bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effects of Carbamazepine, Valproic Acid and Phenobarbital on the Oxidative and Antioxidative Balance in Epileptic Children
Authors: Aycicek Ali , Iscan Akin
Published: December 2006

Background: Oxidative stress has been related in a wide variety of ways with nervous tissue. We studied the effect of antiepileptic monotherapy on serum level of total antioxidant capacity, lipid hydroperoxide, total peroxide, oxidative stress index, and individual serum antioxidants such as albumin, bilirubin and uric acid. Patients and Methods: We studied 122 subjects including healthy controls, untreated epileptic patients and epileptic patients treated with valproic acid, carbamazepine or phenobarbital. Serum total antioxidant capacity was measured as an index of antioxidants, and total peroxide was measured as index of oxidative stress. The serum concentrations of uric acid, albumin, bilirubin and lipid hydroperoxide were monitored simultaneously. Results: We found that serum total antioxidant capacity levels were significantly decreased in the untreated group compared with the controls. Serum total peroxide levels were markedly increased in the untreated and carbamazepine-treated groups compared to in the controls; and lipid hydroperoxide and oxidative stress index levels were significantly higher in the phenobarbital-treated group than in the controls. Uric acid concentrations were significantly lower in the valproic-acid-treated group than in the untreated group, and total bilirubin concentrations were higher in the untreated group than in the controls. Conclusion: Epileptic children exposed to oxidative stress and conventional antiepileptic drugs change the oxidative/antioxidative balance. The serum oxidant and antioxidant status of epileptic children with valproic acid monotherapy are better regulated compared with children with carbamazepine and phenobarbital monotherapy.
Brain Lesions on MRI in Elderly Patients with Type 2 Diabetes Mellitus
Authors: van Harten Barbera , Oosterman Joukje M. , Potter van Loon Bert-Jan , Scheltens Philip , Weinstein Henry C.
Published: December 2006

Background and Purpose: Diabetes mellitus (DM) type 2 has been associated with poor cognitive performance and dementia, particularly in elderly patients. The exact mechanisms underlying the cognitive dysfunction in DM remain unclear. Imaging studies of the brain could be helpful to give more insight into possible structural brain lesions underlying these cognitive dysfunctions. Therefore, we performed a study in independently living patients with DM type 2 in order to investigate the association between DM and brain imaging abnormalities. Methods: The study population consisted of 45 patients with DM type 2 without hypertension (mean age 73.4 ± 5.1 years, mean duration 16.5 ± 11.5 years), 45 patients with DM type 2 and hypertension (mean age 73.5 ± 6.1 years, mean duration 11.9 ± 9.2 years) and 44 control subjects (mean age 73.1 ± 5.4 years). All patients and control subjects underwent an MRI of the brain. White matter lesions (WML), cerebral atrophy and medial temporal lobe atrophy were rated by a standardized visual rating scale. Lacunar infarcts were defined as focal hypo-intensities on fluid-attenuated inversion recovery sequences with a hyperintense rim around it. Results: WML occurred more frequently in diabetic patients with hypertension as well as without hypertension. Significantly more deep WML were found in DM patients with and without hypertension when compared to control subjects, whereas no difference was found in the occurrence of periventricular hyperintensities. In all 3 groups, lacunar infarcts occurred sporadically. A trend towards higher atrophy scores was seen in patients with DM compared to control subjects. Conclusions: The data of this cross-sectional study suggest that type 2 DM is an independent risk factor for deep WML in the independently living elderly patients.
Contribution of Nerve Biopsy to Unclassified Neuropathy
Authors: Schweikert Kathi , Fuhr Peter , Probst Alphonse , Tolnay Marcus , Renaud Susanne , Steck Andreas J.
Published: December 2006

Objectives: To evaluate the diagnostic yield of nerve biopsy in patients with peripheral neuropathy of undetermined cause despite extensive diagnostic workup. Methods: From November 2001 through January 2004, 38 patients underwent nerve biopsy because of unclassified neuropathy. Results: The etiology of the neuropathies could be defined in 14 patients (37%), i.e. in 15% of chronic symmetric, 30% of chronic asymmetric, 50% of subacute symmetric and 62.5% of subacute asymmetric neuropathies. The biopsy was diagnostic in 6 patients (16%), where it showed a vasculitis, and supportive in 8 patients (21%). Conclusions: The contribution of nerve biopsy to the diagnosis of peripheral neuropathy was highest in acute and subacute asymmetric forms of neuropathy and lowest in chronic symmetric forms. The main indication for nerve biopsy remains the diagnosis of vasculitic neuropathy, a potentially treatable disorder.
Anthropometric Determinants of a Clustering of Lipid-Related Metabolic Risk Factors in Overweight and Non-Overweight Adolescents – Influence of Cardiorespiratory Fitness
Authors: Mesa José L. , Ortega Francisco B. , Ruiz Jonatan R. , Castillo Manuel J. , Tresaco Beatriz , Carreño Francisco , Moreno Luis A. , Gutiérrez Ángel , Bueno Manuel
Published: December 2006

