Treatment outcomes for older patients with relapsed/refractory aggressive lymphoma receiving salvage chemotherapy and autologous stem cell transplantation are similar to younger patients: a subgroup analysis from the phase III CCTG LY.12 trial.

Background: High-dose therapy and autologous stem cell transplantation (ASCT) is often considered for older patients (age >60 years) with relapsed/refractory aggressive lymphomas. Although registry data support the safety and potential efficacy of this approach, there are no prospective trials evaluating outcomes of ASCT in older patients. We evaluated the result of second-line chemotherapy and ASCT in older versus younger patients in the CCTG randomized LY.12 trial. Patients and methods: From August 2003 to November 2011, 619 patients with relapsed/refractory aggressive lymphoma were randomized to gemcitabine, dexamethasone, cisplatin (GDP) or dexamethasone, cytarabine, cisplatin (DHAP); 177 patients (28.6%) enrolled were >60.0 years of age (range, 60-74) and 442 were ≤60.0 years of age. After two to three cycles, responding patients proceeded to ASCT. Intention-to-treat analysis was used to compare response rate, transplantation rate, event-free survival (EFS) and overall survival (OS) between patients aged ≤60.0 and >60.0 years. Results: Patient characteristics were comparable between the two cohorts, except a larger proportion of older patients had high International Prognostic Index risk scores. Response to salvage therapy was 48.6% for patients aged >60.0 versus 43.0% for those aged ≤60.0 (P = 0.21). Transplantation rates were also similar: 50.3% versus 49.8% (P = 0.87) for older versus younger patients. Rates of febrile neutropenia and adverse events requiring hospitalization were comparable for older and younger patients (30.5% versus 22.9% and 37.9% versus 32.1%, respectively). With a median follow-up of 53 months, there was no difference in 4-year OS (36% and 40% for patients aged >60.0 and ≤60.0 years, P = 0.42), or 4-year EFS (20% versus 28%, P = 0.43). Mortality from salvage therapy was 8/174 (4.60%) and 5/436 (1.15%), and 100-day mortality post-ASCT was 7/88 (8.06%) and 4/219 (1.85%). Conclusion: This subgroup analysis suggests that older patients derive similar benefit from salvage therapy and ASCT to younger patients, with acceptable toxicity. ClinicalTrials.gov Identifier: NCT00078949.

The Opioid Analgesic Reduction Study (OARS) Pilot: A Double-Blind Randomized Multicenter Trial.

BACKGROUND: With addiction rates and opioid deaths increasing, health care providers are obligated to help stem the opioid crisis. As limited studies examine the comparative effectiveness of fixed-dose combination nonopioid analgesia to opioid-containing analgesia, a comparative effectiveness study was planned and refined by conducting a pilot study. METHODS: The Opioid Analgesic Reduction Study (OARS) pilot, a stratified, randomized, multisite, double-blind clinical trial, was designed to test technology and procedures to be used in the full OARS trial. Participants engaged in the full protocol, enabling the collection of OARS outcome data. Eligible participants reporting to 1 of 5 sites for partial or full bony impacted mandibular third molar extraction were stratified by biologic sex and randomized to 1 of 2 treatment groups, OPIOID or NONOPIOID. OPIOID participants were provided 20 doses of hydrocodone 5 mg/acetaminophen 300 mg. NONOPIOID participants were provided 20 doses of ibuprofen 400 mg/acetaminophen 500 mg. OARS outcomes data, including pain experience, adverse effects, sleep quality, pain interference, overall satisfaction, and remaining opioid tablets available for diversion, were collected via surveys, electronic medication bottles, eDiary, and activity/sleep monitor. RESULTS: Fifty-three participants were randomized with 50 completing the OARS pilot protocol. Across all outcome pain domains, in all but 1 time period, NONOPIOID was better in managing pain than OPIOID (P < 0.05 level). Other outcomes suggest less pain interference, less adverse events, better sleep quality, better overall satisfaction, and fewer opioid-containing tablets available for diversion. DISCUSSION: Results suggest patients requiring impacted mandibular third molar extraction would benefit from fixed-dose combination nonopioid analgesia. KNOWLEDGE TRANSFER STATEMENT: Study results suggest fixed-dose nonopioid combination ibuprofen 400 mg/acetaminophen 500 mg is superior to opioid-containing analgesic (hydrocodone 5 mg/acetaminophen 500 mg). This knowledge should inform surgeons and patients in the selection of postsurgical analgesia.

