bluuebunny/crossref_metadata_2025 huggingface dataset:
Experimental study of five föhn events during the Mesoscale Alpine Programme: From synoptic scale to turbulence
Authors: Lothon Marie , Druilhet A. , Bénech B. , Campistron B. , Bernard S. , Saïd F.
Published: July 2003

Aircraft measurements made during the Mesoscale Alpine Programme are used to investigate the atmospheric turbulence inside the large Rhine Valley on the north side of the Alps during five föhn events induced by a southerly to south‐westerly flow. Prior to that goal, an analysis based on the observations of different instruments provides the mesoscale and large‐scale atmospheric conditions encountered during the aircraft flights. The temporal and spatial structure of the föhn event of 20 October 1999 is presented as an example. In this case, the three‐dimensional structure of the turbulence is investigated. An estimate of the different components of the turbulent kinetic energy budget is attempted. It shows that the source of the turbulence is mainly mechanical. In spite of the high inhomogeneity of the turbulence in space and between the cases, the study of five cases allows the description of some general features of the föhn events, such as the plume of turbulence extending downwards in the valley and the near homogeneity of the dissipative length‐scale. Copyright © 2003 Royal Meteorological Society.
The effects of changing resolution on mesocale modelling of line convection and slantwise circulations in FASTEX IOP16
Authors: Lean Humphrey W. , Clark Peter A.
Published: July 2003

Data are presented from modelling a rapidly developing cyclone, in intensive observation period 16 of the Fronts and Atlantic Storm Tracks Experiment, using the new non‐hydrostatic version of the Met Office Unified Model at a number of different horizontal and vertical resolutions. The model produces a good representation of the system, including multiple fronts with line convection, cloud heads and slantwise cross‐frontal circulations similar to those seen in the observations. Results from the model with various grid lengths, from 60 km nested down to 2 km with 45 vertical levels, show that more realistic detail is produced as the grid length is reduced but that the large‐scale structures remain consistent. By spectral analysis it is found that structures on scales shorter than approximately five grid lengths are attenuated. The line convection at the fronts is aliased onto the grid‐length scale except in the 2 km model where evidence of a three‐dimensional structure starts to appear. The 2 and 4 km models have also been run with enhanced vertical resolutions. It is concluded that whilst a 24 km 45‐level model is sufficient to represent the overall frontal structure, a model with resolution at least 2 km in the horizontal and 90 vertical levels is required to represent small‐scale multiple slantwise circulations similar to those observed in the dropsonde data. © Crown copyright 2003.
Atmosphere–sea‐ice low‐frequency variability with a simple model of the southern hemisphere
Authors: Garric G. , Venegas S. A. , Tansley C. E. , James I. N.
Published: July 2003

A simple primitive‐equation general circulation model (SGCM) is used as a representation of an ‘aqua‐planet’ (with no orography) to model constant southern‐hemisphere‐winter conditions. The statistical significance of the decadal and quasi‐biennial variability is first assessed in a long‐time SGCM run by means of a frequency‐domain statistical decomposition. The modelled long‐wave atmospheric pattern is then associated with the observed southern‐hemisphere ‘annular mode’, as suggested by previous studies using the same SGCM.

A simple linear relationship between the low‐level wind and the ice velocity is then introduced into the SGCM to investigate the feedbacks between the sea‐ice cover and the baroclinic waves. The zonal mean state reached by the sea‐ice cover in a long coupled run (a few hundred years) exhibits characteristics similar to the observations. Investigation of the low‐frequency variability in the coupled simulation leads to the following results: (1) statistically significant variability is observed on interdecadal, decadal, interannual and quasi‐biennial time‐scales; (2) interdecadal, decadal and quasi‐biennial signals are associated with the atmospheric annular mode that forces changes in the northward extent of the sea‐ice cover at all Southern Ocean longitudes; (3) the interannual signal (3–6 year period) exhibits spatio‐temporal patterns and propagation speed similar to the well‐known ‘Antarctic circumpolar wave’. Copyright © 2003 Royal Meteorological Society.
Zonal‐mean transport characteristics of ECMWF re‐analysis data
Authors: Bratseth Arne M.
Published: July 2003

Transport characteristics for a dataset from a global data assimilation system (European Centre for Medium‐Range Weather Forecasts re‐analyses for 1993) are analysed by constructing an advection–diffusion operator with tracer‐transport properties as close as possible to the zonally and seasonally averaged tracer advection. This is achieved by computing a best‐fit flux–gradient relation for a large number of artificial tracers. The meridional circulation of the advection–diffusion operator (the transport velocity) is thermally direct almost everywhere. It is similar to the Transformed Eulerian Mean (TEM) residual circulation in most of the stratosphere, but is much weaker than this circulation in the extratropical troposphere. The diffusivity tensor has a complicated structure where transport barriers and ‘surf zones’ can be identified. The structure is strongly connected to the zonal wind, with distinct minima in the jet‐stream areas. The zonal acceleration due to effects other than the transport circulation is studied. It is shown that this acceleration has a tendency to be strong when the mixing is strong and vice versa. Copyright © 2003 Royal Meteorological Society.
Characteristics of mixed‐phase clouds. I: Lidar, radar and aircraft observations from CLARE'98
Authors: Hogan R. J. , Francis P. N. , Flentje H. , Illingworth A. J. , Quante M. , Pelon J.
Published: July 2003

