Physical Violence and Aggression in Parkinson's Disease: A Systematic Review.

BACKGROUND: Physical violence and aggression (PVA), defined as behaviors with the potential to cause bodily injury, are unfortunate risks in the management of all-cause neurodegenerative dementias. While dementia in Parkinson's disease (PD) may not be evident for many years after clinical onset, neuropsychiatric disturbances occur at all stages of the disease. At issue is whether PVA in PD is associated with clinical factors that can be targets for prevention and management in the absence of a prevailing dementia syndrome. OBJECTIVE: This systematic review examined the extent to which PVA in PD without dementia is a clinically significant concern and whether it is associated with factors that could warrant proactive management. METHODS: A systematic search of 9 electronic databases used MeSH headings and equivalent terms for PD, aggression, and violence. Eligible manuscripts were original articles that were published in peer-reviewed journals and reported on adults with PD in the awake state with PVA as possible outcomes. Extracted data included study design, PD ascertainment methods and characteristics, PVA assessment methods, subject demographics, psychiatric and medical comorbidities, and pertinent results. Inciting and confounding factors were extracted from case reports. Quality assessment tools were applied in accordance with the study design (e.g., observational, qualitative, or case report). RESULTS: The search identified 10 manuscripts: 2 observational quantitative studies (total n with PD = 545), 1 qualitative study (n with PD = 20), and 7 case reports (n = 7). The observational studies suggested that PVA is less common than other neuropsychiatric disturbances, but heterogeneous methods and quality concerns prevented further conclusions. In the case reports, all patients were male, and most were early onset. In 6 of the reports, PVA occurred in the context of bilateral subthalamic nucleus deep brain stimulation. CONCLUSIONS: PVA, while relatively rare in PD, can be a significant management issue that is associated with select premorbid characteristics and antiparkinsonian motor treatments. As PVA may be under-reported, further understanding of its frequency, causes, risk factors, and outcomes would benefit from its systematic assessment, ideally using self-report and informant-based questionnaires.

Problems With Medium-Sized Joints: Wrist Conditions.

Common wrist conditions include fractures and other injuries, osteoarthritis, radial epiphysitis, joint instability, de Quervain tenosynovitis, carpal tunnel syndrome, ganglion cyst, and ulnar neuropathy. The initial history and physical examination, with particular focus on the anatomic structures of the wrist, can narrow the differential diagnosis. Magnetic resonance imaging study can be used to identify soft tissue masses and occult osseous processes, particularly with scaphoid fractures. Computed tomography scan is useful in cases of bony abnormalities, high clinical suspicion of occult fracture, and surgical planning. Musculoskeletal ultrasonography can help identify soft tissue injuries, synovitis, or edema. It also can assess for nerve pathology, such as increased median nerve surface area in carpal tunnel syndrome. Management of common wrist fractures, such as distal radius, carpal, and scaphoid fractures, includes nonsurgical and surgical options, immobilization, and referral for further management or surgical consultation. Other wrist conditions, including overuse conditions such as carpometacarpal osteoarthritis or radial epiphysitis, can be managed conservatively initially. Ganglion cysts can be managed with immobility and rest initially, or aspiration or surgical excision. Ulnar neuropathy is the result of local compression of the ulnar nerve at the level of the carpal bones. It typically is managed with activity modification and splinting.

Problems With Medium-Sized Joints: Elbow Conditions.

For patients with elbow pain, a comprehensive history and physical examination can identify the mechanism of injury and specific tests can help determine the underlying pathology. When imaging is indicated, x-ray typically is the initial modality. Indications for ultrasonography include the need for static, dynamic, and stress visualization of elbow cartilage, tendons, ligaments, and osseous structures. Magnetic resonance imaging study is preferred for assessment of chronic elbow pain because of its ability to detect bone marrow edema, tendinopathy, nerve entrapment, and joint effusion. In children, common elbow conditions and injuries include supracondylar fracture, posterior elbow dislocation, medial epicondyle apophysitis (Little Leaguers elbow), ulnar collateral ligament injury, and chronic lateral elbow pain. Primary and secondary bony ossification centers and the presence of growth plates affect management of these conditions in children. In adults, common conditions and injuries are radial head fractures, lateral epicondylitis, medial epicondylitis, and ulnar nerve compression. Radial head fractures are categorized according to the Modified Mason Classification. Patients with type III and IV fractures should be referred for surgical management. Lateral and medial epicondylitis are overuse injuries diagnosed based on signs and symptoms. Surgical management should be considered for patients who do not improve with conservative management.

