Objective. There is limited theory regarding the real-world implementation of mental health care in the primary care setting: a type of organizational coordination intervention. The purpose of this study was to develop a theory to conceptualize the potential causes of barriers and facilitators to how local sites responded to this mandated intervention to achieve coordinated mental health care. Methods. Data from 65 primary care and mental health staff interviews across 16 sites were analyzed to identify how coordination was perceived one year after an organizational mandate to provide integrated mental health care in the primary care setting. Results. Standardized referral procedures and communication practices between primary care and mental health were influenced by the organizational factors of resources, training, and work design, as well as provider-experienced organizational boundaries between primary care and mental health, time pressures, and staff participation. Organizational factors and provider experiences were in turn influenced by leadership. Conclusions. Our emergent theory describes how leadership, organizational factors, and provider experiences affect the implementation of a mandated mental health coordination intervention. This framework provides a nuanced understanding of the potential barriers and facilitators to implementing interventions designed to improve coordination between professional groups.

The renoprotective mechanisms of hemeoxygenase-1 (HO-1) in diabetic nephropathy remain to be investigated. We hypothesize that HO-1 protects the kidney from diabetic insult via lowering renal oxidative stress and inflammation. We used control and diabetic SHR with or without HO-1 inducer cobalt protoporphyrin (CoPP) treatment for 6 weeks. Urinary albumin excretion levels were significantly elevated in diabetic SHR compared to control and CoPP significantly attenuated albumin excretion. Immuno-histochemical analysis revealed an elevation in TGF-β staining together with increased urinary collagen excretion in diabetic versus control SHR, both of which were reduced with CoPP treatment. Renal oxidative stress markers were greater in diabetic SHR and reduced with CoPP treatment. The increase in renal oxidative stress was associated with an elevation in renal inflammation in diabetic SHR. CoPP treatment also significantly attenuated the markers of renal inflammation in diabetic SHR. In vitro inhibition of HO with stannous mesoporphyrin (SnMP) increased glomerular NADPH oxidase activity and inflammation and blocked the anti-oxidant and anti-inflammatory effects of CoPP. These data suggest that the reduction of renal injury in diabetic SHR upon induction of HO-1 are associated with decreased renal oxidative stress and inflammation, implicating the role of HO-1 induction as a future treatment of diabetic nephropathy.

Objective

The goals in the current studies were to determine if elasticity in blood vessels is compromised in circadian clock mutant mice (Bmal1-knockout/Bmal1-KO and Per-triple knockout/Per-TKO) and if matrix metalloproteinases might confer these changes in compliance.

Methods and Results

High resolution ultrasound in vivo revealed impaired remodelling and increased pulse wave velocity in arteries of Bmal1-KO and Per-TKO mice. In addition, compliance of remodelled arteries and naïve, pressurized arterioles ex vivo from Bmal1-KO mice and Per-TKO mice was reduced, consistent with stiffening of the vascular bed. The observed vascular stiffness was coincident with dysregulation of MMP-2 and MMP-9 in Bmal1-KO mice. Further, inhibition of matrix metalloproteinases improved indices of pathological remodeling in WT mice, but the effect was abolished in Bmal1-KO mice.

Conclusions

These data reveal that circadian clock dysfunction contributes to hardening of arteries, which may involve impaired control of the extracellular matrix composition.

Background/Aims. Pancreatic ductal adenocarcinoma (PDA) has etiological association with chronic inflammation. Elevated circulating levels of inflammatory mediators, such as monocyte chemoattractant protein-1 (MCP-1), are found in obese individuals. We hypothesized that serum MCP-1 levels are elevated in obese PDA patients. Methods. ELISA was used to analyze MCP-1 serum levels in PDA (n = 62) and intraductal papillary mucinous neoplasms (IPMN) (n = 27). Recursive partitioning statistical analysis investigated the relationship between log MCP-1 and clinicopathological parameters. Results. Log MCP-1 values were significantly (P < 0.05) elevated in patients with BMI ≥ 37.5. In patients with BMI < 37.5, average log MCP-1 values were significantly elevated in PDA patients when compared to IPMN patients. Within the IPMN group, higher log MCP-1 levels correlated with increased age. Recursive partitioning analysis of IPMN versus PDA revealed a strategy of predicting characteristics of patients who are more likely to have cancer. This strategy utilizes log MCP-1 as the primary factor and also utilizes smoking status, gender, and age. Conclusion. MCP-1 is a promising biomarker in pancreatic cancer. The potential of using MCP-1 to distinguish PDA from IPMN patients must be studied in larger populations to validate and demonstrate its eventual clinical utility.

