Hirschsprung disease in a large birth cohort

The incidence of Hirschsprung disease was studied in a series of almost 700,000 consecutive livebirths in British Columbia from 1964-1982, by means of the records of a health surveillance registry that uses multiple sources of ascertainment. The estimated liveborn incidence rate for Hirschsprung disease was 1 in 4,417 livebirths (156 cases out of 689,118 livebirths). Data pertaining to sex ratio, additional anomalies, recurrence, and mortality were also analyzed over the caseload period 1952 to 1983. A total of 29.8% of cases had some additional anomaly--the majority being nonregional anomalies in other systems or more distantly in the gastrointestinal tract. Cardiovascular and gastrointestinal anomalies not a direct consequence of Hirschsprung disease were the most frequent additional anomalies found, occurring in 10 and 12 of 178 cases, respectively. Sensorineural anomalies were also frequent, occurring in 12 of 178 cases. Clinical implications arising from the study regarding the neonatal assessment of infants with these anomalies are discussed.     

Association of HFE common mutations with Parkinson's disease, Alzheimer's disease and mild cognitive impairment in a Portuguese cohort

Background  

Pathological brain iron deposition has been implicated as a source of neurotoxic reactive oxygen species in Alzheimer (AD) and Parkinson diseases (PD). Iron metabolism is associated with the gene hemochromatosis (HFE Human genome nomenclature committee ID:4886), and mutations in HFE are a cause of the iron mismetabolism disease, hemochromatosis. Several reports have tested the association of HFE variants with neurodegenerative diseases, such as AD and PD with conflicting results.     

The relationship between bone density and the physical performance of ambulatory patients with Parkinson's disease

Compared to the general population, Parkinson's disease (PD) patients have a higher risk of hip fracture and secondary osteoporosis. In the general population, it is known that physical performance is related to bone density. However, the relationship between bone density and physical performance in ambulatory PD patients has not been studied. This study investigated the relationship between bone density and physical performance in ambulatory PD patients. Fourteen ambulatory PD patients (9 men and 5 women; mean age, 67.3+/-7.7 years; Hoehn & Yahr stages 1-3) were enrolled. Bone density of the right calcaneus was assessed using a speed of sound (SOS) ultrasound measurement device. Disease severity was categorized using the Japanese Unified Parkinson Disease Rating Scale (UPDRS). Furthermore, to assess physical performance, lower extremity strength, 10 m gait time, and body sway were measured. Since SOS is strongly affected by age and gender, it was standardized by the patient's age and gender, and the t-score was calculated with the use of SOS. Significant correlations were found between the t-score and UPDRS,lower extremity strength, and 10 m gait time. When the 4 parts of the UPDRS were analyzed separately, only the correlation between part IV and the t-score was not significant. The findings of this study suggest that higher disease severity and weaker lower extremity physical performance decreased bone density in ambulatory PD patients. Therefore, in order to prevent hip fractures in ambulatory PD patients, assessing the UPDRS and lower extremity physical performance may be clinically useful.     

Classification of dynamics of a model of motor coordination and comparison with Parkinson's disease data

In our recent reports motor coordination of human lower limbs has been investigated during pedaling a special kind of ergometer which allows its left and right pedals to rotate independently. In particular, relative phase between left and right rotational-velocity waveforms of the pedals and their amplitude modulation have been analyzed for patients with Parkinson's disease (PD). Several patients showed peculiar interlimb coordination different from the regular anti-phase pattern of normal subjects. We have reported that these disordered patterns could be classified into four groups. Moreover, it has been demonstrated that a mathematical model could reproduce most of the disordered patterns. Such a model includes a schematization of the central pattern generator with two identical half-centers mutually coupled and two tonic control signals from higher motor centers, each of which inputs to one of the half-centers. Depending on the intensities of the tonic signals and on the differences between them, the model could generate a range of dynamics comparable to the clinically observed disordered patterns. In this paper, we explore the dynamics of the model by varying the intensities of the tonic signals in the model. Using the same method used for classifying the clinical data, the dynamics of the model are classified into several groups. The classified groups for the simulated data are compared with those for the clinical data to look at qualitative correspondence. Our systematic exploration of the model's dynamics in a wide range of the parameter space has revealed global organization of the bifurcations including Hopf bifurcations and cascades of period-doubling bifurcations among others, suggesting that the bifurcations, induced by instability of stable dynamics of the human motor control system, are responsible for the emergence of the disordered coordination in PD patients.     

