Cross-sectional relations of urinary sodium excretion to cardiac structure and hypertrophy. The Framingham Heart Study

BACKGROUND: Increased sodium intake has been positively associated with high blood pressure (BP) and hypertensive target organ damage, but associations with cardiac structure in nonhypertensive individuals have yielded inconsistent results. We tested the hypothesis that sodium intake is associated with left ventricular (LV) mass and left ventricular hypertrophy (LVH), independent of BP, in the community. METHODS: We analyzed the cross-sectional relationships between urinary sodium excretion and LV measurements in a community-based sample of 2660 Framingham Offspring Study participants (mean age 58 years, 56% women and 44% men). Participants with known coronary artery disease, congestive heart failure, or renal failure as well as those using diuretics were excluded. Urinary sodium excretion was measured on a spot urine sample and was indexed to urinary creatinine. RESULTS: In sex-specific, multivariable linear regression models adjusting for covariates known to influence LV measurements, log urinary sodium was not associated with LV mass, wall thickness, end-diastolic dimensions, or left atrial size in either sex. Urinary sodium was not related to LVH defined as LV mass >/= sex-specific 80th percentile value. In analyses restricted to hypertensive individuals (n = 983, 470 women), urinary sodium was not associated with LV mass or LVH. CONCLUSIONS: In our large community-based sample, urinary sodium excretion was not related to LV mass, function, or hypertrophy.     

A comparison of the short-term effects of oral conjugated equine estrogens versus transdermal estradiol on C-reactive protein, other serum markers of inflammation, and other hepatic proteins in naturally menopausal women

OBJECTIVE: Our objective was to compare the effects of oral vs. transdermal estrogen therapy on C-reactive protein (CRP), IL-6, E- and P-selectin, intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule-1, serum amyloid A, transferrin, prealbumin, IGF-I, SHBG, thyroxine-binding globulin (TBG), and cortisol-binding globulin (CBG) in naturally menopausal women. DESIGN: This was a randomized, open-label crossover clinical trial. A 6-wk withdrawal from prior hormone therapy (baseline) was followed in randomized order by 12-wk oral conjugated equine estrogens (CEEs) (0.625 mg/d) and 12-wk transdermal estradiol (E2) (0.05 mg/d), with oral micronized progesterone (100 mg/d) given continuously during both regimens. RESULTS: A total of 27 women enrolled, and 25 completed both treatment periods. Nine parameters changed significantly during oral CEE (median percent change from baseline; P value): CRP (192%; P <0.001); E-selectin (-16.3%; P = 0.003); P-selectin (-15.3%; P = 0.012); ICAM-1 (-5%; P = 0.015); transferrin (5.3%; P = 0.024); IGF-I (-30.5%; P < 0.001); SHBG (113%; P < 0.001); TBG (38%; P < 0.001); and CBG (20%; P < 0.001). With transdermal E2, only three parameters changed significantly and to a lesser degree: ICAM-1 (-2.1%; P = 0.04); IGF-I (-12.5%; P < 0.001); and SHBG (2.6%; P = 0.042). During oral CEE the intrasubject changes in CRP correlated strongly with the changes in serum amyloid A (r = 0.805; P < 0.001), and were only weakly associated with the changes in SHBG (r = 0.248; nonsignificant), TBG (0.430; P = 0.031), and CBG (r = 0.072; nonsignificant). The log-log relationship between CRP and IL-6 observed at baseline showed a parallel shift during oral CEE, suggesting an amplified hepatic response or a greater sensitivity to IL-6 stimulation. CONCLUSION: Compared with oral CEE, transdermal E2 exerts minimal effects on CRP and the other inflammation and hepatic parameters.     

Kinetics and viral protein specificity of the cytotoxic T lymphocyte response in healthy adults immunized with live attenuated varicella vaccine.

