Osteoclasts and their circulating precursors in rheumatoid arthritis: Relationships with disease activity and bone erosions.

Patients with rheumatoid arthritis (RA) have very different outcomes, particularly with regard to bone erosions. Since osteoclasts are responsible for bone destruction adjacent to rheumatoid synovium, profiling osteoclasts from circulating precursors in RA could help identify patients at risk for bone destruction. In this study, we sought to determine whether the functional characteristics of osteoclasts generated from their blood precursors were modified by RA activity or were intrinsic to osteoclasts and associated with the RA phenotype (erosive or not). Osteoclasts were generated in vitro from peripheral blood mononuclear cells (PBMCs) of subjects with RA (n = 140), as well as sex- and age-matched healthy controls (n = 101). Osteoclastic parameters were analyzed at baseline and during the follow-up for up to 4 years, with regular assessment of RA activity, bone erosions, and bone mineral density (BMD). As a validation cohort, we examined RA patients from the Early Undifferentiated PolyArthritis (EUPA) study (n = 163). The proportion of CD14+ PBMC was higher in RA than in control subjects, but inversely correlated with the 28-joint disease activity score (DAS28). Also surprisingly, in osteoclast cultures from PBMCs, active RA was associated with lower osteoclastogenic capacity, while in vitro bone resorption per osteoclast and resistance to apoptosis were similar in both active and quiescent RA. In a small subgroup analysis, osteoclasts from subjects with recent RA that had progressed at four years to an erosive RA exhibited at baseline greater resistance to apoptosis than those from patients remaining non-erosive. Our findings establish that when RA is active, circulating monocytes have a reduced potential to generate osteoclasts from PBMCs in vitro. In addition, osteoclasts associated with erosive disease had resistance to apoptosis from the start of RA.

Modified Texture Food Use is Associated with Malnutrition in Long Term Care: An Analysis of Making the Most of Mealtimes (M3) Project.

OBJECTIVE: Modified texture food (MTF), especially pureed is associated with a high prevalence of under-nutrition and weight loss among older adults in long term care (LTC); however, this may be confounded by other factors such as dependence in eating. This study examined if the prescription of MTF as compared to regular texture food is associated with malnutrition risk in residents of LTC homes when diverse relevant resident and home-level covariates are considered. DESIGN: Making the Most of Mealtimes (M3) is a cross-sectional multi-site study. SETTING: 32 LTC homes in four Canadian provinces. PARTICIPANTS: Regular (n= 337) and modified texture food consumers (minced n= 139; pureed n= 68). MEASUREMENTS: Malnutrition risk was determined using the Mini Nutritional Assessment short-form (MNA-SF) score. The use of MTFs, and resident and site characteristics were identified from health records, observations, and standardized assessments. Hierarchical linear regression analyses, accounting for clustering, were performed to determine if the prescription of MTFs is associated with malnutrition risk while controlling for important covariates, such as eating assistance. RESULTS: Prescription of minced food [F(1, 382)=5.01, p=0.03], as well as pureed food [F(1, 279)=4.95, p=0.03], were both significantly associated with malnutrition risk among residents. After adjusting for age and sex, other significant covariates were: use of oral nutritional supplements, eating challenges (e.g., spitting food out of mouth), poor oral health, and cognitive impairment. CONCLUSIONS: Prescription of minced or pureed foods was significantly associated with the risk of malnutrition among residents living in LTC facilities while adjusting for other covariates. Further work needs to consider improving the nutrient density and sensory appeal of MTFs and target modifiable covariates.

Using a sequential explanatory mixed method to evaluate the therapeutic window of opportunity for initiating osteoporosis treatment following fragility fractures.

Interventions targeting patients with recent fragility fracture and their physician were most successful at initiating osteoporosis treatment during the first 12 months. This window of opportunity had already closed after 1 year. The reasons for declining or accepting the intensive intervention were explored in patients still untreated at 12 months. INTRODUCTION: A fragility fracture (FF) event identifies patients most likely to benefit from osteoporosis treatment. Nonetheless, most FF patients go untreated. Our objective was to determine how long an incident FF remains a strong incentive to initiate osteoporosis treatment. METHODS: A total of 1086 men and women over age 50 with a recent FF event were assigned to either standard care (SC), to minimal (MIN), or intensive (INT) interventions targeting patients and their family physician to initiate osteoporosis treatment. Inpatients with FF (mainly hip) evaluated by rheumatologists were also included in a specialized group (SPE; n = 324). At 1 year, untreated patients in both the SC and the MIN groups were offered an INT intervention. The cohort was followed through 48 months. A qualitative analysis of patient-centered decision-making associated with initiation of treatment was conducted. RESULTS: In MIN and INT groups, osteoporosis treatment was initiated in 41.0 and 54.3% of untreated patients by 12 months, respectively, compared to 68.4% in SPE and 18.9% in SC groups; initiation rates drastically dropped thereafter. Over 4863 patient-years of follow-up, the rates of new FF were 3.4 per 100 patient-years, without significant differences between patients with initial major or minor FF, nor between control or intervention groups. Failure by patients and physicians to recognize FF as a sign of underlying bone disease contributed the most to lack of treatment. CONCLUSION: While incident FFs are an ideal opportunity for starting osteoporosis treatment, 1 year later, the therapeutic window of opportunity has already closed.

