A low cost virtual reality system for home based rehabilitation of the arm following stroke: a randomised controlled feasibility trial.

OBJECTIVE: To assess the feasibility of conducting a randomised controlled trial of a home-based virtual reality system for rehabilitation of the arm following stroke. DESIGN: Two group feasibility randomised controlled trial of intervention versus usual care. SETTING: Patients' homes. PARTICIPANTS: Patients aged 18 or over, with residual arm dysfunction following stroke and no longer receiving any other intensive rehabilitation. INTERVENTIONS: Eight weeks' use of a low cost home-based virtual reality system employing infra-red capture to translate the position of the hand into game play or usual care. MAIN MEASURES: The primary objective was to collect information on the feasibility of a trial, including recruitment, collection of outcome measures and staff support required. Patients were assessed at three time points using the Wolf Motor Function Test, Nine-Hole Peg Test, Motor Activity Log and Nottingham Extended Activities of Daily Living. RESULTS: Over 15 months only 47 people were referred to the team. Twenty seven were randomised and 18 (67%) of those completed final outcome measures. Sample size calculation based on data from the Wolf Motor Function Test indicated a requirement for 38 per group. There was a significantly greater change from baseline in the intervention group on midpoint Wolf Grip strength and two subscales of the final Motor Activity Log. Training in the use of the equipment took a median of 230 minutes per patient. CONCLUSIONS: To achieve the required sample size, a definitive home-based trial would require additional strategies to boost recruitment rates and adequate resources for patient support.

Seminal plasma and prostaglandin E2 up-regulate fibroblast growth factor 2 expression in endometrial adenocarcinoma cells via E-series prostanoid-2 receptor-mediated transactivation of the epidermal growth factor receptor and extracellular signal-regulated kinase pathway.

BACKGROUND: Prostaglandin E(2) (PGE(2)) has been shown to modulate angiogenesis and tumour progression via the E-series prostanoid-2 (EP2) receptor. Endometrial adenocarcinomas may be exposed to endogenous PGE(2) and exogenous PGE(2), present at high concentration in seminal plasma. METHODS: This study investigated fibroblast growth factor 2 (FGF2) mRNA expression and cell signalling in response to seminal plasma or PGE(2), using an endometrial adenocarcinoma (Ishikawa) cell line stably expressing the EP2 receptor (EP2 sense cells) and endometrial adenocarcinoma explants. RESULTS: Seminal plasma and PGE(2) induced a significant up-regulation of FGF2 expression in EP2 sense but not parental untransfected Ishikawa (wild-type) cells (P < 0.05). These effects were inhibited by co-treatment with EP2 receptor antagonist or inhibitors of protein kinase A, c-Src, epidermal growth factor receptor (EGFR) kinase or extracellular signal-regulated kinase (ERK) signalling. The treatment of EP2 sense cells with seminal plasma induced cAMP accumulation and phosphorylation of c-Src, EGFR kinase and ERK via the EP2 receptor. Finally, seminal plasma and PGE(2) significantly increased FGF2 mRNA expression in endometrial adenocarcinoma tissue explants via the EP2 receptor (P < 0.05). CONCLUSIONS: Seminal plasma and PGE(2) can similarly activate FGF2 expression and EP2 receptor signalling in endometrial adenocarcinoma cells. These data highlight the potential for seminal plasma exposure to facilitate tumorigenesis-angiogenesis in endometrial adenocarcinomas in vivo.

Systematic evaluation of current control devices used by people with intellectual disabilities in non-immersive virtual environments.

Virtual environments have a role to play in facilitating the acquisition of living skills in people with intellectual disabilities, improving their cognitive skills and providing them with entertainment. However, the currently recommended devices to allow navigation in and interaction with the environments are difficult to use. Using a methodology established in an earlier study, the study aims to systematically document the performance of users with the currently recommended devices in order to (i) inform the design of a usable control device or devices and (ii) act as a baseline against which they can be evaluated. 40 people with severe intellectual disabilities aged 21-67 years used four environments with an equal number of sessions with the different devices being evaluated. Results indicate that when forward movement is provided by the software using the mouse for both navigation and interaction allows better performance both initially and after exposure than using the fire button on the joystick. When the user had to initiate forward movement with the navigation device, the joystick allowed better performance than the arrows on the keyboard. Preventing slippage of the joystick base would make its use much easier and it is suggested that separate devices are retained for navigation and interaction.

Expression and regulation of the prokineticins (endocrine gland-derived vascular endothelial growth factor and Bv8) and their receptors in the human endometrium across the menstrual cycle.

