Derivation of an occupational exposure limit for inorganic borates using a weight of evidence approach.

Inorganic borates are encountered in many settings worldwide, spurring international efforts to develop exposure guidance (US EPA, 2004; WHO, 2009; ATSDR, 2010) and occupational exposure limits (OEL) (ACGIH, 2005; MAK, 2011). We derived an updated OEL to reflect new data and current international risk assessment frameworks. We assessed toxicity and epidemiology data on inorganic borates to identify relevant adverse effects. International risk assessment frameworks (IPCS, 2005, 2007) were used to evaluate endpoint candidates: reproductive toxicity, developmental toxicity, and sensory irritation. For each endpoint, a preliminary OEL was derived and adjusted based on consideration of toxicokinetics, toxicodynamics, and other uncertainties. Selection of the endpoint point of departures (PODs) is supported by dose-response modeling. Developmental toxicity was the most sensitive systemic effect. An OEL of 1.6mgB/m(3) was estimated for this effect based on a POD of 63mgB/m(3) with an uncertainty factor (UF) of 40. Sensory irritation was considered to be the most sensitive effect for the portal of entry. An OEL of 1.4mgB/m(3) was estimated for this effect based on the identified POD and an UF of 1. An OEL of 1.4mgB/m(3) as an 8-h time-weighted average (TWA) is recommended.

International spinal cord injury musculoskeletal basic data set.

OBJECTIVES: To develop an International Spinal Cord Injury (SCI) Musculoskeletal Basic Data Set as part of the International SCI Data Sets to facilitate consistent collection and reporting of basic musculoskeletal findings in the SCI population. SETTING: International. METHODS: A first draft of an SCI Musculoskeletal Basic Data Set was developed by an international working group. This was reviewed by many different organizations, societies and individuals over 9 months. Revised versions were created successively. RESULTS: The final version of the International SCI Musculoskeletal Basic Data Set contains questions on neuro-musculoskeletal history before spinal cord lesion; presence of spasticity/spasms; treatment for spasticity within the last 4 weeks; fracture(s) since the spinal cord lesion; heterotopic ossification; contracture; the location of degenerative neuromuscular and skeletal changes due to overuse after SCI; SCI-related neuromuscular scoliosis; the method(s) used to determine the presence of neuromuscular scoliosis; surgical treatment of the scoliosis; other musculoskeletal problems; if any of the musculoskeletal challenges above interfere with activities of daily living. Instructions for data collection and the data collection form are freely available on the International Spinal Cord Society (ISCoS) website (www.iscos.org.uk). CONCLUSION: The International SCI Musculoskeletal Basic Data Set will facilitate consistent collection and reporting of basic musculoskeletal findings in the SCI population.

Human health risks from mercury exposure from broken compact fluorescent lamps (CFLs).

Human health risk to infants/toddlers and adults was evaluated based on two exposure scenarios from compact fluorescent lamp (CFL) breakage; first in a room with no ventilation and no clean-up, and second in a room with adequate ventilation and clean-up. Concentration data from multiple exposure scenarios tested in a study by Stahler et al. (2008) were compared to human toxicity benchmarks to calculate hazard quotients. For the no clean-up scenario, hazard quotients were generally less than 1, suggesting an unlikely health risk. When the room was ventilated and the broken CFL was cleaned-up, mercury concentrations were generally lower. A review of release scenarios, along with duration-adjusted toxicity benchmarks, indicated that few releases produced levels of concern, but some scenarios resulted in exceedance of risk targets and require further study. Uncertainties in this screening characterization include assumptions about room size, ventilation, age of lamp, the distribution of mercury in the room, and also the choice of the toxicity benchmarks used to develop the hazard quotients.

Efficacy and safety study of arbaclofen placarbil in patients with spasticity due to spinal cord injury.

