDX1, a beta-cell development gene. When differentiated to the pancreatic lineage, his induced pluripotent stem cells stalled at the definitive endoderm stage. Metabolomic analysis of the cells revealed that this was associated with leucine hypersensitivity during transition from the definitive endoderm to the pancreatic progenitor stage, and RNA-sequencing showed defects in leucine-sensitive mTOR pathways contribute to the differentiation deficiency. CRISPR-Cas9 manipulation of the PDX1 variant demonstrated that it is necessary and sufficient to confer leucine sensitivity and the differentiation block, likely due to disruption of binding of the transcriptional regulator NFY to the PDX1 5’-UTR, leading to decreased PDX1 expression at the early pancreatic progenitor stage. Thus, the combination of an underlying defect in leucine catabolism characteristic of KPD with a functionally relevant heterozygous variant in a critical beta-cell gene that confers increased leucine sensitivity and inhibits endocrine cell differentiation resulted in the phenotype of late-onset beta-cell failure in this patient. We define the molecular pathogenesis of a diabetes syndrome and demonstrate the power of multi-omics analysis of patient-specific stem cells for clinical discovery.

Mixed acidic-alkaline refluxate is a major pathogenic factor in chronic esophagitis progressing to Barrett's esophagus (BE). We hypothesized that epidermal growth factor (EGF) can interact with COX-2 and peroxisome proliferator-activated receptor-γ (PPARγ) in rats surgically prepared with esophagogastroduodenal anastomosis (EGDA) with healthy or removed salivary glands to deplete salivary EGF. EGDA rats were treated with 1) vehicle, 2) EGF or PPARγ agonist pioglitazone with or without EGFR kinase inhibitor tyrphostin A46, EGF or PPARγ antagonist GW9662 respectively, 3) ranitidine or pantoprazole, and 4) the selective COX-2 inhibitor celecoxib combined with pioglitazone. At 3 mo, the esophageal damage and the esophageal blood flow (EBF) were determined, the mucosal expression of EGF, EGFR, COX-2, TNFα, and PPARγ mRNA and phospho-EGFR/EGFR protein was analyzed. All EGDA rats developed chronic esophagitis, esophageal ulcerations, and intestinal metaplasia followed by a fall in the EBF, an increase in the plasma of IL-1β, TNFα, and mucosal PGE2content, the overexpression of COX-2-, and EGF-EGFR mRNAs, and proteins, and these effects were aggravated by EGF and attenuated by pioglitazone. The rise in EGF and COX-2 mRNA was inhibited by pioglitazone but reversed by pioglitazone cotreated with GW9662. We conclude that 1) EGF can interact with PG/COX-2 and the PPARγ system in the mechanism of chronic esophagitis; 2) the deleterious effect of EGF involves an impairment of EBF and the overexpression of COX-2 and EGFR, and 3) agonists of PPARγ and inhibitors of EGFR may be useful in the treatment of chronic esophagitis progressing to BE.NEW & NOTEWORTHY Rats with EGDA exhibited chronic esophagitis accompanied by a fall in EBF and an increase in mucosal expression of mRNAs for EGF, COX-2, and TNFα, and these effects were exacerbated by exogenous EGF and reduced by removal of a major source of endogenous EGF with salivectomy or concurrent treatment with tyrphostin A46 or pioglitazone combined with EGF. Beneficial effects of salivectomy in an experimental model of BE were counteracted by PPARγ antagonist, whereas selective COX-2 inhibitor celecoxib synergistically with pioglitazone reduced severity of esophageal damage and protected esophageal mucosa from reflux. We propose the cross talk among EGF/EGFR, PG/COX-2, and proinflammatory cytokines with PPARγ pathway in the mechanism of pathogenesis of chronic esophagitis progressing to BE and EAC.

The objective of this study was to identify the relationship between metabolic syndrome (MetS) and pressure ulcers (PrU), after controlling for demographic and injury characteristics, socioeconomic factors, health behaviors and fatigue among participants with spinal cord injury (SCI). This cross-sectional study recruited 350 participants with SCI from a hospital in the western region of the USA. Blood tests and physical examination were performed. Waist circumference, high-density cholesterol, triglycerides, blood pressure and fasting glucose were used to diagnose MetS according to Criteria for Clinical Diagnosis of Metabolic Syndrome defined by the American Heart Association. All other variables were self-reported. Three-stage multivariate logistic regression models were conducted to evaluate the effects of three sequential sets of predictors, including demographic/injury, socio-environmental/behavioral and health factors, basing the order of analysis on the Theoretical Risk and Prevention Model. The prevalence of PrU and MetS was 11.0% (n=36) and 35.3% (n=115), respectively. Ethnicity, smoking, alcohol consumption and MetS were statistically associated with PrU in the full model. Participants who were non-Hispanic (odds ratio (OR)=10.30, 95% confidence interval (CI): 3.46–30.65), smokers (OR=2.69, 95% CI: 1.00–7.27) and drank over 30 drinks per month (OR=5.26, 95% CI: 1.24–22.26) had greater odds of having a PrU compared with those who were Hispanic, non-smokers and non-drinkers, respectively. We also observed a positive association between MetS and PrU (ORMetS=3.71, 95% CI: 1.45–9.52), even after controlling for all other factors. Participants who had MetS had higher odds of PrU than those without MetS after adjusting for multiple covariates. Unhealthy behaviors such as smoking and excess drinking were positively associated with PrU.

Melatonin is a tryptophan-derived molecule with pleiotropic activities which is produced in all living organisms. This “sleep” hormone is a free radical scavenger, which activates several anti-oxidative enzymes and mechanisms. Melatonin, a highly lipophilic hormone, can reach body target cells rapidly, acting as the circadian signal to alter numerous physiological functions in the body. This indoleamine can protect the organs against a variety of damaging agents via multiple signaling. This review focused on the role played by melatonin in the mechanism of esophagoprotection, starting with its short-term protection against acute reflux esophagitis and then investigating the long-term prevention of chronic inflammation that leads to gastroesophageal reflux disease (GERD) and Barrett’s esophagus. Since both of these condition are also identified as major risk factors for esophageal carcinoma, we provide some experimental and clinical evidence that supplementation therapy with melatonin could be useful in esophageal injury by protecting various animal models and patients with GERD from erosions, Barrett’s esophagus and neoplasia. The physiological aspects of the synthesis and release of this indoleamine in the gut, including its release into portal circulation and liver uptake is examined. The beneficial influence of melatonin in preventing esophageal injury from acid-pepsin and acid-pepsin-bile exposure in animals as well as the usefulness of melatonin and its precursor, L-tryptophan in prophylactic and supplementary therapy against esophageal disorders in humans, are also discussed.

Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are human neuromuscular disorders associated with mutations of simple repetitive sequences in affected genes. The abnormal expansion of CTG repeats in the 3′-UTR of the DMPK gene elicits DM1, whereas elongated CCTG repeats in intron 1 of ZNF9/CNBP triggers DM2. Pathogenesis of both disorders is manifested by nuclear retention of expanded repeat-containing RNAs and aberrant alternative splicing. The precise determination of absolute numbers of mutant RNA molecules is important for a better understanding of disease complexity and for accurate evaluation of the efficacy of therapeutic drugs. We present two quantitative methods, Multiplex Ligation-Dependent Probe Amplification and droplet digital PCR, for studying the mutant DMPK transcript (DMPKexpRNA) and the aberrant alternative splicing in DM1 and DM2 human tissues and cells. We demonstrate that in DM1, the DMPKexpRNA is detected in higher copy number than its normal counterpart. Moreover, the absolute number of the mutant transcript indicates its low abundance with only a few copies per cell in DM1 fibroblasts. Most importantly, in conjunction with fluorescence in-situ hybridization experiments, our results suggest that in DM1 fibroblasts, the vast majority of nuclear RNA foci consist of a few molecules of DMPKexpRNA.