Stable restoration of the sarcoglycan complex in dystrophic muscle perfused with histamine and a recombinant adeno-associated viral vector.

Limb-girdle muscular dystrophies 2C-F represent a family of autosomal recessive diseases caused by defects in sarcoglycan genes. The cardiomyopathic hamster is a naturally occurring model for limb-girdle muscular dystrophy caused by a primary deficiency in delta-sarcoglycan. We show here that acute sarcolemmal disruption occurs in this animal model during forceful muscle contraction. A recombinant adeno-associated virus vector encoding human delta-sarcoglycan conferred efficient and stable genetic reconstitution in the adult cardiomyopathic hamster when injected directly into muscle. A quantitative assay demonstrated that vector-transduced muscle fibers are stably protected from sarcolemmal disruption; there was no associated inflammation or immunologic response to the vector-encoded protein. Efficient gene transduction with rescue of the sarcoglycan complex in muscle fibers of the distal hindlimb was also obtained after infusion of recombinant adeno-associated virus into the femoral artery in conjunction with histamine-induced endothelial permeabilization. This study provides a strong rationale for the development of gene therapy for limb-girdle muscular dystrophy.

Carbon nanotubes as injection electrodes for organic thin film transistors.

We have investigated the charge injection efficiency of carbon nanotube electrodes for organic semiconducting layers and compared their performance to that of traditional noble metal electrodes. Our results reveal that charge injection from a single carbon nanotube electrode is more than an order of magnitude more efficient than charge injection from metal electrodes. Moreover, organic thin film transistors that use arrays of carbon nanotube electrodes display considerable effective mobilities (0.14 cm(2)/(V.s)) and nearly ideal linear output characteristics. These results indicate that carbon nanotubes should be considered a viable alternative to metal electrodes for next-generation organic field-effect transistors.

Destabilizing and stabilizing forces to assess equilibrium during everyday activities.

Postural stability is essential to functional activities. This paper presents a new model of dynamic stability which takes into account both the equilibrium associated with the body position over the base of support (destabilizing force) and the effort the subject needs to produce to keep his/her centre of mass inside the base of support (stabilizing force). The ratio between these two forces (destabilizing over stabilizing) is calculated to provide an overall index of stability for an individual. Preliminary results from data collected during walking at preferred and maximal safe speed in four older adults (aged from 64 to 84yr) showed that both forces are lower for subjects with reduced maximal gait speed. In addition, the stabilizing force increases by 2-3 times from preferred to maximal speed, while the destabilizing force barely changes with gait speed. Overall, the model through the index of stability attributes lower dynamic stability to subjects with lower maximal gait speed. These preliminary results call for larger-scale studies to pursue the development and validation of the model and its application to different functional tasks.

Effects of long jumps, reversible aggregation, and Meyer-Neldel rule on submonolayer epitaxial growth.

We demonstrate, using kinetic Monte Carlo simulations of submonolayer epitaxial growth, that long jumps and reversible aggregation have a major impact on the evolution of island morphologies. Long jumps are responsible for a supra-Arrhenius behavior of the effective diffusion coefficient as the attachment and detachment kinetics give rise to a bimodal island size distribution that depends on temperature and long jump extent limits. As the islands density increases with temperature, the average size of stable islands reaches a maximum before decreasing. We have also observed that the diffusion coefficient cannot be used alone to predict the evolution of island sizes and morphologies, the relative rate of each process having a major importance. Our theoretical developments are of direct relevance for materials systems such as Au, Pd, Ag, Cu, Ni, H/Si , H/W(110), Co/Ru , and Co/Ru(S), that are known for exhibiting a compensation effect that cannot be contained within experimental uncertainties.

A chair with a platform setup to measure the forces under each thigh when sitting, rising from a chair and sitting down.

