The assessment of sarcopenia and the frailty phenotype in the outpatient care of older people: implementation and typical values obtained from the Newcastle SarcScreen project.

PURPOSE: Sarcopenia and the frailty phenotype both indicate older adults at risk of adverse health outcomes and yet are not widely assessed in practice. We developed the Newcastle SarcScreen to enable assessment of these two ageing syndromes during clinical care. In the setting of our Older People's Medicine Day Unit, our aims were to describe the implementation of the SarcScreen and to examine the typical values obtained. METHODS: The SarcScreen comprised height, weight, questions (three on the Fried frailty phenotype and five on the SARC-F questionnaire), grip strength and gait speed. We analysed data from 552 patients completing the SarcScreen. We expressed grip strength as Z-scores (number of standard deviations above the mean expected for a patient's age and sex). RESULTS: It was possible to implement the SarcScreen. In 552 patients (65.9% females) with mean age 80.1 (7.7) years, grip strength was feasible in 98.2% and gait speed in 82.1%. Gait speed was typically not assessed due to mobility impairment. Most patients had weak grip strength (present in 83.8%), slow gait speed (88.8%) and the frailty phenotype (66.2%). We found a high prevalence of probable sarcopenia and the frailty phenotype across all age groups studied. This was reflected by low grip strength Z-scores, especially at younger ages: those aged 60-69 had grip strength 2.7 standard deviations (95% CI 2.5-2.9) below that expected. CONCLUSION: It is possible to implement an assessment of sarcopenia and the frailty phenotype as part of the routine outpatient care of older people.

Periodontitis is associated with cognitive impairment among older adults: analysis of NHANES-III.

BACKGROUND: Periodontitis is ubiquitous and associated with serological evidence of exposure to periodontal organisms, systemic inflammation and vascular disease. Dementia is a major public health problem likely related to a complex interaction between genetics and diseases associated with systemic inflammation, including diabetes, smoking and stroke. METHODS: To assess relationships between systemic exposure to periodontal pathogens and cognitive test outcomes, data were analysed from the Third National Health and Nutrition Examination Survey (NHANES-III), a nationally representative cross sectional observational study among older adults. We included 2355 participants >or=60 years who completed measures of cognition and Poryphyromonas gingivalis IgG. Using SUDAAN, logistic regression models examined the association of P gingivalis IgG with cognitive test performance. RESULTS: Poor immediate verbal memory (<5/9 points) was prevalent in 5.7% of patients, and 6.5% overall had impaired delayed recall (<4/9); 22.1% had difficulty with serial subtractions (<5/5 trials correct). Individuals with the highest P gingivalis IgG (>119 ELISA Units (EU)) were more likely to have poor delayed verbal recall (OR 2.89, 95% CI 1.14 to 7.29) and impaired subtraction (OR 1.95, 95% CI 1.22 to 3.11) than those with the lowest (

Eosinophilic vasculitis in an isolated central nervous system distribution.

BACKGROUND: Eosinophilic vasculitis has been described as part of the Churg-Strauss syndrome, but affects the central nervous system (CNS) in <10% of cases; presentation in an isolated CNS distribution is rare. We present a case of eosinophilic vasculitis isolated to the CNS. CASE REPORT: A 39-year-old woman with a history of migraine without aura presented to an institution (located in the borough of Queens, New York, USA; no academic affiliation) in an acute confusional state with concurrent headache and left-sided weakness and numbness. Laboratory evaluation showed increased cerebrospinal fluid (CSF) protein level, but an otherwise unremarkable serological investigation. Magnetic resonance imaging showed bifrontal polar gyral-enhancing brain lesions. Her symptoms resolved over 2 weeks without residual deficit. After 18 months, later the patient presented with similar symptoms and neuroradiological findings involving territories different from those in her first episode. Again, the CSF protein level was high. She had a raised C reactive protein level and erythrocyte sedimentation rate. Brain biopsy showed transmural, predominantly eosinophilic, inflammatory infiltrates of medium-sized leptomeningeal arteries without granulomas. She improved, without recurrence, when treated with a prolonged course of corticosteroids. CONCLUSIONS: To our knowledge, this is the first case of non-granulomatous eosinophilic vasculitis isolated to the CNS. No aetiology for this patient's primary CNS eosinophilic vasculitis has yet been identified. Spontaneous resolution and recurrence of her syndrome is an unusual feature of the typical CNS vasculitis and may suggest an environmental epitope with immune reaction as the cause.

