bluuebunny/crossref_metadata_2025 huggingface dataset:
M17, a gene specific for germinal center (GC) B cells and a prognostic marker for GC B-cell lymphomas, is dispensable for the GC reaction in mice
Authors: Schenten Dominik , Egert Angela , Pasparakis Manolis , Rajewsky Klaus
Published: February 2006

In T-cell–dependent antibody responses, antigen-specific B cells undergo a phase of secondary antibody diversification in germinal centers (GCs). Somatic hypermutation (SHM) introduces mutations into the rearranged immunoglobulin (Ig) variable (V) region genes, and class-switch recombination (CSR) alters the Ig heavy (H) chain constant region. Aberrant SHM or CSR is thought to contribute to the development of GC-derived B-cell malignancies. Diffuse large B-cell lymphomas (DLBCLs) are a heterogeneous group of such GC-derived tumors. Based on their gene expression profile, DLBCLs can be divided into activated B-cell–like and GC-like subgroups. The human gene HGAL is predominantly expressed in GCs. It is also part of the gene expression signature of GC-like DLBCL, and its high expression in DLBCL has been associated with a better clinical prognosis. We have generated mice deficient of the HGAL homologue M17 in order to investigate its functional significance. The mutant animals form normal GCs, undergo efficient CSR and SHM, and mount T-cell–dependent antibody responses similar to wild-type controls. Thus, M17 is dispensable for the GC reaction, and its potential function in the pathogenesis of DLBCL remains elusive.
Cellular localization and trafficking of tissue factor
Authors: Mandal Samir K. , Pendurthi Usha R. , Rao L. Vijaya Mohan
Published: February 2006

Tissue factor (TF) is the cellular receptor for clotting factor VIIa (FVIIa). The formation of TF-FVIIa complexes on cell surfaces triggers the activation of coagulation cascade and cell signaling. In the present study, we characterized the subcellular distribution of TF and its transport in fibroblasts by dual immunofluorescence confocal microscopy and biochemical methods. Our data show that a majority of TF resides in various intracellular compartments, predominantly in the Golgi. Tissue factor at the cell surface is localized in cholesterol-rich lipid rafts and extensively colocalized with caveolin-1. FVIIa binding to TF induces the internalization of TF. Of interest, we found that TF-FVIIa complex formation at the cell surface leads to TF mobilization from the Golgi with a resultant increase in TF expression at the cell surface. This process is dependent on FVIIa protease activity. Overall, the present data suggest a novel mechanism for TF expression at the cell surface by FVIIa. This mechanism could play an important role in hemostasis in response to vascular injury by increasing TF activity where and when it is needed.
Prothrombin 20210G>A is an ancestral prothrombotic mutation that occurred in whites approximately 24 000 years ago
Authors: Zivelin Ariella , Mor-Cohen Ronit , Kovalsky Victoria , Kornbrot Nurit , Conard Jacqueline , Peyvandi Flora , Kyrle Paul A. , Bertina Rogier , Peyvandi Ferial , Emmerich Joseph , Seligsohn Uri
Published: February 2006

Prothrombin 20210G>A and factor V Leiden are common prothrombotic mutations in whites for which founder effects have been established. In this study, we analyzed the frequencies of 5 single nucleotide polymorphisms (SNPs) and 9 microsatellites flanking the prothrombin gene (F2) in 88 homozygotes for 20210A and 66 homozygotes for 20210G. For estimating the age of the prothrombin 20210G>A mutation, we used the DMLE+2.0 program, which analyzed linkage disequilibria between the mutation and the multiple markers that had been assessed. This analysis yielded an age estimate of 23 720 years (95% credible set, 19 080-31 340 years). A similar analysis by the DMLE+2.0 program was performed on 5 SNPs from previously studied homozygotes for factor V Leiden and controls that yielded an age estimate of 21 340 years (95% credible set, 16 880-29 480 years). The occurrence of the 2 mutations in whites toward the end of the last glaciation and their presently wide distribution in whites suggest selective evolutionary advantages for which some evidence was reported (diminished blood loss) or is controversial (protection against infections).
False-positive detection of recombinant human erythropoietin in urine following strenuous physical exercise
Authors: Beullens Monique , Delanghe Joris R. , Bollen Mathieu
Published: February 2006

Erythropoietin (Epo) is a glycoprotein hormone that promotes the production of red blood cells. Recombinant human Epo (rhEpo) is illicitly used to improve performance in endurance sports. Doping in sports is discouraged by the screening of athletes for rhEPO in urine. The adopted test is based on a combination of isoelectric focusing and double immunoblotting, and distinguishes between endogenous and recombinant human Epo. We show here that this widely used test can occasionally lead to the false-positive detection of rhEpo (epoetin-β) in postexercise, protein-rich urine, probably because the adopted monoclonal anti-Epo antibodies are not monospecific.
Miscalculating One’s Enemies: Russian Military Intelligence before the Russo-Japanese War
Authors: Menning Bruce W.
Published: February 2006

On the basis of archival and printed sources, this article examines the role that Russian military intelligence played in miscalculating the Japanese threat before the outbreak of the Russo-Japanese war of 1904-05. The treatment focuses on three general problem areas: assessments of Japanese military and naval strength and combat readiness; perceptions of war imminence and the related possibility of surprise; and Japanese intentions. Evidence indicates that the overall quality of intelligence was uneven, although reasonably accurate with regard to the Japanese navy. However, genuine situational and structural constraints clouded perceptions of the Japanese ground forces. Still other constraints obscured Russian perceptions of war imminence and Japanese intentions. The cumulative result was that Russia would enter far eastern conflict at a substantial disadvantage.
The Association of Obesity and Hyperandrogenemia during the Pubertal Transition in Girls: Obesity as a Potential Factor in the Genesis of Postpubertal Hyperandrogenism
Authors: McCartney Christopher R. , Prendergast Kathleen A. , Chhabra Sandhya , Eagleson Christine A. , Yoo Richard , Chang R. Jeffrey , Foster Carol M. , Marshall John C.
Published: February 2006

Context: Adolescent hyperandrogenemia is considered a forerunner of adult polycystic ovary syndrome, but its etiology remains uncertain.

