A New Evolutionary Algorithm-Based Home Monitoring Device for Parkinson's Dyskinesia.

Parkinson's disease (PD) is a neurodegenerative movement disorder. Although there is no cure, symptomatic treatments are available and can significantly improve quality of life. The motor, or movement, features of PD are caused by reduced production of the neurotransmitter dopamine. Dopamine deficiency is most often treated using dopamine replacement therapy. However, this therapy can itself lead to further motor abnormalities referred to as dyskinesia. Dyskinesia consists of involuntary jerking movements and muscle spasms, which can often be violent. To minimise dyskinesia, it is necessary to accurately titrate the amount of medication given and monitor a patient's movements. In this paper, we describe a new home monitoring device that allows dyskinesia to be measured as a patient goes about their daily activities, providing information that can assist clinicians when making changes to medication regimens. The device uses a predictive model of dyskinesia that was trained by an evolutionary algorithm, and achieves AUC>0.9 when discriminating clinically significant dyskinesia.

What to do when people with Parkinson's disease cannot take their usual oral medications.

People with Parkinson's disease have limited brain reserves of endogenous dopamine; thus, their medications must not be omitted or delayed as this may lead to a significant drop in brain dopamine levels. This has two main clinical consequences: first, a deterioration in disease control, with distressing symptoms such as tremor, pain, rigidity, dysphagia and immobility, and second, an increased risk of developing the life-threatening complication of neuroleptic malignant-like syndrome. Common reasons for people with Parkinson's disease being unable to take their oral medications are neurogenic dysphagia from progressive disease or concurrent illness, gastroenteritis, iatrogenic 'nil by mouth' status especially perioperatively, and impaired consciousness level. Here we outline alternative methods to give dopaminergic drugs in the acute setting to people with Parkinson's disease who cannot take their usual oral treatment, namely using dispersible preparations in thickened fluids, an enteral tube, a transdermal patch or subcutaneous injections.

Cognitive impairment in Parkinson's disease.

Cognitive impairment is a significant non-motor symptom of Parkinson's disease (PD). Longitudinal cohort studies have demonstrated that approximately 50% of those with PD develop dementia after 10 years, increasing to over 80% after 20 years. Deficits in cognition can be identified at the time of PD diagnosis in some patients and this mild cognitive impairment (PD-MCI) has been studied extensively over the last decade. Although PD-MCI is a risk factor for developing Parkinson's disease dementia there is evidence to suggest that PD-MCI might consist of distinct subtypes with different pathophysiologies and prognoses. The major pathological correlate of Parkinson's disease dementia is Lewy body deposition in the limbic system and neocortex although Alzheimer's related pathology is also an important contributor. Pathological damage causes alteration to neurotransmitter systems within the brain, producing behavioural change. Management of cognitive impairment in PD requires a multidisciplinary approach and accurate communication with patients and relatives is essential.

Surgical treatment for chronic thromboembolic pulmonary hypertension: an historical perspective.

Chronic thrombotic occlusion of the pulmonary arteries that results in pulmonary hypertension is now recognized as being relatively common, and surgical treatment of the condition is being increasingly applied throughout the world. However, the condition was not described until 90 years ago, and just 60 years ago less than 200 cases of the syndrome had been reported. At that time the condition was thought to be inoperable. Surgery for the acute phase of pulmonary embolism was attempted beginning 100 years ago, with minimal success until cardiopulmonary bypass was developed and could be used to stabilize the patient during induction of anesthesia and the surgical removal of the embolus. Pulmonary endarterectomy was suggested as a possible surgical approach to the chronic condition in 1956, and the first planned pulmonary endarterectomy was performed in 1957. Over the next thirty years several operations were attempted in Europe and the United States. By 1989 it is likely that fewer than 250 cases of pulmonary endarterectomy had been attempted, with a mortality rate of greater than 20%. Some cases of pulmonary endarterectomy had been carried out successfully at the University of California, San Diego (UCSD), beginning in 1970. The technique of the operation was refined, and in 2003 the results of 1,500 of these operations performed at UCSD were described, with a mortality rate of less than 5%. The good results obtained in San Diego encouraged other groups internationally to start their own programs and the operation is now well established, with good results. The following discourse traces the development of surgery, first for acute pulmonary embolism, and also, growing out of that experience, an operation for chronic pulmonary embolism.

