Developing A Conceptual Framework for Early Intervention Vocational Rehabilitation for People Following Spinal Cord Injury.

PURPOSE: Early intervention vocational rehabilitation (EIVR) can improve return to work (RTW) outcomes for people with spinal cord injury (SCI). However, mechanisms explaining how and why EIVR works are not well understood. This study aims to develop a conceptual framework describing key mechanisms of EIVR intervention effect following SCI. METHODS: We synthesised data from a realist literature review with data from interviews of people with SCI (n = 30), a survey of people with SCI who had received EIVR (n = 37), a focus group of EIVR providers and a focus group of community vocational providers. We first synthesised the literature review and interviews to develop an initial programme theory describing the contexts in which mechanisms are activated to produce EIVR outcomes. Then we used data from the survey and focus groups to further refine the EIVR programme theory. Finally, a conceptual framework was developed to support knowledge dissemination. RESULTS: By ensuring consistent messaging across the multi-disciplinary team, EIVR programmes establish and maintain hope that work is possible following injury. Conversations about work allow individuals to determine the priority of work following injury. These conversations can also improve self-efficacy by providing individualized support to envisage pathways toward RTW goals and maintain worker identity. The synthesised study findings highlight the contexts and resources required to trigger activation of these mechanisms. CONCLUSIONS: EIVR key mechanisms of effect are not specific to SCI as a health condition, therefore enabling this framework to be applied to other populations who face similar impairments and return to work barriers.

Ten-year survival and seven-year functional results of cementless Oxford unicompartmental knee replacement: A prospective consecutive series of our first 1000 cases.

BACKGROUND: Cementless fixation is an alternative to cemented unicompartmental knee replacement (UKR), with several advantages over cementation. This study reports the ten-year survival and seven-year clinical outcome of cementless Oxford unicompartmental knee replacement (OUKR). METHODS: This prospective study describes the clinical outcome and survival of the first 1000 consecutive cementless medial OUKRs implanted at two centres for recommended indications. RESULTS: The 10-year survival was 97% (CI 95%: 92-100%), with 25 knees being revised. The commonest reason for revision was progression of arthritis laterally, which occurred in nine knees, followed by primary dislocation of the bearing, which occurred in six knees. There were two dislocations secondary to trauma and a ruptured ACL, and two tibial plateau fractures. Although there were no definite cases of aseptic loosening, two early revisions were related to tibial fixation: one for pain and a radiolucent line and one for incomplete seating of the component with a radiolucent line. There were four revisions for pain, but the cause of the pain was uncertain: in one there was tibial overhang and in two there was patellofemoral degeneration, which possibly contributed to the pain. There were no deep infections. The mean OKS improved from 23 (SD 8) to 42 (SD 7) at a mean follow-up of 7.0 years (p < 0.001). There was no significant difference in survival or clinical outcome between the designer and independent centre. CONCLUSIONS: The cementless OUKR is a safe and reproducible procedure with excellent 10-year survival and clinical results in the hands of both designer and independent surgeons.

Evaluation of the accuracy of common weight estimation formulae in a Zambian paediatric surgical population.

Limited resources and access to healthcare in sub-Saharan Africa are associated with high rates of malnourished children, although many countries globally are demonstrating increasing childhood obesity. This study evaluated how well current age- or height-based formulae estimate the weight of children undergoing surgery in Zambia. All children under 14 years of age presenting for elective surgery at the University Teaching Hospital, Lusaka, had both height and weight measured. Their actual weight was compared against estimated weight from various formulae. The Broselow tape outperformed all the age-based formulae, demonstrating the lowest median percentage error of -5.8%, with 46.0% of estimates falling within 10% of the actual measured weight (p < 0.001). Of the 1111 children who were eligible for World Health Organization growth standard appraisal, 88 (8%) met the weight criteria for severe acute malnutrition. Our results are consistent with other studies in finding that the Broselow tape is the best estimator of weight in a lower middle-income country, followed by the original Advanced Paediatric Life Support formula if the Broselow tape is unavailable.

