ABSTRACT
BACKGROUND AND AIMS: Adults with congenital heart disease (ACHD) are at risk of overweight and obesity, two major health problems, though underweight can be a negative prognostic factor too. Awareness of the body mass index (BMI) in ACHD is very limited. The present study describes the use and prevalence of BMI in Italian symptomatic hospitalized ACHD patients in relation to complexity by Bethesda system classification, diagnosis, sex and age. METHODS AND RESULTS: We classified 1388 ACHD patients, aged 18-69 years, on the basis of their BMI, and compared them to the Italian reference population. In our total ACHD population we found a significantly higher prevalence of underweight compared to the Italian reference population (6.34% vs 3.20%). ACHD women were more underweight than men. Underweight decreased with age. Overweight was significantly less frequent in the total ACHD population (26.73% compared to 31.70%) in the Italian reference population. Men were more likely to be overweight than women. In statistical terms obesity was similar in the Italian reference population (10.50%) and our ACHD population (9.58%). Both overweight and obesity increased with age. Results were comparable using a diagnostic anatomical-functional classification and the Bethesda system classification. CONCLUSIONS: In our cohort of ACHD the prevalence of underweight was double that of the Italian reference population. The prevalence of overweight was lower, while obesity was similar. Since BMI does not account for differences in body fat distribution, a future aim will be to quantify the visceral component of the adipose tissue in ACHD patients and examine their body composition in order to reflect their risk of acquired cardiovascular disease better, and either to maintain or achieve an adequate visceral component.
Subject(s)
Body Mass Index , Heart Defects, Congenital/epidemiology , Inpatients , Obesity/epidemiology , Thinness/epidemiology , Adiposity , Adolescent , Adult , Age Distribution , Aged , Female , Heart Defects, Congenital/diagnosis , Heart Defects, Congenital/physiopathology , Humans , Italy/epidemiology , Male , Middle Aged , Obesity/diagnosis , Obesity/physiopathology , Prevalence , Prognosis , Retrospective Studies , Risk Assessment , Risk Factors , Sex Distribution , Thinness/diagnosis , Thinness/physiopathology , Young AdultABSTRACT
A growing body of evidence links the analysis of the KIR genotype and the presence of their HLA-B and -C ligands to a wide repertoire of human diseases. We noticed that, using a panel of 184 Caucasoid donors, a limited number of HLA alleles were incorrectly supratyped by previously described pyrosequence-based assays. Here we describe a simple implementation of the reported methods that corrects all the discrepancies found with HLA-B and -C molecular typing and allows establishing a quick and high-throughput method for the determination of HLA-Bw4 I(80), Bw4T(80), Bw6 and HLA-C1 or -C2 supratype.
Subject(s)
HLA-B Antigens/classification , HLA-C Antigens/classification , High-Throughput Nucleotide Sequencing/methods , Histocompatibility Testing/methods , Sequence Analysis, DNA/methods , Alleles , Base Sequence , HLA-B Antigens/genetics , HLA-C Antigens/genetics , Humans , Killer Cells, Natural/immunology , Molecular Typing/methods , Receptors, KIR/genetics , T-Lymphocytes/immunologyABSTRACT
We report the results of a family-based study of LRRK2 G2019S penetrance in Parkinson disease. We studied 19 families identified through the analysis of unrelated consecutive patients. The cumulative incidence of the disease was 15% at 60 years, 21% at 70 years, and 32% at 80 years. This study provides accurate estimates of G2019S penetrance by minimizing the selection bias.