Geste Antagoniste Effects on Motor Performance in Dystonia-A Kinematic Study.

Background: The kinematic effects of gestes have not previously been studied. The mechanism(s) by which these sensory tricks modify dystonic movement is not well understood. Objectives: A kinematic investigation of the geste phenomenon in patients with dystonia. Methods: Twenty-three patients with dystonia associated with a geste were studied. Twenty-nine healthy controls also participated. Fifteen seconds of finger tapping was recorded by electromagnetic sensors, and the task was repeated with geste. Separable motor components were extracted using a custom-written MATLAB script. Performance with and without geste was compared using Wilcoxon signed ranks testing. Results: Speed and fluency of finger tapping is impaired in dystonia. When patients executed their geste, speed of movement (amplitude × frequency) increased (P < 0.0001), and halts decreased (P = 0.007). Conclusions: That gestes improve not only dystonic muscle contraction but also the efficiency of voluntary movement suggests a broad influence at the premotor control stage.

Costs of implementing and maintaining comprehensive school health: the case of the Annapolis Valley Health Promoting Schools program.

OBJECTIVE: Comprehensive school health (CSH) is increasingly receiving renewed interest as a strategy to improve health and learning. The present study estimates the costs associated with implementing and maintaining CSH. METHODS: We reviewed the accounting information of all schools in the Annapolis Valley Health Promoting Schools (AVHPS) program in 2008/2009. We considered support for nutrition and physical activity programs by the public system, grants, donations, fundraising and volunteers. RESULTS: The annual public funding to AVHPS to implement and maintain CSH totaled $344,514, which translates, on average, to $7,830 per school and $22.67 per student. Of the public funding, $140,500 was for CSH, $86,250 for breakfast programs, $28,750 for school food policy programs, and the remainder for other subsidized programs. Grants, donations and fundraising were mostly locally acquired. They totaled $127,235, which translates, on average, to $2,892 per school or $8.37 per student. The value of volunteer support was estimated to be equivalent to the value of grants, donations and fundraising combined. Of all grants, donations, fundraising and volunteers, 20% was directed to physical activity programs and 80% to nutrition programs. DISCUSSION: The public costs to implement and maintain CSH are modest. They leveraged substantial local funding and in-kind contributions, underlining community support for healthy eating and active living. Where CSH is effective in preventing childhood overweight, it is most likely cost-effective too, as costs for future chronic diseases are mounting. CSH programs that are proven effective and cost-effective have enormous potential for broad implementation and for reducing the public health burden associated with obesity.

Significant cognitive decline in Parkinson's disease exacerbates the reliance on visual feedback during upper limb reaches.

While upper limb reaches are often made in a feed-forward manner, visual feedback during the movement can be used to guide the reaching hand towards a target. In Parkinson's disease (PD), there is evidence that the utilisation of this visual feedback is increased. However, it is unclear if this is due solely to the characteristic slowness of movements in PD providing more opportunity for incorporating visual feedback to modify reach trajectories, or whether it is due to cognitive decline impacting (feed-forward) movement planning ability. To investigate this, we compared reaction times and movement times of reaches to a target in groups of PD patients with normal cognition (PD-NC), mild cognitive impairment (PD-MCI) or dementia (PD-D), to that of controls with normal cognition (CON-NC) or mild cognitive impairment (CON-MCI). Reaches were undertaken with full visual feedback (at a 'natural' and 'fast-as-possible' pace); with reduced visual feedback of the reaching limb to an illuminated target; and without any visual feedback to a remembered target with eyes closed. The PD-D group exhibited slower reaction times than all other groups across conditions, indicative of less efficient movement planning. When reaching to a remembered target with eyes closed, all PD groups exhibited slower movement times relative to their natural pace with full visual feedback. Crucially, this relative slowing was most pronounced for the PD-D group, compared to the PD-MCI and PD-NC groups, suggesting that substantial cognitive decline in PD exacerbates dependence on visual feedback during upper limb reaches.

