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Biomedical subjects

W Young

Publications and source records attributed to W Young.

At least 37 records · Page 2Linked to original sources
PubMed2000

Bridging the gap: from discovery to clinical trials in spinal cord injury.

Recently, the Kent Waldrep National Paralysis Foundation initiated a think tank intended to bridge several gaps and achieve several goals in regard to spinal cord injury (SCI) research and funding. Affiliated with the need to bridge a pathophysiological gap in spinal parenchyma and/or reorganize remaining circuitry after injury is a need to bridge resource gaps for timely funding for translational research, gaps in knowledge between researchers, and between researchers/clinicians and SCI patients. The epistemology of cure was examined and redefined to include transitional recoveries and advances. Modes and mechanisms of funding have been evaluated and where deficits were perceived, suggestions have been made to expedite and increase the number and breadth of funding opportunities. Innovative infrastructure changes are submitted. We discuss the progression of clinical trials as well as offer suggestions to facilitate benchtop-to-bedsite translation of valuable research to the customer. Highlights of recently completed, in progress, and future trials are detailed. Finally, we submit five essential processes required to promote advances to the SCI patient population: discovery, development, clinical trials, evaluation, and rehabilitation. These ideas are intended to facilitate entry of serious dialogue and to ultimately improve the lives of patients living with SCI.

Clinical Trials as Topic↗
PubMed2000

Clinical measurement, statistical analysis, and risk-benefit: controversies from trials of spinal injury.

BACKGROUND: The National Acute Spinal Cord Injury Studies have been a series of trials assessing the role of pharmacologic agents in the prevention of secondary neuronal damage after acute spinal cord injury. METHODS: The trials were multicenter randomized, controlled studies. RESULTS: Two trials have demonstrated the efficacy of high-dose methylprednisolone in improving neurologic and functional recovery and have shown a reassuring safety profile. CONCLUSION: This study responds to a recent commentary on these trials and examines in particular the roles of clinical measurement, statistical analysis, and risk benefit in assembling evidence for or against innovative therapies.

Anti-Inflammatory Agents↗
PubMed1999

Regional variations in the use of home care services in Ontario, 1993/95.

BACKGROUND: Although regional variations in the use of many health care services have been reported, little attention has been devoted to home care practices. Given the dramatic shift in care settings from hospitals to private homes, it is important to determine the extent to which home care practices vary by geographic region. METHODS: Data from the Canadian Institute for Health Information and the Ontario Home Care Administration System database were used to assess regional variations in rates of home care use following inpatient care and same-day surgery for the fiscal years 1993, 1994 and 1995. Various measures of regional variation were employed. RESULTS: Of the 2,870,695 inpatient separations and 1,803,307 same-day surgery separations during the study period, 359,972 and 64,541, respectively, were followed by home care. The rate of home care use per 100 separations was 12.5 for inpatients and 3.6 for same-day surgery patients. There was a a 3.5-fold regional variation in the rates of home care use following inpatient care and a 7-fold variation in rates of use following same-day surgery. Additional home care funding to attain calculated target rates was estimated to be $48.9 million (30% of expenditures for patients recently discharged from hospital over the study period). For a 20% increase in service provision it was estimated that an additional injection of $42.2 million is required. INTERPRETATION: The wide regional variations in rates of home care use highlight the importance of modifying home care funding to ensure that all residents of Ontario have equal access to services. To achieve this our estimates suggest that a substantial increase in home care funding is warranted.

Acute Disease↗
PubMed1999

Trends in clinical and economic outcomes of coronary angioplasty from 1992 to 1995: a population-based analysis.