This paper describes the design, technical characteristics and first results of an adjustable instrumented chair with a sitting surface that records the forces under each thigh. The seat includes a force platform assembly suitable for measuring the magnitude, position and direction of the force applied to each thigh while sitting or rising from the chair. The natural frequency of the chair fixed to the floor was found to be 14.0 +/- 2 Hz with an estimated damping of xi = 0.20. Static tests showed that the maximal errors were 2% of the full-scale output (726 N vertically, 164 N horizontally) for both vertical and horizontal forces. The root mean square error of the center of pressure location was estimated as 5 mm. Preliminary data on the net joint moment at the hips of one healthy subject computed with and without consideration for the forces under the thighs revealed significant amplitude differences. In conclusion, the results indicate that the characteristics of the instrumented chair are acceptable and the chair can be used to assess the biomechanics of sitting and sit-to-stand and stand-to-sit tasks in various subject populations.

Ethidium bromide-induced loss of mitochondrial DNA from primary chicken embryo fibroblasts.

Chicken embryo fibroblasts in uridine-containing medium are inherently resistant to the growth-inhibitory effect of ethidium bromide. The drug was found to inhibit the incorporation of [3H]thymidine into mitochondrial DNA circular molecules. Mitochondrial DNA was quantitated by DNA-DNA reassociation kinetics with a probe of chicken liver mitochondrial DNA. A mean number of 604 copies of mitochondrial DNA per cell was found. This number decreased progressively in cells exposed to ethidium bromide, and by day 13 ca. one copy of mitochondrial DNA was detected per cell. When the cells were then transferred to drug-free medium, the number of copies increased very slowly as a function of time. On the other hand, analyses of DNA extracted from cell populations exposed to ethidium bromide for 20 or more days, with or without subsequent transfer to drug-free medium, revealed very little or no mitochondrial DNA by reassociation kinetics or by Southern blot hybridization of AvaI- or HindIII-digested total cellular DNA. As a result of the elimination of mitochondrial DNA molecules, the establishment of cell populations with a respiration-deficient phenotype was confirmed by measuring cytochrome c oxidase activity as a function of the number of cell generations and the absorption spectrum of mitochondrial cytochromes.

Evaluation of a hybrid system for three-dimensional measurement of trunk posture in motion.

Ambulatory assessment of trunk posture is important in improving our understanding of the risk of low back injury. Recently, small inertial sensors combining accelerometers, gyroscopes and magnetometers were developed and appear to be promising for measuring human movement. However, the validity of such sensors for assessing three-dimensional (3D) trunk posture in motion has not been documented. The purpose of this study was to evaluate a hybrid system (HS) composed of two inertial sensors for the 3D measurement of trunk posture. A secondary purpose was to explore the utility of adding another source of information, a potentiometer, to measure the relative rotation between both sensors in order to improve the validity of the system. The first sensor was placed over the sacrum and the second on the upper part of the thorax. Both sensors were linked by a flexible rod with a potentiometer. A complementary quaternion filter algorithm was used to estimate trunk orientation by taking advantage of the nine components of each sensor and the potentiometer. The HS's orientations were compared to those obtained from a 3D optoelectronic system. Validation of the HS was performed in three steps in which six subjects had to perform manual handling tasks in: (1) static postures; (2) dynamic motions of short duration (30s); and (3) dynamic motions of long duration (30min). The results showed that the root mean square (RMS) error of the HS was generally below 3 degrees for the flexion and lateral bending axes, and less than 6 degrees for the torsion axis, and that this error was lower for the short-duration tests compared to the long-duration one. The potentiometer proved to be an essential addition, particularly when the magnetometer signals were corrupted and only the gyroscope and accelerometer could be combined. It is concluded that the HS can be a useful tool for quantifying 3D trunk posture in motion.

Benefit of continuous treatment for responders with newly diagnosed multiple myeloma in the randomized FIRST trial.

