bluuebunny/crossref_metadata_2025 huggingface dataset:
Low Prevalence of Hypercalciuria in Japanese Children
Authors: Kaneko Kazunari , Tsuchiya Kumi , Kawamura Risako , Ohtomo Yoshiyuki , Shimizu Toshiaki , Yamashiro Yuichiro , Yamada Toshiyuki , Yamauchi Kuniaki , Kitagawa Teruo
Published: April 2003

Background/Aim: There are several factors, such as race, age, sex, and geographical variations, associated with renal stone formation. Although it is known that the prevalence of urolithiasis in Japanese children is low, the reason remains obscure. We hypothesize that the low prevalence of urolithiasis is associated with the urinary calcium excretion. The aim of our study was to investigate the prevalence of hypercalciuria in Japanese children. Methods: This investigation is a population-based school survey. A group of 529 healthy Japanese children was screened for hypercalciuria by measurement of the urinary Ca/Cr ratio using the morning fasting urine. In addition, the urinary Na/Cr ratio was also calculated for each subject. Results: Hypercalciuria regarded as an urinary Ca/Cr value of more than 0.17 was noted only in 3 out of 529 children (0.6 %), while most cases (494/529, 93.4%) demonstrated hypocalciuria (urinary Ca/Cr <0.05). The mean urinary Ca/Cr value was 0.024 in all subjects combined. Linear regression analysis revealed a positive direct correlation between urinary Ca/Cr and Na/Cr values (rs = 0.14, p < 0.01). The urinary Ca/Cr ratio was not related to age in either sex. Conclusions: The present study demonstrates that the prevalence of hypercalciuria in Japanese children is low as compared with other countries, even though absorptive hypercalciuria and dietary hypercalciuria might be missed in this setting. This low prevalence of hypercalciuria may be associated with the lower prevalence of urolithiasis in Japanese children. As it is suggested that a low dietary intake of calcium and sodium may play some role in the low urinary calcium excretion, a randomized, controlled study comparing the efficacy of different modes of therapy, such as a low-calcium diet and/or a low-salt diet, might provide valuable information for the prevention of urolithiasis.
Stimulation of the Central Median Thalamic Nucleus for Epilepsy
Authors: Velasco Francisco , Velasco Marcos , Jimenez Fiacro , Velasco Ana Luisa , Marquez Irma
Published: April 2003

Electrical stimulation of the centromedian thalamic nucleus (ESCM) has been used in cases of difficult to control seizures with multifocal onset in frontal and temporal lobes, as well as in cases of seizures with no evidence of focal onset, such as Lennox-Gastaut syndrome. The stimulation program consists of 1 min stimulation on one side, 4 min interval OFF stimulation and 1 min stimulation on the other side, alternating from one side to the other for 24 h, at 60–130 Hz, 2.5–5.0 V, 0.21–0.45 ms. 49 cases have been treated and followed for periods of 6 months to 15 years. Results indicate that ESCM is highly efficient to control generalized tonic clonic seizures (GTC), atypical absences (AA) and tonic seizures (TS) and less efficient to control complex partial seizures (CxP).
IgA Nephropathy in a Patient with Polycythemia vera
Authors: Chung Jaegul , Park Pae Gun , Song Kyung-il
Published: April 2003

IgA nephropathy (IgAN) is one of the most frequent forms of glomerulonephritis (GN). However, its association with polycythemia vera (PV) has rarely been described. We report a case of IgAN combined with PV. The patient was a 46-year-old male with chronic renal failure, heavy proteinuria and erythrocytosis. He also presented hypertension and hematuria as well as splenomegaly, high arterial oxygen saturation and elevated leukocyte alkaline phosphatase activity. Possible causes of secondary erythrocytosis were ruled out. The renal biopsy revealed mesangial proliferative GN with predominant IgA deposition in mesangium. He was diagnosed as having IgAN and PV concomitantly. After administration of hydroxyurea, enalapril and felodipine, blood cell count and blood pressure normalized, while azotemia persisted. There was also a partial remission of the heavy proteinuria. We describe a case of IgAN associated with PV, and possible pathophysiologic relationships between two diseases are discussed with review of the literature.
Prospective Evaluation of an In-Center Daily Hemodialysis Program
Authors: André Mauro B. , Rembold Simone M. , Pereira Claudia M. , Lugon Jocemir R.
Published: April 2003

Short duration daily hemodialysis (DHD) emerges as a well-tolerated alternative to standard hemodialysis (SHD). In this prospective study 5 patients in SHD were recruited to participate in an in-center DHD program. The SHD consisted of 3 sessions of 4 h each per week. Nonproportional mixture machines without an ultrafiltration control device and low flow dialyzers were used. For DHD, dialysis equipment and procedures were kept the same. Dialysis sessions, however, began at 6 p.m. (from Monday to Saturday) and lasted 2 h. Data from the last 6 months on SHD of the same patients were compared with the ones from each semester on DHD. Bone biopsy was performed at start and at the end of the 2-year study period. Hypotensive episodes, hypertensive crisis, cramps and headaches became 7–10 times less frequent in daily dialysis. A significant fractional increase (∼12%) was seen in mean values for hematocrit. Predialysis urea levels as well as predialysis creatinine levels declined significantly. Also lower during the daily dialysis period were the mean values for both phosphorus and Ca×P product. Significant increases were found in serum bicarbonate, albumin and in dry weight. The frequency of mean blood pressure ≧110 mm Hg on arrival for dialysis was significantly lower in every semester on daily hemodialysis. A significant twofold improvement in quality of life scoring was observed. Finally, daily hemodialysis also seemed to be beneficial to low turnover bone disease and bone aluminum deposition. These beneficial effects occurred despite of an increase in the frequency of missing days. Results from the present study which prospectively addressed the role of in-center short daily hemodialysis in the management of ESRD are encouraging.
Effect of Ethanol on Human Sleep EEG Using Correlation Dimension Analysis
Authors: Kobayashi Toshio , Madokoro Shigeki , Wada Yuji , Misaki Kiwamu , Nakagawa Hiroki
Published: April 2003