Background: People with diabetes and kidney disease have a high risk of cardiovascular events and progression of kidney disease. Sodium glucose co-transporter 2 inhibitors lower plasma glucose by reducing the uptake of filtered glucose in the kidney tubule, leading to increased urinary glucose excretion. They have been repeatedly shown to induce modest natriuresis and reduce HbA1c, blood pressure, weight, and albuminuria in patients with type 2 diabetes. However, the effects of these agents on kidney and cardiovascular events have not been extensively studied in patients with type 2 diabetes and established kidney disease. Methods: The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial aims to compare the efficacy and safety of canagliflozin ­versus placebo at preventing clinically important kidney and cardiovascular outcomes in patients with diabetes and established kidney disease. CREDENCE is a randomized, double-blind, event-driven, placebo-controlled trial set in in 34 countries with a projected duration of ∼5.5 years and enrolling 4,401 adults with type 2 diabetes, estimated glomerular filtration rate ≥30 to 2, and albuminuria (urinary albumin:creatinine ratio >300 to ≤5,000 mg/g). The study has 90% power to detect a 20% reduction in the risk of the primary outcome (α = 0.05), the composite of end-stage kidney disease, doubling of serum creatinine, and renal or cardiovascular death. Conclusion: CREDENCE will provide definitive evidence about the effects of canagliflozin on renal (and cardiovascular) outcomes in patients with type 2 diabetes and established kidney disease. Trial Registration: EudraCT number: 2013-004494-28; ClinicalTrials.gov identifier: NCT02065791.

The paper presents a methodology of using multi-objective differential evolutionary approach to optimize a cancer chemotherapeutic treatment. The structure of optimal and suboptimal solutions will be presented. The constrained Pareto sub-optimal solutions are discussed. The performance assessment of non-dominated and dominated solutions is analyzed to help physicians to choose the most effective solution according to the approximation set of Pareto front.

Spinocerebellar ataxia type 3 (SCA3/MJD) is a neurodegenerative disease triggered by the expansion of CAG repeats in the ATXN3 gene. Here, we report the generation of the first humanized ataxin-3 knock-in mouse model (Ki91), which provides insights into the neuronal and glial pathology of SCA3/MJD. First, mutant ataxin-3 accumulated in cell nuclei across the Ki91 brain, showing diffused immunostaining and forming intranuclear inclusions. The humanized allele revealed expansion and contraction of CAG repeats in intergenerational transmissions. CAG mutation also exhibited age-dependent tissue-specific expansion, which was most prominent in the cerebellum, pons and testes of Ki91 animals. Moreover, Ki91 mice displayed neuroinflammatory processes, showing astrogliosis in the cerebellar white matter and the substantia nigra that paralleled the transcriptional deregulation of Serpina3n, a molecular sign of neurodegeneration and brain damage. Simultaneously, the cerebellar Purkinje cells in Ki91 mice showed neurodegeneration, a pronounced decrease in Calbindin D-28 k immunoreactivity and a mild decrease in cell number, thereby modeling the degeneration of the cerebellum observed in SCA3. Moreover, these molecular and cellular neuropathologies were accompanied by late behavioral deficits in motor coordination observed in rotarod and static rod tests in heterozygous Ki91 animals. In summary, we created an ataxin-3 knock-in mouse model that combines the molecular and behavioral disease phenotypes with the genetic features of SCA3. This model will be very useful for studying the pathogenesis and responses to therapy of SCA3/MJD and other polyQ disorders.

BACKGROUND Degludec is an ultralong-Acting, once-daily basal insulin that is approved for use in adults, adolescents, and children with diabetes. Previous open-label studies have shown lower day-To-day variability in the glucose-lowering effect and lower rates of hypoglycemia among patients who received degludec than among those who received basal insulin glargine. However, data are lacking on the cardiovascular safety of degludec. METHODS We randomly assigned 7637 patients with type 2 diabetes to receive either insulin degludec (3818 patients) or insulin glargine U100 (3819 patients) once daily between dinner and bedtime in a double-blind, treat-To-Target, event-driven cardiovascular outcomes trial. The primary composite outcome in the time-To-event analysis was the first occurrence of an adjudicated major cardiovascular event (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) with a prespecified noninferiority margin of 1.3. Adjudicated severe hypoglycemia, as defined by the American Diabetes Association, was the prespecified, multiplicity-Adjusted secondary outcome. RESULTS Of the patients who underwent randomization, 6509 (85.2%) had established cardiovascular disease, chronic kidney disease, or both. At baseline, the mean age was 65.0 years, the mean duration of diabetes was 16.4 years, and the mean (±SD) glycated hemoglobin level was 8.4±1.7%; 83.9% of the patients were receiving insulin. The primary outcome occurred in 325 patients (8.5%) in the degludec group and in 356 (9.3%) in the glargine group (hazard ratio, 0.91; 95% confidence interval, 0.78 to 1.06; P

Chronic spinal cord injury (SCI) is associated with an increase in risk factors for cardiovascular disease (CVD). In the general population, atherosclerosis in women occurs later than in men and usually presents differently. Associations between risk factors and incidence of CVD have not been studied in women with SCI.To determine which risk factors for CVD are associated with increased carotid intima-media thickness (CIMT), a common indicator of atherosclerosis, in women with SCI.One hundred and twenty-two females older than 18 years with traumatic SCI at least 2 years prior to entering the study were evaluated. Participants were asymptomatic and without evidence of CVD. Exclusion criteria were acute illness, overt heart disease, diabetes, and treatment with cardiac drugs, lipid-lowering medication, or antidiabetic agents. Measures for all participants were age, race, smoking status, level and completeness of injury, duration of injury, body mass index, serum lipids, fasting glucose, hemoglobin A1c, and ultrasonographic measurements of CIMT. Hierarchical multiple linear regression was conducted to predict CIMT from demographic and physiologic variables.Several variables were significantly correlated with CIMT during univariate analyses, including glucose, hemoglobin A1c, age, and race/ethnicity; but only age was significant in the hierarchical regression analysis.Our data indicate the importance of CVD in women with SCI.

Huntington disease (HD) is a dominantly inherited disorder caused by a CAG expansion mutation in the huntingtin (HTT) gene, which results in the HTT protein that contains an expanded polyglutamine tract. The adult form of HD exhibits a late onset of the fully symptomatic phase. However, there is also a long presymptomatic phase, which has been increasingly investigated and recognized as important for the disease development. Moreover, the juvenile form of HD, evoked by a higher number of CAG repeats, resembles a neurodevelopmental disorder and has recently been the focus of additional interest. Multiple lines of data, such as the developmental necessity of HTT, its role in the cell cycle and neurogenesis, and findings from pluripotent stem cells, suggest the existence of a neurodevelopmental component in HD pathogenesis. Therefore, we discuss the early molecular pathogenesis of HD in pluripotent and neural stem cells, with respect to the neurodevelopmental aspects of HD. Electronic supplementary material The online version of this article (doi:10.1007/s12035-017-0477-7) contains supplementary material, which is available to authorized users.

