bluuebunny/crossref_metadata_2025 huggingface dataset:
Complement anaphylatoxin C5a neuroprotects through regulation of glutamate receptor subunit 2 in vitro and in vivo
Authors: Mukherjee Piali , Thomas Sunil , Pasinetti Giulio Maria
Published: January 2008

Background

The complement system is thought to be involved in the pathogenesis of numerous neurological diseases. We previously reported that pre-treatment of murine cortico-hippocampal neuronal cultures with the complement derived anaphylatoxin C5a, protects against glutamate mediated apoptosis. Our present study with C5a receptor knock out (C5aRKO) mice corroborates that the deficiency of C5a renders C5aRKO mouse more susceptible to apoptotic injuryin vivo. In this study we explored potential upstream mechanisms involved in C5a mediated neuroprotectionin vivoandin vitro.

Methods

Based on evidence suggesting that reduced expression of glutamate receptor subunit 2 (GluR2) may influence apoptosis in neurons, we studied the effect of human recombinant C5a on GluR2 expression in response to glutamate neurotoxicity. Glutamate analogs were injected into C5aRKO mice or used to treatin vitroneuronal culture and GluR2 expression were assessed in respect with cell death.

Results

In C5aRKO mice we found that the neurons are more susceptible to excitotoxicity resulting in apoptotic injury in the absence of the C5a receptor compared to WT control mice. Our results suggest that C5a protects against apoptotic pathways in neuronsin vitroandin vivothrough regulation of GluR2 receptor expression.

Conclusion

Complement C5a neuroprotects through regulation of GluR2 receptor subunit.
Cartilage preservation by inhibition of Janus kinase 3 in two rodent models of rheumatoid arthritis
Authors: Milici Anthony J , Kudlacz Elizabeth M , Audoly Laurent , Zwillich Samuel , Changelian Paul
Published: January 2008

Introduction

CP-690550 is a small molecule inhibitor of Janus kinase 3 (JAK3), a critical enzyme in the signaling pathway of multiple cytokines (interleukin (IL)-2, -7, -15 and -21) that are important in various T cell functions including development, activation and homeostasis. The purpose of this study was to evaluate CP-690550 in murine collagen-induced (CIA) and rat adjuvant-induced (AA) models of rheumatoid arthritis (RA).

Methods

CIA and AA were induced using standard protocols and animals received the JAK3 inhibitor via osmotic mini-pump infusion at doses ranging from 1.5–15 mg/kg/day following disease induction. Arthritis was assessed by clinical scores in the CIA models and paw swelling monitored using a plethysmometer in the AA model until study conclusion, at which time animals were killed and evaluated histologically.

Results

CP-690550 dose-dependently decreased endpoints of disease in both RA models with greater than 90% reduction observed at the highest administered dose. An approximate ED50 of approximately 1.5 mg/kg/day was determined for the compound based upon disease endpoints in both RA models examined and corresponds to CP-690550 serum levels of 5.8 ng/ml in mice (day 28) and 24 ng/ml in rats (day 24). The compound also reduced inflammatory cell influx and joint damage as measured histologically. Animals receiving a CP-690550 dose of 15 mg/k/d showed no histological evidence of disease.

Conclusion

The efficacy observed with CP-690550 in CIA and AA suggests JAK3 inhibition may represent a novel therapeutic target for the treatment of RA.
Phase I and Pharmacokinetic Study of Imatinib Mesylate in Patients With Advanced Malignancies and Varying Degrees of Liver Dysfunction: A Study by the National Cancer Institute Organ Dysfunction Working Group
Authors: Ramanathan Ramesh K. , Egorin Merrill J. , Takimoto Chris H.M. , Remick Scot C. , Doroshow James H. , LoRusso Patricia A. , Mulkerin Daniel L. , Grem Jean L. , Hamilton Anne , Murgo Anthony J. , Potter Douglas M. , Belani Chandra P. , Hayes Michael J. , Peng Bin , Ivy S. Percy
Published: January 2008

Purpose

To develop dosing guidelines and to evaluate the pharmacokinetics of imatinib in patients with liver dysfunction (LD).

Patients and Methods

Patients (N = 89) with varying solid tumors and liver function were stratified into four groups according to serum total bilirubin and AST and were treated with escalating doses of imatinib. Plasma and urine were assayed for concentrations of imatinib and its active metabolite, CGP74588 .

Results

In the mild LD group, dose-limiting toxicity, specifically nausea/vomiting and fatigue, occurred in two patients at the 600 mg/d dose level. In the moderate and severe LD groups, the maximal dose evaluated was 300 mg/d. Grade 3 to 4 toxicities consisted primarily of liver function test elevations (24%), nausea/vomiting (10%), fatigue (6%), and edema (5%). After the first imatinib dose, the mean (± SD) dose-normalized areas under the plasma concentration-time curve from time 0 to infinity (AUC0-∞) were 162 ± 155, 171 ± 72, 182 ± 157, and 185 ± 172 (μg/mL × h)/mg for normal, mild, moderate, and severe LD groups, respectively. Renal excretion of imatinib was less than 10% of the total dose in all groups.

