Movement System Diagnoses for Balance Dysfunction: Recommendations From the Academy of Neurologic Physical Therapy's Movement System Task Force.

The movement system was identified as the focus of our expertise as physical therapists in the revised vision statement for the profession adopted by the American Physical Therapy Association in 2013. Attaining success with the profession's vision requires the development of movement system diagnoses that will be useful in clinical practice, research, and education. To date, only a few movement system diagnoses have been identified and described, and none of these specifically address balance dysfunction. Over the past 2 years, a Balance Diagnosis Task Force, a subgroup of the Movement System Task Force of the Academy of Neurologic Physical Therapy, focused on developing diagnostic labels (or diagnoses) for individuals with balance problems. This paper presents the work of the task force that followed a systematic process to review available diagnostic frameworks related to balance, identify 10 distinct movement system diagnoses that reflect balance dysfunction, and develop complete descriptions of examination findings associated with each balance diagnosis. A standardized approach to movement analysis of core tasks, the Framework for Movement Analysis developed by the Academy of Neurologic Physical Therapy Movement Analysis Task Force, was integrated into the examination and diagnostic processes. The aims of this perspective paper are to (1) summarize the process followed by the Balance Diagnosis Task Force to develop an initial set of movement system (balance) diagnoses; (2) report the recommended diagnostic labels and associated descriptions; (3) demonstrate the clinical decision-making process used to determine a balance diagnosis and develop a plan of care; and (4) identify next steps to validate and implement the diagnoses into physical therapist practice, education, and research. IMPACT: The development and use of diagnostic labels to classify distinct movement system problems is needed in physical therapy. The 10 balance diagnosis proposed can aid in clinical decision making regarding intervention.

A Framework for Movement Analysis of Tasks: Recommendations From the Academy of Neurologic Physical Therapy's Movement System Task Force.

The American Physical Therapy Association's Vision Statement of 2013 asserts that physical therapists optimize movement in order to improve the human experience. In accordance with this vision, physical therapists strive to be recognized as experts in movement analysis. However, there continues to be no accepted method to conduct movement analysis, nor an agreement of key terminology to describe movement observations. As a result, the Academy of Neurologic Physical Therapy organized a task force that was charged with advancing the state of practice with respect to these issues, including the development of a proposed method for movement analysis of tasks. This paper presents the work of the Task Force, which includes (1) development of a method for conducting movement analysis within the context of the movement continuum during 6 core tasks (sitting, sit to stand, standing, walking, step up/down, and reach/grasp/manipulate); (2) glossary of movement constructs that can provide a common language for movement analysis across a range of tasks: symmetry, speed, amplitude, alignment, verticality, stability, smoothness, sequencing, timing, accuracy, and symptom provocation; and (3) recommendations for task and environmental variations that can be systematically applied. The expectation is that this systematic framework and accompanying terminology will be easily adapted to additional patient or client-specific tasks, contribute to development of movement system diagnostic labels, and ultimately improve consistency across patient/client examination, evaluation, and intervention for the physical therapy profession. Next steps should include validation of this framework across patient/client groups and settings.

White Paper: Movement System Diagnoses in Neurologic Physical Therapy.

BACKGROUND AND PURPOSE: The APTA recently established a vision for physical therapists to transform society by optimizing movement to promote health and wellness, mitigate impairments, and prevent disability. An important element of this vision entails the integration of the movement system into the profession, and necessitates the development of movement system diagnoses by physical therapists. At this point in time, the profession as a whole has not agreed upon diagnostic classifications or guidelines to assist in developing movement system diagnoses that will consistently capture an individual's movement problems. We propose that, going forward, diagnostic classifications of movement system problems need to be developed, tested, and validated. The Academy of Neurologic Physical Therapy's Movement System Task Force was convened to address these issues with respect to management of movement system problems in patients with neurologic conditions. The purpose of this article is to report on the work and recommendations of the Task Force. SUMMARY OF KEY FINDINGS: The Task Force identified 4 essential elements necessary to develop and implement movement system diagnoses for patients with primarily neurologic involvement from existing movement system classifications. The Task Force considered the potential impact of using movement system diagnoses on clinical practice, education and, research. Recommendations were developed and provided recommendations for potential next steps to broaden this discussion and foster the development of movement system diagnostic classifications. RECOMMENDATIONS FOR CLINICAL PRACTICE: The Task Force proposes that diagnostic classifications of movement system problems need to be developed, tested, and validated with the long-range goal to reach consensus on and adoption of a movement system diagnostic framework for clients with neurologic injury or disease states.Video Abstract available for more insights from the authors (see Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A198).

Proteasome inhibition induces cytokeratin accumulation in vivo.