Polyglutamine (polyQ) disorders share many similarities, such as a common mutation type in unrelated human causative genes, neurological character, and certain aspects of pathogenesis, including morphological and physiological neuronal alterations. The similarities in pathogenesis have been confirmed by findings that some experimental in vivo therapy approaches are effective in multiple models of polyQ disorders. Additionally, mouse models of polyQ diseases are often highly similar between diseases with respect to behavior and the features of the disease. The common features shared by polyQ mouse models may facilitate the investigation of polyQ disorders and may help researchers explore the mechanisms of these diseases in a broader context. To provide this context and to promote the understanding of polyQ disorders, we have collected and analyzed research data about the characterization and treatment of mouse models of polyQ diseases and organized them into two complementary Excel data tables. The data table that is presented in this review (Part I) covers the behavioral, molecular, cellular, and anatomic characteristics of polyQ mice and contains the most current knowledge about polyQ mouse models. The structure of this data table is designed in such a way that it can be filtered to allow for the immediate retrieval of the data corresponding to a single mouse model or to compare the shared and unique aspects of many polyQ models. The second data table, which is presented in another publication (Part II), covers therapeutic research in mouse models by summarizing all of the therapeutic strategies employed in the treatment of polyQ disorders, phenotypes that are used to examine the effects of the therapy, and therapeutic outcomes. Electronic supplementary material The online version of this article (doi:10.1007/s12035-012-8315-4) contains supplementary material, which is available to authorized users.

Mouse models of human diseases are created both to understand the pathogenesis of the disorders and to find successful therapies for them. This work is the second part in a series of reviews of mouse models of polyglutamine (polyQ) hereditary disorders and focuses on in vivo experimental therapeutic approaches. Like part I of the polyQ mouse model review, this work is supplemented with a table that contains data from experimental studies of therapeutic approaches in polyQ mouse models. The aim of this review was to characterize the benefits and outcomes of various therapeutic strategies in mouse models. We examine whether the therapeutic strategies are specific to a single disease or are applicable to more than one polyQ disorder in mouse models. In addition, we discuss the suitability of mouse models in therapeutic approaches. Although the majority of therapeutic studies were performed in mouse models of Huntington disease, similar strategies were also used in other disease models. Electronic supplementary material The online version of this article (doi:10.1007/s12035-012-8316-3) contains supplementary material, which is available to authorized users.

Fibroblast growth factor 1 (FGF1) and its receptors (FGFRs) regulate crucial biological processes such as cell proliferation and differentiation. Aberrant activation of FGFRs by their ligands can promote tumor growth and angiogenesis in many tumor types, including lung or breast cancer. The development of FGF1-targeting molecules with potential implications for the therapy of FGF1-driven tumors is recently being considered a promising approach in the treatment of cancer. In this study we have used phage display selection to find scFv antibody fragments selectively binding FGF1 and preventing it from binding to its receptor. Three identified scFv clones were expressed and characterized with regard to their binding to FGF1 and ability to interfere with FGF1-induced signaling cascades activation. In the next step the scFvs were cloned to scFv-Fc format, as dimeric Fc fusions prove beneficial in prospective therapeutic application. As expected, scFvs-Fc exhibited significantly increased affinity towards FGF1. We observed strong antiproliferative activity of the scFvs and scFvs-Fc in the in vitro cell models. Presented antibody fragments serve as novel FGF1 inhibitors and can be further utilized as powerful tools to use in the studies on the selective cancer therapy.

BACKGROUND Cardiovascular risk factors are common in individuals with chronic spinal cord injury (SCI), and their prevalence increases with age. The actual prevalence of overt cardiovascular disease (CVD) in this population has not been well established. METHODS Electrocardiograms (ECGs) were examined for abnormalities in 43 individuals with abnormal lipid profiles being followed in the outpatient SCI clinic of our institution. The mean age of the study population of predominantly men was 43 +/- 9.9 years and the mean duration of injury 16.6 +/- 8 years. RESULTS ECG abnormalities were common and present in 60.5% of participants. ST-T wave abnormalities were the most commonly observed (35%). Evidence of previous myocardial infarction was present in 7% of all individuals and in 12% of those with ECG abnormalities. The only clinical parameter differentiating the group with normal vs abnormal ECG was the duration of injury (19.5 +/- 8 y vs 12 +/- 5 y; P = 0.0026). Analysis of variance showed that injury duration was the sole predictor of abnormal ECG with 68% accuracy (P = 0.006). Among those with ECG abnormalities, although no significant differences were detected between those with and without evidence of previous myocardial infarction, mean total cholesterol and low-density lipoprotein were higher, and mean high-density lipoprotein was lower. Mean age and injury duration were greater in those with evidence of previous myocardial infarction. CONCLUSION Although age is an important risk factor for CVD in the population of individuals without disabilities, injury duration is at least as important as age in those with SCI. Our findings support the recommendation that individuals with SCI and abnormal lipids should be screened for CVD regardless of age.

Background The polyglutamine (polyQ) family of disorders comprises 9 genetic diseases, including several types of ataxia and Huntington disease. Approximately two decades of investigation and the creation of more than 130 mouse models of polyQ disorders have revealed many similarities between these diseases. The disorders share common mutation types, neurological characteristics and certain aspects of pathogenesis, including morphological and physiological neuronal alterations. All of the diseases still remain incurable. Description The large volume of information collected as a result of the investigation of polyQ models currently represents a great potential for searching, comparing and translating pathogenesis and therapeutic information between diseases. Therefore, we generated a public database comprising the polyQ mouse models, phenotypes and therapeutic interventions tested in vivo. The database is available at http://conyza.man.poznan.pl/. Conclusion The use of the database in the field of polyQ diseases may accelerate research on these and other neurodegenerative diseases and provide new perspectives for future investigation.

Myotonic dystrophy type 1 (DM1) is an autosomal dominant multisystemic disorder caused by expansion of CTG triplet repeats in 3'-untranslated region of DMPK gene. The pathomechanism of DM1 is driven by accumulation of toxic transcripts containing expanded CUG repeats (CUG(exp)) in nuclear foci which sequester several factors regulating RNA metabolism, such as Muscleblind-like proteins (MBNLs). In this work, we utilized very short chemically modified antisense oligonucleotides composed exclusively of locked nucleic acids (all-LNAs) complementary to CUG repeats, as potential therapeutic agents against DM1. Our in vitro data demonstrated that very short, 8- or 10-unit all-LNAs effectively bound the CUG repeat RNA and prevented the formation of CUG(exp)/MBNL complexes. In proliferating DM1 cells as well as in skeletal muscles of DM1 mouse model the all-LNAs induced the reduction of the number and size of CUG(exp) foci and corrected MBNL-sensitive alternative splicing defects with high efficacy and specificity. The all-LNAs had low impact on the cellular level of CUG(exp)-containing transcripts and did not affect the expression of other transcripts with short CUG repeats. Our data strongly indicate that short all-LNAs complementary to CUG repeats are a promising therapeutic tool against DM1.

Polyglutamine (polyQ) hereditary ataxias comprise six disorders, including spinocerebellar ataxia type 1, type 2, Machado–Joseph disease, type 6, type 7, type 17, and dentatorubral-pallidoluysian atrophy. PolyQ ataxias are all neurological disorders, and their pathology is mainly related to dysfunction or loss of neurons in the central nervous system. The mechanisms of the disease are not fully understood and may include a gain and/or loss of function in the mutant protein, which becomes toxic to cells. Transgenic mouse models are very powerful tools for exploring polyQ ataxias. These models are created to study the following two aspects: the disease process and potential therapies for hereditary ataxias that are currently incurable. Therefore, in this chapter, we review the variety of mouse models of polyQ ataxias and discuss the aspects of ataxia pathogenesis that have been discovered via mouse models of particular diseases. Moreover, we review studies that test the feasibility of particular therapeutic strategies in mouse models of polyQ ataxia. This chapter complements our other reviews and databases and has been intensively updated with new models and therapeutic approaches.