Conclusion

Imatinib exposure (as measured by the dose-normalized AUC) did not differ between patients with normal liver function and those with LD. The maximal recommended dose of imatinib for patients with mild LD is 500 mg/d. Dosing guidelines for patients with moderate and severe LD remain undetermined.
Phase I and Pharmacokinetic Study of Imatinib Mesylate in Patients With Advanced Malignancies and Varying Degrees of Renal Dysfunction: A Study by the National Cancer Institute Organ Dysfunction Working Group
Authors: Gibbons Joseph , Egorin Merrill J. , Ramanathan Ramesh K. , Fu Pingfu , Mulkerin Daniel L. , Shibata Stephen , Takimoto Chris H.M. , Mani Sridhar , LoRusso Patricia A. , Grem Jean L. , Pavlick Anna , Lenz Heinz-Josef , Flick Susan M. , Reynolds Sherrie , Lagattuta Theodore F. , Parise Robert A. , Wang Yanfeng , Murgo Anthony J. , Ivy S. Percy , Remick Scot C.
Published: January 2008

Purpose

This study was undertaken to determine the safety, dose-limiting toxicities (DLT), maximum-tolerated dose (MTD), and pharmacokinetics of imatinib in cancer patients with renal impairment and to develop dosing guidelines for imatinib in such patients.

Patients and Methods

Sixty adult patients with advanced solid tumors and varying renal function (normal, creatinine clearance [CrCL] ≥ 60 mL/min; mild dysfunction, CrCL 40 to 59 mL/min; moderate dysfunction, CrCL 20 to 39 mL/min; and severe dysfunction, CrCL < 20 mL/min) received daily imatinib doses of 100 to 800 mg. Treatment cycles were 28 days long.

Results

The MTD was not reached for any group. DLTs occurred in two mild group patients (600 and 800 mg) and two moderate group patients (200 and 600 mg). Serious adverse events (SAEs) were more common in the renal dysfunction groups than in the normal group (P = .0096). There was no correlation between dose and SAEs in any group. No responses were observed. Several patients had prolonged stable disease. Imatinib exposure, expressed as dose-normalized imatinib area under the curve, was significantly greater in the mild and moderate groups than in the normal group. There was a positive correlation between serum alpha-1 acid glycoprotein (AGP) concentration and plasma imatinib, and an inverse correlation between plasma AGP concentration and imatinib clearance. Urinary excretion accounted for 3% to 5% of the daily imatinib dose.

Conclusion

Daily imatinib doses up to 800 or 600 mg were well tolerated by patients with mild and moderate renal dysfunction, respectively, despite their having increased imatinib exposure.
Long-Term Results From a Randomized Phase II Trial of Standard- Versus Higher-Dose Imatinib Mesylate for Patients With Unresectable or Metastatic Gastrointestinal Stromal Tumors Expressing KIT
Authors: Blanke Charles D. , Demetri George D. , von Mehren Margaret , Heinrich Michael C. , Eisenberg Burton , Fletcher Jonathan A. , Corless Christopher L. , Fletcher Christopher D.M. , Roberts Peter J. , Heinz Daniela , Wehre Elisabeth , Nikolova Zariana , Joensuu Heikki
Published: January 2008

Purpose

The outcome of patients diagnosed with advanced gastrointestinal stromal tumor (GIST) and treated long-term with imatinib mesylate is unknown. A previous report of a randomized phase II trial of imatinib mesylate in patients with incurable GIST detailed high response rates at both the 400 and the 600 mg/d dose levels. We conducted a long-term analysis of patients treated on the trial, including patients followed during an extension phase, to evaluate survival, patterns of failure, and potential prognostic factors, including tumor mutational status.

Patients and Methods

Patients with advanced GIST were enrolled onto an open-label, multicenter trial and were randomly assigned (1:1) to receive imatinib 400 versus 600 mg/d. Data were prospectively collected on KIT mutational status, total tumor area, and other potential prognostic factors. Patients were followed for a median of 63 months.

Results

One hundred forty-seven patients were enrolled: 73 were in arm A (imatinib 400 mg/d), and 74 were in arm B (imatinib 600 mg/d). Response rates, median progression-free survival, and median overall survival were essentially identical on both arms, and median survival was 57 months for all patients. Forty-one patients overall (28%) remained on the drug long-term. Female sex, the presence of an exon 11 mutation, and normal albumin and neutrophil levels were independently associated with better survival.

Conclusion

Nearly 50% of patients with advanced GIST who were treated with imatinib mesylate survived for more than 5 years, regardless of a 400 or 600 mg/d starting dose.
Improved Survival After Lymphadenectomy for Nodal Metastasis From an Unknown Primary Melanoma
Authors: Lee Chris C. , Faries Mark B. , Wanek Leslie A. , Morton Donald L.
Published: January 2008

Purpose

No primary lesion is identified in 10% to 20% of patients presenting with palpable evidence of regional metastatic melanoma. Because the prognostic significance of unknown primary melanoma (MUP) is unclear, we compared clinical outcomes of patients with MUP and known primary melanoma (MKP) with regional nodal metastases.

Patients and Methods

We reviewed our 13,000-patient prospective melanoma database (1971 through 2005) to identify patients managed with regional lymphadenectomy for palpable nodal metastases from MUP or MKP. Multivariate analysis identified prognostic factors significant for survival. MUP and MKP were then matched by significant covariates. Overall survival (OS) was estimated by Kaplan-Meier method and compared by log-rank analysis.

Results

Multivariate analysis of data from 1,571 study patients identified four significant covariates associated with worse prognosis: age ≥ 60 years (hazard ratio [HR] = 1.294; P = .0017), male sex (HR = 1.335; P = .0004), nodal tumor burden ≥ one (HR = 1.256; P < .0001), and known primary (HR = 1.507; 95% CI, 1.220 to 1.862; P = .0001). Five-year OS was significantly higher for 262 patients with MUP than for 1,309 patients with MKP (55% ± 6% v 44% ± 3%; P = .0021). Computerized matching of MUP and MKP by four significant covariates (age, sex, nodal tumor burden, and decade of diagnosis) yielded 221 matched pairs. Median and 5-year OS rates were 165 months and 58% ± 7%, respectively, for MUP as compared with 34 months and 40% ± 7%, respectively, for MKP (P = .0006).

