Caring for older veterans with chronic low back pain using a geriatric syndrome approach: Rationale and methods for the aging back clinics (ABC) trial.

The purpose of the ongoing trial is to improve care of older Veterans with chronic low back pain (CLBP, i.e., low back pain for ≥6 months on ≥ half the days). Current CLBP care is limited by being either overly spine-focused or non-specifically prescribed and both approaches frequently lead to suboptimal reduction in pain and improvement in function. Through prior studies we have laid the foundation for a patient-centered approach to care for older Veterans with CLBP in which the spine is a source of vulnerability but not the sole treatment target. The approach considers CLBP a geriatric syndrome, a final common pathway for the expression of multiple contributors rather than a disease of the spine. We describe here the rationale and design of a randomized controlled trial to test the efficacy of an older Veteran-centered approach to CLBP care in "Aging Back Clinics (ABCs)" compared with Usual Care (UC). Three hundred thirty Veterans age 65-89 with CLBP will be randomized to ABCs or UC and followed for 12 months after randomization. We will assess the impact of ABCs on our primary outcome of pain-associated disability with the Oswestry Disability Index at 6 and 12 months, and secondary outcomes of pain intensity, health-related quality of life, balance confidence, mobility and healthcare utilization. If shown efficacious, the approach tested in ABCs has the potential to transform the care of older adults with CLBP by improving the quality of life for millions, reducing morbidity and saving substantial healthcare costs.

Resistance to 1,25D-induced differentiation in human acute myeloid leukemia HL60-40AF cells is associated with reduced transcriptional activity and nuclear localization of the vitamin D receptor.

The anti-neoplastic effects of 1,25-dihydroxyvitamin D3 (1,25D) are well documented in numerous tumor cell systems and animal models of cancer. However, despite this pre-clinical success, the clinical use of 1,25D is currently impeded by the dose-limiting hypercalcemia, and the risk of development of resistance to 1,25D. In this study, we investigated the mechanism of resistance to 1,25D of HL60-40AF cells, a model of drug-resistant acute myeloid leukemia, derived from HL60 cells by cultivation in the presence of 1,25D. The data indicate that transcriptional activity of vitamin D receptor (VDR) in 40AF cells increases only briefly when the cells are treated with 1,25D, despite greater basal cellular levels of VDR protein in the resistant than in the 1,25D-sensitive cells. Analysis of the 40AF VDR mRNA sequence indicated alterations in the 5' untranslated region (UTR), but coding domain variations were not observed. When resistance to 1,25D-induced differentiation of 40AF cells was reversed by a combination of 1,25D with potentiators of differentiation (plant derived antioxidants and a p38MAPK inhibitor), an increase in the level of nuclear VDR, as well as an increase in CYP24 mRNA expression was observed. These data suggest that decreased ability of 1,25D to induce VDR nuclear localization and the consequent VDR target gene transcription may be an important reason for the resistance of 40AF cells to 1,25D. Further, our data show that VDR localization and phosphorylation can be increased by combining 1,25D with potentiators of differentiation. Analysis of the mechanisms that underlie the reduction and potentiation of 1,25D-mediated changes in VDR activity may lead to the identification of new cellular targets that enhance 1,25D-induced monocytic differentiation.

c-Jun N-terminal kinase 2 (JNK2) antagonizes the signaling of differentiation by JNK1 in human myeloid leukemia cells resistant to vitamin D.

1,25-Dihydroxyvitamin D3 (1,25D) induces differentiation of myeloid leukemia cells, but resistant cells are also encountered. We studied the mechanistic basis for the resistance in a model system using enhancers of 1,25D, the antioxidant carnosic acid and a kinase inhibitor SB202190. Knock-down (KD) of JNK2p54 unexpectedly increased the intensity of differentiation induced by the 1,25D, carnosic acid and SB202190 (DCS) combination. This was associated with upregulation of activated JNK1p46, and the transcription factors regulated by the JNK pathway, c-Jun, ATF2 and JunB, as well as C/EBP beta. In contrast, KD of JNK1p46 reduced the intensity of DCS-induced differentiation, and partially abrogated activation of c-Jun/AP-1 transcription factors.

