bluuebunny/crossref_metadata_2025 huggingface dataset:
Intact Endothelium-Dependent Dilation and Conducted Responses in Resistance Vessels of Hypercholesterolemic Mice in vivo
Authors: Wölfle Stephanie E. , de Wit Cor
Published: September 2005

Atherosclerosis and hyperlipidemia impair endothelium-dependent nitric oxide (NO)-mediated dilations in conducting arteries. In addition to NO, the endothelium releases an endothelium-derived hyperpolarizing factor (EDHF) in response to acetylcholine (ACh), which is particularly important in microvessels and initiates a dilation that conducts along the vessel through gap junctional communication. The expression of connexins is, however, altered by hypercholesterolemia. Therefore, we studied endothelium-dependent dilations and their conduction in murine hypercholesterolemic models. Dilations were assessed by intravital microscopy in arterioles with a diameter of ∼35 µm in ApoE and LDL receptor (LDLR–/–)-deficient mice after superfusion or locally confined application of ACh. ACh induced comparable concentration-dependent dilations in wild-type, LDLR–/–, and ApoE–/– mice fed a normal or high-cholesterol diet, however EC50 was slightly higher in ApoE–/– mice. Furthermore, the NO donor sodium-nitroprusside dilated arterioles to a similar extent (∼60%). Locally initiated ACh dilations (∼68%) conducted up to a distance of 1,100 µm without significant attenuation even under severe hypercholesterolemic conditions. Since ACh dilation in the arterioles of mice is mainly mediated via EDHF, we conclude that hypercholesterolemia does not alter EDHF release and efficacy. This conclusion is confirmed by an intact conducted response since EDHF is a prerequisite for this response. The intact conduction also suggests that gap-junctional communication is functionally preserved in these models.
Ethnic Variation in Hypertension Among Premenopausal and Perimenopausal Women
Authors: Lloyd-Jones Donald M. , Sutton-Tyrrell Kim , Patel Ami S. , Matthews Karen A. , Pasternak Richard C. , Everson-Rose Susan A. , Scuteri Angelo , Chae Claudia U.
Published: September 2005

Data are sparse regarding hypertension prevalence, treatment, and control among some ethnic groups of American women. Furthermore, the effects of ethnicity on hypertension, independent of other factors that vary with ethnicity, are poorly understood. We examined the prevalence of hypertension (defined as systolic ≥140 or diastolic ≥90 mm Hg or receiving treatment), treatment, and control (to <140/<90 mm Hg) in a multiethnic study of premenopausal and perimenopausal women. Stepwise multivariable logistic regression was used to select covariates associated with hypertension. Among 3292 women, 46.9% were white, 28.3% were black, 8.7% were Hispanic, 7.6% were Chinese, and 8.5% were Japanese. Among these 5 ethnic groups, respectively, there was substantial variation in prevalence of normal blood pressure levels (<120/<80 mm Hg; 59.9%, 35.4%, 16.8%, 67.2%, and 63.7%) and hypertension (14.5%, 38.1%, 27.6%, 12.8%, and 11.0%). After multivariable adjustment, hypertension prevalence was 2 to 3× higher among black and Hispanic women but similar among Chinese and Japanese women compared with white women. Among hypertensive participants, prevalence of antihypertensive treatment was highest among blacks (58.9%) and whites (55.2%) and lowest among Chinese (34.4%). Prevalence of control to goal blood pressure levels was highest among whites (43.0%) and Japanese (38.7%) and markedly lower among Hispanic women (11.4%). Compared with whites, black and Hispanic women have significantly higher prevalence of hypertension independent of other factors, whereas Chinese and Japanese women have similar prevalence. Treatment and control rates vary considerably across ethnicities. Greater efforts must be made to improve hypertension awareness, treatment, and control in all middle-aged women, particularly those in ethnic minority groups.
Synergistic Neovascularization by Mixed Transplantation of Early Endothelial Progenitor Cells and Late Outgrowth Endothelial Cells
Authors: Yoon Chang-Hwan , Hur Jin , Park Kyung-Woo , Kim Ji-Hyun , Lee Choon-Soo , Oh Il-Young , Kim Tae-Youn , Cho Hyun-Jai , Kang Hyun-Jae , Chae In-Ho , Yang Han-Kwang , Oh Byung-Hee , Park Young-Bae , Kim Hyo-Soo
Published: September 2005

Background—

Two types of cells are cultured from the human peripheral blood, early endothelial progenitor cells (EPCs) and outgrowth endothelial cells (OECs), as previously reported. Here, we further characterize these cells, especially with respect to their different origins and functions both in vitro and in vivo. We also investigated whether the combination of these different cell types shows synergism during neovascularization.

Methods and Results—

Early EPCs were heterogeneously made up of both CD14
+
monocyte-derived cells, which secrete cytokines, and CD14
−
-derived cells, which contain high levels of CD34
+
KDR
+
cells. OECs were cultured almost exclusively from CD14
−
cells, not CD14
+
cells, and were distinct from mature endothelial cells in terms of proliferation potential, KDR
+
expression level, and telomerase activity. A portion of cells from CD14
−
cells and early EPCs produced rapidly proliferating, capillary-forming cells in both the Matrigel plug and the ischemic hind limb similar to OECs. Early EPCs and OECs expressed receptors for vascular endothelial growth factor and interleukin-8, cytokines secreted by early EPCs. There was a differential increase in matrix metalloproteinases (MMPs): MMP-9 in early EPCs and MMP-2 in OECs. In vitro, the angiogenic capability of the 2 cell types was augmented by mutual interaction through cytokines and MMPs. Injection of a mixture of the 2 cells resulted in superior neovascularization in vivo to any single-cell-type transplantation.

