Efficacy and safety of delafloxacin compared with vancomycin plus aztreonam for acute bacterial skin and skin structure infections: a Phase 3, double-blind, randomized study.

BACKGROUND: Delafloxacin is an investigational anionic fluoroquinolone in development for oral or intravenous administration for the treatment of infections caused by Gram-positive (including MRSA), Gram-negative, atypical and anaerobic organisms. OBJECTIVES: To establish the non-inferiority of delafloxacin compared with vancomycin plus aztreonam for the treatment of acute bacterial skin and skin structure infections and to compare the safety of the two antimicrobials. PATIENTS AND METHODS: A Phase 3, multicentre, randomized, double-blind, active-controlled study with 660 patients compared delafloxacin 300 mg or vancomycin 15 mg/kg plus aztreonam 2 g each administered twice daily intravenously for 5-14 days. Non-inferiority was evaluated by objective response (≥20% erythema reduction) at 48-72 h after initiation of study drug, investigator subjective assessment of outcome and microbiological responses. Clinical Trials Registration: NCT01811732. EudraCT number: 2012-001767-71. RESULTS: In the ITT analysis set, the objective response was 78.2% in the delafloxacin arm and 80.9% in the vancomycin/aztreonam arm (mean treatment difference, -2.6%; 95% CI, -8.78% to 3.57%). Investigator-assessed cure was similar between the two groups at follow-up (52.0% versus 50.5%) and late follow-up (70.4% versus 66.6%). Bacterial eradication of MRSA was 100% and 98.5% in the delafloxacin group and the vancomycin/aztreonam group, respectively. Frequency of treatment-emergent adverse events in the delafloxacin and vancomycin/aztreonam groups was similar. Treatment-emergent adverse events leading to study drug discontinuation were higher in the vancomycin/aztreonam group compared with the delafloxacin group (4.3% versus 0.9%). CONCLUSIONS: Delafloxacin, an anionic fluoroquinolone, was statistically non-inferior to vancomycin/aztreonam at 48-72 h following the start of therapy and was well tolerated as monotherapy in the treatment of acute bacterial skin and skin structure infections.

Validation of a suite of ERP and QEEG biomarkers in a pre-competitive, industry-led study in subjects with schizophrenia and healthy volunteers.

OBJECTIVE: Complexity and lack of standardization have mostly limited the use of event-related potentials (ERPs) and quantitative EEG (QEEG) biomarkers in drug development to small early phase trials. We present results from a clinical study on healthy volunteers (HV) and patients with schizophrenia (SZ) that assessed test-retest, group differences, variance, and correlation with functional assessments for ERP and QEEG measures collected at clinical and commercial trial sites with standardized instrumentation and methods, and analyzed through an automated data analysis pipeline. METHODS: 81 HV and 80 SZ were tested at one of four study sites. Subjects were administered two ERP/EEG testing sessions on separate visits. Sessions included a mismatch negativity paradigm, a 40 Hz auditory steady-state response paradigm, an eyes-closed resting state EEG, and an active auditory oddball paradigm. SZ subjects were also tested on the Brief Assessment of Cognition (BAC), Positive and Negative Syndrome Scale (PANSS), and Virtual Reality Functional Capacity Assessment Tool (VRFCAT). RESULTS: Standardized ERP/EEG instrumentation and methods ensured few test failures. The automated data analysis pipeline allowed for near real-time analysis with no human intervention. Test-retest reliability was fair-to-excellent for most of the outcome measures. SZ subjects showed significant deficits in ERP and QEEG measures consistent with published academic literature. A subset of ERP and QEEG measures correlated with functional assessments administered to the SZ subjects. CONCLUSIONS: With standardized instrumentation and methods, complex ERP/EEG testing sessions can be reliably performed at clinical and commercial trial sites to produce high-quality data in near real-time.

Catecholamine and dibutyryl cyclic AMP effects on myosin adenosine triphosphatase in cultured rat heart cells.

Catecholamines and dibutyryl adenosine 3', 5'-monophosphate (dibutyryl cyclic AMP) increase the activity of myosin adenosine triphosphatase in cultured rat heart cells. Dichloroisoproterenol, an inhibitor of the beta receptor of the catecholamines, inhibits the action of the catecholamines but not of cyclic AMP.

Erythroid differentiation of K562 cells: mixed colonies as an index of delayed expression of commitment.

