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OBJECTIVES: To compare the effects of combined hydrotherapy and land-based physiotherapy (combined) with land-based physiotherapy only (land) on cost, health-related quality of life (HRQoL) and outcome of disease in children with juvenile idiopathic arthritis (JIA). Also to determine the cost-effectiveness of combined hydrotherapy and land-based physiotherapy in JIA. DESIGN: A multicentre randomised controlled, partially blinded trial was designed with 100 patients in a control arm receiving land-based physiotherapy only (land group) and 100 patients in an intervention arm receiving a combination of hydrotherapy and land-based physiotherapy (combined group). SETTING: Three tertiary centres in the UK. PARTICIPANTS: Patients aged 4-19 years diagnosed more than 3 months with idiopathic arthritides, onset before their 16th birthday, stable on medication with at least one active joint. INTERVENTIONS: Patients in the combined and land groups received 16 1-hour treatment sessions over 2 weeks followed by local physiotherapy attendances for 2 months. MAIN OUTCOME MEASURES: Disease improvement defined as a decrease of > or =30% in any three of six core set variables without there being a 30% increase in more than one of the remaining three variables was used as the primary outcome measure and assessed at 2 months following completion of intervention. Health services resource use (in- and outpatient care, GP visits, drugs, interventions, and investigations) and productivity costs (parents' time away from paid work) were collected at 6 months follow-up. HRQoL was measured at baseline and 2 and 6 months following intervention using the EQ-5D, and quality-adjusted life-years (QALYs) were calculated. Secondary outcome measures at 2 and 6 months included cardiovascular fitness, pain, isometric muscle strength and patient satisfaction. RESULTS: Seventy-eight patients were recruited into the trial and received treatment. Two months after intervention 47% patients in the combined group and 61% patients in the land group had improved disease with 11 and 5% with worsened disease, respectively. The analysis showed no significant differences in mean costs and QALYs between the two groups. The combined group had slightly lower mean costs (-6.91 pounds Sterling) and lower mean QALYs (-0.0478, 95% confidence interval -0.11294 to 0.0163 based on 1000 bootstrap replications). All secondary measures demonstrated a mean improvement in both groups, with the combined group showing greater improvements in physical aspects of HRQoL and cardiovascular fitness. CONCLUSIONS: JIA is a disease in which a cure is not available. This research demonstrates a beneficial effect from both combined hydrotherapy and land-based physiotherapy treatment and land-based physiotherapy treatment alone in JIA without any exacerbation of disease, indicating that treatments are safe. The caveat to the results of the cost-effectiveness and clinical efficacy analysis is that the restricted sample size could have prevented a true difference being detected between the groups. Nevertheless, there appears to be no evidence to justify the costs of building pools or initiating new services specifically for use in this disease. However, this conclusion may not apply to patients with unremitting active disease who could not be entered into the trial because of specified exclusion criteria. For this group, hydrotherapy or combined treatment may still be the only physiotherapy option. Further research is suggested into: the investigation and development of appropriate and sensitive outcome measures for use in future hydrotherapy and physiotherapy trials of JIA; preliminary studies of methodologies in complex interventions such as physiotherapy and hydrotherapy to improve recruitment and ensure protocol is acceptable to patients and carers; hydrotherapy in the most common paediatric user group, children with neurological dysfunction, ensuring appropriate outcome measures are available and methodologies previously tried; patient satisfaction and compliance in land-based physiotherapy and hydrotherapy and European studies of hydrotherapy in rare disorders such as JIA.

