bluuebunny/crossref_metadata_2025 huggingface dataset:
Male Serial Homicide
Authors: DeFronzo James , Ditta Ashley , Hannon Lance , Prochnow Jane
Published: January 2007

Psychiatric approaches have usually been used to explain male serial homicide. But multifactor explanations of the phenomenon suggest that aspects of culture and social structure may also play important roles. The current study attempts to evaluate the multifactor approach by examining whether cultural and structural variables might contribute to explaining the considerable interstate differences in the incidence of male serial killer activity. Separate analyses were conducted for two different state-level male serial killer rates, one based on the state where male serial killers received their early socialization and the other based on the state where male serial killers murdered their largest number of victims. Consistent with the multifactor approach, the results indicated that aspects of culture and social structure were able to account for much of the male serial killer variation among states.
Can aerobic treadmill training reduce the effort of walking and fatigue in people with multiple sclerosis: a pilot study
Authors: Newman M A , Dawes H , van den Berg M , Wade D T , Burridge J , Izadi H
Published: January 2007

Impaired mobility in multiple sclerosis (MS) is associated with high-energy costs and effort when walking, gait abnormalities, poor endurance and fatigue. This repeated measures trial with blinded assessments investigated the effect of treadmill walking at an aerobic training intensity in 16 adults with MS. The intervention consisted of 12 sessions of up to 30 minutes treadmill training (TT), at 55–85% of age-predicted maximum heart rate. The primary outcome measure was walking effort, measured by oxygen consumption (mL/kg per metre), during treadmill walking at comfortable walking speed (CWS). Associated changes in gait parameters using the ‘Gait-Rite’ mat, 10-m time and 2-minute distance, and Fatigue Severity Scale were examined. Following training, oxygen consumption decreased at rest (P = 0.008), CWS increased (P = 0.002), and 10-m times (P = 0.032) and walking endurance (P = 0.020) increased. At increased CWS, oxygen consumption decreased (P = 0.020), with a decreased time spent in stance in the weaker leg (P = 0.034), and a greater stride distance with the stronger leg (P = 0.044). Reported fatigue levels remained the same. Aerobic TT presents the opportunity to alter a motor skill and reduce the effort of walking, whilst addressing cardiovascular de-conditioning, thereby, potentially reducing effort and fatigue for some people with MS.
Therapeutic efficacy of plasma exchange in NMO-IgG-positive patients with neuromyelitis optica
Authors: Watanabe S , Nakashima I , Misu T , Miyazawa I , Shiga Y , Füjihara K , Itoyama Y
Published: January 2007

Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system (CNS) with a poor prognosis in terms of the optic-spinal function. Recently, a serum autoantibody (NMO-IgG) binding to the blood–brain barrier region was detected exclusively in patients with NMO and its high risk group. We treated six NMO-IgG-positive patients (all female; age 21–67 years old, median 41; three with optic neuritis and three with myelitis) who were unresponsive to high-dose intravenous methylprednisolone (HIMP), with plasma exchange (PE) (three to five exchanges, 2–3 L each). Three of the patients(one with optic neuritis and two with myelitis) showed definite functional improvement following PE. The clinical improvement started to appear after one or two exchanges, while there was little or no improvement in the other three patients. Such quick clinical responses to PE suggest a pathogenetic role of humoral immune factors in NMO, although delayed responses to the corticosteroid therapy might have contributed to the therapeutic efficacy, in part. Further clinical and in vitro studies are needed to determine whether the removal of NMO-IgG is directly relevant to the therapeutic efficacy. PE may hasten the functional recovery from corticosteroid-resistant relapses in some NMO-IgG-positive patients with NMO.
Observation of children's physical activity levels in primary school: Is the school an ideal setting for meeting government activity targets?
Authors: Waring Michael , Warburton Peter , Coy Martin
Published: January 2007

Given the commitment (and funding) by the British government to promote physical activity among all ages, and despite the inevitable political manipulation of physical education (PE) and school sport, there is now an ideal opportunity to focus on primary schools as a key target group for the future. This study determined the physical activity levels of a sample of pre-adolescents over time in a primary school setting. 374 children (5–11 yrs) were directly observed for a total of 30,650 minutes. Continuous observations of 374 primary PE lessons, 374 break times and 215 lunch times were undertaken between 1999 and 2004. The actual intensity and type of activities taking place were also recorded in five-minute blocks of time. The children were engaged in activity of at least moderate intensity for 11.8 percent of the total time observed, being more active in PE lessons and break times than in lunch times. Boys were shown to be more active than girls, recording activity of at least moderate intensity for 13 percent of total time compared to 10 percent for girls. Given the available data, the primary school is not delivering on its potential to be a good setting to promote physical activity.
Seeing the natural world: a tension between pupils' diverse conceptions as revealed by their visual representations and monolithic science lessons
Authors: Reiss Michael , Boulter Carolyn , Tunnicliffe Sue Dale
Published: January 2007

In this article, the authors report on drawings of the natural environment produced by a sample of 13–14-year-olds. One of their interests is the extent to which these young people see the world in the way rewarded in science lessons. With rare exceptions, school science generally assumes that for any scientific issue there is a single valid scientific conception so that alternative conceptions are misconceptions. The drawings reveal a plurality of ways in which the natural environment is portrayed and we conclude that there is scientific as well as other worth in this diversity. The authors argue that schools need to take account of this diversity; many pupils will not be interested in a single, monolithic depiction of the natural world in their school science lessons.
Recent Trends inGospel of ThomasResearch (1991-2006): Part I, The Historical Jesus and the Synoptic Gospels
Authors: Perrin Nicholas
Published: January 2007

