bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of hospitals' structural clinical integration on efficiency and patient outcome
Authors: Lee Kwangsoo , Wan Thomas T. H.
Published: October 2002

The objective of this study was to examine the relationships among structural clinical integration, average total charge, and adverse patient outcomes. The conceptual framework of this study is based on Donabedian's triadic model for outcomes research on structure, process, and outcome. Retrospective data were obtained from multiple sources: (1) the American Hospital Association (AHA) annual survey in 1997; (2) the Area Resource File (ARF) data set in 1997; (3) the Dorenfest IHDS + database (version 2); and (4) the National Inpatient Sample (NIS) data set in 1997. A cross-sectional study design was used. Outcomes indicators were risk-adjusted with logistic regression, and the Medicare case-mix index was used for the risk-adjustment of the efficiency indicator. LISREL (LInear Structural RELationship) was used to test the hypotheses that structural clinical integration is negatively related to average total charge, and that average total charge is positively related to adverse patient outcomes. The risk-adjustment models were successful in discriminating the patients who suffered adverse events. Significant associations were found between structural clinical integration and average total charge per admission, between average total charge per admission and surgical complication, and between surgical complication and in-hospital death. However, the implementation of structural clinical integration did not show the expected reduction in total charge per admission. This study confirms Donabedian's model for outcomes research. However, the study found that hospitals with highly integrated structures showed no immediate financial benefit. Structural clinical integration has only an indirect effect on patient care outcomes.
A study and comparative analysis of managerial and leadership effectiveness in the National Health Service: an empirical factor analytic study within an NHS Trust hospital
Authors: Hamlin R. G.
Published: October 2002

The research described in this article was concerned primarily with identifying the criteria of managerial/leadership effectiveness applying at the middle and front line levels of management within an NHS Trust Hospital using critical incident technique and factor analysis methods. The findings suggest that the self-perceptions of managers and the perceptions of superiors and subordinates are very similar, and only differ on a limited number of criteria. This challenges the 'perspective-specific' models of managerial effectiveness advocated by some researchers. The results are compared against those from a near identical study carried out by the author within one part of the British Civil Service, and the results from a different but comparable factor analytic study carried out by other researchers elsewhere in the NHS. The results suggest the existence of generalized criteria of managerial effectiveness, which lend considerable support to the notion of the 'universally effective manager'. This challenges the 'contingent models' of managerial effectiveness advocated by various expert commentators. In addition, the research supports the new model of transformational leadership offered by Alimo-Metcalfe and Alban-Metcalfe for application within both the NHS and local government, and adds to the empirical base supporting the current drive towards evidence-based practice in management within the healthcare sector.
Strategic relatedness in mergers and financial performance: the case of the health maintenance organization industry in the United States
Authors: Weech-Maldonado Robert
Published: October 2002

Knowledge and identification of strategic factors associated with favourable post-acquisition performance can be of benefit to both managers and shareholders. From a management perspective, the identification of contextual factors that can influence postmerger performance is 'strategic' in nature, and should be considered in the analysis of future acquisitions. Within the context of the health maintenance organization (HMO) industry, this study examines the impact of strategic relatedness on postmerger financial performance. Strategic relatedness is conceptualized as similarity between the acquirer and target HMOs in terms of operational efficiency, marketing orientation, organizational structure and profit orientation. Regression analysis showed that similarity in operational efficiency and similarity in HMO structure were associated with better postmerger financial performance. However, marketing orientation similarity and profit orientation similarity were not significantly related to postmerger performance. This finding suggests that HMO mergers involving firms with similar strategic orientations and similar approaches to the delivery of care have greater strategic fit and experience better financial performance.
Recent Developments in the Design and Performance of Road Traffic Noise Barriers
Authors: Samuels Stephen , Ancich Eric
Published: October 2002

This paper deals with some recent developments in the design and performance of roadside barriers that are applied as a means of controlling road traffic noise. It is a review paper that is based on the outcomes of literature and information searches undertaken for and on behalf of the Roads and Traffic Authority of NSW. Some interesting, ongoing developments in the design and performance of traffic noise barriers have been identified. In particular, three types of innovative barrier designs were identified that appear to offer the potential for increased attenuation without the need for substantial increases in barrier height. Each of these developments is considered in some detail in the paper and recommendations are made of the possibility of pursuing them further.
Adaptive state feedback control by orthogonal approximation functions
Authors: Del Vecchio D. , Marino R. , Tomei P.
Published: October 2002

For a class of feedback linearizable systems a state feedback adaptive control based on orthogonal approximation functions is designed, under the assumption of matching conditions for the uncertainties and of known bounds on a given compact set for the unknown non‐linear function. By virtue of Bessel inequality, the bound on the unknown non‐linear function gives a bound on the norm of the optimal weight vector for any choice of the number of approximating functions, which allows us to design a robust state feedback adaptive scheme with parameter projections. The resulting control algorithm has several advantages over available schemes: it does not requirea prioribounds on the approximation error and on the optimal weight vector; it is repeatable, since the set of initial conditions for the state and the parameter estimates from which a class of reference signals is tracked is explicitly given; it characterizes theL∞andL2performance of the tracking error in terms of both the approximation and the parameter estimation error; it gives full flexibility in the choice of the number of approximating orthogonal functions. Copyright © 2002 John Wiley & Sons, Ltd.
Association of maturation, sex, and body fat in cardiorespiratory fitness
Authors: Mota Jorge , Guerra Sandra , Leandro Carol , Pinto Armando , Ribeiro JosÉ C. , Duarte JosÉ A.
Published: October 2002