Conclusion

Lymphadenectomy is effective for nodal metastasis from MUP. The significantly better postoperative survival for MUP versus MKP suggests a strong endogenous immune response against the primary melanoma. Immunologic studies to identify cell-mediated and antibody components of this response may lead to new approaches for determining melanoma prognosis and treatment.
Osteosarcoma: The Addition of Muramyl Tripeptide to Chemotherapy Improves Overall Survival—A Report From the Children's Oncology Group
Authors: Meyers Paul A. , Schwartz Cindy L. , Krailo Mark D. , Healey John H. , Bernstein Mark L. , Betcher Donna , Ferguson William S. , Gebhardt Mark C. , Goorin Allen M. , Harris Michael , Kleinerman Eugenie , Link Michael P. , Nadel Helen , Nieder Michael , Siegal Gene P. , Weiner Michael A. , Wells Robert J. , Womer Richard B. , Grier Holcombe E.
Published: January 2008

Purpose

To compare three-drug chemotherapy with cisplatin, doxorubicin, and methotrexate with four-drug chemotherapy with cisplatin, doxorubicin, methotrexate, and ifosfamide for the treatment of osteosarcoma. To determine whether the addition of muramyl tripeptide (MTP) to chemotherapy enhances event-free survival (EFS) and overall survival in newly diagnosed patients with osteosarcoma.

Patients and Methods

Six hundred sixty-two patients with osteosarcoma without clinically detectable metastatic disease and whose disease was considered resectable received one of four prospectively randomized treatments. All patients received identical cumulative doses of cisplatin, doxorubicin, and methotrexate and underwent definitive surgical resection of primary tumor. Patients were randomly assigned to receive or not to receive ifosfamide and/or MTP in a 2 × 2 factorial design. The primary end points for analysis were EFS and overall survival.

Results

In the current analysis, there was no evidence of interaction, and we were able to examine each intervention separately. The chemotherapy regimens resulted in similar EFS and overall survival. There was a trend toward better EFS with the addition of MTP (P = .08). The addition of MTP to chemotherapy improved 6-year overall survival from 70% to 78% (P = .03). The hazard ratio for overall survival with the addition of MTP was 0.71 (95% CI, 0.52 to 0.96).

Conclusion

The addition of ifosfamide to cisplatin, doxorubicin, and methotrexate did not enhance EFS or overall survival for patients with osteosarcoma. The addition of MTP to chemotherapy resulted in a statistically significant improvement in overall survival and a trend toward better EFS.
Failure to Detect Measles Virus Ribonucleic Acid in Bone Cells from Patients with Paget’s Disease
Authors: Matthews Brya G. , Afzal Muhammad A. , Minor Philip D. , Bava Usha , Callon Karen E. , Pitto Rocco P. , Cundy Tim , Cornish Jill , Reid Ian R. , Naot Dorit
Published: January 2008

Background: Paget’s disease is a condition of focal accelerated bone turnover. Electron-microscopy investigations of osteoclasts from pagetic lesions have identified nuclear inclusion bodies that have a similar appearance to viral nucleocapsid particles. Subsequently, RNA from several paramyxoviruses has been detected in pagetic tissue, and it was suggested that these viruses, in particular measles, might play a role in the etiology of Paget’s disease. We have tested for measles virus sequences in osteoblasts and bone marrow cells collected from pagetic lesions and healthy bone.

Methods: Bone and bone marrow samples were taken from Paget’s patients and control subjects, and cells were cultured from each of these tissues. RNA was extracted from 13 osteoblast cultures and 13 cultures of bone marrow cells derived from pagetic lesions, and from 26 and 23 control osteoblast and bone marrow cultures, respectively. These samples were sourced from 22 patients with Paget’s disease and 31 controls. RT-PCR-nested PCR amplification was used for the detection of the genes for the measles nucleocapsid and matrix proteins.

Results: Measles virus sequences were not detected in any of the pagetic or control samples. However, measles virus sequences were identified in samples of a measles virus culture isolate included as a positive control, and in a brain sample from a patient with subacute sclerosing panencephalitis, a condition associated with chronic measles infection.

Conclusion: The results of the study do not support the hypothesis that measles virus plays a role in the pathogenesis of Paget’s disease.
Metabolic Profile in Sons of Women with Polycystic Ovary Syndrome
Authors: Recabarren Sergio E. , Smith Rosita , Rios Rafael , Maliqueo Manuel , Echiburú Bárbara , Codner Ethel , Cassorla Fernando , Rojas Pedro , Sir-Petermann Teresa
Published: January 2008

Context: Polycystic ovary syndrome (PCOS) is a common endocrine-metabolic disorder with strong familial aggregation. It has been demonstrated that parents and brothers of PCOS women exhibit insulin resistance and related metabolic defects. However, metabolic phenotypes in sons of PCOS women have not been described.

Objective: Our objective was to assess the metabolic profiles in sons of women with PCOS during different stages of life: early infancy, childhood, and adulthood.

Design: Eighty sons of women with PCOS (PCOSS) and 56 sons of control women without hyperandrogenism (CS), matched for age, were studied. In early infancy, glucose and insulin were determined in the basal sample. In children and adults, a 2-h oral glucose tolerance test was performed with measurements of glucose and insulin. Adiponectin, leptin, C-reactive protein, SHBG, and serum lipids were determined in the basal sample during the three periods.