Problems With Medium-Sized Joints: Ankle Conditions.

The ankle is the cause of many musculoskeletal injuries. Knowledge of ankle anatomy and physiology can provide an initial framework to help clinicians formulate a differential diagnosis. A thorough history should be obtained, with a focus on mechanism of injury and symptom duration to hone the differential diagnosis and physical examination. Specific diagnostic maneuvers allow for evaluation of individual structures and assessment of ankle stability. The Ottawa Ankle Rules can assess the need for x-rays and help rule out underlying fracture. Lateral and medial ankle sprains and Achilles tendinopathy are among the most common ankle conditions in the primary care setting. These sprains are managed with ankle protection with a splint, brace, or other device; the rest, ice, compression, and elevation (RICE) protocol; and a short course of nonsteroidal anti-inflammatory drugs (NSAIDs). Management of Achilles tendon conditions typically consists of the RICE protocol, activity reduction, physical therapy or clinician-directed exercises, NSAIDs, and, in severe cases, short-term immobilization. For patients with stable ankle fractures, various orthoses can be used for immobilization. Orthopedic consultation should be sought for patients with unstable ankle fractures.

Problems With Medium-Sized Joints: Neck Conditions.

The incidence of neck pain in US primary care settings ranges from 10% to 21% per year. A key component in evaluation of patients with neck pain is identification of red flag signs or symptoms that indicate the need for urgent evaluation for possible serious conditions. These include fever, unexplained weight loss, trauma, vision changes, new or severe headache, and altered mental status, among others. Patients with acute onset or worsening chronic neck pain without trauma or red flag signs or symptoms should be assessed initially with x-ray. Magnetic resonance imaging study is recommended for patients with progressive neurologic symptoms, neurologic compromise, suspected infection, or other red flag signs or symptoms. Common conditions and injuries associated with neck pain in the primary care setting include cervical strains and sprains, cervical spondylosis, cervical discogenic pain, cervical radiculopathy and myelopathy, whiplash, cervical fracture, and postural pain. Most patients with neck pain without red flag signs or symptoms recover with conservative management, however, there is little evidence to support these treatments. Pharmacotherapy includes nonsteroidal anti-inflammatory drugs, acetaminophen, and muscle relaxants. Small benefits have been shown for combination exercise programs, mind-body programs, and acupuncture. Referral for surgical management is indicated for patients with progressive neurologic deficits.

HummingFlow: novel single twist-drill access for ventricular drainage, irrigation, monitoring, and automated local drug delivery in subarachnoid hemorrhage.

OBJECTIVE: The management of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage (aSAH) remains one of the most important targets for neurocritical care. Advances in monitoring technology have facilitated a more thorough understanding of the pathophysiology and therapeutic approaches, but interventions are generally limited to either systemic therapies or passive CSF drainage. The authors present a novel approach that combines a multimodal monitoring bolt-based system with an irrigating ventricular drain capable of delivering intrathecal medications and describe their early experience in patients with aSAH. METHODS: The authors performed a retrospective review of cases treated with the combined Hummingbird multimodal bolt system and the IRRAflow irrigating ventriculostomy. RESULTS: Nine patients were treated with the combined multimodal bolt system with irrigating ventriculostomy approach. The median number of days to clearance of the third and fourth ventricles was 3 days in patients with obstructive intraventricular hemorrhage. Two patients received intrathecal alteplase for intraventricular hemorrhage clearance, and 2 patients received intrathecal nicardipine as rescue therapy for severe symptomatic angiographic vasospasm. CONCLUSIONS: Combined CSF drainage, irrigation, multimodality monitoring, and automated local drug delivery are feasible using a single twist-drill hole device. Further investigation of irrigation settings and treatment approaches in high-risk cases is warranted.