This article, the first of a two-part series, reviews research between 1991 and 2006 dealing with the Gospel of Thomas. It focuses on two questions: (1) whether the Coptic sayings collection preserves material going back to the historical Jesus, and (2) whether it is dependent on the synoptic Gospels or attests to an independent line of tradition, relatively uninfluenced by the canonical texts. In connection with the former issue, the article observes that Thomas is little used in contemporary Jesus scholarship and seeks to elucidate reasons for this. As to whether or not the author of Thomas was privy to our synoptic gospels, scholarship has been undergoing an ever-deepening entrenchment of positions. This has not only resulted in a scholarly culture that resists making generalizations regarding Thomas’s origins, but has also provoked new approaches to explicating those origins. The article closes with suggestions for future study.
Apocalypses and Apocalypticism in Antiquity (Part I)
Authors: DiTommaso Lorenzo
Published: January 2007

This paper, in two parts, discusses the significant scholarship on apocalypses and apocalypticism in antiquity published since Mysteries and Revelations: Apocalyptic Studies since the Uppsala Conference (Collins and Charlesworth [eds.] 1991). Part 1 contains (1) the introduction, sections on studies that address issues of (2) taxonomy and definitions, and (3) function and settings, plus the first half of the section dealing with (4) origins and influences, specifically Ancient Near Eastern and classical. The bibliographies are part-specific, but their entries are integrated.
Observations on Some Biblical Citations in Ephrem's Commentary on Genesis
Authors: LUND JEROME A.
Published: January 2007

The biblical citations recorded by Ephrem in section VI of his Commentary on Genesis (Gen. 5.32-9.16) support the Peshitta textual stream represented by MS 5bl = 8/5bl as over against that represented by MS 7al. Ephrem's approach of weaving the biblical text into the fabric of his retelling ofthe story of Genesis affects the evaluation of potential variant readings. Stylistic improvement, compression, abbreviation, and lexical substitution for the purpose of drawing together large stretches of text characterize his biblical citations.
Sonographic Assessment of Gallbladder Motility in the Ibo Population of Nigeria: A Feasibility Study
Authors: Ugwu A. C. , Ovuoba K. N. , Udo B. , Nwobi I. C. , Egwu A. O.
Published: January 2007

Gallbladder motility is affected in some gallbladder diseases. Reference values for normal gallbladder motility have not been established. The aim of this study is to establish multiple regression equations and reference values for predicting gallbladder motility in adult Nigerians. Forty healthy volunteers underwent serial sonographic scanning of the gallbladder between January and June 2005. Gallbladder volumes were calculated by ellipsoid approximation, and the 20th-minute gallbladder emptying rate (GBER) and gallbladder contraction index (GBCI) were computed. Anthropometric variables were equally measured. Multiple linear regression equations were derived using GBCI and GBER as dependent variables with age and body mass index as independent variables. The standard deviations for GBER were 0.429 and 0.457 in men and women, respectively, whereas the standard deviations for GBCI were 16.81 and 18.81 for men and women, respectively.
Nonredundant roles for Stat5a/b in directly regulating Foxp3
Authors: Yao Zhengju , Kanno Yuka , Kerenyi Marc , Stephens Geoffrey , Durant Lydia , Watford Wendy T. , Laurence Arian , Robinson Gertraud W. , Shevach Ethan M. , Moriggl Richard , Hennighausen Lothar , Wu Changyou , O'Shea John J.
Published: January 2007

Stats (signal transducers and activators of transcription) regulate multiple aspects of T-cell fate. T regulatory (Treg) cells are a critical subset that limits immune responses, but the relative importance of Stat5a/b versus Stat3 for Treg cell development has been contentious. We observed that peripheral CD25+CD4+ T cells were reduced in Stat5ΔN mice; however, the levels of Foxp3, a transcription factor that is critical for Treg cells, were normal in splenic CD4+ T cells even though they were reduced in the thymus. In contrast, complete deletion of Stat5a/b (Stat5−/−) resulted in dramatic reduction in CD25- or Foxp3-expressing CD4+ T cells. An intrinsic requirement was demonstrated by reduction of Stat5a/b in CD4-expressing cells and by stem cell transplantation using Stat5−/− fetal liver cells. Stat5a/b were also required for optimal induction of Foxp3 in vitro and bound directly to the Foxp3 gene. Reduction of Stat3 in T cells did not reduce the numbers of Treg cells in the thymus or spleen; however, Stat3 was required for IL-6–dependent down-regulation of Foxp3. Therefore, we conclude that Stat5a/b have an essential, nonredundant role in regulating Treg cells, and that Stat3 and Stat5a/b appear to have opposing roles in the regulation of Foxp3.
Overestimating resistance in field testing of malaria parasites: simple methods for estimating high EC50 values using a Bayesian approach
Authors: Stepniewska Kasia , Chotivanich Kesinee , Brockman Alan , Day Nicholas PJ , White Nicholas J
Published: January 2007

Conventional methods of assessing in-vitro antimalarial drug-concentration effect relationships in field testing of fresh isolates assess each parasite isolate individually. This leads to systematic overestimation of EC50values for the most resistant isolates, and thus overestimation of the degree of resistance. In antimalarial drug-susceptibility studies conducted on the north-western border of Thailand the overestimation of EC50for the most resistant isolate ranged from 15% for artesunate to 43% for mefloquine. If isolates cannot be stored for re-testing, more accurate estimations of the degree of resistance can be obtained using a Bayesian approach to data analysis which is described here.
Direct non-cell autonomous Pax6 activity regulates eye development in the zebrafish
Authors: Lesaffre Brigitte , Joliot Alain , Prochiantz Alain , Volovitch Michel
Published: January 2007

Background

Modifications in Pax6 homeogene expression produce strong eye phenotypes. This suggested to us that eye development might be an appropriate model to verify if homeoprotein intercellular passage has important functions in early development. Similar to other homeoproteins, Pax6 has two domains that enable secretion and internalization by live cells and, thus, intercellular passage. In principle, a straightforward way to test the hypothesis would be to mutate one of the two sequences to produce a 'cell autonomous only' Pax6. However, this was not possible because these sequences are in the homeodomain and their modification would affect Pax6 transcriptional properties. We have thus developed an approach aimed at blocking Pax6 only in the extracellular milieu of developing zebrafish embryos.