This study investigated the possible role of the newly discovered endocrine gland-derived vascular endothelial growth factors and their cognate receptors in the human endometrium during the menstrual cycle. Endocrine gland-derived vascular endothelial growth factors are also known as prokineticin (PK) 1 and PK2 and their receptors as PKR1 and PKR2. Expression of PK1 was elevated in the secretory compared with the proliferative phase of the menstrual cycle (P < 0.05). There was no temporal variation in expression of PK2, PKR1, or PKR2. PK1 and PK2 and their receptors were localized to multiple cellular compartments, including glandular epithelial, stromal, and endothelial cells in the endometrium and endothelial and smooth muscle cells in the myometrium. The elevation in PK1 expression in the secretory phase of the menstrual cycle indicated potential regulation of PK1 by progesterone. To investigate this, endometrial tissue was treated with 1 microM (micromol/liter(-1)) progesterone for 24 h, and PK1 expression was assessed by quantitative RT-PCR. Treatment with 1 microM ( micromol/liter(-1)) progesterone resulted in 2.91 +/- 0.75-fold elevation in PK1 expression, compared with controls (P < 0.05). These data identify a paracrine role for the PKs and their receptors in endometrial vascular function.

Temporal expression and signalling of prostacyclin receptor in the human endometrium across the menstrual cycle.

Prostacyclin (PGI(2)) synthesis and function in the human uterus has been implicated in the regulation of the process of normal and dysfunctional menstruation. PGI(2) synthesis is elevated during normal menstruation and is also associated with blood loss in women who suffer from heavy menses. This study was designed to outline further the role of PGI(2) in menstruation by investigating the temporal pattern and site of expression of prostaglandin I synthase (PGIS) and the prostacyclin receptor (IP receptor) in the non-pregnant human endometrium across the menstrual cycle. Quantitative RT-PCR demonstrated increased expression of PGIS and IP receptor during the menstrual phase of the cycle compared with all other phases (P < 0.05). Furthermore, PGIS and IP receptor were localised to the glandular epithelium, stromal and endothelial cells in the basal and functional layers of the endometrium. Functionality of the IP receptor in the human endometrium was assessed by measuring cAMP generation following treatment with 100 nmol l(-1) of the PGI(2) analogue, iloprost. cAMP generation was significantly higher in endometrial tissue collected during the proliferative compared with the secretory phase of the menstrual cycle (P < 0.05). In conclusion, this study has confirmed increased expression and signalling of PGIS and IP receptor during the menstrual phase and outlines a potential autocrine/paracrine role for PGI(2) on several cellular compartments in the endometrium including the endothelium. This may underscore a pivotal role for PGI(2) receptor signalling in normal and dysfunctional menstruation.

Design guidelines for interactive multimedia learning environments to promote social inclusion.

PURPOSE: There is a continuing need for guidelines to aid in the design of Interactive Multimedia Learning Environments (IMLE) to promote effective learning. The project introduced in this paper looks at an important subset of this problem, the design of interactive learning environments to promote social inclusion. METHOD: A consortium of six partners contributed toward defining learning material to develop a range of work based skills, including horticulture, IT and catering. These were then developed into IMLE prototypes. Formative evaluation of these prototypes then revealed a range of usability problems, which were grouped into generic types and frequency of occurrence. RESULTS: The most important and frequently occurring problems were used to distil a set of design guidelines for the development of effective IMLE. The results from this usability content analysis were also used to refine the initial prototypes to improve their usability and effectiveness. CONCLUSIONS: These guidelines, termed the Greenhat Design Guidelines, can be adopted for use by all multimedia developers aiming to promote the social inclusion of vulnerable or socially disadvantaged groups of people. The refined IMLE can be accessed via the Greenhat Server to improve the employment-related skills of socially excluded people.

Refined mapping of the human serotonin transporter (SLC6A4) gene within 17q11 adjacent to the CPD and NF1 genes.

The SLC6A4 gene encodes the serotonin transporter, the target of an important class of antidepressant drugs (serotonin selective reuptake inhibitors). Polymorphisms in the SLC6A4 gene have been reported to be associated with susceptibility to depression and other psychiatric disorders. We have constructed a 1 Mb YAC and PAC contig which harbours both the SLC6A4 and the carboxypeptidase D (CPD) genes. The order of loci within the contig was cen-D17S975-D17S1549-24R-D17S1294-SLC6A4-28L+ ++-(CPD, D17S2009, D17S2004)-D17S2120-ter. Both genes were deleted in one of 17 neurofibromatosis type 1 (NF1) patients carrying submicroscopic NF1 contiguous gene deletions.