Analysis of cohort studies with multivariate and partially observed disease classification data

Complex diseases like cancers can often be classified into subtypes using various pathological and molecular traits of the disease. In this article, we develop methods for analysis of disease incidence in cohort studies incorporating data on multiple disease traits using a two-stage semiparametric Cox proportional hazards regression model that allows one to examine the heterogeneity in the effect of the covariates by the levels of the different disease traits. For inference in the presence of missing disease traits, we propose a generalization of an estimating equation approach for handling missing cause of failure in competing-risk data. We prove asymptotic unbiasedness of the estimating equation method under a general missing-at-random assumption and propose a novel influence-function-based sandwich variance estimator. The methods are illustrated using simulation studies and a real data application involving the Cancer Prevention Study II nutrition cohort.     

Provision of preventive health care in systemic lupus erythematosus: data from a large observational cohort study

Introduction  

Cancer and infections are leading causes of mortality in systemic lupus erythematosus (SLE) after diseases of the circulatory system, and therefore preventing these complications is important. In this study, we examined two categories of preventive services in SLE: cancer surveillance (cervical, breast, and colon) and immunizations (influenza and pneumococcal). We compared the receipt of these services in SLE to the general population, and identified subgroups of patients who were less likely to receive these services.     

Quantitative assessment of gait determinants during single stance via a three-dimensional model--Part 2. Pathological gait

A three-dimensional model for normal gait formulated in Part 1 is now altered to simulate the dynamics of pathological walking. Mechanisms fundamental to the production of a normal gait pattern are systematically removed, in order to assess contributions from individual gait determinants. Four separate pathological cases are studied: a model neglecting ankle plantarflexor activity; absence of stance knee flexion-extension and foot and knee interaction; both pelvic list and transverse pelvic rotation removed; and finally, a model with all major gait determinants missing. These are used collectively to show that stance knee flexion-extension and foot and knee interaction successively dominate lower-extremity dynamical response during the single support phase of normal gait. The hip abductor muscles, while effecting pelvic list, serve to stabilize this limb, rather than actively determine whole-body vertical acceleration. Mechanisms compensating for a loss in joint motion are also explored. Complete ankle loss may be successfully compensated with increased hip abductor muscle activity; the loss of both ankle and knee, however, demand unacceptable levels of vertical pelvic displacement.     

Experimentation in persons wtih a neurodegenerative disease

Neurodegenerative diseases, of which the Alzheimer's disease, are more and more frequently the object of researches and new experiments. One wishes these experiments to be promising. Experiment with persons affected by a degenerative disease can begin at a moment when the subject is capable, and can be pursued beyond his incapacity. Law authorizes that a person of full age incapable of giving consent be subject of experiment. On the other hand, from the report of the incapacity, consent has to come from the legal representative: the mandatary, tutor or curator. The mandate given in anticipation of the mandator's incapacity empowers another person (the mandatary) to represent her. The use of this mandate confines the inconveniences of the mandator's incapacity to an interruption of the experiment for a duration of some weeks.     

A genomewide analysis provides evidence for novel linkages in inflammatory bowel disease in a large European cohort

Inflammatory bowel disease (IBD) is characterized by a chronic relapsing intestinal inflammation, typically starting in early adulthood. IBD is subdivided into two subtypes, on the basis of clinical and histologic features: Crohn disease and ulcerative colitis (UC). Previous genomewide searches identified regions harboring susceptibility loci on chromosomes 1, 3, 4, 7, 12, and 16. To expand our understanding of the genetic risk profile, we performed a 9-cM genomewide search for susceptibility loci in 268 families containing 353 affected sibling pairs. Previous linkages on chromosomes 12 and 16 were replicated, and the chromosome 4 linkage was extended in this sample. New suggestive evidence for autosomal linkages was observed on chromosomes 1, 6, 10, and 22, with LOD scores of 2.08, 2.07, 2.30, and 1.52, respectively. A maximum LOD score of 1.76 was observed on the X chromosome, for UC, which is consistent with the clinical association of IBD with Ullrich-Turner syndrome. The linkage finding on chromosome 6p is of interest, given the possible contribution of human leukocyte antigen and tumor necrosis-factor genes in IBD. This genomewide linkage scan, done with a large family cohort, has confirmed three previous IBD linkages and has provided evidence for five additional regions that may harbor IBD predisposition genes.     

Risk of osteoporotic fracture in a large population-based cohort of patients with rheumatoid arthritis

Introduction  

Although osteoporosis has been reported to be more common in patients with rheumatoid arthritis (RA), little is known whether the risk of osteoporotic fractures in these patients differs by age, sex, and anatomic site.     

