A study investigating short- and medium-term effects on function, bone mineral density and lean tissue mass post-total knee replacement in a Caucasian female post-menopausal population: implications for hip fracture risk.

UNLABELLED: Significant increased hip fracture incidence has been reported in the year following total knee replacement. This study demonstrates that bone and muscle loss is a post-surgical consequence of total knee replacement, alongside poor outcomes in function and activity potentially contributing to reduced quality of life and increased hip fracture risk. INTRODUCTION: A significant increase in hip fracture incidence in the year following total knee replacement (TKR) surgery has been reported. This study investigated function and activity following TKR and the effects of limited mobility on bone and muscle loss and their potential contribution to hip fracture risk. METHODS: Changes in dual-energy X-ray absorptiometry (DXA) (GE Lunar Prodigy, Bedford MA), bone mineral density (BMD) at the neck of femur (NOF), total hip region (TH) and lumbar spine were measured alongside leg lean tissue mass (LLTM) in post-menopausal Caucasian females following TKR (N = 19) compared to controls (N = 43). Lumbar spine trabecular bone scores (TBSs) were calculated. Ipsilateral/contralateral weight bearing, lower limb function, 3-day pedometer readings, pain levels and falls were also recorded. Measurements were obtained at pre-surgery baseline and at 6 weeks, 6 months and 12 months post-surgery. RESULTS: No statistically significant differences were demonstrated between groups at baseline bilaterally in LLTM or BMD at the NOF and TH. Losses in ipsilateral NOF and TH BMD and contralateral LLTM were significantly higher in the TKR group at 6 months. Impairment in function and weight bearing persisted in the TKR group 12 months post-operatively alongside deficits in bilateral muscle mass and ipsilateral NOF and TH BMD. Falls incidence was not significantly higher in the TKR group. CONCLUSIONS: Bone loss at the hip with associated muscle loss is a consequence of TKR that, in addition to poor patient outcomes in function and activity, potentially contributes to increased hip fracture risk in the year following surgery.

"It's what's behind the mask": Psychological diversity in compassionate patient care.

INTRODUCTION: The Francis Report recommended an increased focus on compassion in healthcare, and recognition and non-judgmental acceptance of diversity is fundamental in compassionate patient care. The aim of this study was to achieve a wider understanding of diversity that includes individual patient needs, expectations, perceptions and feelings during diagnostic imaging. METHODS: Using thirty-four semi-structured interviews with individual patients, this qualitative study explored their experiences of undergoing diagnostic radiography examinations and asked what compassionate care meant to them and how it is perceived and manifested in the brief, task-focussed and highly technical diagnostic projection imaging encounter. Data were analysed using Thematic Analysis. RESULTS: Four key themes were identified from the analysis; these were: feelings and vulnerability; hidden emotions; professionalism and valued qualities and communication. CONCLUSION: Diversity is defined not only in terms of socio-cultural differences but also psychological ones, i.e. individual emotional and attitudinal characteristics, some of which may be consciously or unconsciously concealed. In order that patients are treated equitably and all of their care needs met, recommendations include a broader focus in education and training to include adapting communication skills and techniques in perception and expression of non-verbal cues. Further research into the pressures specific to the time-pressured, task-focussed, highly technical and rapid turnover environment of projection imaging radiography and how this impacts upon compassionate patient care would make a useful contribution to the field.

Disuse osteopenia following leg fracture in postmenopausal women: Implications for HIP fracture risk and fracture liaison services.

INTRODUCTION: Disuse osteopenia is a known consequence of reduced weight-bearing and has been demonstrated at the hip following leg injury but has not been specifically studied in postmenopausal women. METHOD: Bilateral DXA (GE Lunar Prodigy) bone mineral density (BMD) measurements were taken at the neck of femur (NOF), total hip region (TH) and lumbar spine in postmenopausal female groups comprising controls (N = 43), new leg fractures (#<3wks) (N = 9), and participants who had sustained a leg fracture more than one year previously (#>1yr) (N = 24). #>1yr were assessed at a single visit and the remaining groups at intervals over twelve months. Weight-bearing, function, 3-day pedometer readings, and pain levels were also recorded. RESULTS: The #<3wks demonstrated significant (p < 0.05) losses in ipsilateral TH BMD at 6 weeks from baseline 0.927 ± 0.137 g/cm2, to 0.916 ± 0.151 g/cm2 improving to 0.946 ± 0.135 g/cm2 (n.s) at 12 months following gradual return to normal function and weight-bearing activity. The #>1yr scored significantly below controls in almost all key physical and functional outcomes demonstrating a long-term deficit in hip bone density on the ipsilateral side. CONCLUSION: The clinical significance of post-fracture reduction in hip BMD is a potential increased risk of hip fracture for a variable period that may be mitigated after return to normal function and weight-bearing. Improvement at 12 months in #<3wks is not consistent with #>1yr results indicating that long-term impairment in function and bone health may persist for some leg fracture patients. Unilateral bone loss could have implications for Fracture Liaison Services when assessing the requirement for medication post fracture.