Lymphocyte subset analyses in blood, spleen and lymph nodes of female Sprague-Dawley rats after short or prolonged exposure to a 50 Hz 100-microT magnetic field.

Based primarily on the results of in vitro studies, it has been suggested that power-line (50 or 60 Hz) magnetic fields (MFs) may reduce immune function, which could lower resistance to infection or cancer. This study was conducted to evaluate the influence of acute and chronic in vivo exposure to a linearly polarized 50 Hz MF on immune function in female Sprague-Dawley rats. Groups of rats were exposed continuously to the MF at a flux density of 100 microT for periods of 3 days, 14 days or 13 weeks. For each exposure period, one control group of rats was sham-exposed together with each MF-exposed group. Experimental end points included analyses of T-lymphocyte subsets as well as other immune cells involved in cell-mediated immune responses, i.e. natural killer (NK) cells, B lymphocytes, macrophages, and granulocytes in blood, spleen and mesenteric lymph nodes. In addition, immunohistochemical methods were used to detect proliferating and apoptotic cells in the various compartments of spleen tissue. The results obtained failed to demonstrate a significant effect of short or prolonged MF exposure on different types of leukocytes, including lymphocyte subsets. Furthermore, the experiments on the in vivo proliferation activity of lymphocytes and the extent of apoptosis in spleen samples did not indicate a difference between the MF-exposed and sham-exposed groups, indicating that MF exposure does not affect the mechanisms involved in the control of lymphocyte homeostasis. The lack of MF effects in the immune tests used in the present in vivo study makes it highly unlikely that MF exposure induces immunotoxicity, at least under the experimental conditions used. However, the data do not exclude the possibility that functional alterations in T-cell responses to mitogens and in NK cell activity as recently described for MF-exposed rodents may be one mechanism involved in the carcinogenic effects of MF exposure observed in some models of co-carcinogenesis.

Exposure of Sprague-Dawley rats to a 50-Hertz, 100-microTesla magnetic field for 27 weeks facilitates mammary tumorigenesis in the 7,12-dimethylbenz[a]-anthracene model of breast cancer.

We have shown previously (W. Löscher et al., Cancer Lett., 71: 75-81, 1993; M. Mevissen et al., Carcinogenesis (Lond.), 17: 903-910, 1996) that 50-Hz magnetic fields (MFs) of low [50 or 100 microTesla (T)] flux density enhance mammary gland tumor development and growth in the 7,12-dimethylbenz[a]anthracene (DMBA) model of breast cancer in female Sprague Dawley rats. In these previous experiments, groups of rats were given 20 mg of DMBA (four weekly gavage doses of 5 mg each) and were MF- or sham-exposed for 13 weeks. The objective of the present study was to examine whether the use of a lower dose of DMBA (10 instead of 20 mg per rat), MF exposure of the rats before DMBA injection, and the increase of the MF exposure period after DMBA application to 26 weeks enhance the effect of MF on tumor development and growth. A group 99 rats was exposed to a homogeneous, horizontally polarized 100-microT MF of 50-Hz for 24 h/day for 7 days/week; another group of 99 rats was sham-exposed under the same environmental conditions as the MF-exposed rats. The exposure chambers were identical for MF-exposed and sham-exposed animals. The age of the rats was 45-49 days at the onset of exposure; duration of MF or sham exposure was 27 weeks. DMBA was administered p.o. at a dose of 10 mg/rat after 1 week of MF or sham exposure. The animals were palpated once weekly from week 6 onwards to assess the development of mammary tumors. At the end of the exposure period, the animals were killed for the determination of number and volume and histological verification of mammary tumors. All of the recordings were done in a blinded fashion; i.e., the investigators were not aware which animals were MF- or sham-exposed. Mammary tumor development and growth was significantly enhanced by MF exposure, the most marked effect on tumor incidence (190% above sham control) being observed 13 weeks after DMBA administration. At the time of necropsy, i.e., 26 weeks after DMBA administration, the incidence of histologically verified mammary tumors was 50.5% in controls and 64.7% in MF-exposed rats, the difference being statistically significant. More marked intergroup differences were recorded when tumor incidence was separately evaluated for each of the six mammary complexes, the most pronounced MF effect on tumor incidence being seen in the cranial thoracic complex. The data substantiate that, at least under the experimental conditions used in our laboratory, 50-Hz, 100-microT MF exposure significantly facilitates the development and growth of mammary tumors in the DMBA rat model of breast cancer.

Exposure of rats to a 50-Hz, 100 muTesla magnetic field does not affect the ex vivo production of interleukins by activated T or B lymphocytes.