Conclusions—

Distinct origins of the different types of EPCs exist that have different functions in neovascularization. Mixed transplantation of these cells results in synergistic neovascularization through cytokines and MMPs.
Acculturation and Socioeconomic Position as Predictors of Coronary Calcification in a Multiethnic Sample
Authors: Diez Roux Ana V. , Detrano Robert , Jackson Sharon , Jacobs David R. , Schreiner Pamela J. , Shea Steven , Szklo Moyses
Published: September 2005

Background—

Coronary calcium has recently emerged as a marker of subclinical coronary heart disease. Although there has been much interest in race differences in calcification, heterogeneity within race or ethnic groups has not been investigated.

Methods and Results—

Data from the Multi-Ethnic Study of Atherosclerosis (MESA), a population-based study of coronary calcification, were used to investigate acculturation and socioeconomic position as predictors of coronary calcification within 2553 non-Hispanic whites, 1734 non-Hispanic blacks, 1457 Hispanics, and 797 Chinese residing in the United States. Coronary calcium was assessed by chest CT. Relative risk regression and linear regression were used to estimate adjusted associations of sociodemographic variables with the presence and amount of calcium. Not being born in the United States was associated with a lower prevalence of calcification in blacks (relative prevalence [RP], 0.75; 95% confidence limit [CL], 0.61 to 0.94) and Hispanics (RP, 0.89; 95% CL, 0.81 to 0.98) after adjustment for age, sex, income, and education. Years in the United States was positively associated with prevalence of calcification in non–US-born Chinese (adjusted RP per 10 years in United States, 1.06; 95% CL, 1.01 to 1.11) and non–US-born blacks (RP, 1.59; 95% CL, 1.22 to 2.06). Low education was associated with a higher prevalence of calcification in whites (adjusted RP for no high school versus complete college, 1.17; 95% CL, 1.05 to 1.32) but with lower prevalence of calcification in Hispanics (RP, 0.91; 95% CL, 0.77 to 1.09) (
P
for interaction=0.02). US birth and time in the United States were also positively associated with the extent of calcification in persons with detectable calcium. These differences did not appear to be accounted for by smoking, body mass index, LDL and HDL cholesterol, hypertension, and diabetes.

Conclusions—

Acculturation and socioeconomic factors are associated with differences in the prevalence and amount of coronary calcification within whites, Chinese, blacks, and Hispanics. The presence of this heterogeneity needs to be acknowledged in the quantification and investigation of race/ethnic differences.
Left Ventricular Reverse Remodeling but Not Clinical Improvement Predicts Long-Term Survival After Cardiac Resynchronization Therapy
Authors: Yu Cheuk-Man , Bleeker Gabe B. , Fung Jeffrey Wing-Hong , Schalij Martin J. , Zhang Qing , van der Wall Ernst E. , Chan Yat-Sun , Kong Shun-Ling , Bax Jeroen J.
Published: September 2005

Background—

In patients with severe heart failure and dilated cardiomyopathy, cardiac resynchronization therapy (CRT) improves left ventricular (LV) systolic function associated with LV reverse remodeling and favorable 1-year survival. However, it is unknown whether LV reverse remodeling translates into a better long-term prognosis and what extent of reverse remodeling is clinically relevant, which were investigated in this study.

Methods and Results—

Patients (n=141) with advanced heart failure (mean±SD age, 64±11 years; 73% men) who received CRT were followed up for a mean (±SD) of 695±491 days. The extent of reduction in LV end-systolic volume (LVESV) at 3 to 6 months relative to baseline was examined for its predictive value on long-term clinical outcome. The cutoff value for LV reverse remodeling in predicting mortality was derived from the receiver operating characteristic curve. Then the relation between potential predictors of mortality and heart failure hospitalizations were compared by Kaplan-Meier survival analysis, followed by Cox regression analysis. There were 22 (15.6%) deaths, mostly due to heart failure or sudden cardiac death. The receiver operating characteristic curve found that a reduction in LVESV of ≥9.5% had a sensitivity of 70% and specificity of 70% in predicting all-cause mortality and of 87% and 69%, respectively, for cardiovascular mortality. With this cutoff value, there were 87 (61.7%) responders to reverse remodeling. In Kaplan-Meier survival analysis, responders had significantly lower all-cause morality (6.9% versus 30.6%, log-rank χ
2
=13.26,
P
=0.0003), cardiovascular mortality (2.3% versus 24.1%, log-rank χ
2
=17.1,
P
<0.0001), and heart failure events (11.5% versus 33.3%, log-rank χ
2
=8.71,
P
=0.0032) than nonresponders. In the Cox regression analysis model, the change in LVESV was the single most important predictor of all-cause (β=1.048, 95% confidence interval=1.019 to 1.078,
P
=0.001) and cardiovascular (β=1.072, 95% confidence interval=1.033 to 1.112,
P
<0.001) mortality. Clinical parameters were unable to predict any outcome event.

