NMCD is growing up: short thoughts on a teenager's life.
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Cardiovascular Diseases↗
Biomedical subjects
G Riccardi
Publications and source records attributed to G Riccardi.
The TB structural genomics consortium: a resource for Mycobacterium tuberculosis biology.
The TB Structural Genomics Consortium is an organization devoted to encouraging, coordinating, and facilitating the determination and analysis of structures of proteins from Mycobacterium tuberculosis. The Consortium members hope to work together with other M. tuberculosis researchers to identify M. tuberculosis proteins for which structural information could provide important biological information, to analyze and interpret structures of M. tuberculosis proteins, and to work collaboratively to test ideas about M. tuberculosis protein function that are suggested by structure or related to structural information. This review describes the TB Structural Genomics Consortium and some of the proteins for which the Consortium is in the progress of determining three-dimensional structures.
Amino Acid Sequence↗
Insulin sensitivity is increased and fat oxidation after a high-fat meal is reduced in normal-weight healthy men with strong familial predisposition to overweight.
OBJECTIVE: To evaluate whether postprandial abnormalities of energy expenditure and/or lipid oxidation are present in healthy, normal-weight subjects with a strong family history of obesity and thus at high risk to become obese. DESIGN: Case-control study. SUBJECTS: A total of 16 young healthy men participated in the study. Eight subjects had both parents overweight (father's and mother's body mass index (BMI) >25 kg/m(2)) and eight had both parents with normal body weight (father's and mother's BMI<25 kg/m(2), respectively). The group of subjects with overweight parents was similar to that with normal-weight parents (control group) in terms of BMI (23.7+/-1.7 vs 22.7+/-1.1 kg/m(2)) (M+/-s.d.) and fat-free body mass (FFM) (60.5+/-4.9 vs 58.4+/-2.0 kg), but was slightly older than the control group (25.4+/-3.3 vs 22.7+/-2.4 y; P<0.05). MEASUREMENTS: Energy expenditure (EE) was measured by indirect calorimetry, and blood samples were taken for the evaluation of metabolic variables in the fasting state and every hour for 8 h after a standard fat-rich meal (protein 15%, carbohydrate 34%, fat 51%, 4090 kJ). RESULTS: Fasting plasma glucose, cholesterol, HDL-cholesterol, triglyceride, free fatty acid (FFA) and leptin concentrations were similar in both groups of participants, but subjects with overweight parents has significantly lower plasma insulin concentrations (5.11+/-0.51 vs 7.07+/-1.56 microU/ml; P<0.007) and HOMA index of insulin resistance (1.1+/-0.1 vs 1.6+/-0.4; P<0.01). Postprandial plasma glucose, triglyceride, FFA and leptin concentrations were similar in the two groups, whereas insulin levels were significantly lower in the group with both parents overweight at 3, 5, 6, 7 and 8 h. Fasting and postprandial EE, and fasting lipid and carbohydrate oxidation were similar in both groups. On the contrary, postprandial carbohydrate oxidation (incremental area under curve) was significantly higher (196.25+/-94.75 vs 75.88+/-74.72 mg/kg FFM x 8 h; P<0.007) and that of lipid oxidation lower (90.93+/-80.32 vs 163.68+/-108.22 mg/kg FFM x 8 h; P<0.05) in the group of subjects with overweight parents. CONCLUSION: Normal-weight subjects with a strong family history of obesity present a reduced lipid oxidation in the postprandial period and a metabolic profile characterized by low plasma insulin levels and the HOMA index, which is compatible with increased insulin sensitivity. These metabolic characteristics may be considered as early predictors of weight gain and are probably genetically determined.
Adult↗
The role of modulation of GH/IGF-I axis in the development of diabetic proliferative retinopathy.
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Diabetic Retinopathy↗
Dietary fibre in treatment of diabetes: myth or reality?
