bluuebunny/crossref_metadata_2025 huggingface dataset:
Autoantibodies against the fibrinolytic receptor, annexin 2, in antiphospholipid syndrome
Authors: Cesarman-Maus Gabriela , Ríos-Luna Nina P. , Deora Arunkumar B. , Huang Bihui , Villa Rosario , Cravioto Maria del Carmen , Alarcón-Segovia Donato , Sánchez-Guerrero Jorge , Hajjar Katherine A.
Published: February 2006

The association of thrombosis and gestational morbidity with antiphospholipid antibodies is termed antiphospholipid syndrome (APS). Annexin 2 (A2) is a profibrinolytic endothelial cell surface receptor that binds plasminogen, its tissue activator (tPA), and β2-glycoprotein I (β2GPI), the main antigen for antiphospholipid antibodies. Here, we evaluate A2 as a target antigen in APS. Serum samples from 434 individuals (206 patients with systemic lupus erythematosus without thrombosis, 62 with APS, 21 with nonautoimmune thrombosis, and 145 healthy individuals) were analyzed by enzyme-linked immunosorbent assay (ELISA) and immunoblot for antiphospholipid and A2 antibodies. Anti-A2 antibodies (titer > 3 SDs) were significantly more prevalent in patients with APS (22.6%; venous, 17.5%; arterial, 34.3%; and mixed thrombosis, 40.4%) than in healthy individuals (2.1%, P < .001), patients with nonautoimmune thrombosis (0%, P = .017), or patients with lupus without thrombosis (6.3%, P < .001). Anti–A2 IgG enhanced the expression of tissue factor on endothelial cells (6.4-fold ± 0.13-fold SE), blocked A2-supported plasmin generation in a tPAdependent generation assay (19%-71%) independently of β2GPI, and inhibited cell surface plasmin generation on human umbilical vein endothelial cells (HUVECs) by 34% to 83%. We propose that anti-A2 antibodies contribute to the prothrombotic diathesis in antiphospholipid syndrome.
Molecular pathogenesis of Fanconi anemia: recent progress
Authors: Taniguchi Toshiyasu , D'Andrea Alan D.
Published: February 2006

A rare genetic disease, Fanconi anemia (FA), now attracts broader attention from cancer biologists and basic researchers in the DNA repair and ubiquitin biology fields as well as from hematologists. FA is a chromosome instability syndrome characterized by childhood-onset aplastic anemia, cancer or leukemia susceptibility, and cellular hypersensitivity to DNAcrosslinking agents. Identification of 11 genes for FA has led to progress in the molecular understanding of this disease. FA proteins, including a ubiquitin ligase (FANCL), a monoubiquitinated protein (FANCD2), a helicase (FANCJ/BACH1/BRIP1), and a breast/ovarian cancer susceptibility protein (FANCD1/BRCA2), appear to cooperate in a pathway leading to the recognition and repair of damaged DNA. Molecular interactions among FA proteins and responsible proteins for other chromosome instability syndromes (BLM, NBS1, MRE11, ATM, and ATR) have also been found. Furthermore, inactivation of FA genes has been observed in a wide variety of human cancers in the general population. These findings have broad implications for predicting the sensitivity and resistance of tumors to widely used anticancer DNA crosslinking agents (cisplatin, mitomycin C, and melphalan). Here, we summarize recent progress in the molecular biology of FA and discuss roles of the FA proteins in DNA repair and cancer biology.
The First Frontgau: East Prussia, July 1944
Authors: Noble Alastair
Published: February 2006

The Red Army’s advance towards the frontiers of East Prussia in the summer of 1944 raised the spectre of the war coming home to Germany. Panic spread throughout the Reich as Germans contemplated the province’s likely fate. However, through a combination of coercion and rhetoric, which appealed to the patriotic instincts of East Prussians, the party authorities were able to stabilize the situation and prolong Nazi rule for a few more months. The Nazi response to the crisis in East Prussia set a pattern which would be repeated on other battle fronts in subsequent months.
Prognostic Factors in Primary Cutaneous B-Cell Lymphoma: The Italian Study Group for Cutaneous Lymphomas
Authors: Zinzani Pier Luigi , Quaglino Pietro , Pimpinelli Nicola , Berti Emilio , Baliva Gianandrea , Rupoli Serena , Martelli Maurizio , Alaibac Mauro , Borroni Giovanni , Chimenti Sergio , Alterini Renato , Alinari Lapo , Fierro Maria Teresa , Cappello Nazario , Pileri Alessandro , Soligo Davide , Paulli Marco , Pileri Stefano , Santucci Marco , Bernengo Maria Grazia
Published: February 2006

Purpose

Primary cutaneous B-cell lymphomas (PCBCLs) are a distinct group of primary cutaneous lymphomas with few and conflicting data on their prognostic factors.

Patients and Methods

The study group included 467 patients with PCBCL who were referred, treated, and observed in 11 Italian centers (the Italian Study Group for Cutaneous Lymphomas) during a 24-year period (1980 to 2003). All of the patients were reclassified according to the WHO–European Organisation for Research and Treatment of Cancer (EORTC) classification.

Results

Follicle center lymphoma (FCL) accounted for 56.7% of occurrences, followed by marginal-zone B-cell lymphoma (MZL; 31.4%); diffuse large B-cell lymphoma (DLBCL), leg type, was reported in 10.9% of patients. Radiotherapy was the first-line treatment in 52.5% of patients and chemotherapy was the first-line treatment in 24.8% of patients. The complete response rate was 91.9% and the relapse rate was 46.7%. The 5- and 10-year overall survival (OS) rates were 94% and 85%, respectively. Compared with FCL/MZL, DLBCL, leg type, was characterized by statistically significant lower complete response rates, higher incidence of multiple cutaneous relapses and extracutaneous spreading, shorter time to progression, and shorter OS rates. The only variable with independent prognostic significance on the OS was the clinicopathologic diagnosis according to the WHO-EORTC classification (DLBCL, leg-type, showed a significantly worse prognosis v FCL and MZL; P < .001), whereas the only variable with independent prognostic significance on disease-free survival was the presence of a single cutaneous lesion (P = .001).

