bluuebunny/crossref_metadata_2025 huggingface dataset:
Vitamin D Status Predicts Physical Performance and Its Decline in Older Persons
Authors: Wicherts Ilse S. , van Schoor Natasja M. , Boeke A. Joan P. , Visser Marjolein , Deeg Dorly J. H. , Smit Jan , Knol Dirk L. , Lips Paul
Published: March 2007

Context: Vitamin D deficiency is common among older people and can cause mineralization defects, bone loss, and muscle weakness.

Objective: The aim of this study was to investigate the association of serum 25-hydroxyvitamin D (25-OHD) concentration with current physical performance and its decline over 3 yr among elderly.

Design: The study consisted of a cross-sectional and longitudinal design (3-yr follow-up) within the Longitudinal Aging Study Amsterdam.

Setting: An age- and sex-stratified random sample of the Dutch older population was used.

Other Participants: Subjects included 1234 men and women (aged 65 yr and older) for cross-sectional analysis and 979 (79%) persons for longitudinal analysis.

Main Outcome Measure(s): Physical performance (sum score of the walking test, chair stands, and tandem stand) and decline in physical performance were measured.

Results: Serum 25-OHD was associated with physical performance after adjustment for age, gender, chronic diseases, degree of urbanization, body mass index, and alcohol consumption. Compared with individuals with serum 25-OHD levels above 30 ng/ml, physical performance was poorer in participants with serum 25-OHD less than 10 ng/ml [regression coefficient (B) = −1.69; 95% confidence interval (CI) = −2.28; −1.10], and with serum 25-OHD of 10–20 ng/ml (B = −0.46; 95% CI = −0.90; −0.03). After adjustment for confounding variables, participants with 25-OHD less than 10 ng/ml and 25-OHD between 10 and 20 ng/ml had significantly higher odds ratios (OR) for 3-yr decline in physical performance (OR = 2.21; 95% CI = 1.00–4.87; and OR = 2.01; 95% CI = 1.06–3.81), compared with participants with 25-OHD of at least 30 ng/ml. The results were consistent for each individual performance test.

Conclusions: Serum 25-OHD concentrations below 20 ng/ml are associated with poorer physical performance and a greater decline in physical performance in older men and women. Because almost 50% of the population had serum 25-OHD below 20 ng/ml, public health strategies should be aimed at this group.
In Vitro Glycoxidized Low-Density Lipoproteins and Low-Density Lipoproteins Isolated from Type 2 Diabetic Patients Activate Platelets via p38 Mitogen-Activated Protein Kinase
Authors: Calzada Catherine , Coulon Laurent , Halimi Déborah , Le Coquil Elodie , Pruneta-Deloche Valérie , Moulin Philippe , Ponsin Gabriel , Véricel Evelyne , Lagarde Michel
Published: March 2007

Context: Platelet hyperactivation contributes to the increased risk for atherothrombosis in type 2 diabetes and is associated with oxidative stress. Plasma low-density lipoproteins (LDLs) are exposed to both hyperglycemia and oxidative stress, and their role in platelet activation remains to be ascertained.

Objective: The aim of this study was to investigate the effects of LDLs modified by both glycation and oxidation in vitro or in vivo on platelet arachidonic acid signaling cascade. The activation of platelet p38 MAPK, the stress kinase responsible for the activation of cytosolic phospholipase A2, and the concentration of thromboxane B2, the stable catabolite of the proaggregatory arachidonic acid metabolite thromboxane A2, were assessed.

Results: First, in vitro-glycoxidized LDLs increased the phosphorylation of platelet p38 MAPK as well as the concentration of thromboxane B2. Second, LDLs isolated from plasma of poorly controlled type 2 diabetic patients stimulated both platelet p38 MAPK phosphorylation and thromboxane B2 production and possessed high levels of malondialdehyde but normal α-tocopherol concentrations. By contrast, LDLs from sex- and age-matched healthy volunteers had no activating effects on platelets.

Conclusions: Our results indicate that LDLs modified by glycoxidation may play an important contributing role in platelet hyperactivation observed in type 2 diabetes via activation of p38 MAPK.
Low Dietary Sodium and Exogenous Angiotensin II Infusion Decrease Plasma Adiponectin Concentrations in Healthy Men
Authors: Lely A. Titia , Krikken Jan A. , Bakker Stephan J. L. , Boomsma Frans , Dullaart Robin P. F. , Wolffenbuttel Bruce H. R. , Navis Gerjan
Published: March 2007

Content: Adiponectin has antiinflammatory and vascular protective effects and may improve insulin sensitivity. Animal data suggest a role of the renin-angiotensin aldosterone system (RAAS) in the regulation of adiponectin.

Objective: Our objective was to investigate the role of the RAAS in regulation of adiponectin in humans in vivo. To this purpose we studied the effects of physiological (change in sodium status) and pharmacological modulation of RAAS activity (angiotensin II infusion and enalapril treatment) on plasma adiponectin.

Design, Setting, and Patients: Thirty-five healthy male volunteers (aged 26 ± 9 yr) were studied after two 7-d periods: one on a low-sodium diet (LS, 50 mmol Na+ per day) and one on a high-sodium diet (HS, 200 mmol Na+ per day). At the end of each period, adiponectin was measured, and its response to angiotensin II infusion (0.3, 1, and 3 ng/kg·min all during 1 h) was determined. Additionally, all subjects received 1 wk treatment of enalapril 20 mg once daily (angiotensin converting enzyme inhibition) during the HS.

Main Outcome Measure: We measured plasma adiponectin concentrations during LS and HS and in response to angiotensin II infusion.