Diabetes is a plurimetabolic disease characterised mainly by glucose metabolism abnormalities that lead to the development of acute and long-term complications. Long-term complications are rapidly increasing, which explains the higher mortality due to cardiovascular events in diabetic patients compared to the general population. A poor blood glucose control is known to be an important risk factor for the development of cardiovascular complications, and dietary fibre - particularly the soluble type - plays an important role in controlling plasma glucose concentrations and other risk factors associated with diabetes. Nevertheless, there are still some doubts as to whether it is possible to achieve, in free-living diabetic patients, good compliance to a high fibre diet without using fibre supplements or foods fortified with fibre, and whether the beneficial effects of this diet on blood glucose control, observed in acute or in medium-term studies, are clinically relevant also in the longterm. Recently, a wealth of convincing evidence has confirmed the hypothesis that, in diabetic patients, dietary fibre decreases postprandial plasma glucose, insulin and triglyceride concentrations, and has a clinically relevant hypocholesterolaemic effect. These data also show that: 1) it is possible to increase dietary fibre by consuming exclusively natural foods, with a satisfactory compliance in free-living diabetic patients also in the long-term, due to its minimal side-effects; and 2) the beneficial metabolic effects of dietary fibre are long-lasting and clinically relevant, as shown by the lower plasma glycosylated haemoglobin levels, reduced rate of hypoglycaemic episodes and improved cardiovascular profile both in type 1 and type 2 diabetic patients.
Blood Glucose↗
Fasting plasma free fatty acid concentrations and Pro12Ala polymorphism of the peroxisome proliferator-activated receptor (PPAR) gamma2 gene in healthy individuals.
BACKGROUND: The Pro12Ala polymorphism of the peroxisome proliferator-activated receptor (PPAR) gamma gene has been associated in some, but not all, studies with lower body mass index (BMI) and improved insulin sensitivity; how an altered transcriptional activity of PPARgamma2 could influence insulin sensitivity is currently unclear. The free fatty acids (FFAs) released from adipose tissue triglycerides via lipolysis are key mediators of impaired insulin sensitivity; however, no study has described the relationship of the Pro12Ala mutation with circulating levels of FFAs under physiological conditions. OBJECTIVE: To investigate in a population-based sample of Caucasians the relation of the Pro12Ala polymorphism with plasma concentrations of FFAs and other markers of lipid and glucose metabolism described as components of the insulin resistance syndrome. SUBJECTS: Four hundred and thirty-eight nondiabetic employees of the Italian Telephone Company, aged 35-65 years, randomly selected from a total population of 3900 participants in a company-sponsored health screening. MEASUREMENTS: The Pro12Ala polymorphism of the PPARgamma was studied together with plasma FFAs, insulin, glucose, triglycerides, high density lipoprotein (HDL) cholesterol, blood pressure and anthropometry. The Homeostatic Model Assessment (HOMA) index was calculated as a measure of insulin resistance. RESULTS: Carriers and noncarriers of the Pro12Ala polymorphism showed very similar circulating levels of FFA (0.46 +/- 0.2 vs. 0.47 +/- 0.2, NS); plasma glucose, triglycerides, HDL cholesterol and blood pressure were also similar in the two groups with or without the polymorphism. To allow for the possible confounding effect of obesity, a separate analysis was conducted in overweight (BMI > or = 25 kg/m(2)) and normal-weight people (BMI < 25 kg/m(2)). Circulating plasma FFA concentrations, as well as triglycerides, blood pressure and HOMA, were significantly higher in overweight than normal-weight, as expected, but no significant differences were detected between carriers and noncarriers of the Pro12Ala polymorphism within each BMI group (0.49 +/- 0.2 vs. 0.48 +/- 0.2, NS, and 0.44 +/- 0.2 vs. 0.47 +/- 0.2, NS, in overweight and normal-weight, respectively). The Pro12Ala polymorphism was also analysed across increasing quartiles of FFA concentrations and no relationship was observed between the frequency of the polymorphism and FFA values (overall chi2 = 0.48, NS). CONCLUSION: This study does not show any relationship between the Pro12Ala polymorphism of the PPARgamma gene and fasting FFAs in the general population. The possibility of a different handling of FFAs under different conditions (i.e. postprandial) cannot be excluded and remains to be explored.
Adult↗
Summary of the scientific conference on dietary fatty acids and cardiovascular health: conference summary from the nutrition committee of the American Heart Association.
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American Heart Association↗
Substituting dietary saturated for monounsaturated fat impairs insulin sensitivity in healthy men and women: The KANWU Study.