BACKGROUND Elevated plasma levels of creatine kinase (CPK) are found in various neuromuscular conditions as a result of muscle damage and necrosis. Elevated CPK has also been described in elite wheelchair athletes and in able-bodied individuals after strenuous exercise. METHODS The incidence of elevated CPK in individuals with spinal cord injury (SCI) has not been well established. We reviewed laboratory data from 581 individuals with chronic SCI. RESULTS Most individuals with SCI (73.3%) had CPK values within 95% confidence intervals for able-bodied individuals. The highest levels were seen in African Americans (21% had CPK values > 95 confidence intervals for able-bodied individuals). Significant associations between CPK and the following independent variables were identified: impairment group, gender, duration of injury, body mass index, and ethnic group. Multiple regression analysis revealed significant correlations between CPK and oxygen consumption (beta .37, P < .01) in 32 individuals who performed the exercise test. CONCLUSIONS These findings are important for clinicians evaluating symptoms of fatigue and myopathy in individuals with SCI.

Cardiometabolic syndrome in individuals who are aging with spinal cord injury (SCI) increases the risk of cardiovascular disease and diabetes. Longitudinal research is needed on the natural progression of cardiometabolic syndrome in SCI.To identify the magnitude of changes in biomarkers of cardiometabolic syndrome and diabetes over time in people aging with SCI, and to discern how these biomarkers relate to demographics of race/ethnicity and sex.This cohort study was a follow-up of a convenience sample of 150 participants (mean age, 51.3; duration of SCI, 27.3 years) from a full cohort of 845 who participated in research in which physiologic and serologic data on cardiovascular disease had been prospectively collected (1993-1997). Inclusion criteria were adults with traumatic-onset SCI. Average years to follow-up were 15.7 ± 0.9. Assessments were age, race, level and completeness of injury, duration of injury, blood pressure, body mass index, waist circumference, serum lipids, fasting glucose, hemoglobin A1c, and medications used. Primary outcome was meeting at least 3 of the criteria for cardiometabolic syndrome.The frequency of cardiometabolic syndrome increased significantly from 6.7% to 20.8% or 38.2% according to 2 definitions. It was significantly higher in Hispanics and apparently higher in women. Diabetes increased significantly by a factor of 6.7.Our data indicate clinically important increases in the frequency of cardiometabolic syndrome, especially among Hispanic and female participants, and a similar increase in diabetes among individuals aging with SCI. Clinical practice guidelines need to be customized for women and Hispanics with SCI.

This review was designed to provide an update on the role of asymmetric arginine (ADMA), the endogenous inhibitor of nitric oxide (NO) synthase in the pathophysiology of the upper gastrointestinal (GI) tract. Numerous studies in the past confirmed that NO is a multifunctional endogenous gas molecule involved in most of the body organs' functional and metabolic processes including the regulation of gastrointestinal (GI) secretory functions, motility, maintenance of GI integrity, gastroprotection and ulcer healing. NO is metabolized from L-arginine by enzymatic reaction in the presence of constitutive NO synthase. In upper GI tract, NO acts as a potent vasodilator known to increase gastric mucosa blood flow, regulates the secretion of mucus and bicarbonate, inhibits the gastric secretion and protects the gastric mucosa against the damage induced by a variety of damaging agents and corrosive substances. In contrast, ADMA first time described by Vallance and coworkers in 1992, is synthesized by the hydrolysis of proteins containing methylated arginine amino acids located predominantly within the nucleus of cells. This molecule has been shown to competitively inhibit NO synthase suggesting its regulatory role in the functions of vascular endothelial cells and systemic circulation in humans and experimental animals. Nowadays, ADMA is a potentially important risk factor for coronary artery diseases and a marker of cardiovascular risk. Increased plasma levels of ADMA have been documented in several conditions that are characterized by endothelial dysfunction, including hypertension, hypercholesterolemia, hyperglycemia, renal failure and tobacco exposure. The role of ADMA in other systems including GI-tract has been so far less documented. Nevertheless, ADMA was shown to directly induce oxidative stress and cell apoptosis in gastric mucosal cells in vitro and to contribute to the inflammatory reaction associated with major human pathogen to gastric mucosa, Helicobacter pylori (H.pylori). Infection of gastric mucosa with this germ or H. pylori water extract led to marked increase in the plasma concentration of ADMA and significantly inhibited bicarbonate secretion, considered as one of the important components of upper GI-tract defense system. When administered to rodents, ADMA aggravated gastric mucosal lesions injury induced by cold stress, ethanol and indomethacin and this worsening effect on gastric lesions was accompanied by the significant increase in the plasma level of ADMA. This exaggeration of gastric lesions by ADMA was coincided with the inhibition of NO, the suppression of gastric blood flow and excessive release of proinflammatory cytokine TNF-α. This metabolic analog of L-arginine applied to rats was exposed to water immersion and restraint stress and ischemia-reperfusion, causing an elevation of plasma levels of ADMA and gastric MDA content, which is the marker of lipid peroxidation. These effects, including the rise in the plasma levels of ADMA in rats with stress and ischemia-reperfusion-induced gastric lesions, were attenuated by concomitant treatment with L-arginine, the substrate for NO-synthase, and superoxide dismutase (SOD), a reactive oxygen metabolite scavenger added to ADMA. We conclude that ADMA could be considered as an important factor contributing to the pathogenesis of gastric mucosal damage and inflammatory reaction in H. pylori-infected stomach due to inhibition of NO, suppression of GI microcirculation, and the proinflammatory and proapoptotic actions of this arginine analog.

The decrease in pancreatic exocrine secretion during the course of acute pancreatitis is a well-documented process. However, the mechanisms underlying this reduced pancreatic function are not fully understood. To analyze pancreatic protein synthesis and secretion during and after cerulein-induced pancreatitis, we performed the plasma amino acid consumption test on conscious rats. After stimulation with 1 microgram cerulein/kg/h sc for 1 h, the control group with intact pancreas exhibited a decrease in plasma amino acid by about 15%, and this decrease could be abolished by the administration of the specific CCK-receptor antagonist, loxiglumide. Protein and amylase secretion were augmented by cerulein to about 400% of control values. Upon supramaximal stimulation of the pancreas with cerulein (20 micrograms/kg/h sc for 5 h), we observed a profound decrease of pancreatic secretion, which was accompanied by a more prolonged and more pronounced decrease of plasma amino acids (25%). Two hours after cessation of the supramaximal stimulation of pancreatic secretion (to induce pancreatitis), the administration of 1 microgram/kg/h of cerulein for 1 h resulted in a further decrease of amino plasma acid level, whereas no stimulation of exocrine pancreatic secretion was observed. Eighteen hours later, repeated administration of 1 microgram/kg/h of cerulein was still able to induce amino acid decrease by 20%, but again, no stimulation of exocrine pancreatic secretion was detectable. We conclude that, in the time course of acute cerulein-induced hyperstimulation, there might be an imbalance between synthesis of pancreatic enzymes (reflected by amino acid consumption) and the release of exocrine pancreatic secretion into the duodenum, which may be explained by leakage of proteolytic enzymes from damaged acinar cells into the extracellular space of the pancreas.