Results: The suppression of the RAAS by HS elicited a significant rise in adiponectin [LS baseline, 11.9 (8.3–16.2) μg/liter; HS baseline, 14.4 (11.2–20.4) μg/liter; P < 0.05]. All doses of angiotensin II elicited a profound decrease in adiponectin during both conditions [LS 3 ng/kg·min, 7.4 (6.3–8.9) μg/liter; HS 3 ng/kg·min, 8.4 (7.3–9.9) μg/liter; both P < 0.001 vs. baseline]. Angiotensin converting enzyme inhibition induced a significant rise in adiponectin [16.6 (10.6–20.9) μg/liter, P < 0.05 vs. HS].

Conclusion: Physiological and pharmacological modulation of RAAS affects plasma adiponectin with lower concentrations during the high angiotensin II conditions. The therapeutic potential of RAAS blockade as a tool to correct hypoadiponectinemia should be explored further.
Dose-Response Effects of Free Fatty Acids on Glucose and Lipid Metabolism during Somatostatin Blockade of Growth Hormone and Insulin in Humans
Authors: Gormsen L. C. , Jessen N. , Gjedsted J. , Gjedde S. , Nørrelund H. , Lund S. , Christiansen J. S. , Nielsen S. , Schmitz O. , Møller N.
Published: March 2007

Context: GH and other stress hormones stimulate lipolysis, which may result in free fatty acid (FFA)-mediated insulin resistance. However, there are also indications that FFAs in the very low physiological range have the same effect.

Objective: The objective of the study was to address systematically the dose-response relations between FFAs and insulin sensitivity.

Design: We therefore examined eight healthy men for 8 h (6 h basal and 2 h glucose clamp) on four occasions.

Intervention: Intralipid was infused at varying rates (0, 3, 6, 12 μl·kg−1·min−1); lipolysis was blocked by acipimox; and endogenous GH, insulin, and glucagon secretion was blocked by somatostatin and subsequently replaced at fixed rates.

Results: This resulted in four different FFA levels between 50 and 2000 μmol/liter, with comparable levels of insulin and counterregulatory hormones. Both in the basal state and during insulin stimulation, we saw progressively decreased glucose disposal, nonoxidative glucose disposal, and forearm muscle glucose uptake at FFA levels above 500 μmol/liter. Apart from forearm glucose uptake, the very same parameters were decreased at low FFA levels (∼50 μmol/liter). FFA rate of disposal was linearly related to the level of FFAs, whereas lipid oxidation reached a maximum at FFA levels approximately 1000 μmol/liter.

Conclusion: In the presence of comparable levels of all major metabolic hormones, insulin sensitivity peaks at physiological levels of FFAs with a gradual decrease at elevated as well as suppressed FFA concentrations. These data constitute comprehensive dose-response curves for FFAs in the full physiological range from close to zero to above 2000 μmol/liter.
Reduction of Elevated Serum Retinol Binding Protein in Obese Children by Lifestyle Intervention: Association with Subclinical Inflammation
Authors: Balagopal Prabhakaran , Graham Timothy E. , Kahn Barbara B. , Altomare Astride , Funanage Vicky , George Donald
Published: March 2007

Context: Retinol binding protein (RBP4), secreted primarily from the liver and adipose tissues, was recently proposed as a link between obesity and insulin resistance. The role of RBP4 in pediatric obesity, its relationship with subclinical inflammation, and its response to lifestyle changes are not elucidated.

Objective: The objective of the study was to determine in children: 1) the status of RBP4 levels in lean vs. obese; 2) the relationship between RBP4 levels and subclinical inflammation; and 3) the effect of lifestyle-only intervention on RBP4 levels.

Design, Setting, and Patients: Lean and obese children (n = 21) matched for age (>14 yr to < 18 yr) and maturity stage (Tanner IV) were studied at baseline and with lifestyle intervention in obese subjects only (n = 15).

Intervention: Patients received 3 months of randomized and controlled physical activity-based lifestyle intervention.

Main Outcome Measure: RBP4 levels in children before and after intervention and the relationship between RBP4 and subclinical inflammation were measured.

Results: Higher RBP4 levels were found in the obese group vs. lean group (P = 0.005). RBP4 correlated with not only indices of obesity and insulin resistance but also inflammatory factors (r = 0.63 and 0.64 for C-reactive protein and IL-6, respectively, P < 0.01). Intervention reduced RBP4 levels by approximately 30% (P = 0.001), and RBP4 reduction was correlated with the magnitude of decrease in inflammatory factors (P = 0.01).

Conclusion: Alterations in serum RBP4 occur at an early age in the clinical course of obesity and appear to correlate with subclinical inflammation. Lifestyle intervention almost entirely reversed the raised RBP4 levels in obese children. Future studies should determine whether elevation of RBP4 is a direct trigger for the insulin resistance and subclinical inflammation implicated in the premature development of cardiovascular disease and diabetes.
Different ADAMs have distinct influences on Kit ligand processing: phorbol-ester-stimulated ectodomain shedding of Kitl1 by ADAM17 is reduced by ADAM19
Authors: Kawaguchi Nobuko , Horiuchi Keisuke , Becherer J. David , Toyama Yoshiaki , Besmer Peter , Blobel Carl P.
Published: March 2007