Conclusions—

A reduction in LVESV of 10% signifies clinically relevant reverse remodeling, which is a strong predictor of lower long-term mortality and heart failure events. This study suggests that assessing volumetric changes after an intervention in patients with heart failure provides information predictive of natural history outcomes.
Person-Centered E-Learning in Action: Can Technology Help to Manifest Person-Centered Values in Academic Environments?
Authors: Motschnig-Pitrik Renate
Published: September 2005

Person-centered significant or experiential learning as developed by Carl Rogers addresses the learner at three levels: intellect, social skills, and feelings or intuitions. Although the added value of personal growth, improved creativity, interpersonal skills, and better problem-solving capabilities is well documented in the literature, its transition into higher education practice clearly lags behind because of the increased effort required to facilitate person-centered courses. The goal, therefore, is to make person-centered learning and teaching more effective and feasible by enriching it with elements of computer-supported learning (“e-learning”), resulting in a blended approach: person-centered e-learning (PCeL). This article discusses expressions of Rogers’ core conditions in learning situations, the contributions and limitations of technology support, manifestations of PCeL in a course on project management, students’ reactions, and results of an empirical study regarding students’ motivation. Finally, the article shares some personal experiences of the author in the form of a catalogue of PCeL practices.
Empathy, Psychotherapy Integration, and Meditation: A Buddhist Contribution to the Common Factors Movement
Authors: Andersen David T.
Published: September 2005

Clinicians from several theoretical approaches have explored the common ground between Buddhism and Western psychotherapeutic models. In this article, the synthesis of Buddhism and psychotherapy is considered from the context of psychotherapy integration. Toward that end, the Buddhism and psychotherapy literature and the psychotherapy outcome research is reviewed with a focus on the findings of therapy equivalence and common factors among treatment approaches. Empathy and the relationship variables factor are discussed; it is argued that Buddhist meditation contains a dialectic between striving and self-acceptance. An essential aspect of meditation is seen as identical to an essential component in therapeutic personality change. It is argued that therapist empathy and meditation promote a self-directed empathy that enhances the interdependence, integration, and cohesion of self. Several approaches to the integration of psychotherapy and Buddhist meditation are compared to the views presented here, and recommendations are offered for the clinical application of meditation training.
Doc Tales
Authors: Golden Larry , Alamía Jennifer , Baker Ria , Chilson Sally , Choucroun Pierre , Cook Katrina , de Vries-Kell Sabina , Marbach Christina , Peters Scott
Published: September 2005

Acceptance into a doctoral program is personally affirming and gives rise to optimism. It is also true that any change in the life of a person, even an apparently positive one, causes stress. The first cohort of students in a new doctoral program in counseling writes about the impact of embarking on a doctorate on themselves and their significant others. Although some of these students are young and single, most are “nontraditional” and have the family and work responsibilities that accrue as one ages.
Assessment of an Interactive Computer-Based Patient Prenatal Genetic Screening and Testing Education Tool
Authors: Griffith Jennifer M. , Sorenson James R. , Bowling J. Michael , Jennings-Grant Tracey
Published: September 2005

The Enhancing Patient Prenatal Education study tested the feasibility and educational impact of an interactive program for patient prenatal genetic screening and testing education. Patients at two private practices and one public health clinic participated ( N = 207). The program collected knowledge and measures of anxiety before and after use of the tool. Time in various prenatal visit activities was collected prior to and after the introduction of the education tool. Providers completed an assessment of their experiences with patients who had used the program. Results indicate that patient knowledge significantly increased from pre to post ( p = .0001) with no increase in anxiety ( p = .31). Time in clinic activities, including overall visit time, increased. A majority of providers indicated that the program disrupted clinic flow. This assessment suggests that the program increases patient knowledge and does not increase patient anxiety. However, challenges remain to using this program in a clinic setting.
Early block to erythromegakaryocytic development conferred by loss of transcription factor GATA-1
Authors: Stachura David L. , Chou Stella T. , Weiss Mitchell J.
Published: September 2005

Transcription factor GATA-1 is essential at multiple stages of hematopoiesis. Murine gene targeting and analysis of naturally occurring human mutations demonstrate that GATA-1 drives the maturation of committed erythroid precursors and megakaryocytes. Prior studies also suggest additional, poorly defined, roles for GATA-1 at earlier stages of erythromegakaryocytic differentiation. To investigate these functions further, we stimulated Gata1- murine embryonic stem-cell-derived hematopoietic cultures with thrombopoietin, a multistage cytokine. Initially, the cultures generated a wave of mutant megakaryocytes. However, these were rapidly overgrown by a unique population of thrombopoietin-dependent blasts that express immature markers and proliferate indefinitely. Importantly, on restoration of GATA-1 function, these cells differentiated into both erythroid and megakaryocytic lineages, suggesting that they represent bipotential progenitors. Identical cells are also present in vivo, as indicated by flow cytometry and culture analysis of fetal livers from Gata1- chimeric mice. Our findings indicate that loss of GATA-1 impairs the maturation of megakaryocyte-erythroid progenitors. This defines a new role for GATA-1 at a relatively early stage of hematopoiesis and provides potential insight into recent discoveries that human GATA1 mutations promote acute megakaryoblastic leukemia, a clonal malignancy with features of both erythroid and megakaryocyte maturation.
Drug use and harm reduction in Afghanistan
Authors: Todd Catherine S , Safi Naqibullah , Strathdee Steffanie A
Published: September 2005

Opium has been cultivated in Afghanistan since 1100 A.D., although production has steadily increased since 1979. Currently, Afghanistan produces three-quarters of the global opium supply, with injection drug use and HIV currently following the opium trade route through Central Asia. Although systematic studies are lacking, heroin use appears to be on the rise in Afghanistan. The purpose of this paper is to briefly provide historical background and current statistics for drug production and use in Afghanistan, to discuss the new government's policies towards problem drug use and available rehabilitation programs, and to assess Afghan harm reduction needs with consideration of regional trends.
Development and validation of a psychosocial screening instrument for cancer
Authors: Linden Wolfgang , Yi Dahyun , Barroetavena Maria Cristina , MacKenzie Regina , Doll Richard
Published: September 2005

Background

We are reporting on the development of a psychosocial screening tool for cancer patients. The tool was to be brief, at a relatively low reading level, capture psychological variables relevant to distress and health-related quality-of-life in cancer patients, possess good reliability and validity, and be free of copyright protection.

