A cross-sectional study of walking, balance and upper limb assessment scales in people with cervical dystonia.

Cervical dystonia (CD) is a neurological movement disorder causing the neck to move involuntarily away from the neutral position. CD is a network disorder, involving multiple brain areas and, therefore, may impair movement in parts of the body other than the neck. This study used clinical assessments to investigate walking, balance and upper limb function (UL) in people with CD; the reliability of scoring these assessments and examined for relationship between CD severity, usual exercise and clinical assessments. We conducted a prospective observational cohort study of participants with isolated, focal, idiopathic CD. Participants were assessed by experienced physiotherapists and completed three questionnaires and eight clinical assessments of fear of falling, balance confidence, walking, balance, UL function and usual exercise. Results were compared to published data from healthy adults and other neurological populations. Twenty-two people with mild to moderate CD participated. Fear of falling, gross UL function and usual exercise were worse in people with CD compared with healthy adults, while walking, balance and distal UL function were similar to healthy populations. All assessments were reliably performed by physiotherapists, and we found no correlations between the severity of dystonia or usual exercise and performance on the physical assessments. Routine performance of clinical assessment of walking and balance are likely not required in people with mild to moderate CD; however, fear of falling and gross upper limb function should be assessed to determine any problems which may be amenable to therapy.

Tailoring the homing capacity of human Tregs for directed migration to sites of Th1-inflammation or intestinal regions.

Cell-based therapy with CD4+ FOXP3+ regulatory T cells (Tregs) is a promising strategy to limit organ rejection and graft-vs-host disease. Ongoing clinical applications have yet to consider how human Tregs could be modified to direct their migration to specific inflammation sites and/or tissues for more targeted immunosuppression. We show here that stable, homing-receptor-tailored human Tregs can be generated from thymic Tregs isolated from pediatric thymus or adult blood. To direct migration to Th1-inflammatory sites, addition of interferon-γ and IL-12 during Treg expansion produced suppressive, epigenetically stable CXCR3+ TBET+ FOXP3+ T helper (Th)1-Tregs. CXCR3 remained expressed after injection in vivo and Th1-Tregs migrated efficiently towards CXCL10 in vitro. To induce tissue-specific migration, addition of retinoic acid (RA) during Treg expansion induced expression of the gut-homing receptors α4ß7-integrin and CCR9. FOXP3+ RA-Tregs had elevated expression of the functional markers latency-associated peptide and glycoprotein A repetitions predominant, increased suppressive capacity in vitro and migrated efficiently to healthy and inflamed intestine after injection into mice. Homing-receptor-tailored Tregs were epigenetically stable even after long-term exposure to inflammatory conditions, suppressive in vivo and characterized by Th1- or gut-homing-specific transcriptomes. Tailoring human thymic Treg homing during in vitro expansion offers a new and clinically applicable approach to improving the potency and specificity of Treg therapy.

Validation of Fear of Falling and Balance Confidence Assessment Scales in Persons With Dystonia.

BACKGROUND AND PURPOSE: Falls are problematic for people living with neurological disorders and a fear of falling can impact on actual falls. Fear of falling is commonly assessed using the Falls Self-Efficacy Scale International (FES-I) or the Activities-specific Balance Confidence (ABC) Scale. These scales can predict risk of falling. We aimed to validate the FES-I and the ABC in persons with dystonia. METHODS: We conducted an online survey of people with dystonia, collecting information on demographics, 6-month falls history, dystonia disability, and the FES-I and ABC scales. Scales were validated for structural validity and internal consistency. We also examined goodness-of-fit, convergent validity, and predictive validity, and determined cutoff scores for predicting falls risk. RESULTS: Survey responses (n = 122) showed that both FES-I and ABC scales have high internal validity and convergent validity with the Functional Disability Questionnaire in persons with dystonia. Each scale examines a single factor, fear of falling (FES-I) and balance confidence (ABC). At least one fall was reported by 39% of participants; the cutoff value for falls risk was found to be 29.5 and 71.3 for the FES-I and the ABC respectively. DISCUSSION AND CONCLUSIONS: The FES-I and the ABC scales are valid scales to examine fear of falling and balance confidence in persons with dystonia. Fear of falling is high and balance confidence is low and both are worse in those with dystonia who have previously fallen.Video Abstract available for more insights from the authors (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A182).