Kit ligand (Kitl), the ligand for the Kit receptor tyrosine kinase, plays important roles in hematopoiesis, gametogenesis and melanogenesis. Kitl is synthesized as a membrane-anchored precursor that can be processed to produce the soluble growth factor. Here, we evaluated the role of ADAM (a disintegrin and metalloprotease) metalloproteases in ectodomain shedding of Kitl. We found that both ADAM17 and ADAM19 affect Kitl1 shedding, albeit in different ways. Overexpression of ADAM19 resulted in decreased levels of Endo-H-resistant mature Kitl1, thereby reducing the amount of Kitl that is shed from cells following stimulation with phorbol esters. ADAM17 was identified as the major phorbol-ester-stimulated sheddase of Kitl1, whereas ADAMs 8, 9, 10, 12 and 15 were not required for this process. ADAM17 also emerged as the major constitutive and phorbol-ester-stimulated sheddase of Kitl2 in mouse embryonic fibroblasts. Mutagenesis of the juxtamembrane domain of Kitl2 showed no stringent sequence requirement for cleavage by ADAM17, although two nonadjacent stretches of four amino acid residues were identified that are required for Kitl2 shedding. Taken together, this study identifies a novel sheddase, ADAM17, for Kitl1 and Kitl2, and demonstrates that ADAM19 can reduce ADAM17-dependent phorbol-ester-stimulated Kitl1 ectodomain shedding.
MAPK interacts with XGef and is required for CPEB activation during meiosis inXenopusoocytes
Authors: Keady Brian T. , Kuo Peiwen , Martínez Susana E. , Yuan Lei , Hake Laura E.
Published: March 2007

Meiotic progression in Xenopus oocytes, and all other oocytes investigated, is dependent on polyadenylation-induced translation of stockpiled maternal mRNAs. Early during meiotic resumption, phosphorylation of CPE-binding protein (CPEB) is required for polyadenylation-induced translation of mRNAs encoding cell cycle regulators. Xenopus Gef (XGef), a Rho-family guanine-exchange factor, influences the activating phosphorylation of CPEB. An exchange-deficient version of XGef does not, therefore implicating Rho-family GTPase function in early meiosis. We show here that Clostridium difficile Toxin B, a Rho-family GTPase inhibitor, does not impair early CPEB phosphorylation or progression to germinal vesicle breakdown, indicating that XGef does not influence these events through activation of a Toxin-B-sensitive GTPase. Using the inhibitors U0126 for mitogen-activated protein kinase (MAPK), and ZM447439 for Aurora kinase A and Aurora kinase B, we found that MAPK is required for phosphorylation of CPEB, whereas Aurora kinases are not. Furthermore, we do not detect active Aurora kinase A in early meiosis. By contrast, we observe an early, transient activation of MAPK, independent of Mos protein expression. MAPK directly phosphorylates CPEB on four residues (T22, T164, S184, S248), but not on S174, a key residue for activating CPEB function. Notably, XGef immunoprecipitates contain MAPK, and this complex can phosphorylate CPEB. MAPK may prime CPEB for phosphorylation on S174 by an as-yet-unidentified kinase or may activate this kinase.
The SUMO protease SENP5 is required to maintain mitochondrial morphology and function
Authors: Zunino Rodolfo , Schauss Astrid , Rippstein Peter , Andrade-Navarro Miguel , McBride Heidi M.
Published: March 2007

Mitochondria are dynamic organelles that undergo regulated fission and fusion events that are essential to maintain metabolic stability. We previously demonstrated that the mitochondrial fission GTPase DRP1 is a substrate for SUMOylation. To further understand how SUMOylation impacts mitochondrial function, we searched for a SUMO protease that may affect mitochondrial dynamics. We demonstrate that the cytosolic pool of SENP5 catalyzes the cleavage of SUMO1 from a number of mitochondrial substrates. Overexpression of SENP5 rescues SUMO1-induced mitochondrial fragmentation that is partly due to the downregulation of DRP1. By contrast, silencing of SENP5 results in a fragmented and altered morphology. DRP1 was stably mono-SUMOylated in these cells, suggesting that SUMOylation leads to increased DRP1 mediated fission. In addition, the reduction of SENP5 levels resulted in a significant increase in the production of free radicals. Reformation of the mitochondrial tubules by expressing the dominant interfering DRP1 or by RNA silencing of endogenous DRP1 protein rescued both the morphological aberrations and the increased production of ROS induced by downregulation of SENP5. These data demonstrate the importance of SENP5 as a new regulator of SUMO1 proteolysis from mitochondrial targets, impacting mitochondrial morphology and metabolism.
Aliskiren for Renin Inhibition: A New Class of Antihypertensives
Authors: Tassell Benjamin W Van , Munger Mark A
Published: March 2007

Objective:

To review the safety, efficacy, pharmacology, pharmacokinetics, and drug interactions of aliskiren for the treatment of mild-to-moderate hypertension.

Data Sources:

A literature search was conducted using MEDLINE (1966'January 2007), International Pharmaceutical Abstracts (1970'January 2007), and Cochrane database (2006) for the key words aliskiren or SPP100. References of selected articles were also reviewed. Abstract data were included only in the absence of significant published data.

Study Selection And Data Extraction:

Available English-language data from reviews, abstracts, and clinical trials were selected. For review of efficacy, randomized controlled trials were preferred.

Data Synthesis:

Aliskiren is a renin inhibitor, the first in a new class of antihypertensives. As renin catalyzes the rate-limiting step of the renin–angiotensin system (RAS), renin inhibition may offer a theoretical advantage over other RAS inhibitors, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). In short-term clinical trials (≤8 wk) of subjects with mild-to-moderate hypertension, single daily doses of aliskiren 150–300 mg produced significant systolic and diastolic blood pressure reduction similar to that achieved with ACE inhibitors and ARBs, with placebo-like tolerability, without an elevation in heart rate or evidence of tolerance.

Conclusions:

Aliskiren appears to be a safe and effective treatment option in mild-to-moderate hypertension. Although long-term outcome data have not been published, aliskiren is a promising option for RAS inhibition.
Effect of Angiotensin-Converting Enzyme Inhibitors or Angiotensin Receptor Blockers on the Frequency of Post-Cardiothoracic Surgery Atrial Fibrillation
Authors: Coleman Craig I , Makanji Sagar , Kluger Jeffrey , White C Michael
Published: March 2007

Background:

A recent meta-analysis demonstrated that angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) reduce the incidence of new-onset atrial fibrillation by nearly 50%. However, the ability of ACE inhibitors or ARBs to prevent post-cardiothoracic surgery (CTS) atrial fibrillation, when used postoperatively, has yet to be evaluated.

