Matrix metalloproteinases.

Remodeling of extracellular matrix is crucial for many physiological (cell migration, proliferation, growth, and development) and pathological (remodeling of heart, carcinogenesis, metastasis, etc.) events. Thus, the interaction between cells and extracellular matrix plays a key role in normal development and differentiation of organism and many pathological states as well. Changes in extracellular matrix are regulated by a system of proteolytic enzymes that are responsible for proteolysis of huge quantity of extracellular matrix components. Matrix metalloproteinases (MMPs) represent the main group of regulating proteases in ECM. Ability of matrix metalloproteinases to modify the structural integrity of tissues is essential for certain aspects of normal physiology and pathology. The ability to process molecules such as growth factors, receptors, adhesion molecules, other proteinases, and proteinase inhibitors makes MMPs potent controllers of physiological and pathological events in the cell microenvironment. Overactivation of MMPs has been implicated in numerous disease states.

Matrix metalloproteinases and their role in oncogenesis: a review.

The extracellular matrix (ECM) provides a physical framework for the cells and functions as a gel medium. Remodeling of the ECM is crucial during physiological cell migration, proliferation, growth, and development. Thus, the interaction between cells and the ECM plays a key role in normal development and differentiation of organisms. However, remodeling of the ECM also occurs in many pathological states. Changes in the ECM are regulated by a system of proteolytic enzymes that are responsible for the proteolysis of a huge quantity of ECM components. Matrix metalloproteinases (MMPs) represent the main group of regulating proteases in the ECM. By regulating the composition and integrity of the ECM, this group of enzymes is essential for cell proliferation, differentiation, and processes of apoptosis. However, deregulation or activation of MMP expression is a feature of numerous pathologic conditions including tumorigenesis and metastasis. The aim of this article is to provide a brief overview of MMPs, their nomenclature and structure, and their role in the development of tumors and metastases.

Maternal autoimmune thyroiditis and congenital malformations of newborns in a cohort of Slovak women.

BACKGROUND: Aim of this study was to compare the thyroidal status of mothers to children with and without congenital malformations (CM). METHODS: We examined 129 mothers of newborns with CM and 228 mothers without CM. The assessment included particular history, physical examination, thyroid ultrasonography, fT4, TSH, and anti-TPO measurement of mothers and comparison to birth proportions of newborns. RESULTS: The total volume of the thyroid gland and anti-TPO levels were significantly higher in mothers of the group with CM (p < 0.001 and p < 0.01, respectively). The birth weight and length were significantly lower in the group with congenital malformation when compared to controls (p < 0.0001 and p < 0.001, respectively). CONCLUSIONS: Based on the results of our study, we suggest that thyroid diseases of a mother might participate in congenital malformations of their newborn, although no direct association between thyroid autoantibodies and congenital malformations has been described as of yet.

Tobacco consumption in relation to causes of death in an urban population of north India.

BACKGROUND: Noncommunicable diseases have become a public heath problem in India concomitant with economic development, leading to increases in tobacco consumption, obesity, and changes in diet and lifestyle. Although observation suggests that tobacco consumption is a major risk factor for deaths due to circulatory, pulmonary, and malignant diseases, such studies are not available from most populations in developing countries. SUBJECTS AND METHODS: For the period 1999-2001, we studied the randomly selected records of death of 2222 (1385 men and 837 women) decedents, aged 25-64 years, out of 3034 death records overall from the records at Municipal Corporation, Moradabad. All the families of these deceased could be contacted individually to find out the causes of death, by scientist/doctor administered, informed consented, verbal autopsy questionnaire, completed with the help of the spouse and local treating doctor practicing in the appropriate healthcare region. Social classes and tobacco intakes were assessed by a questionnaire. RESULTS: The prevalence of tobacco consumption, including chewing + smoking, were 45% (n = 623) among men and 15% (n = 125) among women decedents. However, smoking was observed in 20% and tobacco chewing in 30% of male decedents, while only 6% of female decedents smoked and 10% chewed tobacco. Social class had no impact on tobacco consumption in men but did influence one subgroup >55 years among women, ie, among those who had the highest tobacco consumption. Tobacco intakes were significantly more common among decedents dying due to circulatory, malignant, and pulmonary diseases, compared with other causes (men 61.1%, 76.6%, pulmonary 77.3% vs 31%, P < 0.001; women 27.5%, 75.9%, pulmonary 24.6% vs 0.42%, P < 0.001) of mortality, respectively. Pulmonary causes included chronic bronchitis and asthma. Circulatory diseases (29.1%, n = 646) including heart attacks (10.0%), stroke (7.8%), valvular heart disease (7.2%, n = 160), sudden cardiac death and inflammatory cardiac disease, each (2.0%, n = 44) were the second most common causes of deaths, after infections (41.1%, n = 915). Malignant neoplasm (5.8%, n = 131), injury (14.0%, n = 313), and miscellaneous causes of deaths, including diabetes mellitus (2.2%, n = 49) were noted in 9.1%, (n = 202) of death records. Cancers of the lung (1.6%), oral cavity (1.5%), liver (1.1%), stomach (0.9%), breast (0.31%), uterus, cervix, and ovary (0.27%) were relatively common causes for deaths due to malignancy. CONCLUSIONS: This study shows that tobacco consumption appears to be a major contributor to deaths due to circulatory diseases and malignant diseases in India. Social class status had little impact on tobacco consumption in male decedents. Rapid changes in diet and lifestyle, increases in tobacco consumption, and possibly aging of the population, appear to be strongly associated with mortality due to cardiovascular diseases and cancer in this middle-income country.

