Age-associated changes in functional response to CXCR3 and CXCR5 chemokine receptors in human osteoblasts

The expression and functional activity of CXC chemokine receptors were evaluated in human osteoblasts (OB) obtained post-trauma from old donors compared to very young donors. It was found that CXCR1 and CXCR4 were only expressed by old but not young donors' cells. In contrast, CXCR3 and CXCR5 were expressed by both young and old donors. We functionally evaluated CXCR3/CXCL10 and CXCR5/CXCL13 receptor/ligand pairs by analysing cell proliferation and the release of N-acetyl-β-D-glucosaminidase (NAG), an enzyme that degrades glycosaminoglycans and hyaluronic acid. CXCL10 and CXCL13 induced a dose-dependent increase of cell proliferation in OB from young donors while cell proliferation of OB in old donors was not affected. By contrast, CXCL10 and CXCL13 induced a significantly higher NAG release in OB from old donors compared to young ones. These data demonstrate a significant age-dependent difference in the response of OB to CXCL10 and CXCL13 stimulation. These chemokines induce an inverse response of OB from old and young donors, which suggests a role of ageing in the modulation of cellular response of bone cells. This revised version was published online in July 2006 with corrections to the Cover Date.     

Early life stress enhances the vulnerability to chronic psychosocial stress and experimental colitis in adult mice

Early life stress enhances the vulnerability to both mood and chronic inflammatory disorders, suggesting a link between these stress-related disorders. To study this, we exposed male C57BL/6 mice to early life stress [maternal separation (MS), 3 h/d, d 1-14] and to adult chronic psychosocial stress [chronic subordinate colony housing (CSC)] and measured changes in neuroendocrine parameters and in the severity of a chemically induced colitis. In both unseparated and MS mice, 19 d of CSC exposure resulted in a transient decrease in body weight gain, increased anxiety-related behavior, and decreased vasopressin mRNA expression in the hypothalamic paraventricular nucleus compared with respective nonstressed mice. However, only CSC-stressed MS mice showed elevated CRH mRNA expression in the paraventricular nucleus and reduced plasma corticosterone. Subsequent treatment with dextran sulfate sodium (1%, 7 d) resulted in a more severe colonic inflammation in MS compared with unseparated mice. This was indicated by an increased histological damage score and increased TNF secretion (nonstressed MS mice), more severe body weight loss and inflammatory reduction in colon length (CSC-stressed MS mice), and increased interferon-gamma secretion (nonstressed and CSC-stressed MS mice). In conclusion, early life stress and subsequent exposure to chronic psychosocial stress in adulthood induced neuroendocrine abnormalities, which likely contributed to enhanced vulnerability to chemically induced colitis. The combined use of MS and CSC represents a potential animal model providing novel (patho)physiological insights into the complex interactions between neuroendocrine and inflammatory actions upon chronic stress exposure. These findings may further help to reveal mechanisms of hypocortisolemic disorders.     

Toll-like receptor-4 deficiency attenuates doxorubicin-induced cardiomyopathy in mice

BACKGROUND: Cardiac inflammation and generation of oxidative stress are known to contribute to doxorubicin (Dox)-induced cardiomyopathy. Toll-like receptors (TLRs) are a part of the innate immune system and are involved in cardiac stress reactions. Since TLR4 might play a relevant role in cardiac inflammatory signalling, we investigated whether or not TLR4 is involved in Dox-induced cardiotoxicity. METHODS AND RESULTS: Five days after a single injection of Dox (20 mg/kg; i.p.), left ventricular pressure-volume loops were measured in wild-type and TLR4-deficient mice (TLR4-/-) Dox-treated and control mice. Analyses of possible pathophysiological mechanisms were performed in left ventricular tissue and isolated myocytes, respectively. Dox injection resulted in an impairment of left ventricular function and neurohumoral activation, indexed by increased ET-1 expression. This was further associated with an increase in cardiac oxidative stress, inflammation and apoptosis, as indicated by an up-regulation of cardiac lipid peroxidation, TNF-alpha expression and enhanced content of TUNEL-positive cells. In contrast, TLR4-/- Dox mice showed improved left ventricular function with reduced oxidative and inflammatory stress response including reduced cardiac apoptosis. These results were found to be associated with an increase of GATA-4 expression. CONCLUSIONS: TLR4 deficiency improves left ventricular function and attenuates pathophysiological key mechanisms in Dox-induced cardiomyopathy.     

Estrogens,but not androgens,regulate expression and functional activity of oxytocin receptor in rabbit epididymis

Previous binding and contractility studies indicate that oxytocin (OT) receptors are present in rabbit epididymis. To investigate the effect of changing endocrine milieu on OT responsiveness, we induced hypogonadism (hypo) in rabbits with a single administration of a long-acting GnRH analog, triptorelin, and we replaced hypogonadal rabbits with different sex steroids. After 2 months from triptorelin administration, testosterone (T) plasma levels were decreased and OT responsiveness abolished. Administration of T to hypo rabbits restored T plasma levels but not OT sensitivity. Because Western blot analysis indicated that both estrogen receptors and aromatase are expressed in the epididymis, we treated hypo rabbits with estradiol valerate (E2v). E2v not only completely restored OT responsiveness but also even amplified it. Accordingly, Northern and Western blot analysis indicated that both OT receptor gene and protein were strongly induced by E2v but not by T. Surprisingly, also the class I estrogen receptor antagonist, tamoxifen restored OT sensitivity in hypo rabbits. To verify whether endogenous estradiol is involved in the regulation of OT receptor responsiveness, we treated intact rabbits with an aromatase inhibitor, letrozole. Blocking aromatase activity almost completely abolished OT sensitivity. These findings suggest a new function of estrogens in the male: regulation of OT responsiveness in epididymis.     