Objective:

To evaluate the impact of postoperative ACE inhibitor or ARB use on the incidence of post-CTS atrial fibrillation.

Methods:

We performed a retrospective cohort study of propensity score matched patients who underwent CTS at a single institution from January 2004 through December 2005. Patients who received either an ACE inhibitor or an ARB within 24 hours of surgery were propensity score matched for common predictors of post-CTS atrial fibrillation (age >70 y, preoperative digoxin use, postoperative β-blocker or amiodarone use, β-blockor intolerance, valve surgery, male sex, and history of diabetes mellitus, smoking, chronic obstructive pulmonary disease, prior cardiothoracic surgery) in a 1:1 ratio with patients who did not receive an ACE inhibitor or an ARB. Multivariate logistic regression was used to generate adjusted odds ratios to minimize the impact of baseline confounders.

Results:

A total of 1469 patients underwent CTS during the study evaluation period. Postoperatively, 188 received an ACE inhibitor or an ARB and were matched to 188 control patients. Mean ± SD age of matched patients was 68.1 ± 11.8 years, 66% were men, 42% underwent valve surgery, and 69% and 35% received postoperative β-blockade and amiodarone, respectively. Patients who received an ACE inhibitor or an ARB did not experience a significant reduction in post-CTS atrial fibrillation compared with control patients (adjusted OR 0.95; 95% CI 0.57 to 1.56; p = 0.83).

Conclusions:

In this evaluation, postoperative ACE inhibitor or ARB use was not associated with a reduction in post-CTS atrial fibrillation. A study of preoperative, longer-term ACE inhibitor and/or ARB therapy is needed to determine the benefits of that strategy.
Advances in Anticoagulation Management: The Role of Pharmacy
Authors: Smythe Maureen A
Published: March 2007

2006 marked the 40th year of publication for The Annals. Throughout its history, The Annals has provided important contributions to the development of clinical pharmacy. In 2007, we are continuing to publish articles reflecting on the history of clinical pharmacy through the eyes of practitioners, including those pioneering clinical pharmacy, as well as those who have more recently entered the profession and a well-established specialty. In addition, we are presenting articles and editorials from the early history of The Annals that have given direction and shape to the practice of clinical pharmacy (see page 496).
Expression and Localization of Plasma Transglutaminase Factor XIIIA in Bone
Authors: Nakano Yukiko , Al-Jallad Hadil F. , Mousa Aisha , Kaartinen Mari T.
Published: March 2007

Transglutaminases (TGs) are protein crosslinking enzymes involved in cell adhesion and signaling and matrix stabilization and maturation, in many cell types and tissues. We previously described that in addition to transglutaminase 2 (TG2), cultured MC3T3-E1 osteoblasts also express the plasma TG Factor XIIIA (FXIIIA). Here we report on the expression and localization of FXIIIA in bone in vivo and provide confirmatory in vitro data. Immuno-histochemistry and in situ hybridization demonstrated that FXIIIA is expressed by osteoblasts and osteocytes in long bones formed by endochondral ossification (femur) and flat bones formed primarily by intramembranous ossification (calvaria and mandible). FXIIIA immuno-reactivity was localized to osteoblasts, osteocytes, and the osteoid. RT-PCR analysis revealed FXIIIA expression by both primary osteoblasts and by the MC3T3-E1 osteoblast cell line. Western blot analysis of bone and MC3T3-E1 culture extracts demonstrated that FXIIIA is produced mainly as a small, 37-kDa form. Sequential RT-PCR analysis using overlapping PCR primers spanning the full FXIIIA gene showed that the entire FXIIIA gene is expressed, thus indicating that the 37-kDa FXIIIA is not a splice variant but a product of posttranslational proteolytic processing. Forskolin inhibition of osteoblast differentiation revealed that FXIIIA processing is regulated by the protein kinase A pathway.
Expression of Liver X Receptor α in Rat Fetal Tissues at Different Developmental Stages
Authors: Sakamoto Azusa , Kawasaki Takashi , Kazawa Toshihiro , Ohashi Riuko , Jiang Shuying , Maejima Takashi , Tanaka Toshiya , Iwanari Hiroko , Hamakubo Takao , Sakai Juro , Kodama Tatsuhiko , Naito Makoto
Published: March 2007

The liver X receptor (LXR) is a nuclear receptor that acts as a sterol sensor and metabolic regulator of cholesterol and lipid homeostasis. Using a novel LXRα-specific antibody for immunohistochemistry, we evaluated cellular expression of LXRα in fetal rat tissues. In the fetal liver, LXRα-positive macrophages appeared at 12 days and their number peaked at 18 days of gestation. In contrast, hepatocytes expressed LXRα during the later stage of gestation, suggesting the functional development of the liver during ontogeny. Later, macrophages in spleen and thymus expressed LXRα, and some mononuclear cells in the vascular lumen compatible to primitive/fetal macrophages in the fetal circulation were found to express LXRα. In vitro, rat monocytes did not express LXRα, but monocyte-derived macrophages cultured in the presence of macrophage-colony stimulating factor revealed the distinct expression of LXRα in nucleoli. These findings suggest that LXRα plays a role in the differentiation of fetal macrophages, particularly hepatic macrophages, in rat development.
Actin-binding Proteins Coronin-1a and IBA-1 are Effective Microglial Markers for Immunohistochemistry
Authors: Ahmed Zeshan , Shaw Gerry , Sharma Ved P. , Yang Cui , McGowan Eileen , Dickson Dennis W.
Published: March 2007