Cytokines and the nervous system II: Actions and mechanisms of action.

Cytokines exert diverse actions on the PNS and the CNS and have been implicated in neuronally mediated responses to disease and injury. Certain cytokines participate in the central control of host systemic responses to disease, acting as signals to and within the brain. These molecules are also involved in neuronal degeneration and repair in the PNS and CNS, and have been proposed as mediators of various neuropathologies. The actions, mechanisms of action and potential strategies for modifying cytokines in the nervous system will be considered in this review, which continues the discussion of cytokine expression and recognition published in the February issue of TINS.

Cytokines and the nervous system. I: Expression and recognition.

Cytokines are a heterogeneous group of polypeptide mediators that have been associated classically with activation of the immune system and inflammatory responses. An increasing number of related mediators is now included in this category and most of them have been shown to act on a variety of tissues, including the PNS and CNS. Cytokines and their receptors are expressed in tissues of these nervous systems, and might derive from invading immune, or resident, cells. Trauma in peripheral tissues might also induce cytokine-mediated events in the CNS, via either the circulation or secondary induction within the brain. In this first of a two-part review, the general properties, expression and recognition of these cytokines with respect to the nervous system are discussed.

Bioassay of interleukin-1 in serum and plasma following removal of inhibitory activity with polyethylene glycol.

Serum and plasma normally inhibit the responsiveness of the indicator cells used in bioassays for interleukin-1 (IL-1). A precipitation step with 12% polyethylene glycol (PEG) was found to remove material responsible for such inhibition. The IL-1 bioassay could be performed in the presence of a 3% concentration of PEG and recovery of added natural IL-1 from plasma or serum was essentially complete.

Simple, sensitive and specific bioassay of interleukin-1.

This paper describes a convenient method for the culture of sub-lines of the murine T cell cloned line, D10.G4.1, and the use of these lines in a highly sensitive and specific bioassay for interleukin-1 (IL-1). The cells are cultured with IL-1, interleukin-2 (IL-2), and concanavalin A (ConA), in the absence of feeder cells or antigen. Assays are routinely carried out in the presence of saturating IL-2, which enhances sensitivity and ensures that further IL-2 will not give false positives. Addition of interleukin-4 (IL-4) has a similar effect and can be used together with IL-2 where there is a potential for interference from either cytokine. The assay is not affected by high concentrations of human interleukin-6 or tumour necrosis factor-alpha (TNF-alpha) and only minimally affected by high concentrations of murine TNF-alpha.

Reduction of meningeal macrophages does not decrease migration of granulocytes into the CSF and brain parenchyma in experimental pneumococcal meningitis.

Leukocyte infiltration of the CSF and brain parenchyma and other parameters of inflammation during pneumococcal meningitis were investigated after reduction of meningeal macrophages in rabbits by intracisternal injection of dichloromethylene-diphosphonate (Cl2MDP)-containing liposomes. Macrophages in the meninges were reduced, in median, by approximately 77% after three intrathecal injections of 100 microl of liposomes containing Cl2MDP at 12 h intervals. Production of the cytokines interleukin-1 and tumor necrosis factor-alpha as well as infiltration of the CSF and nervous tissue by leukocytes was not significantly altered in infected animals after treatment with Cl2MDP-containing liposomes. The median CSF concentration of neuron specific enolase (NSE) as a parameter of neuronal damage was higher in infected Cl2MDP-treated animals (median [median (25th/75th percentiles): 44.7 (33.2/54.3) microg/l vs. 13.9 (10.4/23.9) microg/l; P = 0.01]). Therefore, the reduction of meningeal macrophages does not appear to attenuate inflammation in the subarachnoid space in experimental pneumococcal meningitis. Meningeal macrophages seem, however, to be important for the protection of neuronal tissue in bacterial meningitis.