The aims of this cross‐sectional study were 1) to estimate changes in body composition and cardiorespiratory fitness across stages of pubertal maturation, and 2) to describe the relationship between maturity status and body fatness, regional fat distribution, and cardiorespiratory fitness. The sample consisted of 494 children (254 males, 240 females), 8–16 years of age. Height and weight were measured with standard anthropometric methods. Percentage of fat (%F) was estimated from two skinfold thicknesses and regional fat distribution was estimated by the ratio of the subscapular to the triceps skinfold (S/T ratio). Biological maturity was based on self‐assessment of breast stages in females and pubic hair stages in males. A maximal multistage 20‐m shuttle run was used to predict maximal aerobic capacity from maximal aerobic speed. Both VO2max and 20SRT‐time were used as indicators of cardiorespiratory fitness. ANCOVA with age as the covariate was used. There were significant differences among girls across pubertal stages. Among boys, only weight and height differed significantly by stage of maturity. When adjusted for maturity status, cardiorespiratory fitness expressed either as VO2/kg body mass or 20SRT‐time was inversely associated with %F in both sexes. This suggests that sexual maturity status alone accounts for a small portion of the variance in aerobic fitness. Height, %F and the S/T ratio were also significantly associated with VO2/kg body mass and 20SRT‐time. Am. J. Hum. Biol. 14:707–712, 2002. © 2002 Wiley‐Liss, Inc.
Improved rig for dynamically calibrating skinfold calipers: Comparison between Harpenden and Slim Guide instruments
Authors: Hewitt G.B. , Withers R.T. , Brooks A.G. , Woods G.F. , Day L.A.
Published: October 2002

This article describes an improved rig for the dynamic calibration of skinfold calipers. The new unit is 5% lighter and almost 60% smaller than its predecessor (Carlyon et al., 1996, 1998) with a 9.5 mm solid aluminium base and a quick release caliper mount providing stability to both the rig and caliper. Automation of the gap controller with an electric motor standardizes the jaw opening and closing velocity, thereby enabling hands‐free operation. Frictional losses in the moving components of the rig have been reduced by replacing the main bush of the swing arm with a bearing, reducing the mass of the swing arm, adding a support wheel to the end of the swing arm, and replacing fishing swivels with a universal joint to allow for changes in the opening screw angle as the caliper's arm moves through its arc. This rig can also be adapted to different types of calipers by changing the position of the load cell, microswitches, and the caliper mount. A universal mounting bracket that can be secured to almost any table supports the rig in a vertical plane when calibrating the load cell. To demonstrate the versatility of the calibration rig, preliminary data are presented for the upscale and downscale jaw pressures of seven Harpenden and seven Slim Guide calipers. Am. J. Hum. Biol. 14:721–727, 2002. © 2002 Wiley‐Liss, Inc.
Association between bone mineral density (DXA), body structure, and body composition in middle‐aged men
Authors: Langendonck Leen Van , Claessens Albrecht L. , Lefevre Johan , Thomis Martine , Philippaerts Renaat , Delvaux Katrien , Lysens Roeland , Eynde Bavo Vanden , Beunen Gaston
Published: October 2002

The association between bone mass, body structure, and body composition was explored in 156 men, 40 years of AGE. Bone mineral density (total body, lumbar spine, left arm, and left leg) was obtained by dual‐energy X‐ray absorptiometry (DXA; Hologic QDR 4500A). Body structure was determined from a battery of anthropometric dimensions with a principal components analysis. Body composition was estimated with DXA. From the 24 anthropometric dimensions, three components were extracted and identified as muscle, fat, and skeletal length. Significant correlations between the muscle component and all BMD measurements (r = 0.28–0.44) were obtained. Except for BMD of the left arm, which correlated significantly, but negatively, with the fat component (r = −0.16), no significant relations were found between the fat component and BMD. There were significant correlations between lean mass, fat mass, and BMD measurements. The correlations were higher between lean mass and BMD (r = 0.22–0.44) than between fat mass and BMD (r = 0.08–0.24). The multiple regression analysis revealed that except for BMD of the left arm only lean mass or the muscle component, and not fat mass or the fat component, were independent predictors of BMD. It is concluded that the principal anthropometric determinant of BMD in middle‐aged men is lean mass or muscle. Am. J. Hum. Biol. 14:735–742, 2002. © 2002 Wiley‐Liss, Inc.
Age‐related pattern of body density and body composition of Japanese men and women 18–59 years of age
Authors: Tahara Y. , Moji K. , Aoyagi K. , Tsunawake N. , Muraki S. , Mascie‐Taylor C.G.N.
Published: October 2002