This study identifies the actin-binding protein, coronin-1a, as a novel and effective immunohistochemical marker for microglia in both cell cultures and in formaldehyde-fixed, paraffin-embedded tissue. Antibodies to coronin-1a effectively immunostained microglia in human, monkey, horse, rat, and mouse tissues, even in tissues stored for long periods of time. The identity of coronin-1a-immunoreactive cells as microglia was confirmed using double immunolabeling with cell type-specific markers as well as by morphological features and the distribution of immunoreactive cells. These properties are shared by another actin-binding protein, IBA-1. Unlike IBA-1, coronin-1a immunoreactivity was also detected in lymphocytes and certain other hematopoietic cells. The results indicate that both coronin-1a and IBA-1 are robust markers for microglia that can be used in routinely processed tissue of humans and animals. Because both coronin-1a and IBA-1 are actin-binding proteins that play a role in rearrangement of the membrane cytoskeleton, it suggests that these proteins are critical to dynamic properties of microglia.
New Immortalized Cell Lines of Patients With Small Supernumerary Marker Chromosome
Authors: Tönnies Holger , Pietrzak Joanna , Bocian Ewa , MacDermont Kay , Kuechler Alma , Belitz Britta , Trautmann Udo , Schmidt Angela , Schulze Berndt , Rodríguez Laura , Binkert Franz , Yardin Catharine , Kosyakova Nadezda , Volleth Marianne , Mkrtchyan Hasmik , Schreyer Isolde , von Eggeling Ferdinand , Weise Anja , Mrasek Kristin , Liehr Thomas
Published: March 2007

Sixteen newly established cell lines with small supernumerary marker chromosomes (sSMC) derived from chromosomes 1, 2, 4, 6, 7, 8, 14, 15, 16, 18, 19, 21, and 22 are reported. Two sSMC are neocentric and derived from 15q24.1-qter and 2q35-q36, respectively. Two further cases each present with two sSMC of different chromosomal origin. sSMC were characterized by multicolor fluorescence in situ hybridization for their chromosomal origin and genetic content. Moreover, uniparental disomy of the sister chromosomes of the sSMC was excluded in all nine cases studied for that reason. The 16 cases provide information to establish a refined genotype-phenotype correlation of sSMC and are available for future studies.
Impaired Cerebellar Development and Function in Mice Lacking CAPS2, a Protein Involved in Neurotrophin Release
Authors: Sadakata Tetsushi , Kakegawa Wataru , Mizoguchi Akira , Washida Miwa , Katoh-Semba Ritsuko , Shutoh Fumihiro , Okamoto Takehito , Nakashima Hisako , Kimura Kazushi , Tanaka Mika , Sekine Yukiko , Itohara Shigeyoshi , Yuzaki Michisuke , Nagao Soichi , Furuichi Teiichi
Published: March 2007

Ca2+-dependent activator protein for secretion 2 (CAPS2/CADPS2) is a secretory granule-associated protein that is abundant at the parallel fiber terminals of granule cells in the mouse cerebellum and is involved in the release of neurotrophin-3 (NT-3) and brain-derived neurotrophic factor (BDNF), both of which are required for cerebellar development. The human homolog gene on chromosome 7 is located within susceptibility locus 1 of autism, a disease characterized by several cerebellar morphological abnormalities. Here we report thatCAPS2knock-out mice are deficient in the release of NT-3 and BDNF, and they consequently exhibit suppressed phosphorylation of Trk receptors in the cerebellum; these mice exhibit pronounced impairments in cerebellar development and functions, including neuronal survival, differentiation and migration of postmitotic granule cells, dendritogenesis of Purkinje cells, lobulation between lobules VI and VII, structure and vesicular distribution of parallel fiber–Purkinje cell synapses, paired-pulse facilitation at parallel fiber–Purkinje cell synapses, rotarod motor coordination, and eye movement plasticity in optokinetic training. Increased granule cell death of the external granular layer was noted in lobules VI–VII and IX, in which high BDNF and NT-3 levels are specifically localized during cerebellar development. Therefore, the deficiency of CAPS2 indicates that CAPS2-mediated neurotrophin release is indispensable for normal cerebellar development and functions, including neuronal differentiation and survival, morphogenesis, synaptic function, and motor leaning/control. The possible involvement of theCAPS2gene in the cerebellar deficits of autistic patients is discussed.
Translation Speed Compensation in the Dorsal Aspect of the Medial Superior Temporal Area
Authors: Lee Brian , Pesaran Bijan , Andersen Richard A.
Published: March 2007

The dorsal aspect of the medial superior temporal area (MSTd) is involved in the computation of heading direction from the focus of expansion (FOE) of the visual image. Our laboratory previously found that MSTd neurons adjust their focus tuning curves to compensate for shifts in the FOE produced by eye rotation (Bradley et al., 1996) as well as for changes in pursuit speed (Shenoy et al., 2002). The translation speed of an observer also affects the shift of the FOE. To investigate whether MSTd neurons can adjust their focus tuning curves to compensate for varying translation speeds, we recorded extracellular responses from 93 focus-tuned MSTd neurons in two rhesus monkeys (Macaca mulatta) performing pursuit eye movements across displays of varying translation speeds. We found that MSTd neurons had larger shifts in their tuning curves for slow translation speeds and smaller shifts for fast translation speeds. These shifts aligned the focus tuning curves with the true heading direction and not with the retinal position of the FOE. Because the eye was pursuing at the same rate for varying translation speeds, these results indicate that retinal cues related both to translation speed and extraretinal signals from pursuit eye movements are used by MSTd neurons to compute heading direction.
Cell-Autonomous TrkB Signaling in Presynaptic Retinal Ganglion Cells Mediates Axon Arbor Growth and Synapse Maturation during the Establishment of Retinotectal Synaptic Connectivity
Authors: Marshak Sonya , Nikolakopoulou Angeliki Maria , Dirks Ron , Martens Gerard J. , Cohen-Cory Susana
Published: March 2007