Conclusion

Our study identifies a possible PCBCL subclassification and the extent of cutaneous involvement as the two most relevant prognostic factors in PCBCL. These data can be considered reasonably as the clinical background for an appropriate management strategy.
Effect of Primary Hyperparathyroidism on Volumetric Bone Mineral Density and Bone Geometry Assessed by Peripheral Quantitative Computed Tomography in Postmenopausal Women
Authors: Charopoulos Ioannis , Tournis Symeon , Trovas George , Raptou Panagiota , Kaldrymides Philippos , Skarandavos Gregory , Katsalira Katerina , Lyritis George P.
Published: February 2006

Context: Primary hyperparathyroidism (PH) is characterized by inappropriate PTH elevation with or without hypercalcemia. Bone disease involves catabolic action at cortical sites, whereas cancellous sites and geometry might be relatively preserved.

Objective: Our objective was to examine the effect of PH on quantitative and qualitative bone characteristics using peripheral quantitative computed tomography at the tibia in postmenopausal women with PH and healthy controls.

Design and Setting: We conducted a cross-sectional study at a tertiary referral center.

Patients: Fifty-two postmenopausal women with PH and 56 healthy controls, comparable for age and anthropometric measures, participated.

Intervention: There was no intervention.

Main Outcome Measure: We assessed volumetric bone mineral density (vBMD), bone mineral content (BMC), cortical thickness, cortical and trabecular area, peri- and endosteal circumference, and polar stress strength index assessed by peripheral quantitative computed tomography of the left tibia at 4% (cancellous), 14% (transition zone), and 38% (cortical) from the distal end.

Results: At 4%, there was a significant decrease of trabecular BMC and vBMD (P < 0.001), effect particularly evident in hypercalcemic patients, whereas trabecular area was comparable. At 38%, cortical BMC (P < 0.01), vBMD (P < 0.01), area (P < 0.05), and thickness (P < 0.001) were reduced in the PH group, particularly in hypercalcemic patients. Endosteal circumference increased (P < 0.001), whereas periosteal circumference was comparable, indicating cancellization of cortical bone. At 14%, polar stress strength index was significantly decreased (P < 0.01) in hypercalcemic patients, indicating impairment of bone mechanical properties.

Conclusions: Normocalcemic PH is characterized by catabolic actions at both cortical and cancellous sites (38 and 4%, respectively), an effect accentuated in hypercalcemic patients. Cortical geometric properties are adversely affected even in normocalcemic patients, whereas trabecular properties are generally preserved.
Acute Ovarian Failure in the Childhood Cancer Survivor Study
Authors: Chemaitilly Wassim , Mertens Ann C. , Mitby Pauline , Whitton John , Stovall Marilyn , Yasui Yutaka , Robison Leslie L. , Sklar Charles A.
Published: February 2006

Context: Defined as the loss of ovarian function within 5 yr of diagnosis, acute ovarian failure (AOF) is known to develop in a subset of survivors of pediatric and adolescent cancers. Its precise incidence is unknown, and data concerning its risk factors are limited.

Objective: Our objective was to determine the incidence of and patient/treatment factors associated with AOF in a large cohort of pediatric cancer survivors.

Design and Setting: We conducted a retrospective cohort, multicenter study.

Patients: Female participants from the Childhood Cancer Survivor Study who were greater than 18 yr of age were considered for inclusion. We excluded survivors who received cranial irradiation at doses of more than 3000 cGy, those with hypothalamic/pituitary tumors, and survivors who underwent bilateral oophorectomy. Survivors who reported never menstruating or who had ceased having menses within 5 yr after their cancer diagnosis were considered to have AOF.

Main Outcome: We assessed incidence and risk factors for AOF.

Results: Of a total of 3390 eligible survivors, 215 cases (6.3%) developed AOF. Survivors with AOF were older at diagnosis and more likely to have been diagnosed with Hodgkin’s lymphoma or to have received abdominal or pelvic radiotherapy than survivors without AOF. Among survivors with AOF, 116 (54%) had received at least 1000-cGy ovarian irradiation. In a multivariable logistic regression model, increasing doses of ovarian irradiation, exposure to procarbazine, and exposure to cyclophosphamide at ages 13–20 yr were independent risk factors for AOF.

Conclusions: AOF develops in a small subset of survivors, especially those treated with at least 1000-cGy ovarian radiation. These results will facilitate patient counseling and selection of candidates for newer fertility preservation techniques.
Adrenomedullin and CGRP interact with endogenous calcitonin-receptor-like receptor in endothelial cells and induce its desensitisation by different mechanisms
Authors: Nikitenko Leonid L. , Blucher Nicola , Fox Stephen B. , Bicknell Roy , Smith David M. , Rees Margaret C. P.
Published: February 2006