Risk of Subsequent Fragility Fractures Observed After Low-Trauma Ankle Fractures.

While fragility fractures (FFs) are one of the strongest predictors of subsequent osteoporotic fractures, it remains unclear whether low-trauma ankle fractures have this ability. The aim of the study was to identify the characteristics of patients with low-trauma ankle FFs who develop subsequent FFs. The OPTIMUS initiative is a strategy to improve osteoporosis treatment post-FF in orthopedic clinics. FRAX scores without BMD (FRAX-BMI) were calculated at time of inclusion. Recurrent FFs were recorded over a 48-month follow-up. All FFs were X-ray-confirmed. A total of 265 patients with initial ankle FF were included (190 women; mean age 62.8 ± 9.6 years), of whom 15 developed new FFs. Patients with ankle FFs had longer time until recurrence and lower 2-year incidence of recurrent FFs (3.2%) compared with those having wrist FFs (9.0%) or other initial FFs (9.6%), and 4-year incidence rates of 6.2, 13.4, and 15.3%, respectively (log-rank test, p = 0.001). With an ankle FF at inclusion, recurrent FFs were more frequent in patients with previous FF (6.2 per 100 patient-years; p < 0.01) or high-risk FRAX-BMI scores pre- or post-FF (2.4 or 2.0 per 100 patient-years, respectively; ns), compared to patients without any of these conditions (0.7 per 100 patient-years). Ankle FFs represent a clinical opportunity for identifying at-risk patients who should be targeted for treatment (previous FFs and/or high-risk FRAX). Because of mechanical factors and other contributors involved, ankle FFs themselves do not predict subsequent FFs overall, and their inclusion in FRAX-BMI risk calculation may thus not be warranted.

Quantitative assessment of haemolysis secondary to modern infusion pumps.

BACKGROUND: Although most studies have shown that little haemolysis is induced by infusion pumps, there are some notable exceptions. Only limited data are available on the actual infusion pumps that are most used in hospitals in Quebec and elsewhere, namely, the Infusomat® Space (peristaltic), Plum A+™ (piston) and Colleague® CXE (shuttle) pumps. METHODS: Haemolysis and potassium levels were compared before and after the use of the three different infusion pumps. Using 135 units of packed red blood cells (RBCs) aged from 10 to 28 days, 27 measurements were taken for each pump at various flow rates (30, 60, 150, 300 and 450 ml/h) and were compared with measurements taken before using the pumps. The range of flow rates was chosen to cover those of paediatric and adult transfusions. RESULTS: The shuttle- and piston-type pumps resulted in low haemolysis levels. The peristaltic-type pump produced significantly more haemolysis, which worsened at low flow rates, but the absolute value of haemolysis remained within the range recommended by the regulatory agencies in North America and Europe. Approximately two-thirds of the haemolysis produced by the peristaltic-type pump seemed to be secondary to the use of an antisiphon valve (ASV) on the transfusion line recommended by the manufacturer. Potassium levels did not increase with the use of the pumps. CONCLUSION: Modern infusion pumps widely used in hospitals in Quebec and elsewhere produce non-threatening levels of haemolysis during the transfusion of packed RBCs aged from 10 to 28 days. ASVs appear to induce additional haemolysis, and we do not recommend using them for blood transfusion.

Systematic review of the relationship between childcare educators' practices and preschoolers' physical activity and eating behaviours.

The role of childcare educators is important given that 81% of preschoolers living in developed countries receive childcare outside their home. Since children learn by observing and imitating others, childcare educators may play a role in promoting healthy eating behaviours and physical activity in young children. Six databases were searched for quantitative peer-reviewed, English or French primary studies reporting the correlates, predictors or effectiveness of childcare educators' practices on preschoolers' healthy eating and physical activity behaviours. Risk of bias was assessed using the Quality Assessment Tool for Quantitative Studies. Fifteen articles were included in this review: 10 measured physical activity levels and five assessed eating behaviours. The quality score was rated as low for eight of these articles, and as moderate for the remaining seven. Two of four cross-sectional studies reported a positive relationship between educators and children's behaviours. Eleven intervention studies reported significant favourable effects of interventions. Educators may play a positive role in promoting healthy behaviours in children, but this is mainly based on a small number of intervention type studies of low or moderate quality. The influence of specific components of educators' practices on children's healthy eating and physical activity behaviours remains inconclusive.