Antigen-induced unresponsiveness in contact sensitivity: association of depressed T lymphocyte proliferative responses with decreased interleukin 6 secretion.

Topical exposure of mice to the contact allergen oxazolone induces both 4 persistent antigen-specific down-regulation of subsequent lymph node cell (LNC) proliferative responses stimulated by the same chemical and a more transient depression of LNC proliferative responses provoked by exposure to unrelated chemical sensitizers: the latter being associated with antigenic competition in contact sensitivity. In this paper a relationship between reduced LNC proliferative activity and the secretion of interleukin 6 (IL-6) is described. Pretreatment of mice with oxazolone caused a persistent, dose-dependent inhibition of LNC proliferative activity and a parallel reduction of IL-6 secretion when mice were re-exposed, at a different site, to the same chemical. Consistent with dendritic cells (DC) being the major source of IL-6 within allergen-activated lymph nodes, depletion of Thy-lt T lymphocytes did not compromise production of this cytokine. Although in mice pretreated with oxazolone IL-6 secretion by cultured LNC was impaired markedly, the initial IL-6 content of freshly isolated LNC was apparently normal. These data suggest that the down-regulation of lymphocyte proliferative responses induced by exposure of mice to oxazolone, and the consequential impaired responsiveness, is associated with, and possibly secondary to, the reduced secretion by lymph node DC of IL-6, a cytokine that is a costimulator of T lymphocyte activation and the production of which correlates closely with the vigour of LNC proliferative activity.

The role of TNF-alpha in fever: opposing actions of human and murine TNF-alpha and interactions with IL-beta in the rat.

1. The role of tumour necrosis factor-alpha (TNF-alpha) in fever is controversial. Some studies have indicated that TNF-alpha acts as a cryogen to inhibit fever, while others suggest that TNF-alpha is an endogenous pyrogen which mediates fever. The majority of studies in experimental animals supporting a cryogenic action have been conducted using human (h)TNF-alpha, which has been shown to bind only to one (p55) of the two TNF-alpha receptors in rodents. 2. The aim of the present investigation was to study the role of TNF-alpha in fever by comparing effects of hTNF-alpha, which binds only to the p55 receptor, with those of murine (m) TNF-alpha, which binds to both p55 and p75 TNF-alpha receptors, and to investigate the relationship between TNF-alpha and interleukin-1 (IL-1), an important endogenous pyrogen. 3. Injection of hTNF-alpha (0.3-10 micrograms kg-1, i.p.) had no effect on core temperature in conscious rats (measured by remote radiotelemetry), whereas mTNF-alpha (3 micrograms kg-1) induced fever which was maximal 1 h after the injection (38.2 +/- 0.2 degrees C compared to 37.3 +/- 0.1 degrees C in controls). Intracerebroventricular (i.c.v.) administration of either form of TNF-alpha elicited dose-dependent fever at doses higher than 0.12 microgram kg-1. 4. Peripheral injection of hIL-1 beta (1 microgram kg-1) resulted in fever (38.3 +/- 0.2 degree C compared to 37.2 +/- 0.1 degrees C in controls at 2 h), which was significantly attenuated (P < 0.01) by co-administration of a sub-pyrogenic dose of hTNF-alpha (1 microgram kg-1), but was unaffected by co-administration of mTNF-alpha (0.1 or 0.3 microgram kg-1, i.p.). In contrast, intracerebroventricular (i.c.v.) co-administration of a sub-pyrogenic dose (0.12 microgram kg-1) of hTNF-alpha did not attenuate fever induced by intraperitoneal (i.p.) injection of IL-1 beta, and sub-pyrogenic dose (0.12 microgram kg-1, i.c.v.) of mTNF-alpha significantly prolonged the febrile response to IL-1 beta. Pretreatment of animals with anti-TNF-alpha antiserum (i.c.v.) did not affect the febrile response to systemic IL-1 beta. 5. Animals injected i.p. with a pyrogenic dose of mTNF-alpha developed fever (38.2 +/- 0.2 degrees C compared to 37.3 +/- 0.1 degrees C in controls 2 h after the injection) that was completely abolished by peripheral administration of IL-1ra (2 mg kg-1, P < 0.001), while i.c.v. administration of IL-1ra (400 micrograms/rat) did not affect mTNF-alpha-induced fever. 6. These data indicate that endogenous TNF-alpha is probably a pyrogen and that previous results suggesting cryogenic actions of TNF-alpha resulted from the use of a heterologous protein in the rat. The markedly contrasting effects of mTNF-alpha and TNF-alpha could result from different interactions with the two TNF-alpha receptor subtypes. The data also suggest that fever induced by exogenous TNF-alpha is mediated via release of IL-1 beta in peripheral tissues, but not in the brain.