AIMS/HYPOTHESIS: The amount and quality of fat in the diet could be of importance for development of insulin resistance and related metabolic disorders. Our aim was to determine whether a change in dietary fat quality alone could alter insulin action in humans. METHODS: The KANWU study included 162 healthy subjects chosen at random to receive a controlled, isoenergetic diet for 3 months containing either a high proportion of saturated (SAFA diet) or monounsaturated (MUFA diet) fatty acids. Within each group there was a second assignment at random to supplements with fish oil (3.6 g n-3 fatty acids/d) or placebo. RESULTS: Insulin sensitivity was significantly impaired on the saturated fatty acid diet (-10%, p = 0.03) but did not change on the monounsaturated fatty acid diet (+2%, NS) (p = 0.05 for difference between diets). Insulin secretion was not affected. The addition of n-3 fatty acids influenced neither insulin sensitivity nor insulin secretion. The favourable effects of substituting a monounsaturated fatty acid diet for a saturated fatty acid diet on insulin sensitivity were only seen at a total fat intake below median (37E%). Here, insulin sensitivity was 12.5% lower and 8.8% higher on the saturated fatty acid diet and monounsaturated fatty acid diet respectively (p = 0.03). Low density lipoprotein cholesterol (LDL) increased on the saturated fatty acid diet (+4.1%, p < 0.01) but decreased on the monounsaturated fatty acid diet (MUFA) (-5.2, p < 0.001), whereas lipoprotein (a) [Lp(a)] increased on a monounsaturated fatty acid diet by 12% (p < 0.001). CONCLUSIONS/INTERPRETATION: A change of the proportions of dietary fatty acids, decreasing saturated fatty acid and increasing monounsaturated fatty acid, improves insulin sensitivity but has no effect on insulin secretion. A beneficial impact of the fat quality on insulin sensitivity is not seen in individuals with a high fat intake (> 37E%).
Adult↗
Effect of acute exogenous hyperinsulinaemia on very low density lipoprotein subfraction composition in normal subjects.
Subtle abnormalities of very-low-density lipoprotein (VLDL) composition and distribution seem to be associated with increased cardiovascular risk. The aims of this study were first, to evaluate whether hyperinsulinaemia per se is able to produce VLDL abnormalities and second, whether this occurs through a stimulation of lipolytic enzymes. Eight normal male volunteers, age 36 +/- 7 years (M +/- SD), body mass index (BMI) 26+/-3 kg m-2, underwent a 5-h euglycaemic hyperinsulinaemic clamp (1.2 mU insulin/kg b.w. min-1). Nine sex, age and BMI comparable subjects underwent control experiments (saline infusion). Three VLDL subfractions of decreasing size were isolated by density gradient ultracentrifugation; lipoprotein lipase (LPL) and hepatic lipase (HL) post-heparin plasma activities were determined by the 3H-labelled triolein method. Hyperinsulinaemia ( approximately 65 mU mL-1) produced the expected plasma free fatty acid suppression. Triglyceride levels were reduced in total VLDL (- 27 +/- 32% vs. + 38 +/- 52% after saline, P < 0.05) and in the larger VLDL (- 56 +/- 19 vs. + 34 +/- 38, P < 0.001). Moreover the relative contribution of the larger subfraction was decreased (- 39 +/- 15% vs. - 3 +/- 21%, P < 0.01), while the percentage of smaller particles was increased (+17 +/- 20 vs. - 9 +/- 22, P < 0.05). LPL and HL activities were decreased to the same degree during either insulin or saline infusion. Exogenous hyperinsulinaemia produced lipoprotein abnormalities partially similar to those previously shown in type 1 diabetic patients, indicating that these abnormalities may be secondary to insulin therapy.
Acute Disease↗
Characteristics of some wheat-based foods of the Italian diet in relation to their influence on postprandial glucose metabolism in patients with type 2 diabetes.
