Emergence of penicillin-nonsusceptible Streptococcus pneumoniae clones expressing serotypes not present in the antipneumococcal conjugate vaccine

BACKGROUND: Penicillin-nonsusceptible Streptococcus pneumoniae isolates are confined mainly to a few serogroups. Capsular transformation may serve as a mechanism for spreading antibiotic resistance to new serotypes. METHODS: Antibiogram and molecular typing, by pulsed-field gel electrophoresis (PFGE), were performed on 46 nasopharyngeal and middle ear fluid (MEF) isolates expressing serotype 11A, 45 MEF isolates expressing serotype 15B/C (recovered during 1998-2003 from Israeli children <5 years old), and 57 MEF isolates expressing serotype 19F (recovered during 1998-2001 from Costa Rican children <7.5 years old). RESULTS: PFGE patterns showed that 49 (86%) of 57 serotype 19F isolates and 19 (41%) of 46 serotype 15B/C isolates were closely related. The vast majority of these isolates (80% of serotype 19F and 100% of serotype 15B/C isolates) were nonsusceptible to penicillin. Multilocus sequence typing (MLST) data show that the serotype 15B/C isolates belonged to the ST346 cluster, whereas the serotype 19F isolates were a single-locus variant of ST346. For serotype 11A isolates, PFGE patterns and MLST analysis showed that 8 (80%) of the 10 penicillin-nonsusceptible isolates belonged to a single clone--namely, ST156--which was identical to the international Spain9V-3 clone. CONCLUSIONS: Penicillin-nonsusceptible pneumococcal clones of serotypes not related to those included in the 11-valent conjugate vaccines may derive from capsular transformation of vaccine-related serotypes. Of particular concern was the detection of serotype 11A variants of the successful international Spain9V-3 clone. This phenomenon, although seemingly rare at present, can have implications for the long-term effectiveness of the conjugate vaccines.     

Adrenocorticotropin induces mitogen-activated protein kinase phosphatase 1 in Y1 mouse adrenocortical tumor cells

ACTH signaling pathway includes the action of both protein kinases, mainly cAMP-dependent protein kinase (protein kinase A, PKA), and serine/threonine and tyrosine phosphatases. MAPK phosphatase-1 (MKP-1) is a dual activity protein phosphatase involved in the dephosphorylation of MAPK. To determine whether MKP-1 is a component of ACTH cascade, here we investigate the expression levels of MKP-1 gene in Y1 mouse adrenocortical tumor cells under ACTH stimulation. ACTH transiently increased MKP-1 mRNA and protein levels. MKP-1 mRNA increase occurred at 30 min, peaked at 1 h (6-fold), and returned to basal levels thereafter. The ACTH-mediated mRNA increase was blunted by actinomycin D and enhanced by cycloheximide. A cell permeable cAMP analog, 8-bromo-cAMP, also transiently induced MKP-1 mRNA (4-fold) and the PKA inhibitor N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamid abolished this effect. In contrast, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamid only partially reduced the effect of ACTH, suggesting the participation of PKA-independent mechanisms in the hormone-induced MKP-1 expression. In addition, we show that the rise in intracellular Ca(2+) and protein kinase C activation had a potent synergic effect on ACTH- and 8-bromo-cAMP-mediated MKP-1 induction. In summary, our findings demonstrate that MKP-1 is another component of ACTH signaling cascade and indicate that this hormone may potentially down-regulate MAPKs.     

Prevalence and clinical associations of prolonged prothrombin time in adult untreated coeliac disease

INTRODUCTION: Untreated coeliac disease may induce malabsorption of many nutrients. It may also induce vitamin K deficiency, which causes prolongation of the prothrombin time. The aim of the present study was to evaluate the prevalence and associations of prolonged prothrombin time in a series of coeliac adults. METHODS: We carried out a cross-sectional analysis of data collected on 390 adults with untreated coeliac disease diagnosed from January 1997 to December 2000. Prolonged prothrombin time was defined as INR > or = 1.4. RESULTS: A prolonged prothrombin time was found in 72 coeliac patients (18.5%). Parenteral vitamin K therapy was required in 5.6% of patients. Patients with prolonged prothrombin time had significant lower values of haemoglobin, iron, proteins, cholesterol and serum aspartate transaminase, and significantly higher prevalence of diarrhoea, weight loss, abdominal pain and low bone mineral density in comparison with patients with normal prothrombin time. However, low bone density was present in 11.6% of patients with normal INR. A prolonged prothrombin time was only found in a few patients with subclinical coeliac disease (0.9%). CONCLUSIONS: Data indicate that the prevalence of prolonged prothrombin time is about 20% in a large series of adult untreated coeliac patients. A prolonged prothrombin time was significantly related to all the markers of severe malabsorption, including low mineral density. Our suggestion is that vitamin K related proteins may also play a role in determining or worsening calcium homeostasis disorders in coeliac disease. The very low prevalence of coagulation disorders in subclinical coeliac disease indicates that there is no need to screen for coeliac disease in patients with isolated coagulation disorders.     