Current assays overestimate 25-hydroxyvitamin D3 and underestimate 25-hydroxyvitamin D2 compared with HPLC: need for assay-specific decision limits and metabolite-specific assays.

BACKGROUND: Clinical demand for quick, cheap, precise and accurate 25-hydroxyvitamin D (25(OH)D) results has led to the development of a variety of assay methods. Lack of standardization of these methods has resulted in inter-method disagreement and challenged whether current assays recognize 25(OH)D2 and 25(OH)D3 equally. METHODS: We studied 172 patient samples from hip fracture cases using DiaSorin (DS) and IDS radioimmunoassays and the Nichols Advantage-automated protein binding assay (NA-CLPBA) in comparison to high-performance liquid chromatography (HPLC). 52 patient samples were analysed before and after three months treatment with 1000 IU of daily ergocalciferol (vitamin D2). RESULTS: Linear regression analysis in pre-treatment samples demonstrated a positive Y-intercept for each immunoassay compared with HPLC, and a slope that varied from 0.64 (IDS) to 0.97 (DS, NA-CLPBA). Bland Altman analysis demonstrated that all the three assays had a proportional positive bias relative to HPLC at values from 20 to 50 nmol/L. Regression analysis of post-treatment samples demonstrated a slope that was not significantly different from zero for the IDS and NA-CLPBA and 0.2 for the DS method, with a positive intercept for all assays of between 8 and 22, indicating less than 50% of 25(OH)D2 measured by HPLC was detected. CONCLUSIONS: These results demonstrate the need for assay-specific decision limits for 25(OH)D3 in order to define appropriate thresholds for treatment institution. Treatment with vitamin D2 may not be accurately monitored with any of the three commercial assays studied. Clinicians and biochemists who continue to use 25(OH)D assays need to be urgently informed of these issues.

Interleukin-8 and anti-interleukin-8 autoantibodies in gingival crevicular fluid from patients with periodontitis.

Interleukin-8 (IL-8) is believed to play an important role in the pathogenesis of various forms of periodontitis. In addition, the anti-IL-8 autoantibody has been recently recognized as a potent modulator of IL-8 function. In the current study, the concentrations of IL-8 and its autoantibody in gingival crevicular fluid from patients with chronic generalized periodontitis were compared to those in gingival crevicular fluid from patients with refractory chronic periodontitis. Gingival crevicular fluids were collected from patients treated in a private periodontal clinic. Nine patients who were identified as having chronic generalized periodontitis and four with refractory chronic periodontitis were selected for the study. Patients included in the latter group had undergone supportive periodontal therapy for more than 10 years, and during that time had experienced many episodes of periodontal destruction. The gingival crevicular fluid concentrations of total protein, IL-8, free anti-IL-8 autoantibody and IL-8 bound to the autoantibody (anti-IL-8:IL-8 complexes) were examined. There were no differences in concentration of total protein, but significantly higher levels of IL-8 were detected in patients with chronic generalized periodontitis in comparison to patients with refractory chronic periodontitis (P < 0.05). In addition, anti-IL-8:IL-8 complexes were present in 90% of patients with chronic generalized periodontitis, but in only 50% of patients with refractory chronic periodontitis. The results suggest that elevated concentrations of free and complexed IL-8 can differentiate patients with chronic generalized periodontitis from patients with refractory chronic periodontitis.

The relationship between field tests of anaerobic power and 10-km run performance.

