A History of Dystonia: Ancient to Modern

Before 1911, when Hermann Oppenheim introduced the term dystonia, this movement disorder lacked a unifying descriptor. While words like epilepsy, apoplexy, and palsy have had their meanings since antiquity, references to dystonia are much harder to identify in historical documents. Torticollis is an exception, although there is difficulty distinguishing dystonic torticollis from congenital muscular torticollis. There are, nevertheless, possible representations of dystonia in literature and visual art from the pre-modern world. Eighteenth century systematic nosologists such as Linnaeus, de Sauvages, and Cullen had attempted to classify some spasmodic conditions, including torticollis. But only after Charcot's contributions to clinical neuroscience were the various forms of generalized and focal dystonia clearly delineated. They were categorized as névroses: Charcot's term for conditions without an identifiable neuroanatomical cause. For a time thereafter, psychoanalytic models of dystonia based on Freud's ideas about unconscious conflicts transduced into physical symptoms were ascendant, although there was always a dissenting “organic” school. With the rise of subspecialization in movement disorders during the 1970s, the pendulum swung strongly back toward organic causation. David Marsden's clinical and electrophysiological research on the adult-onset focal dystonias was particularly important in establishing a physical basis for these disorders. We are still in a period of “living history” of dystonia, with much yet to be understood about pathophysiology. Rigidly dualistic models have crumbled in the face of evidence of electrophysiological and psychopathological overlap between organic and functional dystonia. More flexible biopsychosocial frameworks may address the demand for new diagnostic and therapeutic rationales

How to use pen and paper tasks to aid tremor diagnosis in the clinic

When a patient presents with tremor, it can be useful to perform a few simple pen and paper tests. In this article, we explain how to maximise the value of handwriting and of drawing Archimedes spirals and straight lines as clinical assessments. These tasks take a matter of seconds to complete but provide a wealth of information that supplements the standard physical examination. They aid the diagnosis of a tremor disorder and can contribute to its longitudinal monitoring. Watching the patient’s upper limb while they write and draw may reveal abnormalities such as bradykinesia, dystonic posturing and distractibility. The finished script and drawings can then be evaluated for frequency, amplitude, direction and symmetry of oscillatory pen movements and for overall scale of penmanship. Essential, dystonic, functional and parkinsonian tremor each has a characteristic pattern of abnormality on these pen and paper tests

Health at the writing desk of John Ruskin: a study of handwriting and illness

Though John Ruskin (1819 – 1900) is remembered principally for his work as a theorist, art critic, and historian of visual culture, he wrote exhaustively about his health in his correspondence and diaries. Ruskin was prone to recurring depressive and hypochondriacal feelings in his youth and adulthood. In 1871, at the age of 52, he developed an illness with relapsing psychiatric and neurological features. He had a series of attacks of brain disturbance, and a deterioration of his mental faculties affected his writing for years before curtailing his career a decade before he died. Previous writers have suggested he had a psychiatric malady, perhaps schizophrenia or schizo-affective disorder. But the more obvious conclusion from a close medical reading of Ruskin’s descriptions of his illness is he had some sort of ‘organic’ brain illness. This paper aims to give insight into the relationship between Ruskin’s state of wellbeing and the features of his writing through a palaeographical study of his letters and diary entries. We examine the handwriting for physical traces of Ruskin’s major brain illness, guided by the historical narrative of the illness. We also examine Ruskin’s recording of his experiences for what they reveal about the failure of his health and its impact on his work. Ruskin’s handwriting does not have clear-cut pathological features before around 1885, though suggestions of subtle writing deficits were present as early as 1876. After 1887, Ruskin’s handwriting shows fixed pathological signs—tremor, disturbed letter formation and features that reflect a slow and laborious process of writing. These observations are more than could be explained by normal ageing, and suggest the presence of a neurological deficit affecting writing control. Our findings are consistent with conclusions that we drew from the historical record—that John Ruskin had an organic neurological disorder with cognitive, behavioural, psychiatric, and motor effects

A Kinematic Study of Progressive Micrographia in Parkinson's Disease

Progressive micrographia is decrement in character size during writing and is commonly associated with Parkinson's disease (PD). This study has investigated the kinematic features of progressive micrographia during a repetitive writing task. Twenty-four PD patients with duration since diagnosis of <10 years and 24 age-matched controls wrote the letter “e” repeatedly. PD patients were studied in defined off states, with scoring of motor function on the Unified Parkinson's Disease Rating Scale Part III. A digital tablet captured x-y coordinates and ink-pen pressure. Customized software recorded the data and offline analysis derived the kinematic features of pen-tip movement. The average size of the first and the last five letters were compared, with progressive micrographia defined as >10% decrement in letter stroke length. The relationships between dimensional and kinematic features for the control subjects and for PD patients with and without progressive micrographia were studied. Differences between the initial and last letter repetitions within each group were assessed by Wilcoxon signed-rank test, and the Kruskal-Wallis test was applied to compare the three groups. There are five main conclusions from our findings: (i) 66% of PD patients who participated in this study exhibited progressive micrographia; (ii) handwriting kinematic features for all PD patients was significantly lower than controls (p < 0.05); (iii) patients with progressive micrographia lose the normal augmentation of writing speed and acceleration in the x axis with left-to-right writing and show decrement of pen-tip pressure (p = 0.034); (iv) kinematic and pen-tip pressure profiles suggest that progressive micrographia in PD reflects poorly sustained net force; and (v) although progressive micrographia resembles the sequence effect of general bradykinesia, we did not find a significant correlation with overall motor disability, nor with the aggregate UPDRS-III bradykinesia scores for the dominant arm

Developmental Expression and Glucocorticoid Control of the Leptin Receptor in Fetal Ovine Lung.