Nash MS, Lewis JE, Dyson-Hudson TA, Szlachcic Y, Yee F, Mendez AJ, Spungen AM, Bauman WA. Safety, tolerance, and efficacy of extended-release niacin monotherapy for treating dyslipidemia risks in persons with chronic tetraplegia: a randomized multicenter controlled trial. Objective To test the safety, tolerance, and efficacy of extended-release niacin monotherapy on dyslipidemia in persons with chronic tetraplegia. Design Placebo-controlled, blinded, multicenter, randomized controlled trial. Setting Three spinal cord injury research/rehabilitation centers. Participants Persons with chronic tetraplegia (N=54) and low plasma high-density lipoprotein cholesterol (HDL-C) levels. Intervention Extended-release niacin monotherapy (48 weeks; n=31) on a dose-titration schedule versus matched placebo (n=23). Main Outcome Measures Safety was assessed by using percentages of treatment-emergent adverse events and increased levels of hepatic transaminases, uric acid, glycosylated hemoglobin, and fasting glucose. Tolerance was assessed by using participant reports for frequency and intensity of adverse effects of extended-release niacin. Primary effectiveness outcomes were fasting HDL-C level and plasma total cholesterol (TC)/HDL-C ratio. Secondary outcomes included plasma low-density lipoprotein cholesterol (LDL-C) and TC levels and LDL-C/HDL-C ratio. Results Significant increases in fasting HDL-C levels (24.5%) were accompanied by decreases in TC/HDL-C and LDL-C/HDL-C ratios, LDL-C levels, and TC levels (all P Conclusions Extended-release niacin monotherapy is safe, tolerated, and effective for most persons with chronic tetraplegia. Special precautions for changes in bowel habits and postadministration hypotension should be observed.

Ventricular arrhythmias are not uncommon in patients with hypertension, are often attributed to left ventricular hypertrophy and are thought to be associated with an increased risk of sudden death. However, underlying silent coronary artery disease, another potential cause of ventricular arrhythmias, is often present in the same patient group. Therefore, the prevalence of ventricular arrhythmias was prospectively examined in 183 consecutive asymptomatic men with hypertension with neither clinical nor electrocardiographic (ECG) evidence of coronary artery disease in whom technically adequate echocardiograms could be obtained. After previous therapy had been withdrawn for ≥4 days, each patient underwent exercise or dipyridamole thallium-201 scintigraphy, 48-h Holter ambulatory ECG monitoring and echocardiography for measurement of the left ventricular mass index. Forty patients (22%) had frequent ventricular ectopic activity, defined on the basis of >10 premature ventricular complexes/h (38 patients) or ventricular tachycardia (11 patients), or both.A higher proportion of patients with than without a reversible thallium-201 defect had frequent premature ventricular complexes (33% vs. 18%, p < 0.02) or ventricular tachycardia (14% vs. 4%, p < 0.02). Similarly, more patients with than without left ventricular hypertrophy (defined as left ventricular mass index ≥134 g/m2) had frequent premature ventricular complexes (29% vs. 15%. p < 0.05) and ventricular tachycardia (12% vs. 2%, p < 0.01). By stepwise logistic regression analysis, both findings were independent predictors of ventricular arrhythmia, which was present in 53% of patients with both abnormalities, but in only 12% of those with neither abnormality. In addition, ventricular arrhythmias were more common in patients who had than in those who had not previously been treated with a diuretic drug, even though there were no differences between patients in serum electrolytes at the time of study.These results indicate that silent myocardial ischemia and left ventricular hypertrophy are independently associated with ventricular arrhythmias in patients who are asymptomatic and have mild to moderate hypertension.

Hypertensive patients with left ventricular hypertrophy (LVH) have increased cardiovascular morbidity and mortality. Experimental studies indicate the importance of both the alpha and beta components of the adrenergic nervous system in the development and reversal of LVH. Therefore labetalol (L), a combined alpha and beta blocker, and propranolol (P), a nonselective beta blocker, were evaluated in a randomized, double-blind study of 35 hypertensive patients with echocardiographic evidence of LVH. Following 2 weeks of placebo, L or P was titrated as needed and tolerated to maximum total daily doses of 1600 mg and 640 mg, respectively. A thiazide diuretic was added if necessary for blood pressure control. M-mode echocardiograms were performed at baseline and after 1, 3, 6 and 12 months of blood pressure control. The echocardiograms were read independently by two blinded observers for end-diastolic dimension and wall thicknesses, and left ventricular mass. Fractional shortening, cardiac output, and peripheral vascular resistance were derived using standard formulas. Both drugs reduced blood pressure significantly and comparably. Significant changes in the echocardiographic measurements were observed as early as 1 month and usually persisted throughout the study. Both drugs decreased posterior wall thickness; however, only the decrease in propranolol group achieved statistical significance. Septal wall thickness was reduced by L at 3 and 12 months. End-diastolic dimension increased significantly in the L-treated group at 3, 6, and 12 months of therapy, whereas P had no effect on this measurement. As a consequence, the calculated left ventricular mass index was reduced by P throughout the study, but remained essentially unchanged by L until the twelfth month. Neither drug adversely affected fractional shortening. Cardiac output was significantly reduced by P, but unchanged by L, despite similar effects on heart rate by both drugs. Thus, despite their similar effects on blood pressure, L and P had different effects on cardiac morphology, which may reflect varying responses to alpha-and beta-adrenergic blockade.

Background Barrett's Esophagus (BE) is the precancerous lesion for esophageal adenocarcinoma (EAC). Several studies have indicated that obesity, especially abdominal, is a risk factor for BE. In addition, recent studies have shed light on the role of adipokines (leptin, adiponectin) and inflammatory biomarkers in the development of BE. However, the role of obesity and its biomarkers in the neoplastic progression of BE is unclear. The goal of our cohort study was to evaluate the association between baseline obesity (measured by WHR and BMI) and proand anti-inflammatory biomarkers (circulating adiponectin, leptin, IL1b, IL-6, IL-8, IL-10, and IL-12) and risk of progression to dysplasia or EAC. Methods We evaluated prospectively recruited BE cases during 2008-2013. All patients completed a questionnaire on GERD symptoms and medication use, and had anthropometric measurements (height, weight, waist and hip circumference) and a research blood sample was collected at baseline. BE was defined by endoscopic appearance combined with pathologic findings of intestinal metaplasia. We included patients who had at least one follow up endoscopy through November 19th 2014. BE neoplastic progression was defined as change from non-dysplastic BE to low grade dysplasia (LGD), high grade dysplasia (HGD), or EAC; or change from LGD to HGD or EAC; or change of HGD to EAC. The main exposures were baseline BMI, WHR and circulating levels of biomarkers. Major confounding factors were medications (PPI, statin, H2RA, aspirin, NSAID), GERD (symptoms, severity, frequency) and demographics (race, age, sex). The risk of neoplastic progression was examined in multivariate Cox proportional hazards analysis. Results A total of 178 patients with BE met the inclusion and exclusion criteria; 98% men, 92% white and average age 61.8 years. At baseline, 94% of patients had non-dysplastic BE. In a follow up of 804 patient years, 34 patients (19.10%) progressed to dysplastic BE, and the other 144 patients (80.9%) remained nondysplastic. The likelihood of BE neoplastic progression showed a non-significant increase with obesity (BMI>30) (adjusted HR=3.07, 95%CI 0.74-12.7) and high WHR (adjusted HR: 1.66, 0.22-12.7), and a significant decrease with elevated log IL-1 β I (HR=0.33, 95%C0.120.88) adjusted for age, race, sex, NSAID and statin. There were no associations with circulating serum levels of adiponectin, leptin, IL-6, IL-8, IL-10 or IL-12 levels. Conclusions The data are suggestive of a role for obesity and low levels of anti-inflammatory cytokine (IL-1 β) in the neoplastic progression of BE. These preliminary findings need to be confirmed in a larger dataset and longer follow up. Associations between baseline obesity and inflammation and risk of progression