BDNF contributes to the activity-dependent establishment and refinement of visual connectivity. InXenopus, BDNF applications in the optic tectum influence retinal ganglion cell (RGC) axon branching and promote synapse formation and stabilization. The expression patterns of BDNF and TrkB suggest that BDNF specifically regulates the maturation of RGC axons at the target. It is possible, however, that BDNF modulates retinotectal synaptic connectivity by differentially influencing presynaptic RGC axons and postsynaptic tectal cells. Here, we combined single-cell expression of a dominant-negative TrkB–enhanced green fluorescent protein (GFP) fusion protein with confocal microscopy imaging in liveXenopustadpoles to differentiate between presynaptic and postsynaptic actions of BDNF. Disruption of TrkB signaling in individual RGCs influenced the branching and synaptic maturation of presynaptic axon arbors. Specifically, GFP–TrkB.T1 overexpression increased the proportion of axons with immature, growth cone-like morphology, decreased axon branch stability, and increased axon arbor degeneration. In addition, GFP–TrkB.T1 overexpression reduced the number of red fluorescent protein–synaptobrevin-labeled presynaptic specializations per axon terminal. In contrast, overexpression of GFP–TrkB.T1 in tectal neurons did not alter synaptic number or the morphology or dynamic behavior of their dendritic arbors. Electron microscopy analysis revealed a significant decrease in the number of mature synaptic profiles and in the number of docked synaptic vesicles at retinotectal synapses made by RGC axons expressing GFP–TrkB.T1. Together, our results demonstrate that presynaptic TrkB signaling in RGCs is a key determinant in the establishment of visual connectivity and indicate that changes in tectal neuron synaptic connectivity are secondary to the BDNF-elicited enhanced stability and growth of presynaptic RGCs.
Microcircuitry for Two Types of Achromatic Ganglion Cell in Primate Fovea
Authors: Calkins David J. , Sterling Peter
Published: March 2007

Synaptic circuits in primate fovea have been quantified for midget/parvocellular ganglion cells. Here, based on partial reconstructions from serial electron micrographs, we quantify synaptic circuits for two other types of ganglion cell: the familiar parasol/magnocellular cell and a smaller type, termed “garland.” The excitatory circuits both derive from two types of OFF diffuse cone bipolar cell, DB3 and DB2, which collected unselectively from at least 6 ± 1 cones, including the S type. Cone contacts to DB3 dendrites were usually located between neighboring triads, whereas half of the cone contacts to DB2 were triad associated. Ribbon outputs were as follows: DB3, 69 ± 5; DB2, 48 ± 4. A complete parasol cell (30 μm dendritic field diameter) would collect from ∼50 cones via ∼120 bipolar and ∼85 amacrine contacts; a complete garland cell (25 μm dendritic field) would collect from ∼40 cones via ∼75 bipolar and ∼145 amacrine contacts. The bipolar types contributed differently: the parasol cell received most contacts (60%) from DB3, whereas the garland cell received most contacts (67%) from DB2. We hypothesize that DB3 is a transient bipolar cell and that DB2 is sustained. This would be consistent with their relative inputs to the brisk-transient (parasol) ganglion cell. The garland cell, with its high proportion of DB2 inputs plus its high proportion of amacrine synapses (70%) and dense mosaic, might correspond to the local-edge cell in nonprimate retinas, which serves finer acuity at low temporal frequencies. The convergence of S cones onto both types could contribute S-cone input for cortical areas primary visual cortex and the middle temporal area.
Auditory Cortical Plasticity in Learning to Discriminate Modulation Rate
Authors: van Wassenhove Virginie , Nagarajan Srikantan S.
Published: March 2007

The discrimination of temporal information in acoustic inputs is a crucial aspect of auditory perception, yet very few studies have focused on auditory perceptual learning of timing properties and associated plasticity in adult auditory cortex. Here, we trained participants on a temporal discrimination task. The main task used a base stimulus (four tones separated by intervals of 200 ms) that had to be distinguished from a target stimulus (four tones with intervals down to ∼180 ms). We show that participants' auditory temporal sensitivity improves with a short amount of training (3 d, 1 h/d). Learning to discriminate temporal modulation rates was accompanied by a systematic amplitude increase of the early auditory evoked responses to trained stimuli, as measured by magnetoencephalography. Additionally, learning and auditory cortex plasticity partially generalized to interval discrimination but not to frequency discrimination. Auditory cortex plasticity associated with short-term perceptual learning was manifested as an enhancement of auditory cortical responses to trained acoustic features only in the trained task. Plasticity was also manifested as induced non-phase–locked high gamma-band power increases in inferior frontal cortex during performance in the trained task. Functional plasticity in auditory cortex is here interpreted as the product of bottom-up and top-down modulations.
PDP1ε Functions Downstream of the Circadian Oscillator to Mediate Behavioral Rhythms
Authors: Benito Juliana , Zheng Hao , Hardin Paul E.
Published: March 2007