The purpose of this study was to investigate the relationship between several field tests of anaerobic power and distance running performance. Thirty-six trained runners (20 men and 16 women; mean +/- SD age, 27.9 +/- 5.7 years) participated in this study. Tests of anaerobic power consisted of a 50-m sprint, vertical jumps from a static take-off position and with a countermovement, a plyometric leap test, and a 300-m sprint. The results indicated that gender, height, weight, percent body fat, 50-m sprint time, the height and power of both types of vertical jumps, plyometric leap distance, and the 300-m sprint time were significantly correlated with 10-km run time (p < or = 0.05) in the total subject pool (N = 36). Stepwise multiple regression identified the plyometric leap distance to explain 73.9% of the variance in run time. When combined with 300-m sprint time, 77.9% of the variance (standard error of the estimate, 2.92 minutes) was explained. The regression equation developed is Y' (10-km time) = 57.22 - 5.15(plyometric leap distance in meters) + 0.27(300-m sprint time in seconds). The results indicate that anaerobic power is significantly related to distance running performance and may explain a meaningful percentage of variability in 10-km run time. Therefore, it may be beneficial for distance runners to supplement aerobic training with some power and speed development such as plyometrics and sprinting.

The effect of azithromycin and clarithromycin on ex vivo interleukin-8 (IL-8) release from whole blood and IL-8 production by human alveolar macrophages.

We investigated the effects of azithromycin and clarithromycin, two antibiotics that possess a broad spectrum of antimicrobial activity (including antimycobacterial activity), on interleukin-8 (IL-8) release from human whole blood leucocytes and lung macrophages. Ex vivo stimulation of leukocytes with either of the antibiotics (0.04-40 mg/L) significantly increased IL-8 secretion. Incubation of alveolar macrophages with different concentrations of azithromycin or clarithromycin modified IL-8 production: it increased at a drug concentration of 4 mg/L and decreased at concentration of 400 mg/L. Our findings suggest that azithromycin and clarithromycin may alter IL-8 production, thus enhancing the clinical effectiveness of these antibiotics.

Anti-interleukin 8 autoantibody: interleukin 8 complexes in the acute respiratory distress syndrome. Relationship between the complexes and clinical disease activity.

Increased levels of interleukin 8 (IL-8) are found in bronchoalveolar lavage (BAL) fluids from patients with the acute respiratory distress syndrome (ARDS). However, IL-8 is not an efficient predictor of the course of ARDS. Our prior studies demonstrated that IL-8 present in lung fluids from patients with ARDS is associated with anti-IL-8 autoantibodies (anti-IL-8:IL-8 complexes). These data led us to hypothesize that the complexes might better predict the development of acute lung injury. Accordingly, we measured concentrations of free and complexed IL-8 in BAL fluids from 19 patients at risk and 45 with established ARDS on Days 1, 3, 7, 14, and 21 after the onset of ARDS. The concentrations of anti-IL-8:IL-8 complexes in patients with ARDS on Day 1 were significantly higher than in patients at risk (p < 0.05). There was a significant association between anti-IL-8:IL-8 complex concentrations and the onset of ARDS (p = 0.03). Similarly, anti-IL-8:IL-8 complex concentrations were significantly higher in patients on Day 1 of ARDS who later died (p < 0.05), and the association between high anti-IL-8: IL-8 complex concentrations and the probability of dying was significant (p = 0.03). The presence of anti-IL-8:IL-8 complexes in BAL fluids of patients with ARDS is an important prognostic indicator for the development and outcome of ARDS.

Specific binding of IL-8 to rabbit alpha-macroglobulin modulates IL-8 function in the lung.

OBJECTIVE AND DESIGN: The purpose of this study was to compare chemotactic activity of IL-8 alone with that of IL-8 reacted with rabbit alpha-macroglobulins (alphaM) in vivo. METHODS: Initially the binding of recombinant human IL-8 (rhIL-8) to rabbit alphaM was studied. 125I-labeled rhIL-8 was incubated with alphaM, and electrophoresed on native 5% gels or SDS-polyacrylamide 4-20% gradient gels. Next, rhIL-8 or rhIL-8 bound to alphaM was administered via an endotracheal tube to rabbit's lungs. TREATMENT: An endotracheal tube was wedged into a segment of the lobe of each lung, and a sample instilled through the tube into this segment. After 4 h the lungs were lavaged. RESULTS: rhIL-8 bound to alphaM retained its full chemotactic activity in vitro but exhibited a diminished ability to induce the influx of neutrophils into the rabbit lung. CONCLUSIONS: The data suggest that alphaM may facilitate IL-8 clearance from the lung.