Introduction

Cigarette smoke and nicotine are among the leading environmental risk factors for developing pancreatic ductal adenocarcinoma (PDA). We showed recently that nicotine induces osteopontin (OPN), a protein that plays critical roles in inflammation and tumor metastasis. We identified an OPN isoform, OPNc, that is selectively inducible by nicotine and highly expressed in PDA tissue from smokers. In this study, we explored the potential proinflammatory role of nicotine in PDA through studying its effect on the expression of monocyte chemoattractant protein- (MCP)-1 and evaluated the role of OPN in mediating these effects.

Methods

MCP-1 mRNA and protein in PDA cells treated with or without nicotine (3–300 nM) or OPN (0.15–15 nM) were analyzed by real time PCR and ELISA. Luciferase-labeled promoter studies evaluated the effects of nicotine and OPN on MCP-1 transcription. Intracellular and tissue colocalization of OPN and MCP-1 were examined by immunofluorescence and immunohistochemistry.

Results

Nicotine treatment significantly increased MCP-1 expression in PDA cells. Interestingly, blocking OPN with siRNA or OPN antibody abolished these effects. Transient transfection of the OPNc gene in PDA cells or their treatment with recombinant OPN protein significantly (P<0.05) increased MCP-1 mRNA and protein and induced its promoter activity. MCP-1 was found in 60% of invasive PDA lesions, of which 66% were smokers. MCP-1 colocalized with OPN in PDA cells and in the malignant ducts, and correlated well with higher expression levels of OPN in the tissue from patients with invasive PDA.

Conclusions

Our data suggest that cigarette smoking and nicotine may contribute to PDA inflammation through inducing MCP-1 and provide a novel insight into a unique role for OPN in mediating these effects.

Females are less sensitive to the hypertensive effects of angiotensin II compared to males, although the molecular mechanisms responsible are unknown. We hypothesize that differential activation of angiotensin II, Ang (1–7), AT1, AT2, and mas levels in the renal cortex of male and female spontaneously hypertensive rats contribute to sex differences in the blood pressure response to angiotensin II infusion. Males had a greater increase in blood pressure following angiotensin II infusion than females (males: 150±2 to 186±3 mmHg; females: 137±3 to 160±4 mmHg; p<0.05). Angiotensin II infusion resulted in comparable increases in plasma and renal cortical angiotensin II levels in both sexes. Renal cortical Ang (1–7) levels were higher in female rats under basal conditions (195±10 vs. 67±11 ng/gram cortex, p<0.05) and following angiotensin II infusion (281±25 vs. 205±47 ng/gram cortex, p<0.05) compared to male rats. In the renal cortex of male rats, angiotensin II infusion decreased AT1 protein expression and increased AT2 expression with no change in mas expression. In female rats there was an increase in mas receptor protein expression with angiotensin II infusion although AT1 and AT2 expression were unchanged. Male and female rats were then treated with the Ang (1–7) mas receptor antagonist, A-779, in the absence and presence of angiotensin II. A-779 equalized the blood pressure response to angiotensin II in males and females (blood pressure at the end of treatment: males, 166±4; females, 164±5 mmHg). In conclusion, Ang (1–7) contributes to the sex difference in angiotensin II-induced increases in blood pressure in spontaneously hypertensive rats.

Individuals with Down syndrome (DS) exhibit a cholinergic deficiency similar to that found in Alzheimer’s disease. Cholinesterase inhibitors, used to treat Alzheimer’s disease, may improve cognitive function in individuals with DS. This is the first investigation of the safety and efficacy of rivastigmine (an acetyl and butyryl cholinesterase inhibitor) on specific cognitive domains in pediatric DS. Eleven subjects with DS (ages 10–17 years) were treated with a liquid formulation of rivastigmine. Four subjects experienced no adverse events (AEs). Seven subjects reported AEs that were mild, transient and consistent with adverse events typically noted with cholinesterase inhibitors. Significant improvements were found in over-all adaptive function (Vineland Adaptive Behavior Scales and Clinician’s Interview-Based Impression of Change), attention (Leiter Attention Sustained tests A and B), memory (NEPSY: Narrative and Immediate Memory for Names subtests) and language (Test of Verbal Expression and Reasoning and Clinical Evaluation of Language Fundamentals–Preschool) domains. Improved language performance was found across all functional levels. These results underscore the need for larger, controlled studies employing a carefully constructed test battery capable of measuring the full scope of performance across multiple domains and a wide range of functional levels.