Chronic ethanol ingestion leads to inhibition of proteasomal activity. As a consequence, proteins accumulate in liver cells. Cytokeratin accumulation as seen in alcoholic hepatitis could lead to the formation of Mallory bodies. In order to study the phenomenon of cytokeratin accumulation in liver cells, rats were fed ethanol or dextrose for 1 month and some were given the proteasome inhibitor, PS-341, to augment the inhibitory effect of ethanol feeding. This was done to study the involvement of proteasome inhibition in the process of cytokeratin accumulation. There was a marked increase in the accumulation of polyubiquitinated proteins, and heat shock proteins (hsp) 25 and 70 in the liver of rats treated with PS-341. Similarly, cytokeratin-8 (CK-8) levels were markedly increased in the liver homogenates of rats fed ethanol when given PS-341. When normal mouse cultured hepatocytes were transfected with cytokeratin-18 (CK-18) tagged with red fluorescent protein (RFP), CK-18 aggresomes formed because proteasome was overloaded. These data provide new evidence that proteasome inhibition is involved in cytokeratin accumulation, when aggresomes are formed in tissue culture. Accumulation of cytokeratin in this way may ultimately lead to Mallory body formation as seen in alcoholic hepatitis.

The proteasome inhibitor, PS-341, causes cytokeratin aggresome formation.

Mallory body (MB) experimental induction takes 10 weeks of drug ingestion. Therefore, it is difficult to study the dynamics and mechanisms involved in vivo. Consequently, an in vitro study was done using primary tissue culture of hepatocytes from drug-primed mice livers in which MBs had already formed. The hypothesis to be tested was that MBs are cytokeratin aggresomes, which form when hepatocytes have a defective ubiquitin-proteasome pathway by which turnover of cytokeratin proteins is prevented. To test this hypothesis, primary tissue cultures of the hepatocytes from normal and MB-forming livers were incubated with the proteasome inhibitor PS-341 and then the cytokeratin filaments and the filament connecting proteins, that is, beta-actin, and ZO1, were visualized by immunofluorescence microscopy. PS-341 caused detachment of the cytokeratins from the cell surface plasma membrane. The cytokeratin filaments retracted toward the nucleus and cytokeratin aggresomes formed. In human livers, MBs showed colocalization of cytokeratin-8 (CK-8) with ubiquitin but not with beta-actin or ZO1. Mouse hepatoma cell lines were studied using PS-341 to induce cytokeratin aggresome formation. In these cell lines, the cytokeratin filaments first retracted toward the nucleus then formed cytokeratin-ubiquitin aggresomes polarized at one side of the nucleus. At the same time, the cells became dissociated from each other, however. The results simulated MB formation. MBs differ from cytokeratin aggresomes both morphologically and in ultrastructure.

The role of the ubiquitin-proteasome pathway in the formation of mallory bodies.

The dynamics of Mallory body (MB) formation are difficult to follow in vivo. Because of the lack of an in vitro mouse hepatocyte culture model, a cellular extract approach was developed. In this model an immunoprecipitate was obtained using an antibody to cytokeratin-8 (CK-8). The isolate contained a large number of compounds: CK-8, ubiquitin, a frameshift mutation of ubiquitin (UBB(+1)), proteasomal subunits beta5 (a catalytic subunit of the 20S proteasome) and Tbp7 (an ATPase subunit of the 26S proteasome), transglutaminase, tubulin, heat shock proteins 90 and 70, and MBs. In Western blots, CK-8 immunoprecipitates showed colocalization of these components in a complex of proteins colocalized in a high-molecular-weight smear. When the CK-8 immunoprecipitate was incubated with the isolate of proteasomes and an energy generating source (ATP), the components of the ubiquitinated protein smear increased. These observations taken together with the in vivo observation that these proteins colocalized at the edge of the MB shown in the present study suggest that these proteins form aggregates through covalent binding of CK-8, ubiquitin, and the proteasomes. Covalent aggregation is suggested by the fact that the protein complex found in the high-molecular-weight smear that forms in vitro fails to dissociate in SDS. This protein complex is present in the CK-8 immunoprecipitates of livers forming MBs but not in control livers. In conclusion, the results support the concept that Mallory bodies are aggresomes which form as the result of the failure of the ubiquitin-proteasome complex to adequately eliminate cytokeratins destined for proteolysis.

The importance of cycling of blood alcohol levels in the pathogenesis of experimental alcoholic liver disease in rats.

BACKGROUND & AIMS: Rats fed ethanol at a constant rate through a permanent intragastric cannula have a regular fluctuation in blood alcohol level (BAL) and urine alcohol level (UAL). The level of ethanol peaks every 6-10 days. The question is how the liver differs at the peaks and troughs of the UAL cycle. Hypoxic injury is postulated to occur at the peaks. Therefore, liver injury may be different at the peaks and troughs. METHODS: Many parameters were measured at the peaks, troughs, and controls for comparison. RESULTS: Indicators of hypoxic injury at the peaks included ATP reduction, a shift to the reduced state in the NADH/NAD ratio, an increase in expression of vascular endothelial growth factor, an increase in the pathology score at the peaks, and an increase in adduct formation using pimonidazole. Liver nitrites, number of granulocytes, liver weight/body weight ratio, cytochrome P450 2E1 protein, and chymotrypsin-like activity changed in the same direction compared with control values. CONCLUSIONS: The results indicate that hypoxic injury occurs at the peaks. There was a marked shift in NADH/NAD redox state at the peaks caused by hypoxia. This shift could account for the reduced rate of ethanol elimination by alcohol dehydrogenase at the peaks.

