Menopausal stage differences in endothelial resistance to ischemia-reperfusion injury

Background: In postmenopausal women, reduced ovarian function precedes endothelial dysfunction and attenuated endothelial resistance to ischemia-reperfusion (IR) injury. We hypothesized that IR injury would lower endothelial function, with premenopausal women demonstrating the greatest protection from injury, followed by early, then late postmenopausal women. Methods: Flow-mediated dilation (FMD) was assessed at baseline and following IR injury in premenopausal (n = 11), early (n = 11; 4 ± 1.6 years since menopause), and late (n = 11; 15 ± 5.5 years since menopause) postmenopausal women. Results: There were significant group differences in baseline FMD (p = 0.007); post hoc analysis revealed a similar resting FMD between premenopausal (7.8% ± 2.1%) and early postmenopausal (7.1% ± 2.7%), but significantly lower FMD in late postmenopausal women (4.5% ± 2.3%). Results showed an overall decline in FMD after IR injury (p < 0.001), and a significant condition*time interaction (p = 0.048), with early postmenopausal women demonstrating the most significant decline in FMD following IR. Conclusion: Our findings indicate that endothelial resistance to IR injury is attenuated in healthy early postmenopausal women

Reply to: Hypoxia treatment of Parkinson’s disease may disrupt the circadian system

Background Introduction In recent years, increasing attention has been given to hypoxia-based treatment for persons with neurodegenerative and mitochondrial disease, as reflected by the significant rise in publications from basic [1], preclinical [2] and clinical [3, 4] research groups. Hypoxia treatment is based on the idea of hypoxic conditioning and adaptations induced by hypoxia. Recently, we published a protocol paper to assess the safety, feasibility, and acute symptomatic effects of single sessions of continuous and intermittent hypoxia (for 45 min, at FiO2 0.133 and 0.163) in persons with Parkinson’s disease (PD) [3]. In Coste & Touitou’s recent correspondence [5] to our protocol [6], they highlighted the potential for circadian rhythm disturbances induced by hypoxia in PD. This interesting insight is based on their two different studies, in which a phase shift in circadian rhythm (as measured by cortisol and melatonin) was observed after eight-hours-long ‘chronic’ exposure to hypoxia [7, 8]. Coste & Touitou [6] carefully considered that hypoxia-based interventions could therefore induce changes in circadian rhythm, and this may in turn affect the outcome of these interventions. Here, we discuss important differences between chronic hypoxia, which resembles hypoxia as a disease model for sleep apnea, and hypoxic conditioning

Hybrid Equation/Agent-Based Model of Ischemia-Induced Hyperemia and Pressure Ulcer Formation Predicts Greater Propensity to Ulcerate in Subjects with Spinal Cord Injury

Pressure ulcers are costly and life-threatening complications for people with spinal cord injury (SCI). People with SCI also exhibit differential blood flow properties in non-ulcerated skin. We hypothesized that a computer simulation of the pressure ulcer formation process, informed by data regarding skin blood flow and reactive hyperemia in response to pressure, could provide insights into the pathogenesis and effective treatment of post-SCI pressure ulcers. Agent-Based Models (ABM) are useful in settings such as pressure ulcers, in which spatial realism is important. Ordinary Differential Equation-based (ODE) models are useful when modeling physiological phenomena such as reactive hyperemia. Accordingly, we constructed a hybrid model that combines ODEs related to blood flow along with an ABM of skin injury, inflammation, and ulcer formation. The relationship between pressure and the course of ulcer formation, as well as several other important characteristic patterns of pressure ulcer formation, was demonstrated in this model. The ODE portion of this model was calibrated to data related to blood flow following experimental pressure responses in non-injured human subjects or to data from people with SCI. This model predicted a higher propensity to form ulcers in response to pressure in people with SCI vs. non-injured control subjects, and thus may serve as novel diagnostic platform for post-SCI ulcer formation. © 2013 Solovyev et al

Randomized controlled trial of intermittent hypoxia in Parkinson’s disease: study rationale and protocol

