GPCR homomers and heteromers: A better choice as targets for drug development than GPCR monomers?

G protein-coupled receptors (GPCR) are targeted by many therapeutic drugs marketed to fight against a variety of diseases. Selection of novel lead compounds are based on pharmacological parameters obtained assuming that GPCR are monomers. However, many GPCR are expressed as dimers/oligomers. Therefore, drug development may consider GPCR as homo- and hetero-oligomers. A two-state dimer receptor model is now available to understand GPCR operation and to interpret data obtained from drugs interacting with dimers, and even from mixtures of monomers and dimers. Heteromers are distinct entities and therefore a given drug is expected to have different affinities and different efficacies depending on the heteromer. All these concepts would lead to broaden the therapeutic potential of drugs targeting GPCRs, including receptor heteromer-selective drugs with a lower incidence of side effects, or to identify novel pharmacological profiles using cell models expressing receptor heteromers.     

Unveiling Case‐Control Relationships in Designing a Simple and Powerful Method for Detecting Gene‐Gene Interactions

The detection of gene‐gene interactions (i.e., epistasis) in the human genome is becoming decisive for the complete characterization of the genetic factors associated with complex binary traits. Despite the fact that many methods have been developed to address this challenging issue, their performance still remains insufficient. We will show how case and control groups store complementary information regarding interactions, and the use of this fundamental property in the design of a new, rapid, and highly powerful epistasis analysis method. Unlike previous approaches where statistical methods are tested over a very limited range of situations, we have performed an exhaustive evaluation of the power of our new method. To this end, we also propose a more comprehensive interpretation of epistasis in which genotype interactions may be of risk, protective, or neutral. In this extended view of genetic interactions, we demonstrate that our method has superior performance than existing approaches, thus, providing a highly powerful tool for the identification of gene‐gene interactions associated with binary traits.     

A new antibiotic nortriterpene quinone methide from Maytenus catingarum.

15alpha-Hydroxy-21-keto-pristimerine (1), a new nortriterpene quinone methide was isolated from the root bark of Maytenus catingarum along with other well-known related compounds, including pristimerine (2), tingenone, and 20alpha-hydroxy-tingenone. The structure of 1 was determined by means of 1H and 13C NMR spectroscopy, including homonuclear and heteronuclear correlations. Compound 1 showed antibiotic activity against Gram-positive bacteria.     

Consumption of gluten-free products: should the threshold value for trace amounts of gluten be at 20, 100 or 200 p.p.m.?

OBJECTIVE: The threshold of gluten contamination in gluten-free products of both dietary and normal consumption is under debate. The objective of this study was to gather information on consumption of gluten-free products intended for dietary use of people under a gluten-free diet. This information is essential to ascertain the exposure of coeliac patients to gluten through their diet and deduce the maximum gluten content that these products should contain to guarantee a safe diet. METHODS: A diet diary of consumption of gluten-free products intended for dietary use was distributed to the coeliac societies of two typical Mediterranean countries (Italy and Spain) and two Northern countries (Norway and Germany). The diet diary included a self-weigh table of the selected food items and a 10-day consumption table. Results were reported in percentiles as distributions were clearly right skewed. RESULTS: The respondents included in the study accounted for 1359 in Italy, 273 in Spain, 226 in Norway and 56 in Germany. Gluten-free products intended for dietary use contributed significantly to the diet of coeliac patients in Italy, Germany and Norway and to a lesser degree in Spain. The most consumed gluten-free product in all countries was bread, and it was double consumed in the Northern countries (P<0.001). Mediterranean countries showed consumption of a wider variety of gluten-free foods and pasta was eaten to a large degree in Italy. CONCLUSIONS: The differences between Northern and Mediterranean countries were not in the total amount of gluten-free products but in the type of products consumed. The observed daily consumption of gluten-free products results in the exposure to rather large amounts of gluten, thus the limit of 200 p.p.m. should be revised. A limit of 20 p.p.m. for products naturally gluten-free and of 100 p.p.m. for products rendered gluten-free is proposed to guarantee a safe diet and to enable coeliac patients to make an informed choice. These limits should be revised as new data become available.     