Our study was designed to investigate the influence of alcohol on sleep using the correlation dimension (D2) analysis. Polysomnography (PSG) was performed in 10 adult human males during a baseline night (BL-N) and an ethanol (0.8 g/kg body weight) night (Et-N). The mean D2 values during the Et-N and BL-N decreased significantly from wakefulness to stages 1, 2, and 3+4 of nonrapid eye movement (non-REM) sleep, and increased during REM sleep. The mean D2 of the sleep electroencephalogram (EEG) during stage 2 during the Et-N was significantly higher than during BL-N. In addition, the mean D2 values of the sleep EEG for the second, third and fourth sleep cycles during the Et-N were significantly higher than during the BL-N. These significant differences between BL-N and Et-N were not recognized by spectral and visual analyses. Our results suggest that D2 is a potentially useful parameter for quantitative analysis of the effect of ethanol on sleep EEGs throughout the entire night.
Modified Technique of Gasless Laparoscopic Cholecystectomy in a Developing Country: A 5-Year Experience
Authors: Nande Anand G. , Shrikhande Shailesh V. , Rathod Vipulroy , Adyanthaya Kishor , Shrikhande Vinayak N.
Published: April 2003

Background: Concerns and disadvantages associated with pneumoperitoneum have led surgeons to search for alternative techniques of exposure in laparoscopic surgery. We devised a modified technique of gasless laparoscopic cholecystectomy based on the concept of mechanical retraction of the abdominal wall. Patients and Methods: 337 males and 663 females, mean age 52 (7–87) years and mean weight 68 (28–126) kg, with gallstone disease and subjected to this technique were evaluated retrospectively (1992–1997). Towel clips were applied at 3 points on the abdominal wall and it was lifted without creating a pneumoperitoneum. A single surgical team specialized and experienced in biliary surgery performed all the surgeries. Results: Of 1,000, 46 patients weighing more than 85 kg required a combination of mechanical abdominal wall retraction and minimal pressure pneumoperitoneum (5 mm Hg). The conversion rate was 6% but none were related to limitations of the technique. Technique-related morbidity was minimal. No common bile duct or visceral injury was recorded and mortality was 0%. Conclusion: Gasless laparoscopic cholecystectomy is a feasible, safe and effective alternative to the pneumoperitoneum technique. It probably costs less and is therefore more useful in developing countries. However, it has limitation in overweight patients who are infrequently encountered in our population.
The Influence of Voluntary Muscle Contractions upon the Onset and Modulation of Tinnitus
Authors: Ganz Sanchez Tanit , Guerra Gaby Cecilia Yupanque , Lorenzi Maria Cecilia , Brandão Ana Laura , Bento Ricardo Ferreira
Published: April 2003

Objective: To evaluate the frequency of tinnitus onset (in normal subjects) and modulation (in tinnitus patients) during muscle contractions, estimating possible risk factors. Material and Method: This case-control study enrolled 121 tinnitus patients and 100 healthy volunteers who underwent medical history, ENT examination and 16 maneuvers of muscular contraction (head, neck and limbs). Modulation data were compared between patients with and without normal audiometry, well-defined diagnosis and symptoms of craniomandibular disorders. Results: The ability to modulate tinnitus (65.3%) was significantly higher than that to originate tinnitus (14.0%). The head and neck musculature was significantly more efficient than that of the limbs. Audiometric pattern, well-defined etiology and symptoms of craniomandibular disorders showed no relation to tinnitus modulation. Conclusions: Somatic modulation is a characteristic aspect of tinnitus.
Effectiveness of Glass-Ionomer (ART) and Amalgam Restorations in the Deciduous Dentition: Results after 3 Years
Authors: Taifour D. , Frencken J.E. , Beiruti N. , van ‘t Hof M.A. , Truin G.J.
Published: April 2003

This study compared the survival of restorations produced through the atraumatic restorative treatment (ART) approach using glass-ionomer with those produced through the traditional approach using amalgam (MTA) in deciduous dentitions over a period of 3 years. Using a parallel group design, 835 grade 1 children, aged 6–7 years, participated. A total of 482 children were treated through the ART and 353 children through the MTA approach. Eight dentists produced a total of 1,891 single- and multiple-surface restorations. After 3 years, 22.1% of the restorations were lost for evaluation. There was a statistically significant difference in the combined survival of all single- and multiple-surface restorations between the two approaches in favour of the ART approach (p = 0.04). The study revealed a 3-year cumulative survival percentage of single-surface ART and MTA restorations of 86.1 and 79.6%, respectively. The difference was statistically significant (p = 0.03). The main reasons for both single-surface ART and MTA restorations to fail was ‘restoration missing’ followed by ‘gross marginal defect’. The 3-year cumulative survival percentages of multiple-surface ART and MTA restorations were 48.7 and 42.9%, respectively. The difference was not statistically significant (p > 0.05). The 3-year survival percentages of single- and multiple- surface ART and MTA restorations varied widely amongst the 8 operators with an operator effect (p = 0.001) for multiple-surface MTA restorations. It can be concluded that the ART approach using glass-ionomer yielded better results in treating dentinal lesions in deciduous teeth than did the traditional approach using amalgam after 3 years. It is recommended to select the ART approach to complement the other activities of the school oral health programme.
Psychosurgery
Authors: Laitinen Lauri V.
Published: April 2003