Gsx1 expression defines neurons required for prepulse inhibition.

In schizophrenia, cognitive overload is thought to reflect an inability to suppress non-salient information, a process which is studied using prepulse inhibition (PPI) of the startle response. PPI is reduced in schizophrenia and routinely tested in animal models and preclinical trials of antipsychotic drugs. However, the underlying neuronal circuitry is not well understood. We used a novel genetic screen in larval zebrafish to reveal the molecular identity of neurons that are required for PPI in fish and mice. Ablation or optogenetic silencing of neurons with developmental expression of the transcription factor genomic screen homeobox 1 (gsx1) produced profound defects in PPI in zebrafish, and PPI was similarly impaired in Gsx1 knockout mice. Gsx1-expressing neurons reside in the dorsal brainstem and form synapses closely apposed to neurons that initiate the startle response. Surprisingly, brainstem Gsx1 neurons are primarily glutamatergic despite their role in a functionally inhibitory pathway. As Gsx1 has an important role in regulating interneuron development in the forebrain, these findings reveal a molecular link between control of interneuron specification and circuits that gate sensory information across brain regions.

Sex differences in social interaction behaviors in rats are mediated by extracellular signal-regulated kinase 2 expression in the medial prefrontal cortex.

Considerable sex differences occur in the incidence and prevalence of anxiety disorders where women are more anxious than men, particularly in situations where social interaction is required. In preclinical studies, the social interaction test represents a valid animal model to study sex differences in social anxiety. Indeed, female rats engage less in conspecific interactions than their male counterparts, which are behaviors indicative of higher social anxiety in female rats. In this work, we implicated extracellular signal-regulated kinase 2 (ERK2) in the medial prefrontal cortex (mPFC) in mediating social interaction. Indeed, female rats' had lower ERK2 expression compared to male rats, and overexpression of ERK2 in the mPFC increases their social interaction to the level seen in their male counterparts. These data indicate that the sexually dimorphic expression of ERK2 mediates social anxiety-like behaviors.

Juvenile and adult rats differ in cocaine reward and expression of zif268 in the forebrain.

Adolescents are more likely to experiment with and become addicted to drugs of abuse. A number of studies indicate that the developmental forebrain may be responsible for making adolescents vulnerable to the addictive properties of such drugs. The aim of this study was to first compare behavioral responses to novelty and cocaine between juvenile and adult rats and then compare levels of the immediate-early gene zif268 activation in several forebrain areas via in situ hybridization. We found that juveniles demonstrated higher locomotion scores and required a higher dose of cocaine than adults to establish a conditioned place preference. Additionally, at this higher dose, juvenile rats exhibited higher levels of zif268 mRNA in the prefrontal cortex compared with adults. A developmental effect for increased zif268 mRNA was also observed in the striatum and nucleus accumbens, but there was no interaction with the cocaine dose. These findings hold interesting implications for the study of the molecular mechanisms underlying juvenile drug addiction.

Dining experience, foodservices and staffing are associated with quality of life in elderly nursing home residents.

PURPOSE: Few studies have quantitatively investigated potential relationships between quality of life (QOL) in long term care (LTC) and foodservices. OBJECTIVE: To investigate if dining experiences, and food and nutritional services affect elderly nursing home residents' QOL. DESIGN AND PARTICIPANTS: A total of 395 residents in 38 nursing homes participated in this cross-sectional study. MEASUREMENTS: Information on dining experiences and QOL was gathered by face-to-face interviews with cognitively intact residents; primary institutional caregivers completed a questionnaire for cognitively impaired residents. Additional data were also obtained from participants' medical charts and from administrators and foodservice managers. Multivariate ordinary least squares (OLS) regression was used to determine which institutional characteristics were related to QOL. RESULTS: Number of dining companions, autonomy in relation to food, tray meal delivery service, and ratio of residents per resident assistant were significantly related to QOL in both cognitively intact and cognitively impaired residents. For cognitively intact residents, number of medical conditions, therapeutic menus, and use of china dishes were also related to QOL. For cognitively impaired residents, independence with eating and frequency of menu revision were also related to QOL. CONCLUSION: Modifying certain aspects of food and nutritional services, as well as residents' dining experience, may improve QOL of elderly LTC residents.

Effect of sarcoplasmic reticulum (SR) calcium content on SR calcium release elicited by small voltage-clamp depolarizations in frog cut skeletal muscle fibers equilibrated with 20 mM EGTA.