Hb Amsterdam [alpha32(B13)Met--Ile (alpha2)]: a new unstable variant associated with an alpha-thalassemia phenotype and a new African polymorphism

We have characterized a new abnormal hemoglobin (Hb) at position 32 of the alpha-globin chain. The proband, a 38-year-old woman of Surinamese Black ancestry, was referred to the Academic Hospital in Amsterdam, The Netherlands, after 3 years of Prednisone treatment in Surinam. Kidney failure was diagnosed at the Nephrology Department, Free University Medical Center, Amsterdam, The Netherlands; the cortisone treatment was interrupted and dialysis was started. At this stage, a microcytic hypochromic anemia was observed with high reticulocyte (40%) and ferritin (500 microg/L) levels, and hemoglobinopathy was suspected. No abnormal bands were visible on alkaline electrophoresis and high performance liquid chromatography (HPLC). The Hb A2 level was normal (2.7%) and the erythrocyte count was low (3.59 x 10(12)/L) with a normal haptoglobin level (68 mg/100 mL). None of the common alpha-thalassemia (thal) deletion defects were present. The beta-globin gene sequence was normal but the alpha2-globin gene sequence revealed an ATG-->ATA transition at codon 32, changing the methionine into an isoleucine residue. The mutation, called Hb Amsterdam, was observed in the mother of the proband, who was also heterozygous for the--alpha3.7-thal deletion and affected by a moderate microcytic hypochromic anemia. Both Hb Amsterdam and the--alpha(-3.7) allele were found in association with a new polymorphism, IVS-I-39 (C-->T), previously observed in our laboratory in seven patients of African origin, on both the alpha1 and alpha2 genes. In addition, Hb Amsterdam was also associated with the common African alpha2 polymorphism (G-->CTCGGCCC at position 7238 and T-->G at position 7174). Hb Amsterdam is the first mutation ever described at codon alpha32, a position involved in alpha1/beta1 interaction. The possibility of a contribution of this mutation to the nephropatic state of the proband is discussed.     

Hospital readmission of persons with hip fracture following medical rehabilitation

A significant percentage of older adults hospitalized and treated for hip fracture are readmitted to a hospital within six months. We analyzed information from a national database, the Uniform Data System for Medical Rehabilitation. Records for 8,236 patients (1994-98) who received inpatient medical rehabilitation following treatment for hip fracture were examined. Mean age was 76.51 years (S.D. = 12.48) with 71% female and 79% non-Hispanic White. The primary outcome measure was incidence of hospital readmission 0-180 days post-discharge. The hospital readmission rate was 16.7%. A Cox regression model predicting rehospitalization included the following variables (p < 0.05): basic daily living skills, age, length of stay, ethnicity, and gender. There was a statistically significant difference in the percent of male versus female patients rehospitalized for Hispanic subjects but not for non-Hispanic white or African American subjects. The greatest variability occurred among male patients. A total of 18.1% of non-Hispanic White males and 16.8% of African American males were rehospitalized. In contrast, only 10.1% of Hispanic males were rehospitalized. Basic daily living skills, length of hospital stay, age, ethnicity and gender were variables associated with hospital readmission following medical rehabilitation in persons with hip fracture. These variables should be considered in developing intervention programs to reduce the risk of hospital readmission.     

Association of Hospital Employee Satisfaction with Patient Safety and Satisfaction within Veterans Affairs Medical Centers

Background

Employee satisfaction is thought to impact performance. However, which aspects of employee satisfaction matter most is unknown. We utilized data from the Veterans Affairs Medical Centers(VAMC) via their Strategic Analytics for Improvement and Learning program to examine the association between organizational satisfaction as well as job-specific satisfaction with measures of patient safety, patient satisfaction, and hospital rating.

Suppressor screen in Mpl-/- mice: c-Myb mutation causes supraphysiological production of platelets in the absence of thrombopoietin signaling

Genetic screens in lower organisms, particularly those that identify modifiers of preexisting genetic defects, have been used successfully to order components of complex signaling pathways. To date, similar suppressor screens have not been used in vertebrates. To define the molecular pathways regulating platelet production, we have executed a large-scale modifier screen with genetically thrombocytopenic Mpl(-/-) mice by using N-ethyl-N-nitrosourea mutagenesis. Here we show that mutations in the c-Myb gene cause a myeloproliferative syndrome and supraphysiological expansion of megakaryocyte and platelet production in the absence of thrombopoietin signaling. This screen demonstrates the utility of large-scale N-ethyl-N-nitrosourea mutagenesis suppressor screens in mice for the simultaneous discovery and in vivo validation of targets for therapeutic discovery in diseases for which mouse models are available.