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Silent Disease

August 2009

Guidelines for the early detection of osteoporosis and prediction of fracture risk. Council of the National Osteoporosis Foundation.

OBJECTIVE: To assess methods available in clinical practice for the early detection of osteoporosis and prediction of fracture risk, and to set guidelines for their use. To make recommendations regarding cost-effective screening of asymptomatic subjects by physicians. OPTIONS: Three methods to predict fracture risk are considered: (i) clinical risk factor analysis; (ii) biochemical tests; and (iii) techniques to measure bone mass. Mass (unselected) screening is compared with screening only those at risk of sustaining a fracture. The optimal age/time of screening and therapeutic intervention thresholds are also considered. OUTCOMES: The main potential outcomes considered are the morbidity and mortality of advanced osteoporosis and fracture; the accuracy, precision, safety and costs of screening tests; and treatment for those at risk. EVIDENCE: Based on the results of published recommendations of international osteoporosis societies, World Health Organisation guidelines and expert opinion. VALUES: The guidelines were developed by the National Osteoporosis Foundation in conjunction with other specialists and societies. A workshop attended by all the osteodensitometrists in the country was held in August 1994 to obtain consensus on recommendations. There were no major disputes about the content. The guidelines are intended to optimise health care of society as a whole and are not geared to individual patients. BENEFITS, HARMS AND COSTS: Up to 20% of victims of hip fracture die within 1 year and less than 50% ever regain the functional capability to lead an independent life. The cost of acute fracture care in the USA exceeded $10 billion in 1990. Early intervention has been shown to reduce the rate of vertebral and hip fractures by 50 - 70%. The cost of fracture care and of selected screening has not been measured in this country. Measurement of bone mass is safe, accurate and precise. RECOMMENDATIONS: (i) Measurement of bone mass employing dual-energy X-ray absorptiometry (DEXA) is at present the method of choice to predict hip and vertebral fracture risk. A single measurement can correctly identify the majority of those at risk. (ii) Densitometric screening of all (asymptomatic) women cannot be recommended, and selective screening according to specific indications is suggested. Densitometry is indicated at any age if the indication is valid. (iii) Guidelines for the interpretation of bone mass data, including therapeutic intervention thresholds, are suggested.

S Afr Med J. 1996 Sep;86(9):1113-6

Detection of coronary artery disease in asymptomatic patients with type 2 diabetes mellitus.

In type 2 diabetes mellitus (DM2) patients, coronary artery disease (CAD) generally is detected in an advanced stage, whereas an asymptomatic stage is commonly missed. Abnormal myocardial perfusion during stress myocardial contrast echocardiography (MCE) and significant CAD were similar, irrespective of risk factor (RF) profile in our patients, but coronary anatomy differed. An “aggressive” diagnostic approach, requiring coronary angiography in asymptomatic DM2 patients with < or = 1 associated RF for CAD and abnormal MCE, identified silent CAD, characterized by a more favorable angiographic anatomy. The criterion of > or = 2 RFs did not help to identify patients with a higher prevalence of CAD and is only related to a more severe coronary atherosclerosis with unfavorable anatomy.OBJECTIVES: We sought to verify the effectiveness of current American Diabetes Association screening guidelines in identifying asymptomatic patients with coronary artery disease (CAD) in type 2 diabetes mellitus (DM2). BACKGROUND: In DM2 patients, CAD generally is detected in an advanced stage with an extensive atherosclerosis and poor outcome, whereas CAD in an asymptomatic stage is commonly missed. METHODS: This study included 1,899 asymptomatic DM2 patients (age < or = 60 years). Of these, 1,121 had > or = 2 associated risk factors (RFs), group A, and the remaining 778 had < or = 1 RF, group B, for CAD. All patients underwent dipyridamole myocardial contrast echocardiography (MCE), and in those with myocardial perfusion defects, the anatomy of coronary vessels was analyzed by selective coronary angiography. RESULTS: In the two study groups, the prevalence of abnormal MCE (59.4% vs. 60%, p = 0.96) and of a significant CAD (64.6% vs. 65.5%, p = 0.92) was similar, irrespective of RF profile. But coronary anatomy differed: group B had a lower prevalence of three-vessel disease (7.6% vs. 33.3%, p < 0.001), of diffuse disease (18.0% vs. 54.9%, p < 0.001), and of vessel occlusion (3.8% vs. 31.2%, p < 0.001), whereas one-vessel disease was more frequent (70.6% vs. 46.3%, p < 0.001). Coronary anatomy did not allow any revascularization procedure in 45% of group A patients. CONCLUSIONS: An “aggressive” diagnostic approach, requiring coronary angiography in asymptomatic DM2 patients with < or =1 associated RF for CAD and abnormal MCE, identified patients with a subclinical CAD characterized by a more favorable angiographic anatomy. The criterion of > or =2 RFs did not help to identify asymptomatic patients with a higher prevalence of CAD and is only related to a more severe CAD with unfavorable coronary anatomy.