BACKGROUND: The impact of recent developments in coronary angioplasty on the broad spectrum of patients treated in routine practice is largely undefined. Analysis of population-based data can provide insight into trends in clinical outcomes and associated costs of coronary angioplasty procedures. METHODS AND RESULTS: With the use of a comprehensive hospital discharge database covering more than 11 million Canadians, we analyzed 12,748 first-time angioplasty procedures performed from 1992 to 1995 inclusive. Patient demographics and major adverse events were recorded. With the use of forward linkage, readmissions within 12 months were classified according to procedure performed and/or most responsible diagnosis. The proportion of patients readmitted, the number of readmissions per index procedure, and diagnosis-specific readmission costs were compared by calendar year. Over the 4-year study period, there was a 21% increase in the annual volume of index procedures. There were no statistically significant differences between 1992 and 1995 in sex distribution, mean age, comorbid conditions, length of stay, or need for coronary bypass surgery related to the index procedure. The all-cause readmission rate declined from 51.6% to 47.2% between 1992 and 1995 (P <.001), primarily because of a decline in the admission rate for repeat revascularization from 24.8% to 19.6% (P <.001). The 12-month readmission cost declined by $435 (1994 Canadian dollars) per patient. CONCLUSIONS: The clinical outcomes of coronary angioplasty in a broad cohort of patients have improved in recent years. Although readmissions within 1 year of an angioplasty procedure remain common, the number related to repeat revascularization has declined, with an associated decline in downstream costs.

Aged↗
PubMed1999

M2 receptors in genito-urinary smooth muscle pathology.

In vitro bladder contractions in response to cumulative carbachol doses were measured in the presence of selective muscarinic antagonists from rats which had their major pelvic ganglion bilaterally removed (denervation, DEN) or from rats in which the spinal cord was injured (SCI) via compression. DEN induced both hypertrophy (505+/-51 mg bladder weight) and a supersensitivity of the bladders to carbachol (EC50=0.7+/-0.1 uM). Some of the SCI rats regained the ability to void spontaneously (SPV). The bladders of these animals weighed 184+/-17 mg, significantly less than the bladders of non voiding rats (NV, 644+/-92 mg). The potency of carbachol was greater in bladder strips from NV SCI animals (EC50=0.54+/-0.1 uM) than either bladder strips from SPV SCI (EC50=0.93+/-0.3 microM), DEN or control (EC50=1.2+/-0.1 microM) animals. Antagonist affinities in control bladders for antagonism of carbachol induced contractions were consistent with M3 mediated contractions. Antagonist affinities in DEN bladders for 4-diphenlacetoxy-N-methylpiperidine methiodide (4-DAMP, 8.5) and para fluoro hexahydrosilodifenidol (p-F-HHSiD, 6.6); were consistent with M2 mediated contractions, although the methoctramine affinity (6.5) was consistent with M3 mediated contractions. p-F-HHSiD inhibited carbachol induced contraction with an affinity consistent with M2 receptors in bladders from NV SCI (pKb=6.4) animals and M3 receptors in bladders from SPV SCI animals (pKb=7.9). Subtype selective immunoprecipitation of muscarinic receptors revealed an increase in total and an increase in M2 receptor density with no change in M3 receptor density in bladders from DEN and NV SCI animals compared to normal or sham operated controls. M3 receptor density was lower in bladders from SPV SCI animals while the M2 receptor density was not different from control. This increase in M2 receptor density is consistent with the change in affinity of the antagonists for inhibition of carbachol induced contractions and may indicate that M2 receptors or a combination of M2 and M3 receptors directly mediate smooth muscle contraction in bladders from DEN and NV SCI rats.

Animals↗
PubMed1999

GABA increases refractoriness of adult rat dorsal column axons.

We applied randomized double pulse stimulation for assessing the effects of GABA and a GABAA antagonist on compound action potentials in dorsal column axons isolated from adult rat. We stimulated the axons with double pulses at 0.2 Hz and randomly varied interpulse intervals between 3, 4, 5, 8, 10, 20, 30, 50 and 80 ms. Action potentials were measured using glass micropipettes. The first pulse was used to condition the response activated by the second test pulse. Concentrations of GABA of 1 mM, 100 microM and 10 microM did not affect action potential amplitudes or latencies activated by conditioning pulses. In the control studies, before drug administration, test pulses induced response amplitudes that were significantly decreased at 3-, 4- and 5-ms interpulse intervals. The test action potential amplitudes were 84.6 +/- 2.5%, 89.0 +/- 3.9% and 93.3 +/- 3.6% (mean +/- S.E.M.) of conditioning pulse levels, respectively. At 3-ms interpulse intervals, test response latencies were prolonged to 104.3 +/- 1.0%, but were unchanged at the other interpulse intervals. The 10 microM, 100 microM and 1 mM concentrations of GABA affected test response amplitudes. Application of 100 microM GABA reduced the amplitudes of test responses at 3-, 4-, 5- and 8-ms interpulse intervals, to 59.2 +/- 3.0%, 70.0 +/- 3.0%, 80.2 +/- 1.1% and 88.6 +/- 3.6% of the conditioning pulse amplitudes, respectively. At both 100 microM and 1 mM concentrations, GABA significantly prolonged the latencies of test responses. Treatment with 100 microM GABA prolonged the latencies of test responses at 3-, 4- and 5-ms interpulse intervals, to 119.3 +/- 3.1%, 107.3 +/- 2.8% and 105.5 +/- 2.5% of conditioning pulse latencies, respectively. The addition of 100 microM bicuculline methochloride, a GABAA antagonist, eliminated the effects of 100 microM GABA. The combined application of GABA and bicuculline (both 100 microM) did not affect amplitudes or latencies of test responses. These results suggest that GABA(A) receptor subtypes are present on the spinal dorsal column axons of adult rat, and that they modulate the excitability of the axons. The randomized double pulse methods reveal that GABA increases refractoriness of adult rat dorsal column axons.

