Remodeling of resistance arteries in renal failure: effect of endothelin receptor blockade

Remodeling of vessels is a known feature of renal failure, but it is unclear whether this represents an appropriate or inappropriate response to the known changes in blood flow, shear stress, and wall tension. To investigate remodeling in response to variations in blood flow, first-order mesenteric arteries were exposed to high- and low-flow conditions via the ligation of second-order branches, according to the technique described by Pourageaud and De Mey. The resulting changes in vessel geometric features, relative proportions of intima and media, submicroscopic structure, and immunostaining for proliferating cell nuclear antigen (PCNA), endothelin-1 (ET-1), and ET(A) receptors were assessed in first-order mesenteric arteries under low-flow and high-flow conditions. Subtotally nephrectomized (SNX) animals were compared with sham-operated rats. Animals either were left untreated or were treated with the ET(A) receptor antagonist (ET-RA) LU-135252, because of suggestions in the literature that ET is involved in vascular remodeling in uremia. A highly significant increase in intimal thickness was noted in low-flow arteries (4.21 +/- 1.39 microm) of SNX animals, compared with normal-flow arteries (2.06 +/- 0.61 microm), but this increase was not observed in sham-operated rats (1.38 +/- 0.77 in low-flow arteries versus 2.40 +/- 0.35 microm in normal-flow arteries). The increase in intimal thickness in low-flow arteries was abrogated by ET-RA. The medial thickness was increased in untreated SNX animals (19.5 +/- 3.61 microm), compared with sham-operated rats, and this increase was also prevented by ET-RA. The medial thickness was not affected by low flow in either sham-operated or SNX animals. In parallel, the number of PCNA-positive intimal cells was higher in low-flow, but not high-flow, arteries of SNX rats, compared with sham-operated rats. No significant change was observed in sham-operated animals. In the media, the number of PCNA-positive cells was higher in untreated SNX animals than in sham-operated rats. The number was even more markedly increased in high-flow, but not low-flow, vessels. This increase was abrogated by ET-RA. It is concluded that, in uremic animals, the response of the intima to low flow and the response of the media to high flow are exaggerated. Both responses are apparently mediated by ET.     

Check-up examinations from the cardiologic viewpoint

The concept of the primary prevention of coronary disease is certainly widely accepted today and supports check-up visits of apparently healthy persons. The goals of check-up's viewed by the cardiologist are the detection of coronary risk factors and the identification of asymptomatic patients with coronary disease to initial preventive measures. In some instances, a personal health problem forces the patient to a check-up visit. The major coronary risk factors of heredity, cigarette-smoking, hypercholesteremia, hypertension can be detected by taking the history, performing a physical examination and a blood-sampling for cholesterol. Additional investigations such as an ECG or an exercise-test are only indicated in symptomatic patients or in persons at high coronary risk.     

Localized Ewing tumor of bone: final results of the cooperative Ewing's Sarcoma Study CESS 86.

PURPOSE: Cooperative Ewing's Sarcoma Study (CESS) 86 aimed at improving event-free survival (EFS) in patients with high-risk localized Ewing tumor of bone. PATIENTS AND METHODS: We analyzed 301 patients recruited from January 1986 to July 1991 (60% male; median age 15 years). Tumors of volume >100 mL and/or at central-axis sites qualified patients for "high risk" (HR, n = 241), and small extremity lesions for "standard risk" (SR, n = 52). Standard-risk patients received 12 courses of vincristine, cyclophosphamide, and doxorubicin alternating with actinomycin D (VACA); HR patients received ifosfamide instead of cyclophosphamide (VAIA). Tumor sites were pelvis (27%), other central axis (28%), femur (19%), or other extremity (26%). The initial tumor volume was <100 mL in 33% of cases and > or =100 mL in 67%. Local therapy was surgery (23%), surgery plus radiotherapy (49%), or radiotherapy alone (28%). Event-free survival rates were estimated by Kaplan-Meier analyses, comparisons were done by log-rank test, and risk factors were analyzed by Cox models. RESULTS: On May 1, 1999 (median time under study, 133 months), the 10-year EFS was 0.52. Event-free survival did not differ between SR-VACA (0.52) and HR-VAIA (0.51, P =.92). Tumor volume of >200 mL (EFS, 0.36 v 0.63 for smaller tumors; P =.0001) and poor histologic response (EFS, 0.38 v 0.64 for good responders; P =.0007) had negative impacts on EFS. In multivariate analyses, small tumor volumes of <200 mL, good histologic response, and VAIA chemotherapy augured for fair outcome. Six of 301 patients (2%) died under treatment, and four patients (1.3%) developed second malignancies. CONCLUSION: Fifty-two percent of CESS 86 patients survived after risk-adapted therapy. High-risk patients seem to have benefited from intensified treatment that incorporated ifosfamide.     