Adrenomedullin (AM) and calcitonin gene-related peptide (CGRP) are related peptides with distinct pharmacological profiles. Calcitonin-receptor-like receptor (CRLR, now known as CL) can function as either an AM receptor or a CGRP receptor, when cotransfected with receptor-activity-modifying proteins (RAMPs) that define ligand-binding specificity. The aim of the present study was to determine the role of endogenously expressed CL (EndoCL) in generating endogenous AM and CGRP receptors. We raised anti-human CL antibody and identified microvascular endothelial cells (MVECs) as a major CL-expressing cell type in tissues by immunohistochemistry. Cultured MVECs continue to express EndoCL as well as fully active endogenous AM- and CGRP-sensitive receptors in vitro, as demonstrated by the ability of both peptides to induce migration and Akt phosphorylation. We therefore tested the hypothesis that endothelial EndoCL can interact with both AM and CGRP by examining receptor internalisation and desensitisation (loss of the ability to induce Akt phosphorylation). We found that agonist-mediated internalisation of EndoCL occurs in response to AM but not CGRP in MVECs. However, AM-induced EndoCL internalisation was blocked by antagonists of both AM and CGRP receptors: AM22-52 and CGRP8-37, respectively. Furthermore, AM-induced EndoCL internalisation resulted in desensitisation not only of AM but also of CGRP receptors. Finally, CGRP also induced desensitisation of both endogenous AM and CGRP receptors, but did not mediate EndoCL internalisation despite interaction with this receptor. Thus, EndoCL interacts with both AM and CGRP, and simultaneously acts as a receptor for both peptides (i.e acting as an endogenous AM/CGRP receptor) in endothelial cells. Interaction with either ligand is sufficient to induce EndoCL desensitisation to both AM and CGRP, but differential mechanisms are involved since only AM induces EndoCL internalisation. These novel findings regarding regulation of EndoCL function in endothelial cells are likely to be of importance in conditions where AM or CGRP levels are elevated, such as cardiovascular disease, diabetes and inflammation.
The number of PML nuclear bodies increases in early S phase by a fission mechanism
Authors: Dellaire Graham , Ching Reagan W. , Dehghani Hesam , Ren Ying , Bazett-Jones David P.
Published: February 2006

Promyelocytic leukemia (PML) nuclear bodies have been implicated in a variety of cellular processes including apoptosis, tumour suppression, anti-viral response, DNA repair and transcriptional regulation. PML nuclear bodies are both positionally and structurally stable over extended periods of interphase. As demonstrated in this study, the structural stability is lost as cells enter S phase, evidenced both by distortions in shape and by fission and fusion events. At the end of this period of structural instability, the number of PML nuclear bodies has increased by a factor of twofold. Association of the fission products with chromatin implies that the PML nuclear bodies respond to changes in chromatin organisation or topology, and thus could play a role in monitoring genome integrity during DNA synthesis or in the continued maintenance of functional chromosomal domains prior to mitosis.
Disruption of G1-phase phospholipid turnover by inhibition of Ca2+-independent phospholipase A2 induces a p53-dependent cell-cycle arrest in G1 phase
Authors: Zhang Xu Hannah , Zhao Chunying , Seleznev Konstantin , Song Keying , Manfredi James J. , Ma Zhongmin Alex
Published: February 2006

The G1 phase of the cell cycle is characterized by a high rate of membrane phospholipid turnover. Cells regulate this turnover by coordinating the opposing actions of CTP:phosphocholine cytidylyltransferase and the group VI Ca2+-independent phospholipase A2 (iPLA2). However, little is known about how such turnover affects cell-cycle progression. Here, we show that G1-phase phospholipid turnover is essential for cell proliferation. Specific inhibition of iPLA2 arrested cells in the G1 phase of the cell cycle. This G1-phase arrest was associated with marked upregulation of the tumour suppressor p53 and the expression of cyclin-dependent kinase inhibitor p21cip1. Inactivation of iPLA2 failed to arrest p53-deficient HCT cells in the G1 phase and caused massive apoptosis of p21-deficient HCT cells, suggesting that this G1-phase arrest requires activation of p53 and expression of p21cip1. Furthermore, downregulation of p53 by siRNA in p21-deficient HCT cells reduced the cell death, indicating that inhibition of iPLA2 induced p53-dependent apoptosis in the absence of p21cip1. Thus, our study reveals hitherto unrecognized cooperation between p53 and iPLA2 to monitor membrane-phospholipid turnover in G1 phase. Disrupting the G1-phase phospholipid turnover by inhibition of iPLA2 activates the p53-p21cip1 checkpoint mechanism, thereby blocking the entry of G1-phase cells into S phase.
Sp1 and Sp3 foci distribution throughout mitosis
Authors: He Shihua , Davie James R.
Published: February 2006

The mammalian transcription factors Sp1 and Sp3 compete for the same DNA binding sites but play different roles in the regulation of expression of numerous genes. It is known that, in the interphase nucleus, Sp1 and Sp3 are organized into distinct foci. In this study, we show that throughout the mitotic process, while being displaced from the condensed chromosomes and dispersed throughout the cell, Sp1 and Sp3 maintain their separate punctate distributions. In metaphase, both Sp1 and Sp3 foci show a high degree of colocalization with microfilaments, suggesting that F-actin is involved in the organization of Sp1 and Sp3 foci during mitosis. Constant Sp1 and Sp3 levels were observed during mitosis, signifying a recovery of the pre-existing Sp1 and Sp3 population in newly formed nuclei. In late telophase, Sp1 and Sp3 are equally segregated between daughter cells, and their subnuclear organization as distinct foci is restored in a sequential fashion with Sp3 regrouping into the newly formed nuclei prior to Sp1. Both Sp1 and Sp3 return to the nuclei ahead of RNA polymerase II. Our results support a model in which entry of Sp1, Sp3 and RNA polymerase II into the newly formed nuclei is an ordered process.
Biogenesis of caveolae: a structural model for caveolin-induced domain formation
Authors: Parton Robert G. , Hanzal-Bayer Michael , Hancock John F.
Published: February 2006