J Am Coll Cardiol. 2006 Jan 3;47(1):65-71

Electrophysiological markers of rapid cognitive decline in mild cognitive impairment.

Electroencephalography (EEG) is an easily accessible and low-cost modality that might prove to be a particularly powerful tool for the identification of subtle functional changes preceding structural or metabolic deficits in progressive mild cognitive impairment (PMCI). Most previous contributions in this field assessed quantitative EEG differences between healthy controls, MCI and Alzheimer’s disease(AD) cases leading to contradictory data. In terms of MCI conversion to AD, certain longitudinal studies proposed various quantitative EEG parameters for an a priori distinction between PMCI and stable MCI. However, cross-sectional comparisons revealed a substantial overlap in these parameters between MCI patients and elderly controls. Methodological differences including variable clinical definition of MCI cases and substantial interindividual differences within the MCI group could partly explain these discrepancies. Most importantly, EEG measurements without cognitive demand in both cross-sectional and longitudinal designs have demonstrated limited sensitivity and generally do not produce significant group differences in spectral EEG parameters. Since the evolution of AD is characterized by the progressive loss of functional connectivity within neocortical association areas, event-modulated EEG dynamic analysis which makes it possible to investigate the functional activation of neocortical circuits may represent a more sensitive method to identify early alterations of neuronal networks predictive of AD development among MCI cases. The present review summarizes clinically significant results of EEG activation studies in this field and discusses future perspectives of research aiming to reach an early and individual prediction of cognitive decline in healthy elderly controls.

Front Neurol Neurosci. 2009;24:39-46

Quantitative EEG in early Alzheimer’s disease patients - power spectrum and complexity features.

The goal of this study was to investigate the EEG signs of early stage Alzheimer’s disease (AD) by conventional analyses and by methods quantifying linear and nonlinear EEG-complexity. The EEG was recorded in 12 mild AD patients and in an age-matched healthy control group (24 subjects) in both eyes open and eyes closed conditions. Frequency spectra, Omega-complexity and Synchronization likelihood were calculated on the data. In the patients a significant decrease of the relative alpha and increase of the theta power were found. Remarkably increased Omega-complexity and lower Synchronization likelihood were observed in AD in the 0.5-25 Hz frequency ranges. It is concluded that both spectral- and EEG-complexity changes can be found already in the early stage of AD in a wide frequency range. Application of conventional EEG analysis methods in combination with quantification of EEG-complexity may improve the chances of early diagnosis of AD.

Int J Psychophysiol. 2008 Apr;68(1):75-80

Abnormal EEG complexity in patients with schizophrenia and depression.