Assessing the Severity of Cervical Dystonia: Ask the Doctor or Ask the Patient?

Background: Assessing disease severity can be performed using either clinician-rated scales (CRS) or patient-rated outcome (PRO) tools. These two measures frequently demonstrate poor correlations. Objectives: To determine if the correlation between a CRS and PRO for motor features of cervical dystonia (CD) improves by accounting for non-motor features. Methods: Subjects with CD (N = 209) were evaluated using a CRS (Toronto Western Spasmodic Torticollis Rating Scale, TWSTRS) and a PRO (Cervical Dystonia Impact Profile, CDIP-58). Results: Linear regression revealed a weak correlation between the two measures, even when considering only the motor subscales of each. The strength of this relationship improved with a regression model that included non-motor symptoms of pain, depression, and disability. Conclusions: These results argue that the results of motor assessments in a PRO for CD cannot be fully appreciated without simultaneous assessment of non-motor co-morbidities. This conclusion might apply to other disorders, especially those with frequent non-motor co-morbidities.

From basic science to clinical practice: Can cognitive behavioural therapy tasks be augmented with enhanced episodic specificity?

Individuals with depression typically remember their past in a generalised manner, at the cost of retrieving specific event memories. This may impair engagement with cognitive behavioural therapy (CBT) tasks that use concrete episodic information to challenge maladaptive beliefs, potentially limiting their therapeutic benefit. Study 1 demonstrated that an episodic specificity induction increased detail and specificity of autobiographical memory in people with major depression, relative to control conditions (N = 88). We therefore examined whether the induction enhanced the efficacy of CBT tasks that depend on episodic memory - cognitive reappraisal (Study 2, N = 30), evidence gathering (Study 2, N = 30), and planning behavioural experiments (Study 3a, N = 30). Across all three tasks, there were no significant differences in emotion- or belief-change between the specificity and control conditions. Although the induction temporarily enhanced specificity in depressed individuals, it did not significantly augment the efficacy of CBT tasks theorised to benefit from the use of specific mnemonic information.

Post-Traumatic Stress Disorder and Risk of Degenerative Synucleinopathies: Systematic Review and Meta-Analysis.

OBJECTIVE: A systematic review was conducted to answer whether adult-onset post-traumatic stress disorder (PTSD) is associated with increased risk of Parkinson's disease (PD) and related synucleinopathies. DESIGN: A systematic search of Medline (Ovid), Embase (Elsevier), PsycInfo (Ovid), Cochrane Library (Wiley), and Web of Science (Clarivate) was performed using MeSH headings and equivalent terms for PTSD, PD, DLB, and related disorders. SETTING: No restrictions. PARTICIPANTS: Eligible articles were published in peer-reviewed journals, sampled adult human populations, and treated PTSD and degenerative synucleinopathies as exposures and outcomes, respectively. MEASUREMENTS: Extracted data included diagnostic methods, sample characteristics, matching procedures, covariates, and effect estimates. Bias assessment was performed with the Newcastle-Ottawa scale. Hazard ratios were pooled using the random effects model, and the Hartung-Knapp adjustment was applied due to the small number of studies. RESULTS: A total of six articles comprising seven unique samples (total n = 1,747,378) met eligibility criteria. The risk of PD was reported in three retrospective cohort studies and one case-control study. Risk of DLB was reported in one retrospective cohort, one case-control, and one prospective cohort study. No studies addressed potential relationships with multiple system atrophy or pure autonomic failure. Meta-analysis of hazard ratios from four retrospective cohort studies supported the hypothesis that incident PTSD was associated with PD and DLB risk (pooled HR 1.88, 95% C.I. 1.08-3.24; p = 0.035). CONCLUSIONS: The sparse literature to-date supports further investigations on the association of mid- to late-life PTSD with Parkinson's and related neurodegenerative disorders.

