Secretory defects induced by immunosuppressive agents on human pancreatic beta-cells

Despite the considerable interest for islet and pancreas transplantation, remarkably little is known about the direct effects of immunosuppressive drugs on human β-cell function. We measured different insulin secretory parameters and insulin gene expression of human islets cultured for 5 days in the presence of mycophenolate mofetil (MMF), cyclosporin A (CsA), tacrolimus (FK506) or a mixture of 3 cytokines. Basal insulin release after exposure to cytokines and FK506 was significantly higher than in control islets. Responsiveness to an acute glucose stimulus did not differ significantly between control and treated islets. However, absolute incremental insulin responses (Δ-AUCs) of islets exposed to cytokines or FK506 were significantly higher compared to islets exposed to CsA or MMF, mainly because of the higher basal release. Indeed, maximal over basal release (stimulation index, SI) tended to be lower in islets exposed to FK506 than in control islets. Insulin gene expression was significantly reduced only in islets exposed to CsA. FK506 was, among those tested, the immunosuppressive drug that most profoundly altered the normal insulin secretory pattern of human β-cells, whereas CsA was the only inhibiting insulin gene expression. Although the abnormalities induced by the immunosoppressive drugs utilized in this study were modest, these in vitro data are consistent with the reported in vivo diabetogenicity of CsA and FK506 and point to MMF as the ideal immunosuppressive agent from a pancreatic β-cell point of view. Received: 26 November 2001 / Accepted in revised form: 19 June 2002 Correspondence to A.M. Davalli     

Malaria in travelers in Rhode Island: a review of 26 cases.

PURPOSE: We reviewed our experience with malaria in two community hospitals in Rhode Island from 1986 to 1990. RESULTS: Twenty-six patients with malaria were identified. Fifteen patients were immigrants who had acquired malaria while visiting their country of origin, particularly West Africa. Fever was present in 67% of cases and gastrointestinal complaints were prominent in 26%. Individuals with a past history of malaria could accurately distinguish current malarial infections from other febrile illnesses. Two patients developed cerebral malaria. Plasmodium falciparum was identified in 77% of the cases. CONCLUSIONS: Malaria is an important diagnosis that United States physicians must consider in the medical evaluation of returning travelers. A significant increase in the number of cases of P. falciparum acquired in East Africa has been reported in recent years. P. falciparum infection must be rapidly diagnosed and treated since delays may result in complications of malaria that may lead to death. Mefloquine is currently recommended by the Centers for Disease Control for prevention of malaria in travelers visiting countries endemic for chloroquine-resistant malaria. This change may alter the epidemiology of malaria in the United States in the future.     

Cardiovascular effects of a combination of vecuronium and low-dose fentanyl in atropinized and non-atropinized subjects]

The cardiovascular effects of the pharmacologic association of low-dose fentanyl (2 micrograms/kg) and vecuronium (120 micrograms/kg) have been studied in 38 ASA I and II atropinized and non-atropinized patients scheduled for abdominal surgery during induction of anaesthesia with thiopentone or propofol. Whatever the induction agent used, heart rate was consistently reduced in patients not receiving an anticholinergic drug, while it was unchanged in patients treated with atropine intravenously. In non-atropinized patients impressively lower minimum heart rates were observed during induction of anaesthesia with thiopentone. In this last group one patient suffered from a cardiac arrest resolved without sequelae. In patients treated with the association between vecuronium and low doses of fentanyl a pretreatment with atropine is always indicated. Propofol seems to be a better induction agent than thiopentone.     

Analysis of sports‐relevant polymorphisms in a large Brazilian cohort of top‐level athletes

In recent years, there have been an increasing number of genetic variants associated with athletic phenotypes. Here, we selected a set of sports‐relevant polymorphisms that have been previously suggested as genetic markers for human physical performance, and we examined their association with athletic status in a large cohort of Brazilians. We evaluated a sample of 1,622 individuals, in which 966 were nonathletes, and 656 were athletes: 328 endurance athletes and 328 power athletes. Only the AGT M268T minor allele was nominally associated with the endurance status. Conversely, we found that seven polymorphisms are more frequent in power athletes (MCT1 D490E, AGT M268T, PPARG P12A, PGC1A G482S, VEGFR2 Q472H, NOS3 C/T, and ACTN3 R577X). For all of these polymorphisms, power athletes were more likely than nonathletes or endurance athletes to carry the major allele or the homozygous genotype for the major allele. In particular, MCT1 D490E, AGT M268T, NOS3 C/T, and ACTN3 R577X showed stronger associations. Our findings support a role for these variants in the achievement of power athletic status in Brazilians: MCT1 D490E (T allele), AGT M268T (G allele), PPARG (C allele), PGC1A G482S (C allele), VEGFR2 Q472H (T allele), NOS3 C/T (T allele), and ACTN3 R577X (R allele).     