The effects of endogenous and synthetic glucocorticoids on fetal lung maturation are well-established, although the role of leptin in lung development before birth is unclear. This study examined mRNA and protein levels of the signalling long-form leptin receptor (Ob-Rb) in fetal ovine lungs towards term, and after experimental manipulation of glucocorticoid levels in utero by fetal cortisol infusion or maternal dexamethasone treatment. In fetal ovine lungs, Ob-Rb protein was localised to bronchiolar epithelium, bronchial cartilage, vascular endothelium, alveolar macrophages and type II pneumocytes. Pulmonary Ob-Rb mRNA abundance increased between 100 (0.69 fractional gestational age) and 144 days (0.99) of gestation, and by 2-4-fold in response to fetal cortisol infusion and maternal dexamethasone treatment. In contrast, pulmonary Ob-Rb protein levels decreased near term and were halved by glucocorticoid treatment, without any significant change in phosphorylated signal transducer and activator of transcription-3 (pSTAT3) at Ser727, total STAT3 or the pulmonary pSTAT3:STAT3 ratio. Leptin mRNA was undetectable in fetal ovine lungs at the gestational ages studied. These findings demonstrate differential control of pulmonary Ob-Rb transcript abundance and protein translation, and/or post-translational processing, by glucocorticoids in utero. Localisation of Ob-Rb in the fetal ovine lungs, including alveolar type II pneumocytes, suggests a role for leptin signalling in the control of lung growth and maturation before birth.This work was supported by the Biotechnology and Biological Sciences Research Council (grant numbers S18103 and BB/H01697X/1).This is the final version of the article. It first appeared from PLoS via http://dx.doi.org/10.1371/journal.pone.013611

Protocol for a home-based integrated physical therapy program to reduce falls and improve mobility in people with Parkinson’s disease

Background The high incidence of falls associated with Parkinson’s disease (PD) increases the risk of injuries and immobility and compromises quality of life. Although falls education and strengthening programs have shown some benefit in healthy older people, the ability of physical therapy interventions in home settings to reduce falls and improve mobility in people with Parkinson’s has not been convincingly demonstrated.Methods/design 180 community living people with PD will be randomly allocated to receive either a home-based integrated rehabilitation program (progressive resistance strength training, movement strategy training and falls education) or a home-based life skills program (control intervention). Both programs comprise one hour of treatment and one hour of structured homework per week over six weeks of home therapy. Blinded assessments occurring before therapy commences, the week after completion of therapy and 12 months following intervention will establish both the immediate and long-term benefits of home-based rehabilitation. The number of falls, number of repeat falls, falls rate and time to first fall will be the primary measures used to quantify outcome. The economic costs associated with injurious falls, and the costs of running the integrated rehabilitation program from a health system perspective will be established. The effects of intervention on motor and global disability and on quality of life will also be examined. Discussion This study will provide new evidence on the outcomes and cost effectiveness of home-based movement rehabilitation programs for people living with PD

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Analysis of Serological Biomarkers of SARS-CoV-2 Infection in Convalescent Samples From Severe, Moderate and Mild COVID-19 Cases.

Precision monitoring of antibody responses during the COVID-19 pandemic is increasingly important during large scale vaccine rollout and rise in prevalence of Severe Acute Respiratory Syndrome-related Coronavirus-2 (SARS-CoV-2) variants of concern (VOC). Equally important is defining Correlates of Protection (CoP) for SARS-CoV-2 infection and COVID-19 disease. Data from epidemiological studies and vaccine trials identified virus neutralising antibodies (Nab) and SARS-CoV-2 antigen-specific (notably RBD and S) binding antibodies as candidate CoP. In this study, we used the World Health Organisation (WHO) international standard to benchmark neutralising antibody responses and a large panel of binding antibody assays to compare convalescent sera obtained from: a) COVID-19 patients; b) SARS-CoV-2 seropositive healthcare workers (HCW) and c) seronegative HCW. The ultimate aim of this study is to identify biomarkers of humoral immunity that could be used to differentiate severe from mild or asymptomatic SARS-CoV-2 infections. Some of these biomarkers could be used to define CoP in further serological studies using samples from vaccination breakthrough and/or re-infection cases. Whenever suitable, the antibody levels of the samples studied were expressed in International Units (IU) for virus neutralisation assays or in Binding Antibody Units (BAU) for ELISA tests. In this work we used commercial and non-commercial antibody binding assays; a lateral flow test for detection of SARS-CoV-2-specific IgG/IgM; a high throughput multiplexed particle flow cytometry assay for SARS-CoV-2 Spike (S), Nucleocapsid (N) and Receptor Binding Domain (RBD) proteins); a multiplex antigen semi-automated immuno-blotting assay measuring IgM, IgA and IgG; a pseudotyped microneutralisation test (pMN) and an electroporation-dependent neutralisation assay (EDNA). Our results indicate that overall, severe COVID-19 patients showed statistically significantly higher levels of SARS-CoV-2-specific neutralising antibodies (average 1029 IU/ml) than those observed in seropositive HCW with mild or asymptomatic infections (379 IU/ml) and that clinical severity scoring, based on WHO guidelines was tightly correlated with neutralisation and RBD/S antibodies. In addition, there was a positive correlation between severity, N-antibody assays and intracellular virus neutralisation