Endurance training-induced cardiac remodeling in a guinea pig athlete's heart model.

Besides the health benefits of regular exercise, high-level training-above an optimal level-may have adverse effects. In this study, we investigated the effects of long-term vigorous training and its potentially detrimental structural-functional changes in a small animal athlete's heart model. Thirty-eight 4-month-old male guinea pigs were randomized into sedentary and exercised groups. The latter underwent a 15-week-long endurance-training program. To investigate the effects of the intense long-term exercise, in vivo (echocardiography, electrocardiography), ex vivo, and in vitro (histopathology, patch-clamp) measurements were performed. Following the training protocol, the exercised animals exhibited structural left ventricular enlargement and a significantly higher degree of myocardial fibrosis. Furthermore, resting bradycardia accompanied by elevated heart rate variability occurred, representing increased parasympathetic activity in the exercised hearts. The observed prolonged QTc intervals and increased repolarization variability parameters may raise the risk of electrical instability in exercised animals. Complex arrhythmias did not occur in either group, and there were no differences between the groups in ex vivo or cellular electrophysiological experiments. Accordingly, the high parasympathetic activity may promote impaired repolarization in conscious exercised animals. The detected structural-functional changes share similarities with the human athlete's heart; therefore, this model might be useful for investigations on cardiac remodeling.

Nutrition and Physical Activity Clinical Practice Guidelines for Older Adults Living with Frailty.

BACKGROUND: We developed clinical practice guidelines to provide health care providers with evidence-based recommendations for decisions related to the effective management of frailty and pre-frailty using nutrition and physical activity interventions. METHODS: We based the recommendations on two systematic reviews with meta-analyses. Nutrition, physical activity, and combined nutrition and physical activity interventions for adults ≥65y were considered if study populations were identified as frail using a frailty tool or assessment. Risk of bias and certainty of evidence were evaluated. We included physical outcomes, mobility, frailty, cognitive function, activities of daily living, falls, quality of life, diet quality, energy/fatigue levels, health services use, and caregiver outcomes. RESULTS: Overall, mobility improvements were moderate with nutritional strategies that optimize dietary intake, various types of physical activity interventions, and interventions that combine nutrition and physical activity. Physical outcomes, such as body mass and muscle strength, improved moderately with nutritional strategies and interventions that combined nutrition with physical activity. Frailty status improved with multi-component physical activity interventions. Strong recommendations include optimizing dietary intake, performing physical activity, and adopting interventions that combine nutrition and physical activity. We strongly recommend various types of physical activity including muscle strengthening activities, mobilization or rehabilitation exercises, and multi-component physical activity interventions. INTERPRETATION: Tailored nutrition and physical activity interventions based on individual goals and health status are associated with improved clinical and physical outcomes. While the recommendations facilitate shared decision-making, we identified sparse application of validated frailty assessments and lack of standardized research outcomes as critical gaps in knowledge.

Moving Towards Common Data Elements and Core Outcome Measures in Frailty Research.

With aging populations around the world, frailty is becoming more prevalent increasing the need for health systems and social systems to deliver optimal evidence based care. However, in spite of the growing number of frailty publications, high-quality evidence for decision making is often lacking. Inadequate descriptions of the populations enrolled including frailty severity and frailty conceptualization, lack of use of validated frailty assessment tools, utilization of different frailty instruments between studies, and variation in reported outcomes impairs the ability to interpret, generalize and implement the research findings. The utilization of common data elements (CDEs) and core outcome measures (COMs) in clinical trials is increasingly being adopted to address such concerns. To catalyze the development and use of CDEs and COMs for future frailty studies, the Canadian Frailty Network (www.cfn-nce.ca; CFN), a not-for-profit pan-Canadian nationally-funded research network, convened an international group of experts to examine the issue and plan the path forward. The meeting was structured to allow for an examination of current frailty evidence, ability to learn from other COMs and CDEs initiatives, discussions about specific considerations for frailty COMs and CDEs and finally the identification of the necessary steps for a COMs and CDEs consensus initiative going forward. It was agreed at the onset of the meeting that a statement based on the meeting would be published and herein we report the statement.