Sites of action of IL-1 in the development of fever and cytokine responses to tissue inflammation in the rat.

1. The objective of the present study was to determine the sites of action of the cytokine, interleukin-1 (IL-1), in the febrile response to local inflammation in the rat, by comparing the importance of IL-1 in the local tissues, the circulation and the brain. This was achieved by injecting lipopolysaccharide (LPS, 100 micrograms kg-1) into a subcutaneous air pouch and testing the effects of blocking IL-1 action with the human recombinant interleukin-1 receptor antagonist (IL-1ra) injected either into the air pouch, intraperitoneally (1 mg kg-1, 0 + 1 h, i.p.), or intracerebroventricularly (200 micrograms/rat, 0 + 1 h, i.c.v.). 2. To investigate the effect of IL-1ra on fever and the induction of local and circulating cytokines (IL-1 and IL-6), separate experiments were performed in which groups of animals were killed 1.5, 3 or 5 h after LPS injection. Plasma and pouch fluid samples were collected for bioassay of IL-1 and IL-6. 3. Injection of LPS into the air pouch significantly increased (1.5 degrees C) body temperature, local (air pouch) concentrations of bioactive IL-1 and IL-6, and circulating bioactive IL-6, compared to saline-treated controls. 4. Injection of IL-1ra into the pouch significantly attenuated LPS fever (P < 0.001). This decrease in body temperature was associated with significant inhibition of local IL-1 bioactivity 1.5 (96%), 3 (84%) and 5 h (72%), and in bioactive IL-6 in pouch lavage fluid 1.5 (45%) and 5 h (35%), after LPS injection. The concentration of bioactive IL-6 in the plasma was significantly reduced (39%) at 3 h, when temperature was approaching the maximal value. 5. Both systemic (i.p.) and central (i.c.v.) administration of IL-1ra significantly attentuated LPS fever (P < 0.05). However, it had no effect on either local concentrations of bioactive IL-1 or IL-6, or circulating IL-6, at any of the sample points. 6. These data suggest that IL-1 is released locally, at the site of tissue inflammation and that it is an important mediator of the febrile response to local inflammation. The results also indicate that IL-1 produced locally may contribute to the production of IL-6 which is released into the circulation, and that IL-1 has important actions in the generation of fever at other sites, including the brain.

Inhibition of lymphocyte activation by gold sodium thiomalate.

Activation of lymphoid cells by both T and B cell mitogens was inhibited by gold sodium thiomalate (GST). The action of GST did not appear to be exerted at early stages of lymphocyte activation. Inhibition by GST was sustained throughout 4 days of culture. The inhibitory effect of GST was reduced at low serum concentrations. Sodium thiomalate and sodium chloroaurate were also able to inhibit lymphocyte activation.

Mechanisms of activation of the pituitary-adrenal axis by tissue injury in the rat.

To characterize the mechanisms of the pituitary-adrenal (P-A) response to tissue injury, rats were injected intramuscularly (IM) with turpentine. This resulted in marked elevations in the plasma concentrations of ACTH and corticosterone within the first hour after injection, which were attenuated by either total deafferentation of the medial basal hypothalamus (MBH) or neonatal capsaicin pretreatment. The plasma concentrations of corticosterone remained elevated for 18 h in the turpentine-injected rats, despite a return of ACTH toward control values (by 2-4 h). Bioactive concentrations of interleukin-6 (IL-6) in plasma rose markedly after turpentine, and its concentrations were significantly correlated with plasma corticosterone concentrations 4-8 h after turpentine. Pretreatment with IL-1 receptor antagonist (IL-1ra) attenuated the release of IL-6 and had a marginal effect on the corticosterone response 6 h after turpentine. These results suggest that the early and late phase of the P-A response to tissue injury are mediated by different mechanisms.

Ubiquitous interleukin-1 alpha in fetal bovine serum may mislead the experimental results in vitro.