Results are presented from two case‐studies during the 1998 Cloud Lidar And Radar Experiment (CLARE'98) in which mixed‐phase clouds were observed by a multitude of ground‐based and airborne instruments. In both cases supercooled liquid water was present in the form of highly reflective layers in lidar imagery, while the radar echo was dominated by the contribution from the much larger ice particles. In the first case‐study, four individual liquid‐water layers were observed by an airborne nadir‐pointing polarimetric lidar at temperatures between −7°C and −15°C, embedded within a warm‐frontal ice cloud. Their phase was confirmed by the in situ measurements and by their very low depolarization of the lidar signal. The effective droplet radius ranged from 2 to 5 µm. Simultaneous temperature and vertical‐wind measurements by the aircraft demonstrated that they were generated by a gravity wave with a wavelength of around 15 km. Thin sector plates grew rapidly in the high‐supersaturation conditions and were responsible for the high values of differential reflectivity measured by the ground‐based radar in the vicinity of the layers. In the second case‐study a liquid‐water altocumulus layer was observed at −23°C, which was slowly glaciating. Profiles of liquid and ice extinction coefficient, water content and effective radius were derived from the remote measurements taken in both cases, using radar–lidar and dual‐wavelength radar techniques to size the ice particles; where in situ validation was available, agreement was good. Radiative‐transfer calculations were then performed on these profiles to ascertain the radiative effect of the supercooled water. It was found that, despite their low liquid‐water path (generally less than 10 – 20 g m−2), these clouds caused a significant increase in the reflection of solar radiation to space, even when cirrus was present, above which the long‐wave signal dominated. In the cases considered, their capacity to decrease the net absorbed radiation was at least twice as large as that of the ice. The layers were typically 100–200 m thick, suggesting that they are unlikely to be adequately represented by the resolutions of current forecast and climate models. These results suggest that a spaceborne lidar and radar would be ideally suited to characterizing the occurrence and climatological importance of mixed‐phase clouds on a global scale. © Royal Meteorological Society, 2003. P. N. Francis's contribution is Crown copyright.
Pediatric medicine and the genetic disorders of the Amish and Mennonite people of Pennsylvania
Authors: Morton D. Holmes , Morton Caroline S. , Strauss Kevin A. , Robinson Donna L. , Puffenberger Erik G. , Hendrickson Christine , Kelley Richard I.
Published: July 2003

The Clinic for Special Children in Lancaster County, Pennsylvania, is a community‐supported, nonprofit pediatric medical practice for Amish and Mennonite children who have genetic disorders. Over a 14‐year period, 1988–2002, we have encountered 39 heritable disorders among the Amish and 23 among the Mennonites. We emphasize early recognition and long‐term medical care of children with genetic conditions. In the clinic laboratory we perform amino acid analyses by high‐performance liquid chromatography (HPLC), organic acid analyses by gas chromatography/mass spectrometry (GC/MS), and molecular diagnoses and carrier tests by polymerase chain reaction (PCR) amplification and sequencing or restriction digestion. Regional hospitals and midwives routinely send whole‐blood filter paper neonatal screens for tandem mass spectrometry and other modern analytical methods to detect 14 of the metabolic disorders found in these populations as part of the NeoGen Inc. Supplemental Newborn Screening Program (Pittsburgh, PA). Medical care based on disease pathophysiology reduces morbidity, mortality, and costs for the majority of disorders. Among our patients who are homozygous for the same mutation, differences in disease severity are not unusual. Clinical problems typically arise from the interaction of the underlying genetic disorder with common infections, malnutrition, injuries, and immune dysfunction that act through classical pathophysiological disease mechanisms to influence the natural history of disease. © 2003 Wiley‐Liss, Inc.
Genetic heritage of the Old Order Mennonites of southeastern Pennsylvania
Authors: Puffenberger E.G.
Published: July 2003

The Old Order Mennonites of southeastern Pennsylvania are a religious isolate with origins in 16th‐century Switzerland. The Swiss Mennonites immigrated to Pennsylvania over a 50‐year period in the early 18th century. The history of this population in the United States provides insight into the increased incidence of several genetic diseases, most notably maple syrup urine disease (MSUD), Hirschsprung disease (HSCR), and congenital nephrotic syndrome. A comparison between the Old Order Mennonites and the Old Order Amish demonstrates the unique genetic heritage of each group despite a common religious and geographic history. Unexpectedly, several diseases in both groups demonstrate allelic and/or locus heterogeneity. The population genetics of the 1312T → A BCKDHA gene mutation, which causes classical MSUD, are presented in detail. The incidence of MSUD in the Old Order Mennonites is estimated to be 1/358 births, yielding a corrected carrier frequency of 7.96% and a mutation allele frequency of 4.15%. Analysis of the population demonstrates that repeated cycles of sampling effects, population bottlenecks, and subsequent genetic drift were important in shaping the current allele frequencies. A linkage disequilibrium analysis of 1312T → A mutation haplotypes is provided and discussed in the context of the known genealogical history of the population. Finally, data from microsatellite marker genotyping within the Old Order Mennonite population are provided that show a significant but modest decrease in genetic diversity and elevated levels of background linkage disequilibrium. © 2003 Wiley‐Liss, Inc.
Anabaptist genealogy database
Authors: Agarwala Richa , Biesecker Leslie G. , Schäffer Alejandro A.
Published: July 2003