Comparison of the efficiency of Na+/Ca2+ exchanger or Na+/H+ exchanger inhibition and their combination in reducing coronary reperfusion-induced arrhythmias.

During ischaemia/reperfusion, the rise in [Na(+)](i), induced by simultaneous depression of the Na(+)/K(+)-ATPase and activation of the Na(+)/H(+) exchanger (NHE), shifts the Na(+)/Ca(2+) exchanger (NCX) into reverse transport mode, resulting in Ca(2+)(i)overload, which is a critical factor in enhancing the liability to cardiac arrhythmias. The inhibition of NHE, and recently NCX has been suggested to effectively protect the heart from reperfusion-induced arrhythmias. In this study, we investigated and compared the efficacy of individual or the simultaneous inhibition of the NHE and NCX against reperfusion-induced arrhythmias in Langendorff-perfused rat hearts by applying a commonly used regional ischaemia-reperfusion protocol. The NHE and NCX were inhibited by cariporide and SEA0400 or the novel, more selective ORM-10103, respectively. Arrhythmia diagrams calculated for the reperfusion period were analysed for the incidence and duration of extrasystoles (ESs), ventricular tachycardia (VT) and ventricular fibrillation (VF). NHE inhibition by cariporide was highly efficient in reducing the recorded reperfusion-induced arrhythmias. Following the application of SEA0400 or ORM-10103, the number and duration of arrhythmic periods were efficiently or moderately decreased. While both NCX inhibitors effectively reduced ESs, the most frequently triggered arrhythmias, they exerted limited or no effect on VTs and VFs. Of the NCX inhibitors, ORM-10103 was more effective. Surprisingly, the simultaneous inhibition of the NCX and NHE failed to significantly improve the antiarrhythmic efficacy reached by NCX blockade alone. In conclusion, although principal simultaneous NHE+NCX inhibition should be highly effective against all types of the recorded reperfusion-induced arrhythmias, NCX inhibitors, alone or in combination with cariporide, seem to be moderately suitable to provide satisfactory cardioprotection - at least in the present arrhythmia model. Since ORM-10103 and SEA0400 are known to effectively inhibit after-depolarisations, it is suggested that their efficacy and that of other NCX inhibitors may be higher and more pronounced in the predominantly Ca(2+)(i)-dependent triggered arrhythmias.

Evaluation of serum sialic acid and carcinoembryonic antigen for the detection of early-stage colorectal cancer.

Various expressions of elevated serum sialic acid (total sialic acid, TSA: lipid-associated sialic acid, LASA; LASA/TSA; TSA normalized to total protein, TSA/TP) have been evaluated and compared with increased serum carcinoembryonic antigen (CEA) levels for the detection of early-stage colorectal cancer. This evaluation was done blindly on a coded panel of 320 sera from staged colorectal cancer patients and controls provided by the Mayo Clinic--National Cancer Institute Diagnostic Bank. Unlike the findings of a previous preliminary study (Tautu et al., JNCI 80:1333-1337, 1988), the ratio of LASA/TSA was not useful for detecting early-stage (Dukes A and B) colorectal cancer. However, TSA and TSA/TP values were significantly elevated in each colorectal cancer subgroup compared with normal controls. TSA and TSA/TP values displayed a marginally better discriminatory power than CEA values in the case of Dukes A subgroup with respect to normal controls. CEA still appears to be the best single overall marker for discriminating between colorectal cancers and controls. However, multiple marker analysis using CEA and TSA (and related markers) appears to be more sensitive than CEA alone for detecting colorectal cancer.

Obstructing carcinoma of the cecum.