Subject(s)
Genetic Counseling/methods , Glycine/genetics , Parkinson Disease/genetics , Penetrance , Protein Serine-Threonine Kinases/genetics , Serine/genetics , Adult , Age of Onset , Aged , Aged, 80 and over , DNA Mutational Analysis , Family Health , Female , Genetic Predisposition to Disease , Humans , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 , Male , Middle Aged , MutationABSTRACT
BACKGROUND: Mutations in the gene Leucine-Rich Repeat Kinase 2 (LRRK2) were recently identified as the cause of PARK8 linked autosomal dominant Parkinson's disease. OBJECTIVE: To study recurrent LRRK2 mutations in a large sample of patients from Italy, including early (<50 years) and late onset familial and sporadic Parkinson's disease. RESULTS: Among 629 probands, 13 (2.1%) were heterozygous carriers of the G2019S mutation. The mutation frequency was higher among familial (5.1%, 9/177) than among sporadic probands (0.9%, 4/452) (p<0.002), and highest among probands with one affected parent (8.7%, 6/69) (p<0.001). There was no difference in the frequency of the G2019S mutation in probands with early v late onset disease. Among 600 probands, one heterozygous R1441C but no R1441G or Y1699C mutations were detected. None of the four mutations was found in Italian controls. Haplotype analysis in families from five countries suggested that the G2019S mutation originated from a single ancient founder. The G2019S mutation was associated with the classical Parkinson's disease phenotype and a broad range of onset age (34 to 73 years). CONCLUSIONS: G2019S is the most common genetic determinant of Parkinson's disease identified so far. It is especially frequent among cases with familial Parkinson's disease of both early and late onset, but less common among sporadic cases. These findings have important implications for diagnosis and genetic counselling in Parkinson's disease.
Subject(s)
Mutation , Parkinson Disease/genetics , Protein Serine-Threonine Kinases/genetics , Adult , Aged , Alleles , Base Sequence , Female , Founder Effect , Heterozygote , Humans , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 , Male , Middle Aged , Molecular Sequence DataABSTRACT
Mutations of the GJB2 gene, encoding Connexin 26, are the most common cause of hereditary congenital hearing loss in many countries, and account for up to 50% of cases of autosomal-recessive non-syndromic deafness. By contrast, only a few GJB2 mutations have been reported to cause an autosomal-dominant form of non-syndromic deafness. We report on a family from southern Italy in whom dominant, non-syndromic, post-lingual hearing loss is associated with a novel missense mutation in the GJB2 gene. Direct sequencing of the gene showed a heterozygous G-->A transition at nucleotide 535, resulting in an aspartic acid to asparagine amino acid substitution at codon 179 (D179N). This mutation occurred in the second extracellular domain (EC2), which would seem to be very important for connexon-connexon interaction.
Subject(s)
Connexins/genetics , Genes, Dominant , Hearing Loss/genetics , Mutation, Missense , Amino Acid Substitution , Connexin 26 , Connexin 30 , Connexins/metabolism , DNA Mutational Analysis , Female , Hearing Loss/physiopathology , Humans , Male , PedigreeABSTRACT
Certain chemokines act as natural antagonists of human immunodeficiency virus (HIV) by blocking key viral coreceptors, such as CCR5 and CXCR4, on the surface of susceptible cells. Elucidating the structural determinants of the receptor-binding and HIV-inhibitory functions of these chemokines is essential for the rational design of derivative molecules of therapeutic value. Here, we identify the structural determinants of CCR5 recognition and antiviral activity of the CC chemokine RANTES, showing that critical residues form a solvent-exposed hydrophobic patch on the surface of the molecule. Moreover, we demonstrate that the biological function is critically dependent on dimerization, resulting in the exposure of a large ( approximately 180 A2), continuous hydrophobic surface. Relevant to the development of novel therapeutic approaches, we designed a retroinverted RANTES peptide mimetic that maintained both HIV- and chemotaxis-antagonistic functions.