An evaluation of inpatient morbidity and critical care provision in Zambia.

The aim of this study was to objectively measure demand for critical care services in a southern African tertiary referral centre. We carried out a point prevalence study of medical and surgical admissions over a 48-h period at the University Teaching Hospital, Lusaka, recording the following: age; sex; diagnosis; Human Immunodeficiency Virus (HIV) status and National Early Warning Score. One-hundred and twenty medical and surgical admissions were studied. Fifty-four patients (45%) had objective evidence of a requirement for critical care review and potential or probable admission to an intensive care unit, according to the Royal College of Physicians (UK) guidelines. A greater than expected HIV rate was also noted; 53 of 75 tested patients (71%). When applied to the estimated 17,496 annual acute admissions, this would equate to 7873 patients requiring critical care input annually at this hospital alone. In contrast to this demand, we identified 109 critical care beds nationally, and only eight at this institution.

The five-year radiological results of the uncemented Oxford medial compartment knee arthroplasty.

This study reports on the first 150 consecutive Oxford cementless unicompartmental knee arthroplasties (UKA) performed in an independent centre (126 patients). All eligible patients had functional scores (Oxford knee score and high activity arthroplasty score) recorded pre-operatively and at two- and five-years of follow-up. Fluoroscopically aligned radiographs were taken at five years and analysed for any evidence of radiolucent lines (RLLs), subsidence or loosening. The mean age of the cohort was 63.6 years (39 to 86) with 81 (53.1%) males. Excellent functional scores were maintained at five years and there were no progressive RLLs demonstrated on radiographs. Two patients underwent revision to a total knee arthroplasty giving a revision rate of 0.23/100 (95% confidence interval 0.03 to 0.84) component years with overall component survivorship of 98.7% at five years. There were a further four patients who underwent further surgery on the same knee, two underwent bearing exchanges for dislocation and two underwent lateral UKAs for disease progression. This was a marked improvement from other UKAs reported in New Zealand Joint Registry data and supports the designing centre's early results.

Selective, efficient modulation of activated CD4+ αßT cells by the novel humanized antibody GZ-αßTCR targeting human αßTCR.

Allograft rejection and immunosuppression are two major issues in transplantation medicine. The specific targeting of alloreactive T cells, the initiators and promoters of allograft rejection, would be a promising strategy to reduce unwanted T-cell responses and side effects of lifelong immunosuppression. The novel humanized monoclonal antibody GZ-αßTCR, specific for the human αßT-cell receptor, was tested in vitro and in vivo for its specificity and efficacy to modulate the αßT-cell compartment. GZ-αßTCR moderately induced apoptosis in resting αßT cells in vitro, an effect considerably amplified in activated T cells. A single dose of GZ-αßTCR significantly reduced human CD45(+)CD3(+) T cells in vivo, with a preferential modulation of CD4(+) αßT cells. Importantly, naive T cells, the T-cell subset from which alloreactivity emanates, were significantly reduced. Simultaneously, a significant, compensatory increase of γδ T cells was observed in vitro and in vivo in both humanized mouse models examined. GZ-αßTCR did not induce cytokines and was well tolerated. Thus, specificity and high efficacy make GZ-αßTCR a powerful tool to selectively eliminate putatively detrimental T-cell subsets, a major goal in transplantation medicine. At the same time, GZ-αßTCR spares γδ and natural killer cells, thus leaving the recipient's immune system competent for cell-mediated immunoregulation and cell-mediated immunity.

Osmotic demyelination syndrome following rapid correction of hyponatraemia.

We report a case of a young male with adrenal hypoplasia who presented following water intoxication with severe hyponatraemia and seizures. He required a period of intensive care and over the initial 24 h his serum sodium corrected at average of 0.9 mmol x l(-1) h(-1). He subsequently developed osmotic demyelination syndrome. Following supportive treatment he made a full recovery. Severe hyponatraemia carries a risk of cerebral oedema with a significant mortality, yet correcting it too rapidly can result in osmotic demyelination syndrome, again with potentially disastrous consequences. It may be difficult to determine the duration and aetiology of the hyponatraemia and this is necessary to guide treatment. There is no consensus about the optimal rate of correction of hyponatraemia but formulae such as the Adrogue and Madias formula can be used to guide treatment with normal or hypertonic saline. Continuous veno-venous haemofiltration has been used effectively in this setting.

c-Cbl negatively regulates platelet activation by glycoprotein VI.