Two separate, independent experiments were conducted to evaluate the effects of exposure of rats to a 50-Hz linearly polarized, 100 microT magnetic field (MF) on the ex vivo production of interleukins (ILs) by mitogen-stimulated splenic lymphocytes. IL-1 and IL-2 were determined by proliferation assays, using IL-dependent murine T cell lines. In the first experiment, female Sprague-Dawley rats were treated with 7,12-dimethylbenz[a]anthracene (DMBA] at a dose of 20 mg per rat (four weekly gavage doses of 5 mg), and were either MF-exposed or sham-exposed for 14 weeks. This experimental protocol has previously been shown to result in a significant increase in breast cancer growth in response to MF exposure. Furthermore, MF exposure at 50-100 microT for 3 months was recently found to induce a suppressed ex vivo proliferation of splenic T cells in response to mitogen stimulation, which could be a result of reduced IL production of spleen lymphocytes. However, the present experiments failed to demonstrate any significant difference between MF- and sham-exposed groups in production of IL-1 by mitogen-activated splenic B cells. In a second experiment, shorter MF exposure periods were studied with respect to IL production from mitogen-stimulated B and T cells. Groups of rats were MF- or sham-exposed for 1 day, 1 week, or 2 weeks, followed by preparation and activation of spleen lymphocytes. No significant difference in IL-1 or IL-2 production from stimulated B or T cells was seen. The data indicate that in vivo MF exposure of rats does not affect the ex vivo IL production of B or T lymphocytes, suggesting that the recently reported changes in T cell proliferation in response to MF exposure may not be mediated via alterations in B or T cell IL production.

Neuroticism and polymorphisms in the serotonin transporter gene.

BACKGROUND: There is evidence for an association between two different polymorphisms of the human serotonin transporter gene (5-HTT) and the personality trait of neuroticism and affective disorder. METHODS: We studied the association between neuroticism and polymorphisms in the 5HTT-linked promoter region and in a variable number tandem repeat region (VNTR) of the 5-HTT gene in 204 people aged over 60 derived from a random sample of men and women in the general population. Approximately half of the subjects were in the top 20% of neuroticism scorers and half in the bottom 20%. RESULTS: There were no significant differences in allelic or genotypic frequencies between the high and low neuroticism scorers. There was highly significant linkage disequilibrium between the two 5-HTT gene polymorphisms, and haplotype analysis showed no association between neuroticism level and haplotype. CONCLUSIONS: Reports of an association between two 5-HTT gene polymorphisms and the personality trait of neuroticism are not supported by these results.

Presence of multiple functional polyadenylation signals and a single nucleotide polymorphism in the 3' untranslated region of the human serotonin transporter gene.

The human serotonin transporter (hSERT) gene is a candidate for involvement in the aetiology of affective disorders. In humans, multiple transcripts of the gene have been detected by northern blot analysis of brain and other tissues. We performed 3' rapid amplification of cDNA ends to identify the common sites of polyadenylation in hSERT mRNA from human JAR cells and whole blood. Two major polyadenylation sites were identified: one 567 bp downstream of the stop codon, consistent with the usage of the polyadenylation signal AATGAA, and a second site 690 bp downstream of the stop codon. The putative polyadenylation signal upstream of this site contained a single nucleotide polymorphism (AG/TTAAC). However, allelic variation at this site did not influence polyadenylation site usage, and there were no significant differences in the abundance of the two alleles of this polymorphism between 329 control subjects, 158 individuals with major depression, and 130 individuals with bipolar affective disorder. This single nucleotide polymorphism in the 3' untranslated region of the hSERT gene should provide a useful genetic marker in the evaluation of hSERT as a candidate gene influencing susceptibility to mood disorders.

Effect of low-intensity 50-Hz magnetic fields on kindling acquisition and fully kindled seizures in rats.

The possibility that chronic exposure to power-line frequency (50 Hz) magnetic fields (MFs) might affect the acquisition or characteristics of focal and generalized seizures in amygdala kindled rats was studied. Acute, short-lasting 50-Hz MF exposure of fully kindled rats at either 1 or 100 microT had no effect on afterdischarge threshold (ADT) or seizure parameters recorded at ADT. In the chronic experiments, rats with electrodes implanted in the basolateral amygdala were exposed to a 50-Hz, 100-microT (1 Gauss) MF or to a sham field condition before and after onset of daily electrical stimulations over the whole period of kindling development. The focal seizure threshold (ADT) was determined before and after kindling development in MF exposed and sham exposed rats. Pre-kindling ADT was significantly increased by MF exposure. Exposed rats needed about the same number of stimulations to kindle than sham exposed rats, but the cumulative afterdischarge duration to reach criterion (i.e., a stage 5 seizure) was significantly reduced in MF exposed animals. Post-kindling ADT was similar in the two groups, but MF exposed rats showed a significantly higher threshold for generalized seizures. The data indicate that chronic exposure of rats to a 50-Hz, 100-microT MF exerts weak inhibitory effects on some seizure parameters of the kindling model.