Carcinoma of the cecum, the third most common location for malignancy of the large bowel, was examined with attention centered upon cecal cancers producing obstruction. Reviewing 136 patients revealed 11 obstructing lesions (8.1%) presenting as distal small bowel obstructions. The mean age of the patients was 74 years. All but one patient had resection for cure which consisted of a right hemicolectomy with ileotransverse colostomy. There was no operative mortality or significant morbidity. Bowel obstruction due to cecal carcinoma is an infrequent occurrence arising in elderly patients and carries a poor survival rate due to advanced disease at the time of diagnosis and treatment.

Serum sialic acid and carcinoembryonic levels in the detection and monitoring of colorectal cancer.

Total sialic acid (TSA), total protein (TP), TSA normalized to total TP (TSA/TP), and carcinoembryonic antigen levels were determined in 146 consecutive colorectal patients. These results were compared with results from 73 people with nonmalignant gastrointestinal disease, and with results from 96 normal controls. All malignancies were staged according to the Astler-Coller modification of Dukes' classification for colorectal cancer. All blood samples were drawn before surgical therapy. The TSA/TP ratio for colorectal cancer was 13.4 (mg/gm) in contrast to 12.1 (mg/gm) for pathologic controls, and 9.7 (mg/gm) for normal controls. Student's t test showed a P value less than 0.001 for normal controls and a P value less than 0.001 for pathologic controls. The TSA/TP also showed statistical significance in Dukes A, B2, C, and D subgroups when compared with normal controls. There were only four patients with stage C1 carcinoma, thus statistical analysis would be questionable. In contrast, carcinoembryonic antigen levels showed no significant elevations until Dukes C2 tumors were encountered. These preliminary findings suggest that TSA/TP ratio may detect colorectal cancer patients with less tumor burden and be more beneficial as a tumor marker than CEA for monitoring patients with colorectal cancer.

Improved procedure for determination of serum lipid-associated sialic acid: application for early diagnosis of colorectal cancer.

We have developed a simple and reliable procedure for determining serum levels of lipid-associated sialic acid (LASA) in crude preparations. This method extracts essentially all gangliosides, excludes glycoprotein-bound sialic acid, and gives LASA values (0.5-1.0 mg/dL) in good agreement with values for isolated serum gangliosides. The procedure was used to determine serum levels of LASA in patients with colorectal cancer, in patients with nonmalignant diseases (pathological control subjects), and in normal control subjects. The results indicated that the percentages of total sialic acid (TSA) comprised by LASA (LASA/TSA X 100) were elevated in patients with the earliest stages of colorectal cancer, compared with percentages in normal control subjects (P less than .001) and pathological control subjects (P less than .01).

Total and lipid-associated serum sialic acid levels in cancer patients with different primary sites and differing degrees of metastatic involvement.

Serum total sialic acid (TSA) and lipid-associated sialic acid (LASA) levels have drawn considerable interest because of carbohydrate aberrations in malignant cells. The current investigation determined the TSA, LASA, total protein (TP), and TSA/TP values for 171 cancer patients with various primary sites and differing degrees of metastatic disease, 102 patients with nonmalignant diseases (pathologic controls), and 42 normal individuals. Data analysis indicated significant (p less than 0.01) increases in the mean (+/- SD) TSA and TSA/TP values in the cancer patients (78.1 +/- 19.2 mg/dl and 12.4 +/- 3.8 mg/g, respectively) and in the pathologic controls (76.0 +/- 7.5 mg/dl and 11.6 +/- 2.5 mg/g) when compared to the normal controls (67.3 +/- 7.1 mg/dl and 9.0 +/- 1.1 mg/g), and a significant decrease in the mean TP values in the cancer patients (6.4 +/- 1.1 g/dl) and pathologic controls (6.6 +/- 1.1 g/dl) when compared to normal controls (7.5 +/- 0.5 g/dl). No significant difference was observed between groups in LASA values. Further analysis of the data in patient subgroups based on the tissue involved, specific disease, or severity of the malignancy indicated that the lack of specificity of the markers was due primarily to restricted subgroups and that the sensitivity of TSA and TSA/TP increased as the malignancy became more severe. The results show that TSA/TP was the most useful of the markers tested for detecting malignancies. This marker should prove useful for monitoring malignant disease recurrence and/or progression and for evaluating the effectiveness of various therapeutic approaches.