Cognitive dysfunction and neuropsychiatric aspects of Parkinson's disease.

Movement abnormalities, by definition, and cognitive changes, to varying extents, affect every patient with Parkinson's disease (PD) and are attributed to the underlying neurodegenerative disease. Various psychiatric disorders occur in most patients at some point over the course of PD, including in the prodromal phase. Even though psychiatric disturbances tend to aggravate motor and cognitive deficits, they are under-recognized and under-treated, and the role of the underlying neurological disease is often minimized. To provide an integrated approach to understanding neuropsychiatric aspects of PD, this chapter reviews how cognitive changes in PD relate to the common psychiatric disturbances in PD along with the prevalence, phenomenology, pathophysiology, and treatment of each.

Dream Enactment Behaviors Associated With Posttraumatic Stress Disorder.

The investigators aimed to draw attention to current debates surrounding the etiologies of dream enactment behaviors in patients with posttraumatic stress disorder (PTSD). The phenomenological overlap between PTSD-related nocturnal symptoms, rapid eye movement sleep behavior disorder (RBD), and trauma-associated sleep disorder (TASD) is discussed. Strategies used to diagnose and manage dream enactment behaviors, whether due to RBD or another confounding sleep disorder, are considered. Finally, the need for further research on the pathophysiological overlap and integrated treatment of PTSD, RBD, and, possibly, TASD is highlighted.

Finding common ground: Toward comparable indicators of adaptive capacity of tree species to a changing climate.

Adaptive capacity, one of the three determinants of vulnerability to climate change, is defined as the capacity of species to persist in their current location by coping with novel environmental conditions through acclimation and/or evolution. Although studies have identified indicators of adaptive capacity, few have assessed this capacity in a quantitative way that is comparable across tree species. Yet, such multispecies assessments are needed by forest management and conservation programs to refine vulnerability assessments and to guide the choice of adaptation measures. In this paper, we propose a framework to quantitatively evaluate five key components of tree adaptive capacity to climate change: individual adaptation through phenotypic plasticity, population phenotypic diversity as influenced by genetic diversity, genetic exchange within populations, genetic exchange between populations, and genetic exchange between species. For each component, we define the main mechanisms that underlie adaptive capacity and present associated metrics that can be used as indices. To illustrate the use of this framework, we evaluate the relative adaptive capacity of 26 northeastern North American tree species using values reported in the literature. Our results show adaptive capacity to be highly variable among species and between components of adaptive capacity, such that no one species ranks consistently across all components. On average, the conifer Picea glauca and the broadleaves Acer rubrum and A. saccharinum show the greatest adaptive capacity among the 26 species we documented, whereas the conifers Picea rubens and Thuja occidentalis, and the broadleaf Ostrya virginiana possess the lowest. We discuss limitations that arise when comparing adaptive capacity among species, including poor data availability and comparability issues in metrics derived from different methods or studies. The breadth of data required for such an assessment exemplifies the multidisciplinary nature of adaptive capacity and the necessity of continued cross-collaboration to better anticipate the impacts of a changing climate.

Ultrasound-Triggered Delivery of Iproplatin from Microbubble-Conjugated Liposomes.

The PtIV prodrug iproplatin has been actively loaded into liposomes using a calcium acetate gradient, achieving a 3-fold enhancement in drug concentration compared to passive loading strategies. A strain-promoted cycloaddition reaction (azide- dibenzocyclooctyne) was used to attach iproplatin-loaded liposomes L(Pt) to gas-filled microbubbles (M), forming an ultrasound-responsive drug delivery vehicle [M-L(Pt)]. Ultrasound-triggered release of iproplatin from the microbubble-liposome construct was evaluated in cellulo. Breast cancer (MCF-7) cells treated with both free iproplatin and iproplatin-loaded liposome-microbubbles [M-L(Pt)] demonstrated an increase in platinum concentration when exposed to ultrasound. No appreciable platinum uptake was observed in MCF-7 cells following treatment with L(Pt) only or L(Pt)+ultrasound, suggesting that microbubble-mediated ultrasonic release of platinum-based drugs from liposomal carriers enables greater control over drug delivery.