The author describes the three commonly practiced surgical methods in the treatment of mental illness, i.e., cingulotomy, anterior capsulotomy, and posteromedial hypothalamotomy
Evaluation of Dementia in the Cardiovascular Health Cognition Study
Authors: Lopez Oscar L. , Kuller Lewis H. , Fitzpatrick Annette , Ives Diane , Becker James T. , Beauchamp Norman
Published: April 2003

Objective: To describe a methodology to evaluate dementia and frequency of different types of dementia and prevalence of the Cardiovascular Health Study (CHS). Methods: The CHS is a longitudinal study of cardiovascular disease among community-dwelling individuals over the age of 65. Of the 5,888 participants in the original study, 3,608 had a magnetic resonance imaging (MRI) of the brain in 1991, and formed the cohort for the dementia study. The CHS included yearly measures of cognitive function and, from 1998 to 2000, participants were evaluated for dementia by detailed neurological, and neuropsychological examinations. The possible cases of dementia and mild cognitive impairment (MCI) were adjudicated by a review committee of neurologists and psychiatrists. Results: There were 480 cases of (13.3%) incident dementia in the total sample, 227 (6.3%) prevalent dementia, 577 (16.0%) MCI, and 2,318 (64.4%) normal. The adjudication committee classified 69% of the incident dementia as Alzheimer’s disease (AD), 11% as vascular dementia (VaD), 16% as both, and 4% as other types. There was a substantial agreement between pre- and postMRI diagnosis of types of dementia. The frequency of dementia within the CHS cohort which survived to the end of the study in 1998–1999, was 13.5% for white men, 14.5% for white women, 22.2% for black men and 23.4% for black women. Conclusion: The CHS has developed a methodology for longitudinal studies of dementia in large cohorts and represents the largest study of dementia including cognitive testing, MRI and genetic markers.
Hypothyroidism and Thyroiditis after Therapy for Hodgkin’s Disease
Authors: Illés Árpád , Bíró Edit , Miltényi Zsófia , Keresztes Katalin , Váróczy László , András Csilla , Sipka Sándor , Bakó Gyula
Published: April 2003

During the follow-up of thyroid function of 151 patients with Hodgkin’s disease in complete remission for at least 1 year, 26 cases of subclinical, 12 cases of manifest clinical hypothyroidism and 2 cases of hyperthyroidism (Graves-Basedow disease) were confirmed. Thyroid dysfunction was more frequent in patients who had undergone mantle or neck radiotherapy. Hypothyroidism was most often revealed from the 6th year on following radiotherapy. Thyroid autoantibody positivity was found to be more frequent in patients with thyroid dysfunction, and conversely, thyroid dysfunction was more frequent among the 28 patients with autoantibody positivity. Ultrasound examination and fine needle aspiration cytology of the thyroid confirmed thyroiditis in 96% of the patients with antibody positivity. No relationship was found between thyroiditis and the form of treatment for Hodgkin’s disease. We have found that both neck irradiation and thyroiditis may play a role in the increased number of thyroid dysfunction in patients treated for Hodgkin’s disease. Thyroiditis is not caused by neck radiotherapy but may be the result of immune regulation disorders in Hodgkin’s disease. For substitution or isohormone therapy, levothyroxine is suggested for use. We suggest that examination of the thyroid should be performed at least once a year during the follow-up of Hodgkin’s disease patients.
Peyer’s Patches: Organized Lymphoid Structures for the Induction of Mucosal Immune Responses in the Intestine
Authors: Makala L.H.C. , Suzuki N. , Nagasawa H.
Published: April 2003

Peyer’s patches (PP) comprise transmucosal clusters of lymphoid follicles overlaid with a specialized lympho-epithelium and consequently play a central role in the induction of mucosal immune responses in the gut. Despite considerable achievements in the last 3 decades, in our understanding of how PP are involved in the induction of immune responses, much remains to be learned about these major organized lymphoid organs. The history and current status of PP termed ‘the major inductive site of immune responses’ is reviewed. The present understanding of PP biology and function, taking into account their preferential and unique retention of immune competent cells at specific sites, is discussed.
Psychometric Normalization of a Hyperacusis Questionnaire
Authors: Khalfa S. , Dubal S. , Veuillet E. , Perez-Diaz F. , Jouvent R. , Collet L.
Published: April 2003

Clinical hyperacusis consists of a marked intolerance to ordinary environmental sounds, while hearing thresholds are quite often normal. Hyperacusis appears to be a subjective phenomenon, which is not easily defined or quantified by objective measurements. In order to create a tool suitable to quantify and evaluate various hyperacusis symptoms, a questionnaire screening several aspects of auditory symptomatology has been constructed. Two hundred and one subjects (who were either hyperacusic or not), randomly selected from the general population, were tested. A principal component analysis performed on the correlation matrix of the 14 items of the questionnaire isolated three dimensions: attentional, social, and emotional. The three dimensions had satisfactory internal consistency reliability. The mean ± SD total score was 15 ± 6.7 out of 42 (maximum of hyperacusis) and a score greater than 28 seems to represent a strong auditory hypersensitivity. This new psychometric tool should further be tested on hyperacusic patients to verify its relevance in pathology and define the involvement of the three dimensions statistically obtained on the hyperacusis symptomatology.
Sorbents in Acute Renal Failure and the Systemic Inflammatory Response Syndrome
Authors: Winchester James F. , Kellum John A. , Ronco Claudio , Brady James A. , Quartararo Peter J. , Salsberg Jamie A. , Levin Nathan W.
Published: April 2003