Age‐related patterns of body size and composition were studied in a cross‐sectional sample of Japanese adults 18–59 years of age. Height, weight, the body mass index (BMI), body density (BD), percentage body fat (%Fat), fat mass (FM), fat‐free mass (FFM), and the sum of seven skinfold thicknesses (SF) of 288 men and 552 women were considered. Body density was measured by underwater weighing densitometry. Mean values of height, weight, BMI, BD, %Fat, FM, FFM, and SF of males were 169.0 cm, 65.3 kg, 22.8 kg/m2, 1.0600 g/ml, 17.0%, 11.4 kg, 53.9 kg, and 95.0 mm, respectively, while corresponding values for females were 157.4 cm, 52.9 kg, 21.4 kg/m2, 1.0420 g/ml, 24.4%, 13.1 kg, 39.7 kg, and 128.2 mm, respectively. Height, BD, and FFM correlated negatively with age in both sexes, while weight, BMI, %Fat, FM, and SF correlated positively with age. The highest BD and the lowest %Fat were observed in males ages 20 to <25 years (G20) and in females 25 to <30 years (G25). The lowest BD and highest %Fat were observed in G50 in both sexes. Correlations among parameters of body size and composition were stable with age in each sex. Height correlated negatively with BMI and %Fat in females, but not in males. In males, FM started to increase between G20 and G25 and continued to increase until G50, while SF and BMI remained stable during this period. In females, FM accumulation started around 30 years of age and continued until G50 and was accompanied by increases in SF and BMI. Am. J. Hum. Biol. 14:743–752, 2002. © 2002 Wiley‐Liss, Inc.
Is obesity associated with poor sleep quality in adolescents?
Authors: Gupta Neeraj K. , Mueller William H. , Chan Wenyaw , Meininger Janet C.
Published: October 2002

Obesity has reached epidemic proportions in the U.S. and more developed countries, particularly so among adolescents. A substantial impact on public health could be achieved if other factors causing obesity besides the conventional ones of diet and physical activity could be identified and acted upon. The present study investigates whether there is a link between low sleep quality and obesity in a tri‐ethnic, cross‐sectional sample (n = 383) of male and female adolescents ages 11–16 years old (Heartfelt Study). Sleep quality was expressed as two variables, total sleep time and sleep disturbance time obtained by 24‐hour wrist actigraphy. Percent body fat and body mass index (BMI) were used together to define obesity. The potential influence of demographic and behavioral confounders were considered in models that described the relation of sleep to obesity occurrence. Obese adolescents experienced less sleep than nonobese adolescents (P < 0.01). For each hour of lost sleep, the odds of obesity increased by 80%. Sleep disturbance was not directly related to obesity in the sample, but influenced physical activity level (P < 0.01). Daytime physical activity diminished by 3% for every hour increase in sleep disturbance. The above observations were independent of potential confounding variables. Inadequate and poor sleep quality in adolescents may be important factors to consider in the prevention of childhood obesity. Am. J. Hum. Biol. 14:762–768, 2002. © 2002 Wiley‐Liss, Inc.
Growth pattern of overweight preschool children in the Siouxland WIC Program
Authors: May Richard , Barber Jackie , Simpson Tracy , Winders Nicole , Kuhler Karen , Schroeder Sharon
Published: October 2002

Demographic, nutritional, and anthropometric data were collected from 134 preschool children enrolled in the Siouxland Special Supplemental Nutrition Program for Women, Infants, and Children (WIC). All children were diagnosed as overweight between the ages of 8 months and 3 years. Weight and length/height z‐scores were calculated for birth measurements and for postnatal measurements up to 3 years. The main hypothesis involved stability of weight and length/height z‐scores between successive WIC visits. Average changes in z‐scores between measurements were calculated and tested for significance using paired t‐tests. Multiple regression analysis was used to test relationships between changes in weight z‐scores and demographic/nutritional characteristics. The overweight group had a higher percentage of Hispanic children than the total Siouxland WIC population. Overweight children were also significantly different in terms of birthweight, monthly household income, number in the house, and mother's education level. The children displayed a large average increase in weight z‐scores between birth and 8 months (P < 0.001). Weight z‐scores also increased significantly between 12 and 30 months. Length z‐scores increased significantly between 18 and 30 months but remained lower than weight z‐scores. Initial weight, sex of child, breastfeeding, and household size were significantly related to changes in weight z‐scores among overweight children. Results of recent studies suggest that rapid weight gain in infancy may increase the risk of overweight during later childhood. Am. J. Hum. Biol. 14:769–776, 2002. © 2002 Wiley‐Liss, Inc.
Health‐related quality of life in physically active and sedentary obese women
Authors: Hulens M. , Vansant G. , Claessens A.L. , Lysens R. , Muls E. , Rzewnicki R.
Published: October 2002

The aim was to assess dimensions of health‐related quality of life (HRQL) in women attending an obesity clinic, and to rate differences in HRQL in those with the highest and lowest levels of physical activity (PA). The sample included 113 sedentary and 101 physically active subjects from a total sample of 375 overweight women 16–65 years, with a body mass index (BMI) ≥27.5 kg/m2 consulting at an outpatient Endocrinology Clinic, and 82 lean female volunteers who served as a reference. Weight, height, body composition, PA, physical medical conditions, depression, body image, cognitive‐behavioral conceptualization of obesity, eating behavior, functional status, walking ability, exercise capacity, social functioning, and general health and perceived quality of life were assessed cross‐sectionally. The prevalence of medical conditions and depression was not statistically different (P<0.05) in sedentary and active women. In sedentary obese women, body attitude, walking ability, and aerobic fitness were poorer; the number of people to turn to for social support was smaller; physical attributions about the basis of the subjects obesity were less pronounced; and eating was more the consequence of external triggers or diffuse emotions than in physically active obese women (P<0.05). The findings indicate that a higher level of PA in an obese female clinical population was positively associated with diverse dimensions of HRQL. However, it was not possible to determine if these favorable aspects of HRQL are the cause or the consequence of a higher PA level. Am. J. Hum. Biol. 14:777–785, 2002. © 2002 Wiley‐Liss, Inc.
Distinct craniofacial‐skeletal‐dermatological dysplasia in a patient with W290C mutation in FGFR2
Authors: Shotelersuk Vorasuk , Ittiwut Chupong , Srivuthana Sumarlee , Mahatumarat Charan , Lerdlum Sukalaya , Wacharasindhu Suthipong
Published: October 2002