Objective: Our objective was to explore the hypothesis that peripubertal obesity is associated with hyperandrogenemia.

Design and Setting: We performed a cross-sectional analysis of data obtained at General Clinical Research Centers.

Subjects: Subjects were 41 obese [body mass index (BMI) for age, ≥95%] and 35 normal-weight (BMI for age, <95%) peripubertal girls.

Intervention: We used pooled blood samples (∼0500–0700 h; n = 64) while fasting or single morning (fasting) samples (n = 12).

Main Outcome Measures: We assessed adiposity and androgen concentrations.

Results: BMI correlated with total testosterone (T) (rs = 0.59), SHBG (rs = −0.69), and free T (rs = 0.69); free T was three times as great in obese girls compared with normal-weight girls (P < 0.0001 for all). BMI correlated with insulin (rs = 0.52); both insulin and LH correlated with free T (rs = 0.45 and 0.44, respectively; P < 0.001 for all). When analyzing early pubertal girls (pubertal stages 1–3; n = 36) alone, BMI correlated with total T (rs = 0.65), SHBG (rs = −0.74), and free T (rs = 0.75); free T was five times as great in obese early-pubertal girls (P < 0.001 for all). BMI correlated with insulin (rs = 0.65), and insulin correlated with free T (rs = 0.63, P < 0.01 for both). BMI correlated with free T while simultaneously adjusting for age, pubertal stage, insulin, LH, and dehydroepiandrosterone sulfate.

Conclusion: Peripubertal obesity is associated with marked hyperandrogenemia, which is especially pronounced in early puberty.
Human Sec31B: a family of new mammalian orthologues of yeast Sec31p that associate with the COPII coat
Authors: Stankewich Michael C. , Stabach Paul R. , Morrow Jon S.
Published: February 2006

We have cloned human brain and testis Sec31B protein (also known as secretory pathway component Sec31B-1 or SEC31-like 2; GenBank accession number AF274863). Sec31B is an orthologue of Saccharomyces cerevisiae Sec31p, a component of the COPII vesicle coat that mediates vesicular traffic from the endoplasmic reticulum. Sec31B is widely expressed and enriched in cerebellum and testis. Its predicted sequence of 1180 residues (expected molecular mass 128,711 Da) shares 47.3% and 18.8% similarity to human Sec31A (also known as Sec31; GenBank accession number AF139184) and yeast Sec31p, respectively. The gene encoding Sec31B is located on chromosome 10q24 and contains 29 exons. PCR analysis of exon utilization reveals massive alternative mRNA splicing of Sec31B, with just 16 exons being constitutively utilized in all transcripts. The presence of a stop codon in exon 13 generates two families of Sec31B gene products (each displaying additional patterns of mRNA splicing): a group of full-length proteins (hereafter referred to as Sec31B-F) and also a group of truncated proteins (hereafter referred to as Sec31B-T), distinguished by their utilization of exon 13. Sec31B-F closely resembles Sec31p and Sec31A, with canonical WD repeats in an N-terminal domain that binds Sec13 and a proline-rich C-terminal region that presumably binds Sec23/24. The Sec31B-T group (molecular mass 52,983 Da) contains a preserved WD-repeat domain but lacks the C-terminal proline-rich region. When expressed as a fusion protein with eYFP in cultured cells, Sec31B-F associates with the endoplasmic reticulum and with vesicular-tubular clusters, displays restricted intracellular movement characteristic of COPII vesicle dynamics, co-distributes on organelles with Sec13, Sec31A and Sec23 (markers of the COPII coat), and concentrates with ts045-VSV-G-CFP (VSV-G) when examined early in the secretory pathway or after temperature or nocodazole inhibition. The role of the truncated form Sec31B-T appears to be distinct from that of Sec31B-F and remains unknown. We conclude that Sec31B-F contributes to the diversity of the mammalian COPII coat, and speculate that the Sec31 cage, like Sec24, might be built with isoforms tuned to specific types of cargo or to other specialized functions.
The pH of the digestive vacuole ofPlasmodium falciparumis not associated with chloroquine resistance
Authors: Hayward Rhys , Saliba Kevin J. , Kirk Kiaran
Published: February 2006

Chloroquine resistance in the human malaria parasite, Plasmodium falciparum, arises from decreased accumulation of the drug in the `digestive vacuole' of the parasite, an acidic compartment in which chloroquine exerts its primary toxic effect. It has been proposed that changes in the pH of the digestive vacuole might underlie the decreased accumulation of chloroquine by chloroquine-resistant parasites. In this study we have investigated the digestive vacuole pH of a chloroquine-sensitive and a chloroquine-resistant strain of P. falciparum, using a range of dextran-linked pH-sensitive fluorescent dyes. The estimated digestive vacuole pH varied with the concentration and pKa of the dye, ranging from ∼3.7-6.5. However, at low dye concentrations the estimated digestive vacuole pH of both the chloroquine-resistant and chloroquine-sensitive strains converged in the range 4.5-4.9. The results suggest that there is no significant difference in digestive vacuole pH of chloroquine-sensitive and chloroquine-resistant parasites, and that digestive vacuole pH does not play a primary role in chloroquine resistance.
Upregulation of chondroitin 6-sulphotransferase-1 facilitates Schwann cell migration during axonal growth
Authors: Liu Jun , Chau Chi-Ho , Liu Hengying , Jang Benjamin R. , Li Xiaoguang , Chan Ying-Shang , Shum Daisy K. Y.
Published: February 2006