OBJECTIVE: Schizophrenics are usually unable to perform well on cognitive tasks due to disturbances in cortical information processing that are observable as abnormalities in electroencephalogram (EEG) signals. However, whether such cortical disturbances can be assessed by quantitative EEG analysis remains unclear. The purpose of this study was to characterize EEG disturbances, using the Lempel-Ziv complexity (LZC), in the subjects with schizophrenia at rest or while performing mental arithmetic tasks. The results were compared to those from the subjects with depression and with healthy controls. METHODS: The subjects included 62 schizophrenia patients, 48 depression patients and 26 age-matched healthy controls. EEG was recorded under two conditions: (i) resting with eyes closed, and (ii) a mentally active condition wherein the subjects were asked to subtract 7 from 100 iteratively with their eyes closed. EEG signals were analyzed by LZC and conventional spectral methods. RESULTS: In all the groups, LZC of EEG decreased during the mental arithmetic compared with those under the resting conditions. Both the schizophrenia and the depression groups had a higher LZC (p<0.05) than the controls. Also, the schizophrenia group had a lower LZC (p<0.05) than the depression group during the mental arithmetic task as well as during the resting state. Significant differences in LZC, at some symmetrically located loci (FP1/FP2, F7/F8), between the two hemispheres were found in all the patient groups only during the arithmetic task. CONCLUSIONS: Compared with conventional spectral analysis, LZC was more sensitive to both the power spectrum and the temporal amplitude distribution. LZC was associated with the ability to attend to the task and adapt the information processing system to the cognitive challenge. Thus, it would be useful in studying the disturbances in the cortical information processing patients with depression or schizophrenia. SIGNIFICANCE: LZC of EEG is associated with mental activity. Thus, LZC analysis can be an important tool in understanding the pathophysiology of schizophrenia and depression in future studies.

Clin Neurophysiol. 2008 Jun;119(6):1232-41

Application of electroencephalography to the study of cognitive and brain functions in schizophrenia.

The electroencephalogram (EEG) recorded from the human scalp is widely used to study cognitive and brain functions in schizophrenia. Current research efforts are primarily devoted to the assessment of event-related potentials (ERPs) and event-related oscillations (EROs), extracted from the ongoing EEG, in patients with schizophrenia and in clinically unaffected individuals who, due to their family history and current mental status, are at high risk for developing schizophrenia. In this article, we discuss the potential usefulness of ERPs and EROs as genetic vulnerability markers, as pathophysiological markers, and as markers of possible ongoing progressive cognitive and cortical deterioration in schizophrenia. Our main purpose is to illustrate that these neurophysiological measures can offer valuable quantitative biological markers of basic pathophysiological mechanisms and cognitive dysfunctions in schizophrenia, yet they may not be specific to current psychiatry’s diagnosis and classification. These biological markers can provide unique information on the nature and extent of cognitive and brain dysfunction in schizophrenia. Moreover, they can be utilized to gain deeper theoretical insights into illness etiology and pathophysiology and may lead to improvements in early detection and more effective and targeted treatment of schizophrenia. We conclude by addressing several key methodological, conceptual, and interpretative issues involved in this research field and by suggesting future research directions.

Schizophr Bull. 2007 Jul;33(4):955-70

The value of quantitative electroencephalography in clinical psychiatry: a report by the Committee on Research of the American Neuropsychiatric Association.

The authors evaluate quantitative electroencephalography (qEEG) as a laboratory test in clinical psychiatry and describe specific techniques, including visual analysis, spectral analysis, univariate comparisons to normative healthy databases, multivariate comparisons to normative healthy and clinical databases, and advanced techniques that hold clinical promise. Controversial aspects of each technique are discussed, as are broader areas of criticism, such as commercial interests and standards of evidence. The published literature is selectively reviewed, and qEEG’s applicability is assessed for disorders of childhood (learning and attentional disorders), dementia, mood disorders, anxiety, panic, obsessive-compulsive disorder, and schizophrenia. Emphasis is placed primarily on studies that use qEEG to aid in clinical diagnosis, and secondarily on studies that use qEEG to predict medication response or clinical course. Methodological problems are highlighted, the availability of large databases is discussed, and specific recommendations are made for further research and development. As a clinical laboratory test, qEEG’s cautious use is recommended in attentional and learning disabilities of childhood, and in mood and dementing disorders of adulthood.

J Neuropsychiatry Clin Neurosci. 2006 Fall;18(4):460-500

Is C-reactive protein specific for vascular disease in women?