ATP1A3 related disease manifesting as rapid onset dystonia-parkinsonism with prominent myoclonus and exaggerated startle.

We report ATP1A3-associated rapid-onset dystonia-parkinsonism with an atypical presentation including myoclonus and exaggerated startle in four patients. Their prominence over parkinsonism prompted consideration of a syndromic diagnosis of myoclonus dystonia. ATP1α3 dysfunction in GABAergic neurons could explain these examination findings. The spectrum of ATP1A3-associated movement disorders includes myoclonus-dystonia.

MRI of congenital and developmental abnormalities of the knee.

The knee joint is the one of the most common locations for congenital and developmental musculoskeletal abnormalities. Initial imaging of the knee joint should always begin with conventional radiographs. However, evaluation of the bone marrow, cartilaginous, ligamentous, and other soft-tissue components of the knee joint are better characterized with magnetic resonance imaging (MRI). We present the MRI findings of prevalent congenital and developmental abnormalities in the paediatric knee with particular emphasis on the components of the growing skeleton.

Botulinum toxin assessment, intervention and aftercare for cervical dystonia and other causes of hypertonia of the neck: international consensus statement.

Dystonia in the neck region can be safely and effectively reduced with injections of Botulinum neurotoxin-A and B. People with idiopathic cervical dystonia have been studied the most. Benefits following injection include increased range of movement at the neck for head turning, decreased pain, and increased functional capacity (Class I evidence, level A recommendation). The evidence for efficacy and safety in patients with secondary dystonia in the neck is unclear based on the lack of rigorous research conducted in this heterogeneous population (level U recommendation). Psychometrically sound assessments and outcome measures exist to guide decision-making (Class I evidence, level A recommendation). Much less is known about the effectiveness of therapy to augment the effects of the injection (Class IV, level U recommendation). More research is needed to answer questions about safety and efficacy in secondary spastic neck dystonia, effective adjunctive therapy, dosing and favourable injection techniques.

Botulinum toxin assessment, intervention and aftercare for lower limb disorders of movement and muscle tone in adults: international consensus statement.

Lower limb disorders of movement and muscle tone in adults significantly impact quality of life. The management of the patient with hypertonia is complex and requires a multidisciplinary team working with the patient and family/carers. Botulinum neurotoxin type A (BoNT-A) has been used as a component of this management to reduce lower limb hypertonia, increase passive range of motion and reduce associated pain and requirements for bracing. Adjunctive treatments to augment the effect of BoNT-A include electrical muscle stimulation of the injected muscles and stretching. When determining suitability for injection, the patient's main goals for intervention need to be established. Muscle overactivity must be distinguished from contracture, and the effect of underlying muscle weakness taken into account. Explanation of the injection process, potential adverse effects and post-injection interventions is essential. Assessment at baseline and post-treatment of impairments such as hypertonia, range of motion and muscle spasm are appropriate; however, the Goal Attainment Scale and other validated patient-centred scales can also be useful to assess therapy outcomes. In the future, initiatives should be directed towards examining the effectiveness of BoNT treatment to assist with achievement of functional and participation goals in adults with hypertonia and dystonia affecting the lower limb.

Botulinum toxin assessment, intervention and aftercare for paediatric and adult niche indications including pain: international consensus statement.

Evidence is emerging for the use of botulinum neurotoxin type-A (BoNT-A) for niche indications including pain independent of spasticity. Pain indications such as chronic nociceptive back pain, piriformis syndrome, chronic myofascial pain, pelvic pain, complex regional pain syndrome, facial pain and neuropathic pain are outlined in this paper. Of these, class I evidence is available for the treatment of chronic nociceptive low back pain, piriformis syndrome, myofascial pain, facial pain, neuropathic pain and plantar fasciitis. Peri-operative use of BoNT-A is emerging, with indications including planning for surgery and facilitating surgery, as well as healing and improving analgesia post-operatively. Evidence is limited, although there are some reports that clinicians are successfully using BoNT-A peri-operatively. There is class I evidence showing pre-operative use of BoNT-A has a beneficial effect on outcomes following adductor-release surgery. The use of BoNT for treatment of tremor, other than neck tremor in the setting of cervical dystonia, including evidence for upper limb tremor, cranial tremor and non-dystonic neck tremor is reviewed. The evidence is variable at this stage, and further study is required to develop definitive recommendations for the clinical utility of BoNT-A for these indications.