Cell migration is central to development and post-traumatic regeneration. The differential increase in 6-sulphated chondroitins during axonal growth in both crushed sciatic nerves and brain development suggests that chondroitin 6-sulphotransferase-1 (C6ST-1) is a key enzyme that mediates cell migration in the process. We have cloned the cDNA of the C6ST-1 gene (C6st1) (GenBank accession number AF178689) from crushed sciatic nerves of adult rats and produced ribonucleotide probes accordingly to track signs of 6-sulphated chondroitins at the site of injury. We found C6st1 mRNA expression in Schwann cells emigrating from explants of both sciatic nerve segments and embryonic dorsal root ganglia. Immunocytochemistry indicated pericellular 6-sulphated chondroitin products around C6ST-1-expressing frontier cells. Motility analysis of frontier cells in cultures subjected to staged treatment with chondroitinase ABC indicated that freshly produced 6-sulphated chondroitin moieties facilitated Schwann cell motility, unlike restrictions resulting from proteoglycan interaction with matrix components. Sciatic nerve crush provided further evidence of in vivo upregulation of the C6ST-1 gene in mobile Schwann cells that guided axonal regrowth 1-14 days post crush; downregulation then accompanied declining mobility of Schwann cells as they engaged in the myelination of re-growing axons. These findings are the first to identify upregulated C6st1 gene expression correlating with the motility of Schwann cells that guide growing axons through both developmental and injured environments.
Vesicle-associated membrane protein 7 is expressed in intestinal ER
Authors: Siddiqi Shadab A. , Mahan James , Siddiqi Shahzad , Gorelick Fred S. , Mansbach Charles M.
Published: February 2006

Intestinal dietary triacylglycerol absorption is a multi-step process. Triacylglycerol exit from the endoplasmic reticulum (ER) is the rate-limiting step in the progress of the lipid from its apical absorption to its basolateral membrane export. Triacylglycerol is transported from the ER to the cis Golgi in a specialized vesicle, the pre-chylomicron transport vesicle (PCTV). The vesicle-associated membrane protein 7 (VAMP7) was found to be more concentrated on PCTVs compared with ER membranes. VAMP7 has been previously identified associated with post-Golgi sites in eukaryotes. To examine the potential role of VAMP7 in PCTV trafficking, antibodies were generated that identified a 25 kDa band consistent with VAMP7 but did not crossreact with VAMP1,2. VAMP7 was concentrated on intestinal ER by immunofluorescence microscopy. Immunoelectron microscopy showed that the ER proteins Sar1 and rBet1 were present on PCTVs and colocalized with VAMP7. Iodixanol gradient centrifugation showed VAMP7 to be isodense with ER and endosomes. Although VAMP7 localized to intestinal ER, it was not present in the ER of liver and kidney. Anti-VAMP7 antibodies reduced the transfer of triacylglycerol, but not newly synthesized proteins, from the ER to the Golgi by 85%. We conclude that VAMP7 is enriched in intestinal ER and that it plays a functional role in the delivery of triacylglycerol from the ER to the Golgi.
Sorting of Pmel17 to melanosomes through the plasma membrane by AP1 and AP2: evidence for the polarized nature of melanocytes
Authors: Valencia Julio C. , Watabe Hidenori , Chi An , Rouzaud Francois , Chen Kevin G. , Vieira Wilfred D. , Takahashi Kaoruko , Yamaguchi Yuji , Berens Werner , Nagashima Kunio , Shabanowitz Jeffrey , Hunt Donald F. , Appella Ettore , Hearing Vincent J.
Published: February 2006

Adaptor proteins (AP) play important roles in the sorting of proteins from the trans-Golgi network, but how they function in the sorting of various melanosome-specific proteins such as Pmel17, an essential structural component of melanosomes, in melanocytes is unknown. We characterized the processing and trafficking of Pmel17 via adaptor protein complexes within melanocytic cells. Proteomics analysis detected Pmel17, AP1 and AP2, but not AP3 or AP4 in early melanosomes. Real-time PCR, immunolabeling and tissue in-situ hybridization confirmed the coexpression of AP1 isoforms μ1A and μ1B (expressed only in polarized cells) in melanocytes and keratinocytes, but expression of μ1B is missing in some melanoma cell lines. Transfection with AP1 isoforms (μ1A or μ1B) showed two distinct distribution patterns that involved Pmel17, and only μ1B was able to restore the sorting of Pmel17 to the plasma membrane in cells lacking μ1B expression. Finally, we established that expression of μ1B is regulated physiologically in melanocytes by UV radiation or DKK1. These results show that Pmel17 is sorted to melanosomes by various intracellular routes, directly or indirectly through the plasma membrane, and the presence of basolateral elements in melanocytes suggests their polarized nature.
Identification of palladin isoforms and characterization of an isoform-specific interaction between Lasp-1 and palladin
Authors: Rachlin Andrew S. , Otey Carol A.
Published: February 2006

