Therapeutic approaches to patients with hypereosinophilic syndromes

Hypereosinophilic syndromes (HES) are a heterogeneous group of disorders that range from asymptomatic eosinophilia > 1,500/mL to aggressive disease complicated by life-threatening end organ involvement, including endomyocardial fibrosis and thromboembolism. To complicate matters further, similar clinical manifestations can occur in the setting of marked eosinophilia due to helminth infection, drug hypersensitivity, and other causes. In the past, therapy was guided only by the exclusion of these secondary causes of eosinophilia and the severity of the clinical manifestations. More recently, the availability of novel targeted therapies and a better understanding of the etiologies of some subtypes of HES have necessitated a more structured approach.

The transcription factor encyclopedia

Here we present the Transcription Factor Encyclopedia (TFe), a new web-based compendium of mini review articles on transcription factors (TFs) that is founded on the principles of open access and collaboration. Our consortium of over 100 researchers has collectively contributed over 130 mini review articles on pertinent human, mouse and rat TFs. Notable features of the TFe website include a high-quality PDF generator and web API for programmatic data retrieval. TFe aims to rapidly educate scientists about the TFs they encounter through the delivery of succinct summaries written and vetted by experts in the field.

Pathogenesis and classification of eosinophil disorders: a review of recent developments in the field

Eosinophils and their products play an essential role in the pathogenesis of various reactive and neoplastic disorders. Depending on the underlying disease, molecular defect and involved cytokines, hypereosinophilia may develop and may lead to organ damage. In other patients, persistent eosinophilia is accompanied by typical clinical findings, but the causative role and impact of eosinophilia remain uncertain. For patients with eosinophil-mediated organ pathology, early therapeutic intervention with agents reducing eosinophil counts can be effective in limiting or preventing irreversible organ damage. Therefore, it is important to approach eosinophil disorders and related syndromes early by using established criteria, to perform all appropriate staging investigations, and to search for molecular targets of therapy. In this article, we review current concepts in the pathogenesis and evolution of eosinophilia and eosinophil-related organ damage in neoplastic and non-neoplastic conditions. In addition, we discuss classifications of eosinophil disorders and related syndromes as well as diagnostic algorithms and standard treatment for various eosinophil-related disorders.

Consensus standards for acquisition, measurement, and reporting of intravascular optical coherence tomography studies: a report from the International Working Group for Intravascular Optical Coherence Tomography Standardization and Validation

The purpose of this document is to make the output of the International Working Group for Intravascular Optical Coherence Tomography (IWG-IVOCT) Standardization and Validation available to medical and scientific communities, through a peer-reviewed publication, in the interest of improving the diagnosis and treatment of patients with atherosclerosis, including coronary artery disease.

The Returns to Migration: The Influence of Education and Migration Type

We show the impact of migration type on real wages over time. We create a migration and earnings history from the National Longitudinal Survey of Youth over the period 1979-2002. We estimate the effects of primary, onward, and two types of return migration on real wages using a panel data model with individual, location, and time fixed effects. Panel data are well suited for the study of the returns to U.S. internal migration because the influence of migration on wages has been found to occur years after the event. We differentiate return migration into two types: return to a location with ties that form a geographical anchor (home) and return to a prior place of work. We find that real wage growth varies by migration type. Education attainment is a significant factor in real wage growth. Our results show that onward migration is an important channel by which the monetary rewards to a college education are manifested.

The Resilience of Self-Esteem in Late Adulthood

OBJECTIVE: The authors examined the resilience of self-esteem after loss in the lives of older adults. Specifically, the authors investigated the relationship between loss and change in self-esteem during a 3-year period. METHOD: A subsample of older adults (n = 1,278) from the Americans' Changing Lives Study was used to examine loss in the domains of health, financial security, or work and career and self-esteem before and after the loss. RESULTS: There was a small but significant decrease in self-esteem between Wave I and Wave II of the study. Loss in one of the domains explained less than 1% of the variance in self-esteem change. DISCUSSION: The low incidence of loss and small change in high levels of self-esteem are further evidence of resilience in older adults' psychological well-being. The implications for older adults' use of cognitive strategies to manage losses and promote gains are discussed.