Background Parkinson’s disease (PD) is a neurodegenerative disease for which no disease-modifying therapies exist. Preclinical and clinical evidence suggest that repeated exposure to intermittent hypoxia might have short- and long-term benefits in PD. In a previous exploratory phase I trial, we demonstrated that in-clinic intermittent hypoxia exposure is safe and feasible with short-term symptomatic effects on PD symptoms. The current study aims to explore the safety, tolerability, feasibility, and net symptomatic effects of a four-week intermittent hypoxia protocol, administered at home, in individuals with PD. Methods/Design: This is a two-armed double-blinded randomized controlled trial involving 40 individuals with mild to moderate PD. Participants will receive 45 min of normobaric intermittent hypoxia (fraction of inspired oxygen 0.16 for 5 min interspersed with 5 min normoxia), 3 times a week for 4 weeks. Co-primary endpoints include nature and total number of adverse events, and a feasibility-tolerability questionnaire. Secondary endpoints include Movement Disorders Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part II and III scores, gait tests and biomarkers indicative of hypoxic dose and neuroprotective pathway induction. Discussion This trial builds on the previous phase I trial and aims to investigate the safety, tolerability, feasibility, and net symptomatic effects of intermittent hypoxia in individuals with PD. Additionally, the study aims to explore induction of relevant neuroprotective pathways as measured in plasma. The results of this trial could provide further insight into the potential of hypoxia-based therapy as a novel treatment approach for PD

Leg blood flow measurements using venous occlusion plethysmography during head-up tilt

We tested whether venous occlusion plethysmography (VOP) is an appropriate method to measure calf blood flow (CBF) during head-up tilt (HUT). CBF measured with VOP was compared with superficial femoral artery blood flow as measured by Doppler ultrasound during incremental tilt angles. Measurements of both methods correlated well (r = 0.86). Reproducibility of VOP was fair in supine position and 30° HUT (CV: 11%–15%). This indicates that VOP is an applicable tool to measure leg blood flow during HUT, especially up to 30° HUT

Anastrozole (‘Arimidex’) blocks oestrogen synthesis both peripherally and within the breast in postmenopausal women with large operable breast cancer

The effect of anastrozole on peripheral and tumour aromatase activity and oestrogen levels in postmenopausal patients with oestrogen receptor-rich breast tumours was investigated. Twenty-six patients were randomly allocated to treatment with anastrozole 1 mg (n=13) or 10 mg (n=13), once daily. Before and after 12 weeks' treatment, patients were infused with 3H-Δ4 androstenedione (20 MBq) and 14C-oestrone (E1) (1 MBq) for 18 h. Oestrogens were purified from excised tumours and plasma samples taken after each infusion. Peripheral and tumour aromatase activity and tumour E1 uptake were calculated from levels of 3H and 14C in purified E1 fractions from tumour and plasma. Endogenous tumour oestrogens were measured by radioimmunoassay. Twenty-three patients were available for analysis (1 mg group, n=12; 10 mg group, n=11). Following treatment, anastrozole (1 and 10 mg) markedly inhibited peripheral aromatase in all patients (the difference between pre- and on-treatment values being highly significant P<0.0001). In situ aromatase activity was also profoundly decreased by anastrozole treatment in 16 of 19 tumours (the difference with treatment also being highly significant P=0.0009). Most tumours were able to concentrate E1 beyond levels in the circulation; anastrozole treatment had no consistent effect on uptake of E1. Endogenous tumour levels of both E1 and oestradiol (E2) were significantly reduced with therapy (P=0.028 for E1 and P=0.0019 for E2). Anastrozole (1 and 10 mg daily) effectively suppresses aromatase activity, and subsequently oestrogen levels, within the breast tissue of postmenopausal women with large or locally advanced, operable, oestrogen receptor-rich breast cancers