Method

Item derivation is described, data on reliability and validity as well as norms are reported for three samples of cancer patients (n = 1057; n = 570, n = 101).

Results

The resulting 21-item psychological screen for cancer (PSCAN) assesses perceived social support, desired social support, health-related quality-of-life, anxiety and depression. It has good psychometrics including high internal consistency (alpha averaging .83, and acceptable test-retest stability over 2 months (averaging r = .64). Validity has been established for content, construct and concurrent validity.

Conclusion

PSCAN is considered ready for use as a screening tool and also for following changes in patient distress throughout the cancer care trajectory. It is freely available to all interested non-profit users.
Mucinous cystadenoma of the pancreas with predominant stroma creating a solid tumor
Authors: Ae Lee Won
Published: September 2005

Background

Mucinous cystic neoplasm (MCN) of the pancreas is basically cystic epithelial neoplasm, unilocular or multilocular, occurring almost exclusively in women.

Case presentation

A 51-year-old female presented with a pancreatic mass incidentally found on the abdominal computed tomography. She underwent distal pancreatectomy. The sectioned surface of the pancreas revealed a circumscribed, whitish gray ovoid firm mass with some cystic spaces. Microscopically, glandular or small cystic structures were scattered in the predominant stroma creating a solid appearance. The subepithelial stromal component was composed of cytologically bland looking spindle cells, which resembled ovarian stroma. The stromal cells were reactive to CD 34, vimentin, progesterone receptor and calretinin. The microscopy was consistent with mucinous cystadenoma of the pancreas.

Conclusion

This case of mucinous cystadenoma of the pancreas showed very interesting pathology: It was solid rather than cystic, and accompanied by abundant benign transitional epithelia, which was a very unusual and novel finding in the mucinous cystic neoplasm of the pancreas.
Rats with steroid-induced polycystic ovaries develop hypertension and increased sympathetic nervous system activity
Authors: Stener-Victorin Elisabet , Ploj Karolina , Larsson Britt-Mari , Holmäng Agneta
Published: September 2005

Background

Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder associated with ovulatory dysfunction, abdominal obesity, hyperandrogenism, hypertension, and insulin resistance.

Methods

Our objectives in this study were (1) to estimate sympathetic-adrenal medullary (SAM) activity by measuring mean systolic blood pressure (MSAP) in rats with estradiol valerate (EV)-induced PCO; (2) to estimate alpha1a and alpha2a adrenoceptor expression in a brain area thought to mediate central effects on MSAP regulation and in the adrenal medulla; (3) to assess hypothalamic-pituitary-adrenal (HPA) axis regulation by measuring adrenocorticotropic hormone (ACTH) and corticosterone (CORT) levels in response to novel-environment stress; and (4) to measure abdominal obesity, sex steroids, and insulin sensitivity.

Results

The PCO rats had significantly higher MSAP than controls, higher levels of alpha1a adrenoceptor mRNA in the hypothalamic paraventricular nucleus (PVN), and lower levels of alpha2a adrenoceptor mRNA in the PVN and adrenal medulla. After exposure to stress, PCO rats had higher ACTH and CORT levels. Plasma testosterone concentrations were lower in PCO rats, and no differences in insulin sensitivity or in the weight of intraabdominal fat depots were found.

Conclusion

Thus, rats with EV-induced PCO develop hypertension and increased sympathetic and HPA-axis activity without reduced insulin sensitivity, obesity, or hyperandrogenism. These findings may have implications for mechanisms underlying hypertension in PCOS.
Effects of reduced rebreathing time, in spontaneously breathing patients, on respiratory effort and accuracy in cardiac output measurement when using a partial carbon dioxide rebreathing technique: a prospective observational study
Authors: Tachibana Kazuya , Imanaka Hideaki , Takeuchi Muneyuki , Nishida Tomoyo , Takauchi Yuji , Nishimura Masaji
Published: September 2005

Introduction

New technology using partial carbon dioxide rebreathing has been developed to measure cardiac output. Because rebreathing increases respiratory effort, we investigated whether a newly developed system with 35 s rebreathing causes a lesser increase in respiratory effort under partial ventilatory support than does the conventional system with 50 s rebreathing. We also investigated whether the shorter rebreathing period affects the accuracy of cardiac output measurement.

Method

Once a total of 13 consecutive post-cardiac-surgery patients had recovered spontaneous breathing under pressure support ventilation, we applied a partial carbon dioxide rebreathing technique with rebreathing of 35 s and 50 s in a random order. We measured minute ventilation, and arterial and mixed venous carbon dioxide tension at the end of the normal breathing period and at the end of the rebreathing periods. We then measured cardiac output using the partial carbon dioxide rebreathing technique with the two rebreathing periods and using thermodilution.

