TLR9 bone marrow chimeric mice define a role for cerebral TNF in neuroprotection induced by CpG preconditioning

Systemic preconditioning with the TLR9 ligand CpG induces neuroprotection against brain ischemic injury through a tumor necrosis factor (TNF)-dependent mechanism. It is unclear how systemic administration of CpG engages the brain to induce the protective phenotype. To address this, we created TLR9-deficient reciprocal bone marrow chimeric mice lacking TLR9 on either hematopoietic cells or radiation-resistant cells of nonhematopoietic origin. We report that wild-type mice reconstituted with TLR9-deficient hematopoietic cells failed to show neuroprotection after systemic CpG preconditioning. Further, while hematopoietic expression of TLR9 is required for CpG-induced neuroprotection it is not sufficient to restore protection to TLR9-deficient mice that are reconstituted with hematopoietic cells bearing TLR9. To determine whether the absence of protection was associated with TNF, we examined TNF levels in the systemic circulation and the brain. We found that although TNF is required for CpG preconditioning, systemic TNF levels did not correlate with the protective phenotype. However, induction of cerebral TNF mRNA required expression of TLR9 on both hematopoietic and nonhematopoietic cells and correlated with neuroprotection. In accordance with these results, we show the therapeutic potential of intranasal CpG preconditioning, which induces brain TNF mRNA and robust neuroprotection with no concomitant increase in systemic levels of TNF.     

Self-Coding of Fidelity as a Potential Active Ingredient of Consultation to Improve Clinicians’ Fidelity

A key goal for implementation science is the identification of evidence-based consultation protocols and the active ingredients within these protocols that drive clinician behavior change. The current study examined clinicians’ self-coding of fidelity as a potential active ingredient of consultation for the Attachment and Biobehavioral Catch-up (ABC) intervention. It also examined two other potential predictors of clinician fidelity in response to consultation: dosage of consultation and working alliance. Twenty-nine clinicians (97% female, 62% White, M age?=?34 years) participated in a year of weekly fidelity-focused ABC consultation sessions, for which clinicians self-coded fidelity and received consultant feedback on both their coding and their fidelity. Data from the ABC fidelity measure were available for 1067 sessions coded by consultants, and clinicians’ self-coding accuracy was calculated from 1044 sessions coded by both clinicians and consultants. Alliance was measured with the Working Alliance Inventory—Trainee and Supervisor Versions. The study was observational, and fidelity and self-coding accuracy were modeled across time using hierarchical linear modeling. Clinicians’ ABC fidelity, as well as their self-coding accuracy, increased over the course of consultation. Clinicians’ self-coding accuracy predicted their initial fidelity and growth in fidelity. Working alliance was also linked to fidelity and self-coding accuracy. These results suggest that clinician self-coding should be further examined as an active ingredient of consultation. The study has important implications for the design of consultation procedures and fidelity assessments.

     

Differential effect of Serratia protease on platelet surface glycoproteins Ib and V

The effect of a zinc metalloprotease from Serratia marcescens on platelet surface glycoproteins (GP) Ib and V was analyzed. Increasing protease treatments caused progressive loss of GP Ib with appearance of the major fragment, glycocalicin, in the supernatant solution. No GP V was detected in the supernatant solution, and protease-pretreated platelets had the same capacity as control platelets to release fragment 1 of GP V in response to thrombin. The Serratia protease- pretreated platelets did show the lag before thrombin-induced dense granule secretion, characteristic of platelets modified by pretreatment with other nonstimulating proteases. Treatment with Serratia protease gives the only demonstrated selective loss of GP Ib without apparent effect on GP V. It suggests that GP V (1) does not depend on GP Ib for its association with platelets and (2) is not the substrate for protease modification of platelet function.     

Association of prediagnosis endoscopy with stage and survival in adenocarcinoma of the esophagus and gastric cardia

BACKGROUND: Barrett esophagus, a consequence of chronic gastroesophageal reflux disease, is a premalignant condition for adenocarcinoma of the esophagus and, possibly, the gastric cardia. However, the actual use and clinical impact of upper gastrointestinal endoscopy in screening and surveillance for Barrett esophagus are unknown. METHODS: A cohort included 1633 patients with adenocarcinoma (777 esophagus, 856 cardia) who were 70 years or older. They were diagnosed between 1993 and 1996 and were identified from the Surveillance, Epidemiology and End Results program registry. All claims for upper endoscopy and a diagnosis of Barrett esophagus from 1991 through 1 year before diagnosis were identified from linked Medicare files. RESULTS: One or more upper endoscopies before diagnosis were performed in 9.7% of patients (13.0% esophagus, 6.8% cardia) and a diagnosis of Barrett esophagus was present in only 3.7% of patients. A shift toward earlier stage at diagnosis was observed in patients with previous endoscopy or Barrett diagnosis. For example, 62% of patients with esophageal and 49% of patients with cardia tumors who underwent previous endoscopy presented with in situ or local stage carcinoma, compared with 35% and 27% of other patients, respectively. Receipt of endoscopy was also associated with a reduced risk of death for esophageal adenocarcinoma (relative hazard 0.73, 95% confidence interval 0.57-0.93; P = 0.01), but not for adenocarcinoma of the cardia. CONCLUSIONS: Receipt of upper endoscopy at least 1 year before diagnosis of adenocarcinoma, which may reflect prediagnosis screening, was associated with an earlier tumor stage and improved survival. These data support the role of endoscopic screening and surveillance for Barrett esophagus and highlight the underdiagnosis of populations at risk.     

A prospective study of drinking patterns in relation to risk of type 2 diabetes among men

Using data from a 12-year prospective study, we determined the importance of the pattern of alcohol consumption as a risk factor for type 2 diabetes in a cohort of 46,892 U.S. male health professionals who completed biennial postal questionnaires. Overall, 1,571 new cases of type 2 diabetes were documented. Compared with zero alcohol consumption, consumption of 15-29 g/day of alcohol was associated with a 36% lower risk of diabetes (RR = 0.64; 95% CI 0.53-0.77). This inverse association between moderate consumption and diabetes remained if light drinkers rather than abstainers were used as the reference group (RR = 0.60, CI 0.50-0.73). There were few heavy drinkers, but the inverse association persisted to those drinking >/=50 g/day of alcohol (RR = 0.60, CI 0.43-0.84). Frequency of consumption was inversely associated with diabetes. Consumption of alcohol on at least 5 days/week provided the greatest protection, even when less than one drink per drinking day was consumed (RR = 0.48, CI 0.27-0.86). Compared with infrequent drinkers, for each additional day per week that alcohol was consumed, risk was reduced by 7% (95% CI 3-10%) after controlling for average daily consumption. There were similar and independent inverse associations for beer, liquor, and white wine. Our findings suggested that frequent alcohol consumption conveys the greatest protection against type 2 diabetes, even if the level of consumption per drinking day is low. Beverage choice did not alter risk.     

Relationship of ovesity and disease in 73,532 weight-conscious women.

The relationship between obesity and 18 different disease conditions was examined in a cross-sectional study of 73,000 weight-conscious women (TOPS Club members). The women reported an average of 1.6 disease conditions each (based on their responses on a questionnaire). Age-specific rates of occurrence for the age group 30-49 years were calculated for each disease condition. The conditions that were found to be significantly (P smaller than 0.001) correlated with obesity were diabetes, high blood pressure, gallbladder disease, gout, thyroid disease, heart disease, arthritis, and jaundice. When the crude relative risks of obesity for each disease condition were calculated, diabetes was found to be the highest (4.5), high blood pressure was second (3.3), and gallbladder disease was third (2.7).