Background Rosacea is a common condition of unknown aetiology that is usually accompanied by gastrointestinal symptoms and responds favourably to treatment with antibiotics. Aims/methods This study was designed to examine the prevalence of gastric Helicobacter pylori (Hp) infection verified by 13C-UBT, CLO-test, Hp culture and serology (IgG and IgA) and the presence of Hp in the oral cavity evidenced by CLO-test, Hp culture and saliva anti-Hp antibodies (IgG and IgA). During gastroduodenoscopy antral and fundic biopsy samples were taken for histological evaluation (the Sydney system). This study was performed on 60 subjects 30–70 years old with visible cutaneous rosacea symptoms and 60 age- and gender-matched controls without skin diseases but with dyspeptic symptoms similar to those of rosacea and without endoscopic changes in gastroduodenal mucosa (non-ulcer dyspepsia – NUD). Results The Hp prevalence in rosacea patients was about 88%, compared to 65% in the NUD controls. A noticeable number of rosacea patients showed chronic active gastritis predominantly in antrum but also in the corpus while those with NUD showed only mild gastritis confined to the antrum only. Following the initial examination, a typical 1 week systemic anti-Hp therapy, including omeprazole (2 × 30 mg), clarithromycin (2 × 500 mg) and metronidazole (2 × 500 mg), plus gargling and application of metronidazole paste in the case of Hp oral cavity infection. After the application of the systemic and local therapy in the oral cavity, Hp was eradicated from the stomach in 97% and from the oral cavity in 73% of treated patients. Within 2–4 weeks, the symptoms of rosacea disappeared or decreased markedly in 51 subjects. Summary We conclude that: (1) rosacea is a disorder with various gastrointestinal symptoms closely related to gastritis, especially involving the antrum mucosa; (2) the eradication of Hp leads to improvement of symptoms of rosacea and reduction in related gastrointestinal symptoms; (3) the lack of improvement of cutaneous symptoms in rosacea after eradication of Hp from the gastric mucosa could depend on bacteria in the oral cavity; and (4) rosacea could be considered as one of the extragastric symptoms of Hp infection probably mediated by Hp-related cytotoxins and cytokines.

The purpose of this study was to evaluate the effects of a simple dietary intervention for individuals with chronic spinal cord injury (SCI) and moderately elevated total cholesterol.Baseline and follow-up serum lipid values were obtained on 222 persons with SCI. Eighty-six individuals with total cholesterol200 mg/dL were referred for dietary consultation (group 1). The remainder with values200 mg/dL and no consultation served as controls (group 2).At average follow-up of 16 months, group 1 demonstrated significant declines in total cholesterol and low-density lipoprotein cholesterol (LDL-C), whereas group 2 demonstrated significant increases in total cholesterol. Triglyceride levels followed similar but nonsignificant patterns. There were no significant changes in high-density lipoprotein cholesterol for either group. In group 1, 17% had clinically significant reductions in total cholesterol to200 mg/dL and 21% had reductions of LDL-C from135 mg/dL to135 mg/dL.Dietary intervention should be an initial treatment for those with SCI and moderately elevated total cholesterol, with the expectation that approximately 20% will respond favorably.

To assess whether therapy with hydrochlorothiazide (HCTZ) or the calcium antagonist nitrendipine influences silent ischemia or arrhythmias, we studied 10 asymptomatic hypertensive male patients with positive Tl-201 scintigraphy in a double-blind, crossover protocol. Blood pressure (BP) and 48-h Holter monitoring were obtained after 2 weeks of placebo and 8 weeks each of HCTZ and nitrendipine therapy. Ischemia was defined as greater than 1 mm ST-segment depression lasting greater than 1 min and was quantified by the number of episodes, duration, and area under the curve (AUC). The mean number of PVCs per hour and the number of episodes of ventricular tachycardia (greater than 3 beats) were also assessed. Diastolic BP was significantly reduced by both HCTZ and nitrendipine (98 +/- 6 vs. 90 +/- 6 vs. 88 +/- 7 mm Hg, respectively, p less than 0.05), but systolic BP was unchanged for either drug. The number of ischemic episodes was reduced by nitrendipine, from 2.4 +/- 3 to 0.8 +/- 2, (p less than 0.05) but not by HCTZ (2.4 +/- 3 to 1.5 +/- 3, p = NS). The duration of ischemia (37 +/- 43 vs. 5 +/- 9 min, p less than 0.05) as well as the AUC (41 +/- 45 vs. 7 +/- 14 mm/min, p less than 0.05) were reduced only by nitrendipine. The number of PVCs rose with HCTZ therapy, from 19 +/- 34 to 69 +/- 88 (p less than 0.05) and was unchanged by nitrendipine (19 +/- 34 vs. 19 +/- 40, p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Stimulation of pancreatic sensory nerves by capsaicin produced secretory effects probably caused, at least in part, by the release of CGRP. In the pancreas calcitonin gene-related peptide (CGRP) has been localized in the sensory nerves, but its physiological role is unknown. This study was undertaken to compare the changes of pancreatic enzyme secretion produced by CGRP and by stimulation or destruction of sensory nerves. To stimulate sensory nerves, low doses of capsaicin (0.25–0.5 mg/kg) were given intraduodenally to the conscious rats with chronic pancreatic fistula. To inactivate sensory nerves high doses of capsaicin (100 mg/kg) were given subcutaneously 10 d before tests. For the in vitro experiments pancreatic slices and isolated pancreatic acini were prepared from intact and capsaicin-denervated rats. In conscious rats, CGRP given subcutaneously (5–10 μg/kg) and low doses of capsaicin given intraduodenally reduced basal pancreatic secretion. In isolated pancreatic acini, CGRP (10−10–10−6 M), but not capsaicin, increased basal or secretagog-stimulated amylase release. In pancreatic slices (containing nerve fibers) capsaicin (10−10–10−6 M) increased enzyme secretion, and this secretion was abolished by previous inactivation of sensory nerves by this neurotoxin. Capsaicin deactivation did not affect the secretory response of pancreatic acini to CGRP, cerulein, or urecholine. Sensory denervation by capsaicin did not change basal protein secretion, but reduced that produced by feeding or diversion of pancreatic juice to the exterior during first 2 h of the tests.

The aim of the present study was to determine the role of endogenous nitric oxide (NO) in pancreatic secretion in vivo and amylase release from pancreatic acini in vitro and in caerulein-induced acute pancreatitis in rats. Blockade of NO synthase byN G-nitro-L-arginine (L-NNA) (2.5 mg/kg iv) significantly reduced basal pancreatic protein secretion and that induced by the infusion of CCK (0.5 μg/kg-h), feeding, and the diversion of pancreatic juice in rats with pancreatic fistula. This inhibitory effect was partially reversed when L-arginine (50 mg/kg-h iv) was added to L-NNA. L-Arginine alone (50 mg/kg iv) did not affect basal or caerulein-induced pancreatic secretion. L-NNA, L-arginine, or their combination added in various concentrations to the incubation medium of dispersed acini failed to affect basal or secretagogue (caerulein or urecholine) stimulated amylase release. Infusion of caerulein (5 μg/kg-h) for 5 h produced histological changes of acute edematous pancreatitis accompanied by a marked increase in pancreatic protein content and about 50% reduction in tissue blood flow. L-NNA alone also reduced the pancreatic blood flow and caused a significant increase in pancreatic weight and protein content. L-NNA significantly potentiated the inflammatory changes in the pancreas caused by caerulein. Addition of L-arginine enhanced the pancreatic blood flow and ameliorated the pancreatitis induced by caerulein alone or that combined with L-NNA. We conclude that NO is involved in the stimulation of pancreatic secretion in vivo and exhibits a beneficial effect on pancreatitis, probably by improving the pancreatic blood flow.