Background/Aims: To explore in adolescents the associations between simple anthropometric variables with a continuously distributed summary score for lipid-related metabolic risk in both overweight and non-overweight adolescents, and to test whether these associations are modified by the level of cardiorespiratory fitness. Methods: Cardiorespiratory fitness, BMI, skinfold thicknesses, body circumferences, and a continuously distributed clustering of lipid- related metabolic risk (calculated from LDL and HDL choles- terol, triglycerides, and glucose) were measured in 524 adolescents (265 males, 259 females, 15.3 ± 1.4 years) from the cross-sectional multicentric AVENA study. Participants were classified as overweight (including obesity) or non-overweight. Results: Most anthropometric parameters were univariately related to the continuous lipid-related metabolic risk. However, after multicollinear analysis and generalized linear modelling, suprailiac skinfold thickness in males (p < 0.001, explained variance 12.2%) and waist-to-height ratio in females (p < 0.001, explained variance 10.0%) were the best determinants of the continuous metabolic risk score, after adjustment for age, sexual maturation, and economic status. These associations were slightly weakened in overweight males (p = 0.034) and females (p = 0.087), and did not interact with cardiorespiratory fitness. Conclusion: Our data emphasize the usefulness of suprailiac skinfold thickness in males and waist-to-height ratio in females as simple anthropometric measurements associated to an overall lipid-related metabolic risk, mainly in non-overweight adolescents and regardless their cardiorespiratory status.
Renal Protective Role of Atrial Natriuretic Peptide in Acute Sodium Overload-Induced Inflammatory Response
Authors: Rosón María Inés , Toblli Jorge E. , Della Penna Silvana L. , Gorzalczany Susana , Pandolfo Marcela , Cavallero Susana , Fernández Belisario E.
Published: December 2006

Background: The present study was performed to explore the effect of exogenous infusions of atrial natriuretic peptide (ANP) on the early inflammatory response during acute sodium overload in normal rats. Methods: Sprague Dawley rats were exposed to acute sodium overload (Na 1.5 M). Nonhypotensive doses of ANP (1 and 5 µg ·kg–1 ·h–1) were infused simultaneously with sodium or after sodium infusion in order to evaluate prevention or reversion of the inflammatory response, respectively. We determined inflammation markers in renal tissue by immunohistochemistry. Results: Creatinine clearance was not reduced in any case. Sodium tubular reabsorption increased after sodium overload (334.3 ± 18.7 vs. control 209.6 ± 27.0 mEq·min–1, p < 0.05) without changes in mean arterial pressure. This increase was prevented (228.9 ± 26.4; p < 0.05) and reversed (231.5 ± 13.9; p < 0.05) by ANP-5 µg ·kg–1 ·h–1. Sodium overload increased the expression of: RANTES (38.4.3 ± 0.8 vs. 2.9 ± 0.6%, p < 0.001), transforming-growth-factor-β1 (35.3 ± 1.0 vs. 5.0 ± 0.7%, p < 0.001), α-smooth muscle actin (15.6 ± 0.7 vs. 3.1 ± 0.3%, p < 0.001), NF-ĸB (9.4 ± 1.3 to 2.2 ± 0.5 cells/mm2, p < 0.001), HIF-1α (38.2 ± 1.7 to 8.4 ± 0.8 cells/mm2, p < 0.001) and angiotensin II (35.9 ± 1.3 to 8.2 ± 0.5%, p < 0.001). ANP-5 µg ·kg–1 ·h–1 prevented and reversed inflammation: RANTES (9.2 ± 0.5 and 6.9 ± 0.7, p < 0.001); transforming growth factor-β1 (13.2 ± 0.7 and 10.2 ± 0.5, p < 0.001) and α-smooth muscle actin (4.1 ± 0.4 and 5.2 ± 0.4, p < 0.001). Both prevention and reversion by ANP were associated with downregulation of NF-ĸB (3.2 ± 0.4 and 2.8 ± 0.5, p < 0.001) and angiotensin II (8.2 ± 0.5 and 9.1 ± 0.7, p < 0.001) and diminished hypoxia evaluated through HIF-1α expression (8.4 ± 0.8 and 8.8 ± 0.7, p < 0.001). Conclusion: Our study provides evidence supporting a protective role of ANP in both prevention and reversion of renal inflammation in rats with acute sodium overload.
Effects of Clozapine and Sulpiride on Morphine State-Dependent Memory in the Step-Down Passive Avoidance Test
Authors: Malekmohamadi Nazanin , Heidari Parviz , Sahebgharani Mousa , Zarrindast Mohammad-Reza
Published: December 2006

The effects of antipsychotic drugs sulpiride and clozapine on morphine state-dependent memory of passive avoidance task were examined in mice. Post-training administration of morphine (5 mg/kg) led to state-dependent learning with impaired memory retrieval on the test day which was reversed by pre-test administration of the same dose of the opioid (5 mg/kg). In animals where memory was impaired by post-training morphine, the administration of either sulpiride or clozapine before pre-test morphine reduced the improvement of memory produced by the opioid. Co-administration of sulpiride with clozapine did not potentiate their antagonistic response. In conclusion, the inhibition of improvement of memory retrieval by morphine treatment on the test day by the two dopamine receptor antagonists seems to be induced through two different receptor mechanisms.
A Keratinocyte’s Course of Life
Authors: Houben E. , De Paepe K. , Rogiers V.
Published: December 2006