Action Potentials↗
PubMed1999

Chinese migrants' mental health and adjustment to life in New Zealand.

OBJECTIVE: The purpose of this study was to identify and assess the relative importance of predictors of the self-rated adjustment and psychiatric morbidity of recent Chinese migrants. METHOD: Chinese migrants (n = 271) living in Auckland and aged 15 years or older completed a postal questionnaire that included the Chinese Health Questionnaire (CHQ). The majority of respondents came from Hong Kong and Taiwan. RESULTS: Most respondents did not report major adjustment problems. The psychiatric morbidity rate was 19%. Major predictors of experiencing problems included rejection by locals, being aged 26-35 years or over 45 years and low English proficiency. Major predictors of poor adjustment included unemployment, low English proficiency, lack of university education, younger age, shorter residency, expectations not met and regrets about coming to New Zealand. Predictors of minor mental disorder included regretting coming, female gender and younger age. For migrants resident 2 years or less, unemployment and underemployment were additional risk factors. Mothers with absent husbands and young people with absent parents also had elevated rates of mental disorder. CONCLUSIONS: Although the overall prevalence of mental disorder for this sample of recent migrants appears to be similar to that of the general population, significant risk factors were identified. The findings extend knowledge of the adjustment and the mental health of migrants and provide potential focal points for primary and secondary prevention interventions.

Adolescent↗
PubMed1999

Role of glycemia in acute spinal cord injury. Data from a rat experimental model and clinical experience.

While experimental and clinical evidence indicates that in brain injury blood glucose increases with injury severity and hyperglycemia worsens neurological outcome, the role of blood glucose in secondary mechanisms of neuronal damage after acute spinal cord injury has not yet been investigated. Data from spinal cord ischemia models suggests a deleterious effect of hyperglycemia, likely due to enhanced lactic acidosis, which is primarily dependent on the amount of glucose available to be metabolized. The purpose of this study is to summarize preliminary experimental and clinical observations on the role of blood glucose in acute spinal cord injury. Between 1995 and 1996 we used the New York University (NYU) rat spinal cord injury model to test the following hypotheses: 1) Blood glucose levels increase with injury severity. 2) Fasting protects from hyperglycemia and prevents secondary damage to the spinal cord. 3) Postinjury-induced hyperglycemia (dextrose 5% 2 gm/Kg) enhances spinal lesion volume. From a clinical perspective, we reviewed blood glucose records of 47 patients admitted to the Department of Neurosrgery in Verona, between 1991 and 1995, within 24 hours of acute spinal cord injury in order to determine: a) the incidence of hyperglycemia (> 140 mg/dl); b) the correlation between blood glucose and injury severity; and c) the role of methylprednisolone in affecting blood glucose. Results indicate that in a graded spinal cord injury model: 1) Early after injury, more severe contusions support significantly higher blood glucose levels. 2) Fasting overnight does not directly affect spinal cord lesion volume but influences blood gases, and we observed that a slightly systemic acidosis plays a minor neuroprotective role. Fasting also ensures more consistent normoglycemic baseline blood glucose values. 3) Postinjury-induced moderate hyperglycemia (160-190 mg/dl) does not significantly affect spinal cord injury. In the clinical study, we observed that during the first 24 hours after spinal cord injury: a) Glycemia ranges between 90 and 243 mg/dl (mean value 143 mg/dl), and close to 50% of the patients present blood glucose values higher than normal. b) Methylprednisolone administration is not associated to significantly higher blood glucose levels. c) There is a trend for larger glucose rises with more severe injury.