STUDY DESIGN: Randomized, double-blind, placebo-controlled, two-period crossover. OBJECTIVES: To evaluate the efficacy and safety of arbaclofen placarbil (AP) in patients with spasticity secondary to spinal cord injury (SCI). SETTING: United States and Canada. METHODS: Patients received extended-release AP tablets 10, 20 or 30 mg every 12 h in one of two AP/placebo sequences, with 26 days of each treatment. The primary analysis compared Ashworth scale assessments of muscle tone between AP and placebo for the muscle group with maximum baseline Ashworth score. Secondary endpoints included a patient-rated Severity of Spasticity Scale. RESULTS: In the primary analysis, AP significantly improved Ashworth scores compared with placebo over the dosing interval: least-squares mean reduction versus placebo was 0.60 for AP 20 mg (P=0.0059) and 0.88 for AP 30 mg (P=0.0007). The difference was significant for the pre-morning dose time point, 12 h after the prior evening dose, indicating that efficacy was maintained throughout the dosing interval. Treatment differences for AP 10 mg versus placebo were not significant. Severity of Spasticity ratings were significantly reduced for the combined 20/30-mg group versus placebo (P=0.018). No statistically significant differences between AP and placebo were observed for muscle strength. AP-related AEs were generally mild to moderate in intensity, and none led to early withdrawal or were serious. CONCLUSION: AP was well tolerated at all investigated dosages and, when administered at doses of 20 or 30 mg twice daily, was efficacious in reducing spasticity due to SCI.

Intrathecal drug therapy using the Codman Model 3000 Constant Flow Implantable Infusion Pumps: experience with 17 cases.

OBJECTIVES: The objective of this study was to evaluate the accuracy, reliability, safety, and efficacy of the Codman Model 3000 Constant Flow Implantable Infusion Pump for intrathecal baclofen delivery as a therapeutic option for the treatment of severe spasticity. The distinctive features of this pump include a raised, easily palpable septum, a safety valve protecting the bolus pathway, no programmer needed, and no battery to fail. DESIGN: A total of 17 patients with spinal cord injury, multiple sclerosis, or cerebral palsy were implanted with this pump. The accuracy of the pump and drug treatment efficacy was determined at each visit and adjustments to the dosages were made as required. All the intrathecal drug delivery system complications were reviewed. RESULTS: The expected efficacy was achieved. The accuracy of the implanted pumps ranged from 90-97% (average 94%). There were no complications due to primary pump problems. The complications reported are similar to other implantable infusion devices and include dehiscence of the suture line, pressure ulcer development, formation of seroma, inversion of the pump, baclofen overdose, and catheter failures. CONCLUSION: The Codman Model 3000 Constant Flow Implantable Infusion Pump is an accurate, reliable, and convenient option for patients needing intrathecal baclofen therapy, with complications similar to other available pumps.

Alpha adrenergic and serotonergic agents in the treatment of spastic hypertonia.

In the treatment of patients with problematic spasticity, it is important to consider the following steps: 1. Establish the functional impact of the spasticity. 2. Identify the functional goal to be achieved by treatment. 3. Eliminate any remediable spasticity aggravating factors. 4. Evaluate the effects of previous antispasticity treatments. 5. Consider nonpharmacologic and pharmacologic treatments. 6. Initiate therapy with a low dosage, and titrate judiciously. 7. Stop the titration when functional goal is achieved. 8. If goal is not achieved or if side effects are intolerable, consider a second medication.

Erythrocyte margination and sedimentation in skeletal muscle venules.

Previous studies in skeletal muscle of the dog and cat have shown that venous vascular resistance changes inversely with blood flow and may be due mainly to red blood cell aggregation, a phenomenon present in these species. To determine whether red blood cell axial migration and sedimentation contribute to this effect, we viewed either vertically or horizontally oriented venules of the rat spinotrapezius muscle with a horizontally oriented microscope during acute arterial pressure reduction. With normal (nonaggregating) rat blood, reduction of arterial pressure did not significantly change the relative diameter of the red blood cell column with respect to the venular wall. After induction of red blood cell aggregation in the rat by infusion of Dextran 500, red blood cell column diameter decreased up to 35% at low pseudoshear rates (below approximately 5 s(-1)); the magnitude was independent of venular orientation. In vertically oriented venules, the plasma layer was symmetrical, whereas in horizontally oriented venules, the plasma layer formed near the upper wall. We conclude that, although red blood cell axial migration and sedimentation develop in vivo, they occur only for larger flow reductions than are needed to elicit changes in venous resistance.

Effect of erythrocyte aggregation on velocity profiles in venules.