Update on tizanidine for muscle spasticity and emerging indications.

BACKGROUND: Tizanidine hydrochloride, an alpha(2)-adrenergic receptor agonist, is a widely used medication for the treatment of muscle spasticity. Clinical studies have supported its use in the management of spasticity caused by multiple sclerosis (MS), acquired brain injury or spinal cord injury. It has also been shown to be clinically effective in the management of pain syndromes, such as: myofascial pain, lower back pain and trigeminal neuralgia. This review summarizes the recent findings on the clinical application of tizanidine. OBJECTIVE: Our objective was to review and summarize the medical literature regarding the evidence for the usefulness of tizanidine in the management of spasticity and in pain syndromes such as myofascial pain. METHODS: We reviewed the current medical and pharmacology literature through various internet literature searches. This information was then synthesized and presented in paragraph and table form. RESULTS/CONCLUSION: Tizanidine hydrochloride is a very useful medication in patients suffering from spasticity caused by MS, acquired brain injury or spinal cord injury. It can also be helpful in patients suffering from chronic neck and/or lower back pain who have a myofascial component to their pain. Doses should be started at low dose and gradually titrated to effect.

Calcitriol derivatives with two different side-chains at C-20. Part 4: further chain modifications that alter VDR-dependent monocytic differentiation potency in human leukemia cells.

Signaling of cell differentiation is one of the important physiological functions of the activated vitamin D receptor (VDR). Activation of the VDR can be achieved not only by 1alpha,25-dihydroxyvitamin D(3) (1,25D), the natural ligand, but also by a large number of its analogs. These include a category containing two side chains emanating at C-20, generally referred to as Gemini. The introduction of a cyclopropyl moiety as part of the pro-R side chain provides modified Gemini compounds with increased steric requirement and decreased chain flexibility; the biological consequences of this novel structural variant are subject of this investigation. In general, the resulting 1alpha,25-dihydroxy-(4-hydroxy-4-methyl-pentyl)-21,22-cis-cyclo-cholecalciferols reduced had differentiation and transcriptional potency and induced cell cycle arrest less efficiently, as shown by a decrease in G1/S ratio, when compared to 1,25D. Modifying their calcitriol side chain in the form of a 4-hydroxy-4-trifluoromethyl-5,5,5-trifluoropent-2-ynyl moiety, however, resulted in pronounced induction of differentiation in 1,25D-sensitive and moderate level of differentiation in 1,25D-resistant leukemia cells.

Regulation of C/EBPbeta isoforms by MAPK pathways in HL60 cells induced to differentiate by 1,25-dihydroxyvitamin D3.

C/EBPbeta is known to be important for monocytic differentiation and macrophage function. Here, we found that expression of all three C/EBPbeta isoforms induced in HL60 cells by 1,25-dihydroxyvitamin D3 (1,25D) was upregulated in a sustained manner that correlates with the appearance of monocytic phenotype and with the G1 phase cell cycle arrest. In 1,25D-resistant HL60-40AF cells, isoforms beta-1 and beta-3 were expressed at levels comparable to 1,25D-sensitive HL60-G cells, but isoform beta-2 was difficult to detect. Treatment of sensitive HL60 cells with 1,25D resulted in predominantly nuclear localization of C/EBP isoforms beta-2 and beta-3, while a large proportion of C/EBPbeta-1 remained in the cytoplasm. Attenuation of the MEK-ERK MAPK pathway by the inhibitor PD98059 markedly reduced the expression, 1,25D-induced phosphorylation and nuclear localization of C/EBPbeta-2 and C/EBPbeta-3. Interestingly, only the lower molecular mass isoforms of C/EBPbeta phosphorylated on Thr235 were found in the nuclei, while C/EBPbeta-1 was constitutively phosphorylated and was detected principally in the cytoplasmic fraction. Although the role of C/EBPbeta isoforms in 1,25D-induced differentiation is complex, our results taken together strongly suggest that the phosphorylation of C/EBPbeta isoforms on Thr235 takes place mainly via the MEK-ERK pathway and that C/EBPbeta-2 is the principal transcription factor in this cell system.