Results

A first strategy was to inject a one-cell embryo with a mRNA encoding a secreted single-chain anti-Pax6 antibody. A second, complementary, strategy was to inject a Pax6 antibody in the blastula extracellular milieu. In both cases, 'dissymmetric eyes', 'one eye only' and 'no eye' phenotypes were produced. In most cases, lens phenotypes paralleled retina malformations. Although eye phenotypes were analyzed 30 hours post-fertilization, there was a strong correlation between early eye field asymmetry, early asymmetry in Pax6 expression and later-occurring eye malformations. Several controls were introduced, demonstrating that the effect is specific to Pax6 and cannot be explained by intracellular antibody activities.

Conclusion

This study supports the hypothesis that the Pax6 transcription factor is also a signaling molecule with direct non-cell autonomous activity.
Protein Metabolism in Acromegaly: Differential Effects of Short- and Long-Term Treatment
Authors: Gibney James , Wolthers Troels , Burt Morton G. , Leung Kin-Chuen , Umpleby A. Margot , Ho Ken K. Y.
Published: January 2007

Context: GH acutely increases body protein by stimulating protein synthesis and reducing protein oxidation.

Objective: The objective of the study was to determine whether these changes in protein metabolism are sustained in long-term GH excess and reversed by correction.

Design: We conducted a cross-sectional study in 16 acromegalic and 18 normal subjects and a longitudinal study in which acromegalic subjects were studied before and after short-term (n = 8) or long-term (n = 10) treatment.

Setting: The study was conducted at a clinical research center.

Main Outcome Measures: Whole-body rates of leucine appearance (leucine Ra; an index of protein breakdown), leucine oxidation, and nonoxidative leucine disposal (NOLD; an index of protein synthesis) estimated using infusion of 1-[13C] leucine were measured.

Results: Leucine Ra and NOLD were greater (P < 0.01) in acromegalic compared with normal subjects, whereas leucine oxidation did not differ. Leucine oxidation increased significantly (P < 0.05) after short-term treatment but returned to baseline after long-term treatment. Both leucine Ra and NOLD decreased significantly (P < 0.05) after short- and long-term treatment. Adjustment for body composition did not affect results.

Conclusions: In acromegalic subjects, protein breakdown and synthesis are increased, whereas protein oxidation does not differ from normal subjects. Protein oxidation increases transiently, whereas protein breakdown and synthesis are stably reduced after treatment. Because protein oxidation represents irreversible loss, we conclude that the normal state of protein oxidation found in acromegaly and after long-term treatment represents metabolic adaptation, which maintains protein mass at a steady state after stable changes in GH status.
Malignant Paragangliomas Associated with Mutations in the Succinate Dehydrogenase D Gene
Authors: Havekes B. , Corssmit E. P. M. , Jansen J. C. , van der Mey A. G. L. , Vriends A. H. J. T. , Romijn J. A.
Published: January 2007

Introduction: Malignant paragangliomas have been well described in carriers of mutations of the succinate dehydrogenase B (SDHB) gene, but have rarely been associated with mutations in the succinate dehydrogenase D (SDHD) gene.

Aim: The aim of the study was to report the different clinical expression patterns of malignant paragangliomas in five patients with SDHD (D92Y) mutations observed in approximately 200 SDHD (D92Y) mutation carriers followed in our institution.

Results: Metastasis and/or local tumor invasion was documented 0 (n = 2), 1, 18, and 30 yr after the initial diagnosis of paraganglioma. Malignancy was proven by paraganglioma bone metastases (n = 2), intrathoracic paraganglioma with lymph node metastases, locally invasive head-and-neck paraganglioma with destruction of the petrosal bone, and locally invasive paraganglioma of the bladder with lymph node metastases. Four of the five patients developed catecholamine excess during follow-up due to intraadrenal paraganglioma (pheochromocytoma) (n = 1), extra adrenal paraganglioma (n = 2), and presumed subclinical disease (n = 1).

Conclusion: SDHD mutations (D92Y) are associated with malignant paragangliomas and catecholamine excess with remarkable interindividual variations despite the same mutation. We estimate that the prevalence of malignancy in carriers of D92Y mutations is at least 2.5%.
Pancreatic stellate cells are an important source of MMP-2 in human pancreatic cancer and accelerate tumor progression in a murine xenograft model and CAM assay
Authors: Schneiderhan Wilhelm , Diaz Fredy , Fundel Martin , Zhou Shaoxia , Siech Marco , Hasel Cornelia , Möller Peter , Gschwend Jürgen E. , Seufferlein Thomas , Gress Thomas , Adler Guido , Bachem Max G.
Published: January 2007