Effect of carni Q-gel (ubiquinol and carnitine) on cytokines in patients with heart failure in the Tishcon study.

INTRODUCTION: There is evidence that both carnitine and coenzyme Q 10 (Co Q), which are important for the functioning of myocardial mitochondria, are deficient in patients with congestive heart failure, in association with increased pro-inflammatory cytokines. It is possible that supplementation with ubiquinol and L-carnitine may protect these patients by decreasing inflammation. SUBJECTS AND METHODS: In a randomized, double-blind, placebo-controlled trial, the effects of carni Q-gel (2250 mg/d L-carnitine and 270 mg/d hydrosoluble ubiquinol) were examined for 12 weeks. Thirty-one patients with heart failure received intervention (group A) and another 31 patients served as controls (group B). Serum levels of interleukin (IL)-6, tumour necrosis factor (TNF)-alpha and IL-10 could be studied among 29 patients in each group. Statistical analysis was conducted by analysis of variance and chi square test. RESULTS: Echocardiographic ejection fractions were lower at baseline (38.8 + 7.6 vs. 39.3 + 6.7% in the intervention and control groups, respectively) among both group of patients, indicating class II-IV heart failure. Serum concentration of interleukin-6 (IL-6), a pro-inflammatory cytokine, was high (18.7 +/- 5.8 vs. 15.0 +/- 3.3 pg/ml, normal 0.0-3.9) and IL-10 (anti-inflammatory) was normal (3.4 +/- 1.5 vs. 2.9 +/- 1.0 pg/ml, the normal range is 1.5-3.1 pg/ml) in both groups at baseline. After 12 weeks, there was a marked reduction in IL-6 in the intervention group without such changes in the control group (7.6 +/- 1.5 vs. 11.4 +/- 2.5 pg/ml, P < 0.01. IL-10 showed only the non-significant decrease in both groups from the baseline levels (3.2 +/- 1.0 vs. 2.8 +/- 0.9 pg/ml). TNF-alpha, which was comparable at baseline (17.6 +/- 4.3 vs. 20.0 +/- 5.3 pg/ml), also showed a greater decline in the carni Q-gel group compared to the placebo group (12.5 +/- 3.3 vs. 17.2 +/- 3.2 pg/ml, P < 0.05). Baseline serum CoQ levels (0.21 +/- 0.11 vs. 0.19 +/- 0.10 microg/ml) were low; however, after 12 weeks, serum CoQ showed a significant increase in the carni Q-gel group as compared to the control group (2.7 +/- 1.2 and 0.76 +/- 0.14 microg/ml, respectively). After 12 weeks of treatment, the quality of life visual analogous scale revealed that dyspnoea, palpitation and fatigue, (NYHA class II-III-IV), which were present at rest in all patients at baseline, showed beneficial effects in the intervention group compared to the placebo group. The six-minute walk test showed that there was a significant greater benefit in walking, from the baseline distance in the intervention group (208 +/- 15.8 vs. 281 +/- 20.6 metres, P < 0.02) compared to the placebo group (218.4 +/- 17.6 vs. 260.7 +/- 19.3 metres, P < 0.05). The symptom scale indicated that the majority of patients showed improvement in the intervention group compared to the control group (28 vs. 16 patients, respectively, P < 0.05). Three patients in the intervention group had nausea and vomiting, which were controlled with symptomatic treatment. CONCLUSIONS: These findings indicate that treatment with ubiquinol + L-carnitine can cause a significant reduction in the pro-inflammatory cytokines that are neurohumoural precursors related to sympathetic and parasympathetic activity, which is impaired in patients with heart failure. There was no adverse effect on IL-10. There was a significant improvement in quality of life as well as decrease in NYHA-defined heart failure.

Prevalence of obesity, physical inactivity and undernutrition, a triple burden of diseases during transition in a developing economy. The Five City Study Group.