An adequate permeability barrier function of the mammalian epidermis is guaranteed by the characteristic architecture of the stratum corneum. This uppermost layer consists of a highly organized extracellular lipid compartment which is tightly joined to the corneocytes. The generation of the extracellular lipid compartment and the transformation of the keratinocytes into corneocytes are the main features of epidermal differentiation. However, equally important is the continuous renewal of the stratum corneum, which is insured by a careful balance between the replenishment of new keratinocytes from the proliferating basal layer, and the well-orchestrated loss of the most superficial cells after the so-called ‘epidermal programmed cell death’. In this overview, the complete life of keratinocytes is described, from the proliferative organization to the process of desquamation.
Assessment of Topical Corticosteroid Activity Using the Vasoconstriction Assay in Healthy Volunteers
Authors: Görne R.C. , Greif C. , Metzner U. , Wigger-Alberti W. , Elsner P.
Published: December 2006

Objective and Design: The aim of the study was to evaluate the vasoconstrictive activity of four new galenic preparations of hydrocortisone and to compare it with concentration-equivalent reference preparations. The study comprised two study phases: the pilot study phase and the main study phase. During open, nonrandomized pilot study, the optimal administration period was tested. The main study was performed in a randomized, double-blind intraindividual comparative design. Subjects: Twenty male and female volunteers with healthy skin who responded to topically applied clobetasol-17-propionate before entering the trial participated in this study. Treatment: All subjects received the same treatments. The test preparations new galenic formulation (NGF) hydrocortisone 0.25% cream, NGF hydrocortisone acetate 0.25% cream, NGF hydrocortisone 0.5% cream, and NGF hydrocortisone 1.0% cream were compared with the respective reference preparations Soventol® hydrocortisone (hydrocortisone acetate 0.25%), Hydroderm HC 0.5% cream (hydrocortisone 0.5%), Hydrogalen® cream (hydrocortisone 1.0%) and placebo (vehicle of test preparations). Method: The topical preparations were applied occlusively for 2 h (pilot study) or 24 h (main study) on outlined areas (5 × 5 cm with a distance of 3 cm) of both forearms (4 areas for each). Assessment of vasoconstriction was performed before treatment, and 0.5, 4, 6 and 24 h after treatment (observation period) using a subjective rating scale (OLSEN vasoconstriction score) and measuring the colorimetric parameter a* (redness) by use of the Chroma-Meter (Minolta company, Ahrensburg, Germany). Results: A significant vasoconstriction (positive blanching effect) was measured by use of chromametry for test preparations hydrocortisone 0.25% cream, hydrocortisone 0.5% cream, hydrocortisone 1.0% cream and for the reference preparation Hydrogalen cream compared to placebo 30 min after the end of treatment. In contrast, the reference preparations Soventol hydrocortisone and Hydroderm HC 0.5% did not differ significantly from placebo 30 min after treatment. No statistically significant effect of all formulations was observed 4–24 h after treatment in comparison with placebo. Conclusions: The vasoconstrictive efficacy of test preparations was mostly stronger than the concentration-equivalent reference preparations. This effect was achieved by use of new galenics of test preparations resulting in enhanced skin penetration and improved efficiency. No unwanted side effects were observed during the course of the study despite increased efficacy of the topically applied test preparations.
Early Low-Dose Hydrocortisone in Very Preterm Infants: A Randomized, Placebo-Controlled Trial
Authors: Bonsante F. , Latorre G. , Iacobelli S. , Forziati V. , Laforgia N. , Esposito L. , Mautone A.
Published: December 2006

Background: Several reports indicate a decreased cortisol response to adrenocorticotropic hormone in preterm infants developing chronic lung disease and in preterm infants with refractory hypotension. Low-dose hydrocortisone (HC) may allow for beneficial effects. Objective: Our aim was to assess whether HC is able to increase survival without chronic lung disease. Methods: We performed a double-blind, randomized, placebo-controlled trial. Fifty mechanically ventilated infants (birth weight: 500–1,249 g) were randomized to receive treatment (HC 0.5 mg/kg/12 h for 9 days, then HC 0.5 mg/kg/24 h for 3 days) or placebo. Major outcome was survival without oxygen dependence at 36 weeks of postconceptional age (O2-free survival). Results: The basic characteristics were similar between the two groups. O2-free survival was higher in the HC group (64 vs. 32%). The advantage was particularly evident among infants without antenatal steroids. The mortality rate was 16% in the HC group versus 40% in the control group (difference not significant). Hypotension after recruitment was reduced by HC (0 vs. 30%). The incidence of gastrointestinal perforation and other adverse effects was similar between the two groups. Conclusions: HC prophylaxis improved O2-free survival and early cardiocirculatory function in our population, without important short-term effects. The neurodevelopmental outcome will be assessed at 2 years.
Dipyridamole Promotes Changes in Calbindin-D28k and Tyrosine Hydroxylase Expression in Neonatal Rats
Authors: Hefner K.E. , Butler R. , Ravindra A. , Ahmad Z. , Molina D. , Turner C.P.
Published: December 2006