Cloning of a T cell growth factor that interacts with the beta chain of the interleukin-2 receptor.

A cytokine was identified that stimulated the proliferation of T lymphocytes, and a complementary DNA clone encoding this new T cell growth factor was isolated. The cytokine, designated interleukin-15 (IL-15), is produced by a wide variety of cells and tissues and shares many biological properties with IL-2. Monoclonal antibodies to the beta chain of the IL-2 receptor inhibited the biological activity of IL-15, and IL-15 competed for binding with IL-2, indicating that IL-15 uses components of the IL-2 receptor.

Myoclonus-dystonia: significance of large SGCE deletions.

Myoclonus-dystonia (M-D) is an autosomal-dominant movement disorder caused by mutations in SGCE. We investigated the frequency and type of SGCE mutations with emphasis on gene dosage alterations and explored the associated phenotypes. We tested 35 M-D index patients by multiplex ligation-dependent probe amplification (MLPA) and genomic sequencing. Mutations were found in 26% (9/35) of the cases, all but three with definite M-D. Two heterozygous deletions of the entire SGCE gene and flanking DNA and a heterozygous deletion of exon 2 only were detected, accounting for 33% (3/9) of the mutations found. Both large deletions contained COL1A2 and were additionally associated with joint problems. Further, we discovered one novel small deletion (c.771_772delAT, p.C258X) and four recurrent point mutations (c.289C>T, p.R97X; c.304C>T, p.R102X; c.709C>T, p.R237X; c.1114C>T, p.R372X). A Medline search identified 22 articles on SGCE mutational screening. Sixty-four unrelated M-D patients were described with 41 different mutations. No genotype-phenotype association was found, except in patients with deletions encompassing additional genes. In conclusion, a rigorous clinical preselection of patients and careful accounting for non-motor signs should precede mutational tests. Gene dosage studies should be included in routine SGCE genetic testing.

Prevalence of workplace violence against nurses in Hong Kong.

OBJECTIVES: To determine the prevalence and nature of workplace violence against nurses, and how nurses deal with such aggression; and to identify the risk factors related to violence in the hospital environment. DESIGN: Cross-sectional questionnaire study. SETTING: University teaching hospital, Hong Kong. PARTICIPANTS: All nursing staff in the hospital, except nurses who were unable to read Chinese or who did not have patient contact (eg those worked in administrative positions), were invited to complete a questionnaire. MAIN OUTCOME MEASURES: Demographic data of the respondents, incidence of and risk factors contributing to workplace violence. RESULTS: A total of 420 nurses returned the completed questionnaire (response rate, 25%). Three hundred and twenty (76%; 95% confidence interval, 72-80%) nurses reported abuse of any kind--verbal abuse, 73%; bullying, 45%; physical abuse, 18%; and sexual harassment, 12%. Most (82%) nurses who experienced verbal abuse tended to confide in friends, family members, or colleagues. Some (42%) ignored the incident. Risk factors for workplace violence included: working in male wards and in certain specialties such as the Accident and Emergency Department, Community Nursing Service, and the Orthopaedics and Traumatology Department. CONCLUSION: Workplace violence against nurses is a significant problem in Hong Kong. Further large-scale studies should be conducted to more closely examine the problem.

Regulatory verification on safe use of cytotoxic drugs in veterinary clinics and animal hospitals.

BACKGROUND: Veterinarians are increasingly being asked to provide chemotherapy for veterinary patients. However, chemotherapy agents have cytotoxic effects that can pose a health risk to workers from exposure. There are no published studies examining cytotoxic drug (CTD) contamination in veterinary practices in Australia. METHODS: CTD use at 13 veterinary clinics and animal hospitals across New South Wales (NSW) was verified for compliance with Work, Health and Safety (WHS) legislation on the effectiveness of exposure control measures. Surface swab sampling was performed to detect the restricted carcinogen cyclophosphamide and seven other CTD. A total of 73 surface swab samples were collected from nine locations associated with CTD delivery, storage, treatment and waste disposal at four veterinary practices, with repeat sampling at two veterinary practices. RESULTS: Compliance with WHS legislation for systematic chemical management, including procedures for safe use of carcinogens, in veterinary practices was high: 4 of the 10 key clauses in WHS chemical management were complied with at all 13 verified workplaces. Surface contamination was detected in three locations, with levels of CTD contaminants ranging from 3.54 to 89 ng per sample. DISCUSSION: Results showed that, in general, there were safe systems in place to work with CTD in the veterinary practices that were verified in NSW. Areas for improvement were mainly in administrative measures related to hazardous chemical management. Particular attention should be given to raising awareness of the intrinsic hazards of CTD, through training and hazard information provision to staff.