Mutations in the fibroblast growth factor receptor genes (FGFR) have been known to be associated with many craniosynostosis syndromes with overlapping phenotypes. We studied a 15‐year‐old Thai boy with an unspecified craniosynostosis syndrome characterized by multiple suture craniosynostoses, a persistent anterior fontanel, corneal scleralization, choanal stenosis, atresia of the auditory meatus, broad thumbs and great toes, severe scoliosis, acanthosis nigricans, hydrocephalus, and mental retardation. Radiography revealed bony ankyloses of vertebral bodies of T9–12, humero‐radio‐ulnar joints, intercarpal joints, distal interphalangeal joints of fifth fingers, fibulo‐tibial joints, intertarsal joints, and distal interphalangeal joints of the first toes. The patient was a heterozygous for a 870G → T change resulting in a W290C amino acid substitution in the extracellular domain of the fibroblast growth factor receptor 2 gene (FGFR2). This mutation has previously been reported in a patient with severe Pfeiffer syndrome type 2 that is distinct from the craniosynostosis in our patient. These findings emphasize locus, allelic, and phenotypic heterogeneity of craniofacial‐skeletal‐dermatological syndrome due to FGFR2 mutations. © 2002 Wiley‐Liss, Inc.
Genetic disease in the 1960s: A structural revolution
Authors: Lindee M. Susan
Published: October 2002

From about 1955 to about 1975, an explosion of new institutions, disciplines, databases, interventions, practices, techniques, and ideas turned technically driven human genetics from a medical backwater to an exotic and appealing medical research frontier. In the early 1960s, health care professionals were attracted to the new insights of cytogenetics, including the chromosomal explanation of Down syndrome and of other congenital defects and abnormalities of sexual development. The discovery of a connection between myeloid leukemia and chromosomal abnormalities in leukemic cells made human cytogenetics suddenly relevant to cancer research and diagnosis. Successful dietary treatment of phenylketonuria brought genetic disease into the domain of public health and provoked legislative programs with sweeping long‐term consequences. Meanwhile, those promoting the importance of genetic disease to medical education began to elaborate the idea that disease was literally becoming more genetic, as a consequence of techno‐historical change. In this article, I present an overview of these remarkable events and a framework for understanding how and why they occurred. I emphasize the important roles of family members, religious isolates, legislators, pediatricians, and others who were not trained in genetic science, but who became advocates, at many levels, of genetic medicine. And I suggest that the idea, so important to the Human Genome Project, that “all disease is genetic disease” was structurally realized and institutionalized long before technologies for mapping the genome were available. © 2002 Wiley‐Liss, Inc.
Hunting for a hypoglycemia gene: Severe neonatal hypoglycemia in a consanguineous family
Authors: Molven Anders , Rishaug Unni , Matre Guri E. , Njølstad Pål R. , Søvik Oddmund
Published: October 2002

Hypoglycemia is a dreaded complication in diabetes mellitus patients treated with insulin, but is also a symptom that is observed in many disorders. In some metabolic diseases of early infancy, low blood glucose is the major presentation and the condition can become life‐threatening. Such cases are often attributed to inherited hyperinsulinism. Vidnes and Øyasæter [1977: Pediatr Res 11:943–949] described a son of consanguineous Pakistani parents with severe neonatal hypoglycemia and concluded that the patient probably suffered from an isolated glucagon deficiency. We have continued the investigation of this family, which now includes a hypoglycemic daughter and two healthy children. The original diagnosis is questioned because the second case of hypoglycemia can be explained by hyperinsulinism. We proceeded with microsatellite marker analysis for selected candidate genes under the assumption that the condition is autosomal recessive and that affected children are homozygous for a mutated allele. The four known genetic causes for inborn hyperinsulinism (mutations in the genes ABCC8, KCNJ11, GLUD1, and GCK) were excluded. Furthermore, we eliminated 13 candidate genes coding for transcription factors involved in pancreas development and differentiation. The analysis was also negative for the genes encoding insulin and glucagon, their receptors, and processing enzymes. The identification of a novel gene for persistent neonatal hypoglycemia can be expected to yield fundamental information about glucose homeostasis, and will therefore have implications for the understanding of diabetes as well. © 2002 Wiley‐Liss, Inc.
Gastrointestinal complications of Russell‐Silver syndrome: A pilot study
Authors: Anderson Jeff , Viskochil David , O'Gorman Molly , Gonzales Chad
Published: October 2002

