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Study design:Multicenter, prospective study.Objectives:To assess the occurrence and predictors of return to work after traumatic spinal cord injury (SCI).Setting:Italian rehabilitation centers.Methods:We evaluated patients previously included in the Italian Group for the Epidemiological Study of Spinal Cord Injuries study. A standardised telephone interview was used to collect data after a mean follow-up of 3.8 years. The main outcome measure was employment at the end of follow-up.Results:A total of 403 patients, 336 men and 67 women, with a mean age of 41.8±16.3 years, were included in the follow-up. In all, 42.1% of patients were employed at the moment of the interview, though 62% reported a worsening in their employment level. Predictors of employment were education (P<0.0001), bowel continence (P=0.02), independence in mobility (P=0.0004), ability to drive (P<0.0001), participating in the community (P=0.0001) and ability to live alone (P<0.0001) while age (P<0.0001), being married (P<0.0001), tetraplegia (P=0.03), occurrence of recent medical problems (P=0.002), re-hospitalization (P=0.02), presence of architectonic barriers (P=0.009) and having a public welfare subsidy (P<0.0001), predicted unemployment. On the basis of multivariate analysis, younger age, education, absence of tetraplegia, ability to drive, ability to live alone, previous employment were independent predictors of employment after SCI. Employment at follow-up was related to several indicators of quality of life.Conclusion:Employment after SCI was rather frequent and was related to several patient characteristics and social factors. Specific interventions on the patient and on the social environment may favor employment after SCI and improve quality of life. [ABSTRACT FROM AUTHOR]

Study design:Prospective, multicentred follow-up (FU) observational study.Objectives:Prospectively evaluate survival, complications, re-admissions and maintenance of clinical outcome in people experiencing traumatic spinal cord injury (SCI).Setting:Seven spinal units and 17 rehabilitation centres participating in the previous GISEM (ie Italian Group for the Epidemiological Study of Spinal Cord Injuries) study.Method:A total of 511 persons with SCI, discharged between 1997 and 1999 after their first hospitalisation, were enrolled. A standardised questionnaire was administered via telephone.Results:Of the 608 persons originally enrolled, 36 died between discharge and follow-up (mean 3.8±0.64 years). Of the remainder, 403 completed telephone interviews, 72 refused to participate and 97 could not be contacted. More than half of the patients interviewed (53.6%) experienced at least one SCI-related clinical problem in the 6 months preceding interview; the most frequent being urological complications (53.7%). At least one re-admission was recorded in 56.8% of patients between discharge and FU interview. Of the patients interviewed, 70.5% reported bowel autonomy and 86% bladder management autonomy. On multivariate analysis, lack of bowel/bladder autonomy was the most common variable with a strong predicting value for mortality, occurrence of complications and re-admissions.Conclusion:Re-admission and major complications seem common after SCI and should be considered when planning facilities. Failure to obtain bowel/bladder autonomy upon discharge from rehabilitation proved to be the most common predictive factor of poor outcome during the period between discharge and FU interview.Spinal Cord (2007) 45, 404–410; doi:10.1038/sj.sc.3101991; published online 14 November 2006 [ABSTRACT FROM AUTHOR]