Palladin is a recently described phosphoprotein with an important role in cytoskeletal organization. The major palladin isoform (90-92 kDa) binds to three actin-associated proteins (ezrin, VASP and α-actinin), suggesting that palladin functions as a cytoskeletal scaffold. Here, we describe the organization of the palladin gene, which encodes multiple isoforms, including one (140 kDa) with a similar localization pattern to 90 kDa palladin. Overexpression of the 90 kDa or 140 kDa isoforms in COS-7 cells results in rearrangements of the actin cytoskeleton into super-robust bundles and star-like arrays, respectively. Sequence analysis of 140 kDa palladin revealed a conserved binding site for SH3 domains, suggesting that it binds directly to the SH3-domain protein Lasp-1. Binding of 140 kDa palladin, but not 90 kDa palladin, to Lasp-1 was confirmed by yeast two-hybrid and GST-pull-down assays. Isoform-specific siRNA experiments suggested that 140 kDa palladin plays a role in recruiting Lasp-1 to stress fibers. These results add Lasp-1, an actin-binding protein with a crucial role in cell motility, to the growing list of palladin's binding partners, and suggest that 140 kDa palladin has a specialized function in organizing the actin arrays that participate in cell migration and/or cellular contractility.
The desmosome: cell science lessons from human diseases
Authors: Kottke Margaret D. , Delva Emmanuella , Kowalczyk Andrew P.
Published: February 2006

Human skin diseases have revealed fundamental mechanisms by which cytoskeletal proteins contribute to tissue architecture and function. In particular, the analysis of epidermal blistering disorders and the role of keratin gene mutations in these diseases has led to significant increases in our understanding of intermediate filament biology. The major cell-surface attachment site for intermediate filament networks is the desmosome, an adhesive intercellular junction prominent in the epidermis and the heart. During the past decade, substantial progress has been made in understanding the molecular basis of a variety of epidermal autoimmune diseases, skin fragility syndromes, and disorders that involve a combination of heart and skin defects caused by perturbations in desmosome structure and function. These human diseases reveal key roles for desmosomes in maintaining tissue integrity, but also suggest functions for desmosomal components in signal transduction pathways and epidermal organization.
Multiwalled Carbon Nanotubes Incorporated with Dendrimer Encapsulated with Pt Nanoparticles: An Attractive Material for Sensitive Biosensors
Authors: Zhu Huiyu , Zhu Yihua , Yang Xiaoling , Li Chunzhong
Published: February 2006

Dendrimer encapsulated Pt nanoparticles (Pt-DENs) with a diameter of 2–3 nm were used in combination with multiwalled carbon nanotubes (MWCNTs) for fabricating electrochemical sensors with remarkably improved sensitivity toward glucose. TEM images illustrated the deposition of Pt-DENs on carbon nanotubes whereas cyclic voltammetry (CV) confirmed an electrical contact through MWCNTs between Pt-DENs and electrode. And the MWCNTs incorporated with Pt-DENs modifying Pt/GOx elelctrode-based biosensors response more sensitively to glucose than the electrode modified with MWCNTs alone reported by others. The response time and detection limit of this biosensor was determined to be 5 s, and 2.5 μM, respectively.
Electron Transport in Nanocrystalline TiO2 Films Sensitized with [NBu4]2[cis-Ru(Hdcbpy)2(NCS)2] (N719; [NBu4]+ = Tetrabutyl Ammonium Cation; H2dcbpy = 4,4′-Dicarboxy-2,2′-bipyridine) and [NBu4]2[Ru(Htcterpy)(NCS)3] (B-dye; H3tcterpy = 4,4′,4″-Tricarboxy-2,2′:6′,2″-terpyridine)
Authors: Miyamoto Koji , Yanagida Masatoshi , Sayama Kazuhiro , Sugihara Hideki , Abe Yoshimoto
Published: February 2006

We compared electron transport in nanocrystalline TiO2 films sensitized with [NBu4]2[cis-Ru(Hdcbpy)2(NCS)2] (N719; [NBu4]+ = tetrabutylammonium cation; H2dcbpy = 4,4′-dicarboxy-2,2′-bipyridine) and with [NBu4]2[Ru(Htcterpy)(NCS)3] (B-dye; H3tcterpy = 4,4′,4″-tricarboxy-2,2′:6′,2″-terpyridine). The electron diffusion coefficient (D) and the electron lifetime (τ) of the N719-sensitized TiO2 were comparable to those of B-dye-sensitized TiO2, although the open circuit photovoltage (Voc) of the solar cells based on N719-sensitized TiO2 was ca. 60 mV larger than that of the solar cells based on B-dye-sensitized TiO2. We concluded that the energy of the conduction band edge (Ecb) of TiO2 sensitized with N719 was ca. 50 mV more negative than that of TiO2 sensitized with B-dye.
Duplex-defined spatial anatomy of the saphenopopliteal junction
Authors: Pittathankal A A , Adamson M , Pursell R , Richards T , Galland R B , Magee T R
Published: February 2006

Background: Failure to disconnect the saphenopopliteal junction (SPJ) can occur in spite of duplex marking prior to operation indicating that more information on the short saphenous vein (SSV) termination in addition to the duplex mark is necessary to improve operative outcomes. The aim of this study was to establish the three-dimensional anatomy of the SSV termination to aid in improving operative localization of the SSV and SPJ.

Method: A prospective colour duplex study of 50 consecutive primary refluxing SSV was undertaken. The spatial orientation of the SSV termination in terms of location within the popliteal fossa and depth from the skin was determined.

Results: The SPJ was located in most cases (98%) in the upper lateral quadrant of the popliteal fossa. The median depth of the SPJ beneath the skin was 2.9 (1.6–5.2) cm. The SSV leaves the midline at a distance of approximately 5 (0–8) cm below the midpoint of the popliteal fossa and travels laterally towards the SPJ. It stays close to the skin and makes the descent into the fossa at 2–3 cm below the SPJ. The mean rate of descent between the SPJ and 2 cm below it was 7.0 (1–12) mm/cm, while that between 2 and 4 cm below the SPJ was only 2.3 (0–7) mm/cm.

