Smoking status and differential white cell count in men and women in the EPIC-Norfolk population

The total white blood cell (WBC) count is reported to be an independent predictor of mortality in several prospective studies. We investigated the association between total and differential WBC counts and cigarette smoking habit in a cross-sectional population-based study of 6902 men and 8405 women 39-79 years of age participating between July 1994 and 1997 in the European Prospective Investigation of Cancer (EPIC-Norfolk) study. Main outcome measures included WBC, granulocyte, lymphocyte and monocyte counts measured at a baseline health check and self-reported cigarette smoking habit. The age- and body mass index-adjusted mean total WBC counts were 7.8, 6.4, and 6.2x10(3) per ul (P<0.0001) among male current, former and never smokers, respectively, and 7.4, 6.3 and 6.2x10(3) per ul (P<0.0001), respectively, in women. The greatest absolute and percentage differences between smoking groups were observed for the granulocyte count. Current smoking habit had a stronger effect on mean total WBC counts than cumulative exposure as measured by pack years. Among former smokers mean age- and body mass index-adjusted WBC, granulocyte and lymphocyte counts were inversely related to duration of smoking cessation (P< or =0.02). Smokers who had given up less than 12 months previously had WBC counts substantially lower (6.7 and 6.9x10(3) per ul, respectively, in men and women) than current smokers. In conclusion, the total WBC count and its components (particularly the granulocyte count) are strongly associated with cigarette smoking habit. Smoking cessation may have an almost immediate impact at least on pathophysiologic processes such as inflammation that may be indicated by the WBC count. The apparent almost immediate reversibility of effects of smoking on inflammation, as indicated by the WBC count, may help motivate efforts to stop smoking.     

Treatment preferences among depressed primary care patients

OBJECTIVE: To understand patient factors that may affect the probability of receiving appropriate depression treatment, we examined treatment preferences and their predictors among depressed primary care patients. DESIGN: Patient questionnaires and interviews. SETTING: Forty-six primary care clinics in 7 geographic regions of the United States. PARTICIPANTS: One thousand one hundred eighty-seven English-and Spanish-speaking primary care patients with current depressive symptoms. MEASUREMENTS AND MAIN RESULTS: Depressive symptoms and diagnoses were determined by the Composite International Diagnostic Interview (CIDI) and the Center for Epidemiological Studies Depression Scale (CES-D). Treatment preferences and characteristics were assessed using a self-administered questionnaire and a telephone interview. Nine hundred eight-one (83%) patients desired treatment for depression. Those who preferred treatment were wealthier (odds ratio [OR], 3.7; 95% confidence interval [95% CI], 1.8 to 7.9; P=.001) and had greater knowledge about antidepressant medication (OR, 2.6; 95% CI, 1.6 to 4.4; P≤.001) than those who did not want treatment. A majority (67%, n=660) of those preferring treatment preferred counseling, with African Americans (OR, 2.2; 95% CI, 1.0 to 4.8, P=.04 compared to whites) and those with greater knowledge about counseling (OR, 2.1; 95% CI, 1.6 to 2.7, P≤.001) more likely to choose counseling. Three hundred twelve (47%) of the 660 desiring counseling preferred group over individual counseling. Depression severity was only a predictor of preference among those already in treatment. CONCLUSIONS: Despite low rates of treatment for depression, most depressed primary care patients desire treatment, especially counseling. Preferences for depression treatment vary by ethnicity, gender, income, and knowledge about treatments. Salary support for Dr. Dwight-Johnson from NIMH grant K 12 MH00990-01-01, Partners in Care study funded by Agency for Health Care Policy and Research grant HS08349-02.     

Electrocardiographic and morphometric features in patients with ventricular tachycardia of right ventricular origin

Objective—To study differences between repetitive monomorphic ventricular tachycardia (RMVT) of right ventricular origin, and ventricular tachycardia in arrhythmogenic right ventricular dysplasia (ARVD).
Patients—Consecutive groups with RMVT (n = 15) or ARVD (n = 12), comparable for age and function.
Methods—Analysis of baseline, tachycardia, and signal averaged ECGs, clinical data, and right endomyocardial biopsies. Pathological findings were related to regional depolarisation (QRS width) and repolarisation (QT interval, QT dispersion).
Results—There was no difference in age, ejection fraction, QRS width in leads I, V1, and V6, and QT indices. During ventricular tachycardia, more patients with ARVD had a QS wave in V1 (p < 0.05). There were significant differences for unfiltered QRS, filtered QRS, low amplitude signal duration, and the root mean square voltage content. In the absence of bundle branch block, differences became non-significant for unfiltered and filtered QRS duration. Mean (SD) percentage of biopsy surface differed between RMVT and ARVD: normal myocytes (74(3.4)% v 64.5(9.3)%; p < 0.05); fibrosis (3(1.7)% v 8.9(5.2)%; p < 0.05). When all patients were included, there were significant correlations between fibrosis and age (r = 0.6761), and fibrosis and QRS width (r = 0.5524 for lead I; r = 0.5254 for lead V1; and r = 0.6017 for lead V6).
Conclusions—The ECG during tachycardia and signal averaging are helpful in discriminating between ARVD and RMVT patients. There are differences in the proportions of normal myocytes and fibrosis. The QRS duration is correlated with the amount of fibrous tissue in patients with ventricular tachycardia of right ventricular origin.