The effect of the characteristic desmoplastic reaction of pancreatic cancer on tumor progression is largely unknown. We investigated whether pancreatic stellate cells, which are responsible for the desmoplastic reaction, support tumor progression. Immunohistology revealed that matrix metalloproteinase-2 (MMP-2), which is suggested to promote pancreatic cancer progression, is present in stellate cells adjacent to cancer cells. In vitro, stellate cells exhibited a much higher basal expression of MMP-2 compared with cancer cells. Panc1-, MiaPaCa2- and SW850-conditioned media stimulated MMP-2 release of stellate cells as detected by zymography. Cancer cells expressed and released basigin [BSG, extracellular matrix metalloproteinase inducer (EMMPRIN), CD147], a glycoprotein that is known to stimulate MMP-2 in mesenchymal cells, as detected by immunostaining, western blot and reverse transcription-polymerase chain reaction. Tumor cell-conditioned medium and BSG purified by affinity chromatography from supernatants of cancer cells, but not supernatants depleted from BSG, stimulated expression of MMP-1 and MMP-2 of stellate cells as demonstrated by western blot and zymography. Moreover, the interaction of stellate cells and cancer cells promoted the invasiveness of Panc-1 cells in the chorioallantoic membrane assay and increased the weight of tumors induced by all carcinoma cell lines in nude mice by 2.1-3.7-fold. Our findings support the assumption that the interaction of stellate cells and cancer cells promotes progression of pancreatic cancer.
Update on the Epidemiology of Paget's Disease of Bone
Authors: Cooper Cyrus , Harvey Nicholas C , Dennison Elaine M , van Staa Tjeerd P
Published: January 2007

Paget's disease of bone (PDB) is characterized by rapid bone remodeling and the formation of bone that is structurally abnormal. Recent studies have confirmed that both genetic and environmental factors are important in its etiology. Epidemiological studies in Europe and North America have revealed that PDB shows an increasing frequency of occurrence with age and is more prevalent among men than women. There is marked geographic variation in the prevalence of PDB throughout western nations, with the highest rates reported during the 1970s in Britain. Recent studies of the secular trends in PDB suggest declining rates in both prevalence and severity at diagnosis. Thus, the overall age/sex standardized prevalence rate in Britain during the period 1993–1995 was found to be 2.5% among men and 1.6% among women ≥55 years of age. Prevalence rates had fallen by ∼50% in several of the centers studied, suggesting an environmental contribution to the etiology of this disorder. Similar findings have been reported from other European countries and New Zealand. Recent study of the incidence and clinical manifestations of PDB have emerged from large cohort studies in primary care record linkage resources, such as the General Practice Research Database. Over the period 1988–1999, the incidence rate of clinically diagnosed PDB was found to be 5 per 10,000 person-years among men and 3 per 10,000 person-years among women 75 years of age. The disorder was associated with an increased risk of back pain (RR, 2.1; 95% CI, 1.9–2.3); osteoarthritis (RR, 1.7; 95% CI, 1.5–1.9); and fracture (RR, 1.2; 95% CI, 1.0–1.5). Using life table methodology, the estimated proportion of patients dying within 5 years of follow-up was 32.7% among the cohort with PDB compared with 28.0% among control patients (p < 0.05).
Osteosarcoma in Paget's Disease of Bone
Authors: Hansen Marc F , Seton Margaret , Merchant Anand
Published: January 2007

Paget's disease of bone (PDB) is a focal disorder of bone metabolism first described by Sir James Paget in 1876. It is presumed benign in nature and mediated by abnormal osteoclast function. The incidence of osteosarcomas complicating PDB is estimated at <1%. These cancers occur mostly in persons with long-standing, polyostotic disease and affect patients in their seventh decade or when osteosarcoma is remarkably rare in the general population. Epidemiological studies suggest that this late peak of osteosarcomas is absent in regions where Paget's is infrequently reported. Whereas PDB has a predilection for the axial skeleton, skull, femurs, and tibias, pagetic osteosarcoma tend to spare the spine, and are reported more commonly in the pelvis, femur, humerus, and skull. A molecular basis for the association of osteosarcoma with Paget's disease is unclear. These osteosarcomas are osteogenic in origin, consistently arise in sites of pagetic bone, and may present as metachronous, multifocal lesions. On histopathology, the lesions are usually osteoblastic, and the tumor phenotype is sometimes characterized as an exaggerated, chaotic form of the accelerated bone remodeling that characterizes PDB. New insights from the biology of adolescent osteosarcomas, VCP and SQSTM1 mutations now defined in patients with Paget's disease, and emerging evidence that stromal lesions are present in patients with Paget's disease are changing the way we think about the pathogenesis of PDB and the rare complication of pagetic osteosarcomas.
Nonmalignant Complications of Paget's Disease
Authors: Bone Henry G
Published: January 2007

Paget's disease of bone is a focal or multifocal disorder characterized by intense disorderly remodeling activity at sites of involvement, producing dramatic alterations of local bone architecture. These functional and structural alterations, interacting with the specific characteristics of the site of involvement, account for most of the complications of the disease. This presentation will focus on selected nonneoplastic complications of particular current interest.
Medical Management of Paget's Disease of Bone: Indications for Treatment and Review of Current Therapies
Authors: Siris Ethel S , Lyles Kenneth W , Singer Frederick R , Meunier Pierce J
Published: January 2007