Animals↗
PubMed1999

Therapeutic time window for methylprednisolone in spinal cord injured rat.

Recent clinical trials have reported that methylprednisolone sodium succinate administered within 8 hours improves neurological recovery in human spinal cord injury (SCI). Methylprednisolone, however, was ineffective and possibly even deleterious when given more than 8 hours after injury. This finding suggests that a therapeutic time window exists in spinal cord injury. In order to determine the doses, durations and timing of methylprednisolone treatment for optimal neuroprotection, a single or two bolus dose of methylprednisolone (30 mg/kg) was administered at 10, 30, 120, 150 and 240 min. after three graded spinal cord injury. The primary outcome measure was 24-hour spinal cord lesion volumes estimated from spinal cord Na+ and K+ shifts. A single 30 mg/kg dose of methylprednisolone at 10 min. after injury significantly reduced 24-hour lesion volumes in injured rat spinal cords. However, any other methylprednisolone treatment starting 30 min. or more after injury had no effect on 24-hour lesion volumes compared to the vehicle control group. Moreover, delayed treatment increased lesion volumes in some cases. These results suggest that the NYU SCI model has a very short therapeutic window.

Animals↗
PubMed1999

Relationship between strength qualities and performance in standing and run-up vertical jumps.

BACKGROUND: The purpose of this investigation was to determine the relationships between the strength qualities of the leg extensor musculature and performance in vertical jumps (VJ) performed from a standing position and a run-up. METHODS: Twenty-nine males with experience in jumping activities were tested for vertical jumping capacities with a standing VJ (double leg takeoff) and run-up jumps from a 1, 3, 5 and 7 stride approach (single leg takeoff). The speed-strength and maximum strength qualities of the leg extensors were assessed by tests involving concentric, stretch-shortening cycle (SSC) and isometric muscular actions. Pearson's correlations and stepwise multiple regression was performed to describe the relationships with jumping performance. RESULTS: The speed-strength tests correlated significantly with both jump types (r = 0.55-0.82), but maximum strength did not. A drop jump test considered to measure reactive strength correlated more strongly with the run-up jump than the standing VJ. The standing VJ was best predicted by a low stretch load SSC test, whereas the run-up jump was best predicted by a model that also including the test of reactive strength. CONCLUSION: The role of maximum strength in jumping performance was not clear but speed-strength qualities were considered important. It was concluded that reactive strength is relatively more important for jumping from a run-up than for the standing VJ, and this should be reflected by appropriate training methods and test protocols for the assessment of athletes who jump.

Adult↗
PubMed1998

Bioactive and immunoreactive FSH concentrations in ewe and ram lambs over the first year of life.

Several studies suggest that the concentration of immunoreactive (I) FSH measured in peripheral plasma by radioimmunoassay does not always reflect the level of bioactive (B) hormone capable of eliciting a biological response (e.g. oestradiol synthesis by Sertoli cells in vitro). The aim of this study was to measure both B-FSH and I-FSH concentrations in male and female sheep during the first year of life, and to relate this to pubertal development. The hypothesis being tested was that B-FSH is present in both male and female sheep during the prepubertal period and that discrete changes in B-FSH are associated with the onset of puberty. Eight ewe lambs and eight rams lambs were blood sampled fortnightly form 2 to 52 weeks of age. All samples were assayed for B-FSH content. Pubertal development was monitored in ewe lambs from behavioural oestrus and from plasma progesterone concentrations, and in ram lambs from penile and testicular development and from plasma testosterone concentrations. Mean I-FSH concentrations varied significantly with time after birth, in both females and males (P < 0.01). In contrast, B-FSH was found to vary with time in females only (P < 0.01). Around the expected time of puberty in ram lambs (i.e. at 30-40 weeks of age), and thereafter, I-FSH concentrations were undetectable (< 0.2 ng ml-1), whereas the B-FSH concentrations were measurable at concentrations up to twice the assay detection limit (0.8 ng ml-1) until 38 weeks of age. In ewe lambs, but not ram lambs, there was a significant linear relationship between B-FSH and I-FSH values (R = 0.595; P < 0.005). When standardised about the time of puberty, B-FSH (P < 0.05) but not I-FSH was significantly higher in ewe lambs that failed to reach puberty. No differences for either B-FSH or I-FSH between pubertal and non-pubertal ram lambs were noted. In summary, B-FSH was soften measurable in plasma throughout prepubertal development in sheep and the concentrations often differed from those of I-FSH, especially in ram lambs. However, there appeared to be no discrete change in B-FSH that could be directly related to specific pubertal events. It is concluded that although FSH may be a prerequisite for prepubertal testicular development and/or ovarian follicular growth, it is not a critical factor in determining whether puberty is attained during the first year of life in this seasonally breeding species.