Results: During early infancy, PCOSS showed higher weight (P = 0.038) and weight sd score (P = 0.031) than CS. During childhood, weight (P = 0.003), body mass index (BMI) (P < 0.001), BMI sd score (P < 0.001), waist circumference (P = 0.001), total cholesterol (P = 0.007), and low-density lipoprotein cholesterol (P = 0.022) were higher in PCOSS compared with CS, but after adjusting for BMI, these differences were nonsignificant. During adulthood, PCOSS exhibited higher weight (P = 0.022), BMI (P = 0.046), and waist circumference (P = 0.028) than CS. Fasting insulin (P = 0.030), homeostasis model assessment for insulin resistance (P = 0.034), total cholesterol (P = 0.043), low-density lipoprotein cholesterol (P = 0.034), and 2-h insulin (P = 0.006) were also significantly higher and insulin sensitivity index composite significantly lower in PCOSS than in CS (P = 0.003). After adjusting for BMI, only 2-h insulin and insulin sensitivity index composite remained significantly different.

Conclusions: This study indicates that sons of PCOS women exhibit higher body weight from early infancy. In addition, insulin resistance became evident as the subjects got older, which may place them at risk for the development of type 2 diabetes and cardiovascular disease.
Integrin α9β1 is a receptor for nerve growth factor and other neurotrophins
Authors: Staniszewska Izabela , Sariyer Ilker K. , Lecht Shimon , Brown Meghan C. , Walsh Erin M. , Tuszynski George P. , Safak Mahmut , Lazarovici Philip , Marcinkiewicz Cezary
Published: January 2008

The integrin α9β1 is a multifunctional receptor that interacts with a variety of ligands including vascular cell adhesion molecule 1, tenascin C and osteopontin. We found that this integrin is a receptor for nerve growth factor (NGF) and two other neurotrophins, brain-derived neurotrophic factor and NT3, using a cell adhesion assay with the α9SW480 cell line. Interaction of α9β1 with NGF was confirmed in an ELISA assay by direct binding to purified integrin. α9β1 integrin binds to neurotrophins in a manner similar to another common neurotrophin receptor, p75NTR (NGFR), although α9β1 activity is correlated with induction of pro-survival and pro-proliferative signaling cascades. This property of α9β1 resembles the interaction of NGF with a high affinity receptor, TrkA, however, this integrin shows a low affinity for NGF. NGF induces chemotaxis of cells expressing α9β1 and their proliferation. Moreover, α9β1 integrin is a signaling receptor for NGF, which activates the MAPK (Erk1/2) pathway. The α9β1-dependent chemotactic ability of NGF appears to result from the activation of paxillin.
A palmitoylation cycle dynamically regulates partitioning of the GABA-synthesizing enzyme GAD65 between ER-Golgi and post-Golgi membranes
Authors: Kanaani Jamil , Patterson George , Schaufele Fred , Lippincott-Schwartz Jennifer , Baekkeskov Steinunn
Published: January 2008

GAD65, the smaller isoform of the enzyme glutamic acid decarboxylase, synthesizes GABA for fine-tuning of inhibitory neurotransmission. GAD65 is synthesized as a soluble hydrophilic protein but undergoes a hydrophobic post-translational modification and becomes anchored to the cytosolic face of Golgi membranes. A second hydrophobic modification, palmitoylation of Cys30 and Cys45 in GAD65, is not required for the initial membrane anchoring but is crucial for post-Golgi trafficking of the protein to presynaptic clusters. The mechanism by which palmitoylation directs targeting of GAD65 through and out of the Golgi complex is unknown. Here, we show that prior to palmitoylation, GAD65 anchors to both ER and Golgi membranes. Palmitoylation, however, clears GAD65 from the ER-Golgi, targets it to the trans-Golgi network and then to a post-Golgi vesicular pathway. FRAP analyses of trafficking of GAD65-GFP reveal a rapid and a slow pool of protein replenishing the Golgi complex. The rapid pool represents non-palmitoylated hydrophobic GAD65-GFP, which exchanges rapidly between the cytosol and ER/Golgi membranes. The slow pool represents palmitoylation-competent GAD65-GFP, which replenishes the Golgi complex via a non-vesicular pathway and at a rate consistent with a depalmitoylation step. We propose that a depalmitoylation-repalmitoylation cycle serves to cycle GAD65 between Golgi and post-Golgi membranes and dynamically control levels of enzyme directed to the synapse.
A Novel Blue-green-emitting Phosphor LiBaPO4:Eu2+ for White Light-emitting Diodes
Authors: Wu Zhanchao , Liu Jie , Guo Qingjie , Gong Menglian
Published: January 2008

A novel efficient blue-green-emitting phosphor, LiBaPO4:Eu2+, was prepared by solid-state reaction method. Its excitation band is extending from 250 to 450 nm, which is adaptable to the emission band of near-ultraviolet (NUV) LED chips (350–420 nm). Upon 348-nm light excitation, the phosphor exhibits a strong blue-green emission peaking at 480 nm. A bright blue-green LED was fabricated by incorporating the phosphor with an InGaN-based NUV chip. All the characteristics suggest that LiBaPO4:Eu2+ is a good blue-green phosphor candidate for creating white light in phosphor-converted white LEDs.
Duality of polynucleotide substrates for Phi29 DNA polymerase: 3′→5′ RNase activity of the enzyme
Authors: Lagunavicius Arunas , Kiveryte Zivile , Zimbaite-Ruskuliene Vilma , Radzvilavicius Tomas , Janulaitis Arvydas
Published: January 2008