Conclusion: The SPJ lies at a variable depth beneath the skin in the upper outer quadrant of the popliteal fossa. Locating the incision 2 cm below and medial to the SPJ, where the SSV lies relatively superficial and at a less variable depth, will allow easier identification of the SSV and thus easier localization of the SPJ.
Renal carcinoma extending into the inferior vena cava: vascular surgical aspects
Authors: Vik B F , Angelsen A , Egey A , Myhre H O
Published: February 2006

Objectives: To study surgical technique and results of treatment in patients receiving surgery for renal carcinoma or Wilm's tumour with extension into the vena cava.

Methods: During the period 1993–98, altogether 15 patients received surgery. The investigation was retrospective. All patients were followed until death or at follow-up examination in December 2004.

Results: A transverse laparotomy incision was used in 12 patients and a longitudinal incision in three. Two patients were primarily regarded as inoperable. Cardiopulmonary bypass was applied in one patient. At follow-up five patients were alive from 49 to 82 months postoperatively. The other 10 had died between two and 30 months after surgery, eight from carcinoma and two from other causes.

Conclusion: In conclusion, involvement of the vena cava does not in itself indicate a dismal prognosis in patients with renal carcinoma. The tumour can usually be removed from the vena cava using exposure depending upon the extent of the tumour proximally into the vena cava.
Ovarian vein ablation: coils or surgery?
Authors: Richardson G D , Driver B
Published: February 2006

Objective: The aim of this study is to compare the results, namely improvement in pelvic pain and overall satisfaction with treatment by surgery, or by coils and sclerotherapy, for pelvic congestion syndrome (PCS) when caused by ovarian vein incompetence based on ultrasound assessment. To do so requires a brief description of the diagnosis of PCS and ovarian vein incompetence, and a discussion of the indications for treatment.

Methods: The same questionnaire as used for a previous surgical series in 1989–95 was used for the present study. Independent assessment of responses to the questionnaire using visual analogue scales, together with review of the clinical notes, enabled statistical evaluation of two treatment groups. Treatment was by surgery from 1989 to 1998, and by coils and sclerotherapy from January 1999 to June 2002. Obtaining demographic and presenting symptom data has enabled us to compare the two groups, as well as the results of the two treatments.

Results: There was no significant difference between the demographics and presenting symptoms of surgical and coil treatment groups. Surgical and coil groups combined show a statistically significant reduction in perceived pelvic pain, and overall satisfaction with treatment. There is no difference in reduction of perceived pelvic pain or in overall satisfaction between surgical and coil treatment groups.

Conclusion: Treatment based on ultrasound diagnosis is justified. Surgical ovarian vein ablation should not be considered as having been superseded by coils. The latter has some advantages but also cost implications. Long-term success of coil treatment has not yet been proven. Recanalization of the ovarian vein, if it occurs, can be treated by further coils or surgery.
Phlegmasia caerulea dolens of the left leg due to deep vein compression by giant mesenteric cyst: contribution of the immediate drainage of the cyst to the rapid improvement of symptoms and complete recovery
Authors: Verbo A , Coco C , Manno A , Mattana C , Santoliquido A , Pedretti G , Petito L , Rizzo G , Picciocchi A
Published: February 2006

The first description of phlegmasia caerulea dolens of the leg due to deep vein compression by a giant mesenteric cyst is presented. In particular, the authors stress the role of the drainage of the cystic mass, performed as an emergency procedure, in the rapid improvement of symptoms, prevention of complications and achievement of definitive recovery. On the basis of such unusual case, a wide review of the literature on this subject is reported, aiming to stress the most crucial aspects regarding aetiology, clinical features, complications, therapy and prognosis of this disease.
Results of subfascial endoscopic perforator vein surgery without perioperative marking of perforator veins
Authors: Sonnenberg S , Bitsiadou M , Gidman A , Hopkins N Gowland
Published: February 2006

Objectives:This study assesses the anatomical outcome of subfascial endoscopic perforator vein surgery (SEPS) in cases where no perioperative marking of incompetent perforators was used.

Methods:Patients who had undergone SEPS and who had been investigated with a preoperative duplex ultrasound scan were identified from hospital records. These patients were recalled for a follow-up duplex ultrasound scan, which was compared with the preoperative investigation.

Results:In total, 15 patients (17 limbs) were studied. Four legs (23.5%) had no incompetent perforators at follow-up scan. The remaining 11 limbs (76.8%) all had at least one incompetent perforator. Six limbs (35.2%) showed incompetent perforators in the same position as the incompetent perforators identified at the preoperative duplex scan. A total of 10 incompetent perforators persisted at follow-up (35.7% of preoperatively identified incompetent perforating veins). Nine legs (52.9%) had developed at least one new incompetent perforator since undergoing SEPS.

Conclusion:In our study, a large proportion of incompetent perforators persisted at post-operative follow-up duplex scan. These probably represent perforators missed during surgery. Endoscopy of the subfascial space alone is not a reliable method for incompetent perforator identification. Alternative methods of localization should be employed perioperatively.
RNA secondary structure prediction from sequence alignments using a network ofk-nearest neighbor classifiers
Authors: BINDEWALD ECKART , SHAPIRO BRUCE A.
Published: February 2006

We present a machine learning method (a hierarchical network ofk-nearest neighbor classifiers) that uses an RNA sequence alignment in order to predict a consensus RNA secondary structure. The input to the network is the mutual information, the fraction of complementary nucleotides, and a novel consensus RNAfold secondary structure prediction of a pair of alignment columns and its nearest neighbors. Given this input, the network computes a prediction as to whether a particular pair of alignment columns corresponds to a base pair. By using a comprehensive test set of 49 RFAM alignments, the program KNetFold achieves an average Matthews correlation coefficient of 0.81. This is a significant improvement compared with the secondary structure prediction methods PFOLD and RNAalifold. By using the example of archaeal RNase P, we show that the program can also predict pseudoknot interactions.
Drug-Related Problems on Hospital Admission: Relationship to Medication Information Transfer
Authors: Ong Stephanie W , Fernandes Olavo A , Cesta Annemarie , Bajcar Jana M
Published: February 2006

Background:

Patients with end-stage renal disease (ESRD) are at risk for drug-related problems (DRPs), especially on hospital admission.