Quantitative evaluation of motor function before and after engraftment of dopaminergic neurons in a rat model of Parkinson's disease

Although gait change is considered a useful indicator of severity in animal models of Parkinson's disease, systematic and extensive gait analysis in animal models of neurological deficits is not well established. The CatWalk-assisted automated gait analysis system provides a comprehensive way to assess a number of dynamic and static gait parameters simultaneously. In this study, we used the Catwalk system to investigate changes in gait parameters in adult rats with unilateral 6-OHDA-induced lesions and the rescue effect of dopaminergic neuron transplantation on gait function. Four weeks after 6-OHDA injection, the intensity and maximal area of contact were significantly decreased in the affected paws and the swing speed significantly decreased in all four paws. The relative distance between the hind paws also increased, suggesting that animals with unilateral 6-OHDA-induced lesions required all four paws to compensate for loss of balance function. At 8 weeks post-transplantation, engrafted dopaminergic neurons expressed tyrosine hydroxylase. In addition, the intensity, contact area, and swing speed of the four limbs increased and the distance between the hind paws decreased. Partial recovery of methamphetamine-induced rotational response was also noted.     

Lipoprotein lipase activity is decreased in a large cohort of patients with coronary artery disease and is associated with changes in lipids and lipoproteins

Lipoprotein lipase (LPL) is crucial in the hydrolysis of triglycerides (TG) in TG-rich lipoproteins in the formation of HDL particles. As both these lipoproteins play an important role in the pathogenesis of atherosclerotic vascular disease, we sought to assess the relationship between post-heparin LPL (PH-LPL) activity and lipids and lipoproteins in a large, well-defined cohort of Dutch males with coronary artery disease (CAD). These subjects were drawn from the REGRESS study, totaled 730 in number and were evaluated against 75 healthy, normolipidemic male controls. Fasting mean PH-LPL activity in the CAD subjects was 108 46 mU/ml, compared to 138 44 mU/ml in controls (P < 0.0001). When these patients were divided into activity quartiles, those in the lowest versus the highest quartile had higher levels of TG (P < 0.001), VLDLc and VLDL-TG (P = 0.001). Conversely, levels of TC, LDL, and HDLc were lower in these patients (P = 0.001, P = 0.02, and P = 0.001, respectively). Also, in this cohort PH-LPL relationships with lipids and lipoproteins were not altered by apoE genotypes. The frequency of common mutations in the LPL gene associated with partial LPL deficiency (N291S and D9N carriers) in the lowest quartile for LPL activity was more than double the frequency in the highest quartile (12.0% vs. 5.0%; P = 0.006). By contrast, the frequency of the S447X LPL variant rose from 11.5% in the lowest to 18.3% (P = 0.006) in the highest quartile. This study, in a large cohort of CAD patients, has shown that PH-LPL activity is decreased (22%; P = 0.001) when compared to controls; that the D9N and N291S, and S447X LPL variants are genetic determinants, respectively, in CAD patients of low and high LPL PH-LPL activities; and that PH-LPL activity is strongly associated with changes in lipids and lipoproteins.     

Cognitive impairment in Parkinson's disease and dementia with lewy bodies: a spectrum of disease

Parkinson's disease (PD) is classically thought of as a movement disorder characterized by tremor, rigidity and postural instability. Nevertheless, there is growing recognition of prominent cognitive impairment in PD and related disorders, which is responsible for substantial disability in these patients. This review will focus on cognitive impairment associated with Lewy body pathology, including PD with dementia (PDD) and dementia with Lewy bodies (DLB). We will review the epidemiology, clinical evaluation, underlying mechanisms and treatment of cognitive impairment in these patients. Despite differences between PDD and DLB, there is clinical, neuropathological and radiological overlap between these disorders, supporting the view that they represent a spectrum of disease. These observations suggest that common targets for diagnosis and treatment of these disorders can be identified.     

The occurrence of chronic disease and other conditions in a large population-based cohort of native Californian twins.

We describe the prevalence of chronic diseases and conditions in a large cohort of twins, which has been developed to facilitate studies of the role of genetics and environment in the development of disease. The California Twin Program (CTP) comprises twins born in California between 1908 and 1982. Birth records from all multiple births (256,616 in total) were linked (multiple times between 1990 and 2001) with the California Department of Motor Vehicles (DMV) roster of licensees to obtain address information. The linkages have revealed 161,109 matches and, because of less complete DMV records in some years, were less successful in older females than in all others. To date over 51,000 of these twins have completed a detailed 16-page mailed risk factor questionnaire. Based on estimates of numbers of individuals receiving a questionnaire, our crude response rates are as high as 63.6% (among females currently in their 50s), with an overall crude response rate of 37.9%. Similar to our previous report regarding the first 42,000 twins, the current group who have completed the questionnaire are representative of the population from which they were drawn (in terms of age, sex, race and residential distribution). Self-reported disease frequencies are provided, along with current estimates of future cancer incidence and mortality rates likely to be observed in the group. We outline our plans for cohort expansion, additional studies using the cohort, and future plans for inviting collaboration.     