Background: Perinatal hypoxia alters the concentration of many neurochemicals in the brain, including adenosine, and promotes central nervous system (CNS) disorders in human infants such as periventricular leukomalacia or encephalopathy. Objective: Using the postnatal rat as a model of perinatal human development, we examined the effects of sustained increases in brain adenosine on CNS regions thought to be involved with both planning and execution of motor activity. Methods: To simulate hypoxia-induced changes in adenosine, Sprague-Dawley rats were injected twice daily from postnatal day (P) 3 to P14, with the adenosine uptake inhibitor dipyridamole (DIP) or the A1 adenosine receptor agonist N6-cyclopentyladenosine (CPA). Vehicle-injected animals served as controls. Immunohistochemical and morphological analyses were then performed to examine the expression of calbindin D-28k (CB) and the thickness of the external granule cell layer (eGL) in the cerebellum. Additionally tyrosine hydroxylase (TH) expression in the caudate putamen and ventricular size were also examined. Results: In the cerebellum, both DIP and CPA reduced the number of CB-positive Purkinje cells as well as decreased the thickness of the eGL compared to vehicle. In the caudate putamen we found that DIP but not CPA decreased TH expression when compared to vehicle. Neither agent significantly altered ventricular size when compared to vehicle. Conclusions: These observations suggest that elevations in brain adenosine, which can occur following hypoxia, leads to both neurochemical and cellular changes in regions of the brain which control the planning and execution of motor activity. Thus, therapeutic strategies that target brain regions most sensitive to adenosine may prevent or control at least some of the CNS damage observed following perinatal hypoxia.
Ultrasound-Guided Percutaneous Cholecystostomy for Acute Neonatal Biliary Obstruction
Authors: Helin Radley , Bhat Rama , Rao Bhaskara
Published: December 2006

Use of a percutaneously-inserted cholecystostomy drainage tube is an effective therapeutic option for acute hyperbilirubinemia in severely-ill adult patients, but to our knowledge has not been previously reported in infants. We describe an infant who developed acute extrahepatic biliary tract obstruction with marked conjugated (direct) hyperbilirubinemia, and who was determined to be an unsuitable surgical candidate. Ultrasound-guided percutaneous cholecystostomy was performed and resulted in prompt, significant, and sustained decline in serum bilirubin levels. Potential risks and benefits, as well as suggested indications for the procedure are discussed.
Detection by Flow Cytometry of ESAT-6- and PPD-Specific Circulating CD4+ T Lymphocytes as a Diagnostic Tool for Tuberculosis
Authors: Cosmi Lorenzo , Maggi Laura , Santarlasci Veronica , Liotta Francesco , Frosali Francesca , Angeli Roberta , Mazzetti Marcello , Vultaggio Alessandra , Matucci Andrea , Maggi Enrico , Romagnani Sergio , Annunziato Francesco
Published: December 2006

Background: The identification of mycobacteria represents the gold standard in the diagnosis of tuberculosis (TB), but it is not applicable in all patients, and immunological tests, such as the tuberculin skin test (TST), are not specific and sensitive enough. Methods: By flow cytometry, we measured the CD4 T-cell response to purified protein derivative (PPD) and early secretory antigenic target-6 (ESAT-6) protein using the intracellular cytokine staining technique on whole blood samples obtained from active TB (n = 16), latent TB (n = 17), Bacille Calmette-Guérin (BCG)-vaccinated (n = 11) and healthy (n = 10) donors. All the patients were also tested with conventional TST. Results: The identification by flow cytometry of PPD-specific T lymphocytes upon antigen stimulation of whole blood enables the discrimination of active TB, latent TB and BCG-vaccinated subjects from healthy individuals, whereas the ESAT-6 response discriminated active TB from healthy and BCG-vaccinated individuals. Moreover, this test enables identification of active TB patients who were negative on TST and to distinguish between TB and non-typical mycobacteria TB infections. Conclusions: The identification by flow cytometry of antigen-specific T lymphocytes upon antigen stimulation of whole blood has a better positive predictive value than TST, and could represent a further tool in the diagnosis of TB infection.
Thoracoscopy: Origins Revisited
Authors: Moisiuc Florin V. , Colt Henri G.
Published: December 2006

The ways in which thoracoscopy has evolved wonderfully illustrate how a diagnostic and therapeutic technique can transcend a particular medical or surgical subspecialty. In this review, an in-depth history is provided to enable readers to better understand the nature of minimally invasive endoscopic pleural imaging techniques.
Glutathiolation Regulates Tumor Necrosis Factor-α–Induced Caspase-3 Cleavage and Apoptosis
Authors: Pan Shi , Berk Bradford C.
Published: December 2006

Caspase-3 cleavage and activation are known to play central roles in apoptosis. However, the mechanisms that regulate caspase-3 cleavage remain elusive. Glutaredoxin (Grx) is a ubiquitous redox molecule that is unique in its ability to regulate
S
-glutathiolation (glutathiolation) of proteins. Here we show the essential role of Grx in caspase-3 cleavage via regulation of caspase-3 glutathiolation. Grx activity was significantly upregulated by tumor necrosis factor-α in endothelial cells. Small interference RNA knock down of Grx significantly inhibited tumor necrosis factor-α–induced endothelial cell death because of attenuated caspase-3 cleavage concomitant with increased caspase-3 glutathiolation. Enhanced caspase-3 cleavage by wild-type Grx overexpression was reversed by catalytically inactive Grx (C22S), demonstrating a requirement for thioltransferase activity. Cysteine-to-serine mutations (C163S, C184S, and C220S) of caspase-3 that were predicted to prevent glutathiolation showed increased cleavage compared with wild-type caspase-3. This inverse correlation between caspase-3 glutathiolation and cleavage was further confirmed by the observation that in vitro glutathiolation of caspase-3 inhibited its cleavage with recombinant caspase-8. Furthermore, Grx association with caspase-3 was decreased by tumor necrosis factor-α. These findings demonstrate a novel mechanism of caspase-3 regulation by Grx in tumor necrosis factor-α–induced apoptosis.
Shoulder Pain After Stroke
Authors: Lindgren Ingrid , Jönsson Ann-Cathrin , Norrving Bo , Lindgren Arne
Published: December 2006

Background and Purpose—

Shoulder pain is a well-known complication after stroke, but data on prevalence, predictors, and outcome in unselected stroke populations are limited.