Phi29 DNA polymerase is a small DNA-dependent DNA polymerase that belongs to eukaryotic B-type DNA polymerases. Despite the small size, the polymerase is a multifunctional proofreading-proficient enzyme. It catalyzes two synthetic reactions (polymerization and deoxynucleotidylation of Phi29 terminal protein) and possesses two degradative activities (pyrophosphorolytic and 3′→5′ DNA exonucleolytic activities). Here we report that Phi29 DNA polymerase exonucleolyticaly degrades ssRNA. The RNase activity acts in a 3′ to 5′ polarity. Alanine replacements in conserved exonucleolytic site (D12A/D66A) inactivated RNase activity of the enzyme, suggesting that a single active site is responsible for cleavage of both substrates: DNA and RNA. However, the efficiency of RNA hydrolysis is ∼10-fold lower than for DNA. Phi29 DNA polymerase is widely used in rolling circle amplification (RCA) experiments. We demonstrate that exoribonuclease activity of the enzyme can be used for the target RNA conversion into a primer for RCA, thus expanding application potential of this multifunctional enzyme and opening new opportunities for RNA detection.
An RNA molecule that specifically inhibits G-protein-coupled receptor kinase 2 in vitro
Authors: Mayer Günter , Wulffen Bernhard , Huber Christian , Brockmann Jörg , Flicke Birgit , Neumann Lars , Hafenbradl Doris , Klebl Bert M. , Lohse Martin J. , Krasel Cornelius , Blind Michael
Published: January 2008

G-protein-coupled receptors are desensitized by a two-step process. In a first step, G-protein-coupled receptor kinases (GRKs) phosphorylate agonist-activated receptors that subsequently bind to a second class of proteins, the arrestins. GRKs can be classified into three subfamilies, which have been implicated in various diseases. The physiological role(s) of GRKs have been difficult to study as selective inhibitors are not available. We have used SELEX (systematic evolution of ligands by exponential enrichment) to develop RNA aptamers that potently and selectively inhibit GRK2. This process has yielded an aptamer, C13, which bound to GRK2 with a high affinity and inhibited GRK2-catalyzed rhodopsin phosphorylation with an IC50of 4.1 nM. Phosphorylation of rhodopsin catalyzed by GRK5 was also inhibited, albeit with 20-fold lower potency (IC50of 79 nM). Furthermore, C13 reveals significant specificity, since almost no inhibitory activity was detectable testing it against a panel of 14 other kinases. The aptamer is two orders of magnitude more potent than the best GRK2 inhibitors described previously and shows high selectivity for the GRK family of protein kinases.
Efficacy of Ertapenem for Consolidation Therapy of Extended-Spectrum β-lactamase-Producing Gram-Negative Infections: A Case Series Report
Authors: Berg Melody L , Crank Christopher W , Philbrick Alexander H , Hayden Mary K
Published: January 2008

Background:

Infections caused by extended-spectrum β-lactamase (ESBL)-producing gram-negative organisms are becoming increasingly common and present significant challenges in terms of treatment. Carbapenems is the antibiotic class of choice for treatment of these types of infections. Ertapenem is the newest carbapenem, capable of being dosed once daily, and has some in vitro but little in vivo evidence supporting its use for the treatment ol these resistant infections.

Objective:

To examine the clinical and microbiologic outcomes associated with ertapenem therapy of ESBL-producing Escherichia coli, Klebsiella pneumoniae. and Proteus mirabilis infections.

Methods:

This was a retrospective case series that examined the clinical and microbiologic outcomes of 22 patients who received ertapenem for treatment of an ESBL infection at Rush University Medical Center in Chicago. IL, during 2003–2005.

Results:

The majority (16/22) of patients received ertapenem (or consolidation rather than initial therapy. Different antibiotics most commonly used were other carbapenems, piperacillin/tazobactam, and aminoglycosides. The most common infections treated were lower urinary tract infections and osteomyelitis. Clinical efficacy was determined in all 22 patients, with 20 (91%) patients having a positive outcome, defined as either clinical improvement or clinical cure. The best clinical cure rate was seen with wound infections, where all 3 patients examined were found to be clinically cured. Microbiologic efficacy was determined in 7 patients, with 6 {85.7%) defined as microbiologic cure. One patient was found to be both a clinical and microbiologic failure and was also found to have developed an ertapenem-resistant strain of E. coli.

Conclusions:

These results demonstrate potential microbiologic and clinical efficacy of ertapenem for treatment of ESBL-producing infections and the need for a prospective, randomized study examining its efficacy versus that of other carbapenems.
Hyperoxia Causes Maturation-Dependent Cell Death in the Developing White Matter
Authors: Gerstner Bettina , DeSilva Tara M. , Genz Kerstin , Armstrong Amy , Brehmer Felix , Neve Rachael L. , Felderhoff-Mueser Ursula , Volpe Joseph J. , Rosenberg Paul A.
Published: January 2008