Objective:

To identify and characterize the DRPs experienced by patients with ESRD on admission and Investigate how these DRPs could be related to gaps in medication information transfer.

Methods:

Patients with ESRD admitted to the hospital were prospectively identified and clinically assessed by a pharmacist to identify and categorize DRPs on admission. Each DRP was evaluated to determine whether it could have been caused by a gap in medication information transfer. For DRPs caused in this manner, the interface in the information transfer process where the gap may have occurred was determined.

Results:

A total of 199 DRPs were identified in 47 patients with ESRD over a 12 week period. Ninety-two percent of patients had at least one DRP on admission, with an average of 4.2 ± 2.2 DRPs per patient. The most common DRP identified was indication for drug therapy—patient requires drug but is not receiving it (51.3%). Of the total DRPs, 130 (65%) were related to gaps in medication information transfer, with 21.5% occurring between the inpatient hospital and the ambulatory clinic pharmacists and 17.7% between the admitting physician and the patient.

Conclusions:

Results of this study demonstrate that, in patients with ESRD, DRPs on admission are frequently related to gaps in medication information transfer between healthcare professionals and also between healthcare providers and patients. Improved communication is required at medication information transfer interfaces to prevent these DRPs.
Myelin Formation during Development of the CNS Is Delayed in Matrix Metalloproteinase-9 and -12 Null Mice
Authors: Larsen Peter H. , DaSilva Angelika Goncalves , Conant Katherine , Yong V. Wee
Published: February 2006

The matrix metalloproteinases (MMPs) are implicated in several activities within the nervous system. Although many functions of abnormally elevated MMPs are undesirable, the discrete expression of particular MMP members can have beneficial roles. We previously found that MMP-9 expressed locally around a demyelinating lesion of the spinal cord of adult mice facilitated remyelination. In the current study, we have addressed whether and how MMPs might be required for myelin formation in normal ontogeny. Using a probe for multiple MMPs and the developing mouse optic nerve, we found two members, MMP-9 and -12, to be upregulated during the period of myelin formation. These MMPs partake in myelinogenesis because myelination in the corpus callosum of MMP-9 and/or MMP-12 null mice was deficient from postnatal days 7 to 14 compared with that of wild-type mice. The deficient myelination was correlated with fewer mature oligodendrocytes, but similar precursor cell numbers, in MMP null animals compared with wild type. Because an important growth factor for oligodendrocyte maturation is insulin-like growth factor-1 (IGF-1), we addressed whether this was involved in the deficient myelination in MMP null mice. Indeed, the addition of IGF-1 normalized the lack of maturation of oligodendrocytes that occurred in cultures from MMP-12 null mice. Furthermore, we determined that IGF binding protein 6 (IGFBP-6), which sequesters IGF-1, was a substrate for MMP processing. Finally, we found IGFBP-6 levels to remain high in MMP-deficient mice. These results reveal a novel function for MMP-9 and -12 in developmental myelination likely through regulating IGF-1 bioavailability.
Dissociating the Role of Ventral and Dorsal Premotor Cortex in Precision Grasping
Authors: Davare Marco , Andres Michael , Cosnard Guy , Thonnard Jean-Louis , Olivier Etienne
Published: February 2006

Small-object manipulation is essential in numerous human activities, although its neural bases are still essentially unknown. Recent functional imaging studies have shown that precision grasping activates a large bilateral frontoparietal network, including ventral (PMv) and dorsal (PMd) premotor areas. To dissociate the role of PMv and PMd in the control of hand and finger movements, we produced, by means of transcranial magnetic stimulation (TMS), transient virtual lesions of these two areas in both hemispheres, in healthy subjects performing a grip–lift task with their right, dominant hand. We found that a virtual lesion of PMv specifically impaired the grasping component of these movements: a lesion of either the left or right PMv altered the correct positioning of fingers on the object, a prerequisite for an efficient grasping, whereas lesioning the left, contralateral PMv disturbed the sequential recruitment of intrinsic hand muscles, all other movement parameters being unaffected by PMv lesions. Conversely, we found that a virtual lesion of the left PMd impaired the proper coupling between the grasping and lifting phases, as evidenced by the TMS-induced delay in the recruitment of proximal muscles responsible for the lifting phase; lesioning the right PMd failed to affect dominant hand movements. Finally, an analysis of the time course of these effects allowed us to demonstrate the sequential involvement of PMv and PMd in movement preparation. These results provide the first compelling evidence for a neuronal dissociation between the different phases of precision grasping in human premotor cortex.
Delayed Development of Adult-Generated Granule Cells in Dentate Gyrus
Authors: Overstreet-Wadiche Linda S. , Bensen AeSoon L. , Westbrook Gary L.
Published: February 2006