DESIGN:: Prospective 2-year survey from 1 February 1997 to 31 January 1999. OBJECTIVES:: To compare the route from injury to rehabilitation, and the outcome of care in a large sample of traumatic (T) and nontraumatic (NT) spinal cord lesion (SCL) patients at their ‘first admission’. SETTING:: T and NT SCI patients consecutively admitted to 37 SCL centres in Italy. METHOD:: Data were recorded on simple, computerised, closed-question forms, which were Centrally collected and analysed. Descriptive and inferential analysis was conducted to define the characteristics and compare the T and NT populations, and to identify correlations among the variables examined: time from the event to admission (TEA); pressure sores (PS) on admission; length of stay (LoS) and destination on discharge. RESULTS:: A total of 1014 SCL patients, 67.5% with a lesion of T and 32.5% of NT aetiology were analysed. The subjects in the T group were younger (median 34 versus 58 years), with higher probability of cervical involvement (OR 2.47, CI 1.8-3.4) and completeness of the lesion (OR 3.0, CI 2.3-4.0), shorter median TEA(37 versus 64 days, P<0.0001) and less frequent admission from home (3.6 versus 17.4%) compared to the NT group. TEA and PS on admission were analysed as indicators of the efficacy of the courses from injury to rehabilitation. Longer TEA was reported for people with NT aetiology, admitted to rehabilitation centre (RC), not locally resident, transferred from certain wards and to a lesser degree female subjects and those with complications on admission. PS were associated to completeness of lesion, longer TEA, admission to RC, nonlocal residence and coming from general intensive care units, or general surgery wards. Median LoS was 99 days (mean 116 and range 0-672), and was statistically shorter in the NT group (122 versus 57 median, P<0.00001).Upon discharge, bladder and bowel autonomy were, respectively, obtained in 68.1 and 64.5% of the whole population without significant difference between the T and NT groups. A total of 80.2% of patients were discharged home and the following factors: not living alone, being discharged after longer LoS, having sphincterial autonomy and no PS, were all independent predictors of outcome. CONCLUSION:: There are important obstacles in the admission route to rehabilitation facilities, greater for NT, as longer TEA and more complications on admission testify. Moreover, the LoS is shorter for NT population. Our findings suggest that rehabilitation outcome could be improved through an early multidisciplinary approach and better continuity between acute and rehabilitation care, especially for the ‘neglected’ NT SCL patients.Spinal Cord (2003) 41, 620-628. doi:10.1038/sj.sc.3101521 [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the employment condition of persons with TSCI 4 years after discharge from rehabilitation facilities, as well as the factors related to better outcome. In the follow-up we interviewed 403 persons. We recorded the following variables: current employment status, causes of unemployment and their correlation with demographic status, clinical status and other information. In our results 51.4% of the interviewed persons were unemployed, 34.7% had a job and 7.2% were students. Among the unemployed persons 34% had suffered an accident at work, 31% had been unable to find suitable work and 31% were retired. Employment significantly correlated with younger age, single status, being paraplegic, being autonomous in bladder/bowel management, driving a car and a better quality of life. In the multivariate analysis the factors predicting better outcome were younger age, ability to drive and a better quality of life.

Unlabelled: AIM. The aim of this study is to show the compliance and the test-retest reliability of the questionnaire., Methods: Construction of a structured questionnaire to perform a phone follow-up in 511 persons with traumatic spinal cord injury (SCI) 4 years after discharge from the first rehabilitative hospitalization. The questionnaire is structured in 24 items, comprising exclusion (closed questions) answers and 3 analogic scale answers, divided into 7 aspects: clinical conditions, sentimental relationships, quality of life, autonomy, mobility, occupation, social reintegration. A pilot survey on 20 subjects with SCI, hospitalized in different periods in 2 rehabilitation centers, was performed to check the questionnaire's feasibility and reproducibility. The persons were interviewed twice by telephone, with an interval of about one month, by a psychologist. The questionnaire was completed during one single phone conversation., Results: No missing answers were recorded. The test run for this questionnaire showed high reproducibility based on the large numbers of questions with 100% correspondence between the answers ''before'' and ''after''. For most of the other questions this factor ranged between 80% and 99%, and for 2 questions on the analogic scale between 30% and 50%., Conclusions: The data collected by this pilot survey show the reliability of this questionnaire for all answers, save for the quantification of subjective variables.