Results

With both rebreathing systems, minute ventilation increased during rebreathing, as did arterial and mixed venous carbon dioxide tensions. The increases in minute ventilation and arterial carbon dioxide tension were less with 35 s rebreathing than with 50 s rebreathing. The cardiac output measures with both systems correlated acceptably with values obtained with thermodilution.

Conclusion

When patients breathe spontaneously the partial carbon dioxide rebreathing technique increases minute ventilation and arterial carbon dioxide tension, but the effect is less with a shorter rebreathing period. The 35 s rebreathing period yielded cardiac output measurements similar in accuracy to those with 50 s rebreathing.
Outcome of Ethnic Minorities With Acute or Chronic Leukemia Treated With Hematopoietic Stem-Cell Transplantation in the United States
Authors: Baker K. Scott , Loberiza Fausto R. , Yu Hongmei , Cairo Mitchell S. , Bolwell Brian J. , Bujan-Boza Willem A. , Camitta Bruce M. , Garcia Juan Jose , Ho Winston G. , Liesveld Jane L. , Maharaj Dipnarine , Marks David I. , Schultz Kirk R. , Wiernik Peter , Zander Axel R. , Horowitz Mary M. , Keating Armand , Weisdorf Daniel J.
Published: September 2005

Purpose

We previously reported a higher risk of mortality among Hispanics after allogeneic hematopoietic stem-cell transplantation (HSCT). However, it is not known how specific post-transplantation events (acute or chronic graft-versus-host disease [GVHD], treatment-related mortality [TRM], and relapse) may explain mortality differences. The purpose of this study was to examine the relationship between ethnicity and post-transplantation events and determine their net effect on survival.

Patients and Methods

We identified 3,028 patients with acute myeloid leukemia, acute lymphoblastic leukemia, or chronic myeloid leukemia reported to the International Bone Marrow Transplant Registry between 1990 and 2000 who received an HLA-identical sibling HSCT after a myeloablative conditioning regimen in the United States. There were 2,418 white patients (80%) and 610 ethnic minority patients (20%), of whom 251 were black (8%), 122 were Asian (4%), and 237 were Hispanic (8%). Cox proportional hazards regression was used to compare outcomes between whites and ethnic minorities while adjusting for other significant clinical factors.

Results

No statistically significant differences in the risk of acute or chronic GVHD, TRM, or relapse were found between whites and any ethnic minority group. However, Hispanics had higher risks of treatment failure (death or relapse; relative risk [RR] = 1.30; 95% CI, 1.08 to 1.54; P = .004) and overall mortality (RR = 1.23; 95% CI, 1.03 to 1.47; P = .02).

Conclusion

The higher risks of treatment failure and mortality among Hispanics may be the net result of modest but not statistically significant increases in both relapse and TRM and cannot be accounted for by any single transplantation-related complication. Further studies should examine the role of social, economic, and cultural factors.
PTPN11 (Protein Tyrosine Phosphatase, Nonreceptor Type 11) Mutations and Response to Growth Hormone Therapy in Children with Noonan Syndrome
Authors: Ferreira Lize V. , Souza Silvia A. L. , Arnhold Ivo J. P. , Mendonca Berenice B. , Jorge Alexander A. L.
Published: September 2005

Context: The cause of growth impairment in Noonan syndrome (NS) remains unclear. Mutations in PTPN11 (protein tyrosine phosphatase, nonreceptor type 11) that codify constitutively activated Src homology protein tyrosine phosphatase-2 tyrosine phosphatase and may interfere with GH and IGF-I signaling were identified in approximately 40% of patients with NS.

Objective: The objective of this study was to evaluate the influence of PTPN11 status on response to human GH (hGH) treatment in NS children with short stature.

Setting: This study was performed at a university hospital.

Design: The study design was to conduct a retrospective analysis of 3 yr of hGH treatment and genotyping of PTPN11 in patients with NS.

Patients: Fourteen NS patients, half of them with PTPN11 mutations in heterozygous state, were studied. At the beginning of treatment, there were no clinical or laboratory differences between groups with and without mutations in the PTPN11 gene.

Intervention: Patients were treated with hGH (47 μg/kg·d).

Main Outcome Measures: The main outcome measures were PTPN11 genotype, change in IGF-I levels, and change in height sd score.

Results: Patients with mutations in PTPN11 presented a significantly smaller increment in IGF-I levels during the treatment compared with patients without mutations (86 ± 67 and 202 ± 93 μg/liter, respectively; P = 0.03). hGH treatment significantly improved growth velocity in both groups, with slightly better results observed in patients without mutations. This was translated into greater gains in height sd score relation to baseline during the 3 yr of treatment in patients without mutations (+1.7 ± 0.1) compared with those with mutations (+0.8 ± 0.4; P < 0.01).

Conclusions: Our findings suggest that the presence of PTPN11 mutations in patients with NS indicates a reduced growth response to long-term hGH treatment.
Effects of a β-Blocker on Bone Turnover in Normal Postmenopausal Women: A Randomized Controlled Trial
Authors: Reid Ian R. , Lucas Jenny , Wattie Diana , Horne Anne , Bolland Mark , Gamble Gregory D. , Davidson James S. , Grey Andrew B.
Published: September 2005

Introduction: The central nervous system has been demonstrated to regulate bone mass in mice, possibly via the β2-adrenoreceptors on osteoblasts. β-blockers increase bone mass in mice, and some observational studies have suggested a beneficial effect of these drugs on bone in humans

Experimental Subjects: We studied 41 normal postmenopausal women.