Treatment with a potent bisphosphonate is indicated in patients with Paget's disease who have symptoms likely to respond to reduced bone turnover at pagetic sites. In asymptomatic patients with active disease at sites susceptible to local progression and late complications, treatment is also recommended. Biochemical remission is achievable in a majority of patients with pamidronate, alendronate, risedronate, or zoledronic acid. Indications for medical treatment of active Paget's disease of bone include symptoms referable to sites of the disease such as bone pain, joint pain, and neurological complications; elective surgery at an active pagetic site to reduce intraoperative blood loss from highly vascular bone; management of rare instances of immobilization hypercalcemia with polyostotic disease; and presence of disease activity in asymptomatic patients at sites at risk for future complications to limit progression and possibly lower that risk. The treatment of choice is a potent nitrogen-containing bisphosphonate, including oral alendronate or risedronate or intravenous pamidronate or zoledronic acid. Etidronate and tiludronate are less potent and are second-line choices. Recent data with zoledronic acid indicate that a single infusion of 5 mg is associated with normalization of serum alkaline phosphatase in 89% of patients and a prolonged biochemical remission, making it the most effective therapy available to date. Side effect profiles with alendronate and risedronate include esophageal irritation in a minority of patients. Intravenous pamidronate and zoledronic acid may induce an acute phase reaction with fever and flu-like symptoms with the first dose, primarily in patients who are treatment naïve to nitrogen-containing bisphosphonates. Calcium and vitamin D repletion are mandatory with these potent anti-osteoclast therapies to avoid hypocalcemia. Acquired resistance to etidronate and pamidronate has been reported in some patients, leading to lesser reductions in bone turnover and shorter periods of remission, but substitution with a different bisphosphonate provides a more robust response. It is not known whether resistance to other bisphosphonates in Paget's disease occurs.
Gsα Mutations in Fibrous Dysplasia and McCune-Albright Syndrome
Authors: Weinstein Lee S
Published: January 2007

Fibrous dysplasia (FD) is a focal bone lesion composed of immature mesenchymal osteoblastic precursor cells. Some FD patients also have hyperpigmented skin lesions (café-au-lait spots), gonadotropin-independent sexual precocity, and/or other endocrine and nonendocrine manifestations (McCune-Albright syndrome [MAS]). MAS results from somatic mutations occurring during early development, resulting in a widespread mosaic of normal and mutant-bearing cells, which predicts that the clinical presentation of each patient is determined by the extent and distribution of abnormal cells. These mutations encode constitutively active forms of Gsα, the ubiquitously expressed G protein α-subunit that couples hormone receptors to intracellular cAMP generation. These mutations lead to substitution of amino acid residues that are critical for the intrinsic GTPase activity that is normally required to deactivate the G protein. This leads to prolonged activation of Gsα and its downstream effectors even with minimal receptor activation. This explains why MAS patients have stimulation of multiple peripheral endocrine glands in the absence of circulating stimulatory pituitary hormones and increased skin pigment, which is normally induced by melanocyte-stimulating hormone through Gsα/cAMP. Similar mutations are also present in 40% of pituitary tumors in acromegaly patients and less commonly in other endocrine tumors. FD results from increased cAMP in bone marrow stromal cells, leading to increased proliferation and abnormal differentiation. Parental origin of the mutated allele may also affect the clinical presentation, because Gsα is imprinted and expressed only from the maternal allele in some tissues (e.g., pituitary somatotrophs).
Breast Cancer–Associated Gene 3 (BCA3) Is a Novel Rac1-Interacting Protein
Authors: Yu Kuan-ping , Itokawa Takashi , Zhu Mei-ling , Syam Sujata , Seth Arun , Insogna Karl
Published: January 2007

BCA3 was identified in a yeast two-hybrid screen as a novel Rac1-interacting partner in osteoclasts. BCA3 binds directly to Rac and, in vivo, binds GTP-Rac but not GDP-Rac. Perinuclear co-localization of BCA3 and Rac1 is observed in CSF-1–treated osteoclasts. Overexpression of BCA3 attenuates CSF-1–induced cell spreading. We conclude that BCA3 regulates CSF-1–dependent Rac activation.

Introduction: Rac1, a ubiquitously expressed GTPase, is a mediator of colony-stimulating factor 1 (CSF-1)–dependent actin remodeling in osteoclasts. Because the role of Rac in osteoclasts has not been fully defined, we undertook a yeast two-hybrid screen to identify Rac-interacting partners in these cells.

Materials and Methods: A yeast two-hybrid screen was undertaken using a cDNA library prepared from osteoclast-like cells as prey and either native Rac1 or constitutively active Rac1 (Q61L) as bait. Radiolabeled breast cancer–associated gene 3 (BCA3) protein constructs were generated in vitro using rabbit reticulate lysates and used in vitro binding assays with Rac1. In vivo binding was assessed using myc-tagged Rac1(Q61L) and HA-tagged BCA3. PBD pull-down assays were used to determine if GTP-loaded Rac1 preferentially bound BCA3. Co-localization of Rac1 and BCA3 in osteoclasts was assessed using confocal immunofluorescence. The functional significance of the BCA3–Rac1 interaction was assessed by examining the effect of overexpressing BCA3 in RAW 264.7 cells on the subsequent spreading response to CSF-1.

Results: One of three positive clones from the wildtype Rac1 screen and all three positive clones from the Rac1(Q61L) screen encoded the same protein, BCA3. BCA3 expression in osteoclasts was confirmed by RT-PCR and immunocytochemistry. BCA3 bound directly to Rac1 in vitro. Deletional analysis indicated that amino acids 76–125 in BCA3 are important for its ability to bind Rac. In vivo association of the two proteins was shown by co-immunoprecipitation of BCA3 and Rac1. Only GTP-bound-Rac but not GDP-bound Rac could interact with BCA3 in vivo. Confocal immunocytochemistry showed perinuclear co-localization of BCA3 and Rac1 in CSF-1–treated neonatal rat osteoclasts but not in resting osteoclasts. Overexpression of BCA3 markedly attenuated the spreading response to CSF-1 in RAW 264.7 cells.