Renal replacement therapy in acute renal failure is currently focused on the use of modifications of dialysis (continuous arteriovenous hemofiltration and hemodiafiltration) to remove middle molecular weight toxins, consisting of small proteins, and cytokines involved in the systemic inflammatory response syndrome (SIRS). Conventional high-flux dialyzers are not efficient at removing these molecules, prompting the investigation of sorbents to augment or replace dialysis. Sorbents have been developed to modulate SIRS by targeting cytokines such as IL-1, IL-6, IL-10, IL-18 and TNF, among others. Extensive pre-clinical studies are underway to demonstrate the clinical utility and safety of either adding sorbent hemoadsorption devices to hemodialysis, or the use of such devices alone in SIRS, sepsis, acute renal failure, cardiopulmonary bypass and end-stage renal disease.
Dopaminergic Modulation of Visual-Spatial Working Memory in Parkinson’s Disease
Authors: Costa Alberto , Peppe Antonella , Dell’Agnello Grazia , Carlesimo Giovanni Augusto , Murri Luigi , Bonuccelli Ubaldo , Caltagirone Carlo
Published: April 2003

Visual-spatial working memory (WM) impairment is frequently associated with the early stage of Parkinson’s disease (PD). The aim of this study was to evaluate the performance of a group of PD patients in visual-spatial and visual-object WM tasks and to investigate the effect of administering the dopaminergic agonist apomorphine (experiment 1) or the dopamine precursor L-dopa (experiment 2) on the performance of tests assessing these functions. To study WM processes, the PD patients and age-matched normal controls were given an n-back task paradigm. In both experiments, the PD patients were submitted to two evaluations: one after a 12-hour therapy washout and the other 15 min after a subcutaneous infusion of apomorphine (average 0.04 mg/kg) or 20/30 min after L-dopa intake (200 mg p.o.). The apomorphine infusion had a worsening effect on reaction times in both visual-spatial and visual-object WM tasks, but it did not influence performance accuracy. Instead, L-dopa administration had a ameliorative effect on accuracy and reaction times in both visual-spatial and visual-object tasks. These results highlight the role of dopamine in the modulation of the WM function in PD patients.
Fluoride Concentration in Saliva after Use of Oral Hygiene Products
Authors: Campus Guglielmo , Lallai Maria Rosaria , Carboni Roberto
Published: April 2003

The purpose of this in vivo, single-blind, randomized study was to compare fluoride concentrations in saliva of patients treated with oral hygiene products containing different fluoride salts. The study involved 104 students attending the University of Sassari. Participants were subdivided: group A used a sodium monofluorophosphate (NaMFP) toothpaste; groups B and C used an amine fluoride (AmF) toothpaste; group D used a toothpaste and a mouthwash both based on AmF, and group E used a toothpaste and a varnish both on an NaMFP base. Samples of unstimulated saliva were collected at baseline (t₀), at the end of the 20 days’ treatment phase (t1) and after 24 h, during which the volunteers refrained from any oral hygiene measure (t2). Saliva fluoride concentrations were measured using an ion-specific electrode. All measurements were made in triplicate and analysed statistically using ANOVA. In saliva, the mean fluoride concentration increased significantly in each treatment group. In conclusion, the fluoride concentration in saliva can be maintained to an optimal therapeutic level with the regular use of fluoridated products.
Caries Risk Tests and Salivary Levels of Immunoglobulins to Streptococcus mutans and Candida albicans in Mouthbreathing Syndrome Patients
Authors: Koga-Ito C.Y. , Unterkircher C.S. , Watanabe H. , Martins C.A.P. , Vidotto V. , Jorge A.O.C.
Published: April 2003

The aim of this study was to compare microbiological and salivary variables possibly related to caries risk in treated and untreated mouthbreathing syndrome (MBS) children and control children. Thirty control children, 30 mouthbreathers and 25 treated mouthbreathers were studied for the numbers of lactobacilli, mutans streptococci and yeasts in their saliva. Snyder’s test, salivary flow and buffering capacity were also evaluated. Levels of immunoglobulins to Candida albicans and Streptococcus mutans in the saliva were quantified using ELISA. Considering the results obtained for the microbiological and salivary caries risk tests, no significant differences were observed among the proportions of patients with small/negative and high/moderate caries risk in the studied groups. The level of IgG to S. mutans was significantly higher in the treated MBS group in relation to MBS patients. On the other hand, the median anti-S. mutans IgM level was lower in the treated MBS patients than in the other groups. For the studied anti-Candida immunoglobulins, IgM level was significantly lower in the treated MBS group than in the other groups. No differences were observed for anti-S. mutans and anti-Candida IgA levels among the groups. The findings suggest that mouthbreathing cannot be considered a risk factor for dental caries.
Combined Positron Emission Tomography and Magnetic Resonance Imaging for the Planning of Stereotactic Brain Biopsies in Children: Experience in 9 Cases
Authors: Pirotte Benoit , Goldman Serge , Salzberg Sacha , Wikler David , David Philippe , Vandesteene Arlette , van Bogaert Patrick , Salmon Isabelle , Brotchi Jacques , Levivier Marc
Published: April 2003

Because brain tumors can be histologically heterogeneous, stereotactic brain biopsies (SBB) may lead to inaccurate diagnosis or grading. Positron emission tomography (PET) has been used in pediatric neuro-oncology to help in the understanding and management of brain neoplasms. We combined PET and magnetic resonance (MR) imaging in the planning of SBB in 9 children (5 males and 4 females, aged 2–14 years) with infiltrative, ill-defined brain lesions. Tracers used for PET were 18F-2-fluoro-2-deoxy-D-glucose in 4 cases, 11C-methionine in 2 cases and both tracers in 3 cases. Biopsy targets were selected in hypermetabolic areas. PET-guided SBB provided accurate histological diagnosis in all patients and allowed a reduction of the number of trajectories in lesions located in functional areas. It also helped in better understanding and management of complex cases. This preliminary series suggests that combining PET and MR imaging in the planning of SBB in children (1) improves the diagnostic yield of SBB in infiltrative, ill-defined brain lesions, (2) makes it possible to reduce the sampling in high-risk/functional areas and (3) improves the quality of therapeutic management of pediatric brain tumors.
Light-Dark and Circadian Melatonin Rhythms Are Established de novo in Re-Aggregates of the Embryonic Chicken Retina
Authors: Willbold Elmar , Huhn Jutta , Korf Horst-Werner , Voisin Pierre , Layer Paul G.
Published: April 2003