Methods—

During a 1-year period, 416 first-ever stroke patients were included in the population-based Lund Stroke Register. After 4 months, 327 patients were followed up and 1 year later, the surviving 305 patients were followed up again. General status (National Institutes of Health Stroke Scale score) was registered at stroke onset. Shoulder pain intensity (visual analog scale, score 0 to 30=no–mild and 40 to 100=moderate–severe pain); arm motor function; restricted dressing and/or ambulating; and functional status (Barthel Index) were registered at both follow ups.

Results—

Shoulder pain onset within 4 months after stroke was reported by 71 patients (22%). Among the 61 patients able to score the visual analog scale, 79% had moderate–severe pain. One year later, 8 of these 71 patients had died, 17 had no remaining pain, and 28 additional patients had developed shoulder pain since the first follow up. Lost or impaired arm motor function and high National Institutes of Health Stroke Scale score were predictors of shoulder pain. Shoulder pain restricted daily life often or constantly when dressing for 51%/31% and when ambulating for 29%/13% of the patients at 4 and 16 months, respectively.

Conclusion—

Almost one third of the 327 patients developed shoulder pain after stroke onset, a majority with moderate– severe pain. Shoulder pain restricts patients’ daily life after stroke. The increased risk of shoulder pain for patients with impaired arm motor function and/or low general status needs close attention in poststroke care.
Urbanity, Rurality, and Adolescent Substance Use
Authors: Wilson Jeremy M. , Donnermeyer Joseph F.
Published: December 2006

An important but understudied aspect of substance use research is its relationship to characteristics of the community, including if there are differences in the association between peer and family factors with use between youth living in rural and urban areas. The results of this study are based on a statewide survey of approximately 4,400 youth in a southwestern state. It tested for the inequality of coefficients from regression equations on three measures of substance use: an overall scale, alcohol use, and marijuana use. The relationship of peer influence on substance use was stronger among urban-located youth; however, there were no rural-urban differences for family factors.
Regulation of systemic and local neutrophil responses by G-CSF during pulmonary Pseudomonas aeruginosa infection
Authors: Gregory Alyssa D. , Hogue Lisa A. , Ferkol Thomas W. , Link Daniel C.
Published: December 2006

Granulocyte colony-stimulating factor (G-CSF) regulates the production, maturation, and function of neutrophils. Its expression is often induced during infection, resulting in high concentrations of G-CSF in inflammatory exudates and in the blood, suggesting that it may regulate both local and systemic neutrophil responses. Herein, we characterize the neutrophil response in G-CSFR−/− mice following intratracheal injection with Pseudomonas aeruginosa–laden agarose beads, modeling the pulmonary infection observed in many patients with cystic fibrosis. G-CSFR−/− mice are markedly susceptible to bronchopulmonary P aeruginosa infection, exhibiting decreased survival and bacterial clearance as well as extensive damage to lung tissue. The systemic neutrophil response was mediated primarily by enhanced neutrophil release from the bone marrow rather than increased neutrophil production and was attenuated in G-CSFR−/− mice. Despite normal to increased local production of inflammatory chemokines, neutrophil accumulation into the infected lung of G-CSFR−/− mice was markedly reduced. Moreover, the percentage of apoptotic neutrophils in the lung was elevated, suggesting that G-CSF signals may play an important role in regulating neutrophil survival at the inflammatory site. Collectively, these data provide new evidence that G-CSF signals play important but specific roles in the regulation of the systemic and local neutrophil response following infection.
Family history of hematopoietic malignancies and risk of non-Hodgkin lymphoma (NHL): a pooled analysis of 10 211 cases and 11 905 controls from the International Lymphoma Epidemiology Consortium (InterLymph)
Authors: Wang Sophia S. , Slager Susan L. , Brennan Paul , Holly Elizabeth A. , De Sanjose Silvia , Bernstein Leslie , Boffetta Paolo , Cerhan James R. , Maynadie Marc , Spinelli John J. , Chiu Brian C. H. , Cocco Pier Luigi , Mensah Fiona , Zhang Yawei , Nieters Alexandra , Dal Maso Luigino , Bracci Paige M. , Costantini Adele Seniori , Vineis Paolo , Severson Richard K. , Roman Eve , Cozen Wendy , Weisenburger Dennis , Davis Scott , Franceschi Silvia , La Vecchia Carlo , Foretova Lenka , Becker Nikolaus , Staines Anthony , Vornanen Martine , Zheng Tongzhang , Hartge Patricia
Published: December 2006