Aging↗
PubMed1998

Tumour necrosis factor-alpha-dependent regulation of prostaglandin endoperoxide synthase-2.

Tumour necrosis factor alpha (TNF-alpha)-mediated regulation of prostaglandin endoperoxide synthase-2 (PGHS-2) mRNA levels was examined in murine fibrosarcoma MCA-101 cells. We demonstrated that the formation of prostaglandin E2 (PGE2) is highly dependent on the expression of PGHS-2 enzyme in these cells. TNF-alpha-induced PGE2 production was evident after 12 h and was associated with a significant TNF-alpha-mediated increase in PGHS-2 immunoreactive protein. A specific PGHS-2 inhibitor, NS-398, completely abolished the TNF-alpha-mediated increase in PGE2 production, suggesting that the PGE2 formed in response to TNF-alpha was derived from PGHS-2. TNF-alpha-mediated PGHS-2 mRNA accumulation was observed at 1 h, remained elevated for 24 h, and was blocked by actinomycin D, indicating that TNF-alpha increases PGHS-2 gene transcription. A significant post-transcriptional mechanism also contributed to the increased PGHS-2 mRNA accumulation as the mRNA half-life was approximately 4-5 h in TNF-alpha-stimulated cells. Inhibition of protein tyrosine phosphatases (PTPs) and protein tyrosine kinases (PTKs) inhibited the TNF-alpha-mediated increase in PGHS-2 mRNA levels. We suggest that PTPs and PTKs play a role in the transcriptional and/or post-transcriptional mechanisms that contribute to the regulation of the PGHS-2 gene by TNF-alpha.

Animals↗
PubMed1998

Costs of hysterectomy: does surgical approach make a difference?

We wanted to determine the direct cost of hysterectomies by surgical approach and to estimate the impact on costs if more vaginal hysterectomies were substituted for abdominal hysterectomies for women under 50 years of age. Eleven Ontario (Canada) hospitals provided 1994 cost data based on 1376 hysterectomies. These data were applied to all hysterectomies performed in the province for women under 50 to estimate the cost of subtotal, vaginal (VH), or laparoscopically assisted vaginal hysterectomy (LAVH) relative to total abdominal hysterectomy (TAH). We determined the change in costs if TAHs in Ontario in 1994-1995 had been substituted by VH or LAVH. Teaching and community hospitals were considered separately. VH was less costly than TAH, subtotal, or LAVH. The direct cost for TAH at teaching hospitals was much higher than at community hospitals. Costs relative to TAH were higher for LAVH at community but not at teaching hospitals. From the population baseline rate of 25% VH, 5% LAVH, 10% subtotal, and 60% TAH, we estimated that increasing VH to 45% would lower costs by 2.4%; increasing LAVH to 25% would increase costs by 4.4%. VH is associated with lower costs than TAH or LAVH. However, the magnitude of the substitution and the extent of cost savings should ultimately be based on evaluation of patient outcomes.

Adult↗
PubMed1998

Octreotide as primary therapy for acromegaly.