Caveolae are striking morphological features of the plasma membrane of mammalian cells. Caveolins, the major proteins of caveolae, play a crucial role in the formation of these invaginations of the plasma membrane; however, the precise mechanisms involved are only just starting to be unravelled. Recent studies suggest that caveolae are stable structures first generated in the Golgi complex. Their formation and exit from the Golgi complex is associated with caveolin oligomerisation, acquisition of detergent insolubility, and association with cholesterol. Modelling of caveolin-membrane interactions together with in vitro studies of caveolin peptides are providing new insights into how caveolin-lipid interactions could generate the unique architecture of the caveolar domain.
A Lewis Base-catalyzed Hetero Diels–Alder Reaction between Aldehydes and the Danishefsky’s Diene
Authors: Mukaiyama Teruaki , Kitazawa Takayuki , Fujisawa Hidehiko
Published: February 2006

A lithium methoxide-catalyzed hetero Diels–Alder reaction of aromatic and aliphatic aldehydes with 1-methoxy-3-trimethylsilyloxy-1,3-butadiene (Danishefsky’s diene) is described. It proceeds through the Mukaiyama-Aldol reaction pathway and affords the corresponding 2,3-dihydropyran-4-one skeletons in good to excellent yields.
Preparation of Branched Gold Nanocrystals by an Electrochemical Method
Authors: Zhou Min , Chen Shenhao , Zhao Shiyong
Published: February 2006

A simple electrochemical method is used for synthesis of branched gold nanocrystals in aqueous solution. The branched nanocrystals can be obtained by electrochemical reduction of AuCl4− in the presence of PVP and a small amount of NaOH. The concentration of NaOH in the solution was found to have a profound influence of branch nanostructure formation.
A randomized controlled trial of preoperative infiltration with bupivacaine and adrenaline in varicose vein surgery
Authors: Franks S C , Harmston C , Hickey N C
Published: February 2006

Objectives: Clinical experience suggested that preoperative infiltration of proposed avulsion sites with bupivacaine and adrenaline reduced bleeding associated with varicose vein surgery. This hypothesis was subjected to a randomized controlled trial.

Methods: Twenty patients undergoing bilateral long saphenous vein (LSV) stripping and avulsions were randomized to have one leg infiltrated with 0.25% bupivacaine and the other with 0.25% bupivacaine with adrenaline (1 in 200,000). Following induction of general anaesthesia, 10 mL of local anaesthetic was infiltrated into the groin and 20–30 mL over the marked varicosities down the leg. Bilateral PIN stripping and hook avulsions were performed. Operative blood loss was recorded for each leg and the area of strip-site and avulsion-site bruising was determined five days postoperatively.

Results: There was no difference in the numbers of avulsions between the legs receiving adrenaline (median 12, range 4–23) and controls (median 13, range 4–25), but adrenaline significantly reduced the operative blood loss (median 41 mL, range 17–122) compared with control legs (median 79 mL, range 28–210; P < 0.001, Wilcoxon). There was also a significant reduction in postoperative avulsion-site bruising (median 45 cm2, range 13–101 compared with median 70 cm2, range 34–221; P < 0.001). There was a smaller reduction in strip-site bruising (median 50 cm2, range 14–128 compared with median 62 cm2, range 21–141; P < 0.001).

Conclusions: Preoperative infiltration with bupivacaine and adrenaline is safe and reduces bleeding and bruising associated with varicose vein surgery.
Bilateral varicose vein surgery in the UK
Authors: Overbeck K , Zubrzycka D , Stansby G
Published: February 2006

Objective: To assess the views of surgeons in the UK concerning the surgical management of patients with bilateral varicose veins (BVV) requiring surgery.

Methods: A postal questionnaire was sent to members of the Vascular Society of Great Britain and Ireland. Questions concerned the use of BVV surgery in general, its use on day-case patients and which factors influenced decision-making in this area.

Results: In all, 63% of surgeons never or only occasionally performed BVV surgery as a day case, whereas only 27% never or only occasionally performed BVV surgery on inpatients. The majority (70.2%) were not influenced by patient age or occupation (81.9%). The patient's general health was, however, a factor in decision-making for the majority (60.1%), as was the extent of the varicosities (52.8%). Other important factors were the availability of a second surgeon and a perception that there was likely to be increased morbidity with BVV surgery.

Conclusions: There appears to be considerable variation between individual surgeons in the UK with regard to BVV surgery. This is manifested mainly as a reluctance to perform BVV as a day case by a significant number of surgeons. As there is no randomized trial(s) in this area, no firm guidance can be given. The issue is worthy of further study and may have significant health economic implications.
Combined Factor V Leiden (R506Q) and prothrombin G20210A genotyping in young patients presenting with deep venous thrombosis
Authors: Mansilha A , Araújo F , Severo M , Sampaio S M , Toledo T , Albuquerque R
Published: February 2006

Objective: To evaluate the association between the Factor V Leiden (FV R506Q) and prothrombin gene (FII G20210A) mutations and deep venous thrombosis (DVT) in young people.

Methods: Blood samples were drawn from 199 subjects: 100 healthy controls and 99 unselected patients, with an objectively documented first episode of DVT under 40 years old. DNA analysis was performed using the polymerase chain reaction.

Results: The mean age in the patient cohort was 27 years (range 16–40) and 68 (68.7%) were women. Patient prevalences were 20.6% and 10.1% for FV R506Q and FII G20210A, respectively. In the control group, carrier frequencies were 2% and 5%, respectively. We found an increased overall relative risk of DVT with statistical significance for FV R506Q carriers (OR: 12.8; 95% CI: 2.9–56.7; P < 0.001), but not for FII G20210A mutation (OR: 2.1; 95% CI: 0.7–6.5; P = 0.19).