BACKGROUND: The adapter protein c-Cbl has emerged as having a potential role in negative regulation of immune receptor signaling. The major platelet-signaling receptor for collagen, glycoprotein VI (GpVI), is associated with the Fc receptor (FcR) gamma-chain, and signals through a similar pathway to immune receptors. c-Cbl is tyrosine-phosphorylated in response to stimulation of GpVI, whereas phosphorylation of c-Cbl in thrombin-activated platelets is dependent on fibrinogen binding to the integrin GpIIb/IIIa. OBJECTIVE: To investigate the role of c-Cbl in platelet signaling. METHODS: Murine platelets lacking functional c-Cbl or Src family kinases were analyzed. RESULTS: Phosphorylation of c-Cbl through GpVI is reduced in murine platelets deficient in the Src-family kinases Fyn and Lyn, demonstrating that they lie upstream of c-Cbl phosphorylation. Phosphorylation of several proteins of the GpVI-signaling pathway, including the FcR gamma-chain, Syk and phospholipase Cgamma2 (PLCgamma2), is increased in the absence of c-Cbl. In line with this, aggregation is potentiated in response to the GpVI-specific collagen-related peptide (CRP) after a slight delay. A delay in potentiation is also seen in response to stimulation by thrombin. CONCLUSIONS: These observations demonstrate that c-Cbl negatively regulates platelet responses to GpVI agonists and to thrombin, with the latter effect possibly being mediated downstream of GpIIb/IIIa. c-Cbl may play a physiological role in helping to prevent unwanted platelet activation in vivo.

The role of ITAM- and ITIM-coupled receptors in platelet activation by collagen.

The major activation-inducing collagen receptor glycoprotein VI (GPVI) has been cloned within the last two years. It is a member of the Ig superfamily of proteins and is constitutively associated with the ITAM-bearing Fc receptor gamma-chain (FcR gamma-chain). GPVI signals through a pathway that involves several of the proteins used by Fc, B- and T-lymphocyte receptors and which takes place in glycolipid-enriched membrane domains in the plasma membrane known as GEMs. Responses to GPVI are regulated by PECAM-1 (CD31) and possibly other ITIM-bearing receptors. Despite a pivotal role for GPVI, there are important differences between signalling events to collagen and GPVI-specific ligands. This may reflect a role for co-receptors in the response to collagen.

The snake venom toxin alboaggregin-A activates glycoprotein VI.

The glycoprotein (GP)-Ib-IX-V receptor complex has recently been reported to signal through a pathway similar to that used by the collagen receptor GPVI, with a critical role described for the Fc receptor gamma-chain. The evidence for this was based in part on studies with the GPIbalpha-selective snake venom toxin, alboaggregin-A. In the present study, it is reported that alboaggregin-A has activity at the collagen receptor GPVI in addition to GPIbalpha, and evidence is provided that this contributes to protein tyrosine phosphorylation, shape change, and GPIIb-IIIa-dependent aggregation. This may explain why responses to alboaggregin-A are distinct from those to von Willebrand factor-ristocetin. (Blood. 2001;97:3989-3991)

An analysis of consumer perspectives following contact with an eating-disorders service.