Bronchoscopic balloon dilatation in the management of bronchial stenosis following lung transplantation

BACKGROUND: Bronchial stenosis (BS) is currently found in 7-15% of lung transplantation (LT) recipients. Current treatment strategies have included Nd:Yag laser, cryotherapy, bougie dilatation and stent placement. Bronchoscopic balloon dilatation has been used as alternative treatment in a few cases with controversial results. This is a study to prospectively assess the efficacy of bronchoscopic balloon dilatation as a first step in the management of post-LT BS. METHODS: From January 1995 to December 2002, bronchoscopic balloon dilatation was evaluated as first therapeutic option in all consecutive LT patients with BS. Symptoms, pulmonary function tests, airway diameter and use of other therapeutic techniques were evaluated. RESULTS: A total of 10 out of 284 anastomed airways (3.5%) in 9 out of 152 LT patients were included in the study and follow-up lasted from 6 to 81 months. Dilatation of all but one BS met with initial success: increase of both luminal dimensions and forced vital capacity (P=0.01), and relief of symptoms. Bronchoscopic balloon dilatation long-term follow-up showed effective results in 5 out of 10 (50%) bronchial stenoses, after an average of 4 bronchoscopic balloon dilatation procedures (range 1-8). No severe complications were observed. Stent placement was required in the other 5 bronchial stenoses. CONCLUSIONS: Bronchoscopic balloon dilatation is a safe method that should be considered as first therapeutic treatment of post-LT BS. Its use avoids the need for stent placement in up to 50% of cases.     

Lack of association of serum lipoprotein (a) levels with type-2 diabetes mellitus in patients with angiographically defined coronary artery disease

Multiple studies have demonstrated that elevated serum lipoprotein (a) [Lp(a)] levels are independent predictors for coronary artery disease (CAD) in subjects without diabetes mellitus (DM). However, their contribution in patients with DM is controversial and still requires clarification. We determined serum Lp(a) levels in 355 consecutive Caucasian patients (271 men and 84 women) with angiographically documented CAD, and in 100 control subjects (58 men and 42 women) who were clinically free of cardiovascular disease. In addition, the association of serum Lp(a) levels with type-2 DM in patients with CAD was investigated after reassigning patients according to the diagnosis of type-2 DM (61 men and 40 women with type-2 DM and 210 men and 44 women without). No gender differences in Lp(a) levels were observed between men and women (patients and control subjects). Patients with CAD had higher Lp(a) levels than the control subjects (33 (14-74) vs. 13 (9-29) mg/dl, P<0.001). Elevated Lp(a) levels (defined as >90th percentile of controls) were significantly more prevalent in men and women with CAD (35% and 28%, respectively) than in control subjects (13% and 10%, respectively). Serum Lp(a) levels correlated with LDL cholesterol (r=0.22, P<0.001) and apo B levels (r=0.18, P<0.03) in patients and control subjects. Stepwise discriminant analysis revealed that Lp(a) was an independent risk factor for the presence of CAD, independent of smoking, hypertension, type-2 DM, LDL and HDL cholesterol or apo A1 and B levels. When patients were studied according to the spread of CAD (evaluated as the number of narrowed vessels), no differences in serum Lp(a) levels were observed, nor was there a higher prevalence of elevated Lp(a) levels. Finally, when patients were re-assigned according to the diagnosis of type-2 DM, no effect of apo B and LDL-C levels on Lp(a) was found (r=0.06, P=n.s. and 40.14, P=n.s., respectively) and serum Lp(a) levels neither associated nor contributed to the extent of CAD. Our results showed that serum Lp(a) levels are increased in patients with angiographically documented CAD, but there were no significant differences between diabetic and non-diabetic patients, which indicates that elevated Lp(a) levels are specifically associated with CAD but not with type-2 DM.     

Meningococcal disease in a large urban population (Barcelona, 1987-1992): predictors of dismal prognosis. Barcelona Meningococcal Disease Surveillance Group.