Periventricular leukomalacia is the predominant injury in the preterm infant leading to cerebral palsy. Oxygen exposure may be an additional cause of brain injury in these infants. In this study, we investigated pathways of maturation-dependent oligodendrocyte (OL) death induced by hyperoxiain vitroandin vivo. Developing and mature OLs were subjected to 80% oxygen (0–24 h). Lactate dehydrogenase (LDH) assay was used to assess cell viability. Furthermore, 3-, 6-, and 10-d-old rat pups were subjected to 80% oxygen (24 h), and their brains were processed for myelin basic protein staining. Significant cell death was detected after 6–24 h incubation in 80% oxygen in pre-OLs (O4+,O1−), but not in mature OLs (MBP+). Cell death was executed by a caspase-dependent apoptotic pathway and could be blocked by the pan-caspase inhibitor zVAD-fmk. Overexpression of BCL2 (Homo sapiensB-cell chronic lymphocytic leukemia/lymphoma 2) significantly reduced apoptosis. Accumulation of superoxide and generation of reactive oxygen species (ROS) were detected after 2 h of oxygen exposure. Lipoxygenase inhibitors 2,3,5-trimethyl-6-(12-hydroxy-5-10-dodecadiynyl-1,4-benzoquinone andN-benzyl-N-hydroxy-5-phenylpentamide fully protected the cells from oxidative injury. Overexpression of superoxide dismutase (SOD1) dramatically increased injury to pre-OLs but not to mature OLs. We extended these studies by testing the effects of hyperoxia on neonatal white matter. Postnatal day 3 (P3) and P6 rats, but not P10 pups, showed bilateral reduction in MBP (myelin basic protein) expression with 24 h exposure to 80% oxygen. Hyperoxia causes oxidative stress and triggers maturation-dependent apoptosis in pre-OLs, which involves the generation of ROS and caspase activation, and leads to white matter injury in the neonatal rat brain. These observations may be relevant to white matter injury observed in premature infants.
Differential Tonic GABA Conductances in Striatal Medium Spiny Neurons
Authors: Ade Kristen K. , Janssen Megan J. , Ortinski Pavel I. , Vicini Stefano
Published: January 2008

Medium spiny neurons (MSNs) provide the principal output for the dorsal striatum. Those that express dopamine D2receptors (D2+) project to the globus pallidus external and are thought to inhibit movement, whereas those that express dopamine D1receptors (D1+) project to the substantia nigra pars reticulata and are thought to facilitate movement. Whole-cell and outside-out patch recordings in slices from bacterial artificial chromosome transgenic mice examined the role of GABAAreceptor-mediated currents in dopamine receptor D1+striatonigral and D2+striatopallidal MSNs. Although inhibitory synaptic currents were similar between the two neuronal populations, D2+MSNs showed greater GABAAreceptor-mediated tonic currents. TTX application abolished the tonic current to a similar extent as GABAAantagonists, suggesting a synaptic origin of the ambient GABA. Low GABA concentrations produced larger whole-cell responses and longer GABA channel openings in D2+than in D1+MSNs. Recordings from MSNs in α1−/−mice and pharmacological analysis of tonic currents suggested greater expression of α5-containing GABAAreceptors in D2+than in D1+MSNs. As a number of disorders such as Parkinson's disease, Huntington's chorea, and tardive dyskinesia arise from an imbalance between these two pathways, the GABAAreceptors responsible for tonic currents in D2+MSNs may be a potential target for therapeutic intervention.
Functions of Interneurons in Mouse Cerebellum
Authors: Barmack Neal H. , Yakhnitsa Vadim
Published: January 2008

The output signal of Purkinje cells is conveyed by the modulated discharge of simple spikes (SSs) often ascribed to mossy fiber–granule cell–parallel fiber inputs to Purkinje cell dendrites. Although generally accepted, this view lacks experimental support. We can address this view by controlling afferent signals that reach the cerebellum over climbing and mossy fiber pathways. Vestibular primary afferents constitute the largest mossy fiber projection to the uvula-nodulus. The discharge of vestibular primary afferent mossy fibers increases during ipsilateral roll tilt. The discharge of SSs decreases during ipsilateral roll tilt. Climbing fiber discharge [complex spikes (CSs)] increases during ipsilateral roll tilt. These observations suggest that the modulation of SSs during vestibular stimulation cannot be attributed directly to vestibular mossy fiber afferents. Rather we suggest that interneurons driven by vestibular climbing fibers may determine SS modulation. We recorded from cerebellar interneurons (granule, unipolar brush, Golgi, stellate, basket, and Lugaro cells) and Purkinje cells in the uvula-nodulus of anesthetized mice during vestibular stimulation. We identified all neuronal types by juxtacellular labeling with neurobiotin. Granule, unipolar brush, stellate, and basket cells discharge in phase with ipsilateral roll tilt and in phase with CSs. Golgi cells discharge out of phase with ipsilateral roll tilt and out of phase with CSs. The phases of stellate and basket cell discharge suggests that their activity could account for the antiphasic behavior of CSs and SSs. Because Golgi cells discharge in phase with SSs, Golgi cell activity cannot account for SS modulation. The sagittal array of Golgi cell axon terminals suggests that they contribute to the organization of discrete parasagittal vestibular zones.
Early Prediction of Functional Recovery after Experimental Stroke: Functional Magnetic Resonance Imaging, Electrophysiology, and Behavioral Testing in Rats
Authors: Weber Ralph , Ramos-Cabrer Pedro , Justicia Carlos , Wiedermann Dirk , Strecker Cordula , Sprenger Christiane , Hoehn Mathias
Published: January 2008

Therapeutic success of treatment of cerebral diseases must be assessed in terms of functional outcome. In experimental stroke studies, this has been limited to behavioral studies combined with morphological evaluations and single time point functional magnetic resonance imaging (fMRI) measurements but lacking the access to understanding underlying mechanisms for alterations in brain activation. Using a recently developed blood oxygenation level-dependent fMRI protocol to study longitudinal and intraindividual profiles of functional brain activation in the somatosensory system, we have demonstrated activation reemergence in the original representation field as the basic principle of functional recovery from experimental stroke. No plastic reorganization has been observed at any time point during 7 weeks after stroke induction. Applying combined recording of fMRI and somatosensory evoked potentials, we observed a tight coupling of electrical brain activity and hemodynamic response at all times, indicating persistent preservation of neurovascular coupling. Identification of functional brain recovery mechanisms has important implications for the understanding of brain plasticity after cerebral lesions, whereas preservation of neurovascular coupling is important for the clinical translation of fMRI.
Immediate-Early Gene Expression at Rest Recapitulates Recent Experience
Authors: Marrone Diano F. , Schaner Michael J. , McNaughton Bruce L. , Worley Paul F. , Barnes Carol A.
Published: January 2008