The cytotoxic T lymphocyte (CTL) response was evaluated in adults given live attenuated varicella vaccine, using target cells expressing varicella-zoster virus (VZV) immediate-early protein (IE62) or VZV glycoproteins gpI, gpIV, or gpV to determine viral protein specificity. The frequency of CTL that recognized IE62 was 1:171,000 +/- 46,000 SE in subjects tested 10 days to 8 weeks after the initial vaccine dose; the induction of CTL specific for gpI was equivalent. CTL recognition of VZV proteins was mediated by CD4+ or CD8+ cells. CTL recognition of IE62 and gpIV persisted in vaccinees (tested approximately 4 years later) and was comparable to that in the naturally immune. The mean frequency of CTL specific for gpV was lower (but not significantly) in vaccinees than in naturally immune subjects. Assay of responder cell frequencies showed persistence of equivalent numbers of T lymphocytes that recognized IE62 and gpI in vaccinees and naturally immune subjects. Immunization with this vaccine elicited memory T lymphocyte responses to VZV comparable to those induced by natural infection.     

Haemophagocytic lymphohistiocytosis and Epstein–Barr virus: a complex relationship with diverse origins,expression and outcomes

Epstein–Barr virus (EBV) is a ubiquitous herpesvirus with rare but severe potential for lymphoproliferative complications. EBV is associated with a variety of presentations of haemophagocytic lymphohistiocytosis (HLH). HLH is a life-threatening hyperinflammatory syndrome that can occur in patients with genetic defects associated with dysregulation of the immune response (familial HLH) or arise in patients with underlying infection or malignancy (non-familial or secondary HLH). EBV can both serve as the incidental trigger of familial HLH or as the driving factor in patients with selective inherited vulnerability (e.g. X-linked lymphoproliferative disease). Alternatively, acute infection can idiosyncratically cause non-neoplastic HLH in patients without inherited predisposition (i.e. secondary HLH), while EBV-associated T/natural killer (NK)-cell lymphoproliferative disorders and lymphomas can cause neoplasia-associated HLH. The present review will discern between EBV-associated familial and non-familial HLH and highlight diagnostic and therapeutic considerations. Non-familial EBV-associated HLH is a major diagnostic dilemma, as it represents a diverse spectrum of disease ranging from highly curable (non-neoplastic EBV-HLH) to indolent but incurable (chronic active EBV) to acutely fatal (systemic EBV-positive T-cell lymphoma of childhood). Increased clinical awareness and understanding of this rare and potentially devastating subset of EBV-related complications is desperately needed to improve survival for patients with neoplasia-associated HLH.     

Therapies for multidrug resistant and extensively drug-resistant non-fermenting gram-negative bacteria causing nosocomial infections: a perilous journey toward ‘molecularly targeted’ therapy

Introduction: Non-fermenting Gram-negative bacilli are at the center of the antimicrobial resistance epidemic. Acinetobacter baumannii and Pseudomonas aeruginosa are both designated with a threat level to human health of ‘serious’ by the Centers for Disease Control and Prevention. Two other major non-fermenting Gram-negative bacilli, Stenotrophomonas maltophilia and Burkholderia cepacia complex, while not as prevalent, have devastating effects on vulnerable populations, such as those with cystic fibrosis, as well as immunosuppressed or hospitalized patients.

Areas covered: In this review, we summarize the clinical impact, presentations, and mechanisms of resistance of these four major groups of non-fermenting Gram-negative bacilli. We also describe available and promising novel therapeutic options and strategies, particularly combination antibiotic strategies, with a focus on multidrug resistant variants.

Expert commentary: We finally advocate for a therapeutic approach that incorporates in vitro antibiotic susceptibility testing with molecular and genotypic characterization of mechanisms of resistance, as well as pharmacokinetics and pharmacodynamics (PK/PD) parameters. The goal is to begin to formulate a precision medicine approach to antimicrobial therapy: a clinical-decision making model that integrates bacterial phenotype, genotype and patient’s PK/PD to arrive at rationally-optimized combination antibiotic chemotherapy regimens tailored to individual clinical scenarios.