Functional gait disorder.

Gait disorder is a common accompaniment of functional neurologic disorders. The diagnosis of a functional or psychogenic gait is complex. It requires a sound knowledge of the range of phenomenology observed in organic movement disorders, the ability to evaluate and diagnose nonmovement disorder neurologic symptoms and signs, but additionally knowledge of potential musculoskeletal causes of gait disturbance. A stepwise approach to the analysis of the phenomenology and separation into four (sometimes overlapping) psychogenic gait syndromes is suggested to aid diagnosis: (1) movement disorder mimics; (2) neurologic (nonmovement disorder) mimics; (3) musculoskeletal or biomechanical mimics; and (4) isolated disequilibrium or balance disorders. Accurate diagnosis can lead to effective therapy.

Four cases of orthostatic myoclonus.

Orthostatic unsteadiness (unsteadiness on standing) is a relatively common symptom and can have neurological or non-neurological causes. Glass et al. have recently described a syndrome presenting with unsteadiness or leg jerking during standing or gait initiation difficulty which they have termed orthostatic myoclonus (OM). OM is a disabling syndrome but potentially treatable. It may develop on the background of neurodegenerative disease; other causes include pro-myoclonic drugs such as tricyclic antidepressants. In order to increase awareness of this syndrome, we report four patients with electrophysiologically confirmed OM who were referred to the movement disorder unit for lower limb tremor studies. All four patients presented with unsteadiness on standing. There were no signs suggestive of neurodegenerative disease and three of the patients had a provisional diagnosis of orthostatic tremor. The diagnosis of OM was supported by a surface electromyography showing 9-16Hz, non-rhythmic muscle bursts with burst duration of 50-100ms during standing. OM is unrecognised by many physicians as a cause of orthostatic intolerance. The most common syndrome with which OM may be confused is orthostatic tremor. A correct diagnosis is important as it may respond to treatment with clonazepam, gabapentin or piracetam.

Acute and reversible micrographia in a patient possibly due to cerebral ischaemia.

We report a patient who developed acute and reversible micrographia, presumably due to cerebral ischaemia, on a background of mutism following a pharyngo-laryngectomy 10 years earlier. Magnetic resonance (MR) imaging showed chronic small vessel disease without evidence of an acute ischaemic lesion on diffusion-weighted sequences. Our patient's micrographia improved significantly within 12 days of symptom onset. The MR imaging was performed within 5 days of symptom onset, suggesting that the lesion was either too small for detection or had resolved on diffusion-weighted sequences.

Lesion of thalamic centromedian--parafascicular complex after chronic deep brain stimulation.

A patient with PD who exhibited disabling tremor and prominent dyskinesia underwent deep brain stimulation (DBS) of the left thalamic ventral intermediate nucleus. The electrode migrated and was replaced but with suboptimal clinical response. Two years later, postmortem analysis found the second electrode tip had entered the thalamic centromedian-parafascicular complex. There was a small thalamotomy and cell loss exceeding that found in PD. Thalamic damage may occur in association with DBS for PD.

Aromatic retinoic acid analogues. Synthesis and pharmacological activity.

Aromatic analogues of (all-E)- and 13(Z)-retinoic acids have been synthesized as potential chemopreventive agents for the treatment of epithelial cancer. In the E series, (1E,3E)-1-(4-carboxyphenyl)-2-methyl-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1,3- butadiene (7a), its ethyl ester 5a, and the epoxy ethyl ester 14 displayed excellent activity in the assay for the inhibition of tumor promotor-induced mouse epidermal ornithine decarboxylase, while (1E,3E)-1-(4-carboethoxy-3-methylphenyl)-2-methyl-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1,3-butadiene (5b) was inactive. The 13(Z) analogues, (E)-1-(2-carboxyphenyl)-4-methyl-6-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1,3,5-he xatriene (19) and (E)-1-(2-hydroxyphenyl)-4-methyl-6-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1,3,5-he xatriene (27), had minimal activity.