The present study was aimed at evaluating in patients with type 2 diabetes: (1) the glycaemic response to four starchy foods based on wheat, typical of the Italian diet; (2) the importance of some food characteristics in relation to their effects on postprandial glucose response. Seventeen patients with type 2 diabetes (eleven men and six women) participated in the study. All patients consumed, in random order and on alternate days, 50 g available carbohydrate provided by 90 g white bread and, according to a randomised procedure, an equivalent amount of carbohydrate provided by one (n 8) or two (n 9) of three other different test foods (g): pizza 85, potato dumplings 165, hard toasted bread 60. Foods had a similar nutrient composition. Plasma glucose response, measured for 180 min, was significantly lower after the potato dumplings than after white bread at 90 (P < 0.05), 120 (P < 0.01), and 150 (P < 0.05) min. No difference was observed in postprandial plasma insulin response after the various test foods. The percentage of starch hydrolysed after 5 h in vitro hydrolysis with alpha-amylase was about 30 % lower for potato dumplings than for the other foods. However, no differences in the resistant starch content, the rate of diffusion of simple sugars added to a dialysis tube containing the food, and the viscosity of digesta were observed among the test foods. Scanning electron microscopy of potato dumplings showed a compact structure compatible with impaired accessibility of starch to digestive enzymes. In conclusion, carbohydrate-rich foods typical of the Italian diet which are often consumed as an alternative to pasta dishes are not equivalent in terms of metabolic impact in diabetic patients. Due to their low blood glucose response, potato dumplings represent a valid alternative to other starchy foods in the diabetic diet. Food structure plays an important role in determining starch accessibility to digestion, thus influencing the postprandial blood glucose response.
Analysis of Variance↗
AHA scientific statement: summary of the Scientific Conference on Dietary Fatty Acids and Cardiovascular Health. Conference summary from the Nutrition Committee of the American Heart Association.
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American Heart Association↗
Transcriptional regulation of furA and katG upon oxidative stress in Mycobacterium smegmatis.
The DNA region upstream of katG in Mycobacterium smegmatis was cloned and sequenced. The furA gene, highly homologous to Mycobacterium tuberculosis furA, mapped in this region. The furA-katG organization appears to be conserved among several mycobacteria. The transcription pattern of furA and katG in M. smegmatis upon oxidative stress was analyzed by Northern blotting and primer extension. Although transcription of both furA and katG was induced upon oxidative stress, transcripts covering both genes could not be identified either by Northern blotting or by reverse transcriptase PCR. Specific transcripts and 5' ends were identified for furA and katG, respectively. By cloning M. smegmatis and M. tuberculosis DNA regions upstream of a reporter gene, we demonstrated the presence of two promoters, pfurA, located immediately upstream of the furA gene, and pkatG, located within the terminal part of the furA coding sequence. Transcription from pfurA was induced upon oxidative stress. A 23-bp sequence overlapping the pfurA -35 region is highly conserved among mycobacteria and streptomycetes and might be involved in controlling pfurA activity. Transcription from a cloned pkatG, lacking the upstream pfurA region, was not induced upon oxidative stress, suggesting a cis-acting regulatory role of this region.
Bacterial Proteins↗
Preprandial combination of lispro and NPH insulin improves overall blood glucose control in type 1 diabetic patients: a multicenter randomized crossover trial.
BACKGROUND AND AIM: While lispro insulin has been reported to lower postprandial blood glucose concentrations, less consistent effects have been shown for glycosylated hemoglobin (HbA1c) levels. Aim of this study was to determine whether pre-meal association of NPH, an intermediate-acting insulin, with lispro improves overall glycemic control in type 1 diabetic patients. METHODS AND RESULTS: Eighty-five type 1 diabetic patients were studied in a multicenter randomized comparative (human regular vs lispro insulin) crossover (3-month) study in which NPH insulin was given as a dinner or bedtime injection and at breakfast and lunch if necessary. The number of injections was kept constant: 42% and 58% of patients injected insulin 3 and 4 times per day, respectively. Fasting and preprandial blood glucose levels were similar, while postprandial levels improved after lispro compared to human regular insulin (breakfast: 8.28 +/- 2.39 vs 9.28 +/- 2.72 mmol/l; lunch: 8.33 +/- 2.67 vs 9.06 +/- 2.67 mmol/l, dinner: 8.06 +/- 2.72 vs 9.28 +/- 2.44 mmol/l, ANOVA: p = 0.003). HbA1c also improved after lispro: 8.1 +/- 0.9 vs 8.3 +/- 0.8%, p < 0.05. The rate of hypoglycemia was similar. Patients showed better acceptance of lispro treatment (p < 0.001). CONCLUSIONS: Lispro improves overall blood glucose control in type 1 diabetic patients without increasing the incidence of hypoglycemia. This can be achieved by an optimal combination of lispro insulin with NPH whenever the time intervals between meals are too long.
