Reduced graft-versus-host disease-inducing capacity of T cells after activation, culturing, and magnetic cell sorting selection in an allogeneic bone marrow transplantation model in rats.

Graft-versus-host disease (GvHD), a major complication of allogeneic bone marrow transplantation, has been ascribed to mature T cells in the graft. Because T cells play an important role in engraftment of the bone marrow and decrease the probability of relapse of leukemia, a treatment strategy was developed to preserve the benefits of T cells in the graft and to control the severe complications of GvHD. This can be accomplished by the genetic modification of donor T cells with a suicide gene that allows their selective in vivo elimination and subsequently the abrogation of GvHD. For clinical benefit the alloreactivity of herpes simplex virus thymidine kinase (HSV-TK) gene-transduced T cells should be retained. Therefore, we investigated the influence of gene transduction and the selection procedure on T cells. We demonstrated that activation and culturing of T cells reduce their capacity to induce lethal GvHD in an allogeneic rat bone marrow transplantation model. Furthermore, positive immunomagnetic selection of gene-transduced T cells resulted in loss of the GvHD-inducing capacity of HSV-TK(+) T cells directly after MACS (magnetic cell sorting) selection; this loss could be recovered by a 1-day expansion of the selected T cells. No effect on alloreactivity was observed to be caused by the gene transduction procedure. Our study resulted in the development of an optimized culture and gene transduction protocol with preservation of T cell alloreactivity. Treatment of transplanted rats with ganciclovir resulted in a rapid reduction in the number of HSV-TK(+) T cells in the peripheral blood and in increased survival of the animals.     

The Recognition of Hypothalamo-Neurohypophysial Functions by Developing T Cells

Neuropeptide signals and specific neuropeptide receptors have been described in the thymus supporting the concept of a close dialogue between the neuroendocrine and the immune systems at the level of early T-cell differentiation. In this paper, we review recent data about neurohypophysial (NHP)-related peptides detected in the thymus from different species. We suggest that we are dealing in fact with other member(s) of the NHP hormone family, which seems to exert its activity locally through a novel model of cell-to-cell signaling, that of cryptocrine communication. This model involves exchange of signals between thymic epithelial cells and developing thymocytes. The NHP-related peptides have been shown to trigger thymocyte proliferation and could induce immune tolerance of this highly conserved neuroendocrine family.     

Efficacy and tolerability of a topical NSAID patch (local action transcutaneous flurbiprofen) and oral diclofenac in the treatment of soft-tissue rheumatism

Summary The efficacy and safety of local action transcutaneous flurbiprofen 40 mg [flurbiprofen LAT] patches and diclofenac sodium tablets, 50 mg b.d., were compared in an open, multicentre, randomized, parallel-group study in patients with soft-tissue rheumatism. Patches were replaced at 12-hourly intervals. Clinical assessments were performed after 7 and 14 days of treatment. Fifty-six patients were treated with flurbiprofen LAT and 53 with diclofenac. Six withdrawals (three from each group) occurred during the treatment period.A statistically significant difference was observed in favour of flurbiprofen LAT for the principal measure, namely the investigator's opinion of overall change in clinical condition: 49/53 (92%) patients treated with flurbiprofen LAT had improved by day 14 compared with 36/49 (73%) patients receiving diclofenac sodium (p=0.03; eligible dataset). There were also statistically significant differences in favour of flurbiprofen LAT for the investigator's assessments of the overall severity of the clinical condition (p=0.03; eligible dataset), for the severity of pain at the region treated (p=0.04; intent-to-treat), and for the severity of tenderness (p<0.001; intent-to-treat). Supplementary analgesia (paracetamol) was required by two patients in the flurbiprofen LAT group and by eight diclofenac-treated patients. The difference in favour of flurbiprofen LAT group and by eight diclofenac-treated patients. The difference in favour of flurbiprofen LAT in the average daily consumption of paracetamol was significant (p=0.04). The patients' assessment of severity of pain on movement also favoured flurbiprofen LAT (p =0.049; eligible dataset), but there were no statistically significant differences in day or night pain or quality of sleep. For the patients' opinion of treatment there was, however, a statistically significant difference in favour of flurbiprofen LAT (p=0.02). Of the patients receiving flurbiprofen LAT, 94% regarded it as a convenient form of treatment.With respect to tolerability 8/56 (14%) patients applying flurbiprofen patches reported a total of nine adverse effects (AEs) (mainly local, mild skin irritations), vs 9/52 (17%) patients receiving diclofenac, who reported 12 AEs. Most AEs in the enteric-coated diclofenac group were of a gastrointestinal nature (one of which was severe). In terms of the proportion of patients reporting AEs related to the digestive system, there was a statistically significant difference in favour of flurbiprofen LAT (p=0.011).In conclusion, local treatment of soft-tissue rheumatism with flurbiprofen LAT was demonstrably superior to benchmark oral therapy with diclofenac sodium over a 2-week period in terms of both efficacy and gastrointestinal tolerability. Flurbiprofen LAT provided both an effective and convenient form of topical SAID treatment.     