A substantial fraction of adult-generated granule cells in the dentate gyrus survive and integrate into the existing neuronal network. These newborn neurons must navigate the environment of the adult brain, a setting that is presumably less optimized for neuronal maturation compared with that in the developing brain. We used EGFP (enhanced green fluorescent protein) expression in newborn granule cells to compare the maturation of adult-generated granule cells to those generated in neonates. Labeled newborn granule cells had indistinguishable physiological properties in adults and neonates, indicating they were at the same functional stage. However, the maturation of adult-generated granule cells was slower than neonatal-generated granule cells. Depolarizing GABAergic network activity and transcription factor activation were reduced in adults relative to neonates, suggesting a role for neural activity in the maturation of newborn granule cells. Consistent with this idea, maturation was altered in mice lacking the GABA synthetic enzyme GAD65 (glutamic acid decarboxylase 65). Together, these results provide evidence that activity-dependent processes in the local environment influence the maturation of newborn granule cells.
Umami Responses in Mouse Taste Cells Indicate More than One Receptor
Authors: Maruyama Yutaka , Pereira Elizabeth , Margolskee Robert F. , Chaudhari Nirupa , Roper Stephen D.
Published: February 2006

A number of gustatory receptors have been proposed to underlie umami, the taste ofl-glutamate, and certain other amino acids and nucleotides. However, the response profiles of these cloned receptors have not been validated against responses recorded from taste receptor cells that are the native detectors of umami taste. We investigated umami taste responses in mouse circumvallate taste buds in an intact slice preparation, using confocal calcium imaging. Approximately 5% of taste cells selectively responded tol-glutamate when it was focally applied to the apical chemosensitive tips of receptor cells. The concentration–response range forl-glutamate fell approximately within the physiologically relevant range for taste behavior in mice, namely 10 mmand above. Inosine monophosphate enhanced taste cell responses tol-glutamate, a characteristic feature of umami taste. Using pharmacological agents, ion substitution, and immunostaining, we showed that intracellular pathways downstream of receptor activation involve phospholipase C β2. Each of the above features matches those predicted by studies of cloned and expressed receptors. However, the ligand specificity of each of the proposed umami receptors [taste metabotropic glutamate receptor 4, truncated metabotropic glutamate receptor 1, or taste receptor 1 (T1R1) and T1R3 dimers], taken alone, did not appear to explain the taste responses observed in mouse taste cells. Furthermore, umami responses were still observed in mutant mice lacking T1R3. A full explanation of umami taste transduction may involve novel combinations of the proposed receptors and/or as-yet-undiscovered taste receptors.
The Kinetics of Synaptic Vesicle Reacidification at Hippocampal Nerve Terminals
Authors: Atluri Pradeep P. , Ryan Timothy A.
Published: February 2006

After exocytosis, synaptic vesicles are recycled locally in the synaptic terminal and are refilled with neurotransmitter via vesicular transporters. The biophysical mechanisms of refilling are poorly understood, but it is clear that the generation of a proton gradient across the vesicle membrane is crucial. To better understand the determinants of vesicle refilling, we developed a novel method to measure unambiguously the kinetics of synaptic vesicle reacidification at individual synaptic terminals. Hippocampal neurons transfected with synapto-pHluorin (SpH), a synaptic vesicle-targeted lumenal GFP (green fluorescent protein), whose fluorescence is quenched when protonated (pKa∼ 7.1), were rapidly surface-quenched immediately after trains of repetitive electrical stimulation. The recently endocytosed alkaline pool of SpH is protected from such surface quenching, and its fluorescence decay reflects reacidification kinetics. These measurements indicate that, after compensatory endocytosis, synaptic vesicles reacidify with first-order kinetics (τ ∼ 4–5 s) and that their rate of reacidification is subject to slowing by increased external buffer.
Behavioral and Neurochemical Alterations in Mice Lacking the RNA-Binding Protein Translin
Authors: Stein Joel M. , Bergman Wayland , Fang Yanshan , Davison LaKesha , Brensinger Colleen , Robinson Michael B. , Hecht Norman B. , Abel Ted
Published: February 2006

Synapse-specific local protein synthesis is thought to be important for neurodevelopment and plasticity and involves neuronal RNA-binding proteins that regulate the transport and translation of dendritically localized transcripts. The best characterized of these RNA-binding proteins is the fragile X mental retardation protein (FMRP). Mutations affecting the expression or function of FMRP cause fragile X syndrome in humans, and targeted deletion of the gene encoding FMRP results in developmental and behavioral alterations in mice. Translin is an RNA-binding protein that regulates mRNA transport and translation in mouse male germ cells and is proposed to play a similar role in neurons. Like FMRP, translin is present in neuronal dendrites, binds dendritically localized RNA, and associates with microtubules and motor proteins. We reported previously the production of viable homozygoustranslinknock-out mice, which demonstrate altered expression of multiple mRNA transcripts in the brain and mild motor impairments. Here, we report thattranslinknock-out mice also exhibit sex-specific differences in tests of learning and memory, locomotor activity, anxiety-related behavior, and sensorimotor gating, as well as handling-induced seizures and alterations in monoamine neurotransmitter levels in several forebrain regions. Similar behavioral and neurochemical alterations have been observed in mice lacking FMRP, suggesting that both proteins may act within the same neuronal systems and signaling pathways. Our results in mice indicate that mutations in translin may contribute to fragile X-like syndromes, mental retardation, attention deficit hyperactivity disorder, epilepsy, and autism spectrum disorders in humans.
The Role ofFrizzled3andFrizzled6in Neural Tube Closure and in the Planar Polarity of Inner-Ear Sensory Hair Cells
Authors: Wang Yanshu , Guo Nini , Nathans Jeremy
Published: February 2006