In late 1996 we set out to build a computer‐searchable genealogy of the Old Order Amish of Lancaster County, Pennsylvania, for use by geneticists. The goals of the project included: 1) using the genealogy to expedite the mapping of genes mutated in three rare recessive disorders under study at the National Institutes of Health (NIH); 2) building a freely available software package, PedHunter, to answer genetically relevant queries on our database and other similar databases; and 3) providing genealogy assistance to researchers outside NIH. All of these scientific goals had to be accomplished while maintaining the confidentiality of the persons in the database and the confidentiality of preliminary research results. We expanded the project to include complementary data sources that contained many individuals who were Anabaptist, but not Amish, and many individuals who never lived in Lancaster County. For this reason, the project was renamed Anabaptist Genealogy Database (AGDB). All of the initial goals of the project have been accomplished, and we recently marked the 5‐year anniversary of answering the first of over 100 queries by researchers outside NIH. Thus, it is an opportune time to review the construction of AGDB, summarize its usage to date, and speculate on future projects it might stimulate and facilitate. Published 2003 Wiley‐Liss, Inc.
A study of linkage and association of body mass index in the old order Amish
Authors: Platte P. , Papanicolaou G.J. , Johnston J. , Klein C.M. , Doheny K.F. , Pugh E.W. , Roy‐Gagnon M.‐H. , Stunkard A.J. , Francomano C.A. , Wilson A.F.
Published: July 2003

Obesity is thought to have a genetic component with the estimates of heritability ranging from 0.25–0.40. As part of an ongoing study of obesity in the Old Order Amish, seven two‐ and three‐generation families (157 individuals) were assessed for 21 traits related to obesity, including body mass index (BMI) and BMI‐percentile (a standardized distribution of BMI adjusted for age and sex). Genotyping was performed using a panel of 384 short‐tandem repeat markers. In this sample, the estimates of heritability ranged from 0.16–0.31 for BMI and from 0.40–0.52 for BMI‐percentile. Model‐independent linkage analysis identified candidate regions on chromosomes 1, 5, 7, 8, and 11. Given that several markers on 7q were significant for both BMI and BMI‐percentile (P ≤ 0.001) and that the structural locus for leptin was located on 7q, this region was considered to be the primary candidate region. Subsequent typing of additional flanking markers on 7q corroborated the original findings. Tests of intrafamilial association for alleles at markers in this candidate region were significant at similar levels. Although there is some evidence for linkage and association in the region containing leptin, there appears to be stronger evidence for linkage (P ≤ 0.001) and association (P ≤ 0.00001) with BMI in a region 10–15 cM further downstream of leptin, flanked by markers D7S1804 and D7S3070 with peak values from D7S495–D7S1798. Evidence from linkage and association studies suggests that this region (D7S1804–D7S3070) may be responsible, at least in part, for variation in BMI and BMI‐percentile in the Old Order Amish. Published 2003 Wiley‐Liss, Inc.
The major mutation in the RMRP gene causing CHH among the Amish is the same as that found in most Finnish cases
Authors: Ridanpää Maaret , Jain Pawan , Mckusick Victor A. , Francomano Clair A. , Kaitila Ilkka
Published: July 2003

Cartilage‐hair hypoplasia (CHH), or McKusick type metaphyseal chondrodysplasia, was originally described in the Old Order Amish in the United States and subsequently found to be unusually frequent among Finns. The major mutation causing CHH in Finns is a 70A → G nucleotide substitution in the RMRP gene, which encodes the untranslated RNA that is a component of mitochondrial RNA‐processing endoribonuclease. Here we report that the same mutation is the most frequent one, perhaps the only one, in the Amish population in which CHH was first characterized. The fact that the mutation segregates with the same major haplotype in these two populations and others suggests that it is very ancient. Unlike some other ordinarily rare recessive disorders that are limited in their high frequency to a single Amish deme (subisolate), e.g., Ellis‐van Creveld syndrome, CHH occurs in high frequency in at least three distinct Amish demes, indicating, along with genealogic data, that there were multiple heterozygotes among the founders, as proposed by McKusick et al. [1965: Bull Johns Hopkins Hosp 116:231–272]. Published 2003 Wiley‐Liss, Inc.
Type I glutaric aciduria, part 1: Natural history of 77 patients
Authors: Strauss Kevin A. , Puffenberger Erik G. , Robinson Donna L. , Morton D. Holmes
Published: July 2003

Time is that wherein there is opportunity, and opportunity is that wherein there is no great time. … Healing is a matter of time, but it is also a matter of opportunity.

—Hippocrates, Epidemics

Type I glutaric aciduria (GA1) results from mitochondrial matrix flavoprotein glutaryl‐CoA dehydrogenase deficiency and is a cause of acute striatal necrosis in infancy. We present detailed clinical, neuroradiologic, molecular, biochemical, and functional data on 77 patients with GA1 representative of a 14‐year clinical experience. Micrencephalic macrocephaly at birth is the earliest sign of GA1 and is associated with stretched bridging veins that can be a cause of subdural hematoma and acute retinal hemorrhage. Acute striatal necrosis during infancy is the principal cause of morbidity and mortality and leads to chronic oromotor, gastroesophageal, skeletal, and respiratory complications of dystonia. Injury to the putamen is heralded by abrupt‐onset behavioral arrest. Tissue degeneration is stroke‐like in pace, radiologic appearance, and irreversibilty. It is uniformly symmetric, regionally selective, confined to children under 18 months of age, and occurs almost always during an infectious illness. Our knowledge of disease mechanisms, though incomplete, is sufficient to allow a rational approach to management of encephalopathic crises. Screening of asymptomatic newborns with GA1 followed by thoughtful prospective care reduces the incidence of radiologically and clinically evident basal ganglia injury from approximately 90% to 35%. Uninjured children have good developmental outcomes and thrive within Amish and non‐Amish communities. © 2003 Wiley‐Liss, Inc.
Type I glutaric aciduria, part 2: A model of acute striatal necrosis
Authors: Strauss Kevin A. , Morton D. Holmes
Published: July 2003