BACKGROUND: C-reactive protein (CRP) predicts risk for future cardiovascular events in asymptomatic individuals. However, because CRP also predicts total mortality, its specificity for vascular disease is uncertain. OBJECTIVE: To compare the predictive value of CRP for cancer and cardiovascular disease, the major determinants of mortality. DESIGN: Prospective, nested case-control study. SETTING: The Women’s Health Study, an ongoing prospective cohort study involving 2,8345 US women 45 years of age and older who were healthy at the time of enrollment. PARTICIPANTS: 643 women who subsequently developed cancer or had cardiovascular events; 643 age- and smoking-matched women who remained free of either disease during 58-month follow-up. MEASUREMENTS: Baseline CRP levels. RESULTS: Little evidence showed that increasing quartiles of baseline CRP predicted incident cancer (adjusted relative risks, 1.0, 1.2, 1.1, and 1.3; P for trend > 0.2). In contrast, increasing quartiles of baseline CRP were a strong marker of risk for future cardiovascular disease (adjusted relative risks, 1.0, 2.9, 3.4, and 5.6; P for trend < 0.001). CONCLUSION: C-reactive protein appears to independently predict cardiovascular events but not cancer.

Ann Intern Med. 2002 Apr 2;136(7):529-33

Abdominal obesity: a health threat

Abdominal obesity is often associated with a constellation of comorbidities that include central adiposity, insulin resistance, dyslipidemia, and hypertension. Clinical evaluations should include a measurement of waist circumference, which is a good marker of abdominal obesity. Abdominal obesity is closely associated with an elevated outflow of free fatty acids from the visceral fat compartment and dysregulation of adipokine expression, accompanied by increased inflammation. The most serious consequences of abdominal obesity are coronary heart disease and stroke. It is also associated, however, with polycystic ovary syndrome and hepatic steatosis. Weight reduction and increased physical activity should be recommended to patients with a high waist circumference. Patients with abdominal obesity and other classic risk factors are at high cardiovascular risk and require strict monitoring of their blood pressure, LDL-c, and blood glucose. New pharmacological strategies might help manage both abdominal obesity and its metabolic consequences.

Presse Med. 2008 Oct;37(10):1407-14

Testosterone and coronary artery disease.

The strongest independent risk factors for coronary artery disease (CAD) are increasing age and male gender. Whilst a wide variation in CAD mortality exists between countries, a male to female ratio of approximately 2:1 is consistently observed. These observations have led to the assumption that testosterone may exert a detrimental influence on the cardiovascular system. Despite this, coronary atherosclerosis increases with age, whilst a marked fall in serum bioavailable testosterone levels is observed. Similarly, low testosterone levels are also associated with other cardiovascular risk factors and increased expression of mediators of the atherosclerotic process. This in itself suggests that testosterone does not promote atheroma formation. Moreover, epidemiological studies show an inverse relationship between testosterone levels and surrogate markers of atherosclerosis, which suggests that it may be a testosterone deficient state, rather than male sex which is associated with CAD. In cholesterol-fed animal models, atherosclerosis is accelerated by castration and reduced after testosterone replacement therapy. Testosterone has also been shown to improve myocardial ischemia in men with angina pectoris. Consequently, increasing evidence suggests that the process of atherosclerosis is beneficially modulated by testosterone. These studies are the focus of this chapter.

Front Horm Res. 2009;37:91-107

Serum DHEA-S level is associated with the presence of atherosclerosis in postmenopausal women with type 2 diabetes mellitus.