Materials and Methods: We conducted a randomized, placebo- controlled trial, comparing the effects on bone markers of propranolol 160 mg/d and placebo over 3 months.

Results: Serum osteocalcin declined by almost 20% in the first 2 wk of propranolol treatment, and this effect increased over time (P < 0.0001). Other osteoblast markers, procollagen type-I N-terminal propeptide and total alkaline phosphatase activity, were not significantly changed by propranolol. Urine free deoxypyridinoline declined by approximately 10% between 0 and 6 wk (P = 0.019) in the β-blocker group and was stable thereafter. Serum C-terminal telopeptide of type I collagen also showed a small decrease, but this was not significantly different between groups. Serum albumin concentrations decreased by more than 2 g/liter in the first 2 wk of propranolol treatment, remaining stable subsequently (P = 0.007). Serum creatinine tended to increase in the propranolol group (P = 0.06), as did weight. Bone densities in the lumbar spine and total proximal femur did not change significantly in either group.

Conclusions: The present study provides no evidence that β-blocker drugs stimulate bone formation; if anything, propranolol reduces osteoblast activity. It also influences renal function and fluid balance, effects that might indirectly affect bone metabolism. Current evidence does not justify the use of β-blockers for treatment of osteoporosis.
Calcium Absorptive Efficiency Is Positively Related to Body Size
Authors: Barger-Lux M. Janet , Heaney Robert P.
Published: September 2005

Background: Calcium absorption efficiency is a more important determinant of calcium balance than calcium intake itself. The sources of variability in absorptive performance are only partly elucidated.

Purpose: The aim of the study was to explore the relationship between body size and calcium absorption efficiency.

Design and Setting: Metabolic studies were performed on an inpatient metabolic unit in an academic health sciences center.

Subjects: One hundred seventy-eight women, with an average age of 50.2 yr, were studied from one to five times and yielded an aggregate data set containing 633 individual studies.

Methods: Calcium absorption fraction was measured by the dual-tracer method. Observed values were expressed as residuals from predicted values for each woman’s actual calcium intake, using the previously published relationship between intake and absorption.

Results: Absorption residuals were significantly positively correlated with height, weight, and surface area, and after adjusting for estrogen status, these body size variables accounted for approximately 4% of the total variability.

Conclusion: The magnitude of the effect is such that a woman 1.8 m in height would absorb 30+% more calcium from a given intake than a woman 1.4 m tall.
Mutations in CYP11B1 and Congenital Adrenal Hyperplasia in Moroccan Jews
Authors: Paperna Tamar , Gershoni-Baruch Ruth , Badarneh Kader , Kasinetz Leah , Hochberg Ze’ev
Published: September 2005

Context: In Jews of Moroccan descent (MJ), the prevalence of steroid 11β-hydroxylase deficiency (11-OHD) is relatively high, with a carrier rate estimated as approximately one in 40. A single mutation in the CYP11B1 gene (encoding 11β-hydroxylase), R448H, was suggested to account for the disease alleles in this population.

Study Subjects: We screened 236 healthy MJ for R448H.

Results: Only two of the subjects screened were found to be carriers, suggesting that the R448H allele frequency is lower than was assumed previously. An R448H/R448C compound heterozygote patient, diagnosed with 11-OHD, was identified. However, a subsequent screen of MJ subjects for R448C failed to detect any carriers, suggesting that this was a private mutation of this family.

Conclusion: The high incidence of 11-OHD in MJ, therefore, is only partially explained by the presence of R448H as a founder mutation.
Phosphorylation of ezrin on threonine 567 produces a change in secretory phenotype and repolarizes the gastric parietal cell
Authors: Zhou Rihong , Zhu Lixin , Kodani Andrew , Hauser Paul , Yao Xuebiao , Forte John G.
Published: September 2005

Phosphorylation of the membrane-cytoskeleton linker protein ezrin has been functionally linked to acid secretion and vesicle recruitment to the apical secretory membrane in gastric parietal cells. Phosphorylation of the conserved T567 residue of ezrin has been shown to alter the N/C oligomerization of ezrin and promote the formation of actin-rich surface projections in other cells. To test the importance of T567 as a regulatory site for ezrin in parietal cell activation, we incorporated wild-type (WT) and mutant forms of ezrin, including the nonphosphorylatable T567A mutation and a mutant mimicking permanent phosphorylation, T567D. All ezrin constructs included C-terminal cyan-fluorescent protein (CFP) and were incorporated into adenoviral constructs for efficient introduction into cultured parietal cells from rabbit stomach. Fluorescence microscopy was used to localize CFP-ezrin and monitor morphological responses. Accumulation of a weak base (aminopyrine) was used to monitor receptor-mediated acid secretory response of the cultured cells. Similar to endogenous ezrin, WT and T567A CFP-ezrin localized heavily to apical membrane vacuoles with considerably lower levels associated with the surrounding basolateral membrane. Interestingly, H,K-ATPase within cytoplasmic tubulovesicles was incorporated into the apical vacuoles along with WT and T567A mutant ezrin. In these parietal cells secretagogue stimulation produced a striking vacuolar expansion associated with HCl secretion and the secretory phenotype. Expression of T567D CFP-ezrin was quite different, being rarely associated with apical vacuoles. T567D was more typically localized to the basolateral membrane, often associated with long spikes and fingerlike projections. Moreover, the cells did not display secretagogue-dependent morphological changes and, to our surprise, H,K-ATPase was recruited to the T567D CFP-ezrin-enriched basolateral projections. We conclude that T567 phosphorylation, which is probably regulated through Rho signaling pathway, may direct ezrin to membrane-cytoskeletal activity at the basolateral membrane and away from apical secretory activity. The large basolateral expansion is predicted to recruit membranes from sources not normally targeted to that surface.
Subcellular localization of iron regulatory proteins to Golgi and ER membranes
Authors: Patton Stephanie M. , Piñero Domingo J. , Surguladze Nodar , Beard John , Connor James R.
Published: September 2005