Inhibition of mTOR attenuates store-operated Ca2+ entry in cells from endarterectomized tissues of patients with chronic thromboembolic pulmonary hypertension.

Pulmonary vascular remodeling occurs in patients with chronic thromboembolic pulmonary hypertension (CTEPH). One factor contributing to this vascular wall thickening is the proliferation of pulmonary artery smooth muscle cells (PASMC). Store-operated Ca(2+) entry (SOCE) and cytosolic free Ca(2+) concentration ([Ca(2+)](cyt)) in PASMC are known to be important in cell proliferation and vascular remodeling in pulmonary hypertension. Rapamycin is widely known for its antiproliferative effects in injured coronary arteries. Although several reports have suggested favorable effects of rapamycin in animal models of pulmonary hypertension, no reports have been published to date in human tissues. Here we report that rapamycin has an inhibitory effect on SOCE and an antiproliferative effect on PASMC derived from endarterectomized tissues of CTEPH patients. Cells were isolated from endarterectomized tissues obtained from patients undergoing pulmonary thromboendarterectomy (PTE). Immunohistochemical analysis indicated high deposition of platelet-derived growth factor (PDGF) in tissue sections from PTE tissues and increased PDGF receptor expression. PDGF transiently phosphorylated Akt, mammalian target of rapamycin (mTOR), and p70S6 kinase in CTEPH cells from CTEPH patients. Acute treatment (30 min) with rapamycin (10 nM) slightly increased cyclopiazonic acid (10 microM)-induced Ca(2+) mobilization and significantly reduced SOCE. Chronic treatment (24 h) with rapamycin reduced Ca(2+) mobilization and markedly inhibited SOCE. The inhibitory effects of rapamycin on SOCE were less prominent in control cells. Rapamycin also significantly reduced PDGF-stimulated cell proliferation. In conclusion, the data from this study indicate the importance of the mTOR pathway in the development of pulmonary vascular remodeling in CTEPH and suggest a potential therapeutic benefit of rapamycin (or inhibition of mTOR) in these patients.

Chronic Thromboembolic Pulmonary Hypertension.

Chronic thromboembolic pulmonary hypertension occurs when acute thromboemboli fail to dissolve completely. The resulting fibrotic scar tissue within the pulmonary arteries is obstructive and eventually leads to right heart failure. Medical therapy for this condition is supportive, but surgery with pulmonary artery endarterectomy is curative, and carries a low mortality at experienced centers.

Objective assessment of bradykinesia in Parkinson's disease using evolutionary algorithms: clinical validation.

BACKGROUND: There is an urgent need for developing objective, effective and convenient measurements to help clinicians accurately identify bradykinesia. The purpose of this study is to evaluate the accuracy of an objective approach assessing bradykinesia in finger tapping (FT) that uses evolutionary algorithms (EAs) and explore whether it can be used to identify early stage Parkinson's disease (PD). METHODS: One hundred and seven PD, 41 essential tremor (ET) patients and 49 normal controls (NC) were recruited. Participants performed a standard FT task with two electromagnetic tracking sensors attached to the thumb and index finger. Readings from the sensors were transmitted to a tablet computer and subsequently analyzed by using EAs. The output from the device (referred to as "PD-Monitor") scaled from - 1 to + 1 (where higher scores indicate greater severity of bradykinesia). Meanwhile, the bradykinesia was rated clinically using the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) FT item. RESULTS: With an increasing MDS-UPDRS FT score, the PD-Monitor score from the same hand side increased correspondingly. PD-Monitor score correlated well with MDS-UPDRS FT score (right side: r = 0.819, P = 0.000; left side: r = 0.783, P = 0.000). Moreover, PD-Monitor scores in 97 PD patients with MDS-UPDRS FT bradykinesia and each PD subgroup (FT bradykinesia scored from 1 to 3) were all higher than that in NC. Receiver operating characteristic (ROC) curves revealed that PD-Monitor FT scores could detect different severity of bradykinesia with high accuracy (≥89.7%) in the right dominant hand. Furthermore, PD-Monitor scores could discriminate early stage PD from NC, with area under the ROC curve greater than or equal to 0.899. Additionally, ET without bradykinesia could be differentiated from PD by PD-Monitor scores. A positive correlation of PD-Monitor scores with modified Hoehn and Yahr stage was found in the left hand sides. CONCLUSIONS: Our study demonstrated that a simple to use device employing classifiers derived from EAs could not only be used to accurately measure different severity of bradykinesia in PD, but also had the potential to differentiate early stage PD from normality.