Cut muscle fibers from Rana temporaria (sarcomere length, 3.5-3.9 micro(m); 14-16 degreesC) were mounted in a double Vaseline-gap chamber and equilibrated with an external solution that contained tetraethyl ammonium- gluconate and an internal solution that contained Cs as the principal cation, 20 mM EGTA, and 0 Ca. Fibers were stimulated with a voltage-clamp pulse protocol that consisted of pulses to -70, -65, -60, -45, and -20 mV, each separated by 400-ms periods at -90 mV. The change in total Ca that entered into the myoplasm (Delta[CaT]) and the Ca content of the SR ([CaSR]) were estimated with the EGTA/phenol red method (Pape, P.C., D.-S. Jong, and W.K. Chandler. 1995. J. Gen. Physiol. 106:259-336). Fibers were stimulated with the pulse protocol, usually every 5 min, so that the resting value of [CaSR] decreased from its initial value of 1,700-2, 300 microM to values near or below 100 microM after 18-30 stimulations. Three main findings for the voltage pulses to -70, -65, and -60 mV are: (a) the depletion-corrected rate of Ca release (release permeability) showed little change when [CaSR] decreased from its highest level (>1,700 microM) to approximately 1,000 microM; (b) as [CaSR] decreased below 1,000 microM, the release permeability increased to a maximum level when [CaSR] was near 300 microM that was on average about sevenfold larger than the values observed for [CaSR] > 1,000 microM; and (c) as [CaSR] decreased from approximately 300 microM to <100 microM, the release permeability decreased, reaching half its maximum value when [CaSR] was approximately 110 microM on average. It was concluded that finding b was likely due to a decrease in Ca inactivation, while finding c was likely due to a decrease in Ca-induced Ca release.

CGRP innervation and receptors during aging of male and female hepatic rat portal veins.

Calcitonin gene-related peptide (CGRP) innervation and binding sites were studied on hepatic portal veins of male and female rats from 19 days to 22 months of age. CGRP containing nerve fibers were present both in adventitial and medial nerve plexuses, closely apposing to or penetrating into the muscular layers. The density of CGRP innervation was estimated on whole mount preparations and compared during aging. In females, aging did not affect the number of fibers per unit length, although the vessel circumference decreased after 6 months of age. In males, the vessel circumference remained constant during aging, while the density of innervation significantly decreased. Whatever the age or sex of the animals was, no CGRP binding sites were found on portal veins sections by autoradiography. CGRP had no effect on spontaneous contractions of perfused portal veins. The difference observed in the evolution of CGRP innervation density between males and females suggests that CGRP innervation in the rat portal vein may be influenced by gonadal steroids during aging.

Rat common bile duct: structure, pharmacological responsiveness, CGRP innervation, and binding sites.

The wall of the rat common bile duct (CBD) consists of several epithelial ducts embedded in connective tissue which contains some regions with cells weakly stained by an antibody against alpha smooth muscle actin. The hepatic side (HS) is more vascularized than the duodenal side (DS). Calcitonin gene-related peptide (CGRP)-like immunoreactivity is present in nerve fibres penetrating deeply into the CBD wall. On whole-mount preparations, CGRP innervation is mainly associated with blood vessels in the HS, whereas it forms a wide meshed network independent of vasculature in the DS. Abundance of CGRP innervation was compared between both sexes and at different ages. No differences were found in the total number of fibres between males and females except at 4 months of age, when males had statistically more abundant innervation than females. However, during aging, while the abundance of innervation (fibers/mm) remained stable in both HS and DS in females, it significantly decreased in males. Autoradiography demonstrated the presence of 125I-CGRP binding sites in the rat CBD. In vitro, 30% of HS strips showed spontaneous rhythmic contractions but all the strips (autocontractile or not) contracted dose dependently in response to acetylcholine (Ach) or substance P (SP). However, DS strips were neither autocontractile nor responsive to Ach or SP. Perfusion of all strips with 10(-7) M CGRP produced no effects nor influenced Ach- or SP-induced contractions.

Occurrence of CGRP receptors on dedifferentiated smooth muscle cells from media of rat thoracic aorta.

Autoradiographic studies with [125I]-CGRP did not demonstrate receptors on sections from two different regions of 5-week-old rat aorta (of both sexes). By contrast, cultured smooth muscle cells isolated from similar aortic media and passaged 5 to 7 times exhibited specific binding.

The Validation of Brass's Model Life Table System.

Abstract The closeness-of-fit of two-parameter Brass model life-tables to English life-tables is examined. This is done for various life-table functions and various criteria of best fit. Reproductions of computer output give full details of the fits for typical cases from the large selection of cases examined. It was found that the equations to be solved to find the best fit were intractable and the paper gives a simple method of finding an approximate solution to these equations.