Type I glutaric aciduria (GA1) is an inborn error of organic acid metabolism that is associated with acute neurological crises, typically precipitated by an infectious illness. The neurological crisis coincides with swelling, metabolic depression, and necrosis of basal ganglia gray matter, especially the putamina and can be visualized as focal, stroke‐like, signal hyperintensity on MRI. Here we focus on the stroke‐like nature of striatal necrosis and its similarity to brain injury that occurs in infants after hypoxia‐ischemia or systemic intoxication with 3‐nitropropionic acid (NPA). These conditions share several features including abrupt onset, preferential effect in the striatum and age‐specific susceptibility. The pathophysiology of the conditions is reviewed and a model proposed herein. We encourage investigators to test this model in an appropriate experimental system. © 2003 Wiley‐Liss, Inc.
Association between genetic variation of CACNA1H and childhood absence epilepsy
Authors: Chen Yucai , Lu Jianjun , Pan Hong , Zhang Yuehua , Wu Husheng , Xu Keming , Liu Xiaoyan , Jiang Yuwu , Bao Xinhua , Yao Zhijian , Ding Keyue , Lo Wilson H. Y. , Qiang Boqin , Chan Piu , Shen Yan , Wu Xiru
Published: July 2003

Direct sequencing of exons 3 to 35 and the exon–intron boundaries of the CACNA1H gene was conducted in 118 childhood absence epilepsy patients of Han ethnicity recruited from North China. Sixty‐eight variations have been detected in the CACNA1H gene, and, among the variations identified, 12 were missense mutations and only found in 14 of the 118 patients in a heterozygous state, but not in any of 230 unrelated controls. The identified missense mutations occurred in the highly conserved residues of the T‐type calcium channel gene. Our results suggest that CACNA1H might be an important susceptibility gene involved in the pathogenesis of childhood absence epilepsy. Ann Neurol 2003
Alcohol consumption and the incidence of Parkinson's disease
Authors: Hernán Miguel A. , Chen Honglei , Schwarzschild Michael A. , Ascherio Alberto
Published: July 2003

Cigarette smoking and caffeine consumption are associated with a decreased incidence of Parkinson's disease (PD). This inverse association may result from neuroprotective effects of cigarette smoke and caffeine, or from a disinclination of future PD patients to engage in habituating behaviors. We investigated the association between consumption of alcoholic beverages, another potentially habituating behavior, and risk of PD in two large prospective cohorts Nurses' Health Study, and Health Professionals' Follow‐up Study. We detected 415 new cases of PD during follow‐up. Compared with nondrinkers at baseline, the relative rate (95% confidence interval) was 1.0 (0.8–1.3) for drinkers of less than 5gm/day, 1.0 (0.8–1.4) for 5 to less than 15gm/day, 1.1 (0.8–1.6) for 15 to less than 30gm/day, and 0.7 (0.5–1.2) for 30gm/day or more (p for trend = 0.45). Consumption of wine or liquor was not associated with the incidence of PD. Compared with those who consumed beer less than once per month, the relative rate (95% confidence interval) was 0.7 (0.5–0.9) for one to three drinks of beer per month, and 0.7 (0.5, 0.9) for one or more drinks of beer per week. The risk of PD was similar in individuals who usually consume moderate amounts of alcohol and in abstainers. Ann Neurol 2003
Neuronal overexpression of cyclooxygenase‐2 increases cerebral infarction
Authors: Doré Sylvain , Otsuka Takashi , Mito Toshiaki , Sugo Nubuo , Hand Tracey , Wu Liejun , Hurn Patricia D. , Traystman Richard J. , Andreasson Katrin
Published: July 2003

Increases in COX‐2 enzymatic activity and prostaglandin production have been associated with neuronal injury in both acute and age‐related degenerative neurological diseases. In this study, we tested the effects of increased COX‐2 activity in a model of transient focal ischemia using a transgenic mouse model in which human COX‐2 is constitutively expressed selectively in neurons of the striatum, cerebral cortex, and hippocampus. These COX‐2 transgenic mice harbor elevated levels of PGE2 that are 10‐fold higher than nontransgenic levels. A significant increase in infarct volume was observed after middle cerebral artery occlusion with 4 days of reperfusion in COX‐2 transgenic mice as compared with nontransgenic littermates. Pretreatment of nontransgenic mice with the selective COX‐2 inhibitor SC58236 resulted in a significant reduction of infarct volume in nontransgenic mice, consistent with previous pharmacological studies. However, transgenic COX‐2 mice treated with SC58236 did not show a significant reduction. This suggests that chronic increases in COX‐2 expression and enzymatic activity, which can occur in aging and in pathological states characterized by oxidative stress and chronic inflammatory processes, can lead to downstream cellular changes that have a negative impact on neuronal survival in cerebrovascular disease. Ann Neurol 2003
How much phenotypic variation can be attributed to parkin genotype?
Authors: Lohmann Ebba , Periquet Magali , Bonifati Vincenzo , Wood Nick W. , De Michele Giuseppe , Bonnet Anne‐Marie , Fraix Valérie , Broussolle Emmanuel , Horstink Martin W. I. M. , Vidailhet Marie , Verpillat Patrice , Gasser Thomas , Nicholl David , Teive Hélio , Raskin Salmo , Rascol Olivier , Destée Alain , Ruberg Merle , Gasparini Francesca , Meco Giuseppe , Agid Yves , Durr Alexandra , Brice Alexis ,   The French Parkinson's Disease Genetics Study Group and the European Consortium on Genetic Susceptibility in Parkinson's Disease
Published: July 2003