Conclusions: These data establish that BCA3 is a novel Rac1-interacting protein and suggest that it may influence the ability of Rac1 to remodel the actin cytoskeleton.
Nanodomains of Single Ca2+Channels Contribute to Action Potential Repolarization in Cortical Neurons
Authors: Müller Andreas , Kukley Maria , Uebachs Mischa , Beck Heinz , Dietrich Dirk
Published: January 2007

The precise shape of action potentials in cortical neurons is a key determinant of action potential-dependent Ca2+influx, as well as of neuronal signaling, on a millisecond scale. In cortical neurons, Ca2+-sensitive K+channels, or BK channels (BKChs), are crucial for action potential termination, but the precise functional interplay between Ca2+channels and BKChs has remained unclear. In this study, we investigate the mechanisms allowing for rapid and reliable activation of BKChs by single action potentials in hippocampal granule cells and the impact of endogenous Ca2+buffers. We find that BKChs are operated by nanodomains of single Ca2+channels. Using a novel approach based on a linear approximation of buffered Ca2+diffusion in microdomains, we quantitatively analyze the prolongation of action potentials by the Ca2+chelator BAPTA. This analysis allowed us to estimate that the mean diffusional distance for Ca2+ions from a Ca2+channel to a BKCh is ∼13 nm. This surprisingly short diffusional distance cannot be explained by a random distribution of Ca2+channels and renders the activation of BKChs insensitive to the relatively high concentrations of endogenous Ca2+buffers in hippocampal neurons. These data suggest that tight colocalization of the two types of channels permits hippocampal neurons to regulate global Ca2+signals by a high cytoplasmic Ca2+buffer capacity without affecting the fast and brief activation of BKChs required for proper repolarization of action potentials.
Neurofilaments Switch between Distinct Mobile and Stationary States during Their Transport along Axons
Authors: Trivedi Niraj , Jung Peter , Brown Anthony
Published: January 2007

We have developed a novel pulse-escape fluorescence photoactivation technique to investigate the long-term pausing behavior of axonal neurofilaments. Cultured sympathetic neurons expressing a photoactivatable green fluorescent neurofilament fusion protein were illuminated with violet light in a short segment of axon to create a pulse of fluorescent neurofilaments. Neurofilaments departed from the photoactivated regions at rapid velocities, but the overall loss of fluorescence was slow because many of the neurofilaments paused for long periods of time before moving. The frequency of neurofilament departure was more rapid initially and slower at later times, resulting in biphasic decay kinetics. By computational simulation of the kinetics, we show that the neurofilaments switched between two distinct states: a mobile state characterized by intermittent movements and short pauses (average = 30 s) and a stationary state characterized by remarkably long pauses (average = 60 min). On average, the neurofilaments spent 92% of their time in the stationary state. Combining short and long pauses, they paused for 97% of the time, resulting in an average transport rate of 0.5 mm/d. We speculate that the relative proportion of the time that neurofilaments spend in the stationary state may be a principal determinant of their transport rate and distribution along axons, and a potential target of mechanisms that lead to abnormal neurofilament accumulations in disease.
Impaired Stress-Coping and Fear Extinction and Abnormal Corticolimbic Morphology in Serotonin Transporter Knock-Out Mice
Authors: Wellman C. L. , Izquierdo A. , Garrett J. E. , Martin K. P. , Carroll J. , Millstein R. , Lesch K.-P. , Murphy D. L. , Holmes A.
Published: January 2007

A lesser-expressing form of the human 5-HT transporter (5-HTT) gene has been associated with increased fear and anxiety and vulnerability to the effects of stress. These phenotypic abnormalities are linked to functional and anatomical disturbances in a neural pathway connecting the prefrontal cortex (PFC) and amygdala. Likewise, rodent and nonhuman primate studies indicate a major role for PFC and amygdala in the mediation of fear- and stress-related behaviors. We used a 5-HTT knock-out (KO) mouse to examine the effects of genetically driven loss of 5-HTT function for the following: (1) depression-related behavior in response to repeated stress, and pavlovian fear conditioning, extinction, and extinction recall; and (2) dendritic morphology and spine density of Golgi-stained pyramidal neurons in the infralimbic cortex (IL) and the basolateral amygdala (BLA). 5-HTT KO mice exhibited increased depressive-like immobility after repeated exposure to forced swim stress, compared with wild-type (WT) controls. Whereas fear conditioning and fear extinction was normal, 5-HTT KO mice exhibited a significant deficit in extinction recall. The apical dendritic branches of IL pyramidal neurons in 5-HTT KO mice were significantly increased in length relative to WT mice. Pyramidal neurons in BLA had normal dendritic morphology but significantly greater spine density in 5-HT KO mice compared with WT mice. Together, the present findings demonstrate a specific phenotypic profile of fear- and stress-related deficits in 5-HTT KO mice, accompanied by morphological abnormalities in two key neural loci. These data provide insight into the behavioral sequelae of loss of 5-HTT gene function and identify potential neural substrates underlying these phenotypes.
Radiocirurgia nos adenomas hipofisários
Authors: Castro Douglas Guedes de , Salvajoli João Victor , Canteras Miguel Montes , Cecílio Soraya A. Jorge
Published: January 2007