OBJECTIVE: The views of consumers following contact with treatment for eating disorders represent an underresearched aspect of service provision. The aim of this paper is to examine patterns of consumer satisfaction following contact with a specialist eating-disorders service. METHOD: Using both a structured and an open-ended questionnaire format, consumer perspectives were sought routinely through postal survey 3 months after the point of first contact. Responses were analysed from 120 patients who returned their questionnaires during the 2-year period ending in December 1998. RESULTS: Although the structured response format indicated high rates of satisfaction, the open-ended format revealed five categories describing the perceived best and worst aspects following consultation with the service. The category of therapeutic alliance drew the majority of positive comments, while the most frequently cited worst aspect of consultation was the category of treatment type. CONCLUSIONS: People with eating disorders form a unique group of mental health consumers to survey for satisfaction. While approval ratings prompted by both structured and open-ended questions were high, and centred around the theme of therapeutic alliance, the most frequent source of negative commentary was activities and structures considered essential by traditional treatment modalities. This provides important insights into the predicaments of people with eating disorders presenting for treatment, and the importance of developing satisfaction surveys to accommodate such predicaments and concerns.

Evidence for two distinct epitopes within collagen for activation of murine platelets.

It has recently been shown that the monoclonal antibody JAQ1 to murine glycoprotein VI (GPVI) can cause aggregation of mouse platelets upon antibody cross-linking and that collagen-induced platelet aggregation can be inhibited by preincubation of platelets with JAQ1 in the absence of cross-linking (Nieswandt, B., Bergmeier, W., Schulte, V., Rackebrandt, K., Gessner, J. E., and Zirngibl, H. (2000) J. Biol. Chem. 275, 23998-24002). In the present study, we have shown that cross-linking of GPVI by JAQ1 results in tyrosine phosphorylation of the same profile of proteins as that induced by collagen, including the Fc receptor (FcR) gamma-chain, Syk, LAT, SLP-76, and phospholipase C gamma 2. In contrast, platelet aggregation and tyrosine phosphorylation of these proteins were inhibited when mouse platelets were preincubated with JAQ1 in the absence of cross-linking and were subsequently stimulated with a collagen-related peptide (CRP) that is specific for GPVI and low concentrations of collagen. However, at higher concentrations of collagen, but not CRP, aggregation of platelets and tyrosine phosphorylation of the above proteins (except for the adapter LAT) is re-established despite the presence of JAQ1. These observations suggest that a second activatory binding site, which is distinct from the CRP binding site on GPVI on mouse platelets, is occupied in the presence of high concentrations of collagen. Although this could be a second site on GPVI that is activated by a novel motif within the collagen molecule, the absence of LAT phosphorylation in response to collagen in the presence of JAQ1 suggests that this is more likely to be caused by activation of a second receptor that is also coupled to the FcR gamma-chain. The possibility that this response is mediated by a receptor that is not coupled to FcR gamma-chain is excluded on the grounds that aggregation is absent in platelets from FcR gamma-chain-deficient mice.

Paraganglioma of the larynx.

A patient with a laryngeal paraganglioma is presented in which overtly malignant behavior occurred despite a four-year period of symptoms prior to diagnosis. A review of the world literature reveals 52 reported cases of laryngeal paragangliomas. The incidence of malignancy in these neoplasms is often underestimated, as at least 25% of reported cases exhibited a clinically malignant natural history. We believe that the treatment of laryngeal paragangliomas should be based on the assumption that all tumors have a potential for malignant growth. Wide-field surgical excision is the applicable treatment for tumors still localized to the larynx. The results of radical neck dissection for established nodal disease are discouraging. In those patients with palpable lymph nodes, widespread dissemination has usually taken place.

Sensitization produced by repeated administration of naloxone is blocked by food deprivation.

The current study was conducted in order to explore the effects of repeated naloxone administration as a function of food intake. Rats were trained to press a bar to avoid foot-shock. They were allowed either free or restricted access to food. Free-feeding rats developed a strong sensitivity to naloxone, as manifested by an increased shock rate after naloxone injection. When animals were food-deprived, the sensitivity was greatly reduced. A different species (mouse) and two different tests were used to examine further the effects of food intake and pretreatment with naloxone. The mice were given either free access to food or a restricted diet and were pretreated with either naloxone or saline. The effects of food intake and pretreatment with naloxone were examined in terms of motor activity, morphine analgesia and naloxone hyperalgesia. The results showed that prior exposure to naloxone in free-feeding animals enhanced the suppressant effect of naloxone on motor activity and the analgesic effects of morphine (as measured by paw-lick, but not as measured by jump in the hot-plate test), but had no effect on the hyperalgesic effect of naloxone. When mice were food-deprived during naloxone administration, sensitization did not occur. The hypothesis that naloxone sensitivity is due to changes in the number of brain opiate receptors was tested by measuring the number and affinity of [3H]naloxone binding sites on brain membranes from mice chronically treated with naloxone. Neither naloxone pretreatment nor food deprivation affected the number or affinity of binding sites. The gamma-aminobutyric acid antagonist effect of naloxone (as measured by gamma-[3H]aminobutyric acid binding) was also unchanged by naloxone pretreatment. Thus, the basis of the interactions between naloxone and the feeding state remains unclear.