A recent whole organ study in cat skeletal muscle showed that the increase in venous resistance seen at reduced arterial pressures is nearly abolished when the muscle is perfused with a nonaggregating red blood cell suspension. To explore a possible underlying mechanism, we tested the hypothesis that red blood cell aggregation alters flow patterns in vivo and leads to blunted red blood cell velocity profiles at reduced shear rates. With the use of fluorescently labeled red blood cells in tracer quantities and a video system equipped with a gated image intensifier, we obtained velocity profiles in venous microvessels (45-75 microm) of rat spinotrapezius muscle at centerline velocities between 0.3 and 14 mm/s (pseudoshear rates 3-120 s(-1)) under normal (nonaggregating) conditions and after induction of red blood cell aggregation with Dextran 500. Profiles are nearly parabolic (Poiseuille flow) over this flow rate range in the absence of aggregation. When aggregation is present, profiles are parabolic at high shear rates and become significantly blunted at pseudoshear rates of 40 s(-1) and below. These results indicate a possible mechanism for increased venous resistance at reduced flows.

Surgical treatment of pressure ulcers: 20-year experience.

OBJECTIVE: To review the outcomes of surgical management of spinal cord injury (SCI) patients with severe pressure ulcers and to examine likely risk factors for recurrence of pressure ulcers. DESIGN: A retrospective medical record review. SETTING: An SCI unit in a tertiary care facility. PATIENTS: All admissions to the SCI unit for grade 4 pressure ulcers from 1976 to 1996. INTERVENTION: Surgical repair of pressure ulcers. MAIN OUTCOME MEASURE: Complication and recurrence rates of pressure ulcers. RESULTS: Of 598 pressure ulcers, 468 were pelvic area ulcers, of which 431 (92%) were treated surgically. Fifty-three had split-thickness skin grafting, and 380 were treated with 421 surgical procedures (253 fasciocutaneous or cutaneous flaps, 93 muscle or musculocutaneous flaps, 75 primary closures). One hundred eight (26%) of these procedures required some bone work. Suture line dehiscence occurred in 130 (31%), with 45 (11%) requiring reconstruction and 8 (2%) requiring skin grafting to heal. At discharge, 38 (9%) of these pelvic ulcers had not healed. Recurrent admissions occurred in 90 (54%) of the patients. Recurrence of ulcers at the same site occurred in 31% of the total number of ulcers and at a different site in 21%. At the time of the 415 admissions, 336 (81%) of the patients were unemployed; 159 (38%) had grade 8 or lower level of education; and 226 (55%) lived alone or with family but were independent in self-care. Of the 168 patients studied, 45 (27%) were aboriginal (Canadian native), and 59 (35%) had a history of drug or alcohol abuse. CONCLUSIONS: The vast majority of severe pressure ulcers were surgically treated. Complication and recurrence rates are similar to previous reports. Psychosocial problems (unemployment, low level of education, drug or alcohol abuse, poverty in the native communities) appear to increase the risk for pressure ulcer development.

Diameter changes in skeletal muscle venules during arterial pressure reduction.

Previous studies in skeletal muscle have shown a substantial (>100%) increase in venous vascular resistance with arterial pressure reduction to 40 mmHg, but a microcirculatory study showed no significant venular diameter changes in the horizontal direction during this procedure. To examine the possibility of venular collapse in the vertical direction, a microscope was placed horizontally to view a vertically mounted rat spinotrapezius muscle preparation. We monitored the diameters of venules (mean diameter 73. 8 +/- 37.0 microm, range 13-185 microm) oriented horizontally and vertically with a video system during acute arterial pressure reduction by hemorrhage. Our analysis showed small but significant (P < 0.0001) diameter reductions of 1.0 +/- 2.5 microm and 1.8 +/- 3. 1 microm in horizontally and vertically oriented venules, respectively, upon reduction of arterial pressure from 115.0 +/- 26. 3 to 39.8 +/- 12.3 mmHg. The venular responses were not different after red blood cell aggregation was induced by Dextran 500 infusion. We conclude that diameter changes in venules over this range of arterial pressure reduction are isotropic and would likely increase venous resistance by <10%.

Walking index for spinal cord injury (WISCI): an international multicenter validity and reliability study.