A randomised controlled trial evaluating the effect of an individual auditory cueing device on freezing and gait speed in people with Parkinson's disease

Background  

Parkinson's disease is a progressive neurological disorder resulting from a degeneration of dopamine producing cells in the substantia nigra. Clinical symptoms typically affect gait pattern and motor performance. Evidence suggests that the use of individual auditory cueing devices may be used effectively for the management of gait and freezing in people with Parkinson's disease. The primary aim of the randomised controlled trial is to evaluate the effect of an individual auditory cueing device on freezing and gait speed in people with Parkinson's disease.     

Quantitative analysis of upper limbs during gait: a marker set protocol

Purpose: to develop a marker set for simultaneously assessing upper and lower limb biomechanics during gait.Methods: 24 healthy young subjects (mean age: 23.80 years) were assessed quantitatively using an optoelectronic system, two force platform and a video system. Passive markers were positioned according to the proposed marker set which enables acquiring the upper and lower limb movement simultaneously during Gait Analysis. In addition to the traditional parameters obtained from Gait Analysis, the shoulder and elbow angles were computed from markers coordinates of upper limbs; then, some significant parameters were identified and calculated. From shoulder and elbow position, angles, angular velocities, angular acceleration, moments, and powers were calculated for shoulder and elbow joints. Results: Kinematic and kinetic data were obtained in the three planes (sagittal, frontal, and transversal) for the shoulder and in the sagittal plane for the elbow. Normative ranges were obtained for these parameters from data of healthy participants. Conclusions: The proposed experimental set-up enables simultaneous assessment of upper and lower limb movement during gait. Thus, no further trials are required in addition to those acquired during standard gait analysis in order to assess upper limb motion, which also makes the experimental set-up feasible for clinical applications.     

Quantitative functional anatomy of the lower limb with application to human gait

A scheme was developed to classify muscles according to their primary, secondary and tertiary functions, e.g. a muscle which produces primarily a flexion moment may also produce secondary abduction and tertiary internal rotation moments. The functions of muscles crossing the hip and knee joints were computed based upon the changing relative positions of joint centers and muscle origins and insertions during one gait cycle. The function of several of the major muscles crossing the hip and knee joints is reported for the different limb positions corresponding to normal gait. It was found that the amount of force necessary to produce a given moment about a joint was dependent upon the limb position. In addition, the muscle functions changed significantly with limb position. Electrical stimulation of muscles of a paralyzed subject gave qualitative support to the results.     

Single and dual task gait training in people with Parkinson's Disease: A protocol for a randomised controlled trial

Background  

Difficulty performing more than one task at a time (dual tasking) is a common and disabling problem experienced by people with Parkinson disease (PD). If asked to perform another task when walking, people with PD often take shorter steps or walk more slowly. Currently there is uncertainty about whether clinicians should teach people with PD to avoid dual tasking or whether they should encourage them to practice dual tasking with the hope that practice will lead to enhanced performance. This study will address this issue by comparing single to dual task gait training.     

PPAR: a therapeutic target in Parkinson's disease

Parkinson's disease (PD) is a progressive and chronic neurodegenerative disorder, characterized by progressive loss of dopaminergic neurons in substantia nigra. The etiology and pathogenesis of PD is still elusive, however, a large body of evidence suggests a prominent role of oxidative stress, inflammation, apoptosis, mitochondrial dysfunction and proteosomal dysfunction in the pathogenesis of PD. Due to multifactorial nature of the disease, currently available drug therapy cannot halt / slow down the disease progression, and only provides symptomatic relief. Peroxisome proliferator-activated receptor (PPAR), a member of nuclear receptor superfamily, regulates development, tissue differentiation, inflammation, mitochondrial function, wound healing, lipid metabolism and glucose metabolism. Recently, several PPAR agonists were shown to exert neuroprotective activity against oxidative damage, inflammation and apoptosis in several neurodegenerative disorders including Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis and multiple sclerosis. Similarly, regular intake of PPAR activating non-steroidal anti-inflammatory drugs such as indomethacin and ibuprofen was associated with reduced incidence and progression of neurodegenerative disorders in several epidemiological studies. In this article, we review studies relating to the neuroprotective effect of PPAR agonists in in vitro and in vivo models of PD. Similarly, the pharmacological mechanism in neuroprotective actions of PPAR agonists is also reviewed. In conclusion, PPAR agonists exert neuroprotective actions by regulating the expression of a set of genes involved in cell survival processes, and could be a therapeutic target in debilitating neurodegenerative illnesses such as PD.