Unlabelled: The aim of this paper was to assess the effectiveness and safety of baclofen, dantrolene, tizanidine and any other drugs for the treatment of long-term spasticity in spinal cord injury (SCI) patients, as well as the effectiveness and safety of different routes of administration of baclofen. A systematic review of randomised controlled trials (RCTs), within the Cochrane Collaboration Injuries Group, was carried out. The Cochrane Injuries Group Specialised Register, the Cochrane Controlled Trials Register, MEDLINE, EMBASE and CINAHL were searched up to July 2006 without language restriction. Drug companies and experts active in the area were also contacted to find other relevant studies. Two investigators independently identified relevant studies, extracted data and assessed methodological quality of studies resolving disagreement by consensus. Nine out of 55 studies met the inclusion criteria. The heterogeneity among studies did not allow quantitative combination of, Results: Study designs were: 8 crossover, 1 parallel-group trial. Two studies (14 SCI patients) showed a significant effect of intrathecal baclofen in reducing spasticity (Ashworth score and activities of daily living [ADL] performances), compared to placebo, without any adverse effect. The study comparing tizanidine to placebo (118 SCI patients) showed a significant effect of tizanidine in improving Ashworth score but not in ADL performances. The tizanidine group reported significant rates of adverse effects (drowsiness, xerostomia). For the other drugs (gabapentine, clonidine, diazepam, amytal and oral baclofen) the results do not provide evidence for a clinical significant effectiveness. This systematic review indicates that there is insufficient evidence to assist clinicians in a rational approach to antispastic treatment for SCI. Further research is urgently needed to improve the scientific basis of patient care.

T-cell growth is controlled to a large degree by extracellular signals that bind to specific receptors on the surface of cells. A number of these receptors have intrinsic protein tyrosine kinase (PTK) activity. Their action on second messenger generation, and thus on cell proliferation, has been indirectly demonstrated by the decrease in [3H]-thymidine (TdR) uptake that follows co-stimulation of T-cells with mitogens and PTK inhibitors such as genistein (GEN). In this paper we report that the [3H]-TdR uptake assay is not a valid and reliable tool for investigating the proliferative activity of certain T-cell lines. In fact, a concomitant assessment of both [3H]-TdR uptake and cell cycle progression demonstrated that GEN is able to block G2/M progression of Jurkat T-lymphocytes even at doses (5 micrograms/ml) that do not influence [3H]-TdR uptake. Pretreatment with sodium o-vanadate (100 nM) could not reverse the GEN-related cell cycle perturbation, but was able to restore optimal [3H]-TdR uptake. Finally, GEN treatment was able to induce concentration-dependent apoptotic cell death of Jurkat T-cells. The control of cell activation, proliferation and programmed cell death is undoubtedly influenced by receptor-associated PTKs. The final effect on cell survival is almost entirely dependent on the activation state of the cell. The [3H]-TdR uptake assay seems to be inadequate for a correct interpretation of the expected results.

Glucocorticoid hormones (GCH) induce apoptotic cell death in immature thymocytes through an active process, characterized by extensive DNA fragmentation into oligonucleosomal subunits. This requires macromolecular synthesis and is inhibited by interleukins (ILs). We performed experiments to analyse the possible effect of GCH on more differentiated lymphocytes, i.e. peripheral (from lymph nodes and spleen) T-lymphocytes. The results show that in vitro dexamethasone (DEX) induces DNA fragmentation and cell death not only in thymocytes but also in mature T cells. We also tested the possible role of interleukins (ILs) in the modulation of apoptotic cell death. We show that DEX-induced apoptosis is inhibited by IL-2 and IL-4 and that the IL-4 induced inhibition correlates with induction of c-jun (a component of AP-1 transcription factor). Furthermore high doses of IL-2 are able to induce apoptosis in both thymocytes and peripheral T cells. These data indicate that both thymocytes and peripheral T cells undergo apoptosis in response to appropriate stimuli and suggest that GCH and ILs interact in regulating T-lymphocytes apoptotic death.