STUDY DESIGN: Construction of an international walking scale by a modified Delphi technique. OBJECTIVE: The purpose of the study was to develop a more precise walking scale for use in clinical trials of subjects with spinal cord injury (SCI) and to determine its validity and reliability. SETTING: Eight SCI centers in Australia, Brazil, Canada (2), Korea, Italy, the UK and the US. METHODS: Original items were constructed by experts at two SCI centers (Italy and the US) and blindly ranked in an hierarchical order (pilot data). These items were compared to the Functional Independence Measure (FIM) for concurrent validity. Subsequent independent blind rank ordering of items was completed at all eight centers (24 individuals and eight teams). Final consensus on rank ordering was reached during an international meeting (face validation). A videotape comprised of 40 clips of patients walking was forwarded to all eight centers and inter-rater reliability data collected. RESULTS: Kendall coefficient of concordance for the pilot data was significant (W=0. 843, P<0.001) indicating agreement among the experts in rank ordering of original items. FIM comparison (Spearman's rank correlation coefficient=0.765, P<0.001) showed a theoretical relationship, however a practical difference in what is measured by each scale. Kendall coefficient of concordance for the international blind hierarchical ranking showed significance (W=0.860, P<0.001) indicating agreement in rank ordering across all eight centers. Group consensus meeting resulted in a 19 item hierarchical rank ordered 'Walking Index for Spinal Cord Injury (WISCI)'. Inter-rater reliability scoring of the 40 video clips showed 100% agreement. CONCLUSIONS: This is the first time a walking scale for SCI of this complexity has been developed and judged by an international group of experts. The WISCI showed good validity and reliability, but needs to be assessed in clinical settings for responsiveness.

BOLD MRI of the human cervical spinal cord at 3 tesla.

The feasibility of functional MRI of the spinal cord was investigated by carrying out blood oxygen-level dependent (BOLD) imaging of the human cervical spinal cord at a field of 3 T. BOLD imaging of the cervical spinal cord showed an average intensity increase of 7.0% during repeated exercise with the dominant hand with a return to baseline during rest periods. The areas of activation were predominantly on the same side of the spinal cord as the hand performing the exercise, between the levels of the sixth cervical and first thoracic spinal cord segments. The direct correspondence between these areas and those involved with the transmission of motor impulses to the hand, and reception of sensory information from the hand, demonstrates that spinal functional magnetic resonance imaging is feasible. Magn Reson Med 42:571-576, 1999.

Analgesics. Opioids, adjuvants, and others.

The purpose of this article is to summarize the main categories of pain-relieving medications. The authors review a number of analgesic preparations and treatments, with special emphasis on advantages, precautions, limitations, and various routes of administration.

Antispasticity medications.

The article illustrates a practical approach to the challenging management of problematic, generalized spasticity. Use of dose titration to achieve symptomatic relief is described. Currently approved pharmaceuticals used as antispasticity agents and muscle relaxants and other medications with antispasticity effects are reviewed.

Intrathecal drug therapy.

The direct application of drugs for non-hospitalized patients became a practical therapeutic modality with the advent of implantable drug delivery devices, or "pumps". This article describes the use of pumps for the intrathecal infusion of baclofen, morphine and clonidine.

Urinary and gastrointestinal systems medications.

This article reviews the medical management of the neurogenic bladder and bowel. The drugs discussed specifically affect detrusor instability, detrusor weakness, high urethral pressure, low urethral closure pressure, inflammatory cystitis, and chronic constipation.

Intravenous pamidronate attenuates bone density loss after acute spinal cord injury.

OBJECTIVE: To compare the effects of a 6-month treatment with intravenous pamidronate (30-mg infusion once per month) to conventional rehabilitation without pamidronate on bone density of the spine and leg bones and on the excretion rate of N-telopeptide, a urinary marker of bone catabolism, in acutely spinal cord injured patients. DESIGN: A nonrandomized control trial in which 24 spinal cord injured subjects entered the study within 6 weeks of their injury. Fourteen subjects received pamidronate; 10 did not. OUTCOME MEASURES: Bone density measurements by dual x-ray absorptiometry were performed before the initial treatment (within 6 weeks of the injury) and at 3, 6, and 12 months postinjury and was the primary efficacy parameter. Urine for N-telopeptide levels was the secondary efficacy parameter. RESULTS: After acute spinal cord injury, patients treated with intravenous pamidronate had significantly less bone density loss compared with those who did not receive pamidronate (parametric ANOVA, p<.02). Also, ambulatory subjects had significantly less bone density loss over the study period (p<.05) than nonambulatory subjects. In general, a high excretion level of the urinary bone-breakdown product N-telopeptide was found before intravenous pamidronate treatment, followed by a dramatic reduction in excretion after pamidronate treatment. Ambulatory subjects excreted significantly less N-telopeptide than motor-complete subjects at all time points. CONCLUSION: Intravenous pamidronate treatment and ambulatory ability in the first 6 months after an acute spinal cord injury prevents bone density loss.