Conclusions: Our results suggest a possible increase in DVT risk for the young G20210A allele carriers, which can be more expressed in the presence of a circumstantial risk factor. There is extremely strong evidence that the Factor V Leiden mutation is an important risk factor in the development of a first episode of DVT in young people.
Heat dissipation during endovenous laser treatment of varicose veins – is there a risk of nerve injury?
Authors: Beale R J , Mavor A I D , Gough M J
Published: February 2006

Objective: Endovenous laser therapy (EVLT) is a new minimally invasive treatment for varicose veins employing laser ablation of the long saphenous vein (LSV) under tumescent local anaesthesia. Concerns about thermal injury to perivenous nerves (tibial, peroneal, sural) have prevented its use for saphenopopliteal/short saphenous incompetence. This study assesses heat dissipation around the LSV during EVLT.

Methods: In 12 consenting patients undergoing EVLT (Local research ethics committee approved), thermocouples (inserted percutaneously) were positioned (ultrasound control) 3, 5 and 10 mm from the LSV following perivenous injection of tumescent anaesthesia (0.1% lignocaine at room temperature). The 810-nm diode laser delivery system delivered 1-s pulses (12 W power) with 1-s intervals during laser fibre withdrawal at 3 mm/s.

Results: The maximum recorded temperatures at 3, 5 and 10 mm were 43.3°C, 42.0°C and 36.0°C, with median temperatures (±interquartile range) of 34.5°C (30.8–40.0), 33.7°C (30.5–39.9) and 31.1°C (30.3–33.3), respectively.

Conclusions: Although intravascular laser-tip temperatures of up to 1334°C have been recorded in experimental models of EVLT, these results indicate that heat dissipation into adjacent tissues is minimal. Thus, careful ultrasound-guided injection of adequate volumes of perivenous local anaesthetic and the associated heat-sink effect should allow safe use of EVLT in treating saphenopopliteal/short saphenous incompetence.
Mutational analysis of human eIF4AIII identifies regions necessary for exon junction complex formation and nonsense-mediated mRNA decay
Authors: SHIBUYA TOSHIHARU , TANGE THOMAS Ø. , STROUPE M. ELIZABETH , MOORE MELISSA J.
Published: February 2006

The exon junction complex (EJC) is deposited on mRNAs by the process of pre-mRNA splicing and is a key effecter of downstream mRNA metabolism. We previously demonstrated that human eIF4AIII, which is essential for nonsense-mediated mRNA decay (NMD), constitutes at least part of the RNA-binding platform anchoring other EJC components to the spliced mRNA. To determine the regions of eIF4AIII that are functionally important for EJC formation, for binding to other EJC components, and for NMD, we now report results of an extensive mutational analysis of human eIF4AIII. Using GFP-, GST- or Flag-fusions of eIF4AIII versions containing site-specific mutations or truncations, we analyzed subcellular localizations, protein–protein interactions, and EJC formation in vivo and in vitro. We also tested whether mutant proteins could rescue NMD inhibition resulting from RNAi depletion of endogenous eIF4AIII. Motifs Ia and VI, which are conserved among the eIF4A family of RNA helicases (DEAD-box proteins), are crucial for EJC formation and NMD, as is one eIF4AIII-specific region. An additional eIF4AIII-specific motif forms part of the binding site for MLN51, another EJC core component. Mutations in the canonical Walker A and B motifs that eliminate RNA-dependent ATP hydrolysis by eIF4AIII in vitro are of no detectable consequence for EJC formation and NMD activation. Implications of these findings are discussed in the context of other recent results and a new structural model for human eIF4AIII based on the known crystal structure of Saccharomyces cerevisiae eIF4AI.
Frequency of RNA–RNA interaction in a model of the RNA World
Authors: STRIGGLES JOHN C. , MARTIN MATTHEW B. , SCHMIDT FRANCIS J.
Published: February 2006

The RNA World model for prebiotic evolution posits the selection of catalytic/template RNAs from random populations. The mechanisms by which these random populations could be generated de novo are unclear. Non-enzymatic and RNA-catalyzed nucleic acid polymerizations are poorly processive, which means that the resulting short-chain RNA population could contain only limited diversity. Nonreciprocal recombination of smaller RNAs provides an alternative mechanism for the assembly of larger species with concomitantly greater structural diversity; however, the frequency of any specific recombination event in a random RNA population is limited by the low probability of an encounter between any two given molecules. This low probability could be overcome if the molecules capable of productive recombination were redundant, with many nonhomologous but functionally equivalent RNAs being present in a random population. Here we report fluctuation experiments to estimate the redundancy of the set of RNAs in a population of random sequences that are capable of non-Watson-Crick interaction with another RNA. Parallel SELEX experiments showed that at least one in 106random 20-mers binds to the P5.1 stem–loop ofBacillus subtilisRNase P RNA with affinities equal to that of its naturally occurring partner. This high frequency predicts that a single RNA in an RNA World would encounter multiple interacting RNAs within its lifetime, supporting recombination as a plausible mechanism for prebiotic RNA evolution. The large number of equivalent species implies that the selection of any single interacting species in the RNA World would be a contingent event, i.e., one resulting from historical accident.
Statistical and Bayesian approaches to RNA secondary structure prediction
Authors: DING YE
Published: February 2006

Prediction of RNA secondary structure is a fundamental problem in computational structural biology. For several decades, free energy minimization has been the most popular method for prediction from a single sequence. In recent years, the McCaskill algorithm for computation of partition function and base-pair probabilities has become increasingly appreciated. This paradigm-shifting work has inspired the developments of extended partition function algorithms, statistical sampling and clustering, and application of Bayesian statistical inference. The performance of thermodynamics-based methods is limited by thermodynamic rules and parameters. However, further improvements may come from statistical estimates derived from structural databases for thermodynamics parameters with weak or little experimental data. The Bayesian inference approach appears to be promising in this context.
Role of the Bispectral Index in Sedation Monitoring in the ICU
Authors: LeBlanc Jaclyn M , Dasta Joseph F , Kane-Gill Sandra L
Published: February 2006

Objective:

To review and critique evidence for the use of the bispectral index (BIS) in intensive care unit (ICU) patients.