Molecular misreading of the ubiquitin B gene and hepatic mallory body formation.

BACKGROUND & AIMS: Molecular misreading of the ubiquitin B gene has been documented in the cerebral cortex of patients with Alzheimer's disease and Down syndrome. This novel process consists of the unfaithful conversion of genomic information into aberrant transcripts and its subsequent translation into +1 proteins. METHODS: Because Mallory bodies (MBs) also contain ubiquitinated proteins, we stained 11 autopsied and 6 biopsied MB-containing livers from patients with steatohepatitis with an antibody to ubiquitin(+1) to look for the presence of mutant (ubiquitin(+1)) protein. Antibodies to wild-type ubiquitin were used to document the presence of MBs in all cases. RESULTS: Ubiquitin(+1) immunoreactivity was detected in all MB-containing livers with steatohepatitis; no ubiquitin(+1) immunoreactivity was found in 13 MB-free liver controls. A subpopulation (about one third of the MBs) of the MB-containing hepatocytes in autopsied livers showed ubiquitin(+1) immunoreactivity (i.e., ubiquitin and ubiquitin(+1) colocalized in MBs). MB-containing liver biopsy specimens showed colocalization of ubiquitin and ubiquitin(+1) in every MB. Western blot analysis showed an ubiquitin(+1) band of 11 kilodaltons. Molecular misreading of the ubiquitin B gene (DeltaGU) was shown in one of the livers, which contained numerous MBs using an expression cloning strategy. CONCLUSIONS: The results showed that molecular misreading of the ubiquitin B gene occurred in hepatocytes in virtually all of the MB-containing livers tested. Ubiquitin(+1) protein was only found within the MBs and therefore may act by interfering with the degradation of the MBs because ubiquitin(+1) may inhibit proteolytic function of the proteasome.

Coexpression and accumulation of ubiquitin +1 and ZZ proteins in livers of children with alpha(1)-antitrypsin deficiency.

The ZZ variant of alpha(1)-antitrypsin deficiency (AATD) is well known to cause liver damage and cirrhosis in some affected children. Ubiquitin abnormality was recently shown to be significant in AATD in childhood cirrhosis. Molecular misreading (MM), defined as faulty transcription of genomic information from DNA into mRNA, as well as its translation into mutant proteins, has been documented in many pathologic processes where aggregation of abnormal proteins occurs. The misread protein, ubiquitin-B(+1) (UBB(+1)), was recently identified in the hallmarks of various neurological disorders. The objective of this study was to determine whether MM of ubiquitin occurs in AATD. Twelve explanted liver specimens from AATD-affected children with cirrhosis were retrieved from archival sources, along with 10 control liver specimens obtained from autopsies of age-matched children with no clinical, gross anatomic, or histologic evidence of liver disease. Double immunofluorescence studies using rabbit polyclonal antibodies against UBB(+1) and AAT were performed on consecutively sectioned tissue. UBB(+1) immunoreactivity was colocalized with AAT in all cirrhotic AATD livers. The control livers were consistently negative. Ubiquitin MM is prominent in AATD-affected cirrhotic livers. This indicates that for children with AATD and cirrhosis, ubiquitin MM is a necessary cofactor to the aggregation of mutant ZZ isoform of AATD.

Variations in the relationship between the frequency content of EMG signals and the rate of torque development in voluntary and elicited contractions.

Our purpose was to characterize the relationship between EMG mean power frequency (MPF) or median frequency (MF) and rate of torque development in voluntary ballistic and electrically elicited isometric contractions. Twenty-three healthy adults participated in two sets of experiments performed on elbow flexor muscles. For Experiment 1, subjects were asked to generate voluntary ballistic contractions by reaching four different target torque levels (20, 40, 60 and 100% of the maximal voluntary contraction (MVC)) as fast as they could. For Experiment 2, electrical (M-waves) and mechanical (twitches) responses to electrical stimulation of the nerves supplying the biceps brachii and brachioradialis muscles were recorded with the subjects at rest and with a background isometric contraction of 15% MVC. MPF, MF and rate of torque development (% MVC/s) were calculated for both voluntary and elicited contractions. Significant positive correlations were observed between MPF and rate of torque development for the voluntary contractions, whereas significant negative correlations were observed between the two variables for elicited contractions. This suggests that factors other than muscle fiber composition influence the frequency content of EMG signals and/or the rate of torque development, and that the effect of these factors will vary between voluntary and elicited contractions.