Adolescent↗
Contribution of the multidrug efflux pump LfrA to innate mycobacterial drug resistance.
Multidrug resistance (MDR) in bacteria has been associated with efflux pumps that export structurally unrelated compounds and decrease cytoplasmic drug accumulation. To investigate MDR in mycobacteria, we studied the Mycobacterium smegmatis mutant mc(2)11, which is resistant to doxorubicin, tetracycline, rhodamine, ethidium bromide and the hydrophilic fluoroquinolones. A genomic library constructed from this mutant was used to select clones conferring resistance to doxorubicin. Surprisingly, the clone selected encodes the efflux pump LfrA, which has been reported to confer resistance to hydrophilic fluoroquinolones, ethidium bromide, rhodamine, and acriflavine. To define the contribution of LfrA to the innate mycobacterial drug resistance and to the MDR phenotype in mc(2)11, the lfrA gene was disrupted in both the mc(2)11 mutant and the mc(2)155 wild-type parent. LfrA disruption of the wild-type strain decreased resistance to ethidium bromide and acriflavine, and increased accumulation of ethidium bromide. However, disruption of lfrA gene results only in a 2-fold decrease in minimal inhibitory concentrations (MICs) for ciprofloxacin, doxorubicin, rhodamine, and accumulation of [(14)C]ciprofloxacin was unchanged. LfrA disruption of the MDR strain mc(2)11 produced a similar phenotype. Thus, LfrA contributes significantly to the intrinsic MICs of M. smegmatis for ethidium bromide and acriflavine, but not for ciprofloxacin, doxorubicin or rhodamine.
Acriflavine↗
Photoproduction of straight phi(1020) mesons on the proton at large momentum transfer
The cross section for straight phi meson photoproduction on the proton has been measured for the first time up to a four-momentum transfer -t = 4 GeV2, using the CLAS detector at the Thomas Jefferson National Accelerator Facility. At low four-momentum transfer, the differential cross section is well described by Pomeron exchange. At large four-momentum transfer, above -t = 1.8 GeV2, the data support a model where the Pomeron is resolved into its simplest component, two gluons, which may couple to any quark in the proton and in the straight phi.
Journal Article↗
Mycobacterium tuberculosis H37Rv comparative gene-expression analysis in synthetic medium and human macrophage.
Mycobacteria are intracellular pathogens that survive and grow in host macrophages. Following phagocytosis, sustained intracellular bacterial growth depends on its ability to avoid destruction by macrophage-mediated host defences such as lysosomal enzymes, reactive oxygen and the reactive nitrogen intermediates. This suggests that the interaction between host cell and microbe is delicately balanced, and can be tipped in favour of either organism. The identification of Mycobacterium tuberculosis H37Rv (MTB) genes expressed within host cells would contribute greatly to the development of new strategies to fight tuberculosis. In the present study, we compared MTB gene expression in the course of intra- (human macrophages) and extracellular growth (Sauton's medium) to ascertain whether differences might occur between gene-expression patterns in the two habitats of replication. Using reverse-transcriptase polymerase chain reaction (RT-PCR) on a group of 14 MTB-Complex-specific genes, we found that MT10Sa (a small stable RNA), 35 kDa (unknown), ahpC (alkyl hydroperoxide reductase, AhpC), sigF (alternative RNA Polymerase sigma factor), and katG (catalase-peroxidase, HPI) genes are expressed in both the environments, while Ag85B, Ag85C (members of the Antigen 85 Complex), rpoV (RNA Polymerase sigma factor) and ESAT6 (early secretory antigen, 6 kDa) are expressed only in the in vitro culture; on the other hand, Ag85A (Antigen 85 Complex), rpoB (RNA Polymerase beta sub-unit), pab (Protein antigen b), invA and invB genes (encoding proteins that show homologies with p60 of Listeria monocytogenes) are expressed only inside the macrophage. Positive RT-PCR products on cDNAs for these genomic regions were not obtained from approximately 1000-fold more bacteria grown in Laboratory Broth. Identification of M. tuberculosis genes expressed in response to phagocytosis by human macrophages increases our basic understanding of the host-pathogen interaction, and helps to identify bacterial factors necessary for in vivo survival and growth.