A central function of chicken photoreceptors is the rhythmic synthesis of the neurohormone melatonin; however, it is unclear how they can achieve – already before hatching (i.e. without light exposure) – a circadian pacemaker system. Here we studied melatonin synthesis and secretion in rosetted spheroids, which are de novo histotypic spheres, re-aggregated from dissociated retinal cells of chicken embryos. Spheroids were cultured during a 12-hour light/12-hour dark cycle. Shortly after the onset of photoreceptor differentiation in spheroids near day 5 in culture, melatonin secretion set in and, by day 8 in culture, showed distinct dark-light oscillations, with high values during the dark and lower ones during the light period. Concomitantly, expression of two key enzymes of melatonin synthesis, arylalkylamine-N-acetyltransferase (AA-NAT) and hydroxyindole-O-methyltransferase (HIOMT) was detected by northern blot analysis from day 6 onwards, increasing until day 8. Only HIOMT, but not AA-NAT levels were 2- to 3-fold higher at the end of the light compared with the dark phase. Even under permanent darkness, a slight melatonin oscillation was revealed after 6 days. In conclusion, photoreceptors in de novo regenerated retinal spheroids become light-responsive, establish appropriate pathways for melatonin synthesis and secrete more melatonin in the dark. The underlying circadian pacemaker seems to depend on photoreceptor differentiation, not on previous light-dark entrainment.
Physical Trauma and Family History of Neurodegenerative Diseases in Amyotrophic Lateral Sclerosis: A Population-Based Case-Control Study
Authors: Cruz Dominic C. , Nelson Lorene M. , McGuire Valerie , Longstreth Jr. W.T.
Published: April 2003

This population-based case-control study was conducted in three counties in western Washington state (USA) between 1990 and 1994 to assess the association between amyotrophic lateral sclerosis (ALS) and several hypothesized risk factors, including a family history of neurodegenerative diseases, physical trauma (fractures, electrical shocks, and surgeries), rural residence, travel, and medical history. One hundred seventy-four cases with ALS, newly diagnosed by neurologists, were identified through several case-finding methods. Two controls (n = 348), who were matched to each case by gender and age (±5 years), were identified through random digit telephone dialing or Medicare lists. Exposure data were collected through structured in-person interviews. A greater proportion of cases (2.3%) than controls (0.9%) reported a first-degree relative with ALS, resulting in an odds ratio of 3.1 (95% CI, 0.6–15.7). For a positive family history of ALS among second-degree relatives, the odds ratio was 4.0 (95% CI, 1.0–16.6). Overall, reports of first- or second-degree relatives with ALS yielded a significantly elevated odds ratio of 3.3 (95% CI, 1.1–9.9). No association was found with a family history of Alzheimer’s disease or Parkinson’s disease, or with a family history of the neurodegenerative diseases as a group. No significant associations were demonstrated for any of the other factors analyzed, including a history of fractures, electrical shocks, or surgeries, a history of residence in rural areas, a history of travel to areas in the western Pacific where ALS is endemic, and a medical history of polio, polio immunization, or tetanus immunization.
Temporal Constraints on Visually Directed C-Start Responses: Behavioral and Physiological Correlates
Authors: Canfield James G.
Published: April 2003

To study the modulatory influences of visual information on Mauthner (M-) initiated C-start responses, short interval visual stimuli were presented to individual cichlid fish prior to being startled with a sound pulse. Because the axon of each Mauthner neuron activates trunk musculature contralateral to the soma, the initial direction of an ensuing startle response provides a behavioral measure of which cell has been driven closer to threshold by visual cues at the time the sound pulse causes one cell to fire. When an LED was illuminated on one side of the fish for 10 ms prior to a startling sound pulse, cichlids reliably turned toward the visual cue. At durations of 15 and 20 ms, fish turned away from the same stimulus. Thus, behavioral evidence suggests that the M-cell contralateral to a visual stimulus appears to be excited first but visual excitation of the M-cell ipsilateral to the visual stimulus follows and predominates. Consistent with the behavioral results, visually evoked excitatory potentials recorded intracellularly in the cichlid M-cells were complex, with initial PSPs showing latencies of about 11.6 ms from contralateral eye stimulation and 15.5 ms from stimulating the ipsilateral eye. PSP latencies in goldfish were longer and more similar for stimuli to the two eyes (about 22 ms). For contrast, sound-evoked PSPs begin within 2 ms. The relative long latencies for visually regulating M-cell function suggest that vision is most adaptive for biasing response direction prior to rather than during a predator’s attack.
Apolipoprotein A5
, a Newly Identified Gene That Affects Plasma Triglyceride Levels in Humans and Mice
Authors: Pennacchio Len A. , Rubin Edward M.
Published: April 2003

Apolipoprotein A5
(
APOA5
) is a newly described member of the apolipoprotein gene family whose initial discovery arose from comparative sequence analysis of the mammalian
APOA1/C3/A4
gene cluster. Functional studies in mice indicated that alteration in the level of
APOA5
significantly affected plasma triglyceride concentrations. Mice that overexpressed human
APOA5
displayed significantly reduced triglycerides, whereas mice that lacked
apoa5
had a large increase in this lipid parameter. Studies in humans have also suggested an important role for
APOA5
in determining plasma triglyceride concentrations. In these experiments, polymorphisms in the human gene were found to define several common haplotypes that were associated with significant changes in triglyceride concentrations in multiple populations. Several separate clinical studies have provided consistent and strong support for the effect with 24% of whites, 35% of blacks, and 53% of Hispanics who carry
APOA5
haplotypes associated with increased plasma triglyceride levels. In summary,
APOA5
represents a newly discovered gene involved in triglyceride metabolism in both humans and mice whose mechanism of action remains to be deciphered.
Hypercholesterolemia Promotes P-Selectin–Dependent Platelet–Endothelial Cell Adhesion in Postcapillary Venules
Authors: Tailor Anitaben , Granger D. Neil
Published: April 2003

Objective—

The objectives of this study were to determine whether hypercholesterolemia promotes platelet–endothelial cell (P/E) adhesion in murine postcapillary venules and define the contributions of endothelial or platelet associated P-selection to hypercholesterolemia-induced P/E interactions.