The phase 3, randomized Frontline Investigation of Revlimid and Dexamethasone Versus Standard Thalidomide (FIRST) trial investigating lenalidomide plus low-dose dexamethasone until disease progression (Rd continuous) vs melphalan, prednisone and thalidomide for 12 cycles (MPT) and Rd for 18 cycles (Rd18) in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM) showed that Rd continuous prolonged progression-free survival and overall survival compared with MPT. A subanalysis of the FIRST trial was conducted to determine the benefits of Rd continuous in patients with NDMM based on depth of response. Patients randomized 1:1:1 to Rd continuous, Rd18 or MPT were divided into subgroups based on best response: complete response (CR; n=290), ⩾very good partial response (VGPR; n=679), ⩾partial response (PR; n=1 225) or ⩽stable disease (n=299). Over 13% of patients receiving Rd continuous who achieved ⩾VGPR as best response did so beyond 18 months of treatment. Rd continuous reduced the risk of progression or death by 67%, 51% and 35% vs MPT in patients with CR, ⩾VGPR and ⩾PR, respectively. Similarly, Rd continuous reduced the risk of progression or death by 61%, 54% and 38% vs Rd18 in patients with CR, ⩾VGPR and ⩾PR, respectively. In patients with CR, ⩾VGPR or ⩾PR, 4-year survival rates in the Rd continuous arm (81.1%, 73.1% or 64.6%, respectively) were higher vs MPT (70.8%, 59.8% or 57.2%, respectively) and similar vs Rd18 (76.5%, 67.7% and 62.5%, respectively). Rd continuous improved efficacy outcomes in all responding patients, including those with CR, compared with fixed duration treatment.

Sequence and gene organization of the chicken mitochondrial genome. A novel gene order in higher vertebrates.

The 16,775 base-pair mitochondrial genome of the white Leghorn chicken has been cloned and sequenced. The avian genome encodes the same set of genes (13 proteins, 2 rRNAs and 22 tRNAs) as do other vertebrate mitochondrial DNAs and is organized in a very similar economical fashion. There are very few intergenic nucleotides and several instances of overlaps between protein or tRNA genes. The protein genes are highly similar to their mammalian and amphibian counterparts and are translated according to the same variant genetic code. Despite these highly conserved features, the chicken mitochondrial genome displays two distinctive characteristics. First, it exhibits a novel gene order, the contiguous tRNA(Glu) and ND6 genes are located immediately adjacent to the displacement loop region of the molecule, just ahead of the contiguous tRNA(Pro), tRNA(Thr) and cytochrome b genes, which border the displacement loop region in other vertebrate mitochondrial genomes. This unusual gene order is conserved among the galliform birds. Second, a light-strand replication origin, equivalent to the conserved sequence found between the tRNA(Cys) and tRNA(Asn) genes in all vertebrate mitochondrial genomes sequenced thus far, is absent in the chicken genome. These observations indicate that galliform mitochondrial genomes departed from their mammalian and amphibian counterparts during the course of evolution of vertebrate species. These unexpected characteristics represent useful markers for investigating phylogenetic relationships at a higher taxonomic level.

Putative chicken "muscle-specific 7 S RNA" is related to the mitochondrial ATPase 6 gene.

Sequence analysis of the mitochondrial ATPase 6 gene from chicken revealed that its 3' region is virtually identical with a chicken muscle-specific 7 S RNA which was reported to induce the expression of tissue-specific functions in blastoderm explants. Using chicken and quail cell lines depleted of mitochondrial DNA, we demonstrate that the 7 S RNA is encoded by the mitochondrial genome and not by nuclear (repetitive) DNA as suggested previously. Moreover, no 7 S RNA-homologous transcript of the expected length (about 400 bases) is detected, either in these cell lines or in heart and liver tissues. The only RNA species hybridizing with a 7 S RNA-specific probe is an abundant, 900 base long transcript of mitochondrial origin that we identify as the ATPase 8-ATPase 6 fused messenger. We suggest that the characterized muscle-specific 7 S RNA cDNA is derived from an unrelated contaminant in the blastoderm-inducing fraction.

Analgesic efficacy of piroxicam in postoperative dental pain.