Keywords: arrhythmogenic right ventricular dysplasia; electrocardiography; endomyocardial biopsy; ventricular arrhythmias     

G‐CSF Priming,clofarabine, and high dose cytarabine (GCLAC) for upfront treatment of acute myeloid leukemia,advanced myelodysplastic syndrome or advanced myeloproliferative neoplasm

Prior study of the combination of clofarabine and high dose cytarabine with granulocyte colony‐stimulating factor (G‐CSF) priming (GCLAC) in relapsed or refractory acute myeloid leukemia resulted in a 46% rate of complete remission despite unfavorable risk cytogenetics. A multivariate analysis demonstrated that the remission rate and survival with GCLAC were superior to FLAG (fludarabine, cytarabine, G‐CSF) in the relapsed setting. We therefore initiated a study of the GCLAC regimen in the upfront setting in a multicenter trial. The objectives were to evaluate the rates of complete remission (CR), overall and relapse‐free survival (OS and RFS), and toxicity of GCLAC. Clofarabine was administered at 30 mg m^?2 day^?1 × 5 and cytarabine at 2 g m^?2 day^?1 × 5 after G‐CSF priming in 50 newly‐diagnosed patients ages 18–64 with AML or advanced myelodysplastic syndrome (MDS) or advanced myeloproliferative neoplasm (MPN). Responses were assessed in the different cytogenetic risk groups and in patients with antecedent hematologic disorder. The overall CR rate was 76% (95% confidence interval [CI] 64–88%) and the CR + CRp (CR with incomplete platelet count recovery) was 82% (95% CI 71–93%). The CR rate was 100% for patients with favorable, 84% for those with intermediate, and 62% for those with unfavorable risk cytogenetics. For patients with an antecedent hematologic disorder (AHD), the CR rate was 65%, compared to 85% for those without an AHD. The 60 day mortality was 2%. Thus, front line GCLAC is a well‐tolerated, effective induction regimen for AML and advanced myelodysplastic or myeloproliferative disorders. Am. J. Hematol. 90:295–300, 2015. © 2014 Wiley Periodicals, Inc.     

Human microglia and astrocytes constitutively express the neurokinin-1 receptor and functionally respond to substance P

Background

The tachykinin substance P (SP) is recognized to exacerbate inflammation at peripheral sites via its target receptor, neurokinin 1 receptor (NK-1R), expressed by leukocytes. More recently, SP/NK-1R interactions have been associated with severe neuroinflammation and neuronal damage. We have previously demonstrated that NK-1R antagonists can limit neuroinflammatory damage in a mouse model of bacterial meningitis. Furthermore, we have since shown that these agents can attenuate bacteria-induced neuronal and glial inflammatory mediator production in nonhuman primate (NHP) brain explants and isolated neuronal cells, and following in vivo infection.

Methods

In the present study, we have assessed the ability of NHP brain explants, primary human microglia and astrocytes, and immortalized human glial cell lines to express NK-1R isoforms. We have utilized RT-PCR, immunoblot analysis, immunofluorescent microscopy, and/or flow cytometric analysis, to quantify NK-1R expression in each, at rest, or following bacterial challenge. Furthermore, we have assessed the ability of human microglia to respond to SP by immunoblot analysis of NF-kB nuclear translocation and determined the ability of this neuropeptide to augment inflammatory cytokine release and neurotoxic mediator production by human astrocytes using an ELISA and a neuronal cell toxicity assay, respectively.

Results

We demonstrate that human microglial and astrocytic cells as well as NHP brain tissue constitutively express robust levels of the full-length NK-1R isoform. In addition, we demonstrate that the expression of NK-1R by human astrocytes can be further elevated following exposure to disparate bacterial pathogens or their components. Importantly, we have demonstrated that NK-1R is functional in both human microglia and astrocytes and show that SP can augment the inflammatory and/or neurotoxic immune responses of glial cells to disparate and clinically relevant bacterial pathogens.

Conclusions

The robust constitutive and functional expression of the full-length NK-1R isoform by human microglia and astrocytes, and the ability of SP to augment inflammatory signaling pathways and mediator production by these cells, support the contention that SP/NK-1R interactions play a significant role in the damaging neuroinflammation associated with conditions such as bacterial meningitis.