Genistein, a natural isoflavonoid phyto-oestrogen, inhibits the tyrosine kinase activity of growth factor receptors and oncogene products, as well as the in vitro growth of some tumour cell lines. The low incidence of breast cancer in countries with a flavonoid-rich soy-based diet and the protection afforded by soy-derived products against experimental mammary tumours in rats suggest that genistein and other isoflavonoid compounds may exert an anti-tumour activity. We analysed the effects of genistein on cell number and cell cycle progression (flow cytometric analysis of propidium iodide-stained nuclei) of human breast cancer cells (MCF-7) in vitro. Genistein produced a significant, dose-dependent inhibition of MCF-7 cell growth with an ID50 of approximately 40 microM after 72 h of incubation. Cell cycle analysis showed a reversible G2/M arrest in cell cycle progression at 10 microM genistein concentrations, whilst a marked fall in S-phase cell percentage associated with a persistent arrest in G2/M phase was observed in cultures treated with genistein doses equal to or greater than 50 microM. These effects were significant at 24 h of incubation; flow cytometric analysis at later times (48 and 72 h) revealed a population of cells with decreased DNA content and nuclear fragmentation characteristic of apoptosis. Thus, the growth inhibitory activity of genistein in MCF-7 cells results from the sum of cytostatic and apoptotic effects. Since the mitogenic action of insulin and insulin-like growth factor (IGF)-I in MCF-7 cells is a tyrosine kinase-dependent phenomenon, we analysed the genistein impact on S-phase entry produced by insulin in cultures partially synchronised in G0/G1 phase by serum deprivation. Insulin addition after a 36-h culture period in serum-free medium produced a strong increase in the percentage of S-phase cells (from 18.4 +/- 2.3 to 46.2 +/- 4.1 after 24 h) which was almost completely blocked by 100 microM genistein (20.1 +/- 3.1). Immunofluorescence analysis with a fluoresceine isothiocyanate (FITC)-conjugated anti-phosphotyrosine antibody revealed a strong increase in MCF-7 cell staining after insulin stimulation, but not when genistein was added with insulin. In conclusion, the dietary phyto-oestrogen genistein inhibits in vitro growth of MCF-7 human breast cancer cells through blocks in the "critical checkpoints" of cell cycle control and induction of apoptosis. These effects are likely to depend on impairment in the signal transduction pathway from tyrosine kinase receptor(s).

To investigate the mechanisms of growth inhibition exerted by TNF-alpha on tumor cells in vitro, we analyzed the cytokine effects on growth and cell-cycle parameters of cultured MCF-7 human breast cancer cells. TNF-alpha exerted a dose-dependent inhibition of MCF-7 cell growth, which reached its maximum at 1000 U/ml TNF-alpha concentrations. Flow-cytometric analysis of cell nuclei revealed two main components in TNF-alpha activity: an earlier cytostatic effect (G1/S block), was followed by nuclear shrinkage and cytolysis. The 55-60-kDa TNF-alpha receptor is involved in the growth inhibitory activity of the cytokine, since the H398 anti-55-kDa receptor antibody significantly counteracted the cytostatic and cytotoxic effects of TNF-alpha while an antibody (htr-9) with agonistic activity on the same receptor produced both cytostasis and cytolysis. Culture conditions strongly influenced the MCF-7 cell response to TNF-alpha. Serum deprivation of log-growing (i.e., high S phase percentage) cultures potentiated the cytotoxic effect, while reduction in S phase cell percentage by preculture in serum-free medium resulted in a significant inhibition of TNF-alpha action. Mitogenic hormones, such as insulin and 17 beta-estradiol+insulin, restored the sensitivity of MCF-7 cells precultured in serum-free medium to both the cytostatic and cytolytic effects of TNF-alpha. The synthetic glucocorticoid hormone dexamethasone, at micromolar concentrations, counteracted the TNF-alpha effect on MCF-7 cell growth. Flow-cytometric analysis showed that dexamethasone did not antagonize the cytostatic activity of either TNF-alpha or htr-9 agonistic antibody, but only the subsequent cytolysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Glucocorticoid hormones (GCH) and anti-CD3 monoclonal antibodies (MoAbs) induce in mouse thymocytes and T-cell tumor lines an active process of cell death called apoptosis. Interleukins (IL), including IL-1 and IL-2, have been reported to inhibit such apoptosis. In this study we show that IL-4 also reduced the DNA fragmentation characteristic of dexamethasone (DEX)-induced apoptosis in thymocytes. This effect, studied in both time-course and dose-response experiments, was also detected at low IL-4 concentrations (1 U/mL) and against high DEX levels (10(-7) mol/L). The effect of IL-4 was blocked by an anti-IL-4 but not by an anti-IL-1 alpha MoAb, and was thus both specific and direct. Phenotypic analysis showed that IL-4 protects predominantly CD4-CD8- and CD4+CD8- cells. Our findings suggest that intrathymic T-cell development may be influenced by IL-4.