K562 cells demonstrate commitment, defined as the clonal expression of a differentiated phenotype coupled with a limitation in proliferation. Upon exposure to certain agents, K562 cells are induced to synthesize hemoglobin, detectable by benzidine staining. If plated in semisolid medium, they produce benzidine-positive colonies, benzidine-negative colonies, and mixed colonies, the latter containing both positive and negative cells. To test whether or not mixed colonies represent a delay in the expression of commitment, we conducted two types of experiments. The first type showed that, following inducer removal, a delay in plating causes not only a decline in the number of mixed colonies, but also a rise in the proportion of negative colonies, with no change in the proportion of positive colonies. To explain this result, we propose that a plating delay can conceal a negative cell producing a positive cell if that cell division has occurred before plating. Instead of one mixed colony, one observes one positive colony and one other colony, either negative or mixed (depending on subsequent negative-to-positive events). Thus delay does not change the proportion of positive colonies, presumably because they breed true. But delay causes an increase in negative colonies to balance the decrease in mixed colonies due to concealment of negative-to-positive events and provides evidence that the converse, positive-to-negative events, do not occur. The second type of experiment utilized cordycepin, which inhibits commitment. We predicted that, if mixed colonies represent a delay in the expression of commitment, the addition of cordycepin to cells already exposed to thymidine should increase the percentage of mixed colonies. We found that cordycepin does indeed preferentially increase the proportion of mixed colonies. These two types of experiments provide evidence that mixed colonies represent a delay in expression of commitment. Such an inducible system, in which the commitment event and its expression can be separated in time by a generation or more, may provide an opportunity to more fully characterize the commitment process.

Inducers of erythroid differentiation in K562 human leukemia cells.

A variety of agents, including many known to induce erythroid differentiation in Friend murine erythroleukemia cells, were tested for their ability to induce erythroid differentiation in K562 humane erythroleukemia cells. Cells were grown in suspension culture and scored for erythroid differentiation by benzidine staining. Of 39 agents tested, 19 induced erythroid differentiation in K562 cells and 20 did not. A striking effect of the type of serum employed in the medium was observed. The majority of the agents inducing erythroid differentiation in medium containing fetal calf serum showed little activity in medium containing newborn calf serum.

K562 cell erythroid differentiation: requirement for a factor in fetal bovine serum.

K562 human erythroleukemia cells can be induced to make hemoglobin by a variety of inducing agents. Most of these agents are effective in media supplemented with fetal bovine serum (FBS), but not in media supplemented with newborn bovine serum (NBS). The active factor in FBS has an apparent molecular weight of 30,000 daltons and appears to be a protein on the basis of the following properties: lability at 100 degrees C, inactivation by desferrioxamine plus trypsin, resistance to periodate, and resistance to ribonuclease. Media containing NBS can be used for induction if supplemented by either this factor or transferrin of bovine or human origin. The small size of the active factor (mol. wt. approximately 30,000 daltons) indicates that it is not identical to bovine transferrin (mol. wt. approximately 77,000 daltons). However, when iron-saturated bovine transferrin is digested with trypsin, the peptide fragments produced resemble the FBS factor in activity, size, and reaction with antibovine serum transferrin.

Results of directional coronary atherectomy during multicenter preapproval testing. The US Directional Coronary Atherectomy Investigator Group.

Between 1988 and 1990, clinical testing was performed at 12 US institutions using the Simpson Coronary AtheroCath under an Investigational Device Exemption. Data on 1,069 lesions (873 patients) were analyzed and presented to the Food and Drug Administration (FDA) advisory panel in the summer of 1990, forming the basis for approval of this device in September 1990. Analysis of these preapproval data shows a primary success rate of 85% (defined as tissue removal, > or = 20% reduction in stenosis, < 50% residual stenosis after directional atherectomy, and no major complication), with somewhat higher primary success in prior restenosis and noncalcified lesions. Including the use of conventional angioplasty performed after atherectomy, the overall success rate was 92%. One or more major complications occurred in 4.9% of procedures, and included death (0.5%), nonfatal Q-wave myocardial infarction (0.9%), and emergency bypass surgery (4.0%). These complications were more frequent in right coronary, de novo, and diffuse (> 20-mm length) lesions. Six-month angiography results were available in 384 (77%) of 498 lesions eligible for follow-up when the registry closed and showed a restenosis rate (late stenosis > 50%) of 42%. The restenosis rate in both native vessels (30 vs 46%) and bypass grafts (31 vs 68%) was lower in primary (de novo) lesions compared with lesions that had developed restenosis after a prior intervention. Despite the use of prototype atherectomy catheters and still evolving procedural technique, this preapproval experience provided an important initial indication of the situations in which directional coronary atherectomy was most useful and helped set clear standards for performance of this procedure following FDA approval.