Methods and Results—

Wild-type (WT) or P-selectin deficient (P-sel
−/−
) platelets were isolated and labeled with the fluorochrome CFSE and administered to either WT or P-sel
−/−
mice placed on a normal diet (ND) or high cholesterol diet (HCD). Intravital videomicroscopy was used to quantify platelet saltation and firm adhesion. HCD-WT mice exhibited a time-dependent increase in P/E cell interactions (relative to ND-WT). Flow cytometry revealed an increased expression of P-selectin on circulating platelets of HCD-WT mice at 2 weeks compared with ND-WT mice. When WT platelets were monitored in HCD-P-sel
−/−
mice, P/E adhesion was dramatically reduced. However, when P-sel
−/−
platelets were monitored in HCD-WT recipients, P/E adhesive interactions were reduced even further, comparable to ND-WT mice.

Conclusions—

These results indicate that elevated cholesterol levels promote P/E adhesion in postcapillary venules and that whereas both endothelial and platelet P-selectin contribute to hypercholesterolemia-induced recruitment of platelets, platelet-associated P-selectin seems to play a more important role in producing the prothrombogenic phenotype in venules.
Rupture of the Atherosclerotic Plaque
Authors: Cullen Paul , Baetta Roberta , Bellosta Stefano , Bernini Franco , Chinetti Giulia , Cignarella Andrea , von Eckardstein Arnold , Exley Andrew , Goddard Martin , Hofker Marten , Hurt-Camejo Eva , Kanters Edwin , Kovanen Petri , Lorkowski Stefan , McPheat William , Pentikäinen Markku , Rauterberg Jürgen , Ritchie Andrew , Staels Bart , Weitkamp Benedikt , de Winther Menno
Published: April 2003

By its very nature, rupture of the atherosclerotic plaque is difficult to study directly in humans. A good animal model would help us not only to understand how rupture occurs but also to design and test treatments to prevent it from happening. However, several difficulties surround existing models of plaque rupture, including the need for radical interventions to produce the rupture, lack of direct evidence of rupture per se, and absence of convincing evidence of platelet- and fibrin-rich thrombus at the rupture site. At the present time, attention should therefore focus on the processes of plaque breakdown and thrombus formation in humans, whereas the use of animal models should probably be reserved for studying the function of particular genes and for investigating isolated features of plaques, such as the relationship between cap thickness and plaque stability.
Notch Signaling in Vascular Development
Authors: Iso Tatsuya , Hamamori Yasuo , Kedes Larry
Published: April 2003

Notch signaling is an extremely conserved and widely used mechanism regulating cell fate in metazoans. Interaction of Notch receptors (Notch) with their ligands (Delta-like or Jagged) leads to cleavage of the Notch intracellular domain (NICD) that migrates into the nucleus. In the nucleus, NICD associates with a transcription factor, RBP-Jk. The NICD-RBP-Jk complex, in turn, upregulates expression of primary target genes of Notch signaling, such as hairy and enhancer of split (HES) and HES-related repressor protein (HERP) transcriptional repressors. Recent evidence has demonstrated that the Notch pathway is involved in multiple aspects of vascular development, including proliferation, migration, smooth muscle differentiation, angiogenic processes, and arterial-venous differentiation. In this brief review, we focus on ligands, receptors, and target genes of Notch signaling in the vascular system and discuss (1) tissue distribution; (2) gain- and loss-of-function studies; and (3) the role of Notch components in human diseases involving the vascular system.
Amino Terminal 38.9% of Apolipoprotein B-100 Is Sufficient to Support Cholesterol-Rich Lipoprotein Production and Atherosclerosis
Authors: Chen Zhouji , Fitzgerald Robin L. , Saffitz Jeffrey E. , Semenkovich Clay F. , Schonfeld Gustav
Published: April 2003

Objective—

Carboxyl terminal truncation of apolipoprotein (apo)B-100 and apoB-48 impairs their capacity for triglyceride transport, but the ability of the resultant truncated apoB to transport cholesterol and to support atherosclerosis has not been adequately studied. The atherogenicity of apoB-38.9 was determined in this study by using our apoB-38.9–only (
Apob
38.9/38.9
) mice.

Methods and Results—

ApoB-38.9-lipoproteins (Lp-B38.9) circulate at very low levels in
Apob
38.9/38.9
mice as small LDLs or HDLs. Disruption of apoE gene in these mice caused accumulation of large amounts of βVLDL-like LpB-38.9 in plasma. These βVLDL particles were more enriched with cholesteryl esters but poor in triglycerides compared with the apoB-48-βVLDL of the apoB-wild-type/apoE-null (
Apob
+/+
/
Apoe
−/−
) mice. Likewise, apoB-38.9-VLDL secreted by cultured
Apob
38.9/38.9
mouse hepatocytes also had higher ratios of total cholesterol to triglycerides than apoB-48-VLDL secreted by the apoB-48–only hepatocytes. Thus, despite its impaired triglyceride-transporting capacity, apoB-38.9 has a relatively intact capacity for cholesterol transport. Spontaneous aortic atherosclerotic lesions were examined in apoB-38.9–only/apoE-null (
Apob
38.9/38.9
/
Apoe
−/−
) mice at ages 9 and 13 months. Extensive lesions were found in the
Apob
38.9/38.9
/
Apoe
−/−
mice as well as in their
Apob
+/38.9
/
Apoe
−/−
and
Apob
+/+
/
Apoe
−/−
littermates.