Russell‐Silver syndrome (RSS) is a genetic syndrome with clinical manifestations of intrauterine and postnatal growth retardation, normal head circumference, body asymmetry, and distinctive facial appearance. We followed an infant diagnosed with RSS who had occurrence of multiple gastrointestinal complications. Although there are a number of published reports describing gastrointestinal problems associated with RSS, specific gastrointestinal diseases have not been recognized as major features. We hypothesize that gastrointestinal complications may be more frequent in RSS cases than previously reported. To address our hypothesis, we developed a pilot study of RSS cases to identify and characterize associated gastrointestinal complications. Surveys were distributed by MAGIC, a support group for individuals with RSS. Surveys included information on the objective and subjective characteristics used to diagnose RSS, as well as descriptions of gastrointestinal problems. Completed surveys were returned on 135 individuals. We used strict diagnostic guidelines to determine affected status of children reported in our survey. Of the 135 surveys completed, 65 were determined to have clear‐cut RSS. The diagnoses were made without knowledge of the gastrointestinal symptoms of any of the subjects. Of the 65 subjects with “clear cut” RSS, 50 (77%) had gastrointestinal symptoms. Major specific symptoms included gastroesophageal reflux disease (34%), esophagitis (25%), food aversion (32%), and failure to thrive (63%). A common theme in gastrointestinal complications of RSS is significant gastroesophageal reflux that includes esophagitis and food aversion. Results of this survey suggest that there is an association of gastrointestinal complications with RSS that should be addressed in diagnosis as well as management protocols for children with this condition. © 2002 Wiley‐Liss, Inc.
Pulmonary agenesis: Expansion of the VCFS phenotype
Authors: Conway Karen , Gibson Ronald , Perkins Jonathan , Cunningham Michael L.
Published: October 2002

In this report, we describe a child with the typical craniofacial manifestations of velocardiofacial syndrome (VCFS), a 22q11.2 deletion, and unilateral pulmonary agenesis. The 22q11.2 deletion syndromes are associated with malformations presumed to be caused by a disruption of cephalic neural crest cell migration during the fourth week of embryonic development. We suggest that the pulmonary agenesis seen in this case is related to a disruption of the dorsal aortic arch development that selectively interfered with lung bud growth. We suggest that pulmonary agenesis should be considered part of the spectrum of malformations seen in 22q11.2 deletion. © 2002 Wiley‐Liss, Inc.
Fetal akinesia deformation sequence: A study of 30 consecutive in utero diagnoses
Authors: Witters Ingrid , Moerman Philippe , Fryns Jean‐Pierre
Published: October 2002

The etiology of the fetal akinesia deformation sequence (FADS) is heterogeneous and can be the result of neurogenic and myopathic disorders, restrictive dermopathy, teratogen exposure, and intrauterine constraint. We present the prenatal and fetopathological findings in a consecutive series of 30 affected fetuses with normal chromosomal results. According to the in utero time of onset of the fetal akinesia, the severity of the phenotype varied from a severe, generalized FADS in the early‐onset group to milder defects, as isolated distal arthrogryposis in the late‐onset group. No more than 10% (3/30) were diagnosed in the first trimester of pregnancy and all presented a severe phenotype. Twenty‐seven of the thirty (90%) were diagnosed after the first trimester, with a severe FADS in 15/27 and a milder phenotype of distal arthrogryposis in 12/27. In all 30 patients, extensive neuropathological studies (brain, spinal cord, and muscles) were performed. In 16 patients (53%) a specific diagnosis could be made (central nervous system abnormalities 9/16; spinal cord 1/16; primary myopathy 3/16; syndromic 3/16). In 10 others (33%), pathological neuromuscular findings were present but no definitive diagnosis was established. In 4 patients (13%), neuromuscular findings were normal, and the etiology of the FADS remained unexplained. © 2002 Wiley‐Liss, Inc.
Meiotic origin of two ring chromosomes 18 in a girl with developmental delay
Authors: Baumer A. , Giovannucci Uzielli M.L. , Guarducci S. , Lapi E. , Röthlisberger B. , Schinzel A.
Published: October 2002

We report on the cytogenetic, fluorescence in situ hybridization (FISH), and molecular results obtained for a patient with a mild and nonspecific pattern of minor anomalies and developmental delay. In the proband's karyotype one chromosome 18 was replaced by a ring chromosome 18 in all metaphases, with deletion of the terminal regions. Furthermore, 56% of the metaphases contained a supernumerary small ring chromosome. Microdissection followed by FISH analysis demonstrated that the small ring chromosome consisted of material from the pericentromeric region of chromosome 18. The karyotype was defined as 46,XX,r(18)(p11.3q23)[88]/47,XX,r(18)(p11.3q23)+r(18)(p11.22q12.2)[112]. Thus, the patient has a deletion at 18pter and at 18qter, and a mosaic partial trisomy of the pericentromeric region of chromosome 18. We undertook molecular analysis using DNA samples of the patient and her parents in order to clarify the origin and possible mode of formation of the chromosome abnormalities. Our results show a paternal origin of the structurally normal chromosome 18 and a maternal origin for both ring chromosomes 18. Interestingly, the smaller ring chromosome did not arise postzygotically from the larger ring, since the two ring chromosomes contain genetic material derived from the two different maternal chromosomes 18. The abnormalities appear to have arisen during a meiotic division, and it could be speculated that both ring chromosomes 18 arose simultaneously due to complex pairing and recombination events. After fertilization, the small ring chromosome was lost in a subset of cells, thus leading to mosaicism. © 2002 Wiley‐Liss, Inc.
Allelic homogeneity due to a founder mutation in Japanese patients with lattice corneal dystrophy type IIIA
Authors: Tsujikawa Kaoru , Tsujikawa Motokazu , Yamamoto Shuji , Fujikado Takashi , Tano Yasuo
Published: October 2002