Evaluation of miRNA as Biomarkers of Emotional Valence in Pigs.

The ability to assess the welfare of animals is dependent on our ability to accurately determine their emotional (affective) state, with particular emphasis being placed on the identification of positive emotions. The challenge remains that current physiological and behavioral indices are either unable to distinguish between positive and negative emotional states, or they are simply not suitable for a production environment. Therefore, the development of novel measures of animal emotion is a necessity. Here we investigated the efficacy of microRNA (miRNA) in the brain and blood as biomarkers of emotional state in the pig. Female Large White × Landrace pigs (n = 24) were selected at weaning and trained to perform a judgment bias test (JBT), before being exposed for 5 weeks to either enriched (n = 12) or barren housing (n = 12) conditions. Pigs were tested on the JBT once prior to treatment, and immediately following treatment. MiRNA and neurotransmitters were analyzed in blood and brain tissue after euthanasia. Treatment had no effect on the outcomes of the JBT. There was also no effect of treatment on miRNA expression in blood or the brain (FDR p > 0.05). However, pigs exposed to enriched housing had elevated dopamine within the striatum compared to pigs in barren housing (p = 0.02). The results imply that either (a) miRNAs are not likely to be valid biomarkers of a positive affective state, at least under the type of conditions employed in this study, or (b) that the study design used to modify affective state was not able to create differential affective states, and therefore establish the validity of miRNA as biomarkers.

Non-motor phenotypic subgroups in adult-onset idiopathic, isolated, focal cervical dystonia.

BACKGROUND: Non-motor symptoms are well established phenotypic components of adult-onset idiopathic, isolated, focal cervical dystonia (AOIFCD). However, improved understanding of their clinical heterogeneity is needed to better target therapeutic intervention. Here, we examine non-motor phenotypic features to identify possible AOIFCD subgroups. METHODS: Participants diagnosed with AOIFCD were recruited via specialist neurology clinics (dystonia wales: n = 114, dystonia coalition: n = 183). Non-motor assessment included psychiatric symptoms, pain, sleep disturbance, and quality of life, assessed using self-completed questionnaires or face-to-face assessment. Both cohorts were analyzed independently using Cluster, and Bayesian multiple mixed model phenotype analyses to investigate the relationship between non-motor symptoms and determine evidence of phenotypic subgroups. RESULTS: Independent cluster analysis of the two cohorts suggests two predominant phenotypic subgroups, one consisting of approximately a third of participants in both cohorts, experiencing increased levels of depression, anxiety, sleep impairment, and pain catastrophizing, as well as, decreased quality of life. The Bayesian approach reinforced this with the primary axis, which explained the majority of the variance, in each cohort being associated with psychiatric symptomology, and also sleep impairment and pain catastrophizing in the Dystonia Wales cohort. CONCLUSIONS: Non-motor symptoms accompanying AOIFCD parse into two predominant phenotypic sub-groups, with differences in psychiatric symptoms, pain catastrophizing, sleep quality, and quality of life. Improved understanding of these symptom groups will enable better targeted pathophysiological investigation and future therapeutic intervention.

Repeated retrieval of generalized memories can impair specific autobiographical recall: A retrieval induced forgetting account.