Coronary artery disease is responsible for much of the morbidity and mortality in patients with essential hypertension, and these complications have proven to be relatively resistant to antihypertensive therapy. However, the diagnosis of coronary disease in the hypertensive population has been considered problematic. In the present study, 30 asymptomatic patients with mild to moderate hypertension with positive exercise electrocardiograms (ECG) or stress thallium-201 scintigrams underwent coronary angiography to determine the accuracy of these tests for coronary artery disease. The exercise ECG was positive in 25 subjects, of whom 15 had significant coronary lesions and 10 did not. Thallium-201 scintigraphy proved more accurate: 17 of 18 patients with reversible abnormalities had significant obstructive coronary disease anatomically corresponding to the defect, one patient with a fixed defect had normal coronary arteries and was found to have an idiopathic cardiomyopathy, and 9 of 11 without defects had no significant lesions. The results were similar in populations with and without echocardiographic criteria for left ventricular hypertrophy. These findings indicate that despite previous suggestions to the contrary, thallium-201 scintigraphy can accurately diagnose coronary artery disease in most patients with asymptomatic essential hypertension, and that most asymptomatic hypertensive patients with physiologic evidence of myocardial ischemia have associated coronary artery disease.

Individuals with spinal cord injury are at higher risk for developing cardiovascular events, such as myocardial infarction and death. Increased body mass, stress, abnormal glucose metabolism and lipid abnormalities, components of metabolic syndrome, are seen commonly in these individuals. Reduced ability to exercise is at least in part responsible for changes in body composition and metabolism. The prevalence of these abnormalities and its effect on blood vessels in women with spinal cord injury is unknown. Methods and Results Sixty-five women with chronic spinal cord injury, age 43 ± 11 years, predominately Hispanic (40%) underwent laboratory testing, for lipid profile, glucose metabolism and the carotid artery intima-media thickening a surrogate for coronary artery disease. Abnormal lipid profile was present in 59% particularly high triglycerides, mean value of 105± 35 mg/dl. Fasting glucose and Hemoglobin A1C were in high normal range (95 ± 21 mg/dl and 4.7 ± 1.8) respectively. Significant correlations were found between intima-media thickening and age (r = .22, p ≤ 0.04) and with fasting glucose (r = .78, p≤ 0.002) in high spinal cord injury. No correlations existed between intima-media thickening and any lipid fractions. Conclusion Although 59% of women with spinal cord injury had lipid abnormalities these were in mild to moderate range and did not affect blood vessels. Abnormal glucose metabolism had significant effect on cardiovascular system, as measured by intima-media thickening and may lead to future adverse events.

Objective. —Transesophageal echocardiography (TEE) and 12-lead electrocardiography (ECG) are sophisticated techniques that are increasingly being used to monitor for myocardial ischemia during noncardiac surgery. We examined whether the routine use of these techniques has incremental clinical value in identifying patients at high risk for perioperative ischemic outcomes when compared with preoperative clinical data and intraoperative monitoring using continuous two-lead bipolar ECG. Design. —Cohort study. Setting. —Veterans Affairs medical center. Patients. —A total of 332 men undergoing noncardiac surgery who had or were at high risk for coronary artery disease. Interventions. —TEE, 12-lead ECG, and two-lead ECG were performed continuously during noncardiac surgery (47% vascular, 53% nonvascular). Monitoring results were not available to anesthesiologists or surgeons, and data were blindly analyzed after surgery. Main Outcome Measure. —Perioperative ischemic outcomes (cardiac death, nonfatal myocardial infarction, unstable angina). Results. —In a subset of 285 patients who were adequately studied by all three techniques, 111 patients (39%) were identified as having intraoperative myocardial ischemia (by one or more monitoring techniques). By univariate analysis, intraoperative ischemia was associated with all perioperative cardiac outcomes, including ischemic outcomes, congestive heart failure, and ventricular tachycardia ( P ≤.02 for each of the three monitoring techniques). However, when monitoring results for TEE and 12-lead ECG were added to a multivariate model that included preoperative clinical data and continuous two-lead ECG results, the incremental value of TEE was small (odds ratio, 2.6; 95% confidence interval [Cl], 1.2 to 5.7; P =.02) and that of 12-lead ECG was not significant (odds ratio, 1.5; 95% Cl, 0.6 to 3.8). Furthermore, when the multivariate analysis was repeated with only ischemic outcomes, neither TEE nor 12-lead ECG retained significant associations (odds ratio, 2.2; 95% Cl, 0.5 to 9.4, and odds ratio, 1.1; 95% Cl, 0.2 to 6.1, respectively). Conclusion. —When compared with preoperative clinical data and intraoperative monitoring using two-lead ECG, routine monitoring for myocardial ischemia with TEE or 12-lead ECG during noncardiac surgery has little incremental clinical value in identifying patients at high risk for perioperative ischemic outcomes. ( JAMA . 1992;268:210-216)

Objective. —To identify predictors of postoperative myocardial ischemia in patients scheduled to undergo major noncardiac surgery. Design. —Historical, clinical, laboratory, and physiological data were obtained prospectively before and during surgery to identify potential univariate predictors of postoperative myocardial ischemia, which then were entered into multivariate logistic models. Continuous two-lead electrocardiograms before, during, and after surgery were used to identify episodes of myocardial ischemia. Setting. —Department of Veterans Affairs tertiary care hospital. Patients. —A consecutive sample of 474 men at high risk for or with coronary artery disease who were scheduled to undergo major noncardiac surgery (95% compliance rate). Main Outcome Measure. —Significant variables identified by multivariate logistic models that are associated with postoperative myocardial ischemia. Results. —Five major preoperative predictors of postoperative myocardial ischemia were identified: (1) left ventricular hypertrophy by electrocardiogram; (2) history of hypertension; (3) diabetes mellitus; (4) definite coronary artery disease; and (5) use of digoxin. The risk of postoperative myocardial ischemia increased progressively with the number of predictors present: in 22% of patients with no predictors, in 31% with one predictor, in 46% with two predictors, in 70% with three predictors, and in 77% with four predictors. Conclusion. —Patient subgroups who are at high risk for developing postoperative myocardial ischemia and who might benefit the most from intensive Holter monitoring in the postoperative period now can be identified preoperatively. ( JAMA . 1992;268:205-209)

Objective. —To determine the long-term (2-year) cardiac prognosis of high-risk patients undergoing noncardiac surgery and to determine the predictors of long-term adverse cardiac outcome. Design. —Prospective cohort study. Historical, clinical, and laboratory data were collected during the in-hospital period, and at 6 months, 1 year, and 2 years following surgery. Data were analyzed using proportional hazards models. Setting. —University-affiliated Veterans Affairs medical center. Population. —A consecutive sample of 444 patients with or at high risk for coronary artery disease who had undergone elective noncardiac surgery and were discharged from the hospital in stable condition. Main Outcome Measures. —Cardiac death, myocardial infarction, unstable angina, progressive angina requiring coronary artery bypass graft surgery or coronary angioplasty, and new unstable angina requiring hospitalization. Results. —Forty-seven patients (11%) had major cardiovascular complications during a 728-day (median) follow-up period: 24 had cardiac death; 11, nonfatal myocardial infarction; six, progressive angina requiring coronary artery bypass graft surgery or coronary angioplasty; and six, new unstable angina requiring hospitalization. Thirty percent of outcomes occurred within 6 months of surgery and 64% within 1 year. Five independent predictors of long-term outcome were identified. Three predictors reflected the preexisting chronic disease state: (1) the presence of known vascular disease (hazard ratio, 6.1; 95% confidence interval [Cl], 2.5 to 15.0; P P P P P P Conclusions. —The incidence of long-term adverse cardiac outcomes following noncardiac surgery is substantial. At increased risk are patients with chronic cardiovascular disease; at highest risk are patients with acute perioperative ischemic events. We conclude that survivors of in-hospital perioperative ischemic events, specifically myocardial infarction, unstable angina, and postoperative ischemia, warrant more aggressive long-term follow-up and treatment than is currently practiced. ( JAMA . 1992;268:233-239)