TheDrosophilacircadian oscillator is composed of autoregulatoryperiod/timeless(per/tim) andClock(Clk) feedback loops that control rhythmic transcription. In theClkloop, CLOCK-CYCLE heterodimers activatevrille(vri) andPAR domain protein 1ε (Pdp1ε) transcription, then sequential repression by VRI and activation by PDP1ε mediate rhythms inClktranscription. Because VRI and PDP1ε bind the same regulatory element, the VRI/PDP1ε ratio is thought to control the level ofClktranscription. Thus, constant high or low PDP1ε levels in clock cells should eliminateClkmRNA cycling and disrupt circadian oscillator function. Here we show that reducing PDP1ε levels in clock cells by ∼70% via RNA interference or increasing PDP1ε levels by ∼10-fold in clock cells does not alterClkmRNA cycling or circadian oscillator function. However, constant low or high PDP1ε levels in clock cells disrupt locomotor activity rhythms despite persistent circadian oscillator function in brain pacemaker neurons that extend morphologically normal projections into the dorsal brain. These results demonstrate that the VRI/PDP1ε ratio neither controlsClkmRNA cycling nor circadian oscillator function and argue that PDP1ε is not essential forClkactivation. PDP1ε is nevertheless required for behavioral rhythmicity, which suggests that it functions to regulate oscillator output.
Oligomeric Amyloid Decreases Basal Levels of Brain-Derived Neurotrophic factor (BDNF) mRNA via Specific Downregulation of BDNF Transcripts IV and V in Differentiated Human Neuroblastoma Cells
Authors: Garzon Diego J. , Fahnestock Margaret
Published: March 2007

Alzheimer's disease (AD) is a senile dementia characterized by amyloid plaques, neurofibrillary tangles, and synaptic and cell loss. The “amyloid cascade” hypothesis suggests that amyloid-β (Aβ), the peptide deposited as amyloid plaques, is the primary insult in AD. However, debate continues over the mechanism of Aβ toxicity and whether fibrillar or oligomeric Aβ is the active species of the peptide that ultimately causes the synaptic loss and dementia associated with AD. Brain-derived neurotrophic factor (BDNF) is required for survival and function of cells compromised in AD. Decreased BDNF causes defects in long-term potentiation and memory and correlates with cognitive decline. We previously demonstrated that BDNF reduction occurs early in the course of AD, suggesting that decreased BDNF may promote neuronal dysfunction in AD. We also demonstrated that three of seven human BDNF transcripts are specifically downregulated in AD. What pathological feature(s) of AD leads to the decreased BDNF is unknown.

In this study, we administered both fibrillar and oligomeric conformations of Aβ1–42to differentiated SH-SY5Y, a human neuroblastoma cell line, and measured both phosphorylated cAMP response element-binding protein (CREB), a regulator of BDNF transcription, and BDNF total mRNA. We found that oligomeric but not fibrillar preparations of Aβ1–42significantly decrease both phosphorylated CREB and total BDNF mRNA. Furthermore, oligomeric Aβ1–42decreases BDNF transcripts IV and V in these cells, demonstrating that Aβ1–42downregulates the major BDNF transcript decreasedin vivoin the AD brain. Thus, oligomeric Aβ1–42could compromise neuronal function, causing memory loss and cognitive dysfunction by downregulation of BDNF in AD.
Perceptual Functions of Perirhinal Cortex in Rats: Zero-Delay Object Recognition and Simultaneous Oddity Discriminations
Authors: Bartko Susan J. , Winters Boyer D. , Cowell Rosemary A. , Saksida Lisa M. , Bussey Timothy J.
Published: March 2007

The perirhinal cortex (PRh) is widely accepted as having an important role in object recognition memory in humans and animals. Contrary to claims that PRh mediates declarative memory exclusively, previous evidence suggests that PRh has a role in the perceptual processing of complex objects. In the present study, we conducted an examination of the possible role of PRh in perceptual function in rats. We examined whether bilateral excitotoxic lesions of PRh or PPRh (perirhinal plus postrhinal cortices) in the rat would cause deficits in a zero-delay object-recognition task and a simultaneous oddity discrimination task. Both of these tasks measured spontaneous (untrained, unrewarded) behavior, and the stimuli in these experiments were manipulated to produce varying levels of perceptual difficulty. As predicted by simulations using a computational model, rats with PPRh lesions were impaired in object recognition when the stimuli to be discriminated were manipulated to share many features in common. Furthermore, rats with PPRh and PRh lesions were impaired in a simultaneous oddity discrimination task when the stimuli to be discriminated were manipulated explicitly to be more perceptually similar. These findings provide support for the idea that PRh in the rat is important for the perceptual processing of complex objects, in addition to its well established role in memory.
Selective Ablation of Proliferating Microglial Cells Exacerbates Ischemic Injury in the Brain
Authors: Lalancette-Hébert Mélanie , Gowing Geneviève , Simard Alain , Weng Yuan Cheng , Kriz Jasna
Published: March 2007

Here we reportin vivoevidence of a neuroprotective role of proliferating microglial cells in cerebral ischemia. Using transgenic mice expressing a mutant thymidine kinase form of herpes simplex virus driven by myeloid-specific CD11b promoter and ganciclovir treatment as a tool, we selectively ablated proliferating (Mac-2 positive) microglia after transient middle cerebral artery occlusion. The series of experiments using green fluorescent protein-chimeric mice demonstrated that within the first 72 h after ischemic injury, the Mac-2 marker [unlike Iba1 (ionized calcium-binding adapter molecule 1)] was preferentially expressed by the resident microglia. Selective ablation of proliferating resident microglia was associated with a marked alteration in the temporal dynamics of proinflammatory cytokine expression, a significant increase in the size of infarction associated with a 2.7-fold increase in the number of apoptotic cells, predominantly neurons, and a 1.8-fold decrease in the levels of IGF-1. A double-immunofluorescence analysis revealed a ∼100% colocalization between IGF-1 positive cells and Mac-2, a marker of activated/proliferating resident microglia. Conversely, stimulation of microglial proliferation after cerebral ischemia by M-CSF (macrophage colony stimulating factor) resulted in a 1.9-fold increase in IGF-1 levels and a significant increase of Mac2+cells. Our findings suggest that a postischemic proliferation of the resident microglial cells may serve as an important modulator of a brain inflammatory response. More importantly, our results revealed a marked neuroprotective potential of proliferating microglia serving as an endogenous pool of neurotrophic molecules such as IGF-1, which may open new therapeutic avenues in the treatment of stroke and other neurological disorders.
Emergence of Functional Sensory Subtypes as Defined by Transient Receptor Potential Channel Expression
Authors: Hjerling-Leffler Jens , AlQatari Mona , Ernfors Patrik , Koltzenburg Martin
Published: March 2007