Randomized trial of a health communication intervention for parents of children with asthma

Objective: To determine if a health communication intervention targeting parents of high-risk, urban, minority children with asthma could (i) improve parental perceptions of connectedness to and communication with their child's primary care providers (PCP) and (ii) decrease reliance on emergency departments (EDs) and other urgent care services for their child's asthma-related care. Methods: The design was a single blind, parallel groups, randomized controlled trial. Parents were recruited from an ED-based asthma clinic serving primarily low-income, minority children in Washington, DC. The intervention involved face-to-face education on effective communication followed by a single booster call. Standardized instruments were administered to assess primary care connectedness and healthcare utilization at baseline and 2- and 6-months post-enrollment. Results: A total of 150 parents of children 1–12 years old were randomized (77 intervention and 73 usual care), and 137 (91%) were successfully followed for six months. Only at the two-month follow-up time-point, parents in the intervention group were significantly more likely to identify a PCP as the main source of their child's asthma care (adjusted odds ratio: 12.6, 95% confidence interval: 1.1–142.1) and to report a significant reduction in ED visits for asthma care (adjusted incidence rate ratio: 0.3, 95% confidence interval: 0.1–0.8). There was no significant effect on parent communication self-efficacy or number of PCP visits. Conclusions: A brief, in-person health communication intervention for parents of high-risk children with asthma resulted in improved identification of PCPs as the usual source of asthma care and reduced reliance on EDs for asthma care, albeit only for two months post-intervention.     

ACE polymorphism and use of ACE inhibitors: effects on memory performance

Memory is an important cognition function, being fundamental to the development and independence of individuals. Our aim was to investigate the influence apolipoprotein E (APOE) and angiotensin I-converting enzyme (ACE) polymorphism and ACE inhibitors use, besides their interaction on memory performance of healthy subjects over 50 years. The sample consisted of 205 subjects assessed for five types of episodic memory, using Wechsler Memory Scale-Revised (WMS-R), who answered a questionnaire about drug use and were assessed for the ACE insertion/deletion polymorphism and APOE polymorphism. We found no influence of the APOE gene. The use of ACE inhibitors beneficially influenced learning ability scores (p = 0.02). Besides, I allele carriers of ACE polymorphism showed higher verbal memory scores compared with homozygous DD. Also, we observed an interaction influencing learning ability between the ACE polymorphism and the use of inhibitors, the beneficial influence of the I allele was present only in individuals who make use of ACE inhibitors. We conclude that the ACE gene has influence on memory performance, and that this influence is modulated by ACE inhibitors use.     

Impaired Responsiveness to the Platelet P2Y12 Receptor Antagonist Clopidogrel in Patients With Type 2 Diabetes and Coronary Artery Disease

Background

Several studies have shown that patients with diabetes mellitus (DM) exhibit an impaired response to clopidogrel. This may contribute to their increased risk of recurrent atherothrombotic events, despite the use of dual-antiplatelet therapy. The mechanisms for impaired clopidogrel response in DM patients have not been fully elucidated.

Objectives

The aim of this study was to explore the mechanisms for impaired clopidogrel-mediated platelet inhibition in patients with DM using a comprehensive methodological approach embracing both pharmacokinetic (PK) and pharmacodynamic (PD) assessments as well as ex vivo and in vitro investigations.

Methods

Patients (DM, n = 30; non-DM, n = 30) with stable coronary artery disease taking aspirin 81 mg/day and P2Y₁₂ antagonist naive were enrolled. Blood was collected before and at various times (0.5, 1, 2, 4, 6, and 24 h) after a 600-mg loading dose of clopidogrel. PD assessments included vasodilator-stimulated phosphoprotein, light transmission aggregometry, and VerifyNow P2Y₁₂ ex vivo, before and after dosing and following in vitro incubation with escalating concentrations (1, 3, and 10 μM) of clopidogrel’s active metabolite (Clop-AM). Exposure to Clop-AM was also determined.

Results

PD assessments consistently showed that during the overall 24-h study time course, residual platelet reactivity was higher in DM patients compared with non-DM patients. In vitro incubation with Clop-AM revealed altered functional status of the P2Y₁₂ signaling pathway in DM platelets as measured by vasodilator-stimulated phosphoprotein, but not with other PD assays. Clop-AM exposure was ∼40% lower in DM patients than in non-DM patients.

Conclusions

The present study suggests that among DM patients, impaired P2Y₁₂ inhibition mediated by clopidogrel is largely attributable to attenuation of clopidogrel’s PK profile. This is characterized by lower plasma levels of Clop-AM over the sampling time course in DM patients compared with non-DM patients and only modestly attributed to altered functional status of the P2Y₁₂ signaling pathway.