Conclusion—

Deleting the C-terminal 20% from apoB-48 does not impair its ability to transport cholesterol and to support atherosclerosis, thus narrowing the “atherogenic region” of apoB.
Olive Oil and Red Wine Antioxidant Polyphenols Inhibit Endothelial Activation
Authors: Carluccio Maria Annunziata , Siculella Luisa , Ancora Maria Assunta , Massaro Marika , Scoditti Egeria , Storelli Carlo , Visioli Francesco , Distante Alessandro , De Caterina Raffaele
Published: April 2003

Objective—Epidemiology suggests that Mediterranean diets are associated with reduced risk of cardiovascular disease. Because monocyte adhesion to the endothelium is crucial in early atherogenesis, we evaluated whether typical olive oil and red wine polyphenols affect endothelial–leukocyte adhesion molecule expression and monocyte adhesion.

Methods and Results—Phytochemicals in olive oil and red wine, including oleuropein, hydroxytyrosol, tyrosol, elenolic acid, and resveratrol, with or without antioxidant activity, were incubated with human umbilical vein endothelial cells for 30 minutes, followed by co-incubation with bacterial lipopolysaccharide or cytokines to trigger adhesion molecule expression. At nutritionally relevant concentrations, only oleuropein, hydroxytyrosol, and resveratrol, possessing a marked antioxidant activity, reduced monocytoid cell adhesion to stimulated endothelium, as well as vascular cell adhesion molecule-1 (VCAM-1) mRNA and protein by Northern analysis and cell surface enzyme immunoassay. Reporter gene assays with deletional VCAM-1 promoter constructs indicated the relevance of nuclear factor-κB, activator protein-1, and possibly GATA binding sites in mediating VCAM-1 transcriptional inhibition. The involvement of nuclear factor-κB and activator protein-1 was finally demonstrated at electrophoretic mobility shift assays.

Conclusions—Olive oil and red wine antioxidant polyphenols at nutritionally relevant concentrations transcriptionally inhibit endothelial adhesion molecule expression, thus partially explaining atheroprotection from Mediterranean diets.
Regulation of Plasma PAI-1 Concentrations in HAART-Associated Lipodystrophy During Rosiglitazone Therapy
Authors: Yki-Järvinen Hannele , Sutinen Jussi , Silveira Angela , Korsheninnikova Elena , Fisher Rachel M. , Kannisto Katja , Ehrenborg Ewa , Eriksson Per , Hamsten Anders
Published: April 2003

Objective—

Patients with highly active antiretroviral therapy–associated lipodystrophy (HAART+LD+) have high plasminogen activator inhibitor-1 (PAI-1) concentrations for unknown reasons. We determined whether (1) plasma PAI-1 antigen concentrations are related to liver fat content (LFAT) independently of the size of other fat depots and (2) rosiglitazone decreases PAI-1 and LFAT in these patients.

Methods and Results—

In the cross-sectional study, 3 groups were investigated: 30 HIV-positive patients with HAART+LD+, 13 HIV-positive patients without lipodystrophy (HAART+LD−), and 15 HIV-negative subjects (HIV−). In the treatment study, the HAART+LD+ group received either rosiglitazone (8 mg, n=15) or placebo (n=15) for 24 weeks. Plasma PAI-1 was increased in HAART+LD+ (28±2 ng/mL) compared with the HAART+LD− (18±3,
P
<0.02) and HIV− (10±3,
P
<0.001) groups. LFAT was higher in HAART+LD+ (7.6±1.7%) than in the HAART+LD− (2.1±1.1%,
P
<0.001) and HIV− (3.6±1.2%,
P
<0.05) groups. Within the HAART+LD+ group, plasma PAI-1 was correlated with LFAT (
r
=0.49,
P
<0.01) but not with subcutaneous or intra-abdominal fat or serum insulin or triglycerides. In subcutaneous adipose tissue, PAI-1 mRNA was 2- to 3-fold higher in the HAART+LD+ group than in either the HAART+LD− or HIV− group. Rosiglitazone decreased LFAT, serum insulin, and plasma PAI-1 and increased serum triglycerides but had no effect on intra-abdominal or subcutaneous fat mass or PAI-1 mRNA.

Conclusions—

Plasma PAI-1 concentrations are increased in direct proportion to LFAT in HAART+LD+ patients. Rosiglitazone decreases LFAT, serum insulin, and plasma PAI-1 without changing the size of other fat depots or PAI-1 mRNA in subcutaneous fat. These data suggest that liver fat contributes to plasma PAI-1 concentrations in these patients.
Changes in Perlecan Expression During Vascular Injury
Authors: Kinsella Michael G. , Tran Phan-Kiet , Weiser-Evans Mary C.M. , Reidy Michael , Majack Richard A. , Wight Thomas N.
Published: April 2003

Objective—Vascular smooth muscle cells (SMCs), activated by growth factors after arterial injury, migrate and proliferate to expand the intima of the blood vessel. During intimal expansion, proliferation is suppressed and an increasingly large proportion of the neointimal mass is composed of newly synthesized extracellular matrix (ECM). We sough to determine whether the ECM heparan sulfate proteoglycan (HSPG) perlecan, which inhibits SMC proliferation in vitro, also accumulates and limits SMC proliferation during neointimal expansion.