To establish phenotype–genotype correlations in early‐onset parkinsonism, we have compared the phenotype of a large series of 146 patients with and 250 patients without parkin mutations. Although no single sign distinguished the groups, patients with mutations had significantly earlier and more symmetrical onset, dystonia more often at onset and hyperreflexia, slower progression of the disease, and a tendency toward a greater response to levodopa despite lower doses. After forward stepwise multiple logistic regression analysis, dystonia at onset and brisk reflexes were not longer significantly different but were correlated with age at onset rather than the presence of the parkin mutation. Age at onset in carriers of parkin mutations varied as did the rate of progression of the disease: the younger the age at onset the slower the evolution. The genotype influenced the phenotype: carriers of at least one missense mutation had a higher United Parkinson's Disease Rating Scale motor score than those carrying two truncating mutations. The localization of the mutations was also important because missense mutations in functional domains of parkin resulted in earlier onset. Patients with a single heterozygous mutation had significantly later and more asymmetrical onset and more frequent levodopa‐induced fluctuations and dystonia than patients with two mutations. Ann Neurol 2003
Minocycline and doxycycline are not beneficial in a model of Huntington's disease
Authors: Smith Donna L. , Woodman Benjamin , Mahal Amarbirpal , Sathasivam Kirupa , Ghazi‐Noori Shabnam , Lowden Philip A. S. , Bates Gillian P. , Hockly Emma
Published: July 2003

Huntington's Disease (HD) is an inherited neurological disorder causing movement impairment, personality changes, dementia, and premature death, for which there is currently no effective therapy. The modified tetracycline antibiotic, minocycline, has been reported to ameliorate the disease phenotype in the R6/2 mouse model of HD. Because the tetracyclines have also been reported to inhibit aggregation in other amyloid disorders, we have investigated their ability to inhibit huntingtin aggregation and further explored their efficacy in preclinical mouse trials. We show that tetracyclines are potent inhibitors of huntingtin aggregation in a hippocampal slice culture model of HD at an effective concentration of 30μM. However, despite achieving tissue levels approaching this concentration by oral treatment of R6/2 mice with minocycline, we observed no clear difference in their behavioral abnormalities, or in aggregate load postmortem. In the light of these new data, we would advise that caution be exercised in proceeding into human clinical trials of minocycline. Ann Neurol 2003
Quantification of myelinated endings and mechanoreceptors in human digital skin
Authors: Nolano Maria , Provitera Vincenzo , Crisci Claudio , Stancanelli Annamaria , Wendelschafer‐Crabb Gwen , Kennedy William Robert , Santoro Lucio
Published: July 2003

We used immunohistochemistry and confocal microscopy applied to fingertip punch biopsy to study glabrous skin innervation in 14 healthy subjects. In addition to epidermal nerve fibers, we quantified mechanoreceptors and their myelinated afferents. Using digital images and dedicated software, we calculated caliber, internodal and nodal length, and G‐ratio of the last four internodes of the myelinated endings. In our skin samples, we found a mean density of 59.0 ± 29.3 myelinated endings per square millimeter with a mean diameter of 3.3 ± 0.5μm and an internodal length of 79.1 ± 13.8μm. These findings indicate that Aβ fibers undergo drastic changes in their course from the nerve trunk to the target organ, with repeated branching and consequent tapering and shortening of internodal length. Our work demonstrates that skin biopsy can give information on the status of large myelinated endings as well as unmyelinated sensory and autonomic nerves. Since distal endings are primarily involved in distal axonopathy, skin biopsy can be more suitable than sural nerve biopsy to detect early abnormalities. In addition to diagnostic applications, this technique allows clarification of the mode of termination of Aβ fibers and their relationship with mechanoreceptors, leading to relevant electrophysiological speculations. Ann Neurol 2003
Toward a molecular neuropsychiatry of neurodegenerative diseases
Authors: Cummings Jeffrey L.
Published: July 2003

Quantitative neuropsychiatry has provided increasingly precise descriptions of behavioral phenotypes associated with neurodegenerative disorders. Degenerative diseases of the brain are disturbances of protein metabolism, with failure of protein degredation by the ubiquitin‐proteosome system, production of neurotoxic peptide oligomers, and accumulation of intracellular protein deposits. Abnormalities of amyloid beta peptide, alpha‐synuclein protein, and hyperphosphorylated tau protein account for more than 90% of degenerative dementias. Functionally related neuroanatomical systems have shared metabolic characteristics and common vulnerabilities to protein dysmetabolism, providing the basis for phenotypes that reflect the underlying proteotype. Patients with alpha‐synuclein disorders are particularly prone to hallucinations, delusions, and rapid eye movement sleep behavior disorder. Patients with tauopathies manifest disproportionate disinhibition and apathy, and may exhibit compulsions. Alzheimer's disease is a triple proteinopathy with abnormalities of A‐beta, tau, and alpha‐synculein leading to a complex behavioral phenotype. This molecular approach to neuropsychiatry may assist in understanding the mechanisms of degenerative diseases, provide insight into the pathophysiology of neuropsychiatric symptoms, and contribute to monitoring disease‐modifying therapies. Ann Neurol 2003
Olfactory biopsies demonstrate a defect in neuronal development in Rett's syndrome
Authors: Ronnett Gabriele V. , Leopold Donald , Cai Xiaohe , Hoffbuhr Kristen C. , Moses Linda , Hoffman Eric P. , Naidu Sakkubai
Published: July 2003