AopP, a type III effector protein of Aeromonas salmonicida, inhibits the NF-kappaB signalling pathway

Aeromonas salmonicida subsp. salmonicida contains a functional type III secretion system that is responsible for the secretion of the ADP-ribosylating toxin AexT. In this study, the authors identified AopP as a second effector protein secreted by this system. The aopP gene was detected in both typical and atypical A. salmonicida isolates and was found to be encoded on a small plasmid of approximately 6.4 kb. Sequence analysis indicates that AopP is a member of the YopJ family of effector proteins, a group of proteins that interfere with mitogen-activated protein kinase (MAPK) and/or nuclear factor kappa B (NF-kappaB) signalling pathways. AopP inhibits the NF-kappaB pathway downstream of IkappaB kinase (IKK) activation, while a catalytically inactivated mutant, AopPC177A, does not possess this inhibitory effect. Unlike other effectors of the YopJ family, such as YopJ and VopA, AopP does not inhibit the MAPK signalling pathway.

Approaches to the treatment of hypereosinophilic syndromes: a workshop summary report

Hypereosinophilic syndromes are a heterogeneous group of uncommon disorders characterized by the presence of marked peripheral blood eosinophilia, tissue eosinophilia, or both, resulting in a wide variety of clinical manifestations. Although corticosteroids are the first-line therapy for many of these disorders, approaches to the treatment of patients who do not tolerate or are unresponsive to corticosteroids are poorly standardized. A multidisciplinary group of 37 clinicians and scientists participated in a workshop held in May 2005 in Bern, Switzerland to discuss current and future approaches to therapy for 3 eosinophil-mediated disorders: hypereosinophilic syndrome, Churg-Strauss syndrome, and eosinophil-associated gastrointestinal disease. The goal of the workshop was to summarize available data regarding treatment of these disorders to identify the most promising therapies and approaches for further study. There was consensus among all of the participants that the identification of markers of disease progression to assess treatment responses is a research priority for all 3 disorders. Furthermore, the need for newer therapeutic strategies and novel drugs, as well as multicenter trials to assess all treatment modalities, was emphasized.

Hepatitis C coinfection is independently associated with decreased adherence to antiretroviral therapy in a population-based HIV cohort

OBJECTIVE: To characterize the impact of hepatitis C (HCV) serostatus on adherence to antiretroviral treatment (ART) among HIV-infected adults initiating ART. METHODS: The British Columbia HIV/AIDS Drug Treatment Program distributes, at no cost, all ART in this Canadian province. Eligible individuals used triple combination ART as their first HIV therapy and had documented HCV serology. Statistical analyses used parametric and non-parametric methods, including multivariate logistic regression. The primary outcome was > or = 95% adherence, defined as receiving > or = 95% of prescription refills during the first year of antiretroviral therapy. RESULTS: There were 1186 patients eligible for analysis, including 606 (51%) positive for HCV antibody and 580 (49%) who were negative. In adjusted analyses, adherence was independently associated with HCV seropositivity [adjusted odds ratio (AOR), 0.48; 95% confidence interval (CI), 0.23-0.97; P = 0.003], higher plasma albumin levels (AOR, 1.07; 95% CI, 1.01-1.12; P = 0.002) and male gender (AOR, 2.53; 95% CI, 1.04-6.15; P = 0.017), but not with injection drug use (IDU), age or other markers of liver injury. There was no evidence of an interaction between HCV and liver injury in adjusted analyses; comparing different strata of HCV and IDU confirmed that HCV was associated with poor adherence independent of IDU. CONCLUSIONS: HCV-coinfected individuals and those with lower albumin are less likely to be adherent to their ART.

