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.     

Long-term mortality in a cohort of severely obese persons in Italy

Few large studies on Northern European or US populations reported on mortality of severely obese individuals (BMI > or = 40 kg/m(2)). We studied a historical cohort in Italy to compare its mortality with previous findings, to investigate its relationship with BMI in the >40 range, and to provide evidence useful for clinical decision-making on treatment. The cohort comprised 4,837 persons with a BMI > or =40 kg/m(2) and aged > or =18 at first consultation, referred to six centers for obesity treatment between 1975 and 1996. After exclusion of persons with missing personal identification data or those untraceable, 4,498 (972 men, 3,526 women) remained for analyses. We calculated standardized mortality ratios (SMRs) and carried out Cox proportional hazards modeling. General mortality (484 deaths: 153 men, 331 women) was in excess, with SMRs (95% confidence intervals) of 2.78 (2.36-3.26) for men and 2.10 (1.88-2.34) for women. Excess mortality (i) was observed in all BMI categories, except among women weighing 40-42.4 kg/m(2); (ii) increased with increasing BMI; (iii) increased less among persons recruited in recent calendar periods; (iv) was inversely related to age attained at follow-up; and (v) was due to cardiovascular and respiratory diseases and violent deaths but not malignant neoplasms. Excess mortality was similar to that observed in Northern European and US cohorts. Its steady increase with BMI levels > or =40 suggests that benefits proportional to weight reduction are expected and that even limited control may be beneficial. The smaller excess among persons recruited most recently might reflect better treatment.     

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.     

Estimating hazard ratios in cohort data with missing disease information due to death

In clinical and epidemiological studies information on the primary outcome of interest, that is, the disease status, is usually collected at a limited number of follow‐up visits. The disease status can often only be retrieved retrospectively in individuals who are alive at follow‐up, but will be missing for those who died before. Right‐censoring the death cases at the last visit (ad‐hoc analysis) yields biased hazard ratio estimates of a potential risk factor, and the bias can be substantial and occur in either direction. In this work, we investigate three different approaches that use the same likelihood contributions derived from an illness‐death multistate model in order to more adequately estimate the hazard ratio by including the death cases into the analysis: a parametric approach, a penalized likelihood approach, and an imputation‐based approach. We investigate to which extent these approaches allow for an unbiased regression analysis by evaluating their performance in simulation studies and on a real data example. In doing so, we use the full cohort with complete illness‐death data as reference and artificially induce missing information due to death by setting discrete follow‐up visits. Compared to an ad‐hoc analysis, all considered approaches provide less biased or even unbiased results, depending on the situation studied. In the real data example, the parametric approach is seen to be too restrictive, whereas the imputation‐based approach could almost reconstruct the original event history information.     

Pelvic inflammatory disease and the intrauterine device: findings in a large cohort study.

The incidence of pelvic inflammatory disease was investigated among parous women taking part in the Oxford-Family Planning Association contraceptive study. Hospital admission rates for "acute definite" disease were 1.51 per 1000 woman-years among those currently using an intrauterine device (IUD) and 0.14 per 1000 woman-years among those using other methods of birth control (age-standardised relative risk 10.5 to 1 with 95% confidence limits of 5.4 to 1 and 32 to 1). There was little evidence of an increased risk of such disease in ex-users of an IUD. Hospital admission for "chronic definite" disease, on the other hand, was commoner in ex-users of an IUD than in current users. Acute definite disease occurred somewhat more frequently during the early months of use of an IUD than during the later months. While the rate of such disease was increased in users of each type of device, the highest rate (8.1 per 1000 woman-years) was observed in users of the Dalkon shield. This rate, however, was based on only three affected women.     

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.     

Plasma lipid profiling in a large population-based cohort

We have performed plasma lipid profiling using liquid chromatography electrospray ionization tandem mass spectrometry on a population cohort of more than 1,000 individuals. From 10 μl of plasma we were able to acquire comparative measures of 312 lipids across 23 lipid classes and subclasses including sphingolipids, phospholipids, glycerolipids, and cholesterol esters (CEs) in 20 min. Using linear and logistic regression, we identified statistically significant associations of lipid classes, subclasses, and individual lipid species with anthropometric and physiological measures. In addition to the expected associations of CEs and triacylglycerol with age, sex, and body mass index (BMI), ceramide was significantly higher in males and was independently associated with age and BMI. Associations were also observed for sphingomyelin with age but this lipid subclass was lower in males. Lysophospholipids were associated with age and higher in males, but showed a strong negative association with BMI. Many of these lipids have previously been associated with chronic diseases including cardiovascular disease and may mediate the interactions of age, sex, and obesity with disease risk.     

Quantitative assessment of gait determinants during single stance via a three-dimensional model--Part 1. Normal gait

In this two-part paper, a variety of three-dimensional, dynamical models are constructed for simulating the single support phases of normal and pathological human gait. A major objective of this work is to quantify the influence of individual gait determinants on the ground reaction forces generated during normal, level walking. To this end, Part 1 presents a three-dimensional, seven degree-of-freedom model incorporating five of the six fundamental determinants of gait. On the basis of crude muscle-force and/or joint-moment trajectories, body-segmental motions and ground reaction forces are synthesized open loop. Through a quantitative comparison with experimental gait data, the model's predictions are evaluated. Our simulation results suggest that pelvic list is not as dominant a dynamical determinant as either stance knee flexion-extension or foot and knee interaction. Transverse pelvic rotation, however, makes an important contribution by limiting the magnitude of the horizontal ground reaction prior to opposite heel-strike.     

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.     

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.     

Online gait event detection using a large force platform embedded in a treadmill

Gait research and clinical gait training may benefit from movement-dependent event control, that is, technical applications in which events such as obstacle appearance or visual/acoustic cueing are (co)determined online on the basis of current gait properties. A prerequisite for successful gait-dependent event control is accurate online detection of gait events such as foot contact (FC) and foot off (FO). The objective of the present study was to assess the feasibility of online FC and FO detection using a single large force platform embedded in a treadmill. Center-of-pressure, total force output and kinematic data were recorded simultaneously in 12 healthy participants. Online FC and FO estimates and spatial and temporal gait parameters estimated from the force platform data-i.e., center-of-pressure profiles-were compared to offline kinematic counterparts, which served as the gold standard. Good correspondence was achieved between online FC detections using center-of-pressure profiles and those derived offline from kinematic data, whereas FO was detected 31ms too late. A good relative and absolute agreement was achieved for both spatial and temporal gait parameters, which was improved further by applying more fine-grained FO estimation procedures using characteristic local minima in the total force output time series. These positive results suggest that the proposed system for gait-dependent event control may be successfully implemented in gait research as well as gait interventions in clinical practice.     

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.     

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.     

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.     

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.