Os adenomas hipofisários correspondem a aproximadamente 15% dos tumores intracraniais. As modalidades de tratamento incluem microcirurgia, terapia medicamentosa e radioterapia. A microcirurgia é o tratamento primário realizado nos pacientes com adenomas não-funcionantes e na maioria dos adenomas funcionantes. Dentre estes, a exceção são os prolactinomas, cujo tratamento primário é baseado no uso de agonistas dopaminérgicos. Entretanto, cerca de 30% dos pacientes requerem tratamento adicional após a microcirurgia devido à recorrência ou persistência tumoral. Nesses casos, a radioterapia fracionada convencional tem sido tradicionalmente empregada. Mais recentemente, a radiocirurgia tem se estabelecido com uma alternativa terapêutica. A radiocirurgia permite que a dose prescrita seja precisamente conformada ao volume-alvo, e que se poupe os tecidos adjacentes. Portanto, os riscos de hipopituitarismo, alteração visual e vasculopatia são significativamente menores. Além disso, a latência da resposta à radiocirurgia é substancialmente menor do que na radioterapia fracionada convencional. Nesta revisão, procuramos definir a eficácia, segurança e o papel da radiocirurgia no tratamento dos adenomas hipofisários, bem como apresentar os dados preliminares de nossa instituição.
Aspirin therapy is still underutilized among patients with type 2 diabetes
Authors: Leitão Cristiane B. , Krahe Ana L. , Nabinger Gustavo B. , Picon Paula X. , Pecis Miriam , Zaslavsky Lérida M. , Gross Jorge L. , Canani Luis H.
Published: January 2007

The daily use of aspirin in patients with type 2 diabetes mellitus (DM2) reduces significantly cardiovascular events (CVE). In the absence of contraindications, American Diabetes Association (ADA) recommends the use of aspirin to all DM2 patients older than 40 years of age. To evaluate aspirin use among 636 out patients with DM2 who participate in a regional multicenter study in Southern Brazil, a standard questionnaire was used. Patients also underwent a physical examination and laboratorial tests. All patients were older than 40 years (mean 58 ± 11 years old; 42% male) and by ADA guidelines most of them should be using aspirin. However, only 177 (27.5%) were on this medication. The use of aspirin was higher when any CVE were present. However, the percentage of users was still below the expected, not even reaching 50%. In conclusion, even though the use of aspirin is greater in patients with CVE, and its benefits are well documented, it is still underutilized. Strategies to enhance the use of aspirin should be developed to reduce the morbidity and mortality from cardiovascular diseases in patients with DM2.
Avaliação dietética dos pacientes detectados com hiperglicemia na "Campanha de Detecção de Casos Suspeitos de Diabetes" no município de Viçosa, MG
Authors: Batista Maria da C.R. , Priore Silvia E. , Rosado Lina E.F.P.L. , Tinôco Adelson L.A. , Franceschini Sylvia C.C.
Published: January 2007

Este trabalho teve como objetivo avaliar o consumo alimentar atual, qualitativo e quantitativo, de pacientes detectados com hiperglicemia na Campanha de Detecção de Casos Suspeitos de Diabetes, no município de Viçosa, MG. Dos 256 detectados com hiperglicemia em 2001, 156 (61%) foram avaliados em 2004, sendo que o restante havia falecido, mudado de endereço, não aceitou participar do estudo ou não era diabético confirmado. Aplicou-se um questionário de freqüência de consumo alimentar e um recordatório da dieta habitual, ambos testados previamente em população-piloto. Os alimentos mais consumidos diariamente foram óleo vegetal (99%), feijão (94%), arroz (90%), adoçante (80%), vegetais folhosos (63%), leite (61%) e pão francês (54%). A maior parte relatou evitar açúcar, alimentos açucarados e gorduras animais. Os maiores percentuais de inadequação de nutrientes ocorreram para energia (85%), fibras (87%), cálcio (94%), percentual de carboidratos (82%), gorduras monoinsaturadas (91%) e proteínas (58%), sendo os três últimos em relação ao Valor Energético Total ingerido. Os dados encontrados permitiram conhecer os hábitos alimentares desta população e estimar a ingestão de nutrientes, podendo ser úteis ao aconselhamento nutricional, sugerindo orientações específicas que poderão proporcionar uma alimentação mais adequada, contribuindo para melhores condições de saúde e bem-estar.
Análise da associação de atividade física à síndrome metabólica em estudo populacional de nipo-brasileiros
Authors: Doro Antonio R. , Gimeno Suely G.A. , Hirai Amélia T. , Franco Laércio J. , Ferreira Sandra R.G.
Published: January 2007