Risk of avascular necrosis following short term megadose methylprednisolone treatment.

We conducted a prospective cohort study to determine whether administration of large doses of the corticosteroid methylprednisolone following spinal cord injury as recommended in the National Acute Spinal Cord Injury Study-2 (NASCIS-2) protocol results in an increased incidence of avascular necrosis (AVN) of the femoral or humeral head. All subjects were patients treated by a spinal cord injury physician in an Acute Spinal Cord Injury Unit between 1989 and 1996 where some received the megadose steroids while others did not. Patients younger than 15 years and older than 75 years were excluded, as were those with any hip or shoulder disease, with pelvic fracture, or with a history of predisposition to AVN by hip dislocation, excessive alcohol consumption, previous high dose steroid use, or systemic lupus erythematosus. Screening for AVN of the femoral and humeral heads was performed at a minimum of 6 months following injury, using magnetic resonance imaging (MRI). The films were read by a radiologist blinded to the treatment protocol received by the individual subject. Among the 59 spinal cord injured patients who received steroids (age 15-64 years (mean 32 years)), five were female. Among the 32 spinal cord injured subjects who did not receive steroids (age 16 to 65 years (mean 34 years)), seven were female. There was no case of AVN found in either group. Using binomial distribution, we conclude that the true incidence of AVN among the methylprednisolone treated group is less than 5% (alpha < 0.05) and therefore continue to recommend short term (24 h) methylprednisolone therapy.

Relationship of the antispasticity effect of tizanidine to plasma concentration in patients with multiple sclerosis.

BACKGROUND: Spasticity is a serious problem in multiple sclerosis (MS) and many patients do not achieve a satisfactory response to currently available oral antispasticity drugs. Tizanidine hydrochloride, an alpha 2-noradrenergic agonist, has been shown to have an antispasticity effect in single center trials of patients with MS. OBJECTIVE: To compare plasma concentrations of tizanidine with objective measures of muscle tone in patients with MS with moderate to severe spasticity. SETTING: Ten centers, all tertiary referral centers for the specialized treatment of patients with MS, in the United States and Canada. DESIGN: A randomized, double-blind, placebo-controlled, dose-response study of tizanidine hydrochloride (8 or 16 mg). PATIENTS: One hundred forty-two patients with spastic MS who were not taking any interfering medication, such as an antispasticity drug or other alpha-noradrenergic agonist, entered the trial. RESULTS: Tizanidine treatment reduced muscle tone significantly, as shown by improved Ashworth scores and increased knee swing amplitude recorded by the pendulum test, both of which correlated significantly with plasma concentration. Placebo had no significant effect on muscle tone. Dizziness, drowsiness, dry mouth, and fatigue were reported most often in the group treated with tizanidine at peak plasma concentration. CONCLUSIONS: Tizanidine reduces spasticity in MS, and both therapeutic effects and side effects are related to the plasma drug levels.

Cyclical etidronate: its effect on bone density in patients with acute spinal cord injury.

OBJECTIVE: To compare the effects of a 30-week trial of cyclical etidronate therapy (starting within 6 weeks of spinal cord injury [SCI] and conventional rehabilitation without etidronate treatment on the bone density of the lumbar spine and lower extremities of SCI patients. DESIGN: Prospective, randomized control trial. SETTING: Tertiary care, inpatient rehabilitation center. PATIENTS: Acute SCI, within 6 weeks of injury. Thirteen SCI subjects were recruited; 6 were assigned randomly to receive etidronate and 7 to receive conventional treatment. INTERVENTION: Etidronate, 800 mg orally, once per day for 2 weeks of 15 weeks, repeated once. MAIN OUTCOME MEASURES: Dual X-ray absorptiometry of the spine, hip, distal femur, and proximal tibia measured at baseline, 6 months, and 12 months. RESULTS: A significant interaction between etidronate treatment and ambulatory status over time was observed in the bone density of the patients after SCI (p = .0003). The patients who became ambulatory and received etidronate treatment had a preservation of bone density as compared to all other patients who showed a loss of bone density over time. The loss of bone density occurred in the leg bones, not the spine. Cyclical etidronate treatment was tolerated well without adverse or side effects. CONCLUSION: Cyclical etidronate is a feasible treatment and may prevent osteoporosis associated with SCI in patients who eventually walk.