The effects of octreotide (up to 5 yr) as primary treatment in 26 patients with acromegaly were compared with those in 81 patients with acromegaly who received octreotide as secondary or adjunctive therapy after previous surgery and/or pituitary radiation. These patients were part of a multicenter study that took place between 1989-1995. The study was divided into 3 phases beginning with a 1-month placebo-controlled treatment period followed by a 1-month washout period. In the second phase, patients were randomized to treatment with either 100 or 250 micrograms octreotide, sc, every 8 h for 6 months. Octreotide was then discontinued for 1 month and reinitiated at the lower dose for a total mean treatment duration of 39 months. The dose was titrated by each investigator to improve each patient's individual response, which included improvement in symptoms and signs of acromegaly as well as reduction of GH and insulin-like growth factor I (IGF-I) into the normal range. In the second phase of the study, in which patients were randomized to either 100 or 250 micrograms octreotide, three times daily, mean integrated GH and IGF-I concentrations after 3 and 6 months were equivalent in the primary and secondary treatment groups. During long term open label treatment, mean GH fell from 32.7 +/- 5.2 to 6.0 +/- 1.7 micrograms/L 2 h after octreotide injection in the primary therapy group and remained suppressed for a mean period of 24 months (range, 3-60 months). The mean final daily dose was 777 micrograms. In the patients receiving secondary treatment, mean GH fell from 30.2 +/- 7.6 to 5.6 +/- 1.1 micrograms/L after 3 months and remained suppressed for the remainder of the study (average dose, 635 micrograms daily). Mean IGF-I concentrations fell from 5.2 +/- 0.5 x 10(3) U/L (primary treatment group) and 4.7 +/- 0.4 x 10(3) U/L (secondary treatment group) to a mean of 2.2 +/- 0.3 x 10(3) U/L in both groups after 3 months of open label treatment and remained suppressed. IGF-I was reduced into the normal range during at least half of the study visits in 68% of the primary treatment group and in 62% of the secondary treatment group. Patients whose GH levels fell to at least 2 SD below the baseline mean GH were considered responders. There was no significant difference in the percentage of responders in the primary and secondary treatment groups (70% vs. 61%), nor was there a statistical difference in the mean GH concentrations between the groups. Symptoms of headache, increased perspiration, fatigue, and joint pain were reported at baseline by 46%, 73%, 69%, and 85%, respectively, of patients in the primary therapy group and improved during 3 yr of octreotide treatment in 50-100%. Similarly, these acromegaly-related symptoms were reported by 62%, 58%, 78%, and 60% of patients in the secondary therapy group, and improvement was noted in 62-88%. Pituitary magnetic resonance imaging scans were available in 13 of 26 patients in the primary treatment group before and after 6 months of octreotide treatment. Tumor shrinkage was observed in 6 of 13 patients, with reduction in tumor volume greater than 25% in only 3. Of 6 patients with documented tumor shrinkage, IGF-I was reduced into the normal range in 4 patients. Of the 7 remaining patients in whom tumor shrinkage was less than 10%, IGF-I was reduced into the normal range in 4 patients. Of the 7 remaining patients in whom tumor shrinkage was less than 10%, IGF-I was reduced into the normal range in 5 patients. The degree of tumor shrinkage did not correlate with the percent reduction in IGF-I or GH. In summary, octreotide was equally effective in 26 previously untreated acromegalic patients (primary treatment group) and 81 patients previously treated with either surgery or pituitary radiation (secondary treatment group). These observations call into question the current practice of surgical resection of all newly diagnosed GH-secreting pituitary adenomas regardless of the likelihood of cure. (AB

Acromegaly↗
PubMed1998

Expression and secretion of a biologically active glycoprotein hormone, ovine follicle stimulating hormone, by Pichia pastoris.

The methylotrophic yeast, Pichia pastoris, has been used to co-express recombinant genes formed by fusion of the mating factor-alpha (MFalpha) leader and ovine follicle stimulating hormone (oFSH) alpha and beta subunit coding sequences. Pichia strains carrying single copies of the two fusion genes secreted recombinant oFSH (roFSH) to concentrations of approximately 51.0 ng/ml and 17.5 ng/ml, measured by RIA or in vitro bioassay respectively, whereas a strain with two copies of the alpha and one copy of the beta subunit fusion genes secreted roFSH to concentrations of 61 ng/ml (RIA) and 22 ng/ml (bioassay). It appears that the Pichia-derived roFSH had about one-third the in vitro bioactivity of native oFSH or, alternatively, only one-third of the roFSH is bioactive. Measurements of secreted roFSH alpha and beta subunit concentrations indicated less than 10% of alpha and 25-33% of beta subunits were stably dimerized. The receptor binding properties of the roFSH resemble those of native oFSH. In summary this paper reports the production, by P. pastoris, of a heterodimeric glycoprotein hormone (roFSH) that has in vitro biological activity.