Immediate-early genes (IEGs) are tightly coupled to cellular activity and play a critical role in regulating synaptic plasticity. While encoding spatial experience, hippocampal principal cells express IEGs in a behaviorally dependent and cell-specific manner. This expression can be detected through the use of cellular compartment analysis of temporal activity by fluorescencein situhybridization to generate estimates of cellular activity that match direct neuronal recording under comparable conditions. During rest, IEG expression continues to occur in a small number of cells, and the role of this basal expression is unknown. Imaging IEGs expressed during exploration and adjacent rest periods reveals that “constitutive” IEG expression during rest is not random. Rather, consistent with proposed memory consolidation mechanisms, it recapitulates a subset of the pattern generated by recent experience.
Primary Motor Cortex Tuning to Intended Movement Kinematics in Humans with Tetraplegia
Authors: Truccolo Wilson , Friehs Gerhard M. , Donoghue John P. , Hochberg Leigh R.
Published: January 2008

The relationship between spiking activities in motor cortex and movement kinematics has been well studied in neurologically intact nonhuman primates. We examined the relationship between spiking activities in primary motor cortex (M1) and intended movement kinematics (position and velocity) using 96-microelectrode arrays chronically implanted in two humans with tetraplegia. Study participants were asked to perform two different tasks: imagined pursuit tracking of a cursor moving on a computer screen and a “neural cursor center-out” task in which cursor position was controlled by the participant's neural activity. In the pursuit tracking task, the majority of neurons were significantly tuned: 90% were tuned to velocity and 86% were tuned to position in one participant; 95% and 84%, respectively, in the other. Additionally, velocity and position of the tracked cursor could be decoded from the ensemble of neurons. In the neural cursor center-out task, tuning to direction of the intended target was well captured by a log-linear cosine function. Neural spiking soon after target appearance could be used to classify the intended target with an accuracy of 95% in one participant, and 80% in the other. It was also possible to extract information about the direction of the difference vector between the target position and the instantaneous neural cursor position. Our results indicate that correlations between spiking activity and intended movement velocity and position are present in human M1 after the loss of descending motor pathways, and that M1 spiking activities share many kinematic tuning features whether movement is imagined by humans with tetraplegia, or is performed as shown previously in able-bodied nonhuman primates.
Working Memory Capacity Predicts Dopamine Synthesis Capacity in the Human Striatum
Authors: Cools Roshan , Gibbs Sasha E. , Miyakawa Asako , Jagust William , D'Esposito Mark
Published: January 2008

Evidence from psychopharmacological research has revealed that dopamine receptor agents have opposite effects on cognitive function depending on baseline levels of working memory capacity. These contrasting effects have been interpreted to reflect differential baseline levels of dopamine. Here we demonstrate for the first time that working memory capacity as measured by listening span predicts dopamine synthesis capacity in the striatum, indicating that subjects with low working memory capacity have low DA synthesis capacity in the striatum, whereas subjects with high working memory capacity have high DA synthesis capacity in the striatum.
Roles of the Nucleus Accumbens and Amygdala in the Acquisition and Expression of Ethanol-Conditioned Behavior in Mice
Authors: Gremel Christina M. , Cunningham Christopher L.
Published: January 2008

Although progress has been made identifying the neural areas underlying the primary reinforcing effects of ethanol, few studies have examined the neural areas mediating ethanol-induced conditioned effects. Previous work using the conditioned place preference (CPP) procedure implicates the ventral tegmental area (VTA) (Bechtholt and Cunningham, 2005), but the downstream neural areas modulating the conditioned rewarding effects of ethanol have not been identified. Although the nucleus accumbens (Acb) and the amygdala (Amy), which both receive dopamine innervation from the VTA, have been implicated in the primary reinforcing effects of ethanol, the roles these areas play in ethanol-conditioned behaviors are unknown. In the present set of experiments, we use the CPP procedure along with selective electrolytic lesions to examine the neural areas underlying the acquisition and expression of ethanol conditioned behavior. In the acquisition experiment, male DBA/2J mice received bilateral lesions of the Acb or Amy before CPP training. In the expression experiments, mice received bilateral lesions of the Acb, Acb shell, Acb core, and Amy, or unilateral lesions of the Amy after training but before testing. Lesions of the Acb and Amy before training disrupted acquisition and expression of ethanol CPP. However, when given after training, only lesions of the Amy disrupted expression, whereas lesions of the Acb core facilitated loss of responding, of ethanol CPP. For the first time, these results demonstrate the role of the Acb and Amy in the acquisition and expression of ethanol-induced conditioned reward.
Regional Distribution of Cortical Interneurons and Development of Inhibitory Tone Are Regulated by Cxcl12/Cxcr4 Signaling
Authors: Li Guangnan , Adesnik Hillel , Li Jennifer , Long Jason , Nicoll Roger A. , Rubenstein John L. R. , Pleasure Samuel J.
Published: January 2008