Rett's Syndrome (RTT) is a neurodevelopmental disorder resulting from mutation in the mecp2 gene that encodes methyl CpG binding protein 2, a transcriptional repressor. Because this disease primarily affects neurons, tissue is not available during active disease. We used the olfactory system as a model to investigate abnormalities in neuronal development in RTT, because olfactory receptor neurons (ORNs) are replaced throughout life by ongoing postnatal neurogenesis. Thus, even in the adult, the olfactory epithelium contains neurons at various developmental stages. We obtained biopsies of nasal epithelium containing ORNs from RTT patients and age‐matched controls to study the status of the neuronal population using antibodies to stage‐specific developmental markers. There were no postprocedure complications. Compared with age‐matched controls, there were far fewer mature ORNs, as defined by olfactory marker protein expression, and significantly greater numbers of immature neuron‐specific tubulin–positive ORNs present. In RTT biopsies, olfactory marker protein–positive neurons displayed abnormal structure. These results suggest that dysfunction of MeCP2 results in decreased survival of mature ORNs with a compensatory increase in neurogenesis, or a failure of immature neurons to mature. Our study indicates that olfactory biopsies provide a method to study neuronal developmental diseases in adults and children. Ann Neurol 2003
Anticonvulsant properties of acetone, a brain ketone elevated by the ketogenic diet
Authors: Likhodii Sergei S. , Serbanescu Irina , Cortez Miguel A. , Murphy Patricia , Snead O. Carter , Burnham W. McIntyre
Published: July 2003

The ketogenic diet (KD), a treatment for drug‐resistant epilepsy, elevates brain acetone. Acetone has been shown to suppress experimental seizures. Whether elevation of acetone is the basis of the anticonvulsant effects of the KD and whether acetone, like the KD, antagonizes many different types of seizures, however, is unknown. This study investigated the spectrum of the anticonvulsant effects of acetone in animal seizure models. Rats were injected with acetone intraperitoneally. Dose–response effects were measured in four different models: (1) the maximal electroshock test, which models human tonic‐clonic seizures; (2) the subcutaneous pentylenetetrazole test, which models human typical absence seizures; (3) the amygdala kindling test, which models human complex partial seizures with secondary generalization; and (4) the AY‐9944 test, which models chronic atypical absence seizures, a component of the Lennox–Gastaut syndrome. Acetone suppressed seizures in all of the models, with the following ED50's (expressed in mmol/kg): maximal electroshock, 6.6; pentylenetetrazole, 9.7; generalized kindled seizures, 13.1; focal kindled seizures, 26.5; AY‐9944, 4.0. Acetone appears to have a broad spectrum of anticonvulsant effects. These effects parallel the effects of the KD. Elevation of brain acetone therefore may account for the efficacy of the KD in intractable epilepsy. Ann Neurol 2003
Apolipoprotein Eε4 modifies Alzheimer's disease onset in an E280A PS1 kindred
Authors: Pastor Pau , Roe Catherine M. , Villegas Andrés , Bedoya Gabriel , Chakraverty Sumi , García Gloria , Tirado Victoria , Norton Joanne , Ríos Silvia , Martínez Maribel , Kosik Kenneth S. , Lopera Francisco , Goate Alison M.
Published: July 2003

We previously have identified a large kindred from Colombia in which Alzheimer's disease (AD) is caused by the E280A presenilin 1 (PS1) mutation. The objective of this study was to examine whether environmental and genetic factors are responsible for variation in the phenotypic expression of the E280A PS1 mutation. We genotyped coding and promoter polymorphisms of the APOE gene in carriers of the E280A PS1 mutation. Kaplan–Meier product‐limit and Cox proportional hazard models were used in the statistical analyses. DNA was available from 114 carriers of the E280A PS1 mutation, including 52 subjects with AD. APOE ε4 allele carriers were more likely to develop AD at an earlier age than subjects without the ε4 allele (hazard ratio, 2.07; 95% confidence interval, 1.07–3.99; p = 0.030). Subjects with low education were more likely to develop AD later than those with higher education (hazard ratio, 0.476; 95% confidence interval, 0.26–0.87). Low educational level was associated with rural residence (p < 0.001). Promoter APOE variants did not influence either the onset or the duration of the disease. This study is the first to our knowledge to demonstrate that genetic and environmental factors influence age of onset in a kindred with a familial AD mutation. Ann Neurol 2003
Benign hereditary chorea: Clinical, genetic, and pathological findings
Authors: Kleiner‐Fisman Galit , Rogaeva Ekaterina , Halliday William , Houle Sylvain , Kawarai Toshitaka , Sato Christine , Medeiros Helena , St. George‐Hyslop Peter H. , Lang Anthony E.
Published: July 2003

Benign hereditary chorea is an autosomal dominant disorder presenting with childhood‐onset chorea, no dementia, and little or no progression. We present a family with typical clinical features of benign hereditary chorea. Pathological investigation of the brain of an affected family member who died of an unrelated condition showed no significant gross or histological abnormalities. Genetic evaluation showed a novel single nucleotide substitution of intron 2 of the TITF‐1 gene (also referred to as TTF, NKX2.1, and T/ebp) on chromosome 14 which is predicted to have drastic consequences on the maturation processes of TITF‐1. Ann Neurol 2003
Increased Alzheimer pathology in Parkinson's disease related to antimuscarinic drugs
Authors: Perry Elaine K. , Kilford Linda , Lees Andrew J. , Burn David J. , Perry Robert H.
Published: July 2003

The hypothesis that blockade of muscarinic receptors is associated with increased Alzheimer‐type pathology was investigated in Parkinson's disease. Amyloid plaque densities were more than 2.5‐fold higher in cases treated with antimuscarinic medication in the long term compared with untreated or short‐term treated cases (p = 0.005 and 0.00005, respectively). Neurofibrillary tangle densities were also highest in chronic compared with untreated or acute‐treated groups (p = 0.02 and 0.05, respectively). The findings, if replicated, have potential implications for the use of anticholinergic medication in elderly Parkinson's disease patients. Ann Neurol 2003
Frequency and mechanisms of stroke recurrence after cryptogenic stroke
Authors: Bang Oh Young , Lee Phil Hyu , Joo Sung Yeol , Lee Jin Soo , Joo In Soo , Huh Kyoon
Published: July 2003