Arteriolar vasoconstrictive response: comparing the effects of arginine vasopressin and norepinephrine

INTRODUCTION: This study was designed to examine differences in the arteriolar vasoconstrictive response between arginine vasopressin (AVP) and norepinephrine (NE) on the microcirculatory level in the hamster window chamber model in unanesthetized, normotonic hamsters using intravital microscopy. It is known from patients with advanced vasodilatory shock that AVP exerts strong additional vasoconstriction when incremental dosage increases of NE have no further effect on mean arterial blood pressure (MAP). METHODS: In a prospective controlled experimental study, eleven awake, male golden Syrian hamsters were instrumented with a viewing window inserted into the dorsal skinfold. NE (2 microg/kg/minute) and AVP (0.0001 IU/kg/minute, equivalent to 4 IU/h in a 70 kg patient) were continuously infused to achieve a similar increase in MAP. According to their position within the arteriolar network, arterioles were grouped into five types: A0 (branch off small artery) to A4 (branch off A3 arteriole). RESULTS: Reduction of arteriolar diameter (NE, -31 +/- 12% versus AVP, -49 +/- 7%; p = 0.002), cross sectional area (NE, -49 +/- 17% versus AVP, -73 +/- 7%; p = 0.002), and arteriolar blood flow (NE, -62 +/- 13% versus AVP, -80 +/- 6%; p = 0.004) in A0 arterioles was significantly more pronounced in AVP animals. There was no difference in red blood cell velocities in A0 arterioles between groups. The reduction of diameter, cross sectional area, red blood cell velocity, and arteriolar blood flow in A1 to A4 arterioles was comparable in AVP and NE animals. CONCLUSION: Within the microvascular network, AVP exerted significantly stronger vasoconstriction on large A0 arterioles than NE under physiological conditions. This observation may partly explain why AVP is such a potent vasopressor hormone and can increase systemic vascular resistance even in advanced vasodilatory shock unresponsive to increases in standard catecholamine therapy.

Early resuscitation with polymerized bovine hemoglobin reverses acidosis, but not peripheral tissue oxygenation, in a severe hamster shock model

Awake hamsters equipped with the dorsal window chamber preparation were subjected to hemorrhage of 50% of the estimated blood volume. Initial resuscitation (25% of estimated blood volume) with polymerized bovine hemoglobin (PBH) or 10% hydroxyethyl starch (HES) occurred in concert with an equivolumetric bleeding to simulate the early, prehospital setting (exchange transfusion). Resuscitation (25% of estimated blood volume) without bleeding was performed with PBH, HES, or autologous red blood cells (HES-RBCs). Peripheral microcirculation, tissue oxygenation, and systemic hemodynamic and blood gas parameters were assessed. After exchange transfusion, base deficit was -8.6 +/- 3.7 mmol/L (PBH) and -5.1 +/- 5.3 mmol/L (HES) (not significant). Functional capillary density was 17% +/- 6% of baseline (PBH) and 31% +/- 11% (HES) (P < 0.05) and arteriolar diameter 73% +/- 3% of baseline (PBH) and 90% + 5% (HES) (P < 0.01). At the end, hemoglobin levels were 3.7 +/- 0.3 g/dL with HES, 8.2 +/- 0.6 g/dL with PBH, and 10.4 +/- 0.8 g/dL with HES-RBCs (P < 0.01 HES vs. PBH and HES-RBCs, P < 0.05 PBH vs. HES-RBCs). Base excess was restored to baseline with PBH and HES-RBCs, but not with HES (P < 0.05). Functional capillary density was 46% +/- 5% of baseline (PBH), 62% + 20% (HES-RBCs), and 36% +/- 19% (HES) (P < 0.01 HES-RBCs vs. HES). Peripheral oxygen delivery and consumption was highest with HES-RBCs, followed by PBH (P < 0.05 HES-RBCs vs. PBH, P < 0.01 HES-RBCs and PBH vs. HES). In conclusion, the PBH led to a correction of base deficit comparable to blood transfusion. However, oxygenation of the peripheral tissue was inferior with PBH. This was attributed to its negative impact on the peripheral microcirculation caused by arteriolar vasoconstriction.