A role for genetic susceptibility in non-Hodgkin lymphoma (NHL) is supported by the accumulating evidence of common genetic variations altering NHL risk. However, the pattern of NHL heritability remains poorly understood. We conducted a pooled analysis of 10 211 NHL cases and 11 905 controls from the International Lymphoma Epidemiology Consortium (InterLymph) to evaluate NHL risk among those with hematopoietic malignancies in first-degree relatives. Odds ratios (ORs) and 95% confidence intervals (CIs) of NHL and its subtypes were estimated from unconditional logistic regression models with adjustment for confounders. NHL risk was elevated for individuals who reported first-degree relatives with NHL (OR = 1.5; 95% CI = 1.2-1.9), Hodgkin lymphoma (OR = 1.6; 95% CI = 1.1-2.3), and leukemia (OR = 1.4; 95% CI = 1.2-2.7). Risk was highest among individuals who reported a brother with NHL (OR = 2.8; 95% CI = 1.6-4.8) and was consistent for all NHL subtypes evaluated. If a first-degree relative had Hodgkin lymphoma, NHL risk was highest if the relative was a parent (OR = 1.7; 95% CI = 1.0-2.9). If a first-degree relative had leukemia, NHL risk was highest among women who reported a sister with leukemia (OR = 3.0; 95% CI = 1.6-5.6). The pattern of NHL heritability appeared to be uniform across NHL subtypes, but risk patterns differed by specific hematopoietic malignancies and the sex of the relative, revealing critical clues to disease etiology.
Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis
Authors: Cortes Jorge , Rousselot Philippe , Kim Dong-Wook , Ritchie Ellen , Hamerschlak Nelson , Coutre Steven , Hochhaus Andreas , Guilhot Francois , Saglio Giuseppe , Apperley Jane , Ottmann Oliver , Shah Neil , Erben Philipp , Branford Susan , Agarwal Prasheen , Gollerkeri Ashwin , Baccarani Michele
Published: December 2006

The prognosis for patients with chronic myeloid leukemia (CML) in myeloid blast crisis (MBC) or lymphoid blast crisis (LBC) remains poor. Although imatinib can induce responses in a subset of these patients, resistance to the drug develops rapidly. Dasatinib is a novel, oral, multitargeted kinase inhibitor of BCR-ABL and SRC family kinases. After promising phase 1 results, we report the results of phase 2 clinical trials of dasatinib in patients with imatinib-resistant or -intolerant blast crisis CML (MBC, n = 74; LBC, n = 42). At the 8-month follow-up, dasatinib induced major hematologic responses (MaHRs) in 34% and 31% of MBC- and LBC-CML patients and major cytogenetic responses (MCyRs) in 31% and 50% of these patients, respectively. Most (86%) of these MCyRs were complete cytogenetic responses (CCyRs). Responses were rapid and durable: 88% and 46%, respectively, of MBC- and LBC-CML patients achieving MaHR had not experienced disease progression at the 8-month follow-up. Response rates were similar in patients with and without BCR-ABL mutations known to confer resistance to imatinib. Dasatinib was well tolerated. Nonhematologic adverse events were mild to moderate. Cytopenias were common and could be managed by dose modification. Dasatinib is highly active and produces hematologic and cytogenetic responses in a significant number of patients with imatinib-resistant or -intolerant MBC- and LBC-CML. These trials were registered at www.clinicaltrials.gov as #CA180006 and #CA180015.
A common genetic factor for Parkinson disease in ethnic Chinese population in Taiwan
Authors: Fung Hon-Chung , Chen Chiung-Mei , Hardy John , Singleton Andrew B , Wu Yih-Ru
Published: December 2006

Background

Parkinson's disease (PD) is the most common neurodegenerative movement disorder, characterized clinically by resting tremor, bradykinesia, postural instability and rigidity. The prevalence of PD is approximately 2% of the population over 65 years of age and 1.7 million PD patients (age ≥ 55 years) live in China. Recently, a common LRRK2 variant Gly2385Arg was reported in ethnic Chinese PD population in Taiwan. We analyzed the frequency of this variant in our independent PD case-control population of Han Chinese from Taiwan.

Methods

305 patients and 176 genetically unrelated healthy controls were examined by neurologists and the diagnosis of PD was based on the published criteria. The region of interest was amplified with standard polymerase chain reaction (PCR). PCR fragments then were directly sequenced in both forward and reverse directions. Differences in genotype frequencies between groups were assessed by the X
2 test, while X
2 analysis was used to test for the Hardy-Weinberg equilibrium.

Results

Of the 305 patients screened we identified 27 (9%) with heterozygous G2385R variant. This mutation was only found in 1 (0.5%) in our healthy control samples (odds ratio = 16.99, 95% CI: 2.29 to 126.21, p = 0.0002). Sequencing of the entire open reading frame of LRRK2 in G2385R carriers revealed no other variants.

Conclusion

These data suggest that the G2385R variant contributes significantly to the etiology of PD in ethnic Han Chinese individuals. With consideration of the enormous and expanding aging Chinese population in mainland China and in Taiwan, this variant is probably the most common known genetic factor for PD worldwide.
Development and validation of vectors containing multiple siRNA expression cassettes for maximizing the efficiency of gene silencing
Authors: Wang Shunqing , Shi Zhenqi , Liu Wei , Jules Joel , Feng Xu
Published: December 2006

Background

RNA interference (RNAi) was originally identified as a biological process in which short double-stranded RNA (dsRNA) suppress the expression of genes complimentary to the dsRNA. This cellular intrinsic gene silencing mechanism has subsequently been developed as a useful tool for studies of gene function. A major strategy for producing small interfering RNA (siRNA) in cultured cells involves the use of siRNA expression vectors in which a RNA polymerase III (Pol III) promoter and transcription stop signal are designed to constitute a functional siRNA expression cassette for production of siRNA. However, most of the available vectors contain only one siRNA expression cassette.

Results

In order to maximize the efficiency and versatility of the vector-based siRNA approach, we have developed vectors containing multiple (up to six) tandem siRNA expression cassettes. Moreover, we demonstrated that these vectors can be used not only to produce different siRNA to simultaneously suppress the expression of multiple genes but also to maximize the silencing of a singe gene.