Expression of the small heat shock protein HSP 27 in developing human skin

The 27 kDa heat shock protein (HSP 27) is expressed in keratinocytes of the upper epidermal layers, and recent evidence suggests that this protein is involved in the regulation of epidermal differentiation. The expression of HSP 27 was investigated in developing human skin by immunohistochemistry utilizing a specific monoclonal antibody. We used formalin-fixed, paraffin-embedded tissue of abdominal skin obtained from 34 human fetuses ranging between 13 and 30 weeks estimated gestational age (EGA). We found that HSP 27 is not expressed in keratinocytes until week 14 EGA. At this stage staining is observed in the periderm and the upper intermediate cells but not in hair germs. During further development, HSP 27 expression correlates with increasing epidermal differentiation, i.e. shedding of the periderm and beginning of keratinization. HSP 27 expression is confined to the upper cell layers and sparse basal cells. In hair follicles, HSP 27 can be detected in the innermost cell layer of the outer root sheath and in keratinocytes of the bulge identical to what is observed in adult skin. The hair papilla, matrix cells and sebaceous glands are negative for HSP 27 and remain so during further development. In eccrine sweat glands of the 24th week EGA, HSP 27 is confined to the superficial cell layer of the sweat ducts. In the present report we demonstrate differentiation-related expression of HSP 27 in developing human skin. Further in vitro studies will address the molecular function of HSP 27 in epidermal differentiation and development.     

Exogenous Modulation of TGF-β1 Influences TGF-βR-III-Associated Vascularization during Wound Healing in Irradiated Tissue

BACKGROUND AND PURPOSE: Following preoperative radiotherapy prior to ablative surgery of squamous epithelial cell carcinomas of the head and neck region, wound-healing disorders occur. Previous experimental studies showed altered expression of transforming growth factor-(TGF-)beta isoforms following surgery in irradiated graft beds. Altered levels of TGF-beta(1) are reported to promote fibrosis and to suppress vascularization during wound healing, whereas expression of TGF-beta receptor-III (TGF-betaR-III) is associated with vascularization. The aim of the study was to analyze the influence of anti-TGF-beta(1) treatment on TGF-betaR-III-associated vascularization in the transition area between irradiated graft bed and graft. MATERIAL AND METHODS: Wistar rats (male, weight 300-500 g) underwent preoperative irradiation of the head and neck region with 40 Gy (four fractions of 10 Gy each; n = 16 animals). A free myocutaneous gracilis flap taken from the groin was then transplanted to the neck in all rats. The time interval between operation and transplantation was 4 weeks. Eight animals received 1 micro g anti-TGF-beta(1) into the graft bed by intradermal injection on days 1-7 after surgery. On days 3, 7, 14, 28, 56, and 120, skin samples were taken from the transition area between transplant and graft bed and from the graft bed itself. Immunohistochemistry was performed using the ABC-POX method to analyze the TGF-betaR-III and E-selectin expression. Histomorphometry was performed to analyze the percentage and the area of positively stained vessels. RESULTS: A significantly higher expression of TGF-betaR-III was seen in the irradiated and anti-TGF-beta(1)-treated graft bed in comparison to the group receiving preoperative irradiation followed by transplantation alone. The percentage of TGF-betaR-III positively staining capillaries from the total amount of capillaries in the anti-TGF-beta(1)-treated graft bed was higher than in the group irradiated only. The total area of capillaries was also higher in the TGF-beta(1)-treated group. CONCLUSION: Neutralizing of TGF-beta(1) activity in irradiated tissue undergoing surgery leads to a higher expression of TGF-betaR-III and increased vascularization. TGF-betaR-III seems to be associated with newly formed blood vessels during neovascularization in wound healing.     

Effects of instruction by practice assistants on inhaler technique and respiratory symptoms of patients. A controlled randomized videotaped intervention study

BACKGROUND: Many patients with asthma or chronic obstructive pulmonary diseaseuse their medication inhalers incorrectly. General practitioners,pharmacists and other health care providers do not always havethe opportunity to instruct patients in correct inhaler technique. OBJECTIVE: To find out whether the inhaler technique and respiratory symptomsof patients can be improved after instruction by practice assistants. METHODS: Single blind, randomized intervention study in which 48 patientswho had been using a dry powder inhaler for at least one monthtook part. Their inhaler technique was videotaped on two visitswith a two-week interval between visits. The inhaler techniqueon the videos was subsequently scored by two experts on ninecriteria. At both visits the patients completed a questionnaireabout their respiratory symptoms. After the first video, 25patients were randomly chosen to receive instruction from oneof six practice assistants who had followed a one evening courseabout inhaler instruction, and who had been issued an instruction-set. RESULTS: The patients who received instruction had a significantly greaterreduction in number of mistakes at the second visit than thepatients who did not (P = 0.01). The instructed patients alsoreported less dyspnoea at the second visit (P = 0.03). No effectof instruction was found on wheezing, cough and sputum production. CONCLUSION: The inhaler technique of patients can be improved significantlyby the instruction of patients by trained practice assistants,possibly resulting in less dyspnoea. Keywords. Administration-inhalation, obstructive lung diseases, airways symptoms, patient-education, general practice.     