OBJECTIVE AND DESIGN: The objective of the study was to find out the prevalence of overweight, obesity, undernutrition and physical activity status in the urban populations of India. Cross-sectional surveys were conducted in 6-12 urban streets in each of five cities in five different regions of India using a common study protocol and criteria of diagnosis. SUBJECTS AND METHODS: A total of 6940 subjects (3433 women and 3507 men) aged 25 years and above were randomly selected from the cities of Moradabad (n = 2002),Trivandrum (n = 1602), Calcutta (n = 900), Nagpur (n = 894) and Bombay (n = 1542). Evaluation and validation were performed by a physician and dietitian-administered questionnaire at Moradabad. After pooling of data, all subjects were divided into various age groups for men and women. Obesity (body mass index = 30 > kg/m(2)) and overweight (BMI 2 25-29.9 kg/m(2) and > 23 kg/m(2)) as well as waist-hip ratio (> 0.85 in women and > 0.88 in men, central obesity) were calculated and physical activity status assessed by a validated questionnaire. RESULTS: The overall prevalence of obesity was 6.8% (7.8 vs. 6.2%, P < 0.05) and overweight 33.5% (35.0 vs. 32.0%, P < 0.05) among women and men, respectively. The highest prevalence of obesity (7.8%) and overweight (36.9%) was found among subjects aged 35 to 44 years in both sexes. The prevalence of obesity was significantly (P < 0.05) greater in Trivandrum (8.5%), Calcutta (7. 1%) and Bombay (8.3%) compared to Moradabad (6.2%) among women and in Trivandrum (7.4%) and Bombay (7.2%), compared to Nagpur (5.0%) among men. There was a significant decreasing trend in obesity (P < 0.05) and overweight (P < 0.05) with increasing age above 35-44 years in both sexes. The overall prevalence of subjects > 23 kg/m(2) was 50.8% and central obesity 52.6%. The overall prevalence of sedentary behaviour was 59.3% among women and 58.5% among men. Both sedentary behaviour and mild activity showed a significant increasing trend in women after the age of 35-44 years. In men, such a trend was observed above the age of 45 years. Sedentary behaviour was significantly (P < 0.05) greater in Trivandrum, Calcutta, and Bombay compared to Nagpur. Sedentary behaviour was significantly (P < 0.001) associated with obesity in both sexes, compared to non-obese men and women. The overall prevalence of undernutrition was 5.5% (n = 380) which was significantly more common in Moradabad, north and Nagpur, central India compared to other cities. CONCLUSIONS: Obesity, overweight and central obesity and sedentary behaviour coexist with undernutrition, and have become a public health problem in all the five cities of India. The prevalence of obesity and sedentary behaviour was significantly greater in Trivandrum, Calcutta and Bombay compared to Moradabad and Nagpur. Sedentary behaviour was significantly associated with obesity compared to non-obese subjects in both sexes, which may be due to greater economic development in metro cities.

Can brain dysfunction be a predisposing factor for metabolic syndrome?

The various mechanisms that may explain the association between brain dysfunction and the pathogenesis of metabolic syndrome (MS) leading to cardiovascular disease and type 2 diabetes have been reviewed. A Medline search was conducted until September 2003, and articles published in various national and international journals were reviewed. Experts working in the field were also consulted. Compelling evidence was found that saturated and total fat and low dietary n-3 fatty acids and other long-chain polyunsaturated fatty acids (PUFAs) in conjunction with sedentary behavior and mental stress combined with various personality traits can enhance sympathetic activity and increase the secretion of catecholamine, cortisol and serotonin, all of which appear to be underlying mechanisms involved in MS. Excess secretion of these neurotransmitters in conjunction with underlying long-chain PUFA deficiency may damage the neurons in the ventromedial hypothalamus and insulin receptors in the brain, in particular during fetal life, infancy and childhood, and lead to their dysfunction. Since 30-50% of the fatty acids in the brain are long-chain PUFAs, especially omega-3 fatty acids which are incorporated in the cell membrane phospholipids, it is possible that their supplementation may have a protective effect. Omega-3 fatty acids are also known to enhance parasympathetic activity and to increase the secretion of anti-inflammatory cytokines as well as acetylecholine in the hippocampus. It is possible that a marginal deficiency of long-chain PUFAs, especially n-3 fatty acids, due to poor dietary intake during the critical period of brain growth and development in the fetus, and later in the infant and also possibly in the child, adolescent and adult may enhance the release of tumor necrosis factor-alpha (TNF-alpha) interleukin (IL)-1, 2 and 6 and cause neuronal dysfunction. Experimental studies indicate that ventromedial hypothalamic lesions in rats induce hyperphagia, resulting in glucose intolerance and insulin resistance. Treatment with neuropeptide Y abolished hyperphagia and ob mRNA (leptin mRNA) in this animal model. Long-term infusion of norepinephrine and serotonin into the ventromedial hypothalamus impaired pancreatic islet function inasmuch as ventromedial hypothalamic norepinephrine and serotonin levels were elevated in hyperinsulinemic and insulin-resistant animals. Treatment with insulin was associated with restoration of hypothalamic neurotransmitter abnormalities, indicating that ventromedial hypothalamus dysfunction can impair pancreatic beta cells resulting in metabolic abnormalities consistent with MS. Treatment with omega-3 fatty acids, beta blockers, ACE inhibitors, estrogen, and meditation may have a beneficial effect on insulin receptors and ventromedial hypothalamic dysfunction. However, no definite or precise insight into the pathophysiological link between MS, brain function and nutrition is available. Despite this, epidemiological studies and intervention trials indicate that treatment with n-3 fatty acids may be adopted in clinical practice and used to direct therapy for prevention of type 2 diabetes, hypertension, coronary artery disease (CAD), and atherosclerosis, thereby indicating that MS may also respond to this treatment.