At present, there is no proven pharmacologic treatment for cognitive or language impairments in Down syndrome (DS). Cholinergic deficits have been documented in DS and linked to cognitive deficits. This study is a 24-week open-label clinical trial of donepezil hydrochloride for the treatment of language deficits in adults with DS. To our knowledge, this is the first prospective study to evaluate systematically the effects of donepezil, a cholinesterase inhibitor, on specific language domains in DS. The main finding that emerged was an improvement in expressive language performance following donepezil therapy. Despite the multiple methodological limitations, the results raise important questions regarding the role of the cholinergic system in language function and the specific effect of cholinergic therapy in the treatment of language impairment in DS. The results support the need for large-scale controlled studies of the effects of donepezil treatment on language and on other cognitive domains in DS.

High soy (HS) diets are neuroprotective and promote vascular dilatation in the periphery. We hypothesized that a HS diet would promote vascular dilatation in the cerebrovasculature by mimicking estradiol's actions on the endothelial nitric oxide synthase (eNOS) system including increasing eNOS expression and decreasing caveolin-1 expression to increase nitric oxide (NO) production. Ovariectomized rats were fed HS or a soy-free diet (SF) ± low physiological estradiol (E2) for 4 weeks. Neither E2 nor HS altered middle cerebral artery (MCA) structure or vascular responses to acetylcholine, serotonin, or phenylephrine. Estradiol enhanced bradykinin-induced relaxation in an eNOS-dependent manner. Although E2 and HS increased eNOS mRNA expression in the brain and cerebrovasculature, they had no effect on eNOS protein expression or phosphorylation in the MCA. However, E2 decreased caveolin-1 protein in the MCA. In MCAs neither E2 nor HS altered estrogen receptor (ER) alpha expression, but E2 did reduce ER beta levels. These data suggest that HS diets have no effect on vascular NO production, and that E2 may modulate basal NO production by reducing the expression of caveolin-1, an allosteric inhibitor of NOS activity. However, the effects of E2 and HS on the cerebrovasculature are small and may not underlie their protective actions in pathological states.

ERK1/2 has been reported to play a role in vascular dysfunction associated with mineralocorticoid hypertension. We hypothesized that compared to females, an upregulation of ERK1/2 signaling in the vasculature of male rats contributes to augmented contractile responses in mineralocorticoid hypertension. Uninephrectomized (UNI) male and female Sprague-Dawley rats received DOCA pellets (200 mg/animal) and saline to drink for three weeks. Control UNI rats received tap water to drink. Blood pressure, measured by telemetry, was significantly higher in male DOCA rats (191±3 mmHg) compared to female DOCA rats (172±7 mmHg, n=5). DOCA treatment resulted in augmented contractile responses to phenylephrine in aorta (22±3 mN, n=6) and small mesenteric arteries (13±2 mN, n=6) from male DOCA rats vs. UNI male rats (16±3 and 10±2; p<0.05, respectively) and female DOCA rats (15±1mN and 11±1mN, respectively). ERK1/2 inhibition with PD-98059 (10µmol/L) abrogated increased contraction to phenylephrine in aorta (14±2 mN) and small mesenteric arteries (10±2 mN) from male DOCA rats, without any effects in arteries from male UNI or female animals. Compared to the other groups, phosphorylated ERK1/2 levels were increased in aorta from male DOCA rats, whereas mitogen-activated protein kinase phosphatase-1 (MKP-1) expression was decreased. Interleukin-10 plasma levels, which positively regulate MKP-1 activity, were reduced in male DOCA-salt rats. We speculate that augmented vascular reactivity in male hypertensive rats is mediated via activation of the ERK1/2 pathway. Additionally, MKP-1 and interleukin-10 play a regulatory role in this process.

Introduction

Osteopontin (OPN) is a secreted phosphoprotein that confers on cancer cells a migratory phenotype. We showed recently that nicotine, a major risk factor in pancreatic ductal adenocarcinoma (PDA), increases OPN expression in PDA cells. An OPN splice variant, OPNc, supports anchorage independence and maybe the most potent OPN isoform to convey metastatic behavior. In this study, we tested the effect of nicotine on OPNc expression, and analyzed the correlation between total OPN/OPNc levels and patients’ smoking history.

Methods

Real time PCR and UV-light-illumination of ethidium-bromide staining were used to examine the mRNA expression in tissue and in PDA cells treated with or without nicotine (3-300 nM). OPN and OPNc were localized by immunohisotchemistry, and ELISA was used to analyze OPN serum levels.

Results

Nicotine treatment of PDA cells selectively induced denovo expression of OPNc. OPNc was found in 87% of invasive PDA lesions, of which 73% were smokers. The levels of OPNc correlated well with higher expression levels of total OPN in the tissue and serum from patients with invasive PDA.