Assessing functional status: exploring the relationship between the multiple sclerosis functional composite and driving.

OBJECTIVE: To explore the relationship between the Multiple Sclerosis Functional Composite (MSFC), which is comprised of 3 clinical dimensions (arm and hand function, leg function and ambulation, cognition), and an everyday functional skill, driving performance. DESIGN: Cohort study. SETTING: Medical rehabilitation research organization. PARTICIPANTS: Twenty-nine individuals with documented multiple sclerosis (MS) and limited motor decrements. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Driving-related skills were measured by using the overall category rating from the Useful Field of View (UFOV) Test, its 3 subtests, the error and latency scores from the Neurocognitive Driving Test (NDT), subjective (self-report) and objective (Department of Motor Vehicles [DMV] reports) reported driving experience, and number of motor vehicle crashes. Within the group, differences were explored between participants rated as low risk versus moderate-high risk on the UFOV overall score and between participants who reported a change in driving habits after MS versus those who reported no change. RESULTS: The overall MSFC score correlated significantly with the UFOV overall score, the visual-information processing and selective attention subtests of the UFOV, the NDT latency score, as well as with the number of days a week the individual drove and the number of crashes reported by the DMV. An examination of the MSFC components revealed that the cognition component was significantly related to the UFOV overall score, all 3 subtests of the UFOV, and the NDT latency score. The arm and hand function component correlated significantly with NDT latency and the selective attention subtest of the UFOV. Individuals classified as low risk on the UFOV overall had more education, better MSFC scores, and lower NDT latency scores. Only the overall MSFC score distinguished those who reported a change in driving habits after onset of MS. CONCLUSIONS: Problems with everyday functional skills such as driving are accurately identified through the use of the overall MSFC and its components.

Motor vehicle crashes and violations among drivers with multiple sclerosis.

OBJECTIVE: To investigate differences in the incidence of motor vehicle crashes (MVCs) and violations among drivers with multiple sclerosis (MS) when cognitive impairment is present. DESIGN: Archival evaluation of Department of Motor Vehicles (DMV) records. SETTING: Medical rehabilitation research organization. PARTICIPANTS: Community-dwelling drivers, 27 subjects with documented MS (14 MS without cognitive impairment [MS-], 13 MS with cognitive impairment [MS+]) and 17 healthy control subjects, matched on age, sex, and driving experience. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Incidence of MVCs and motor vehicle violations as documented by DMV reports for the past 5 years. RESULTS: MS+ subjects showed a higher incidence of MVCs when compared with control and MS- subjects. No significant difference in the incidence of motor vehicle violations was observed between groups. CONCLUSIONS: The presence of cognitive impairment in drivers with MS can result in an increased risk of MVC involvement.

Telerehabilitation needs: a survey of persons with acquired brain injury.

OBJECTIVE: To survey individuals with acquired brain injury to assess multiple facets of interest, access, and familiarity necessary to implement new telerehabilitation technologies. DESIGN: Anonymous mail survey. SETTING: Community. PARTICIPANTS: Seventy-one respondents to a survey. These individuals had experienced acquired brain injury (predominantly severe traumatic brain injury [TBI]) and were living in the community. Surveys were mailed by a state chapter of the Brain Injury Association to a random selection of members with acquired brain injury. MAIN OUTCOME MEASURE: Survey designed specifically for this investigation. RESULTS: The survey responses indicate that there is great interest in the possibility of accessing telerehabilitative services among individuals with acquired brain injury. In particular, there was strong interest expressed in services that could be used to assist with problems in memory, attention, problem-solving, and activities of daily living. CONCLUSIONS: Telemedicine, and more specifically telerehabilitation, holds great promise as an adjunct to traditional clinical service delivery. Little research in this area has been applied, however, to individuals with acquired brain injuries. Although on the surface, telerehabilitation seems to be an appropriate assessment and treatment modality for individuals with brain injury, it will only succeed if those individuals have the interest-and the access-necessary to use new and evolving technologies.