Conclusion

The vectors containing multiple siRNA expression cassettes can serve as useful tools for maximizing the efficiency of gene silencing.
Identification of ciliary and ciliopathy genes in Caenorhabditis elegansthrough comparative genomics
Authors: Chen Nansheng , Mah Allan , Blacque Oliver E , Chu Jeffrey , Phgora Kiran , Bakhoum Mathieu W , Hunt Newbury C Rebecca , Khattra Jaswinder , Chan Susanna , Go Anne , Efimenko Evgeni , Johnsen Robert , Phirke Prasad , Swoboda Peter , Marra Marco , Moerman Donald G , Leroux Michel R , Baillie David L , Stein Lincoln D
Published: December 2006

Background

The recent availability of genome sequences of multiple related Caenorhabditis species has made it possible to identify, using comparative genomics, similarly transcribed genes in Caenorhabditis elegans and its sister species. Taking this approach, we have identified numerous novel ciliary genes in C. elegans, some of which may be orthologs of unidentified human ciliopathy genes.

Results

By screening for genes possessing canonical X-box sequences in promoters of three Caenorhabditis species, namely C. elegans, C. briggsae and C. remanei, we identified 93 genes (including known X-box regulated genes) that encode putative components of ciliated neurons in C. elegans and are subject to the same regulatory control. For many of these genes, restricted anatomical expression in ciliated cells was confirmed, and control of transcription by the ciliogenic DAF-19 RFX transcription factor was demonstrated by comparative transcriptional profiling of different tissue types and of daf-19(+) and daf-19(-) animals. Finally, we demonstrate that the dye-filling defect of dyf-5(mn400) animals, which is indicative of compromised exposure of cilia to the environment, is caused by a nonsense mutation in the serine/threonine protein kinase gene M04C9.5.

Conclusion

Our comparative genomics-based predictions may be useful for identifying genes involved in human ciliopathies, including Bardet-Biedl Syndrome (BBS), since the C. elegans orthologs of known human BBS genes contain X-box motifs and are required for normal dye filling in C. elegans ciliated neurons.
Intimate Partner Violence
Authors: McHUGH MAUREEN C. , FRIEZE IRENE HANSON
Published: December 2006

Abstract: This review examines multiple forms of intimate partner violence, including women's use of violence, and argues for development of more complex conceptualizations of intimate partner violence. As new victims are identified, partner violence has been reconceptualized. Research findings indicate that women are both victims and perpetrators in intimate partner violence, challenging previous conceptualizations and explanations. The authors argue that how researchers conceptualize intimate partner violence influences how they study and measure it. The authors call for researchers to develop more complex constructions of gender, and to distinguish between distinct forms of intimate partner violence.
Factors That Influence Abusive Interactions between Aging Women and Their Caregivers
Authors: NADIEN MARGOT B.
Published: December 2006

Abstract: Research findings suggest that one or more factors—personality and/or drug or financial dependency, cognitive and personality impairments, contextual factors, or severe stress—render elders vulnerable to caregiver maltreatment (i.e., either abuse or neglect), but may also make them more prone to abusing their caregivers. However, it is often the interaction between elders and caregivers that determines whether maltreatment will actually occur. Maltreatment of elders is less likely when caregivers (1) are free of mental impairments and of drug and personality dependency, (2) are trained to cope with the stress of caregiving and of highly provocative and/or abusive elders, (3) and are adequately reimbursed and socially supported.
Restoring Rape Survivors
Authors: KOSS MARY P.
Published: December 2006

Abstract: Rape results in mental and physical health, social, and legal consequences. For the latter, restorative justice‐based programs might augment community response, but they generate controversy among advocates and policy makers. This article identifies survivors' needs and existing community responses to them. Survivors feel their legal needs are most poorly met due to justice system problems that can be summarized as attrition, retraumatization, and disparate treatment across gender, class, and ethnic lines. Empirical data support each problem and the conclusion that present justice options are inadequate. The article concludes by identifying common ground in advocacy and restorative justice goals and calls for a holistic approach to the needs of rape survivors that includes advocating for expanded justice alternatives. A call to action is issued to implement restorative alternatives to expand survivor choice and offender accountability. Conventional and restorative justice are often viewed as mutually exclusive whereas the author argues they are complementary.
Comparison of Free and Total Forms of Serum Human Kallikrein 2 and Prostate-Specific Antigen for Prediction of Locally Advanced and Recurrent Prostate Cancer
Authors: Steuber Thomas , Vickers Andrew J , Serio Angel M , Vaisanen Ville , Haese Alexander , Pettersson Kim , Eastham James A , Scardino Peter T , Huland Hartwig , Lilja Hans
Published: December 2006

Background: We evaluated the association of total and free forms of serum human kallikrein 2 (hK2) and prostate-specific antigen (PSA) with prostate cancers of unfavorable prognosis.

Methods: We retrospectively measured total PSA (tPSA), free PSA (fPSA), and total hK2 (thK2) in preoperative serum samples from 867 men [and assessed free hK2 (fhK2) measured in 577 of these men] treated with radical prostatectomy for clinically localized prostate cancer. Associations between biomarker concentrations and extracapsular extension, seminal vesicle invasion, and biochemical recurrence (BCR) were evaluated. A subset of patients with PSA ≤10 μg/L, the group most commonly seen in clinical practice in the US, was analyzed.