CONTEXT: Studies on meningococcal disease in large urban communities have rarely been performed and are usually based on passive epidemiologic surveillance. Active surveillance may provide new insights. OBJECTIVES: To determine epidemiologic, clinical, and bacteriological characteristics and predictors of dismal prognosis (death and sequelae) in meningococcal disease. DESIGN: Prospective, population-based study. SETTING: All the acute care hospitals (n = 24) in Barcelona, Spain. PATIENT: The 643 patients whose conditions were diagnosed from 1987 through 1992 were detected by 2 active surveillance methods. OUTCOME MEASURES: Incidence and notification to Public Health Service. Clinical and bacteriological features were determined. Dismal prognosis predictors were determined by logistic regression. RESULTS: Average annual incidence was 6.41 per 100,000 inhabitants, with no clear trend of change (P = .08). Sensitivity of the Public Health Service surveillance system was 69.1%. Children younger than 10 years from the inner city were at higher risk than those from the highest income district (relative risk, 3.00; 95% confidence interval [CI], 1.84-5.06). Increasing annual incidence of serogroup C (0.82-1.29/100,000; P = .008) and decreasing incidence of serogroup B (5.11-2.82/100,000; P = .004) was noted. Average annual mortality was 0.40 per 100,000 inhabitants, while the annual average potential years of life lost was 18 per 100,000 inhabitants. Overall case-fatality rate was 6.4%. Independent predictors of death were hemorrhagic diathesis (odds ratio [OR], 63; 95% CI, 21-194), focal neurologic signs (OR, 10; 95% CI, 3-30), and age 60 years or older (OR, 6; 95% CI, 2-17), whereas preadmission antibiotic therapy was associated with favorable outcome (OR, 0.07; 95% CI, 0.02-0.3). Four percent of survivors presented with sequelae. Independent predictors of sequelae were hemorrhagic diathesis (OR, 21; 95% CI, 3-131), focal neurologic signs (OR, 16; 95% CI, 5-53), age 60 years or older (OR, 7; 95% CI, 2-26), and age between 15 and 59 years (OR, 5; 95% CI, 2-14), whereas preadmission antibiotic therapy had a protective effect (OR, 0.2; 95% CI, 0.04-0.5). CONCLUSIONS: Active epidemiologic surveillance significantly improved detection of cases and allowed us to observe that meningococcal disease still causes much morbidity and mortality, especially among children living in the inner city. Hemorrhagic diathesis, focal neurologic signs, and age were independent predictors of dismal prognosis, whereas preadmission antibiotic therapy had a protective effect.     

Prevalence of articular chondrocalcinosis in elderly subjects in a rural area of Catalonia.

OBJECTIVES--To undertake an epidemiological survey of the prevalence of radiological chondrocalcinosis in the elderly population of Osona, a rural area of Catalonia, north east Spain. METHODS--Knee and wrist radiographs were performed on 261 subjects (141 women, 120 men) aged at least 60 years, who attended a series of 35 general practitioners for various medical problems. RESULTS--Twenty seven subjects had articular chondrocalcinosis, which represents a crude prevalence of 10%. Articular chondrocalcinosis was more often observed in women than in men (14 v 6%). Articular chondrocalcinosis increases in occurrence with age, rising from 7% in subjects aged 60-69 years to 43% in subjects older than 80 years. A similar occurrence of articular chondrocalcinosis was noted in the indigenous population, in which several cases of familial chondrocalcinosis have previously been reported, and in subjects born in other areas of Spain. All but one subject with articular chondrocalcinosis had chondrocalcinosis of the knee. The occurrence of rheumatic disorders did not differ significantly between subjects with articular chondrocalcinosis and those without. CONCLUSIONS--Articular chondrocalcinosis is an age related disorder, which could partly explain the discrepancies in its prevalence reported in previous studies. In most subjects with articular chondrocalcinosis recruited from an unselected population the clinical manifestations are probably mild or even absent.     

Useful pharmacological parameters for G-protein-coupled receptor homodimers obtained from competition experiments. Agonist–antagonist binding modulation

Many G-protein-coupled receptors (GPCRs) are expressed on the plasma membrane as dimers. Since drug binding data are currently fitted using equations developed for monomeric receptors, the interpretation of the pharmacological data are equivocal in many cases. As reported here, GPCR dimer models account for changes in competition curve shape as a function of the radioligand concentration used, something that cannot be explained by monomeric receptor models. Macroscopic equilibrium dissociation constants for the agonist and homotropic cooperativity index reflecting the intramolecular communication within the dopamine D₁ or adenosine A_2A receptor homodimer as well as hybrid equilibrium dissociation constant, which reflects the antagonist/agonist modulation may be calculated by fitting binding data from antagonist/agonist competition experiments to equations developed from dimer receptor models. Comparing fitting the data by assuming a classical monomeric receptor model or a dimer model, it is shown that dimer receptor models provide more clues useful in drug discovery than monomer-based models.     

B 超诊断前置胎盘分型的再探讨

目的 对Ｂ超诊断前置胎盘分型的改进探讨。方法 对３６例前置胎盘患者进行Ｂ超探查。观察胎盘下缘与子宫内口的关系。结果 前置胎盘的Ｂ超声像图可分四类：①胎盘中央部位于宫内口。②胎盘边缘部完全覆盖宫内口。③胎盘下缘至宫内口边缘,未覆盖宫内口。④盈盘位于子宫下截,未达到宫内口。结论 部分性前置胎盘的超声诊断分型担法不确切可予取消。将中央性前置胎盘诊断分两个亚型：中央型、边缘型。