Methods and Results—Perlecan expression and accumulation were analyzed by immunohistochemistry and in situ hybridization during neointima formation after balloon catheter injury to the rat carotid artery. Perlecan expression was low in uninjured vessels and up to 7 days after injury, during maximal SMC proliferation. By 14 days after injury, perlecan was dramatically increased, and immunostaining remained heavy throughout the advanced lesion, 35 to 42 days after injury. Finally, explants of intimal tissue from 35- to 42-day neointimal lesions were digested with glycosaminoglycanases to determine whether endogenous HSPGs inhibit intimal SMC proliferation. SMCs within HS-depleted, but not chondroitinase ABC–treated or mock-incubated, explants were found to proliferate in response to platelet-derived growth factor BB.

Conclusions—HSPGs, such as perlecan, may inhibit the proliferative response of SMCs after vascular injury.
Evidence That Peroxisome Proliferator–Activated Receptor Delta Influences Cholesterol Metabolism in Men
Authors: Skogsberg Josefin , Kannisto Katja , Cassel Tobias N. , Hamsten Anders , Eriksson Per , Ehrenborg Ewa
Published: April 2003

Objective—

The objective of this work was to explore the role of peroxisome proliferator–activated receptor delta (PPARD) in lipid metabolism in humans.

Methods and Results—

PPARD is a nuclear receptor involved in lipid metabolism in primates and mice. We screened the 5′-region of the human gene for polymorphisms to be used as tools in association studies. Four polymorphisms were detected: −409C/T in the promoter region, +73C/T in exon 1, +255A/G in exon 3, and +294T/C in exon 4. The frequencies of the rare alleles were 4.2%, 4.2%, 1.2% and 15.6%, respectively, in a population-based group of 543 healthy men. Only the +294T/C polymorphism showed significant association with a metabolic trait. Homozygotes for the rare C allele had a higher plasma LDL–cholesterol concentration than homozygotes for the common T allele, which was verified in an independent cohort consisting of 282 healthy men. Transfection studies showed that the rare C allele had higher transcriptional activity than the common T allele. Electrophoretic mobility shift assays demonstrated that the +294T/C polymorphism influenced binding of Sp-1. An interaction with the PPAR alpha L162V polymorphism was also detected for several lipid parameters.

Conclusions—

These findings suggest that PPARD plays a role in cholesterol metabolism in humans.
Integral Role of RhoA Activation in Monocyte Adhesion–Triggered Tissue Factor Expression in Endothelial Cells
Authors: Ishibashi Toshiyuki , Sakamoto Takayuki , Ohkawara Hiroshi , Nagata Kenji , Sugimoto Koichi , Sakurada Sotaro , Sugimoto Naotoshi , Watanabe Atai , Yokoyama Keiko , Sakamoto Nobuo , Kurabayashi Masahiko , Takuwa Yoh , Maruyama Yukio
Published: April 2003

Objective—

The role of Rho activation in the regulation of tissue factor (TF) is not clear. This study was undertaken to investigate this in endothelial cells induced by monocyte adhesion.

Methods and Results—

Isolated human peripheral blood monocytes were added to cultured human coronary endothelial cells. Monocyte adhesion to endothelial cells increased the levels of TF antigen in the endothelial cells. The results of transient transfection of the human TF promoter/luciferase gene into endothelial cells indicated that the increase in endothelial expression of the TF gene caused by monocyte adhesion occurred at the transcriptional level. The upregulation of TF was inhibited by statins, and the suppressive effect of statins was reversed by geranylgeranylpyrophosphate. Monocyte adhesion rapidly upregulated the membrane translocation and GTP/GDP exchange of RhoA, but not of Cdc42 or Rac, in endothelial cells. Rho inhibition by C3 exoenzyme or adenovirus-mediated expression of N19RhoA prevented the endothelial upregulation of TF caused by monocyte adhesion, and this was mimicked by Rho-kinase inhibitors. Moreover, monocyte adhesion increased the phosphorylation of nuclear factor-κB p65 in endothelial cells, and this was prevented by statins and Rho inhibition.

Conclusions—

Our study shows that RhoA activation plays an integral role in TF expression in endothelial cells.
Intra-Arterial Tumor Necrosis Factor-α Impairs Endothelium-Dependent Vasodilatation and Stimulates Local Tissue Plasminogen Activator Release in Humans
Authors: Chia Stanley , Qadan Motaz , Newton Richard , Ludlam Christopher A. , Fox Keith A.A. , Newby David E.
Published: April 2003

Objective—Inflammation contributes to the pathogenesis of cardiovascular disease, potentially through the actions of proinflammatory cytokines. We assessed the direct effects of local intra-arterial tumor necrosis factor-α (TNF-α), interleukin-6, and endotoxin on blood flow and endogenous tissue plasminogen activator (t-PA) release in vivo in humans.

Methods and Results—In a double-blind, randomized, placebo-controlled trial, blood flow, plasma cytokine, and fibrinolytic parameters were measured using venous occlusion plethysmography and blood sampling. Ten subjects received intrabrachial TNF-α, interleukin-6, and endotoxin infusions, and 8 additional subjects received intrabrachial infusions of bradykinin, acetylcholine, and sodium nitroprusside after pretreatment with TNF-α. TNF-α but not interleukin-6, endotoxin, or placebo caused a gradual and sustained ≈20-fold increase in plasma t-PA concentrations (P<0.001) that was associated with elevated plasma interleukin-6 concentrations (P<0.05) but without an effect on blood flow or plasminogen activator inhibitor type 1 antigen. Compared with placebo, TNF-α pretreatment impaired bradykinin- and acetylcholine-induced vasodilatation (P<0.03) and resulted in a doubling of bradykinin-induced t-PA release (P<0.05).

Conclusions—Intra-arterial TNF-α causes an acute local vascular inflammation that is associated with impaired endothelium-dependent vasomotion as well as a sustained and substantial increase in endothelial t-PA release. TNF-α has potentially both adverse vasomotor and beneficial profibrinolytic effects on endothelial function.