Involvement of alpha-2-macroglobulin receptor in clearance of interleukin 8-alpha-2-macroglobulin complexes by human alveolar macrophages.

The purpose of this study was to determine if interleukin 8 (IL-8) in complex with alpha2-macroglobulin (alpha-2-M) can be taken up by human alveolar macrophages. First, we demonstrated that human alveolar macrophages have receptors for alpha-2-M but not IL-8. The binding of(125)I-labeled alpha-2-M to the cells was specific and saturable, whereas(125)I-labeled recombinant human IL-8 (rhIL-8) did not bind to macrophages. However,(125)I-rhIL-8-alpha-2-M complexes bound to macrophages, and unlabeled alpha-2-M competed for the binding. We then cultured the cells in the presence of(125)I-rhIL-8-alpha-2-M complexes,(125)I-rhIL-8 alone or buffer for 24 h. Macrophages were lysed, and the released radioactivity measured. IL-8 concentrations in supernatants and cells were also measured using an IL-8 ELISA. When the macrophages were incubated with(125)I-rhIL-8-alpha-2-M complexes there was a significant amount of IL-8 associated with the cells. However, this was not the case when the cells were incubated with(125)I- rhIL-8 alone suggesting that only these complexes were taken-up by human alveolar macrophages. Furthermore, the clearance of complexes was specifically inhibited by a monoclonal antibody against the 515-kDa subunit of the alpha-2-M receptor (alpha-2-MR) but not by an isotopic mouse IgG1. The study shows an important clearance mechanism for IL-8 in the lung.

Effect of aging on CD11b and CD69 surface expression by vesicular insertion in human polymorphonuclear leucocytes.

The exocytosis of intracellular vesicles is an important function of the plasma membrane, which is responsible for hormone secretion, cell surface expression of antigens, ion transporters and receptors, and intracellular and intercellular signalling. Human aging is associated with many physiological and cellular changes, many of which are due to alterations in plasma membrane functioning. Alterations in vesicle externalization with age could account for many of these changes. We investigated whether alterations in vesicle exocytosis occur with increasing age by flow-cytometric determination of CD11b and CD69 expression on the surface of human polymorphonuclear leucocytes (PMN) stimulated with phorbol myristate acetate (PMA), a tumour promoter which binds to and activates protein kinase C (PKC) directly, or with formyl-Met-Leu-Phe (fMLP), which activates PKC indirectly via interactions with a cell surface receptor and G-protein, and subsequent inositol phosphate hydrolysis. Following stimulation with PMA, a decrease in the proportion of PMN expressing CD69 at high levels was observed in elderly compared with young subjects (young, 55.3%; elderly, 43.9%; P=0.01). No aging-related differences in the proportion of PMN expressing CD11b (young, 73.7%; elderly, 68.4%; P=0.15), or in the number of molecules of CD69 or CD11b expressed per cell, were observed. Stimulation with fMLP or low PMA concentrations resulted in full CD11b expression but minimal CD69 expression in both young and elderly subjects. Cells which expressed CD69 had no CD11b expression, while those cells expressing CD11b had minimal CD69 expression. Thus the PMA-induced expression of CD11b and CD69 in human PMN represents two separate processes, only one of which is affected in aging. CD11b expression appears to require a lesser degree of PKC stimulation compared with that required for CD69 expression. The age-associated reduction in PMA-stimulated CD69 expression may occur either at or distal to PKC activation. Such a decrease may contribute to the age-associated impairments in PMN function that contribute, in turn, to immunosenescence.

Effect of age on plasma membrane asymmetry and membrane fluidity in human leukocytes and platelets.