Lattice corneal dystrophies (LCDs) are caused by mutations of the transforming growth factor beta‐induced gene (TGFBI, formerly βig‐h3). LCD type IIIA (LCDIIIA) has been reported mostly from Japan. In this study, we demonstrate allelic homogeneity for Japanese patients with LCDIIIA, using intragenic polymorphic markers. When exon 11 of TGFBI was analyzed, all 18 patients examined were found to be heterozygous for both a P501T mutation and an IVS10‐3C → T variation. On the other hand, none of 54 normal Japanese control subjects had the P501T, and 5 of the controls were heterozygous for IVS10‐3C → T. Haplotype analysis of the patients revealed that both P501T and IVS10‐3C → T were located on the same chromosome, and a significant linkage disequilibrium (P < 0.001, Fisher's exact probability test) was observed between LCDIIIA (P501T) and IVS10‐3C → T. When exon 8 of the gene was analyzed, all these patients possessed the “G allele” of a 1028G/A polymorphism. A significant linkage disequilibrium (P < 0.003; chi‐square test) was also observed between P501T and the G allele in the patients. These results suggest that allelic homogeneity seen in Japanese patients with LCDIIIA may result from a single founder mutation. © 2002 Wiley‐Liss, Inc.
Autopsy case of microcephalic osteodysplastic primordial “dwarfism” type II
Authors: Fukuzawa Ryuji , Sato Seiji , Sullivan Michael J. , Nishimura Gen , Hasegawa Tomonobu , Matsuo Nobutake
Published: October 2002

Microcephalic osteodysplastic primordial “dwarfism” (MOPD) is a group of disorders similar to Seckel syndrome. Three subtypes (types I–III) have been reported. We report here the first autopsy case of MOPD type II. The patient was a Japanese girl with typical clinical and radiological manifestations of MOPD type II. The manifestations included severe intrauterine and postnatal growth failure, microcephaly, a distinctive facial appearance, micromelia, brachytelephalangy, coxa vara, and V‐shaped metaphyses of the distal femora. Other than small cerebral hemispheres, no neuropathological abnormalities were found. Chondro‐osseous histology showed thinning of the growth plate, ballooned chondrocytes, reduced cellularity, lack of zonal and columnar formations, and poor formation of primary trabeculae. These findings suggest that impairment of chondrocytic formation and differentiation is the major pathogenesis of MOPD type II. © 2002 Wiley‐Liss, Inc.
Branchial cyst, sensorineural deafness, congenital heart defect, and skeletal abnormalities: Branchio‐oto‐cardio‐skeletal (BOCS) syndrome?
Authors: Basel‐Vanagaite Lina , Shohat Mordechai , Udler Yevgenia , Karmazin Boaz , Levit Orly , Merlob Paul
Published: October 2002

This article describes a boy with an unusual combination of features, namely, intrauterine growth retardation, short stature, branchial cyst, sensorineural hearing loss, congenital heart defect, rib and vertebral abnormalities, micromelia, brachymesophalangia, and absence of phalanges. We suggest that these findings comprise a new entity of combined branchio‐oto and cardio‐digital developmental field abnormalities, which we termed branchio‐oto‐cardio‐skeletal syndrome. The pattern of inheritance remains uncertain. © 2002 Wiley‐Liss, Inc.
A whole‐genome linkage scan suggests several genomic regions potentially containing QTLs underlying the variation of stature
Authors: Deng Hong‐Wen , Xu Fu‐Hua , Liu Yao‐Zhong , Shen Hui , Deng Hongyi , Huang Qing‐Yang , Liu Yong‐Jun , Conway Theresa , Li Jin‐Long , Davies K.M. , Recker Robert R.
Published: October 2002

Human height is a complex trait under the control of both genetic and environment factors. In order to identify genomic regions underlying the variation of stature, we performed a whole‐genome linkage analysis on a sample of 53 human pedigrees containing 1,249 sib pairs, 1,098 grandparent–grandchildren pairs, 1,993 avuncular pairs, and 1,172 first‐cousin pairs. Several genomic regions were suggested by our study to be linked with human height variation. These regions include 5q31 at 144 cM from pter on chromosome 5 (with a maximum LOD score of 2.14 in multipoint linkage analyses), Xp22 at the marker DXS1060, and Xq25 at DXS1001 on the X chromosome (with LOD scores of 1.95 and 1.91, respectively, in two‐point linkage analyses). Noticeably, Xp22 happens to be the very region where a newly identified gene underlying idiopathic short stature, SHOX, maps. Based on our findings, further confirmation and fine‐mapping studies are to be pursued on expanded samples and/or with denser markers for eventual identification of major functional genes involved in human height variation. © 2002 Wiley‐Liss, Inc.
A cystic fibrosis patient with two novel mutations in mitochondrial DNA: Mild disease led to delayed diagnosis of both disorders
Authors: Wong Lee‐Jun C. , Liang Min‐Hui , Kwon Haeyoung , Bai Ren‐Kui , Alper Özgül , Gropman Andrea
Published: October 2002

A 21‐year‐old woman who has been suspected of mitochondrial cytopathy, but negative for common mitochondrial DNA (mtDNA) point mutations and deletions, was screened for unknown mutations in the entire mitochondrial genome by temporal temperature gradient gel electrophoresis (TTGE). Her asymptomatic mother's blood DNA was also analyzed and used as a reference. Two tRNA regions showing different TTGE patterns between the proband and her mother were sequenced. Two novel mutations, G15995A in tRNApro and A8326G in tRNAlys, were revealed. These mutations are present in heteroplasmic states. They both occurred at a nucleotide position that is highly conserved throughout evolution. This patient is also a compound heterozygote for the cystic fibrosis (CF) mutations, ΔF508 and R347P. The phenotype for R347P has been associated with mild disease. Due to the mild features of the R347P mutation in the CF transmembrane conductance regulator (CFTR) gene and the heterogeneous clinical presentation of the mtDNA disease, the patient was not definitively diagnosed until age 21. This case underscores the importance of a complete mutational analysis of the entire mitochondrial genome when a patient suspected of mitochondrial disorder is negative for common mtDNA mutations. © 2002 Wiley‐Liss, Inc.
Quantitative CSF PCR in Epstein–Barr virus infections of the central nervous system
Authors: Weinberg Adriana , Li Shaobing , Palmer Megan , Tyler Kenneth L.
Published: October 2002