Data Sources:

A computer search of English-language articles in MEDLINE (1966–July 2005), International Pharmaceutical Abstracts (1971–July 2005), and Scientific Citation Index Expanded (1980–July 2005) was conducted. A manual search of abstracts was also performed using the key search terms BIS, sedation, and critical care.

Study Selection and Data Extraction:

Case series, letters, editorials, and clinical studies that evaluated BIS in ICU patients were considered for inclusion.

Data Synthesis:

Nineteen studies comparing the BIS with sedation scales were evaluated, revealing that the BIS trends lower with increasing sedation. The BIS appeared to correlate better when sedation scores were grouped rather than individual values. However, correlations between BIS and subjective scales were low in most studies (r2 0.21–0.93). Additionally, there was poor correlation between drug dosage and the BIS. Randomized, controlled trials demonstrating improved outcomes with BIS monitoring have not been reported.

Conclusions:

Interpreting literature on the usefulness of the BIS in the ICU is difficult for reasons that include heterogeneous populations, different methods of collecting BIS data, and use of different versions of BIS software and hardware. Outcomes data are lacking. The 2002 Society of Critical Care Medicine Sedation Guidelines recommendation that more data are needed before the BIS should be used routinely in the ICU remains unchanged. We recommend that further studies be conducted to determine the optimal method of obtaining BIS data and evaluate the impact of the BIS on relevant patient outcomes.
Are Shorter Courses of Filgrastim Prophylaxis Associated with Increased Risk of Hospitalization?
Authors: Weycker Derek , Hackett James , Edelsberg John S , Oster Gerry , Glass Andrew G
Published: February 2006

Background:

In clinical trials in patients receiving myelosuppressive chemotherapy, 10–11 days of prophylaxis with filgrastim has been found to reduce the incidence of febrile neutropenia. In clinical practice, however, many patients receive shorter courses of therapy, even though the effectiveness of this regimen is unknown.

Objective:

To examine the relationship between duration of filgrastim prophylaxis and risk of hospitalization in patients receiving chemotherapy for non–Hodgkin's lymphoma (NHL), breast cancer, or lung cancer.

Methods:

Using a large, automated, US healthcare claims database, we identified all adults who received chemotherapy for NHL, breast cancer, or lung cancer between 1998 and 2002. For these patients, we identified their first course of chemotherapy and each unique cycle within that course, We then focused attention on all patient cycles in which filgrastim was administered on or before cycle day 5 (filgrastim prophylaxis). Pooling all such cycles, we examined the relationship between duration of filgrastim prophylaxis and risk of hospitalization for neutropenia or infection and risk of hospitalization for any reason, using generalized estimating equations.

Results:

Mean ± SD duration of filgrastim prophylaxis was 6.5 ± 3.1 days across 332 cycles for 133 NHL patients, 6.1 ± 2.9 days across 482 cycles for 205 breast cancer patients, and 4.3 ± 3.1 days across 522 cycles for 260 lung cancer patients. In multivariate analyses, risk of hospitalization for neutropenia or infection was found to decline with each additional day of filgrastim prophylaxis for patients with NHL (OR 0.81; p = 0.003), breast cancer (OR 0.77; p = 0.001), and lung cancer (OR 0.91; p = 0.084). Risk reductions with each additional day of prophylaxis ranged from 15% to 19% for patients with NHL, 17% to 23% for those with breast cancer, and 8% to 9% for those with lung cancer. Similar reductions in risk were noted for all-cause hospitalization.

Conclusions:

Among patients with NHL, breast cancer, or lung cancer, shorter courses of filgrastim prophylaxis may increase the risk of hospitalization.
Membrane Localization of Membrane Type 5 Matrix Metalloproteinase by AMPA Receptor Binding Protein and Cleavage of Cadherins
Authors: Monea Sara , Jordan Bryen A. , Srivastava Sapna , DeSouza Sunita , Ziff Edward B.
Published: February 2006

Matrix metalloproteinases (MMPs) have been proposed to remodel the extracellular environment of neurons. Here, we report that the metalloproteinase membrane-type 5 MMP (MT5-MMP) binds to AMPA receptor binding protein (ABP) and GRIP (glutamate receptor interaction protein), two related postsynaptic density (PSD) PDZ (postsynaptic density-95/Discs large/zona occludens-1) domain proteins that target AMPA receptors to synapses. The MT5-MMP C terminus binds ABP PDZ5 and the two proteins coimmunoprecipitated and colocalized in heterologous cells and neurons. MT5-MMP localized in filopodia at the tips of growth cones in young [2–5 din vitro(DIV)] cultured embryonic hippocampal neurons, and at synapses in mature (21 DIV) neurons. Its enrichment in synaptosomes also indicated a synaptic localization in the mature brain. Deletion of the PDZ binding site impaired membrane trafficking of MT5-MMP, whereas exogenous ABP splice forms that are associated either with the plasma membrane or with the cytosol, respectively, colocalized with MT5-MMP in synaptic spines or recruited MT5-MMP to intracellular compartments. We show that endogenous MT5-MMP is found in cultured neurons and brain lysates in a proenzyme form that is activated by furin and degraded by auto-proteolysis. We also identify cadherins as MT5-MMP substrates. These results suggest that ABP directs MT5-MMP proteolytic activity to growth cones and synaptic sites in neurons, where it may regulate axon pathfinding or synapse remodeling through proteolysis of cadherins or other ECM or cell adhesion molecules.
Sex Chromosome Complement and Gonadal Sex Influence Aggressive and Parental Behaviors in Mice
Authors: Gatewood Jessica D. , Wills Aileen , Shetty Savera , Xu Jun , Arnold Arthur P. , Burgoyne Paul S. , Rissman Emilie F.
Published: February 2006