We investigated the relationship between serum dehydroepiandrosterone-sulfate (DHEA-S) and insulin-like growth factor-I (IGF-I) to various parameters for atherosclerosis in type 2 diabetes. The levels of DHEA-S and IGF-I are known to decrease with aging and thereby might be associated with an increased risk of cardiovascular disease. One hundred forty-eight men and 106 postmenopausal women with type 2 diabetes were assessed in a cross-sectional study. Serum DHEA-S and IGF-I concentrations were measured and brachial-ankle pulse wave velocity (baPWV) and ultrasonographically-evaluated intima-media thickness (IMT) were assessed. Although simple regression analysis showed that log(DHEA-S) and IGF-I in men and log(DHEA-S) in women were significantly and inversely correlated with baPWV and IMT, only log(DHEA-S) in women was still significantly and inversely correlated with these atherosclerotic parameters after multiple regression analysis was adjusted for age, duration of diabetes, BMI, HbA(1C), systolic blood pressure, LDL-Cholesterol (C), serum creatinine, and smoking (Brinkman index). Serum DHEA-S level seemed to be associated with atherosclerosis in diabetic postmenopausal women independent of age, body stature, diabetic status, and other atherosclerotic risk factors, and might be a useful addition to other parameters for assessing the risk of atherosclerosis in this population.

Endocr J. 2008 Aug;55(4):667-75

Anabolic deficiency in men with chronic heart failure: prevalence and detrimental impact on survival.

BACKGROUND: The age-related decline of circulating anabolic hormones in men is associated with increased morbidity and mortality. We studied the prevalence and prognostic consequences of deficiencies in circulating total testosterone (TT) and free testosterone, dehydroepiandrosterone sulfate (DHEAS), and insulin-like growth factor-1 (IGF-1) in men with chronic heart failure (CHF). METHODS AND RESULTS: Serum levels of TT, DHEAS, and IGF-1 were measured with immunoassays in 208 men with CHF (median age 63 years; median left ventricular ejection fraction 33%; New York Heart Association class I/II/III/IV, 19/102/70/17) and in 366 healthy men. Serum levels of free testosterone were estimated (eFT) from levels of TT and sex hormone binding globulin. Deficiencies in DHEAS, TT, eFT, and IGF-1, defined as serum levels at or below the 10th percentile of healthy peers, were seen across all age categories in men with CHF. DHEAS, TT, and eFT were inversely related to New York Heart Association class irrespective of cause (all P<0.01). DHEAS correlated positively with left ventricular ejection fraction and inversely with N-terminal pro-brain natriuretic peptide (both P<0.01). Circulating TT, eFT, DHEAS, and IGF-1 levels were prognostic markers in multivariable models when adjusted for established prognostic factors (all P<0.05). Men with CHF and normal levels of all anabolic hormones had the best 3-year survival rate (83%, 95% CI 67% to 98%) compared with those with deficiencies in 1 (74% survival rate, 95% CI 65% to 84%), 2 (55% survival rate, 95% CI 45% to 66%), or all 3 (27% survival rate, 95% CI 5% to 49%) anabolic endocrine axes (P<0.0001). CONCLUSIONS: In male CHF patients, anabolic hormone depletion is common, and a deficiency of each anabolic hormone is an independent marker of poor prognosis. Deficiency of >1 anabolic hormone identifies groups with a higher mortality.

Circulation. 2006 Oct 24;114(17):1829-37

Niacin for stroke prevention: evidence and rationale.

Low levels of high-density lipoprotein (HDL) cholesterol are associated with increased atherothrombotic events, including stroke. Niacin is a safe and effective means of raising HDL, yet its role in stroke prevention is not well characterized. The purpose of the study is to determine the role of niacin in stroke prevention. A search of the PUBMED database using the keywords niacin, stroke, atherosclerosis, and/or carotid artery was undertaken to identify studies for review. National guidelines from the American Heart Association and National Cholesterol Education Program were reviewed. Treatment of low serum HDL (<40 mg/dL) is an identified goal of dyslipidemic therapy. Niacin is effective in raising HDL levels and reducing cardiovascular events in individuals with high vascular risk and can be used for treatment of stroke patients with low serum HDL. Niacin can be used safely in combination with statins, the first-line dyslipidemic treatment for secondary stroke risk reduction, with increased efficacy. Studies are needed to better define the role for niacin in secondary stroke prevention. Treatment of stroke patients with extended-release (ER) of niacin, alone or in combination with statins, should be considered in stroke patients with atherosclerotic mechanisms with low serum HDL-C levels.