The existence of heterogeneous populations of dorsal root ganglion (DRG) neurons conveying different somatosensory information is the basis for the perception of touch, temperature, and pain. A differential expression of transient receptor potential (TRP) cation channels contributes to this functional heterogeneity. However, little is known about the development of functionally diverse neuronal subpopulations. Here, we use calcium imaging of acutely dissociated mouse sensory neurons and quantitative reverse transcription PCR to show that TRP cation channels emerge in waves, with the diversification of functional groups starting at embryonic day 12.5 (E12.5) and extending well into the postnatal life. Functional responses of voltage-gated calcium channels were present in DRG neurons at E11.5 and reached adult levels by E14.5. Responses to capsaicin, menthol, and cinnamaldehyde were first seen at E12.5, E16.5, and postnatal day 0 (P0), when the mRNA for TRP cation channel, subfamily V, member 1 (TRPV1), TRP cation channel, subfamily M, member 8 (TRPM8), and TRP cation channel, subfamily A, member 1 (TRPA1), respectively, was first detected. Cold-sensitive neurons were present before the expression or functional responses of TRPM8 or TRPA1. Our data support a lineage relationship in which TRPM8- and TRPA1-expressing sensory neurons derive from the population of TRPV1-expressing neurons. The TRPA1 subpopulation of neurons emerges independently in two distinct classes of nociceptors: around birth in the peptidergic population and after P14 in the nonpeptidergic class. This indicates that neurons with similar receptive properties can be generated in different sublineages at different developmental stages. This study describes for the first time the emergence of functional subtypes of sensory neurons, providing new insight into the development of nociception and thermoreception.
Linguistic fieldwork: setting the scene
Authors: Aikhenvald Alexandra Y.
Published: March 2007

Linguistic fieldwork is the backbone of an empirically-based science of linguistics. Firsthand information on barely known minority languages is essential for our understanding of human languages, their structural properties and their genetic relationships. ‘Immersion’ fieldwork as major ‘must’ is contrasted to ‘interview’ fieldwork as a less desirable option. We aim at an open-ended documentation of each language, intended for various audiences, being both accessible and user-friendly. This introductory essay introduces a number of issues concerning linguistic fieldwork, discussed in some detail by the contributors to this issue, each a highly experienced fieldworker and a recognised authority in their fields. This is what makes the issue special.
Fieldwork on Konda, a Dravidian language
Authors: Krishnamurti Bhadriraju
Published: March 2007

In this paper I discuss my experience in working in the late 1950s on Konda, a previously undescribed Dravidian language from Central India, in terms of its phonetics, phonology, morphology and syntax. The analysis and the collection of data involved work with texts and conversations and elicitation of paradigms. This grammar was cast in terms of basic linguistic theorty, without adhering to any of the particular formal models then in vogue, and is the most comprehensive grammar of any minority Dravidian language. It has been instrumental for our understanding of Proto-Dravidian.
Passive Integrated Transponder (PIT) Tagging Did Not Negatively Affect the Short‐Term Feeding Behavior or Swimming Performance of Juvenile Rainbow Trout
Authors: Newby Nathalie C. , Binder Thomas R. , Stevens E. Don
Published: March 2007

Passive integrated transponder (PIT) tagging is a commonly used procedure to identify fish. However, there is a lack of research on the short‐term effects of such tagging. The purpose of our study was to measure the short‐term effects of PIT tagging on the feeding behavior and swimming performance of juvenile rainbow trout Oncorhynchus mykiss. Three experiments were conducted. The treatment groups in the first two experiments consisted of a control group and a PIT‐tagged group. In the first experiment, we timed the latency to resume feeding before and after the experimental day in fish trained to feed with a light cue. In the second experiment, we recorded the amount of food ingested before and after the experimental day in fish that had been fed to satiation every day for a week prior to the experiment. We found no significant differences between control and PIT‐tagged groups for either the latency to resume feeding (time from providing food to food intake) or the amount of food eaten. The third experiment consisted of a fixed‐velocity swimming performance test in which fish that had been tagged 40 d before the test and whose wounds had healed were compared with fish that were tagged on the day of the experiment. We found no significant differences between the fish that had healed wounds and fish that had just been tagged.
Implementing a space-time rainfall model for the Sydney region
Authors: Leonard M. , Metcalfe A. , Lambert M. , Kuczera G.
Published: March 2007

This paper investigates a Spatial Neyman–Scott Rectangular Pulse (SNSRP) model, which is one of only a few models capable of continuous simulation of rainfall in both space and time. The SNSRP is a spatial extension of the Neyman–Scott Rectangular Pulse model at a single point. The model is highly idealized having six parameters: storm arrival, cell arrival, cell radius, cell lifetime and two cell intensity parameters. A spatial interpolation of the scale parameter is used so that the model can be simulated continuously in space, rather than as a multi-site model. The parameters are calibrated using least-squares fits to statistical moments based on data aggregated to hourly and daily totals. The SNSRP model is calibrated to a very large network of 85 gauges over metropolitan Sydney and shows a good agreement to calibrated statistics. A simulation of 50 replicates over the region compares favourably to several observed temporal statistics, with an example given for one site. A qualitative discussion of the simulated spatial images demonstrates the underlying structure of non-advecting cylindrical cells.