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PURPOSE: To characterize the retinal physiology of the zebrafish visual mutant no optokinetic response c (nrc) and to identify the genetic map position of the nrc mutation. METHODS: Electroretinograms were recorded from wild-type and nrc zebrafish larvae between 5 to 6 days postfertilization. Responses to flash stimuli, On and Off responses to prolonged light stimuli, and responses to flash stimuli with constant background illumination were characterized. The glutamate agonist, 2-amino-4-phosphonobutyric acid (APB) was used to examine the photoreceptor specific a-wave component of the electroretinogram. Amplified fragment length polymorphism methodology was used to place the nrc mutation on the zebrafish genomic map. RESULTS: nrc and wild-type zebrafish larvae 5 to 6 days postfertilization have similar threshold responses to light, but the b-wave of the nrc electroretinogram is significantly delayed and reduced in amplitude. On and Off responses of nrc larvae to prolonged light have multiple oscillations that do not occur in normal zebrafish larvae after 5 days postfertilization. Analysis of the b-wave demonstrated a light adaptation defect in nrc that causes saturation at background light levels approximately 1 order of magnitude less than those with wild-type larvae. Application of the glutamate analog, APB, uncovered the photoreceptor component of the electroretinogram and revealed a light adaptation defect in nrc photoreceptors. The nrc mutation was placed approximately 0.2 cM from sequence length polymorphism marker Z7504 on linkage group 10. CONCLUSIONS: The zebrafish mutant nrc is a possible model for human retinal disease. nrc has defects in photoreceptor synaptic transmission and light adaptation. The nrc mutant phenotype shows striking similarities with phenotypes of dystrophin glycoprotein complex mutants, including patients with Duchenne/Becker muscular dystrophy. Localization of the nrc mutation now makes it possible to evaluate candidate genes and clone the nrc gene.

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Hantaan virus, the prototypic member of the Hantavirus genus, causes hemorrhagic fever with renal syndrome in humans. We examined the human memory T-lymphocyte responses of three donors who had previous laboratory-acquired infections with Hantaan virus. We demonstrated virus-specific responses in bulk cultures of peripheral blood mononuclear cells (PBMC) from all donors. Bulk T-cell responses were directed against either Hantaan virus nucleocapsid (N) or G1 protein, and these responses varied between donors. We established both CD4(+) and CD8(+) N-specific cell lines from two donors and CD4(+) G1-specific cell lines from a third donor. All CD8(+) cytotoxic T-lymphocyte (CTL) lines recognized one of two epitopes on the nucleocapsid protein: one epitope spanning amino acids 12 to 20 and the other spanning amino acids 421 to 429. The CTL lines specific for amino acids 12 to 20 were restricted by HLA B51, and those specific for amino acids 421 to 429 were restricted by HLA A1. The N-specific CTL lines isolated from these two donors included both Hantaan virus-specific CTLs and hantavirus cross-reactive CTLs. Responses to both epitopes are detectable in short-term bulk cultures of PBMC from one donor, and precursor frequency analysis confirms that CTLs specific for these epitopes are present at relatively high precursor frequencies in the peripheral T-cell pool. These data suggest that infection with Hantaan virus results in the generation of CTL to limited epitopes on the nucleocapsid protein and that infection also results in the generation of cross-reactive T-cell responses to distantly related hantaviruses which cause the distinct hantavirus pulmonary syndrome. This is the first demonstration of human T-lymphocyte responses to Hantaan virus.

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In a retrospective study of 1126 children with fractures of the proximal third of the femur, three children were found to have isolated fractures of the lesser trochanter. This fracture occurred from a fall in one child and following sporting activities, without a history of injury, in the others. In the latter children, the clinical presentations were similar to those of children with transient synovitis of the hip or Perthes disease. In each child, plain radiographs showed an avulsion fracture of the bony portion of the lesser trochanter. Early and complete recovery followed symptomatic treatment even when there was marked proximal displacement of the avulsed segment of the lesser trochanter.

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Orthopedic conditions of the cervical spine and shoulder can range from benign to life threatening. A careful history and examination are crucial to evaluate these children, and additional investigations may be necessary. The signs and symptoms in these conditions and the indications for referral are discussed.