Variant serum beta-hexosaminidase as a biochemical marker of malignancy.

Previous studies have demonstrated a variant form of beta-hexosaminidase in metastatic tumor tissue of human liver and in sera from cancer patients with liver metastases. The current investigation examined sera for the presence of the variant form of beta-hexosaminidase from a large and heterogeneous group of cancer patients (with different primary sites and differing degrees of metastatic involvement), from normal controls and pathological controls with nonmalignant diseases. Comparison of the total serum beta-hexosaminidase activity levels and the percentage of the total activity comprised of beta-hexosaminidase B (Hex B) revealed no significant differences (P greater than 0.01) between the three groups. Analytical isoelectric focusing indicated that the variant beta-hexosaminidase was present in 80% of 108 cancer patients, 37% of 27 pathological controls and 11% of 18 normal controls. Examination of subgroups of the cancer patients based on the extent of metastasis revealed that there was a significant increase in total serum beta-hexosaminidase activity and the presence of variant beta-hexosaminidase in the sera as the disease progressed. These results suggest that serum beta-hexosaminidase may be a useful marker for monitoring the progression of malignant disease.

beta-Hexosaminidase from colon and sera of dukes-classified colorectal cancer patients: activity levels, isozyme patterns, and kinetic properties.

Total activity levels, isozyme patterns, and kinetic properties of beta-hexosaminidase were studied in crude supernatants of malignant and adjacent, uninvolved normal colon tissues and in sera from 28 Dukes-classified colorectal cancer patients. A significant increase (P less than .001) in both beta-hexosaminidase activity and beta-hexosaminidase specific activity and a significant increase (P less than .01) in the relative percentage of activity comprised by the basic thermostable form of beta-hexosaminidase (Hex B) isozyme were found in malignant tissue compared to the activities seen in uninvolved normal colon tissue. No apparent correlations were found between either beta-hexosaminidase activity levels or relative percentage of Hex B and Dukes category. Kinetic analysis indicated that the thermolabile form of beta-hexosaminidase and Hex B from malignant colon were comparable to the corresponding isozymes from normal colon with regard to thermostability after preincubation at 50 degrees C and pH activity curves (optimum between pH 4.0 and 5.0). Significantly decreased (P less than .05) beta-hexosaminidase activity was found in sera of the 28 colorectal cancer patients (17.3 +/- 5.2 U/ml, mean +/- SD) when compared to the activity in 19 controls with nonmalignant diseases (21.4 +/- 8.2 U/ml) and 17 normal controls (21.3 +/- 6.4 U/ml). Isoelectric focusing indicated that a peak of beta-hexosaminidase activity with an isoelectric point value (9.5) comparable to that of the peak found in increased amounts in malignant colon was detectable in the sera of 36% of the colorectal cancer patients and 11% of the controls.

Early definitive surgery for acute pancreatitis associated with cholelithiasis.

Since the natural history of pancreatitis associated with cholelithiasis is one of recurrence, surgery for the biliary tract disease is mandatory. But appropriate timing of the surgery remains controversial. Seventy-eight patients have been treated with early surgery once a diagnosis of cholelithiasis associated pancreatitis was made. Eighteen patients had previous episodes of nonalcoholic pancreatitis. Utilizing Ranson's prognostic signs, 52 patients had mild pancreatitis and 26 severe. Sixty-eight patients (87%) had surgery within 72 hours after admission and ten patients (13%) within 5 days. All patients had a cholecystectomy and operative cholangiogram performed. Fifty-six (72%) positive operative cholangiograms were obtained and common bile duct exploration revealed choledocholithiasis in 42 patients (75%). No mortality occurred, and four had six complications including mild persistent pancreatitis (two), wound infection (one), urinary tract infection (one), cardiac arrhythmia (one) and heart block requiring permanent pacemaker (one). The average hospital stay was 10.4 days. T-tube cholangiogram done prior to discharge was normal in all patients, and there have been no episodes of recurrent pancreatitis. Early definitive surgery for pancreatitis associated with cholelithiasis is recommended and can be accomplished with minimal morbidity and mortality coupled with judicious utilization of hospital resources.