Across human cultures and mammalian species, sex differences can be found in the expression of aggression and parental nurturing behaviors: males are typically more aggressive and less parental than females. These sex differences are primarily attributed to steroid hormone differences during development and/or adulthood, especially the higher levels of androgens experienced by males, which are caused ultimately by the presence of the testis-determining geneSryon the Y chromosome. The potential for sex differences arising from the different complements of sex-linked genes in male and female cells has received little research attention. To directly test the hypothesis that social behaviors are influenced by differences in sex chromosome complement other thanSry, we used a transgenic mouse model in which gonadal sex and sex chromosome complement are uncoupled. We find that latency to exhibit aggression and one form of parental behavior, pup retrieval, can be influenced by both gonadal sex and sex chromosome complement. For both behaviors, females but not males with XX sex chromosomes differ from XY. We also measured vasopressin immunoreactivity in the lateral septum, which was higher in gonadal males than females, but also differed according to sex chromosome complement. These results imply that a gene(s) on the sex chromosomes (other thanSry) affects sex differences in brain and behavior. Identifying the specific X and/or Y genes involved will increase our understanding of normal and abnormal aggression and parental behavior, including behavioral abnormalities associated with mental illness.
A Novel Family of Adhesion-Like Molecules That Interacts with the NMDA Receptor
Authors: Wang Chang-Yu , Chang Kai , Petralia Ronald S. , Wang Ya-Xian , Seabold Gail K. , Wenthold Robert J.
Published: February 2006

We have identified a novel family of synaptic adhesion-like molecules (SALMs). The family members, SALM1–SALM4, have a single transmembrane (TM) domain and contain extracellular leucine-rich repeats, an Ig C2 type domain, a fibronectin type III domain, and an intracellular postsynaptic density-95 (PSD-95)/Discs large/zona occludens-1 (PDZ) binding domain, which is present on all members except SALM4. SALM1 interacts with PSD-95, synapse-associated protein 102 (SAP102), and SAP97 based on coimmunoprecipitation of detergent-solubilized brain. Distribution studies show that SALM1 is present in synaptic membrane and postsynaptic density fractions but is also distributed in axons and dendrites. Transfection of hippocampal neurons for 4 din vitro(DIV) with SALM1 more than doubles the dendritic lengths of neurons after 48 h, whereas transfection of neurons 14 DIV has no significant effect on neurite outgrowth. Overexpression of SALM1 in 14 DIV neurons recruits NMDA receptors (NR) and PSD-95 to dendritic puncta. This effect is dependent on the PDZ-binding domain of SALM1. SALM1 also enhances surface expression of transfected NR2A subunit. Immunoprecipitation of detergent-solubilized brain membranes with anti-SALM1 antibodies shows coimmunoprecipitation of NR1 and NR2 subunits. After transfection of heterologous cells with NR1 and NR2 cDNAs, through coimmunoprecipitation analyses, we find that SALM1 also interacts with the NMDA receptor NR1 subunit through its extracellular or TM1 domains.
Endogenous Neurogenesis Replaces Oligodendrocytes and Astrocytes after Primate Spinal Cord Injury
Authors: Yang Hong , Lu Paul , McKay Heather M. , Bernot Tim , Keirstead Hans , Steward Oswald , Gage Fred H. , Edgerton V. Reggie , Tuszynski Mark H.
Published: February 2006

Neurogenesis has been described in various regions of the CNS throughout life. We examined the extent of natural cell division and replacement from 7 weeks to 7 months after cervical spinal cord injury in four adult rhesus monkeys. Bromodeoxyuridine (BrdU) injections revealed an increase of >80-fold in the number of newly divided cells in the primate spinal cord after injury, with an average of 725,000 BrdU-labeled cells identified per monkey in the immediate injury zone. By 7 months after injury, 15% of these new cells expressed mature markers of oligodendrocytes and 12% expressed mature astrocytic markers. Newly born oligodendrocytes were present in zones of injury-induced demyelination and appeared to ensheath or remyelinate host axons. Thus, cell replacement is an extensive natural compensatory response to injury in the primate spinal cord that contributes to neural repair and is a potential target for therapeutic enhancement.
The Impact of a Corticotectal Impulse on the Awake Superior Colliculus
Authors: Bereshpolova Yulia , Stoelzel Carl R. , Gusev Alexander G. , Bezdudnaya Tatiana , Swadlow Harvey A.
Published: February 2006