BACKGROUND: We determined whether ageing changes in plasma membrane phospholipid asymmetry were related to changes in membrane physical characteristics. METHODS: Plasma membrane asymmetry was determined in polymorphonuclear leukocytes (PMN), lymphocytes, and platelets from 45 healthy young (mean 29 years, 26 male) and 28 healthy elderly (mean 70 years, 15 male) subjects by flow cytometric measurement of annexin V binding to cell surface phosphatidylserine. Membrane fluidity in lymphocytes and platelets from young and elderly subjects was determined by fluorescence polarization of 1,6-diphenyl- 1,3,5-hexatriene (DPH) and (4-trimethylammonium)-DPH (TMA). RESULTS: In elderly subjects, a higher proportion of lymphocytes had specific annexin V binding to phosphatidylserine (PS) than in young subjects (young: median percentage of cells with specific annexin V binding to PS 5.3 [second to fourth quintiles range 3.8-8.7]; elderly: 8.5 [5.2-17.2]; p = .028). No ageing change in annexin V binding to PMN was observed (young: 35.0% [21.8-53.5]; elderly: 39.6% [27.4-69.8]; p = .42). Platelets had no specific annexin V binding (young: median molecules of annexin V specific binding 3.8 [0.4-11.3]; elderly: -1.4 [-4.8-1.7]; p = .23). Superficial membrane fluidity was increased in lymphocytes (TMA anisotropy, young: 0.271 [0.259-0.289]; elderly: 0.262 [0.242-0.279];p = .004), but not in platelets (young: 0.273 [0.259-0.293]; elderly: 0.269 [0.248-0.284]; p = .12). Lymphocyte annexin V binding correlated with TMA (r = -.65, p = .022), but not DPH anisotropy (r = -.39, p = .18). CONCLUSIONS: Plasma membrane asymmetry is decreased with age in human lymphocytes, but not in human PMN or platelets. The increased proportion of lymphocytes with loss of plasma membrane asymmetry corresponds to the ageing changes in superficial membrane fluidity observed in lymphocytes. Such alterations in lymphocyte plasma membrane structure with age could account for changes in membrane-bound receptor function described with ageing, and may contribute to alterations in immune responsiveness and vascular thrombosis seen in older humans.

Staphylococcal enterotoxin A-induced injury of human lung endothelial cells and IL-8 accumulation are mediated by TNF-alpha.

Staphylococcal enterotoxin A (SEA), a superantigen produced by some strains of Staphylococcus aureus, causes a variety of clinical manifestations ranging from food poisoning to shock. S. aureus can also be associated with the development of acute respiratory distress syndrome, and SEA has been shown to cause an inflammatory reaction in the lung. Therefore, we examined possible interactions between SEA, PBMCs, polymorphonuclear cells (PMNs), and normal human lung microvascular endothelial cells (HMVEC-L), as well as the role of these interactions on the secretion of IL-8. Injury to HMVEC-L, as measured by the release of 51Cr, increased significantly when HMVEC-L were incubated with SEA and PBMCs. IL-8 was secreted by both PBMCs and HMVEC-L. The accumulation of IL-8 in the culture medium of HMVEC-L was increased by SEA in a dose-dependent manner and was directly related to the number of PBMCs present. Although neither anti-human IL-8 nor IL-1 mAb inhibited HMVEC-L cytotoxicity, anti-human TNF-alpha mAb inhibited both the cytotoxicity and IL-8 accumulation completely. When HMVEC-L were incubated with supernatants from SEA-treated PBMCs, HMVEC-L cytotoxicity was comparable with HMVEC-L incubated with SEA and PBMCs at the same time. Although high concentrations of purified PMNs induced HMVEC-L lysis in a dose-dependent manner, the effect of PMNs was not changed in the presence of SEA. These findings suggest that TNF-alpha secreted by SEA-stimulated PBMCs plays a leading role in HMVEC-L injury.

Anti-IL-8 autoantibodies in alveolar fluid from patients with the adult respiratory distress syndrome.