Prevalence of mental illness and its impact on the use of home care and nursing homes: a population-based study of older adults in Manitoba.

OBJECTIVES: To determine the prevalence of mental illness in older adults and its effect on home care and personal care home (PCH) use. METHODS: Using nonidentifying administrative records (fiscal years 1997-1998 to 2001-2002) from the Population Health Research Data Repository housed at the Manitoba Centre for Health Policy, we determined the 5-year period prevalence for individuals aged 55 years and over (119 539 men and 145 752 women) for 3 mental illness categories: cumulative mental disorders (those having a diagnosis of depression, anxiety disorder, personality disorder, schizophrenia, and [or] substance abuse), any mental illness, and dementia. We calculated age-specific and age-adjusted rates of home care and PCH use and the prevalence of mental illness in PCH residents. RESULTS: From the group aged 55 to 59 years to the group aged 90 years or older, the prevalence of mental illness increased with the population's age. The prevalence of any mental illness rose from 32.4% to 45.0% in men and from 42.6% to 51.9% in women, and dementia prevalence rose from 2.0% to 33.6% in men and from 1.3% to 40.3% in women. The age-adjusted annual rates of open home care cases per 1000 population aged 55 and older varied by mental illness grouping (no mental disorder, 57 for men and 91 for women; cumulative mental disorders, 162 for men and 191 for women; dementia, 300 for men and 338 for women). The age-adjusted rates of PCH use per 1000 population aged 75 years and older also varied by mental illness grouping (no mental disorder, 53 for men and 78 for women; cumulative mental disorders, 305 for men and 373 for women; dementia, 542 for men and 669 for women). Among patients admitted to (or resident in) a PCH in 2002-2003, 74.6% (87.1%) had a mental illness, and 46.0% (69.0%) had dementia. CONCLUSIONS: Mental illness affects the use of home care and nursing homes profoundly. Individuals with dementia used home care at 3 times the rate of those having no mental illness diagnosis, and they used PCHs at 8 times the rate.     

Computed tomographic changes of the brain and clinical outcome of patients with seizures and epilepsy after an ischaemic hemispheric stroke.

It is not well established whether seizures and epilepsy after an ischaemic stroke increase the disability of patients. Seventy-two patients with delayed seizures after a hemispheric infarct (37 with a single seizure and 35 with epilepsy) were included in the study. The modified Rankin scale was used to compare disability of the patients at 1 month after stroke and at 2 weeks after single or the last seizure, in case of epilepsy. The size of the X-ray hypoattenuation zone was compared on computed tomographic (CT) scans, performed in the weeks after the stroke and 1 week after single or repeated seizures. Lesion size was determined by superimposing the CT slices on digital cerebral vascular maps, on which the contours of the infarct area were delineated. The extent of the infarcts was expressed as the percentage fraction of the total surface area of the cerebral hemisphere. Groups with a single seizure and with epilepsy were mutually compared. Infarcts predominated in the parieto-temporal cortical regions. In the overall group the median Rankin score worsened significantly after seizures. The average size of the X-ray hypoattenuation zone was also significantly increased on the CT scans after the seizures, compared with those after stroke, without clear evidence of recent infarction. Mutual comparison of patients with a single seizure episode and of those with epilepsy showed only a trend of more severe disability and of increase in lesion size in the post-stroke epilepsy group. Delayed seizures and epilepsy after ischaemic stroke are accompanied by an increase in lesion size on CT and by worsening of the disability of the patients. This study does not allow to determine whether this is due to stroke recurrence or due to additional damage as a result of the seizures themselves.     

Protein kinase C�� expression in breast cancer as measured by real-time PCR, western blotting and ELISA

The protein kinase C (PKC) family of genes encode serine/threonine kinases that regulate proliferation, apoptosis, cell survival and migration. Multiple isoforms of PKC have been described, one of which is PKCδ. Currently, it is unclear whether PKCδ is involved in promoting or inhibiting cancer formation/progression. The aim of this study was therefore to investigate the expression of PKCδ in human breast cancer and relate its levels to multiple parameters of tumour progression. Protein kinase Cδ expression at the mRNA level was measured using real-time PCR (n=208) and at protein level by both immunoblotting (n=94) and ELISA (n=98). Following immunoblotting, two proteins were identified, migrating with molecular masses of 78 and 160 kDa. The 78 kDa protein is likely to be the mature form of PKCδ but the identity of the 160 kDa form is unknown. Levels of both these proteins correlated weakly but significantly with PKCδ concentrations determined by ELISA (for the 78 kDa form, r=0.444, P<0.005, n=91 and for the 160 kDa form, r=0.237, P=0.023, n=91) and with PKCδ mRNA levels (for the 78 kDa form, r=0.351, P=0.001, n=94 and for the 160 kDa form, r=0.216, P=0.037, n=94). Protein kinase Cδ mRNA expression was significantly higher in oestrogen receptor (ER)-positive compared with ER-negative tumours (P=0.007, Mann–Whitney U-test). Increasing concentrations of PKCδ mRNA were associated with reduced overall patient survival (P=0.004). Our results are consistent with a role for PKCδ in breast cancer progression.