Overgeneral autobiographical memory (OGM) refers to the tendency toward increased general memory and reduced specific memory recall, observed in various psychiatric disorders. Previous studies have suggested that inhibitory processes involved in resolving competition between competing memories may reduce memory specificity via retrieval-induced forgetting (RIF). However, it remains unclear whether the repeated retrieval of general memories can induce forgetting of specific memories. We adapted the RIF paradigm to address this question across three experiments. Participants first generated specific memories in response to positively and negatively valenced cue words. They then generated and repeatedly retrieved general memories for half of the cue words. Recall for all of the original specific memories was later tested. Experiment 1 showed that the retrieval practice of general memories reduced the recall of associated specific memories, regardless of cue valence. Experiment 2 demonstrated that this forgetting effect was cue independent, occurring even when novel retrieval cues were used on the final test. Experiment 3 suggested that this effect was competition dependent, finding a greater RIF effect following practice of general memories (high competition) than following a cue-color association task (low competition). These results suggest that repeated retrieval of general memories suppressed specific memory representations through RIF. These findings are discussed in relation to hierarchical models of autobiographical memory, mechanisms that maintain overgeneral memory tendencies, and the role of retrieval in shaping autobiographical memory. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Dystonia and Tremor: A Cross-Sectional Study of the Dystonia Coalition Cohort.

OBJECTIVE: To assess the clinical manifestations and predictors of different types of tremors in individuals with different types of isolated dystonia. METHODS: Clinical manifestations of tremor were assessed in a multicenter, international cross-sectional, cohort study of 2,362 individuals with all types of isolated dystonia (focal, segmental, multifocal, and generalized) recruited through the Dystonia Coalition. RESULTS: Methodical and standardized assessments of all participants in this cohort revealed the overall prevalence of any type of tremor was 53.3%. The prevalence of dystonic tremor varied from 36.9% to 48.4%, depending on criteria used to define it. To identify the factors associated with tremors in dystonia, the data were analyzed by generalized linear modeling and cluster analyses. Generalized linear modeling indicated 2 of the strongest factors associated with tremor included body region affected by dystonia and recruitment center. Tremor was also associated with severity of dystonia and duration of dystonia, but not with sex or race. The cluster analysis distinguished 8 subgroups within the whole cohort; defined largely by body region with dystonia, and secondarily by other clinical characteristics. CONCLUSION: The large number of cases evaluated by an international team of movement disorder experts facilitated the dissection of several important factors that influence the apparent prevalence and phenomenology of tremor in dystonia. These results are valuable for understanding the many differences reported in prior studies, and for guiding future studies of the nosology of tremor and dystonia.

Erratum: Author Correction: Report from a multidisciplinary meeting on anxiety as a non-motor manifestation of Parkinson's disease.

[This corrects the article DOI: 10.1038/s41531-019-0102-8.].

Oxaliplatin and [Pt(R,R-DACH)(panobinostat-2H)] show nanomolar cytotoxicity towards diffuse intrinsic pontine glioma (DIPG).

We report the synthesis of two novel platinum(ii) complexes which incorporate histone deacetylase (HDAC) inhibitors: [PtII(R,R-DACH)(Sub-H)] (1), [PtII(R,R-DACH)(panobinostat-2H)] (2), where SubH = suberoyl-bis-hydroxamic acid; DACH = (1R,2R)-(-)-1,2-diaminocyclohexane and panobinostat = (E)-N-hydroxy-3-[4-[[2-(2-methyl-1H-indol-3-yl)ethylamino]methyl]phenyl]prop-2-enamide. Complexes 1 and 2 were characterised by 1H, 13C, 195Pt NMR spectroscopy and ESI-MS. Whilst oxaliplatin demonstrated considerable cytotoxicity in two patient-derived low-passage paediatric glioma DIPG cell lines (IC50 values of 0.333 µM in SU-DIPG-IV, and 0.135 µM in SU-DIPG-XXI), complex 2 showed even greater cytotoxicities, with IC50 values of 0.021 µM (SU-DIPG-IV), 0.067 µM (BIOMEDE 194) and 0.009 µM (SU-DIPG-XXI). Complex 2 also demonstrated superior aqueous solubility in comparison to panobinostat. Complex 2 released free intact panobinostat under HPLC conditions, as determined by ESI-MS. Incubation of solutions of oxaliplatin (H2O) and panobinostat (DMF) resulted in instantaneous reactivity and precipitation of a panobinostat derivative which was not a platinum complex; the same reactivity was not observed between carboplatin and panobinostat.