Corticotectal (CTect) neurons of layer 5 are large and prominent elements of mammalian visual cortex, with thick apical dendrites that ascend to layer 1, “intrinsically bursting” membrane properties, and fast-conducting descending axons that terminate in multiple subcortical domains. These neurons comprise a major output pathway of primary visual cortex, but virtually nothing is known about the synaptic influence of single CTect impulses on the superior colliculus (SC). Here, we examine the distribution of monosynaptic currents generated in the superficial SC by spontaneous impulses of single CTect neurons. We do this by recording the spikes of CTect neurons and the field potentials that they generate through the depths of the SC. Methods of spike-triggered averaging and current source density analysis are then applied to these data. We show, in fully awake rabbits, that single CTect impulses generate potent, fast-rising monosynaptic currents in the SC similar to those generated in sensory cortex by specific thalamic afferents. These currents are focal in depth, precisely retinotopic, and highly dependent on the conduction velocity of the CTect axon. Moreover, we show that CTect synapses, like thalamocortical synapses, suffer a chronic state of depression in awake subjects that is modulated by preceding interspike interval. However, CTect neurons generated few “bursts,” and postsynaptic responses in the SC were not significantly influenced by a shift from alert to an inattentive state (indicated by hippocampal EEG). Together, our results suggest that single CTect neurons may resemble thalamocortical neurons in their ability to serve as potent “drivers” of postsynaptic targets.
Calpain-Cleaved Collapsin Response Mediator Protein-3 Induces Neuronal Death after Glutamate Toxicity and Cerebral Ischemia
Authors: Hou Sheng T. , Jiang Susan X. , Desbois Angele , Huang Deqi , Kelly John , Tessier Luc , Karchewski Laurie , Kappler Joachim
Published: February 2006

Collapsin response mediator proteins (CRMPs) mediate growth cone collapse during development, but their roles in adult brains are not clear. Here we report the findings that the full-length CRMP-3 (p63) is a direct target of calpain that cleaves CRMP-3 at the N terminus (+76 amino acid). Interestingly, activated calpain in response to excitotoxicityin vitroand cerebral ischemiain vivoalso cleaved CRMP-3, and the cleavage product of CRMP-3 (p54) underwent nuclear translocation during neuronal death. The expression of p54 was colocalized with the terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling-positive nuclei in glutamate-treated cerebellar granule neurons (CGNs) and in ischemic neurons located in the infarct core after focal cerebral ischemia, suggesting that p54 might be involved in neuronal death. Overexpression studies showed that p54, but not p63, caused death of human embryonic kidney cells and CGNs, whereas knock-down CRMP-3 expression by selective small interfering RNA protected neurons against glutamate toxicity. Collectively, these results reveal a novel role of CRMP-3 in that calpain cleavage of CRMP-3 and the subsequent nuclear translocation of the truncated CRMP-3 evokes neuronal death in response to excitotoxicity and cerebral ischemia. Our findings also establish a novel route of how calpain signals neuron death.
Synaptic Vesicle Recycling Adapts to Chronic Changes in Activity
Authors: Virmani Tuhin , Atasoy Deniz , Kavalali Ege T.
Published: February 2006

Synaptic vesicle recycling is essential for maintaining neurotransmission during rhythmic activity. To test whether the demands imposed by ambient activity influences synaptic vesicle trafficking, we compared the kinetics of synaptic depression in hippocampal versus neocortical cultures, which have high and low levels of intrinsic activity, respectively. In response to moderate 10 Hz stimulation, hippocampal synapses depressed less compared with neocortical synapses, although they reused vesicles more slowly. Therefore, during stimulation, hippocampal synapses used more vesicles from the reserve pool, whereas neocortical synapses relied on vesicle reuse. In hippocampal cultures, chronic block of network activity increased synaptic depression by decreasing the rate of vesicle mobilization, with little effect on the rate of vesicle reuse. In contrast, in neocortical cultures, an increase in the normally low network activity reduced synaptic depression by robustly increasing vesicle reuse with no effect on vesicle mobilization. These results suggest that synaptic vesicle trafficking and the resulting synaptic dynamics adapt to meet the changing demands on neurotransmitter release. Furthermore, during these functional modifications, synapses use alternate strategies to adjust to changes in activity.
Lateral Excitation within the Olfactory Bulb
Authors: Christie Jason M. , Westbrook Gary L.
Published: February 2006

Lateral inhibition is a common feature of cortical networks, serving such functions as contrast enhancement. In the olfactory bulb, inhibition is imbedded in the local connectivity at dendrodendritic synapses between mitral cells and interneurons. However, there is also evidence for excitatory interactions between mitral cells despite the lack of direct synaptic connections. This lateral excitation, although a less well recognized feature of the circuit, provides a potentially powerful mechanism to enhance coordinated activity. We examined lateral excitation in paired recordings between mitral cells projecting to the same glomerulus. Trains of action potentials in one mitral cell evoked autoexcitation in the stimulated cell and a prolonged depolarization in the second cell. This lateral excitation was absent in connexin36−/−mice, which lack mitral–mitral cell gap junctions. However, spillover of dendritically released glutamate contributed to lateral excitation during concerted mitral cell excitation or by single-cell activity if glutamate uptake was blocked. Our results suggest that electrical coupling and spillover create a lateral excitatory network within the glomerulus, thus markedly amplifying the sensitivity of each glomerulus to incoming sensory input.
Intact Visual Perception in Memory-Impaired Patients with Medial Temporal Lobe Lesions
Authors: Shrager Yael , Gold Jeffrey J. , Hopkins Ramona O. , Squire Larry R.
Published: February 2006

A recent proposal that structures of the medial temporal lobe support visual perception in addition to memory challenges the long-standing idea that the ability to acquire new memories is separable from other cognitive and perceptual functions. In four experiments, we have put this proposal to a rigorous test. Six memory-impaired patients with well characterized lesions of either the hippocampal region or the hippocampal region plus additional medial temporal lobe structures were assessed on difficult tests of visual perceptual discrimination. Across all four experiments, the patients performed as well as controls. The results show that visual perception is intact in memory-impaired patients with damage to the medial temporal lobe even when perception is assessed with challenging tasks. Furthermore, the results support the principle that the ability to acquire new memories is a distinct cerebral function, dissociable from other perceptual and cognitive functions.