The purpose of this study was to better understand the frequency and mechanisms of stroke recurrence after the stroke with no determined cause (NC). We prospectively studied consecutive patients with acute cerebral infarcts. We divided the patients into five groups (large artery disease [LAD], cardioembolism [CE], small artery disease [SAD], two or more causes [TMC], and NC) and registered recurrent strokes and prognosis for 1 year. Those in the NC group were compared with other subtypes. A total of 204 patients were included; 56 LAD, 22 CE, 62 SAD, 27 TMC, and 37 NC. During follow‐up, there were 7 deaths and 31 first recurrent strokes. Patients of the NC group showed a significantly higher rate (30%) of recurrent stroke than those of other subtypes (LAD 16%; CE 14%; SAD 2%), and it was associated with the existence of mild stenosis (≤50%) on relevant artery or the stenosis of greater than 50% on nonrelevant artery. Occlusive lesions other than significant stenosis of relevant artery may play an important role in the development of stroke recurrence in patients of the NC group. Therefore, from the therapeutic and prognostic point of view, the detection of such occlusive lesions in patients with cryptogenic stroke may be needed.Ann Neurol 2003
Tibial muscular dystrophy in a Belgian family
Authors: Van den Bergh Peter Y. K. , Bouquiaux Olivier , Verellen Christine , Marchand Sylvie , Richard Isabelle , Hackman P. , Udd Bjarne
Published: July 2003

We report a Belgian family with autosomal dominant, late‐onset, distal myopathy with selective foot extensor muscle involvement of the lower legs. Linkage to the tibial muscular dystrophy (TMD) locus 2q31 was not evident at first because of incomplete disease penetrance in a 50‐year‐old asymptomatic family member. An abnormal tibialis anterior muscle biopsy established her subclinical status and linkage of the family to the TMD locus. Mutation analysis showed a disease‐specific, heterozygous point mutation in the last exon, Mex6, of the titin gene. This is the third mutation found in TMD and the second European family with TMD outside the Finnish population, suggesting that titinopathies may occur in various populations. Ann Neurol 2003
Impaired glial glutamate transport in a mouse tuberous sclerosis epilepsy model
Authors: Wong Michael , Ess Kevin C. , Uhlmann Erik J. , Jansen Laura A. , Li Wen , Crino Peter B. , Mennerick Steven , Yamada Kelvin A. , Gutmann David H.
Published: July 2003

Excessive astrocytosis in cortical tubers in tuberous sclerosis complex (TSC) suggests that astrocytes may be important for epileptogenesis in TSC. We previously demonstrated that astrocyte‐specificTsc1gene inactivation in mice (Tsc1cKO mice) results in progressive epilepsy. Here, we report that glutamate transporter expression and function is impaired inTsc1cKO astrocytes.Tsc1cKO mice exhibit decreased GLT‐1 and GLAST protein expression. Electrophysiological assays demonstrate a functional decrease in glutamate transport currents ofTsc1cKO astrocytes in hippocampal slices and astrocyte cultures. These findings suggest thatTsc1inactivation in astrocytes causes dysfunctional glutamate homeostasis, leading to seizure development in TSC. Ann Neurol 2003
No preferential loss of paternal 19q alleles in oligodendroglial tumors
Authors: Hartmann Christian , Mueller Wolf , Lass Ulrike , Stockhammer Florian , von Eckardstein Kajetan , Veelken Julian , Jeuken Judith , Wick Wolfgang , von Deimling Andreas
Published: July 2003

Recently, exclusive loss of paternal 19q alleles in six of six oligodendrogliomas has been reported, indicating that parental imprinting plays a role in these tumors. We examined a series of 10 oligodendrogliomas and 3 oligoastrocytomas with allelic losses on 1p and 19q for the parental origin of the lost alleles. Ten cases lost paternal 1p alleles and 3 cases lost maternal alleles. For 19q, six cases had loss of paternal alleles and seven cases of had loss of maternal alleles. These random distributions do not support the hypothesis that parental imprinting accounts for inactivation of the putative oligodendroglioma tumor suppressor genes. Ann Neurol 2003
Myelination of a fetus with Pelizaeus–Merzbacher disease: Immunopathological study
Authors: Shiraishi Kazuhiro , Itoh Masayuki , Sano Kenji , Takashima Sachio , Kubota Takeo
Published: July 2003

We report an autopsied case of a 21‐gestational‐week fetus with duplication of the proteolipid protein (PLP) gene (PLP1). An immunohistochemical study, which can detect the specific expression of PLP, myelin basic protein, myelin‐associated glycoprotein, and platelet‐derived growth factor receptor α subunit in brain tissues, showed that the myelination was almost the same as that of age‐matched controls. This result suggests that the development and migration of the oligodendrocyte is normal in Pelizaeus–Merzbacher disease until midgestation. To our knowledge, this is the first report of the myelination of a fetus with duplication of the PLP1 gene.
β‐amyloid peptides in cerebrospinal fluid of patients with Creutzfeldt–Jakob disease
Authors: Wiltfang Jens , Esselmann Hermann , Smirnov Alexander , Bibl Mirko , Cepek Lukas , Steinacker Petra , Mollenhauer Brit , Buerger Katharina , Hampel Harald , Paul Sabine , Neumann Manuela , Maler Manuel , Zerr Inga , Kornhuber Johannes , Kretzschmar Hans A. , Poser Sigrid , Otto Markus
Published: July 2003