Emergency department crowding in The Netherlands: managers’ experiences

__Abstract__ __Background__ In The Netherlands, the state of emergency department (ED) crowding is unknown. Anecdotal evidence suggests that current ED patients experience a longer length of stay (LOS) compared to some years ago, which is indicative of ED crowding. However, no multicenter studies have been performed to quantify LOS and assess crowding at Dutch EDs. We performed this study to describe the current state of emergency departments in The Netherlands regarding patients’ length of stay and ED nurse managers’ experiences of crowding. __Methods__ A survey was sent to all 94 ED nurse managers in The Netherlands with questions regarding the type of facility, annual ED census, and patients’ LOS. Additional questions included whether crowding was ever a problem at the particular ED, how often it occurred, which time periods had the worst episodes of crowding, and what measures the particular ED had undertaken to improve patient flow. __Results__ Surveys were collected from 63 EDs (67%). Mean annual ED visits were 24,936 (SD ± 9,840); mean LOS for discharged patients was 119 (SD ± 40) min and mean LOS for admitted patients 146 (SD ± 49) min. Consultation delays, laboratory and radiology delays, and hospital bed shortages for patients needing admission were the most cited reasons for crowding. Admitted patients had a longer LOS because of delays in obtaining inpatient beds. Thirty-nine of 57 respondents (68%) reported that crowding occurred several times a week or even daily, mostly between 12:00 and 20:00. Measures taken by hospitals to manage crowding included placing patients in hallways and using a fasttrack with treatment of patients by trained nurse practitioners. __Conclusions__ Despite a relatively short LOS, frequent crowding appears to be a nationwide problem according to Dutch ED nurse managers, with 68% of them reporting that crowding occurred several times a week or even daily. Consultations delays, laboratory and radiology delays, and hospital bed shortage for patients needing admission were believed to be the most important factors contributing to ED crowding

Piezo1 channels sense whole body physical activity to reset cardiovascular homeostasis and enhance performance

Mammalian biology adapts to physical activity but the molecular mechanisms sensing the activity remain enigmatic. Recent studies have revealed how Piezo1 protein senses mechanical force to enable vascular development. Here, we address Piezo1 in adult endothelium, the major control site in physical activity. Mice without endothelial Piezo1 lack obvious phenotype but close inspection reveals a specific effect on endothelium-dependent relaxation in mesenteric resistance artery. Strikingly, the Piezo1 is required for elevated blood pressure during whole body physical activity but not blood pressure during inactivity. Piezo1 is responsible for flow-sensitive non-inactivating non-selective cationic channels which depolarize the membrane potential. As fluid flow increases, depolarization increases to activate voltage-gated Ca2+ channels in the adjacent vascular smooth muscle cells, causing vasoconstriction. Physical performance is compromised in mice which lack endothelial Piezo1 and there is weight loss after sustained activity. The data suggest that Piezo1 channels sense physical activity to advantageously reset vascular control

Mediterranean spotted fever: clinical and laboratory characteristics of 415 Sicilian children

BACKGROUND: Mediterranean spotted fever (MSF) is an acute febrile, zoonotic disease caused by Rickettsia conorii and transmitted to humans by the brown dogtick Rhipicephalus sanguineus. Nearly four hundred cases are reported every year (mainly from June to September) on the Italian island of Sicily. The aim of the study was to analyze the clinical and laboratory characteristics of patients with MSF and the efficacy of the drugs administered. METHODS: Our study was carried out on 415 children with MSF, during the period January 1997 – December 2004, at the "G. Di Cristina" Children's hospital in Palermo, Sicily, Italy. On admission patients' clinical history, physical and laboratory examination and indirect immunofluorescence antibody test (IFAT) for Rickettsia conorii were performed. Diagnosis was considered confirmed if the patients had an MSF diagnostic score greater than or equal to 25 according to the Raoult's scoring system. All patients were treated with chloramphenicol or with macrolides (clarithromycin or azithromycin). RESULTS: Fever, rash and tache noire were present in 386 (93%), 392 (94.5%) and 263 (63.4%) cases respectively. Eighteen (4.6%) children showed atypical exanthema. Chloramphenicol and newer macrolides all appeared to be effective and safe therapies. CONCLUSION: Clinical features of 415 children with MSF were similar to those reported by other authors except for a lower incidence of headache, arthralgia and myalgia and a higher frequency of epato-splenomegaly. Concerning therapy, clarithromycin can be considered a valid alternative therapy to tetracyclines or chloramphenicol especially for children aged < eight years