Signaling molecules in nonfamilial pulmonary hypertension.

BACKGROUND: Biochemical, genetic, and clinical evidence indicates that smooth-muscle proliferation around small pulmonary vessels is an essential part of the pathogenesis of pulmonary hypertension. Mutations in the bone morphogenetic protein receptor type 2 (BMPR2) have been linked to familial cases of pulmonary hypertension, but the molecular basis of the common nonfamilial forms is unknown. METHODS: We evaluated the pattern of expression of angiopoietin-1, a protein involved in the recruitment of smooth-muscle cells around blood vessels; TIE2, the endothelial-specific receptor for angiopoietin-1; and bone morphogenetic protein receptor type 1A (BMPR1A) and BMPR2 in lung-biopsy specimens from patients with pulmonary hypertension and from normotensive control patients. The effect of angiopoietin-1 on the modulation of BMPR expression was also evaluated in subcultures of human pulmonary arteriolar endothelial cells. RESULTS: The expression of angiopoietin-1 messenger RNA and the protein itself and the phosphorylation of TIE2 were strongly up-regulated in the lungs of patients with various forms of pulmonary hypertension, correlating directly with the severity of disease. A mechanistic link between familial and acquired pulmonary hypertension was demonstrated by the finding that angiopoietin-1 shuts off the expression of BMPR1A, a transmembrane protein required for BMPR2 signaling, in pulmonary arteriolar endothelial cells. Similarly, we found that the expression of BMPR1A was severely reduced in the lungs of patients with various forms of acquired as well as primary nonfamilial pulmonary hypertension. CONCLUSIONS: These findings suggest that all forms of pulmonary hypertension are linked by defects in the signaling pathway involving angiopoietin-1, TIE2, BMPR1A, and BMPR2 and consequently identify specific molecular targets for therapeutic intervention.

Historical perspective: surgery for chronic thromboembolic disease.

This article provides a historical perspective for our current understanding of chronic thromboembolic pulmonary hypertension and surgery for this disease. It chronicles the developments in surgical techniques that have made pulmonary endarterectomy the procedure of choice for obstruction of pulmonary vessels by organized thromboemboli and secondary vessel wall thickening.

Technical advances of pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension.

Pulmonary endarterectomy is the definitive treatment for chronic pulmonary hypertension as the result of thromboembolic disease. Although significant progress has been made over the last decade in recognition, diagnostic modalities, and treatment of this disease, chronic thromboembolic pulmonary hypertension (CTEPH) continues to be severely underdiagnosed and as a consequence pulmonary endarterectomy remains an uncommon procedure. Patients with CTEPH may present with a variety of debilitating cardiopulmonary symptoms. However, once diagnosed, there is no curative role for medical management, and surgery remains the only option. Medical management in these patients is only palliative, and surgery by means of transplantation for this type of pulmonary hypertension is an inappropriate use of resources with less than satisfactory results. In this article we describe the technical advances of pulmonary endarterectomy and the current procedure as it is performed at University of California-San Diego Medical Center.

Outcomes of pulmonary endarterectomy surgery.

Chronic thromboembolic pulmonary hypertension has emerged as one of the leading causes of severe pulmonary hypertension. This disease is estimated to occur in approximately 1 to 5% of all patients who have previously developed an acute pulmonary embolism, although the true prevalence is suspected to be much higher. Chronic thromboembolic pulmonary hypertension is characterized by intraluminal thrombus organization, fibrous stenosis, and vascular remodeling of pulmonary vessels. Pulmonary endarterectomy is an operation that is considered curative for thromboembolic pulmonary hypertension and is therefore superior to transplantation for this condition. This article focuses on the surgical outcomes of patients undergoing pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension and discusses the currently known factors that affect survival after this operation.