Interaction between iron regulatory proteins and iron responsive elements on certain mRNAs is at the core of regulation of intracellular iron homeostasis. Previous results suggested that in cultured cells iron regulatory proteins (IRPs) exist in cytosolic and microsomal subcellular locations and that this distribution is affected by cellular iron status. In this study, we tested the hypothesis that the membrane-associated fractions of iron regulatory proteins are specifically in the endoplasmic reticulum and Golgi membranes. Confocal microscopy revealed that IRP1 could be co-localized to the endoplasmic reticulum and the Golgi apparatus. To examine the intracellular distribution of IRPs biochemically, we used rats fed normal or iron-deficient diets. As expected, the IRPs were found predominantly in the cytosolic fraction. However, subfractionation of crude microsomal preparations revealed IRP1 in the Golgi apparatus. In animals fed an iron-deficient diet, IRP1 was found in the Golgi apparatus and the endoplasmic reticulum. To identify the mechanisms and factors involved in the localization of iron regulatory proteins in the cytosol and membrane fractions, cells were treated with a phorbol ester, a protein kinase C inhibitor (chelerythrine), hydrogen peroxide, interleukin-1β, and 1,2-bis-(o-aminophenoxy)-ethane-N,N,-N′N′-tetraacetic acid tetraacetoxy-methyl ester. The results indicate that iron-regulatory-protein-binding activity in the membrane fraction can be altered by cell stress or iron status and that phosphorylation plays a role in the translocation. As a result of this study we propose a novel model for intracellular distribution of IRPs and identify differences between the two iron regulatory proteins.
Collaborative Services Among Community Pharmacies for Patients with Diabetes
Authors: Storimans Michiel J , Klungel Olaf H , Talsma Herre , Bouvy Marcel L , de Blaey Cornelis J
Published: September 2005

BACKGROUND:

Patients performing self-monitoring of blood glucose (SMBG) may benefit from community pharmacy services. However, wide-scale implementation of these services is limited. Many pharmacy characteristics (eg, physical layout of the pharmacy, knowledge and competence of the pharmacy team) are reported to be relevant when implementing these services. Still, the importance of local agreements on the division of roles with, for example, local general practitioners or diabetes nurses, is less clear.

Objective:

To study the association between local collaboration and the level of services provided by community pharmacies to patients performing SMBG.

METHODS:

In 2004, we performed a cross-sectional survey among all 1692 Dutch community pharmacies. Data were gathered on provision of services for SMBG, local agreements, and pharmacy characteristics. Data were analyzed using logistic regression. Associations were adjusted for pharmacy characteristics.

RESULTS:

About 44% (724) of the community pharmacies returned the questionnaire. Pharmacies that were not involved in local collaborative services on patient counseling reported to provide fewer services compared with those that were involved in such agreements (OR 0.26, 95% CI 0.13 to 0.53). Similar findings were observed for agreements on calibration of SMBG equipment (0.17, 0.04 to 0.71). The associations remained after adjusting for pharmacy characteristics.

CONCLUSIONS:

Local collaboration on the division of roles in diabetes care between healthcare professionals is independently associated with the number of pharmacy services provided to patients performing SMBG.
Ionic Mechanisms Underlying Autonomous Action Potential Generation in the Somata and Dendrites of GABAergic Substantia Nigra Pars Reticulata NeuronsIn Vitro
Authors: Atherton Jeremy F. , Bevan Mark D.
Published: September 2005

Through their repetitive discharge, GABAergic neurons of the substantia nigra pars reticulata (SNr) tonically inhibit the target nuclei of the basal ganglia and the dopamine neurons of the midbrain. As the repetitive firing of SNr neurons persistsin vitro, perforated, whole-cell and cell-attached patch-clamp recordings were made from rat brain slices to determine the mechanisms underlying this activity. The spontaneous activity of SNr neurons was not perturbed by the blockade of fast synaptic transmission, demonstrating that it was autonomous in nature. A subthreshold, slowly inactivating, voltage-dependent, tetrodotoxin (TTX)-sensitive Na+current and a TTX-insensitive inward current that was mediated in part by Na+were responsible for depolarization to action potential (AP) threshold. An apamin-sensitive spike afterhyperpolarization mediated by small-conductance Ca2+-dependent K+(SK) channels was critical for the precision of autonomous activity. SK channels were activated, in part, by Ca2+flowing throughω-conotoxin GVIA-sensitive, class 2.2 voltage-dependent Ca2+channels. Although Cs+/ZD7288 (4-ethylphenylamino-1,2-dimethyl-6-methylaminopyrimidinium chloride)-sensitive hyperpolarization-activated currents were also observed in SNr neurons, they were activated at voltages that were in general more hyperpolarized than those associated with autonomous activity. Simultaneous somatic and dendritic recordings revealed that autonomously generated APs were observed first at the soma before propagating into dendrites up to 120 μm from the somatic recording site. Backpropagation of autonomously generated APs was reliable with no observable incidence of failure. Together, these data suggest that the resting inhibitory output of the basal ganglia relies, in large part, on the intrinsic firing properties of the neurons that convey this signal.
Inhibition of Serotonergic Neurons in the Nucleus Paragigantocellularis Lateralis Fragments Sleep and Decreases Rapid Eye Movement Sleep in the Piglet: Implications for Sudden Infant Death Syndrome
Authors: Darnall Robert A. , Harris Michael B. , Gill W. Hugh , Hoffman Jill M. , Brown Justin W. , Niblock Mary M.
Published: September 2005