Interleukins play a role in the process of T-cell development and, like other cytokines, seem able to modulate apoptosis. Interleukin-2 has been reported to inhibit apoptotic cell death of thymocytes induced in vitro by either activation of CD3/TCR complex or treatment with glucocorticoid hormone. We demonstrate here that IL-2 can provoke DNA fragmentation and cell death of CD4+ CD8+ mouse thymocytes by activating an endogenous apoptotic pathway. Thymocytes, incubated with high IL-2 concentrations in vitro, showed the morphological characteristics of apoptotic cells, including reduction in nuclear size, derangement in chromatin structure, and DNA fragmentation in oligonucleosomal subunits. Inhibition of mRNA and protein synthesis and addition of the PKC-inhibitor H-7, Zn2+ ions, and IL-4 counteracted the IL-2 effect. These data suggest that high IL-2 concentrations may induce an active process of cell death on mouse thymocytes in vitro.

The natural isoflavone genistein inhibits the growth of a number of tumour cell lines in vitro. During investigations on the antiproliferative effects of genistein we observed that, with respect to direct cell counting, a tetrazolium (MTT) colorimetric assay consistently underestimated the growth inhibitory activity of the substance. Cell proliferation was markedly inhibited by genistein in three tumour cell lines (MCF-7, human breast tumour; Jurkat cells, human T-cell leukaemia; L-929, mouse transformed fibroblasts) when cell number was evaluated by direct counting, whereas a 72-h MTT assay failed to reveal any growth-inhibitory effect. Cell cycle analysis by propidium iodide staining and flow-cytometry revealed a G2/M cell cycle arrest after genistein treatment. Genistein-treated cells displayed an increase in cell volume and in mitochondrial number and/or activity, as revealed by enhanced formazan generation and increased uptake of the vital mitochondrial dye rhodamine 123. These results suggest that alterations in cell cycle phase redistribution of tumour cells by genistein may significantly influence mitochondrial number and/or function and, consequently, MTT reduction to formazan. This may constitute an important bias in analysing the effects of genistein, and possibly other drugs that block the G2/M transition, on growth and viability of cancer cells in vitro by MTT assay.

Glucocorticoid hormones (GCH) and IL-2 induce apoptotic cell death by a PKC-dependent mechanism. IL-4 counteracts apoptosis by inhibiting PKC activity. GCH and IL-2 show antagonistic effects on apoptosis when administered together. These data indicate that PKC activation in response to different stimuli can both enhance or reduce thymocyte survival.

Somatostatin (SS) and SS analogs have been shown to exert an antiproliferative effect on several transplantable tumors in animals and to reduce the growth of pancreatic, pituitary, and mammary tumor cells in vitro. We evaluated the effects that the SS analog SMS 201-995 exerts on growth, cell-cycle parameters, and suicidal cell death (apoptosis) of human breast cancer cells (MCF-7) in vitro. SMS 201-995 significantly reduced the MCF-7 cell growth induced by serum, estradiol, insulin, and insulin-like growth Factor-I in both short term and long term experiments. The effect was maximal when 10 nM estradiol was used as mitogen in long term cultures. SMS 201-995 treatment produced a slight but transient accumulation of cells in the G2/M phase but did not cause any noteworthy reduction in the percentage of proliferating cells. There was, instead, a time-related increase in the number of cells with the flow-cytometric characteristics of apoptosis in the cultures treated with the SS analog, which correlated well with its growth-inhibiting activity. It would, therefore, seem that SMS 201-995 exerts its inhibitory effect on MCF-7 cell growth in vitro mainly by enhancing the rate of programmed (or suicidal) cell death in the culture.