Altered allelic distributions of the serotonin transporter gene in migraine without aura and migraine with aura.

Allelic variation of the human serotonin transporter gene (HSERT), a highly plausible candidate gene for susceptibility to migraine, was investigated in 266 individuals with migraine, including 173 having migraine without aura (MO), 94 having migraine with aura (MA), 18 with co-occurrence of MO and MA, plus 133 unaffected controls. The distribution of a polymorphism with different forms of a variable tandem number repeat (VNTR) in intron 2 were compared. The MO group had an over-representation of genotypes with two twelve repeat alleles (STin2.12) and a reduction of genotypes containing one ten repeat (STin2.10) compared to controls. The MA group showed a similar pattern, but also a trend towards an increase in genotypes containing the nine repeat allele of the VNTR (STin2.9). Genotypes containing this allele were found in 6.4% of the MA group compared to 2.3% of controls. The group with co-occurrence of MO and MA had a significantly different pattern of overall allele frequency distribution from controls, reflecting a reduction in genotypes containing the STin2.10 allele and a shift both to STin2.9 carriers and to STin2.12 homozygosity. These results support the view that susceptibility to MO and MA has a genetic component, that these disorders are distinct, and that genetic susceptibility may in some cases be associated with a locus at or near the serotonin transporter gene.

Complex effects of long-term 50 Hz magnetic field exposure in vivo on immune functions in female Sprague-Dawley rats depend on duration of exposure.

In previous studies we have demonstrated that 50 Hz, 100 microT magnetic field (MF) exposure of female Sprague-Dawley rats for 13 weeks significantly enhances the development and growth of mammary tumors in a breast cancer model. The present study was designed to test the hypothesis that, at least in part, the tumor (co)promoting effect of MF exposure is due to MF effects on the immune surveillance system, which is of critical importance in protecting an organism against the development and growth of tumors. For this purpose, female Sprague-Dawley rats of the same age as in the mammary tumor experiments were continuously exposed for different periods (2, 4, 8, and 13 weeks) to a 50 Hz, 100 microT MF. Control groups were sham-exposed simultaneously. Following the different exposure periods, splenic lymphocytes were cultured and the proliferative responses to the T-cell-selective mitogen concanavalin A (Con A) and the B-cell-selective pokeweed mitogen (PWM) were determined. Furthermore, the production of interleukin-1 (IL-1) was determined in the splenocyte cultures. The mitogenic responsiveness of T cells was markedly enhanced after 2 weeks of MF exposure, suggesting a co-mitogenic action of MF. A significant, but less marked increase in T-cell mitogenesis was seen after 4 weeks of MF exposure, whereas no difference from sham controls was determined after 8 weeks, indicating adaptation or tolerance to this effect of MF exposure. Following 13 weeks of MF exposure, a significant decrease in the mitogenic responsiveness of lymphocytes to Con A was obtained. This triphasic alteration in T-cell function (i.e., activation, tolerance, and suppression) during prolonged MF exposure resembles alterations observed during chronic administration of mild stressors, substantiating the hypothesis that cells respond to MF in the same way as they do to other environmental stresses. In contrast to T cells, the mitogenic responsiveness of B cells and IL-1 production of PWM-stimulated cells were not altered during MF exposure. The data demonstrate that MF in vivo exposure of female rats induces complex effects on the mitogenic responsiveness of T cells, which may lead to impaired immune surveillance after long-term exposure.

Allelic variation in the serotonin 5-HT2C receptor gene and migraine.

The 5-HT2C (serotonin-2C) receptor has been implicated along with other components of the 5-HT system in the pathophysiology and pharmacotherapy of migraine. To investigate whether the 5-HT2C receptor gene contributes to the risk of migraine we performed an association study of allelic variation at codon 23 (Cys or Ser) of the gene in 242 migraineurs, including 73 with aura, and 129 controls. No differences nor trends in allele or genotype frequencies were seen in the migraineurs compared to the controls. Neither did the frequencies vary significantly in migraineurs with and without aura, or if men and women were analysed separately. In conjunction with an earlier negative linkage study, these data indicate that the 5-HT2C receptor gene does not contribute to the genetic predisposition to migraine.