Interactions between narcotic agonists, partial agonists andd antagonists evaluated by punished an unpunished behavior in the rat.

The effects of morphine, ketocyclazocine, cyclazocine, and SKF-10,047 were tested alone and in conjunction with naltrexone or naloxone, in rats responding under a multiple fixed-interval 3-min schedule of food presentation. Under this paradigm, electric shock was delivered on a fixed-ratio schedule for responses occurring during alternate schedule components. All of the drugs (except naltrexone and naloxone) decreased average rates of responding maintained by the unpunished component in a dose-dependent manner. The rate-decreasing effects of morphine and ketocyclazocine were antagonized by naltrexone. The rate-decreasing effects of cyclazocine were only slightly reversed by the antagonists, while those effects of SKF-10,047 were not affected by naltrexone. In some animals, certain doses of SKF-10,047 increased unpunished responding. This rate-increasing effect was antagonized by naltrexone. Morphine, ketocyclazocine, cyclazocine, and SKF-10,047 increased responding that was suppressed by electric shock, and these increases were antagonized by naltrexone and naloxone. Thus, the antagonism of opiate effects by narcotic antagonists depends in part on the behavior being evaluated.

Impairment of avoidance behavior following short-term ingestion of ethanol, tertiary-butanol, or pentobarbital in mice.

Acquisition of a shock avoidance task was impaired in mice after cessation of chronic consumption of ethanol, tertiary-butanol (t-butanol), or pentobarbital. The drugs were administered in liquid diets for 7 days after withdrawal of the drugs. The avoidance deficit was also observed 8 days after withdrawal from chronic pentobarbital. There was no apparent relationship between the avoidance deficit and physical dependence, as measured by a decrease in body temperature or convulsions on handling, since at 6 h after withdrawal only moderate withdrawal signs were seen in the mice consuming ethanol or t-butanol, and no withdrawal signs were seen in any of the mice at the time of avoidance testing. These results suggest that impairment of avoidance behavior after chronic exposure is a general effect of central nervous system depressants and, in the case of ethanol, is not due to the production of acetaldehyde.

Effects of acute and chronic administration of phenobarbital and d-amphetamine on schedule-controlled behavior.

The effects of acute and chronic administration of phenobarbital and d-amphetamine were determined in rats responding under a multiple fixed-interval five minute fixed-ratio 30 (mult FI 5 FR 30) schedule of food presentation. After determining the acute effects of each drug, the drugs were injected daily with one group of rats receiving the drugs before each behavioral session while another group received the drugs immediately after each daily session. After four to seven consecutive injections, tolerance developed to the effects of phenobarbital on the average rates of responding under FI and FR schedule components only if the drug was administered before each session. Tolerance was more pronounced for responding druing the terminal portions of the FI component than for responding during either the initial portions of the FI or the FR component. Evidence for a selective tolerance to the effects of the drug on responding during the final segments of the FI was also obtained in rats responding under an FI 5 schedule. In contrast, injection of d-amphetamine for seven to eight consecutive days failed to produce any tolerance to the effects of the drug on responding under mult FI 5 FR 30, FI 5, or FR 30 schedules. These results indicate that the development of tolerance to the effects of phenobarbital depended both upon the temporal relationship of the drug effects to the behavioral testing and upon the schedules controlling behavior. These findings are discussed in terms of theories of behavioral tolerance.