Objective. —To determine the incidence, clinical predictors and prognostic importance of perioperative ventricular arrhythmias. Design. —Prospective cohort study (Study of Perioperative Ischemia). Setting. —University-affiliated Department of Veterans Affairs Medical Center, San Francisco, Calif. Subjects. —A consecutive sample of 230 male patients, with known coronary artery disease (46%) or at high risk of coronary artery disease (54%), undergoing major noncardiac surgical procedures. Measurements. —We recorded cardiac rhythm throughout the preoperative (mean=21 hours), intraoperative (mean=6 hours), and postoperative (mean=38 hours) periods using continuous ambulatory electrocardiographic monitoring. Adverse cardiac outcomes were noted by physicians blinded to information about arrhythmias. Main Results. —Frequent or major ventricular arrhythmias (>30 ventricular ectopic beats per hour, ventricular tachycardia) occurred in 44% of our patients: 21% preoperatively, 16% intraoperatively, and 36% postoperatively. Compared with the preoperative baseline, the severity of arrhythmia increased in only 2% of patients intraoperatively but in 10% postoperatively. Preoperative ventricular arrhythmias were more common in smokers (odds ratio [OR], 4.1; 95% confidence interval [Cl], 1.2 to 15.0), those with a history of congestive heart failure (OR, 4.1; 95% Cl, 1.9 to 9.0), and those with electrocardiographic evidence of myocardial ischemia (OR, 2.2; 95% Cl, 1.1 to 4.7). Preoperative arrhythmias were associated with the occurrence of intraoperative and postoperative arrhythmias (OR, 7.3; 95% CI, 3.3 to 16.0, and OR, 6.4; 95% Cl, 2.7 to 15.0, respectively). Nonfatal myocardial infarction or cardiac death occurred in nine men; these outcomes were not significantly more frequent in those with prior perioperative arrhythmias, albeit with wide Cls (OR, 1.6; 95% CI, 0.4 to 6.2). Conclusion. —Almost half of all high-risk patients undergoing noncardiac surgery have frequent ventricular ectopic beats or nonsustained ventricular tachycardia. Our results suggest that these arrhythmias, when they occur without other signs or symptoms of myocardial infarction, may not require aggressive monitoring or treatment during the perioperative period. (JAMA. 1992;268:217-221)

Of 132 consecutive patients hospitalized during a 5 year period because of active variant angina, 18 died or had a myocardial infarction within 1 month. In 4 patients an episode of pain and S-T elevation unrelieved by calcium antagonist drugs and intravenous nitroglycerin persisted for more than 1 hour, inducing cardiogenic shock and death before the appearance of Q waves and elevated serum enzyme levels. In the other 14 patients myocardial infarction developed in the electrocardiographic leads in which S-T elevation had occurred during attacks of variant angina. Clinical features were not helpful in distinguishing the 18 patients with complications from the other 114. Angina at rest had been present for less than 1 month in 7 of the 18 patients with infarction compared with 31 of 114 in the other group (probability [p] not significant [NS]). Before infarction the artery presumed to be perfusing the involved territory contained a fixed stenosis of 70 percent or more of luminal diameter in 8 of the 14 patients with complications who had coronary arteriograms compared with 50 of 112 in the other group (p = NS). In 13 of the 18 patients, complications occurred in spite of large doses of calcium antagonist drugs. In 11 of these 13, attacks of variant angina were monitored for 3 to 17 days both before and during treatment. All 11 had fewer attacks with treatment and 5 had no attacks. Daily attacks per patient decreased from 4.6 +/- 4.3 to 0.5 +/- 0.7 (mean +/- standard deviation) (p less than 0.01). It is concluded that in variant angina of recent onset myocardial infarction occurs frequently and unpredictably. Myocardial infarction may occur in the absence of severe fixed lesions and in spite of apparent clinical improvement with administration of calcium antagonist drugs.

To determine whether patients with hypertension and especially those with left ventricular hypertrophy have subtle changes in cardiac function, we measured the increase in left ventricular ejection fraction and in systolic blood pressure to end-systolic volume index ratio with exercise in 40 hypertensive patients and 16 age-matched normotensive volunteers. Twenty-two hypertensive patients without hypertrophy had normal end-systolic wall stress at rest and exercise responses. In contrast, the 18 patients with echocardiographic criteria for left ventricular hypertrophy demonstrated a significant increase in end-systolic wall stress at rest compared with normal subjects (69 +/- 16 vs. 55 +/- 15 10(3) x dyne/cm2, p less than 0.05) despite having normal resting left ventricular size and ejection fraction. In patients with left ventricular hypertrophy, the increase in ejection fraction with exercise was less than in the normotensive control subjects (7 +/- 7 vs. 12 +/- 8 units, p less than 0.05), and delta systolic blood pressure to end-systolic volume with exercise was reduced (3.3 +/- 3.8 vs. 8.3 +/- 7.7 mm Hg/ml/m2, p less than 0.05). The hypertensive patients with hypertrophy displayed a shift downward and to the right in the relation between systolic blood pressure to end-systolic volume ratio and end-systolic wall stress compared with control subjects and hypertensive patients without left ventricular hypertrophy. Thus, hypertensive patients with left ventricular hypertrophy by echocardiography and normal resting ejection fraction exhibit abnormal ventricular functional responses to exercise. This finding may have implications in identifying patients at higher risk for developing heart failure.

IN VARIANT angina, myocardial ischemia is caused by transient coronary-arterial spasm.1 , 2 Although altered adrenergic activity has been proposed as the cause of coronary spasm3 , 4 and high circu...

Exercise, ergonovine and the cold pressor test have been used to provoke variant angina attacks. The sensitivity of these three tests was compared in 34 hospitalized patients with well documented, active variant angina who had recently undergone coronary arteriography. The three tests were usually performed on three consecutive days, and 28 of the 34 had the three tests within 1 week. Angina was provoked by ergonovine in all 34 patients, by exercise in 17 and by cold pressor test in only five (p less than 0.005). ST elevation developed during the ergonovine test in 32 (94%), during exercise in 10 (29%) and during the cold pressor test in only three (9%). With ergonovine, one patient had only ST depression and one had no ECG changes. During the cold pressor test two patients had pseudonormalization of abnormally negative T waves and 29 had no ECG changes. Exercise induced T-wave pseudonormalization in four patients, ST depression in nine others and no ECG changes in 11. ST elevation was more frequent with ergonovine than with either of the other tests (p less than 0.0001). ST elevation or T-wave pseudonormalization occurred more often with exercise than with cold (p less than 0.05), but both occurred less often than with ergonovine (p less than 0.0001). We conclude that the sensitivity of the ergonovine test is very high in patients with active variant angina and that exercise will provoke angina with ST elevation in about 30% of these cases. In contrast, the sensitivity of the cold pressor test is too low to be of much clinical value in the diagnosis of variant angina.