Rapid restoration of microcirculatory blood flow with hyperviscous and hyperoncotic solutions lowers the transfusion trigger in resuscitation from hemorrhagic shock

Resuscitation from hemorrhagic shock relies on fluid retransfusion. However, the optimal properties of the fluid have not been established. The aim of the present study was to test the influence of the concentration of hydroxyethyl starch (HES) solution on plasma viscosity and colloid osmotic pressure (COP), systemic and microcirculatory recovery, and oxygen delivery and consumption after resuscitation, which were assessed in the hamster chamber window preparation by intravital microscopy. Awake hamsters were subjected to 50% hemorrhage and were resuscitated with 25% of the estimated blood volume with 5%, 10%, or 20% HES solution. The increase in concentration led to an increase in COP (from 20 to 70 and 194 mmHg) and viscosity (from 1.7 to 3.8 and 14.4 cP). Cardiac index and microcirculatory and metabolic recovery were improved with HES 10% and 20% when compared with 5% HES. Oxygen delivery and consumption in the dorsal skinfold chamber was more than doubled with HES 10% and 20% when compared with HES 5%. This was attributed to the beneficial effect of restored or increased plasma COP and plasma viscosity as obtained with HES 10% and 20%, leading to improved microcirculatory blood flow values early in the resuscitation period. The increase in COP led to an increase in blood volume as shown by a reduction in hematocrit. Mean arterial pressure was significantly improved in animals receiving 10% and 20% solutions. In conclusion, the present results show that the increase in the concentration of HES, leading to hyperoncotic and hyperviscous solutions, is beneficial for resuscitation from hemorrhagic shock because normalization of COP and viscosity led to a rapid recovery of microcirculatory parameters.

Comparative efficacy of two mouthrinses in a 6-month study

Objective: The objective of this study was to compare the effects of a commercial CPC (cetylpyridinium chloride) mouthrinse containing 0.07% CPC (Crest® ProHealth Rinse) versus those provided by a commercial essential flavor oil mouthrinse (Listerine® Antiseptic) on dental plaque accumulation and prevention of gingivitis in an unsupervised 6 month clinical study. Methods: This was a double blind, 6-month, parallel group, positive controlled study involving 128 subjects who were balanced and randomly assigned to either positive control (essential oil) or experimental (CPC) mouthrinse treatment groups. The CPC mouthrinse passed proposed performance assays by the FDA for an OTC CPC mouthrinse. At baseline, subjects received a dental prophylaxis and began unsupervised rinsing twice daily with 20 ml. of their assigned mouthrinse for 30 seconds after brushing their teeth for 1 min. Subjects were assessed for gingivitis and gingival bleeding by the Gingival Index (GI) of Loe and Silness and plaque by the Silness and Loe Plaque Index (PI) at baseline and after 3 and 6 months of product use. Oral soft tissue health was also assessed. Microbiological samples were also taken for community profiling by the DNA-DNA checkerboard method. Results: Results show that after 3 and 6 months use there was no significant difference (p = 0.05) between the CPC and essential oil mouthrinse treatment groups for overall gingivitis status, gingival bleeding, and plaque. At 6 months the covariant (baseline) –adjusted mean GI and bleeding sites numbers for the CPC and essential oil mouthrinses were 0.52 and 0.53 and 5.5 and 6.3, respectively. Both mouth rinses were well tolerated by the subjects. Microbiological community profiles were similar for the 2 treatment group. Conclusion: This study shows that the 0.07% CPC mouthrinse can provide similar plaque and gingivitis benefits to those provided by an essential oil mouthrinse over a 6 month period.