Results: thK2 was the strongest predictor of extracapsular extension and seminal vesicle invasion (areas under the ROC curve [AUC], 0.662 and 0.719, respectively), followed by tPSA (AUC, 0.654 and 0.663). All biomarkers were significant predictors of BCR. hK2 forms, but not PSA forms, remained highly significant for predicting BCR in the low-PSA group. Combining tPSA, fPSA, and thK2 in a multivariable model improved prediction compared with any biomarker used individually (AUC, 0.711, 0.755, and 0.752 for this combination predicting extracapsular extension, seminal vesicle invasion, and BCR, respectively; P <0.001 for all).

Conclusions: Increased concentrations of hK2 in the blood are significantly associated with unfavorable features of prostate cancer, and thK2 is predictive of locally advanced and recurrent cancer in patients with PSA ≤10 μg/L. Independent of tPSA and fPSA, hK2 predicts unfavorable prognosis.
Obesity Management in Women with Polycystic Ovary Syndrome
Authors: Lim Siew S , Clifton Peter M , Noakes Manny , Norman Robert J
Published: December 2006

Obesity and insulin resistance play an important role in initiating or maintaining ill health in polycystic ovary syndrome (PCOS). This implies that treatment that reduces body weight and insulin resistance would alleviate the symptoms of PCOS. Lifestyle modification has been found to be effective in restoring reproductive function in up to 80% of individuals who achieve at least 5% weight loss. However, long-term weight maintenance is a challenge. This article provides a review of reduced glycemic load diets, including low glycemic index, very low carbohydrate, high-protein and high monounsaturated fat diets, on metabolic and reproductive health in PCOS and non-PCOS populations. Dietary trials in non-PCOS women suggest that higher-protein, reduced glycemic load diets were probably more beneficial than the conventional low-fat, high-carbohydrate diet but further studies are required to confirm this in PCOS women. Similarly, the optimal exercise regime for PCOS women remains to be investigated.
Human brain structural change related to acute single exposure to sarin
Authors: Yamasue Hidenori , Abe Osamu , Kasai Kiyoto , Suga Motomu , Iwanami Akira , Yamada Haruyasu , Tochigi Mamoru , Ohtani Toshiyuki , Rogers Mark A. , Sasaki Tsukasa , Aoki Shigeki , Kato Tadafumi , Kato Nobumasa
Published: December 2006

Objective

This study aimed to identify persistent morphological changes subsequent to an acute single‐time exposure to sarin, a highly poisonous organophosphate, and the neurobiological basis of long‐lasting somatic and cognitive symptoms in victims exposed to sarin.

Methods

Thirty‐eight victims of the 1995 Tokyo subway sarin attack, all of whom had been treated in an emergency department for sarin intoxication, and 76 matched healthy control subjects underwent T1‐weighted and diffusion tensor magnetic resonance imaging (DTI) in 2000 to 2001. Serum cholinesterase (ChE) levels measured immediately and longitudinally after the exposure and the current severity of chronic reports in the victims were also evaluated.

Results

The voxel‐based morphometry exhibited smaller than normal regional brain volumes in the insular cortex and neighboring white matter, as well as in the hippocampus in the victims. The reduced regional white matter volume correlated with decreased serum cholinesterase levels and with the severity of chronic somatic complaints related to interoceptive awareness. Voxel‐based analysis of diffusion tensor magnetic resonance imaging further demonstrated an extensively lower than normal fractional anisotropy in the victims. All these findings were statistically significant (corrected p < 0.05).

Interpretation

Sarin intoxication might be associated with structural changes in specific regions of the human brain, including those surrounding the insular cortex, which might be related to elevated subjective awareness of internal bodily status in exposed individuals. Ann Neurol 2006
Neural precursors attenuate autoimmune encephalomyelitis by peripheral immunosuppression
Authors: Einstein Ofira , Fainstein Nina , Vaknin Ilan , Mizrachi‐Kol Rachel , Reihartz Etti , Grigoriadis Nikolaos , Lavon Iris , Baniyash Michal , Lassmann Hans , Ben‐Hur Tamir
Published: December 2006

Objective

Intracerebroventricular or intravenous (IV) injection of neural precursor cells (NPCs) attenuates experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis. Although stem cell therapy was introduced initially for cell replacement, we examine here whether NPCs possess immunomodulatory effects.

Methods

We examined the effects of systemic administration of NPCs on central nervous system (CNS) inflammation in EAE and the interactions between NPCs and T cells in vitro and in vivo.

Results

IV NPC therapy decreased significantly CNS inflammation and tissue injury and attenuated the clinical severity of EAE. IV‐injected NPCs could not be found in the CNS but were detected in lymphoid organs. Coculture experiments showed that NPCs inhibited the activation and proliferation of lymph node–derived T cells in response to CNS‐derived antigens and to nonspecific polyclonal stimuli. The relevance of NPC/lymph node cell interactions in vivo was further demonstrated when lymph node cells obtained from IV NPC‐treated mice exhibited poor encephalitogenicity on transfer to naive mice and caused a markedly milder EAE compared with those obtained from nontreated mice.

Interpretation

IV administration of neural precursors inhibits EAE by a peripheral immunosuppressive effect. Our findings suggest a profound bystander inhibitory effect of NPCs on T‐cell activation and proliferation in the lymph nodes, leading to amelioration of EAE. Ann Neurol 2006