The severity of postoperative dental pain can be variable depending on the type of procedure. Both centrally acting and peripherally acting analgesics, such as nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, and acetaminophen are used. NSAIDs are generally better suited to ambulatory outpatients. The most commonly used postoperative dental pain model includes patients who have undergone surgical removal of impacted third molar teeth. The analgesic efficacy of piroxicam in this pain model was studied both in the United States and in foreign centers. The foreign studies suggest that piroxicam at 20-mg doses produces analgesia in patients with postoperative dental pain. Seven single-dose, randomized, double-blind trials of 798 patients in the United States more clearly evaluated the efficacy of piroxicam. These studies used various doses of piroxicam (5, 10, 20, and 40 mg), aspirin 648 mg, and placebo. Safety results showed that a wide range of piroxicam doses were safe when administered in single doses. Although neither piroxicam 5 mg nor 10 mg produced clinically significant analgesia, 20-mg and 40-mg doses were significantly superior to placebo and both were comparable with aspirin 648 mg over the initial six hours. Piroxicam 20 mg and 40 mg, however, produced significantly longer durations of analgesia than aspirin 648 mg, and it appears that the analgesic effect of piroxicam may extend for up to 24 hours in a substantial proportion of patients.

Polyomavirus large T-antigen binds the "pRb related' protein p130 through sequences in conserved region 2.

The transforming potential of DNA tumor viruses derives mainly from the ability of their encoded oncogene products to interact with cellular proteins. Many of these viral oncoproteins share regions of sequence similarity, designated conserved region 1 and 2, which have been implicated in complex formation with pRb, the product of the retinoblastoma tumor suppressor gene, and related p107 and p130 species. It has now been shown that the EIA protein of adenovirus is able to bind to all three pRb-related proteins through sequences in conserved region 1 and 2. We have shown previously that polyomavirus large T-antigen also interacts with pRb and p107 in vitro. The pRb and p107 binding domains reside between residues 141, 158 which include conserved region 2. In the present study, we demonstrate that polyomavirus large T-antigen also interacted with p130 in vitro through the same sequences in conserved region 2.

Docetaxel and Gemcitabine administered on days 1 and 8 for metastatic non-small cell lung carcinoma (NSCLC): a phase II multicenter trial.

Docetaxel and Gemcitabine are active agents in non-small cell lung carcinoma (NSCLC). They have different mechanism of action, minimal overlapping toxicity, and are easily administered on an outpatient basis. This phase II study evaluated Docetaxel administered with Gemcitabine on days 1 and 8 in a 3-week cycle, to determine its efficacy, while attempting to lower the regimen's toxicity, especially myelosuppression which can occur when Docetaxel is administered at full dose on day 1 only. Forty-three chemonaive patients, 40 evaluable, were entered in this trial between May 2001 and March 2002. Thirty-seven patients had stage IV and three patients had stage III B NSCLC, median age 58 (ages 32-78), median performance status (PS) 1 (range 0-2). They were treated with Docetaxel 36mg/m(2) and Gemcitabine 1000mg/m(2) intravenously on days 1 and 8 in a 3-week cycle. No growth factors were administered. Of 40 evaluable patients, 4 achieved partial response (10%), 25 stable disease (62.5%) and 11 progressive disease (27.5%). Median time-to-disease progression was 15 weeks. Median survival was 7.75 months. One year survival was 32.5% (13 patients). Hematologic toxicity was minimal, non-hematologic toxicity was easily treatable. Docetaxel, when given with Gemcitabine on days 1 and 8 every 3 weeks, is less myelotoxic, yet still an effective treatment for metastatic NSCLC.

Pathway for the strain-driven two-dimensional to three-dimensional transition during growth of Ge on Si(001)

The two-dimensional (2D) to three-dimensional (3D) morphological transition in strained Ge layers grown on Si(001) is investigated using scanning tunneling microscopy. The initial step takes place via the formation of 2D islands which evolve into small ( approximately 180 A) 3D islands with a height to base diameter ratio of approximately 0.04, much smaller than the 0.1 aspect ratio of 105-faceted pyramids which had previously been assumed to be the initial 3D islands. The "prepyramid" Ge islands have rounded bases with steps oriented along <110> and exist only over a narrow range of Ge coverages, 3.5-3.9 monolayers.

Isolation and characterization of hamster brain polyribosome-cytomatrix complexes.