Colony Count, Microbial↗
Beta-blockade therapy in chronic heart failure: diastolic function and mitral regurgitation improvement by carvedilol.
BACKGROUND: In patients with chronic heart failure, the use of carvedilol therapy induces clinical and hemodynamic improvement. However, although the benefits of this beta-blocker have been established in patients with chronic heart failure, the mechanisms underlying them and the changes in left ventricular systolic function, diastolic function, and mitral regurgitation during long-term therapy remain unclear. OBJECTIVE: To identify the clinical and functional effects of carvedilol, focusing on diastolic function and mitral regurgitation variations. METHODS: Forty-five consecutive patients with chronic heart failure (ejection fraction 24% +/- 7%), 17 with dilated ischemic and 28 with nonischemic cardiomyopathy, were treated with carvedilol (mean dose 44 +/- 30 mg) and matched for clinical (New York Heart Association functional class and heart failure duration) and hemodynamic (cardiac index and pulmonary wedge pressure) characteristics to a control group. Clinical and echocardiographic variables were measured in the 2 groups at baseline and after 6 months and the results compared. RESULTS: After 6 months of treatment with carvedilol, left ventricular ejection fraction had increased from 24% +/- 7% to 29% +/- 9% (P <.0001); this change was caused by a reduction in end-systolic volume index (106 +/- 41 vs 93 +/- 37 mL/m(2); P <. 0001). Deceleration time of early diastolic filling increased (134 +/- 74 vs 196 +/- 63 ms; P <.0001). Seventeen of the 27 patients with demonstrated improvement of left ventricular diastolic filling moved from having a restrictive filling pattern to having a normal or pseudonormal left ventricular filling pattern. In the control group, no significant changes in deceleration time of early diastolic filling were found (139 +/- 74 vs 132 +/- 45 ms; P = not significant). The effective regurgitant orifice area decreased significantly in the carvedilol group but not in the control group. These changes were associated with a significant reduction of the mitral regurgitant stroke volume in the carvedilol group (50 +/- 25 vs 16 +/- 13 mL; P <.0001) but not in the control group (57 +/- 29 vs 47 +/- 24 mL; P = not significant). These changes of mitral regurgitation were closely associated with significant improvement of forward aortic stroke volume (r = -.57, P <.0001). These findings were not observed in patients in the control group. CONCLUSIONS: The results of this study show that long-term carvedilol therapy in patients with chronic heart failure was able to prevent or partially reverse progressive left ventricular dilatation. The effects on left ventricular remodeling were associated with a concomitant recovery of diastolic reserve and a decrease of mitral regurgitation, which have been demonstrated to be powerful prognostic predictors in such patients. Overall these findings provide important insights into the pathophysiologic mechanisms by which carvedilol improves the clinical course of patients with chronic heart failure.
Adrenergic beta-Antagonists↗
From digital image processing of colour Doppler M-mode maps to noninvasive evaluation of the left ventricular diastolic function: a dedicated software package.
Noninvasive estimation of diastolic pressure gradients has recently been validated using the space-temporal velocity distribution available from colour Doppler M-mode (CDM). However, the methods currently applied for analysing CDM patterns of left ventricular (LV) filling have limitations, such as lack of automation, subjective variability and limited use of digital velocity map. For this reason, we have developed software able to acquire and process the CDM maps; thus, providing an easily interpretable graphical and numerical display. The pressure field is obtained by approximating the derivatives with centred finite differences via the incompressible Navier-Stokes equations. After digital filtering of the noise and the removal of the colour black spots, the velocity field is utilised to compute the pressure gradient field and the pressure values by spatial integration. It is concluded that automatic quantification of colour CDM patterns is feasible and will be a strategic tool in the investigation of one of the most intriguing topics in cardiology.
Blood Flow Velocity↗