In the mouse,Frizzled3(Fz3) andFrizzled6(Fz6) have been shown previously to control axonal growth and guidance in the CNS and hair patterning in the skin, respectively. Here, we report that Fz3 and Fz6 redundantly control neural tube closure and the planar orientation of hair bundles on a subset of auditory and vestibular sensory cells. In the inner ear, Fz3 and Fz6 proteins are localized to the lateral faces of sensory and supporting cells in all sensory epithelia in a pattern that correlates with the axis of planar polarity. Interestingly, the polarity of Fz6 localization with respect to the asymmetric position of the kinocilium is reversed between vestibular hair cells in the cristae of the semicircular canals and auditory hair cells in the organ of Corti.Vangl2, one of two mammalian homologs of theDrosophilaplanar cell polarity (PCP) genevan Gogh/Strabismus, is also required for correct hair bundle orientation on a subset of auditory sensory cells and on all vestibular sensory cells. In the inner ear of aVangl2mutant (Looptail;Lp), Fz3 and Fz6 proteins accumulate to normal levels but do not localize correctly at the cell surface. These results support the view that vertebrates and invertebrates use similar molecular mechanisms to control a wide variety of PCP-dependent developmental processes. This study also establishes the vestibular sensory epithelium as a tractable tissue for analyzing PCP, and it introduces the use of genetic mosaics for determining the absolute orientation of PCP proteins in mammals.
Characterization of AMPA Receptors Targeted by the Climbing Fiber Transmitter Mediating Presynaptic Inhibition of GABAergic Transmission at Cerebellar Interneuron-Purkinje Cell Synapses
Authors: Satake Shin’Ichiro , Song Si-Young , Cao Qiong , Satoh Hiromasa , Rusakov Dmitri A. , Yanagawa Yuchio , Ling Eng-Ang , Imoto Keiji , Konishi Shiro
Published: February 2006

The climbing fiber (CF) neurotransmitter not only excites the postsynaptic Purkinje cell (PC) but also suppresses GABA release from inhibitory interneurons converging onto the same PC depending on AMPA-type glutamate receptor (AMPAR) activation. Although the CF-/AMPAR-mediated inhibition of GABA release provides a likely mechanism boosting the CF input-derived excitation, how the CF transmitter reaches target AMPARs to elicit this action remains unknown. Here, we report that the CF transmitter diffused from its release sites directly targets GluR2/GluR3 AMPARs on interneuron terminals to inhibit GABA release. A weak GluR3-AMPAR agonist, bromohomoibotenic acid, produced excitatory currents in the postsynaptic PCs without presynaptic inhibitory effect on GABAergic transmission. Conversely, a specific inhibitor of the GluR2-lacking/Ca2+-permeable AMPARs, philanthotoxin-433, did not affect the CF-induced inhibition but suppressed AMPAR-mediated currents in Bergmann glia. A low-affinity GluR antagonist, γ-d-glutamylglycine, or retardation of neurotransmitter diffusion by dextran reduced the inhibitory action of CF-stimulation, whereas blockade of glutamate transporters enhanced the CF-induced inhibition. The results suggest that the CF transmitter released after repeated stimulation overwhelms local glutamate uptake and thereby diffuses from the release site to reach GluR2/GluR3 AMPARs on nearby interneuron terminals. Double immunostaining showed that GluR2/3 subunits and glutamate decarboxylase or synaptophysin are colocalized at the perisomatic GABAergic processes surrounding PCs. Finally, electron microscopy detected specific immunoreactivity for GluR2/3 at the presynaptic terminals of symmetric axosomatic synapses on the PC. These findings demonstrate that the CF transmitter directly inhibits GABA release from interneurons to the PC, relying on extrasynaptic diffusion and local heterogeneity in AMPAR subunit compositions.
Protein Phosphatase 2A RegulatesbimExpression via the Akt/FKHRL1 Signaling Pathway in Amyloid-β Peptide-Induced Cerebrovascular Endothelial Cell Death
Authors: Yin Ke-Jie , Hsu Chung Y. , Hu Xiao-Yan , Chen Hong , Chen Sha-Wei , Xu Jan , Lee Jin-Moo
Published: February 2006

Amyloid-β peptide (Aβ)-induced death in cerebral endothelial cells (CECs) is preceded by mitochondrial dysfunction and signaling events characteristic of apoptosis. Mitochondria-dependent apoptosis engages Bcl-2 family proteins, especially the BH3-only homologues, which play a key role in initiating the apoptotic cascade. Here, we report that the expression ofbim, but not other BH3-only members, was selectively increased in cerebral microvessels isolated from 18-month-old APPsw (Tg2576) mice, a model of cerebral amyloid angiopathy (CAA), suggesting a pivotal role for Bim in Aβ-induced cerebrovascular degenerationin vivo. A similar expression profile was observed in Aβ-treated CECs. Furthermore, Aβ induction ofbimexpression involved a pro-apoptotic transcription factor, FKHRL1. FKHRL1 bound to a consensus sequence in thebimpromoter region and was activated by Aβ beforebimexpression. FKHRL1 activity was negatively regulated by phosphorylation catalyzed by Akt, an anti-apoptotic kinase. Akt upregulation by adenoviral gene transfer inhibited Aβ-induced FKHRL1 activation andbiminduction. In addition, Aβ increased the activity of protein phosphatase 2A (PP2A), a ceramide-activated protein phosphatase. Suppression of PP2A activity by RNA interference or a specific inhibitor, okadaic acid, effectively suppressed Aβ-induced Akt inactivation and FKHRL1 activation, leading to an attenuation ofbimexpression and cell death in CECs. Coimmunoprecipitation experiments revealed that Aβ enhanced the binding of the PP2A regulatory subunit PP2ACαβ to Akt. These results implicate PP2A as an early regulator of Aβ-inducedbimexpression and CEC apoptosis via the Akt/FKHRL1 signaling pathway. We raise the possibility that this pathway may play a role in cerebrovascular degeneration in CAA.