We have developed a method for the isolation of a brain subcellular fraction enriched in both highly aggregated polyribosomes and cytoskeletal proteins. This method is based on gentle dispersion of brain tissue and low speed centrifugation. This fraction is enriched in typical cytoskeletal proteins as glial fibrillary protein, neurofilament proteins and actin. Messenger RNA did not seem to be involved in the polyribosome association to the cytomatrix as shown by the effect of exposure to micrococcal nuclease. On the other hand, in vivo disruption of protein synthesis by acute experimental phenylketonuria, hypothermia or heat-shock did not cause the release of ribosomes from the cytomatrix.

Increased expression of glyceraldehyde-3-phosphate dehydrogenase in cultured astrocytes following exposure to manganese.

Manganism is a disorder characterized by hyperintensities in basal ganglia structures on magnetic resonance imaging which may be the consequence of manganese deposition in these areas. Since manganese is taken up avidly into astrocytes and is known to interfere with cerebral energy metabolism, we studied the effect of this metal on the expression and activity of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in primary cultures of astrocytes. Treatment with 100 microM manganese for 7 days increased both the Vmax and Km values for GAPDH which was not reproducible with other divalent metals. Using RT-PCR, increased GAPDH expression was detected in cells exposed to manganese compared with controls. No changes in cytochrome oxidase activity or ATP levels were observed, and lactate production was unaffected, in manganese-treated cells. These findings provide evidence of a possible role for GAPDH in the mediation of the effects of manganese on central nervous system function.

Effects of ammonia on glutamate transporter (GLAST) protein and mRNA in cultured rat cortical astrocytes.

Ammonia is a neurotoxic substance which accumulates in brain in liver failure and it has been suggested that ammonia plays a key role in contributing to the astrocytic dysfunction characteristic of hepatic encephalopathy. In particular, the effects of ammonia may be responsible for the reduced astrocytic uptake of neuronally-released glutamate and high extracellular glutamate levels consistently seen in experimental models of hepatic encephalopathy. To further address this issue, [(3)H]-D-aspartate uptake was examined in primary rat cortical astrocyte cultures exposed to 5 mM ammonium chloride for a period of 7 days. In addition, reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot studies were performed to examine the mRNA and protein expression respectively of the glutamate transporter GLAST in ammonia-treated cells. Studies revealed a 57% (p<0.05) decrease in [(3)H]-D-aspartate uptake and a concomitant significant decrease in GLAST transporter protein (43%, p<0.05) and mRNA (32%, p<0.05) expression. The reduced capacity of astrocytes to reuptake glutamate following ammonia exposure may result in compromised neuron-astrocyte trafficking of glutamate and could thus contribute to the pathogenesis of the cerebral dysfunction characteristic of hyperammonemic syndromes such as hepatic encephalopathy.

Portacaval anastomosis causes selective alterations of peripheral-type benzodiazepine receptor expression in rat brain and peripheral tissues.

There is a growing body of evidence to suggest that peripheral-type benzodiazepine receptors (PTBRs) and their endogenous ligands are implicated in the pathogenesis of end-organ failure in chronic liver disease. Portal-systemic encephalopathy, a major neuropsychiatric complication associated with chronic liver disease, results in activation of brain PTBR and probably in peripheral organs. In order to address these issues, PTBR mRNA was measured using semi-quantitative RT-PCR in extracts of cerebral cortex, kidney and testis of rats four weeks after end-to-side portacaval anastomosis and sham-operation (controls). Densities of PTBR sites were measured concomitantly by in vitro receptor binding using the selective PTBR ligand [3H]PK11195. Portacaval shunting resulted in a 2 to 3-fold increase in expression of PTBR in brain and kidney and a 37% reduction in expression in testis. Densities of [3H]PK11195 sites changed in parallel with the alterations of gene expression. These findings suggest that selective alterations of PTBR expression are implicated in the pathogenesis of peripheral tissue hypertrophy (kidney) and/or atrophy (testis) which accompanies portal-systemic shunting in chronic liver failure. In brain, activation of PTBR could result in an increase in the production of neurosteroids with potent inhibitory action in the CNS, which could contribute to the pathogenesis of portal-systemic encephalopathy.