Assessment of inspiratory flow limitation in children with sleep-disordered breathing by a nasal cannula pressure transducer system

A nasal cannula pressure transducer system identifies inspiratory flow limitation and increased upper airway resistance in adults with sleep-disordered breathing (SDB). The purpose of this study was to evaluate whether nasal cannula pressure (NCP) detects apneas and hypopneas as well as additional flow-limited events associated with increased airway resistance in children. We studied NCP in 47 patients (ages 2-14 years) referred for SDB to a university-based sleep disorders program during nocturnal polysomnography (NPSG). During NPSG, airflow was assessed simultaneously by thermistor and NCP. There was a high correlation between apneas assessed by thermistor (T) and NCP (r = 0.90, P < 0.0001), and for hypopneas using these two methods (r = 0.94, P = 0.0001). Respiratory driving pressure was indirectly measured with an esophageal pressure catheter. Flow-limited (flattened) NCP waves were associated with significantly higher driving pressure, indicating elevated upper airway resistance, compared to nonflow-limited (rounded) waves during nonrapid eye movement (NREM) (P = 0.05) and rapid eye movement (REM) (P = 0.01) sleep. Patients were classified as either having obstructive sleep apnea syndrome (OSAS) or primary snoring, based on standard NPSG criteria. NCP identified additional respiratory events with a flattened contour (FC) not detected by thermistor. NCP is a noninvasive device that identifies obstructive apneas and hypopneas as well as additional respiratory events associated with flow limitation in children.     

Etiology and Antimicrobial Susceptibility of Middle Ear Fluid Pathogens in Costa Rican Children With Otitis Media Before and After the Introduction of the 7-Valent Pneumococcal Conjugate Vaccine in the National Immunization Program: Acute otitis media microbiology in Costa Rican children

Acute otitis media (AOM) microbiology was evaluated in children after 7-valent pneumococcal conjugate vaccine (PCV7) introduction in Costa Rica (private sector, 2004; National Immunization Program, 2009).This was a combined prospective and retrospective study conducted in a routine clinical setting in San José, Costa Rica. In the prospective part of the study, which was conducted post-PCV7 introduction (2010–2012), standard bacteriological procedures were used to evaluate the etiology and serotype distribution of middle ear fluid samples collected by tympanocentesis or otorrhea from children aged 3–59 months diagnosed with AOM. E-tests were used to evaluate antimicrobial susceptibility in culture-positive samples. Retrospective data recorded between 1999 and 2004 were used for comparison of bacterial etiology and serotype distribution before and after PCV7 introduction. Statistical significance was evaluated in bivariate analyses at the P-value < 0.05 level (without multiplicity correction).Post-PCV7 introduction, Haemophilus influenzae was detected in 118/456 and Streptococcus pneumoniae in 87/456 AOM episodes. Most H. influenzae isolates (113/118) were non-typeable. H. influenzae was more (27.4% vs 20.8%) and S. pneumoniae less (17.1% vs 25.5%) frequently observed in vaccinated (≥2 PCV7 doses or ≥1 PCV7 dose at >1 year of age) versus unvaccinated children. S. pneumoniae non-susceptibility rates were 1.1%, 34.5%, 31.7%, and 50.6% for penicillin, erythromycin, azithromycin, and trimethoprim/sulfamethoxazole (TMP-SMX), respectively. H. influenzae non-susceptibility rate was 66.9% for TMP-SMX. Between pre- and post-PCV7 introduction, H. influenzae became more (20.5% vs 25.9%; P-value < 0.001) and S. pneumoniae less (27.7% vs 19.1%; P-value = 0.002) prevalent, and PCV7 serotype proportions decreased among pneumococcal isolates (65.8% vs 43.7%; P-value = 0.0005). Frequently identified pneumococcal serotypes were 19F (34.2%), 3 (9.7%), 6B (9.7%), and 14 (9.7%) pre-PCV7 introduction, and 19F (27.6%), 14 (8.0%), and 35B (8.0%) post-PCV7 introduction.Following PCV7 introduction, a change in the distribution of AOM episodes caused by H. influenzae and pneumococcal serotypes included in PCV7 was observed in Costa Rican children. Pneumococcal vaccines impact should be further evaluated following broader vaccination coverage.     

Suggestive linkage to chromosome 1q for bone mineral apparent density in Brazilian sister adolescents

ObjectiveTo investigate linkage to chromosome 1q and 11q region for lumbar spine, femoral neck and total body BMD and volumetric BMD in Brazilian sister adolescents aged 10–20-year-old and 57 mothers.MethodsWe evaluated 161 sister pairs (n = 329) aged 10–20 years old and 57 of their mothers in this study. Physical traits and lifestyle factors were collected as covariates for lumbar spine (LS), femoral neck (FN) and total body (TB) BMD and bone mineral apparent density (BMAD). We selected nine microsatellite markers in chromosome 1q region (spanning nearly 33cM) and eight in chromosome 11q region (spanning nearly 34cM) to perform linkage analysis.ResultsThe highest LOD score values obtained from our data were in sister pairs LS BMAD analysis. Their values were: 1.32 (P < 0.006), 2.61 (P < 0.0002) and 2.44 (P < 0.0004) in D1S218, D1S2640 and D1S2623 markers, respectively. No significant LOD score was found with LS and FN BMD/BMAD in chromosome 11q region. Only TB BMD showed significant linkage higher than 1.0 for chromosome 11q region in the markers D11S4191 and D11S937.Discussion/ConclusionsOur results provided suggestive linkage for LS BMAD at D1S2640 marker in adolescent sister pairs and suggest a possible candidate gene (LHX4) related to adolescent LS BMAD in this region. These results reinforce chromosome 1q21-23 as a candidate region to harbor one or more bone formation/maintenance gene. In the other hand, it did not repeat for chromosome 11q12-13 in our population.