Interneurons are born in subcortical germinative zones and tangentially migrate in multiple streams above and below the developing cortex, and then, at the appropriate developmental stage, migrate radially into the cortex. The factors that control the formation of and the timing of exit from the streams remain obscure; moreover, the rationale for this complicated developmental plan is unclear. We show that a chemokine, Cxcl12, is an attractant for interneurons during the stage of stream formation and tangential migration. Furthermore, the timing of exit from the migratory streams accompanies loss of responsiveness to Cxcl12 as an attractant. Mice with mutations in Cxcr4 have disorganized migratory streams and deletion of Cxcr4 after the streams have formed precipitates premature entry into the cortical plate. In addition, constitutive deletion of Cxcr4 specifically in interneurons alters the regional distribution of interneurons within the cortex and leads to interneuron laminar positioning defects in the postnatal cortex. To examine the role of interneuron distribution on the development of cortical circuitry, we generated mice with focal defects in interneuron distribution and studied the density of postnatal inhibitory innervation in areas with too many and too few interneurons. Interestingly, alterations in IPSC frequency and amplitude in areas with excess interneurons tend toward normalization of inhibitory tone, but in areas with reduced interneuron density this system fails. Thus, the processes controlling interneuron sorting, migration, regional distribution, and laminar positioning can have significant consequences for the development of cortical circuitry and may have important implications for a range of neurodevelopmental disorders.
Habituation Reveals Fundamental Chromatic Mechanisms in Striate Cortex of Macaque
Authors: Tailby Chris , Solomon Samuel G. , Dhruv Neel T. , Lennie Peter
Published: January 2008

Prolonged viewing of a chromatically modulated stimulus usually leads to changes in its appearance, and that of similar stimuli. These aftereffects of habituation have been thought to reflect the activity of two populations of neurons in visual cortex that have particular importance in color vision, one sensitive to red–green modulation, the other to blue–yellow, but they have not been identified. We show here, in recordings from macaque primary visual cortex (V1), that prolonged exposure to chromatic modulation reveals two fundamental mechanisms with distinctive chromatic signatures that match those of the mechanisms identified by perceptual observations. In nearly all neurons, these mechanisms contribute to both excitation and to regulatory gain controls, and as a result their habituation can have paradoxical effects on response. The mechanisms must be located near the input layers of V1, before their distinct chromatic signatures diffuse. Our observations suggest that the fundamental mechanisms do not give rise to two distinct L–M and S chromatic pathways. Rather, the mechanisms are better understood as stages in the elaboration of chromatic tuning, expressed in varying proportions in all cells in V1 (and beyond), and made accessible to physiological and perceptual investigation only through habituation.
The Proneural Basic Helix-Loop-Helix GeneAscl1aIs Required for Retina Regeneration
Authors: Fausett Blake V. , Gumerson Jessica D. , Goldman Daniel
Published: January 2008

Unlike mammals, teleost fish can regenerate an injured retina, restoring lost visual function. Little is known of the molecular events that underlie retina regeneration. We previously found that in zebrafish, retinal injury stimulates Müller glia to generate multipotent α1-tubulin(α1T) andpax6-expressing progenitors for retinal repair. Here, we report the identification of a critical E-box in the α1Tpromoter that mediates transactivation by achaete-scute complex-like 1a (ascl1a) during retina regeneration. More importantly, we show that ascl1a is essential for retina regeneration. Within 4 h after retinal injury, ascl1a is induced in Müller glia. Knockdown of ascl1a blocks the induction of α1Tandpax6as well as Müller glial proliferation, consequently preventing the generation of retinal progenitors and their differentiated progeny. These data suggest ascl1a is required to convert quiescent Müller glia into actively dividing retinal progenitors, and that ascl1a is a key regulator in initiating retina regeneration.
Is There an Asian Advantage for Pitch Memory?
Authors: Schellenberg E. Glenn , Trehub Sandra E.
Published: January 2008

ABSOLUTE PITCH (AP) IS THE ABILITY TO IDENTIFY OR produce a musical note in isolation. As traditionally defined, AP requires accurate pitch memory as well as knowledge of note names. The incidence of AP is higher in Asia than it is in North America.We used a task with no naming requirements to examine pitch memory among Canadian 9- to 12-year-olds of Asian (Chinese) or non-Asian (European) heritage. On each trial, children heard two versions of a 5-s excerpt from a familiar recording, one of which was shifted upward or downward in pitch. They were asked to identify the excerpt at the original pitch. The groups performed comparably, and knowledge of a tone language did not affect performance. Nonetheless, Asians performed better on a test of academic achievement. These results provide no support for the contribution of genetics or tone-language use to cross-cultural differences in pitch memory.
Auto relato de situações constrangedoras no trabalho e assédio moral nos bancários: uma fotografia
Authors: Maciel Regina Heloisa , Cavalcante Rosemary , Matos Teresa Glaucia Rocha , Rodrigues Suzineide
Published: January 2008

As definições existentes do assédio moral no trabalho, apesar de ainda não haver um consenso, apontam para a ocorrência de atos negativos ou situações constrangedoras no trabalho que perdurem por um certo período de tempo e freqüência e onde a vítima se sinta intimidada. O objetivo deste trabalho foi identificar e analisar a ocorrência de situações constrangedoras no trabalho, relatadas por bancários brasileiros. O método consistiu na aplicação de um questionário em 2609 bancários. 33,89% da amostra relata ter sido exposta a pelo menos uma das situações constrangedoras apresentadas no questionário. Quando se considera o período de exposição de seis meses e freqüência semanal, 7,97% da amostra relata ter sido assediada. Além disso, as mulheres e o grupo de homo ou bissexuais relatam terem sido assediadas com maior freqüência. Esses resultados mostram que os bancários brasileiros estão expostos ao assédio moral com uma taxa similar às encontradas em estudos europeus.