Conclusions

Our data suggest that smoking and nicotine may contribute to PDA metastatic potential through promoting OPNc expression. Although the direct role of OPNc in PDA progression is not defined, OPNc may have value as a diagnostic and prognostic marker, especially in invasive PDA.

Objectives

This study assessed students’ awareness of radiation exposures and determined the impact a curriculum in clinical radiology (CICR) had on awareness.

Methods

Six hundred seventy medical students at one medical school were studied. CICR was delivered in yearly modules over the 5-year programme. Five hundred twenty-three students (years 1–5), exposed to increasing numbers of CICR modules and 147 students beginning medical school (year 0), represented the study and control groups, respectively. Students completed a multiple choice questionnaire assessing radiation knowledge and radiology teaching.

Results

Most students in the study population received CICR but 87% considered they had not received radiation protection instruction. The percentage of correctly answered questions was significantly higher in the study population than the control group (59.7% versus 38%, p < 0.001). Students who received CICR achieved higher scores than those who did not (61.3% compared with 42.8%, p < 0.001). Increasing exposure to CICR with each year of medical education was associated with improved performance.

Conclusions

Assessment of students’ awareness of radiation exposures in diagnostic imaging demonstrates improved performance with increasing years in medical school and/or increasing exposure to CICR. Findings support the Euroatom 97 directive position, advocating implementation of radiation protection instruction into the undergraduate medical curriculum.

Objectives

This study assessed students’ awareness of radiation exposures and determined the impact a curriculum in clinical radiology (CICR) had on awareness.

Methods

Six hundred seventy medical students at one medical school were studied. CICR was delivered in yearly modules over the 5-year programme. Five hundred twenty-three students (years 1–5), exposed to increasing numbers of CICR modules and 147 students beginning medical school (year 0), represented the study and control groups, respectively. Students completed a multiple choice questionnaire assessing radiation knowledge and radiology teaching.

Results

Most students in the study population received CICR but 87% considered they had not received radiation protection instruction. The percentage of correctly answered questions was significantly higher in the study population than the control group (59.7% versus 38%, p < 0.001). Students who received CICR achieved higher scores than those who did not (61.3% compared with 42.8%, p < 0.001). Increasing exposure to CICR with each year of medical education was associated with improved performance.

Conclusions

Assessment of students’ awareness of radiation exposures in diagnostic imaging demonstrates improved performance with increasing years in medical school and/or increasing exposure to CICR. Findings support the Euroatom 97 directive position, advocating implementation of radiation protection instruction into the undergraduate medical curriculum.

Endothelin (ET) receptor blockade delays the progression of diabetic nephropathy; however, the mechanism of this protection is unknown. Therefore, the aim of this study was to test the hypothesis that ETA receptor blockade attenuates superoxide production and inflammation in the kidney of diabetic rats. Diabetes was induced by streptozotocin (HG), and Sham rats received vehicle treatments. Some rats also received the ETA antagonist ABT-627 (Sham+ABT and HG+ABT; 5 mg·kg−1·day−1, n=8–10/group). During the 10 week study, urinary microalbumin was increased in HG rats and this effect was prevented by ETA receptor blockade. Indices of oxidative stress, urinary excretion of thiobarbituric acid reactive substances (TBARS), 8-hydroxy2-deoxyguanosine (8-OHdG), and H2O2 and plasma TBARS, were significantly greater in HG rats than sham rats. These effects were not prevented by ABT-627. Additionally, renal cortical expression of 8-OHdG and NADPH oxidase subunits was not different between HG and HG+ABT rats. ETA receptor blockade attenuated increases in macrophage infiltration and urinary excretion of TGF-β and PGE2 metabolites in HG rats. Thus, while ABT-627 did not alleviate oxidative stress in HG rats, inflammation and production of inflammatory mediators were reduced in association with prevention of microalbuminuria. These observations indicate that ETA receptor activation mediates renal inflammation TGF-β production in diabetes, and are consistent with the postulate that ETA blockade slows progression of diabetic nephropathy via an anti-inflammatory mechanism.

The pR and pRM promoters of bacteriophage lambda direct transcription in divergent directions from start sites separated by 83 phosphodiester bonds. We had previously shown that the presence of an RNA polymerase at pR interfered with open complex formation at pRM and that this effect was alleviated by the deletion of 10 bp between the two promoters. Here we present a detailed characterization of the dependence of the interference on the interpromoter distance. It was found that the reduced interference between the two promoters is unique to the 10-bp deletion. The relief of interference was demonstrated to be due to the facilitation of a step subsequent to RNA polymerase binding to the pRM promoter. A model to explain these observations is proposed. A search of known Escherichia coli promoters identified three pairs of divergent promoters with similar separations to those investigated here.