Relationship between the paraoxonase (PON1) L55M and Q192R polymorphisms and obesity in a Mexican population: a pilot study

The aim of this study was to examine the relationship between the L55M and Q192R paraoxonase (PON1) polymorphisms and obesity in a population of adult Mexican workers. The study population included 127 adult individuals from the Universidad Autónoma del Estado de Morelos, ranging in age from 20 to 56 years and representing both sexes. Based on body mass index, 63 individuals were classified as obese and 64 as normal weight. The PON1-Q192R and PON1-L55M polymorphisms were determined by restriction fragment length polymorphism PCR analysis. Both arylesterase and paraoxonase activity levels were similar in both groups, whereas systolic pressure, triglyceride, total cholesterol, low-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol, glucose, and insulin levels were higher in the obese group than in the normal-weight group (P < 0.05). An exception was the high-density lipoprotein cholesterol (HDL-C) levels, which were lower in the obese group (P < 0.05). Although the PON1-Q192R polymorphism was not associated with either group, the frequency of the homozygous L genotype for the PON1-L55M polymorphism was higher in the obese group than in the normal-weight group (P < 0.05). In conclusion, this study established a positive association between the PON1-L55M homozygous L genotype and obesity.     

Prevalence of antibody to hantaviruses in humans and rodents in the Caribbean region of Colombia determined using Araraquara and Maciel virus antigens

We tested sera from 286 agricultural workers and 322 rodents in the department of Córdoba, northeastern Colombia, for antibodies against two hantaviruses. The sera were analysed by indirect ELISA using the lysate of Vero E6 cells infected with Maciel virus (MACV) or the N protein of Araraquara virus (ARAV) as antigens for the detection of antibodies against hantaviruses. Twenty-four human sera were IgG positive using one or both antigens. We detected anti-MACV IgG antibodies in 10 sera (3.5%) and anti-ARAV antibodies in 21 sera (7.34%). Of the 10 samples that were positive for MACV, seven (70%) were cross-reactive with ARAV; seven of the 21 ARAV-positive samples were cross-reactive with MACV. Using an ARAV IgM ELISA, two of the 24 human sera (8.4%) were positive. We captured 322 rodents, including 210 Cricetidae (181 Zygodontomys brevicauda, 28 Oligoryzomys fulvescens and 1 Oecomys trinitatis), six Heteromys anomalus (Heteromyidae), one Proechimys sp. (Echimyidae) and 105 Muridae (34 Rattus rattus and 71 Mus musculus). All rodent sera were negative for both antigens. The 8.4% detection rate of hantavirus antibodies in humans is much higher than previously found in serosurveys in North America, suggesting that rural agricultural workers in northeastern Colombia are frequently exposed to hantaviruses. Our results also indicate that tests conducted with South American hantavirus antigens could have predictive value and could represent a useful alternative for the diagnosis of hantavirus infection in Colombia.     

Small molecule agonists of integrin CD11b/CD18 do not induce global conformational changes and are significantly better than activating antibodies in reducing vascular injury

Background

CD11b/CD18 is a key adhesion receptor that mediates leukocyte adhesion, migration and immune functions. We recently identified novel compounds, leukadherins, that allosterically enhance CD11b/CD18-dependent cell adhesion and reduce inflammation in vivo, suggesting integrin activation to be a novel mechanism of action for the development of anti-inflammatory therapeutics. Since a number of well-characterized anti-CD11b/CD18 activating antibodies are currently available, we wondered if such biological agonists could also become therapeutic leads following this mechanism of action.

Methods

We compared the two types of agonists using in vitro cell adhesion and wound-healing assays and using animal model systems. We also studied effects of the two types of agonists on outside-in signaling in treated cells.

Results

Both types of agonists similarly enhanced integrin-mediated cell adhesion and decreased cell migration. However, unlike leukadherins, the activating antibodies produced significant CD11b/CD18 macro clustering and induced phosphorylation of key proteins involved in outside-in signaling. Studies using conformation reporter antibodies showed that leukadherins did not induce global conformational changes in CD11b/CD18 explaining the reason behind their lack of ligand-mimetic outside-in signaling. In vivo, leukadherins reduced vascular injury in a dose-dependent fashion, but, surprisingly, the anti-CD11b activating antibody ED7 was ineffective.

Conclusions

Our results suggest that small molecule allosteric agonists of CD11b/CD18 have clear advantages over the biologic activating antibodies and provide a mechanistic basis for the difference.

General significance

CD11b/CD18 activation represents a novel strategy for reducing inflammatory injury. Our study establishes small molecule leukadherins as preferred agonists over activating antibodies for future development as novel anti-inflammatory therapeutics.     