Retinoic acid analogues. Synthesis and potential as cancer chemopreventive agents.

Analogues of retinoic acid have been synthesized as potential chemopreventive agents against epithelial cancer. Ethyl (E)-9-(2-norbornenyl)-3,7-dimethylnona-2,4,6,8-tetraenoate (9), (E)-3,7-dimethyl-9-(2-ethyl-6,6-dimethyl-1-cyclohexen-1-yl)nona-2,4,6,8-tetraenoic acid (25), and 2-(2'-methoxyethoxy)ethyl retinoate (26) displayed good activity in the inhibition of tumor promoter-induced mouse epidermal ornithine decarboxylase assay. (E)-1-(3-Acetoxyphenyl)-4-methyl-6-(2,6,6-trimethyl-1-cyclohexen-1-yl)hexa1,3,5 -triene (34) had low activity. (E)-5-[2,6-Dimethyl-8-(2,6,6-trimethyl-1-cyclohexen-1-yl)octa-1,3,5,7-tetraen-1 -yl]tetrazole (40) was inactive.

The carcinogenesis bioassay in perspective: application in identifying human cancer hazards.

The selection process for chemicals tested in the rodent carcinogenicity bioassay has been biased toward chemicals suspected of potential carcinogenicity. Results from carcinogenicity bioassays of 400 chemicals tested by the National Cancer Institute/National Toxicology Program (NCI/NTP) were analyzed to determine the dependence of positive results on chemical selection criteria: those suspected of being carcinogenic and those selected based on large volumes produced and widespread exposures. Of these chemicals, 210 (52%) induced carcinogenicity in at least one organ of one sex of one species of the four sex/species groups typically used by NCI/NTP. Only 92 of the 400 chemicals (23%) were positive in two species and thus by international criteria are considered likely to pose a carcinogenic hazard to humans. A total of 267 chemicals (67%) were selected as suspect carcinogens, and 187 (68%) of these were carcinogenic. Suspect chemicals account for 86% of chemicals with at least one positive result and account for 90% of chemicals considered positive in two species. The International Agency for Research on Cancer (IARC) lists only 5 of the 400 chemicals as carcinogenic to humans (group 1) and 10 as probably carcinogenic to humans (group 2A). The majority (80%) of the 133 chemicals selected only on production/exposure considerations were not carcinogenic in animals, even when tested at the maximum tolerated (or minimally toxic) dose. Only 9 (6.8%) were positive in two species, and none is listed in IARC groups 1 or 2A. Thus, on the basis of our analyses we predict that less than 5-10% of the 75,000 chemicals in commercial use might be reasonably anticipated to be carcinogenic to humans.

Multicomponent criteria for predicting carcinogenicity: dataset of 30 NTP chemicals.

This article is in response to the challenge issued to the scientific community by the National Toxicology Program to predict the carcinogenicity potential of 30 chemicals previously selected for long-term carcinogenicity testing. Utilizing the available toxicologic, genetic, and structural information on 30 chemicals previously selected for long-term carcinogenicity testing, we predict that 16 chemicals (53%) would induce some indication of carcinogenic activity in rodents; we further predict that 10 chemicals (33%) would be associated with weak or equivocal carcinogenic responses, and another 4 (13%) would give no indication of carcinogenicity. Our level of certainty is indicated for many of these predictions. Nonetheless, we believe that most instances of guessing whether a chemical would eventually induce cancer in experimental animals and hence represent a carcinogenic hazard to humans are fraught with considerable uncertainty: uncertainty that can only be relieved by long-term testing for carcinogenicity in animals or by conducting an epidemiologic investigation of exposed individuals or groups. We further believe that the day may come when our predictive acumen will be upgraded to such an extent that we might eventually obviate cancer testing. Until then, and in the best interests of public health, however, we urge long term testing of chemicals in animals be continued, at increased pace.