Fetal bovine sera (FBS) from several commercial suppliers were fractionated by gel filtration. Interleukin-1 (IL-1) activity was bioassayed using the IL-1-specific murine T cell line D10(N4)M. All the sera examined contained IL-1-like activity, with molecular weights (M(r)) of 30 kDa and 15-10 kDa. Under isoelectric focusing (IEF), the majority of IL-1 activity in either 30 kDa or 15-10 kDa fractions was focused into a position of pl 5. The activity recovered from either IEF or gel filtration was inhibited by either recombinant human IL-1 receptor antagonist (rhlL-1ra) or by the antibody against human IL-1 alpha. These biological and physicochemical properties strongly suggest that the active molecules were bovine IL-1 alpha and its precursor. There was no correlation between the amount of endotoxin and IL-1 activity. Quantification of the fractionated IL-1 indicated its presence in concentrations of 200-5000 pg/ml equivalent to human IL-1. However, high levels of IL-1 were not apparent in unfractionated FBS. Proliferation of T cells in the presence of FBS absorbed with protein A-Sepharose was greater than that of cells in original FBS. Therefore, the activity in FBS as a whole appeared to result from the balance between IL-1 and the inhibitory molecule(s). These results suggest that data obtained from experiments conducted in the presence of FBS may be influenced by the effect of bovine IL-1.

Involvement of cytokines in cachexia induced by T-cell leukaemia in the rat.

The objective of this study was to investigate the involvement of cytokines (IL-1, IL-6 and TNF-alpha) in cachexia induced by T-cell leukaemia in the rat. Leukaemic rats exhibited a marked and significant increase in circulating IL-6 concentration from days 12-17 corresponding to the period of weight loss after induction of leukaemia. IL-6 plasma bioactivity correlated significantly with spleen weight and weight loss, implicating IL-6 in the cachectic response. In contrast, IL-1 and TNF-alpha plasma bioactivities were not increased compared to control rats, indicating that these cytokines are not circulating mediators of cachexia induced by T-cell leukaemia in the rat. These data suggest that IL-6 produced by the host may contribute to cachexia induced by T-cell leukaemia.

Interleukin (IL)-6 release and fever induced by a pre-formed pyrogenic factor (PFPF) derived from LPS-stimulated macrophages.

A novel pre-formed pyrogenic factor (PFPF), released by LPS-stimulated macrophages, has been identified, that induces an indomethacin-resistant fever. Its activity has to date not been found to match that of any described cytokine. In this study we observed that PFPF induced the release of large amounts of IL-6 from rat peritoneal macrophages. A combination of anti-cytokine antibodies and heat treatment excluded IL-1, tumor necrosis factor (TNF)-alpha and lipopolysaccharide (LPS) as being responsible for this effect. PFPF also induced interleukin (IL)-1, IL-6 and TNF-alpha in a subcutaneous air pouch, as well as increasing plasma IL-6, and induced a fever of 0.58 +/- 0.07 degrees C (3 hours) that was not reduced by indomethacin (2 mg/kg, ip). Preparative isoelectric focusing (IEF) showed that the material responsible for inducing IL-6 release had a pI between 4.7 and 5.8 and corresponded to the IEF pool that induced fever when injected intracerebroventricularly.

Investigating drug induced alopecia.

The propensity of cytotoxic drugs to cause alopecia is well known, but nurses are perhaps less aware of the capacity of other drug groups to cause this unwanted side-effect. Increasing nurses' awareness of the actions of these drugs will enable the association between alopecia and toxicity to be recognised at an early stage, before the distressing effects of drug-induced alopecia develop.

Drugs used to lower high lipid levels.

As part of our occasional series highlighting advances in drug therapy, this article discusses the mechanisms of hyperlipidaemia and the main groups of drugs used to treat the condition including bile acid-binding agents, fibrates, nicotinic acid and its derivatives, statins and fish oils.

Pitfalls in microdialysis methodology: an in vitro analysis of temperature, pressure and catheter use.

Microdialysis of macromolecules within the brain provides a unique insight into physiological and pathological processes occurring within an otherwise inaccessible cranial cavity. The physically restricted nature of the intracranial compartment may present wider variations of pressure and temperature than those experienced in the rest of the body. In this study we attempted to determine the effect of variation of temperature and pressure on a cytokine recovery in vitro. Our results demonstrate that the wide variation of recovery attributable to different catheter use outweighed any effects caused by temperature or pressure. Investigators performing cytokine microdialysis using the CMA 71 system should be aware of the wide inter-catheter variability and potential effects of temperature on recovery.