Corticosteroids, calcium ionophores and anti-CD3 monoclonal antibodies kill mouse thymocytes incubated in vitro. Cell death is preceded by extensive DNA fragmentation into oligonucleosomal subunits. This type of cell death (apoptosis), which physiologically occurs in the intrathymic process of immune cell selection, is usually evaluated by either electrophoretic or colorimetric methods which measure DNA fragmentation in the nuclear extracts. These techniques are unable to determine the percentage of apoptotic nuclei or recognize the apoptotic cells in a heterogeneous cell population. We have developed a flow cytometric method for measuring the percentage of apoptotic nuclei after propidium iodide staining in hypotonic buffer and have compared it with the classical colorimetric and electrophoretic techniques using dexamethasone (DEX)-treated mouse thymocytes. Apoptotic nuclei appeared as a broad hypodiploid DNA peak which was easily discriminable from the narrow peak of thymocytes with normal (diploid) DNA content in the red fluorescence channels. When the DEX-induced apoptosis was inhibited by either low-temperature (4 degrees C) incubation or cycloheximide treatment, no hypodiploid DNA peak appeared. Similarly, thymocyte death induced by sodium azide, a substance with cell-killing activity through non-apoptotic mechanisms, did not result in any variation in the normal DNA peak. The flow cytometric data showed an excellent correlation with the results obtained with both electrophoretic and colorimetric methods. This new rapid, simple and reproducible method should prove useful for assessing apoptosis of specific cell populations in heterogeneous tissues such as bone marrow, thymus and lymph nodes.

Thyroid function tests were evaluated in 38 patients on regular hemodialysis (HD), in 36 on continuous ambulatory peritoneal dialysis (CAPD) and in 39 healthy controls. A significant reduction in total thyroxine (TT4), total triiodothyronine (TT3), reverse (rT3), and free T4 (fT4) mean levels and normal TSH, free T3, TBG and albumin concentrations was found in both HD and CAPD patients. A 'low-T4 syndrome' (serum T4 less than 5 micrograms/dl) was found in 9 CAPD (25%) and 20 HD (53%) patients, but none of them had fT4 levels below the normal laboratory range. The only striking difference between low-T4 HD and low-T4 CAPD patients was the significantly lower TBG and albumin serum levels in CAPD group. Low-T4 HD displayed normal TBG levels but enhanced fT4/TT4 and fT4/TT4 X TBG ratios. We concluded that: the abnormalities in thyroid function tests in patients on long-term dialysis (HD and CAPD) do not express the existence of a true hypothyroidism; a different pathogenesis of the low-T4 syndrome in the CAPD and HD groups may be hypothesized: in the former it could be attributed to a reduction in serum-binding capacity for thyroid hormones, in the latter the relative increase in fT4 percentage despite normal TBG levels suggests either the presence of T4-TBG-binding inhibitor(s), or structural abnormalities of thyroid-hormone-binding proteins.

The present study was designed to examine the effect of low-dose dopamine (DA) infusion rates (0.02 and 0.1 microgram/kg X min) on both basal and TRH-stimulated prolactin release in normal and hyperprolactinemic individuals. Sixteen normally menstruating women in the early follicular phase of a cycle and 23 hyperprolactinemic patients were studied. 0.1 microgram/kg X min DA was infused in 8 normal women and 15 patients with pathological hyperprolactinemia, while 8 normal controls and 8 patients received 0.02 microgram/kg X min DA TRH (200 micrograms, i.v.) was administered alone and at the 180th min of the 5-hour DA infusion in all controls and patients. A significant reduction in serum PRL levels, which was similar in normal women (-59.5 +/- 4.0%, mean +/- SE) and hyperprolactinemic patients (-48.2 +/- 5.5) was observed in response to 0.1 microgram/kg X min DA. In normal cycling women DA infusion significantly (P less than 0.02) reduced the PRL response to TRH with respect to the basal TRH test (delta PRL 45.0 +/- 7.0 vs. 77.9 +/- 15.4 ng/ml). On the contrary, the PRL response to TRH was significantly higher during 0.1 microgram/kg X min DA than in basal conditions in hyperprolactinemic patients, both in absolute (delta PRL 91.8 +/- 17.6 vs. 38.4 +/- 6.8, P less than 0.03) and per cent (198.5 +/- 67.6 vs. 32.1 +/- 7.5, P less than 0.02) values. A normal PRL response to TRH, arbitrarily defined as an increase greater than 100% of baseline, was restored in 11 out of 15 previously unresponsive hyperprolactinemic patients.(ABSTRACT TRUNCATED AT 250 WORDS)