Subject(s)
Anti-HIV Agents/chemistry , Anti-HIV Agents/metabolism , Chemokine CCL5/chemistry , Chemokine CCL5/metabolism , HIV-1/metabolism , Receptors, CCR5/metabolism , Alanine/genetics , Alanine/metabolism , Amino Acid Sequence , Anti-HIV Agents/pharmacology , CCR5 Receptor Antagonists , Cell Line , Chemokine CCL5/analogs & derivatives , Chemokine CCL5/pharmacology , Chemotaxis, Leukocyte/drug effects , Coculture Techniques , Dimerization , Drug Design , Giant Cells/drug effects , Giant Cells/virology , HIV-1/drug effects , Humans , Lymphocytes/drug effects , Lymphocytes/immunology , Models, Molecular , Molecular Mimicry , Mutagenesis/genetics , Peptides/chemical synthesis , Peptides/chemistry , Peptides/metabolism , Peptides/pharmacology , Protein Binding , Protein Conformation , Recombinant Proteins/chemistry , Recombinant Proteins/metabolism , Recombinant Proteins/pharmacology , Reproducibility of Results , Structure-Activity RelationshipABSTRACT
Although selected chemokines act as natural inhibitors of human immunodeficiency virus (HIV) infection, their inherent proinflammatory activity may limit a therapeutic use. To elucidate whether the antiviral and signaling functions of RANTES can be dissociated, several recombinant analogues mutated at the N terminus were generated and functionally compared with the wild-type (WT) molecule, as well as with three previously described mutants. Substitution of selected residues within the N-terminal region caused a marked loss of antiviral potency. By contrast, two unique analogues (C1.C5-RANTES and L-RANTES) exhibited an increased antiviral activity against different CXCR4-negative HIV-1 isolates grown in primary mononuclear cells or in macrophages. This enhanced HIV-blocking activity was associated with an increased binding affinity for CCR5. Both C1.C5-RANTES and L-RANTES showed a dramatically reduced ability to trigger intracellular calcium mobilization via CCR3 or CCR5, while potently antagonizing the action of the WT chemokine. By contrast, two previously described analogues (RANTES(3-68) and AOP-RANTES) maintained a WT ability to trigger CCR5-mediated signaling, while a third one (RANTES(9-68)) showed a dramatic loss of antiviral activity. These data demonstrate that the antiviral and signaling functions of RANTES can be uncoupled, opening new perspectives for the development of chemokine-based therapeutic approaches for HIV infection.
Subject(s)
Anti-HIV Agents/chemistry , Chemokine CCL5/chemistry , HIV-1/drug effects , Anti-HIV Agents/immunology , Anti-HIV Agents/pharmacology , Chemokine CCL5/immunology , Chemokine CCL5/pharmacology , Humans , Receptors, CCR5/immunology , Structure-Activity RelationshipABSTRACT
The effect of 5-HT1 and 5-HT2 receptor agonists administered into the paraventricular hypothalamus was studied on the hyperphagia caused by neuropeptide Y (NPY) injected into the same area. The 5-HT2A/2C receptor agonist DOI (10-20 nmol/0.5 microliter) significantly reduced NPY overeating while the 5-HT1A/1B receptor agonist RU 24969 (3.5-14 nmol/0.5 microliter) and the 5-HT1B/2C receptor agonist mCPP (5-20 nmol/0.5 microliter) had no such effect. The 5-HT2A receptor antagonist spiperone (5 microgram/0.5 microliter) and the corticotropin releasing factor antagonist alpha-helical-CRF9-41 (0.5-1 micrograms/0.5 microliter) completely antagonized the effect of 10 nmol DOI.
Subject(s)
Corticotropin-Releasing Hormone/physiology , Hyperphagia , Neuropeptide Y/pharmacology , Receptors, Serotonin/physiology , Serotonin Receptor Agonists/pharmacology , Amphetamines/pharmacology , Animals , Feeding Behavior/drug effects , Feeding Behavior/physiology , Indoles/pharmacology , Male , Paraventricular Hypothalamic Nucleus , Piperazines/pharmacology , Rats , Rats, Sprague-Dawley , Receptor, Serotonin, 5-HT2A , Receptors, Serotonin/drug effects , Spiperone/pharmacologyABSTRACT
d-Fenfluramine (0.63 mg/kg i.p.), a serotonin (5-hydroxytryptamine, 5-HT) releaser and re-uptake inhibitor, reduced the eating caused by neuropeptide Y (235 pmol) injected into the paraventricular nucleus of the hypothalamus. The 5-HT1 and 5-HT2 receptor antagonist metergoline (1.0 and 2.0 mg/kg i.p.) and the 5-HT1A and 5-HT1B receptor antagonist (+/-)-cyanopindolol (3.0 and 8.0 mg/kg s.c.) significantly antagonized the effect of d-fenfluramine. The 5-HT2A and 5-HT2C receptor antagonist mesulergine (0.1 and 0.3 mg/kg s.c.) and the 5-HT2A receptor antagonist ketanserin (2.5 and 5.0 mg/kg i.p.) did not significantly modify the effect, nor did the 5-HT1A and 5-HT1B receptor antagonist (-)-propranolol (20-40 nmol), injected bilaterally into the paraventricular nucleus of the hypothalamus. The results suggest that d-fenfluramine reduces neuropeptide Y's hyperphagia by indirectly stimulating 5-HT1B receptors outside the paraventricular nucleus of the hypothalamus.