Acute Epstein–Barr virus (EBV) infection of the central nervous system (CNS) is associated with meningoencephalitis and other neurological syndromes and with CNS lymphomas (CNSLs). Diagnosis is based on serological studies and more recently on detection of EBV DNA in cerebrospinal fluid (CSF) by polymerase chain reaction (PCR). We measured EBV DNA by quantitative PCR and EBV mRNA by RT‐PCR in the CSF in patients with EBV‐associated neurological disorders. EBV was identified as the cause of CNS infection in 28 patients: 14 with CNSL, 10 with encephalitis, and 4 with postinfectious neurological complications. CSF analysis showed that patients with CNSL had high EBV load (mean ± standard error of 4.8 ± 0.2 log10 DNA copies/ml) and low leukocyte counts (22 ± 7 cells/μl); encephalitis was characterized by high EBV load (4.2 ± 0.3 log10 DNA copies/ml) and high leukocyte counts (143 ± 62 cells/μl); and patients with postinfectious complications showed low EBV load (3.0 ± 0.2 log10 DNA copies/ml) with high leukocyte counts (88 ± 57 cells/μl). Lytic cycle EBV mRNA, a marker of viral replication, was identified in 10 CSF samples from patients with CNSL and encephalitis. These studies demonstrate the utility of quantitative CSF PCR and establish the presence of lytic cycle EBV mRNA in CSF of patients with EBV‐associated neurological disease.
A susceptibility gene for late‐onset idiopathic Parkinson's disease
Authors: Hicks Andrew A. , Pétursson Hjörvar , Jónsson Thorlákur , Stefánsson Hreinn , Jóhannsdóttir Hrefna S. , Sainz Jesus , Frigge Michael L. , Kong Augustine , Gulcher Jeffrey R. , Stefánsson Kári , Sveinbjörnsdóttir Sigurlaug
Published: October 2002

Eight regions of the genome (PARK1‐8) have been implicated in autosomal dominant and autosomal recessive forms of early‐onset Parkinson's disease. These forms constitute a few of all cases. However, except for a haplotype in six families (PARK3), no study has successfully mapped a gene or described mutations that contribute to the common late‐onset Parkinson's disease. Some have even suggested that a genetic component does not exist. We cross‐matched our nationwide genealogy database with a population‐based list of Icelandic Parkinson's disease patients to search for families with more than one patient. We performed a genomewide scan on 117 patients and 168 of their unaffected relatives within 51 families using 781 microsatellite markers. Allele‐sharing, model‐independent analysis of the results showed linkage to a region on chromosome 1p32 with a logarithm of odds score of 3.9 (Zlr= 4.2). By increasing the information content with additional microsatellite markers in this region, we found that the logarithm of odds score increased to 4.9 (Zlr= 4.8). This result corresponds to an unadjustedpvalue of 1.0 × 10−6andp< 0.005 after adjusting for a genomewide search. We designate this regionPARK10. We therefore have successfully mapped, to genomewide significance, a susceptibility gene for late‐onset Parkinson's disease using multiple families drawn across a whole population. Identification of the susceptibility gene in this region may pave the way for a better understanding of the disease process, which, in turn, may lead to improved diagnostics and therapeutics.
Disruption of the proprioceptive mapping in the medial wall of parkinsonian monkeys
Authors: Escola Ludovic , Michelet Thomas , Douillard Gaelle , Guehl Dominique , Bioulac Bernard , Burbaud Pierre
Published: October 2002

Parkinsonian patients present an impairment of proprioceptor‐guided movement that could imply abnormal processing in the frontal mesial cortex. To test this hypothesis, we compared neuronal response to joint displacement in the supplementary and presupplementary motor areas of two monkeys, before and after the progressive establishment of an 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)–induced parkinsonian syndrome. After MPTP administration, neurons were activated by the passive movement of numerous joints in various directions and no longer simply by one or two joints in one direction. This impairment of the focused selection of proprioceptive inputs, imputable to dopamine depletion, could impede motor planning and thus contribute to akinesia.
Saccadic lateropulsion and upbeat nystagmus: Disorders of caudal medulla
Authors: Tilikete Caroline , Hermier Marc , Pelisson Denis , Vighetto Alain
Published: October 2002

A patient developed a primary position upbeat nystagmus and a left saccadic lateropulsion. Magnetic resonance imaging demonstrated a probable cavernoma at right caudal paramedian medullary level. Anatomical correlations are discussed. Saccadic lateropulsion is attributed to olivocerebellar pathway impairment but usually is described in more rostral medullar lesions. Our case would still support this hypothesis because the lesion could have involved the olivocerebellar pathway at its very caudal level. Upbeat nystagmus could be attributed to impairment of the nucleus intercalatus and/or cell groups of the paramedian tract.
A new locus for spinocerebellar ataxia (SCA21) maps to chromosome 7p21.3‐p15.1
Authors: Vuillaume Isabelle , Devos David , Schraen‐Maschke Susanna , Dina Christian , Lemainque Arnaud , Vasseur Francis , Bocquillon Guy , Devos Patrick , Kocinski Carole , Marzys Christiane , Destée Alain , Sablonnière Bernard
Published: October 2002