CNS Neurosci Ther. 2008 Winter;14(4):287-94

Taurine depletion caused by knocking out the taurine transporter gene leads to cardiomyopathy with cardiac atrophy.

The sulfur-containing beta-amino acid, taurine, is the most abundant free amino acid in cardiac and skeletal muscle. Although its physiological function has not been established, it is thought to play an important role in ion movement, calcium handling, osmoregulation and cytoprotection. To begin examining the physiological function of taurine, we generated taurine transporter- (TauT-) knockout mice (TauTKO), which exhibited a deficiency in myocardial and skeletal muscle taurine content compared with their wild-type littermates. The TauTKO heart underwent ventricular remodeling, characterized by reductions in ventricular wall thickness and cardiac atrophy accompanied with the smaller cardiomyocytes. Associated with the structural changes in the heart was a reduction in cardiac output and increased expression of heart cardiac failure (fetal) marker genes, such as ANP, BNP and beta-MHC. Moreover, ultrastructural damage to the myofilaments and mitochondria was observed. Further, the skeletal muscle of the TauTKO mice also exhibited decreased cell volume, structural defects and a reduction of exercise endurance capacity. Importantly, the expression of Hsp70, ATA2 and S100A4, which are upregulated by osmotic stress, was elevated in both heart and skeletal muscle of the TauTKO mice. Taurine depletion causes cardiomyocyte atrophy, mitochondrial and myofiber damage and cardiac dysfunction, effects likely related to the actions of taurine. Our data suggest that multiple actions of taurine, including osmoregulation, regulation of mitochondrial protein expression and inhibition of apoptosis, collectively ensure proper maintenance of cardiac and skeletal muscular structure and function.

J Mol Cell Cardiol. 2008 May;44(5):927-37

Melatonin in combined therapy of patients with stable angina and arterial hypertension

Study of 2 randomized groups of patients with coronary heart disease, stable exertional angina combined with arterial hypertension, receiving traditional treatment and combined therapy with inclusion of melatonin, was performed. All patients (43 persons at the age from 44 to 69 years) before and after treatment underwent daily monitoring of arterial pressure (AP) by system “BR-102 Schiller”, Switzerland. As a result of study, in the group of traditional treatment positive dynamics such as significant decrease in average daily values of systolic arterial pressure (SAP) from 159.7 +/- 3.4 to 146.1 +/- 4.6 (p = 0.02), diastolic arterial pressure (DAP) from 92.7 +/- 1.2 to 88.6 +/- 1.3 (p = 0.03), average daytime AP indices, average nighttime SAP indices, was noticed. SAP and DAP variability was significantly decreased only at daytime from 23.1 +/- 1.7 to 18.8 +/- 1.4 (p = 0.05) and from 18.1 +/- 0.5 to 16.5 +/- 0.4 respectively. Insufficient decrease in SAP and DAP at nighttime was detected. Inclusion of melatonin in traditional therapy leaded to more expressed decrease in average daily, daytime and nighttime AP indices and significant decrease in load by pressure value (SAP and DAP time indices were significantly reduced both at daytime and at nighttime). Degree of SAP and DAP nighttime decrease initially was upon the average 8.1 +/- 1.1% and 7.0 +/- 1.0% respectively (non-dippers), and after combined treatment was 13.4 +/- 0.9% (p = 0.003) and 11.0 +/- 1.1% (dippers), which proved recovery of normal daily AP profile. Significant decrease in SAP variability at daytime from 22.3 +/- 1.8 to 15.1 +/- 1.2 (p = 0.003), at nighttime from 16.1 +/- 1.4 to 12.7 +/- 1.0 (p = 0.05) in DAP variability at daytime from 17.5 +/- 0.4 to 14.5 +/- 0.4 (p < 0.001), at nighttime from 13.1 +/- 0.7 to 11.1 +/- 0.7 (p = 0.05).

Klin Med (Mosk). 2008;86(9):64-7