Animals↗
PubMed1998

Methylprednisolone or tirilazad mesylate administration after acute spinal cord injury: 1-year follow up. Results of the third National Acute Spinal Cord Injury randomized controlled trial.

OBJECT: A randomized double-blind clinical trial was conducted to compare neurological and functional recovery and morbidity and mortality rates 1 year after acute spinal cord injury in patients who had received a standard 24-hour methylprednisolone regimen (24MP) with those in whom an identical MP regimen had been delivered for 48 hours (48MP) or those who had received a 48-hour tirilazad mesylate (48TM) regimen. METHODS: Patients for whom treatment was initiated within 3 hours of injury showed equal neurological and functional recovery in all three treatment groups. Patients for whom treatment was delayed more than 3 hours experienced diminished motor function recovery in the 24MP group, but those in the 48MP group showed greater 1-year motor recovery (recovery scores of 13.7 and 19, respectively, p=0.053). A greater percentage of patients improving three or more neurological grades was also observed in the 48MP group (p=0.073). In general, patients treated with 48TM recovered equally when compared with those who received 24MP treatments. A corresponding recovery in self care and sphincter control was seen but was not statistically significant. Mortality and morbidity rates at 1 year were similar in all groups. CONCLUSIONS: For patients in whom MP therapy is initiated within 3 hours of injury, 24-hour maintenance is appropriate. Patients starting therapy 3 to 8 hours after injury should be maintained on the regimen for 48 hours unless there are complicating medical factors.

Activities of Daily Living↗
PubMed1998

Tyrosine phosphatase-dependent/tyrosine kinase-independent induction of nuclear factor-kappa B by tumor necrosis factor-alpha: effects on prostaglandin endoperoxide synthase-2 mRNA accumulation.

We previously have demonstrated that tumor necrosis factor-alpha (TNF-alpha) increases prostaglandin endoperoxide synthase-2 (PGHS-2) mRNA accumulation and tyrosine phosphorylation in the fibrosarcoma cell line, MCA-101. Tyrosine kinase inhibitor, genistein, and tyrosine phosphatase inhibitor, phenylarsine oxide (PAO), blocked TNF-alpha-mediated induction of PGHS-2 mRNA in these cells. Because the PGHS-2 promoter has a nuclear factor-kappa B (NF-kappa B) binding motif, which is important for PGHS-2 gene transcription in some cell types, we have evaluated the effects of tyrosine kinase inhibitors and PAO on TNF-alpha-induced NF-kappa B activation. TNF-alpha (1 nM) rapidly induced translocation of NF-kappa B, an event accompanied by degradation of inhibitory protein I kappa B-alpha. N-tosyl-L-phenylalanine chloromethyl ketone (TPCK), a serine protease inhibitor, inhibited I kappa B-alpha degradation and NF-kappa B activation in response to TNF-alpha in a dose-dependent manner (25, 50, 100 microM). TPCK also inhibited PGHS-2 mRNA accumulation. These data suggest that NF-kappa B contributed to PGHS-2 mRNA accumulation in MCA-101 cells stimulated with TNF-alpha. PAO (2.4 microM) completely abolished activation of NF-kappa B and degradation of I kappa B-alpha induced by TNF-alpha at a concentration that blocked PGHS-2 mRNA accumulation. However, four tyrosine kinase inhibitors, genistein, tyrphostin 47, herbimycin A and erbstatin, failed to block translocation of NF-kappa B and degradation of I kappa B-alpha. These data demonstrate that tyrosine kinase pathways are not required for TNF-alpha-induced NF-kappa B activation in MCA-101 cells and suggest that signaling via these pathways mediates TNF-alpha-induced PGHS-2 mRNA accumulation via an NF-kappa B-independent mechanism. Moreover, an upstream tyrosine phosphatase pathway may mediate PGHS-2 mRNA accumulation by TNF-alpha via an NF-kappa B-dependent mechanism.

Arsenicals↗