Decreased levels of β‐amyloid peptide 1‐42 (Aβ1‐42) in cerebrospinal fluid (CSF) are a characteristic feature of Alzheimer's disease (AD) but recently were also observed in Creutzfeldt–Jakob disease (CJD). We analyzed the CSF of patients with CJD, and AD and nondemented controls using a quantitative urea‐based Aβ sodium dodecyl sulfate polyacrylamide gel electrophoresis immunoblot. Like in AD and nondemented controls, we found a highly conserved pattern of carboxyterminally truncated Aβ1‐37/38/39 in addition to Aβ1‐40/42 also in CJD patients. By the introduction of the ratio Aβ1‐39 to Aβ1‐42, CJD and AD can effectively be differentiated. We conclude that the immunoblot shows disease‐specific CSF Aβ peptide patterns in CJD and AD and suppose that measurement of the Aβ peptide pattern seems to be a promising diagnostic tool in the differential diagnosis of dementias. Ann Neurol 2003;54:263–267
Herpesviruses in brains in Alzheimer's and Parkinson's diseases
Authors: Hemling Niina , Röyttä Matias , Rinne Juha , Pöllänen Paju , Broberg Eeva , Tapio Virpi , Vahlberg Tero , Hukkanen Veijo
Published: July 2003

We evaluated the association of HSV‐1, HHV‐6, and VZV with Alzheimer's disease (AD) and Parkinson's disease (PD). Brain specimens for viral DNA polymerase chain reaction represented 34 patients with AD, 40 with PD, and 40 controls. One AD patient (2.9%) was positive for HSV‐1 DNA, 88.2% for HHV‐6 DNA, and 26.5% for VZV DNA; 17.5% of PD patients were HSV‐1 DNA–positive and 75% HHV‐6–positive, whereas 40% had VZV DNA. Twenty‐five percent of the controls were positive for HSV‐1 DNA, 87.5% for HHV‐6, and 27.5% for VZV. HSV‐1, VZV, or HHV‐6 DNA in brains was no additional risk factor for AD.
Early‐onset Parkinson's disease caused by a compound heterozygous DJ‐1 mutation
Authors: Hague Stephen , Rogaeva Ekaterina , Hernandez Dena , Gulick Cindy , Singleton Amanda , Hanson Melissa , Johnson Janel , Weiser Roberto , Gallardo Marisol , Ravina Bernard , Gwinn‐Hardy Katrina , Crawley Anthony , St. George‐Hyslop Peter H. , Lang Anthony E. , Heutink Peter , Bonifati Vincenzo , Hardy John , Singleton Andrew
Published: July 2003

Mutations in DJ‐1 have been linked to an autosomal recessive form of early‐onset parkinsonism. To identify mutations causing Parkinson's disease (PD), we sequenced exons 1 through 7 of DJ‐1 in 107 early‐onset (age at diagnosis up to 50 years) PD subjects. One subject had a frameshift mutation in the first coding exon and an exon 7 splice mutation both predicted to result in a loss of functional protein. This subject was diagnosed with probable PD at age 24 years with asymmetric onset and an excellent response to levodopa therapy. Our observations suggest that sequence alterations in DJ‐1 are a rare cause of early‐onset PD.
“Chemical Bonding and Molecular Geometry”: Comments on a Book Review
Authors: Gillespie R. J. , Popelier P. L. A.
Published: July 2003

A model debate: The recent review of the book “Chemical Bonding and Molecular Geometry” has led to a discussion between the authors and the reviewer regarding the validity of the models chosen and the conclusions drawn.
Reply to the Comments of Gillespie and Popelier
Authors: Frenking Gernot
Published: July 2003

A model debate: The recent review of the book “Chemical Bonding and Molecular Geometry” has led to a discussion between the authors and the reviewer regarding the validity of the models chosen and the conclusions drawn.
Mechanical, morphological, and thermal properties of rigid polyurethane foams blown by distilled water
Authors: Seo W. J. , Jung H. C. , Hyun J. C. , Kim W. N. , Lee Y.‐B. , Choe K. H. , Kim S.‐B.
Published: July 2003

Rigid polyurethane foams (PUFs) were prepared from polymeric 4,4′‐diphenylmethane diisocyanate (PMDI), polyether polyol, 1,4‐butanediol, silicone surfactant, and distilled water. The properties of the synthesized PUF samples were investigated with differential scanning calorimetry, scanning electron microscopy, and a Universal testing machine. The density of the PUF was decreased from 173.7 to 41.7 kg/m3 with an increase in distilled water from 0.5 to 3.0 parts per hundred polyol by weight (php), respectively, with 0 php butanediol. The cell size of the PUF sample increased from 115 to 258 μm with an increase in distilled water from 0.5 to 3.0 php, respectively, with 10 php butanediol. From the results of the thermal analysis of the PUF sample, it was found that the glass‐transition temperatures of the PUF samples were increased from 49.5 to 80.8°C with an increase in distilled water from 0.5 to 3.0 php, respectively, with 0 php butanediol. The results of the investigation of the mechanical properties of the PUF samples showed that the mechanical strength of the PUF samples was increased with the distilled water at equal density. The surfactant effect on the properties of the PUF was studied, and it was observed that the cell size of the PUF samples decreased from 360 to 146 μm with an increase in surfactant from 0 to 0.33 php, respectively. However, the cell size did not change significantly when the surfactant exceeded 0.33 php. The increase of the mechanical strength from 0 to 0.33 php surfactant was attributed to the decrease of the cell size of the PUF samples, and the decrease of the mechanical strength with more than 0.33 php surfactant might be due to the plasticized effect of the PUF samples. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 90: 12–21, 2003