Atypical beta-hexosaminidase in sera of cancer patients with liver metastases.

Previous studies have reported altered isozyme compositions and properties of beta-hexosaminidase in human cancerous tissues, and an atypical beta-hexosaminidase was found previously in metastatic tumor tissue of human liver. The present investigation was concerned with determining if this atypical beta-hexosaminidase could be detected (by analytical column isoelectric focusing) in the sera of cancer patients who have liver metastases. Analyses of sera from 14 cancer patients indicated that 12 contained an atypical beta-hexosaminidase in addition to normal beta-hexosaminidase A and B. Analysis of sera from 15 normal controls and 8 controls with benign disease indicated that the atypical beta-hexosaminidase may be specific for malignant disease. The mean percentage of recovered beta-hexosaminidase activity associated with peaks of beta-hexosaminidase B (i.e., peaks with isoelectric point values at or near that of normal beta-hexosaminidase B) was slightly elevated in cancer sera [37 +/- 9.6% (S.D.)] when compared to normal (32 +/- 9%) and pathological control (29 +/- 10%) sera. The variant beta-hexosaminidase may prove to be a useful general marker for tumor burden or a more specific marker for liver metastases.

Operative risk of general surgical procedures in patients with previous myocardial revascularization.

Eighty general surgical procedures with general anesthesia were performed upon 73 patients who had undergone previous myocardial revascularization for significant coronary artery disease. No deaths occurred in this group of patients. Cardiac complications occurred in two patients. A silent myocardial infarction occurred in one patient while another required a permanent cardiac pacemaker for complete heart block. Six noncardiac complications developed in four patients. We concluded that patients with significant coronary artery disease who have undergone previous myocardial revascularization can tolerate subsequent general surgical procedures with limited risk.

Excisional breast biopsy and roentgenographic examination for mammographically detected microcalcification.

Sixty-two women had excisional breast biopsy for areas of microcalcification detected by mammography with no associated palpable mass. Carcinoma was discovered in 20 patients (32 percent). These cancers ranged in size from 0.6 to 14 mm in greatest diameter. Six patients had multicentric carcinoma, including one synchronous bilateral lobular carcinoma. Axillary metastasis was present in three patients (15 percent), each with multicentric lesions. Chronic cystic mastopathy (55 percent) was the most common finding associated with microcalcification. In six patients (30 percent) with carcinoma, the microcalcification was present only in adjacent tissue and ducts. Generous excisional biopsy, verification of excision of the site of microcalcification by roentgenographic examination of the specimen, and thorough histologic examination by paraffin section are mandatory to detect these early and potentially curable breast carcinomas.

WDHA syndrome caused by pheochromocytoma: report of a case.

A case in which a pheochromocytoma secreted vasoactive intestinal peptide, causing WDHA syndrome, is reported. The patient, a 43-year-old woman, was seen because of intractable watery diarrhea, hypokalemia and weight loss. She was found to have a mass in the right adrenal area. Preoperatively, vasoactive intestinal peptide levels were elevated, and the diagnosis of WDHA syndrome was entertained. Exploratory laparotomy revealed a tumor of the right adrenal gland, measuring 15 x 15 cm, which was resected. Histologic examination revealed it to be a pheochromocytoma. Postoperatively, vasoactive intestinal peptide returned to normal. The patient had complete remission of symptoms, and has remained well since.