Serotonergic receptor binding is altered in the medullary serotonergic nuclei, including the paragigantocellularis lateralis (PGCL), in many infants who die of sudden infant death syndrome (SIDS). The PGCL receives inputs from many sites in the caudal brainstem and projects to the spinal cord and to more rostral areas important for arousal and vigilance. We have shown previously that local unilateral nonspecific neuronal inhibition in this region with GABAAagonists disrupts sleep architecture. We hypothesized that specifically inhibiting serotonergic activity in the PGCL would result in less sleep and heightened vigilance. We analyzed sleep before and after unilaterally dialyzing the 5-HT1Aagonist (±)-8-hydroxy-2-(dipropylamino)-tetralin (8-OH-DPAT) into the juxtafacial PGCL in conscious newborn piglets. 8-OH-DPAT dialysis resulted in fragmented sleep with an increase in the number and a decrease in the duration of bouts of nonrapid eye movement (NREM) sleep and a marked decrease in amount of rapid eye movement (REM) sleep. After 8-OH-DPAT dialysis, there were decreases in body movements, including shivering, during NREM sleep; body temperature and heart rate also decreased. The effects of 8-OH-DPAT were blocked by local pretreatment withN-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexane-carboxamide, a selective 5-HT1Aantagonist. Destruction of serotonergic neurons with 5,7-DHT resulted in fragmented sleep and eliminated the effects of subsequent 8-OH-DPAT dialysis on REM but not the effects on body temperature or heart rate. We conclude that neurons expressing 5-HT1Aautoreceptors in the juxtafacial PGCL are involved in regulating or modulating sleep. Abnormalities in the function of these neurons may alter sleep homeostasis and contribute to the etiology of SIDS.
Low Voltage-Activated Ca2+Channels Are Coupled to Ca2+-Induced Ca2+Release in Rat Thalamic Midline Neurons
Authors: Richter Trevor A. , Kolaj Miloslav , Renaud Leo P.
Published: September 2005

High voltage-activated Ca2+channels are coupled to the release of Ca2+from intracellular stores. Here we present evidence that, in the paraventricular thalamic nucleus and other midline thalamic nuclei, activation of low voltage-activated (LVA) Ca2+channels stimulates Ca2+-induced Ca2+release (CICR) from intracellular stores. Voltage-clamp activation of LVA Ca2+channels in fluo-4 AM-loaded neurons induced an initial transient increase in intracellular Ca2+concentrations ([Ca2+]i) (mean increase, 19.4%; decay time constant, 71 ms) that reflected the entry of extracellular Ca2+. This was followed by a sustained secondary elevation in [Ca2+]i(mean increase, 4.7%; decay time constant, 7310 ms) that was attributable to CICR. Repeated activation of LVA Ca2+channels to evoke CICR caused a progressive buildup of baseline [Ca2+]i(mean increase, 13.12 ± 3.41%) that was reduced by depletion of intracellular Ca2+stores with thapsigargin or caffeine. In contrast, LVA Ca2+channel-evoked CICR was absent from ventrolateral thalamocortical relay neurons, suggesting that LVA Ca2+channel coupling to Ca2+-dependent intracellular signaling may be a property that is unique to nonspecific and midline thalamocortical neurons.
Reduced Cocaine Self-Administration in Muscarinic M5Acetylcholine Receptor-Deficient Mice
Authors: Thomsen Morgane , Woldbye David P. D. , Wörtwein Gitta , Fink-Jensen Anders , Wess Jürgen , Caine S. Barak
Published: September 2005

The reinforcing effects of cocaine have been related to increased extracellular concentrations of dopamine in the ventral striatum. Several studies suggest that M5muscarinic receptors facilitate striatal dopamine release. We tested the hypothesis that the reinforcing effects of cocaine are decreased in M5receptor-deficient mice using chronic intravenous cocaine self-administration in extensively backcrossed mice. We also assessed whether operant performance generally, rather than cocaine self-administration specifically, was altered in the mutant mice. To this end, we evaluated both food-maintained operant behavior and cocaine self-administration under a fixed ratio 1 and a progressive ratio (PR) schedule of reinforcement. We also evaluated acquisition of self-administration in experimentally naive mice using several doses of cocaine. M5receptor deletion decreased self-administration of low to moderate doses of cocaine under a PR schedule of reinforcement and diminished acquisition of self-administration of a low dose in experimentally naive mice. We found no differences between genotypes in food-maintained behavior. The present study extends our previous findings using backcrossed mice and covering various experimental conditions. Our results indicate that M5receptor deletion diminished the reinforcing effects of low doses of cocaine and identified specific conditions under which this may be observed.