Doenças associadas ao sedentarismo podem ser prevenidas por mudanças no estilo de vida. Parte dos benefícios cardiovasculares da atividade física poderia advir de menor grau de inflamação. Este estudo descreve a atividade física de uma população de origem japonesa e analisa sua associação à síndrome metabólica (SM), ajustada para diversas variáveis. Baseou-se em banco de dados previamente constituído a partir de um estudo de base populacional em nipo-brasileiros. Foram incluídos 1330 indivíduos > 30 anos, de ambos os sexos, residentes em Bauru, submetidos a entrevistas, sendo obtidos dados sócio-demográficos, de saúde, de atividade física e de dieta, além de exames médicos e laboratoriais. A avaliação da atividade física enfocou atividades no trabalho e nas horas vagas. O diagnóstico de SM foi baseado em adaptação para asiáticos dos critérios do NCEP. Empregou-se regressão logística, tendo a SM como variável resposta. Homens (46,1%) e mulheres apresentaram médias de idade semelhantes (57,0 ± 12,8 e 56,9 ± 12,2 anos, respectivamente). Houve leve predomínio do sexo feminino. Os homens apresentavam grau de instrução mais elevado e mais freqüentemente eram fumantes (p< 0,001); seus valores médios de IMC, cintura e de pressão arterial (p< 0,001) foram superiores aos das mulheres. Para ambos os sexos, a maioria referia praticar atividades de intensidade leve ou moderada nas horas vagas (81,2% dos homens e 86,6% das mulheres). Quanto ao esforço do trabalho, 87,8% dos homens classificaram seu esforço como leve ou moderado, contra 96,1% das mulheres. A distribuição dos níveis de AF invariavelmente revelou que as mulheres eram mais inativas (p= 0,01). Estratificando-se pela presença da SM, as mulheres e homens com SM eram significantemente mais velhos e apresentavam maiores valores antropométricos. Considerando a duração da caminhada ao trabalho, notou-se tendência a tempo menor entre aqueles com SM (p< 0,078). Conforme esperado, indivíduos com SM apresentaram níveis significantemente maiores de pressão arterial, glicemia, lípides e HOMA-IR quando comparados aos sem SM. O HDL foi menor no grupo com SM, sendo significante no sexo feminino. Os valores médios da PCR foram maiores nos indivíduos com SM. Na regressão logística, a idade, IMC, HOMA-IR e PCR se associaram independentemente à SM, o que não ocorreu com os parâmetros usados para mensurar AF. Nossos achados não permitem afirmar que a inatividade física associa-se à presença de SM numa população nipo-brasileira. A freqüência bastante alta de inatividade física deve ter contribuído para os achados negativos quanto a efeitos protetores da atividade física. O achado de associação da SM à PCR sérica é favorável à hipótese de que um estado inflamatório sub-clínico participe desta síndrome.
Efeito do propiltiouracil sobre a eficácia da dose terapêutica de iodo radioativo (I-131) no hipertiroidismo por doença de graves
Authors: Souza Marcus V.L. de , Buescu Alexandru , Vaisman Mario , Souza Honomar F. de , Luiz Ronir Raggio
Published: January 2007

Com objetivo de avaliar a influência das drogas antitiroidianas (AT) sobre a eficácia da dose terapêutica de iodo radioativo (DT), avaliamos retrospectivamente 226 prontuários de pacientes portadores de doença de Graves submetidos à DT no período entre 1990 e 2001: 58 pacientes sem antitiroidiano (AT), 119 em uso de propiltiouracil (PTU) e 49 em uso de metimazol (MMI). O estado funcional tiroidiano 9-12 meses pós-DT dividia os pacientes entre curados e não curados. Níveis elevados de T4 livre, captação de 131I em 24 h tiveram influência negativa sobre a taxa de cura, assim como menor dose de iodo administrada e maior volume do bócio (p< 0,05). O percentual de pacientes curados em uso de PTU previamente à DT foi de 70,2% (84/119), enquanto nos pacientes em uso de MMI foi de 85,7% (42/49), e de 84,5% (49/58) nos pacientes sem AT pré-DT (p= 0,034). Em modelo de regressão multivariado, T4 livre > 4 ng/dl, maior volume do bócio, dose terapêutica < 10 mCi e o uso prévio de PTU tiveram relação com menores taxas de cura. Quando comparado ao grupo sem AT, concluímos que PTU implica em maior risco de falência pós-DT (OR= 3,13), o mesmo não ocorrendo com MMI (OR= 1,28).
Abscesso hipofisário simulando apoplexia
Authors: Colli Máikel L. , Migowski Jr. Walter , Czepielewski Mauro A. , Ferreira Nelson , Gross Jorge L.
Published: January 2007

O abscesso hipofisário representa uma patologia rara, que, contudo, deve ser considerada na avaliação das massas selares, uma vez que o seu prognóstico depende da drenagem cirúrgica e do uso de antibióticos específicos. A principal manifestação clínica é cefaléia crônica e nem sempre está associada à identificação de um foco infeccioso, o que diminui a probabilidade da sua inclusão nas hipóteses diagnósticas. Apresenta-se o caso de um paciente com abscesso de hipófise e história pregressa de adenoma operado, cefaléia de início recente e hipopituitarismo adquirido, cujo diagnóstico inicial foi de apoplexia pituitária.
Relato de caso: doença celíaca recém-diagnosticada como fator agravante de osteoporose em mulher idosa
Authors: Pereira Camila C. , Corrêa Pedro Henrique S. , Halpern Alfredo
Published: January 2007

Mulher de 63 anos procurou endocrinologista para seguimento de osteoporose. Densitometria óssea revelava T L1-L4= -3,5 DP [Densidade mineral óssea (DMO): 0,766 g/cm²] e Tcolo fêmur= -2,4 DP (DMO: 0,716 g/cm²). Em uso de cálcio e vitamina D há 2 anos. Hipotireoidismo há 5 anos em uso de levotiroxina. Introduzido alendronato 70 mg/semana com ganho significativo de massa óssea no primeiro ano (6,1%, igualmente em coluna e colo de fêmur). Após 5 anos de seguimento, paciente passou a apresentar emagrecimento, anemia e piora dos níveis densitométricos (perda de 12,6% em coluna lombar e 20,9% em colo de fêmur). Anamnese revelou quadro de diarréia intermitente há 2 anos, levando à suspeita de doença celíaca. Pesquisa de anticorpos anti-gliadina e anti-endomísio resultou positiva: 25,3 U/mL (< 20) e 1/5 U/mL (VR: negativo), respectivamente. Bioquímica óssea mostrava cálcio e fósforo normais, paratormônio aumentado: 283 pg/mL (10-65) e marcadores de reabsorção óssea aumentados, sugerindo hiperparatireoidismo secundário à síndrome mal-absortiva. Após 1 ano de dieta isenta de glúten, houve melhora dos sintomas mal-absortivos e importante aumento de DMO (47,3% em coluna lombar e 31,6% em colo de fêmur), reforçando o diagnóstico de doença celíaca como fator agravante de osteoporose nesta paciente.