Evaluation of MycAssay? Aspergillus for Diagnosis of Invasive Pulmonary Aspergillosis in Patients without Hematological Cancer

Methods based on real-time polymerase chain reaction (PCR) can speed up the diagnosis of invasive aspergillosis but are limited by a lack of standardization. We evaluated the commercially available MycAssay™ Aspergillus test for the diagnosis of invasive aspergillosis in patients without hematological cancer. We prospectively collected 322 lower respiratory tract samples (November 2009–January 2011) from 175 patients with lower respiratory tract infection and the following predisposing conditions: solid cancer (16.8%), cirrhosis (16.8%), corticosteroid therapy (71.7%), HIV infection (15.6%), chronic obstructive pulmonary disease (COPD, 52.6%), solid organ transplantation (kidney [1.2%], heart [3%], liver [4.6%]), or none (3.5%). Specimens were obtained when clinically indicated and analyzed in the microbiology laboratory. Aspergillus DNA was extracted and amplified by means of MycXtra® and MycAssay™ Aspergillus. Aspergillus spp. was isolated from 65 samples (31 patients). According to the European Organization for Research and Treatment of Cancer and Bulpa''s criteria (for patients with COPD), 15 had probable invasive aspergillosis. MycAssay™ Aspergillus results were negative (n = 254), positive (n = 54), or indeterminate (n = 14). The sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic odds ratio of the MycAssay™ (first sample/any sample) were 86.7/93, 87.6/82.4, 34.1/34.1, 92.2/100, and 48/68.75. The differences between the proportion of samples with positive PCR determinations (63%) and the proportion of samples with Aspergillus spp. isolation (75%) did not reach statistical significance (P = 0.112). The median time from sample culture to visualization of fungal growth was 3 days, compared with ∼4 hours for MycAssay™ Aspergillus PCR. MycAssay™ Aspergillus showed high sensitivity for the diagnosis of invasive aspergillosis in patients without hematological cancer. Sensitivity increased when multiple samples were used. Compared with fungal culture, PCR significantly reduced the time to diagnosis.     

Population structure of the Chagas disease vector,Triatoma infestans,at the urban–rural interface

The increasing rate of biological invasions resulting from human transport or human‐mediated changes to the environment has had devastating ecological and public health consequences. The kissing bug, Triatoma infestans, has dispersed through the Peruvian city of Arequipa. The biological invasion of this insect has resulted in a public health crisis, putting thousands of residents of this city at risk of infection by Trypanosoma cruzi and subsequent development of Chagas disease. Here, we show that populations of Tria. infestans in geographically distinct districts within and around this urban centre share a common recent evolutionary history although current gene flow is restricted even between proximal sites. The population structure among the Tria. infestans in different districts is not correlated with the geographical distance between districts. These data suggest that migration among the districts is mediated by factors beyond the short‐range migratory capabilities of Tria. infestans and that human movement has played a significant role in the structuring of the Tria. infestans population in the region. Rapid urbanization across southern South America will continue to create suitable environments for Tria. infestans, and knowledge of its urban dispersal patterns may play a fundamental role in mitigating human disease risk.     

Susceptibility of three Colombian Aedes aegypti Linnaeus (Diptera: Culicidae) populations to a Lysinibacillus sphaericus formulation

The increased incidence of vector-borne diseases and insecticide resistance in mosquitos constitute public health concerns in the tropics. Biological control is an effective alternative in the management of Aedes aegypti Linnaeus populations. Lysinibacillus sphaericus a bacterium proved to be harmless for non-target organisms has shown promising entomopathogenic activity. In Colombia, the control of A. aegypti using L. sphaericus has not been contemplated as part of vector control programmes. To assess the susceptibility of three A. aegypti populations to a L. sphaericus formulation consisting of vegetative cells of 2362 and III(3)7 strains, simulated-field bioassays were conducted in the municipalities of Ricaurte in Cundinamarca and Tauramena in Casanare, as well as in the municipal inspection of San Joaquin, Cundinamarca. Sixty larvae were deposited in a test device, which contained nine litres of chlorine-free tap water and 100 ml of the bacterial formulation (10⁹ CFU/ml). Six replicates were set-up for treatment with bacteria and for the control. Larvae mortality was recorded at 24 and 48 hr. The three A. aegypti populations were susceptible to L. sphaericus formulation with a mortality rate higher than 90% at 48 hr. The formulation of L. sphaericus comprised of vegetative cells of 2362 and III(3)7 strains showed promising results that could guarantee the implementation of this formulation to control of A. aegypti populations.     

Inhibition of xc⁻ transporter-mediated cystine uptake by sulfasalazine analogs

A series of sulfasalazine analogs were synthesized and tested for their ability to block cystine-glutamate antiporter system xc? using L-[(14)C]cystine as a substrate. Replacement of sulfasalazine's diazo group with an alkyne group led to an equally potent inhibitor, 2-hydroxy-5-((4-(N-pyridin-2-ylsulfamoyl)phenyl)ethynyl)benzoic acid 6. Our SAR studies also revealed that the carboxylate group of sulfasalazine is essential for its inhibitory activity while the phenolic hydroxyl group is dispensable. Truncated analogs lacking an N-pyridin-2-ylsulfamoyl moiety were less potent than sulfasalazine, but may serve as more tractable templates because of their low molecular weight by applying a variety of fragment growing approaches. Given that sulfasalazine is rapidly metabolized through cleavage of the diazo bond, these analogs may possess a more desirable pharmacological profile as system xc- blockers, in particular, for in vivo studies.