We investigated a French family with a new type of autosomal dominant spinocerebellar ataxia that was excluded from all previously identified genes and loci. The patients exhibited a slowly progressive gait and limb ataxia variably associated with akinesia, rigidity, tremor, and hyporeflexia. A mild cognitive impairment also was observed in some cases. We performed a genomewide search and found significant evidence for linkage to chromosome 7p21.3‐p15.1. Analysis of key recombinants and haplotype reconstruction traced this novel spinocerebellar ataxia locus to a 24cM interval flanked by D7S2464 and D7S516.
Motor cortex activation is preserved in patients with chronic hemiplegic stroke
Authors: Cramer Steven C. , Mark Angela , Barquist Kristin , Nhan Hoang , Stegbauer Keith C. , Price Robert , Bell Kathleen , Odderson Ib R. , Esselman Peter , Maravilla Kenneth R.
Published: October 2002

Many central nervous system conditions that cause weakness, including many strokes, injure corticospinal tract but leave motor cortex intact. Little is known about the functional properties of surviving cortical regions in this setting, in part because many studies have used probes reliant on the corticospinal tract. We hypothesized that many features of motor cortex function would be preserved when assessed independent of the stroke‐affected corticospinal tract. Functional MRI was used to study 11 patients with chronic hemiplegia after unilateral stroke that spared regions of motor cortex. Activation in stroke‐affected hemisphere was evaluated using 3 probes independent of affected corticospinal tract: passive finger movement, a hand‐related visuomotor stimulus, and tapping by the nonstroke index finger. The site and magnitude of cortical activation were similar when comparing the stroke hemisphere to findings in 19 control subjects. Patients activated each of 8 cortical regions with similar frequency as compared to controls, generally with a smaller activation volume. In some cases, clinical measures correlated with the size or the site of stroke hemisphere activation. The results suggest that, despite stroke producing contralateral hemiplegia, surviving regions of motor cortex actively participate in the same proprioceptive, visuomotor, and bilateral movement control processes seen in control subjects.
Rescue of a mitochondrial deficiency causing Leber hereditary optic neuropathy
Authors: Guy John , Qi Xiaoping , Pallotti Francesco , Schon Eric A. , Manfredi Giovanni , Carelli Valerio , Martinuzzi Andrea , Hauswirth William W. , Lewin Alfred S.
Published: October 2002

A G to A transition at nucleotide 11778 in the ND4 subunit gene of complex I was the first point mutation in the mitochondrial genome linked to a human disease. It causes Leber Hereditary Optic Neuropathy, a disorder with oxidative phosphorylation deficiency. To overcome this defect, we made a synthetic ND4 subunit compatible with the “universal” genetic code and imported it into mitochondria by adding a mitochondrial targeting sequence. For detection we added a FLAG tag. This gene was inserted in an adeno‐associated viral vector. The ND4FLAG protein was imported into the mitochondria of cybrids harboring the G11778A mutation, where it increased their survival rate threefold, under restrictive conditions that forced the cells to rely predominantly on oxidative phosphorylation to produce ATP. Since assays of complex I activity were normal in G11778A cybrids we focused on changes in ATP synthesis using complex I substrates. The G11778A cybrids showed a 60% reduction in the rate of ATP synthesis. Relative to mock‐transfected G11778A cybrids, complemented G11778A cybrids showed a threefold increase in ATP synthesis, to a level indistinguishable from that in cybrids containing normal mitochondrial DNA. Restoration of respiration by allotopic expression opens the door for gene therapy of Leber Hereditary Optic Neuropathy.
Mitochondrial respiratory chain function in skeletal muscle of ALS patients
Authors: Echaniz‐Laguna Andoni , Zoll Joffrey , Ribera Florence , Tranchant Christine , Warter Jean‐Marie , Lonsdorfer Jean , Lampert Eliane
Published: October 2002

Evidence implicating mitochondrial dysfunction in the central nervous system of patients with sporadic amyotrophic lateral sclerosis (SALS) has recently been accumulating. In contrast, data on mitochondrial function in skeletal muscle in SALS are scarce and controversial. We investigated the in situ properties of muscle mitochondria in patients with early‐stage SALS and sedentary (SED) controls using the skinned fiber technique to determine whether respiration of muscle tissue is altered in early‐stage SALS in comparison with SED. Musculus vastus lateralis biopsies were obtained from 7 SED group members and 14 patients with early‐stage SALS (mean disease duration, 9 months). Muscle fibers were permeabilized with saponine and then skinned and placed in an oxygraphic chamber to measure basal (V0) and maximal (Vmax) adenosine diphosphate–stimulated respiration rates and to assess mitochondrial regulation by adenosine diphosphate. Muscle oxidative capacity, evaluated with Vmax, was identical in patients in the SALS and SED groups (V0: SALS, 1.1 ± 0.1; SED, 0.8 ± 0.1, μmol 02 · min−1 · gm−1dw and Vmax: SALS, 3.1 ± 0.3; SED, 2.5 ± 0.3, μmol 02 · min−1 · gm−1dw). This study shows an absence of large mitochondrial damage in skeletal muscle of patients with early‐stage SALS, suggesting that mitochondrial dysfunction in the earlier stages of SALS is almost certainly not systemic.