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High levels of immunoreactive cyclooxygenase (Cox; prostaglandin H synthase) are present in synovia from patients with rheumatoid arthritis (RA). We now show that the recently identified inducible isoform of Cox, Cox-2, is expressed in synovia from patients with RA. To further explore modulation of the Cox isoforms in RA synovial tissues, we examined the expression and modulation of Cox-1 and -2 in rheumatoid synovial explant cultures and cultured rheumatoid synovial fibroblast-like cells (synoviocytes). Immunoprecipitation of in vitro labeled proteins and Western blot analysis demonstrated the presence of both Cox-1 and -2 under basal conditions in freshly explanted rheumatoid synovial tissues. De novo synthesis of Cox-2 polypeptide was enhanced by IL-1 beta or PMA, and dramatically suppressed by dexamethasone (dex). Cox-1 expression, under the same conditions, showed only minor variation. Since mRNA for Cox-2 is highly unstable, we examined the regulation of Cox-2 transcripts in cultured rheumatoid synoviocytes. Under basal conditions both Cox-1 and -2 mRNAs were present at low levels, but Cox-2 mRNA was markedly increased by treatment with IL-1 beta or PMA. dex markedly suppressed the induction of Cox-2 mRNA. In sharp contrast, Cox-1 transcripts were not modulated by IL-1 beta or dex. These data suggest that modulation of Cox-2 expression by IL-1 beta and corticosteroids may be an important component of the inflammatory process in synovial tissues from patients with RA.

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Inflammation normally results in enhanced synthesis and secretion of hypothalamic corticotropin-releasing hormone (CRH) which, in turn, exerts antiinflammatory effects by virtue of increased adrenal glucocorticoid production. CRH and CRH binding sites are also expressed in the peripheral nervous and immune systems. Our groups have recently shown that CRH is secreted locally in acute carrageenin-induced inflammation in rats and has predominantly proinflammatory effects. We have also shown that CRH is expressed in the joints of Lewis rats with experimental arthritis. To determine if CRH is present in human inflammatory arthritis, we examined synovial fluids and tissues from patients with rheumatoid arthritis (RA) or osteoarthritis (OA) and normal individuals. We found markedly enhanced expression of immunoreactive CRH in situ in synovium from patients, which was significantly greater in RA than in OA (p < 0.01). CRH concentrations were also significantly higher in RA (140 +/- 33 pg/ml, mean +/- SEM; n = 10) than OA (25 +/- 4 pg/ml; n = 6) synovial fluids (p < 0.005). HPLC showed immunoreactive CRH extracted from RA and OA synovial tissues and fluids coeluted with CRH 1-41. CRH mRNA was present in low levels in synovial tissue from patients with RA and, to a lesser extent, OA. In summary, immunoreactive CRH is locally secreted in the synovium of patients with RA and, at lower levels, OA. These data support the view that CRH functions as an autocrine and/or paracrine mediator of inflammation in humans.

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We present a very large f/1.O prime focus, all-spherical, all-fused-silica catadioptric camera. It contains a two-element airspaced corrector, an f/0.76 primary mirror, and a singlet final element. It accommodates a chromatic range from 0.3 to 1.1µm or more without refocus. It is optimized with an external entrance pupil but can be reoptimized for other pupil distances. In spite of its 30-in. (76.2-cm) focal length, it delivers 12.6-µm (rms) average image diameters to a 3.6-in.- (9.1-cm-) diameter flat focal surface. It is thus well matched to the (7-15µm) pixels and to the size of a (2 × 2) mosaic of today's largest available CCD's.

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An experimental device successfully upconverts ir radiation in the 3.2-5.0-microm wavelength range simultaneously to "visible" light at 0.80-0.88 microm, while preserving frequency coding and is thus applicable to ir spectroscopy. The 1.8-microm bandwidth of ir radiation that is upconverted without temperature or phase match tuning is the largest yet reported. The over-all system quantum efficiency of the upconverter/spectrometer system is 0.01% and could be improved to 0.4%.

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