Sonidegib for the treatment of advanced basal cell carcinoma

Introduction: Advanced and metastatic basal cell carcinomas (BCCs) are rare but still present a severe medical problem. These tumors are often disfiguring and impact the quality of life by pain or bleeding. Based on discovery of the hedgehog (Hh) signaling pathway and its role in the pathogenesis of BCCs, smoothened (SMO) inhibitors have been developed with Sonidegib being the 2nd in class. It is the only Hh pathway inhibitor investigated in a randomized trial accompanied by pharmacodynamic investigations. Also, the disease assessment criteria applied were more stringent than those used in trials of 1st developed SMO inhibitor – vismodegib, and required annotated photographs, MRI as well as multiple biopsies in case of regression.

Areas covered: All available papers from Medline and the abstracts of the most important dermato-oncology meetings were included.

Expert opinion: Sonidegib is a promising medication for advanced BCC and other malignancies, driven by Hh signaling. It presents favorable pharmacokinetic properties and causes class specific toxicity with dose dependent adverse events in muscular and taste bud homeostasis, gastrointestinal symptoms and hair growth. Early after treatment initiation, it impacts the immunesusceptibility of the tumor lesions. Sonidegib deserves further development in combination with other drugs or antibodies, or alternative dosing schedules.     

Systemic inflammation induces COX-2 mediated prostaglandin D2 biosynthesis in mice spinal cord

Although prostaglandin (PG)D2 is one of the main metabolites of the cyclooxygenase (COX) pathway of arachidonate metabolism in the brain, relatively little is known about the regulation of PGD2 biosynthesis in the spinal cord during systemic inflammation. Therefore, the present study was aimed at investigating the effect of endotoxin treatment on spinal PGD2 biosynthesis in BALB/c mice. Spinal inflammatory response to systemic endotoxin was verified by determination of spinal TNFalpha and IL-1beta mRNA. COX-1, COX-2, membrane-bound prostaglandin E synthase-1 (mPGES-1), and lipocalin-type prostaglandin D synthase (L-PGDS) mRNA and protein were determined by RT-PCR and western blot, respectively. The concentrations of immunoreactive PGD2 and PGE2 were measured in superfusion media of spinal cord samples in-vitro. Endotoxin treatment (1 mg/kg; 24 h before) enhanced the expression of COX-2, mPGES-1, and L-PGDS mRNA and protein in spinal cord, while there was no significant effect on COX-1 mRNA and protein. In superfusion media of spinal cord samples obtained from endotoxin treated mice, the concentrations of immunoreactive PGE2 and PGD2 were higher than in the control group suggesting enhanced spinal PG biosynthesis after endotoxin treatment. Addition of the selective COX-2 inhibitor lumiracoxib (100 nM) to the superfusion medium did not significantly affect PGE2 or PGD2 release in spinal cord obtained from non-treated mice. In spinal cord of endotoxin-treated mice, lumiracoxib (100 nM) attenuated PGE2 and PGD2 release to values similar to those observed in tissue obtained from non-endotoxin-treated mice. These results show enhanced expression of spinal L-PGDS and increased spinal PGD2 biosynthesis during systemic inflammation whereby enhanced biosynthesis seems to be dependent primarily on COX-2 activity.     

Nurses' intent to leave the profession: issues related to gender, ethnicity, and educational level

BACKGROUND: The increase in demand for registered nurses will exceed supply by 29% by 2020, which is due in part to difficulties in retaining the existing nursing workforce. The researchers postulated that nursing professionals are experiencing a higher level of job dissatisfiers than motivators, and this is causing a high percentage of nurses to consider leaving the profession. Prior research has found that nurses' dissatisfaction with their working environments is a predictor of their intent to leave their professions; however, few have addressed the demographic characteristics of the population as predictors of this intent. PURPOSE: The purpose of this study was to explore issues relating to the retention of the existing nursing workforce. This article describes the results of a research study that was designed to identify and evaluate the variables that contribute to nurses' intent to leave their profession and the relationships of gender, ethnicity, and educational levels to this intent. METHODOLOGY: Data were collected from 284 nurses, of which 46% indicated that they were considering leaving their profession. Using multiple regression analysis, the researchers were able to test whether certain groups (according to gender, ethnicity, and education levels) had a greater intent to leave the profession and what factors were related to each subgroups' intent to leave. FINDINGS: The results of this study revealed that (a) nurses who are male, are White-non-Hispanic, or have less than a master's degree are more inclined to consider leaving the nursing profession, and (b) benefits were a more important consideration to male and White-non-Hispanic nurses regarding their intent to leave the nursing profession. PRACTICE IMPLICATIONS: In today's environment of low reimbursement and high cost containment, health care managers need to focus on those items that will have the greatest impact on retaining high-quality nurses because nurses "make the critical, cost-effective difference in providing safe, high-quality patient care."