IL-8 is a potent neutrophil attractant and activator. IL-8 has been reported to be involved in the pathogenesis of several diseases, including rheumatoid arthritis, sepsis, psoriasis, and the adult respiratory distress syndrome (ARDS). Our previous studies demonstrated that high concentrations of IL-8 were present in alveolar fluids from patients with ARDS and were associated with increased mortality. In this study we report that a major portion of IL-8 in bronchoalveolar fluids from patients with ARDS is associated with anti-IL-8 autoantibody (anti-IL-8:IL-8 complexes). Free autoantibodies that recognize IL-8 were also detected in these fluids. Next, we examined the properties of anti-IL-8 autoantibodies present in lung fluids from ARDS patients and compared them with autoantibodies from normal plasma and arthritic synovial fluids. The anti-IL-8 autoantibody was polyclonal, and IgG3 and IgG4 were the primary IgG subclasses. Anti-IL-8:IL-8 complexes consisted of one IgG and one IL-8 molecule. In addition, anti-IL-8 autoantibody bound IL-8 with a high affinity (approximately 10(-12) M) and inhibited IL-8 interaction with its specific receptors on neutrophils. The results suggest that anti-IL-8 autoantibodies may regulate IL-8 activity.

Interleukin-8 (IL-8) is a major neutrophil chemotaxin from human alveolar macrophages stimulated with staphylococcal enterotoxin A (SEA).

Since Staphylococcus aureus is an important human pathogen, and infection of the lungs is characterized by neutrophil infiltration we studied the role of a staphylococcal toxin, enterotoxin A (SEA) on the synthesis and secretion of IL-8 by human alveolar macrophages. As SEA concentration was increased, the IL-8 accumulation in the macrophage conditioned medium increased. The concentration of mRNA encoding IL-8 was also elevated in the macrophage in response to increases in SEA concentration. Although the monocytic cell line U937 was able to respond to SEA and secrete IL-8, treatment with PMA prior to SEA stimulation increased the IL-8 accumulation around fifty fold indicating that maturation of the undifferentiated cell to a more macrophage-like cell facilitated IL-8 accumulation. Stimulating human alveolar macrophages with high concentrations of SEA caused an increase in IL-1 accumulation. However, when the cells were incubated with SEA in the presence of IL-1 receptor antagonist, there was no decrease in IL-8 accumulation. Addition of a neutralizing anti-IL-8 monoclonal antibody to the culture medium of SEA-stimulated macrophages significantly reduced the neutrophil chemotactic activity of the medium. These studies showed that IL-8 is a major neutrophil chemotaxin from human alveolar macrophages stimulated with SEA.

Glucocorticoids regulate hippocampal 11 beta-hydroxysteroid dehydrogenase activity and gene expression in vivo in the rat.

Chronic glucocorticoid excess or deficiency is associated with hippocampal dysfunction and neuronal death. 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD), which catalyses the reversible conversion of corticosterone to inactive 11-dehydrocorticosterone, regulates glucocorticoid access to receptors in the kidney and liver in vivo. The enzyme is also present in the hippocampus where it might modulate glucocorticoid action. We examined the effects of corticosteroid manipulations on hippocampal and peripheral 11 beta-OHSD. In the hippocampus, chronic adrenalectomy (10 days) had no effect on 11 beta-OHSD activity, compared to sham-operated controls. Treatment of adrenalectomized animals with dexamethasone (200 micrograms/kg.day-1), but not aldosterone (20 micrograms/kg.day-1), for 10 days significantly increased hippocampal 11 beta-OHSD activity compared with sham or adrenalectomized rats (22% and 23% rise respectively, P < 0.05). These effects reflect changes in transcription of the liver-type 11 beta-OHSD gene, with dexamethasone significantly increasing 11 beta-OHSD mRNA expression in the hippocampus compared with sham or adrenalectomized animals (32% and 70% higher respectively, P < 0.05). In the liver, adrenalectomy significantly reduced 11 beta-OHSD activity (16% lower), which was restored to sham levels by dexamethasone, but not aldosterone. Similar trends were seen in 11 beta-OHSD mRNA expression, although these did not reach significance. None of the manipulations altered 11 beta-OHSD activity or mRNA expression in the kidney. The hippocampal effects of dexamethasone were similar to those of chronic stress (arthritis) which increased 11 beta-OHSD activity (20% rise, P < 0.05), although this was not reflected at the level of mRNA. Thus, hippocampal (and hepatic, but not renal) 11 beta-OHSD appears to be regulated by chronic glucocorticoid manipulations and stress. Hippocampal 11 beta-OHSD may thus ensure optimal long-term corticosterone exposure of glucocorticoid-sensitive neurons.