Induction of the fms proto-oncogene product in HL-60 cells by vitamin D: a flow cytometric analysis.

Agents which induce monocytic characteristics in HL-60 human acute promyelocytic leukemia cells induce mRNA for the fms proto-oncogene, which encodes the receptor for M-CSF. Previous studies of fms expression in HL-60 cells have characterized chiefly induction by phorbol esters of fms mRNA. Our studies of fms expression in HI-60 cells have characterized induction by vitamin D3 of the fms protein. We have used flow cytometry to correlate fms antigen with a monocyte-specific differentiation antigen recognized by antibody MO2 (CD14), with DNA content, and with the nuclear antigen Ki-67, a marker of cell cycling. HL-60 cells were cultured with or without 1 microM vitamin D for 7 days. fms antigen was found on 42 +/- 5.8% of the cells cultured without vitamin D, but on 63 +/- 4.3% of the cells cultured with vitamin D. MO2 binding was detected on only 2 +/- 0.5% of the cells without vitamin D, but on 59 +/- 9% with vitamin D. Cells cultured with vitamin D that were fms-positive were also predominantly (83%) MO2-positive. Analysis of DNA content, measured by propidium iodide staining, showed that 57 +/- 1.5% of cells cultured without vitamin D, but 93 +/- 0.5% of cells cultured with vitamin D, were in the G0/G1 cell cycle phase. Analysis of nuclear antigen Ki-67 revealed that, of the vitamin D-treated cells that were fms-positive, a significant proportion (37%) were still cycling. We conclude that (1) fms is demonstrable on some uninduced HL-60 cells, (2) when HL-60 cells are induced to develop monocytic characteristics by vitamin D, fms induction is part of the program for monocytic differentiation that includes MO2 expression, yet (3) some induced cells expressing fms are still cycling.

Multipotent human hematopoietic cell line K562: lineage-specific constitutive and inducible antigens.

K562 cells have been reported to display a variety of non-erythroid properties. Using 28 lineage-specific monoclonal antibodies, we analysed which antigens are present spontaneously and which are inducible by a variety of agents. The data suggest that (1) antigens of a given lineage are preferentially responsive to certain inducers, e.g. megakaryocytic antigens to phorbol ester, and (2) a given inducer may influence antigens of different lineages in opposite directions, e.g. phorbol dibutyrate, not only induces megakaryocytic antigens, but also decreases granulocyte and erythroid antigens. We conclude that the K562 cell, despite its malignant origin, retains some capacity for expression of alternative programs of differentiation, a characteristic of the normal multipotent hematopoietic stem cell.

Induction of megakaryocytic characteristics in human leukemic cell line K562: polyploidy, inducers, and secretion of mitogenic activity.

Because of the rarity of megakaryocytes in the bone marrow, a cell line inducible for megakaryocytic characteristics provides a valuable model for study. When cultured with phorbol esters, the human multipotent hematopoietic leukemic cell line K562 can be induced to develop many megakaryocytic characteristics, viz. increased cell size, reduced growth rate, megakaryocytic antigens, and expression of the sis proto-oncogene, the structural gene for the B-chain of platelet-derived growth factor. Further aspects of this process are here presented. First, it induces the release of mitogenic activity into the medium. Second, phorbol dibutyrate induces polyploidy, a feature of normal megakaryocyte development. Third, mezerein and teleocidin, nonphorbol ester tumor promotors, also induce development of multinuclearity and polyploidy.

Preparation of physical therapists to work with handicapped infants and their families: current status and training needs.

The purposes of this study were to determine the current status of physical therapists' preparation to work with handicapped and at-risk infants and their families and to identify needs for infant- and family-focused training materials and curricula. Results of a telephone survey of 73 physical therapy programs and a follow-up mail survey of 14 physical therapy programs with infancy specialization options are presented. Students in entry-level programs and postprofessional master's degree programs with infancy specializations commonly received instruction in infancy-related topics. Many students received minimal or no exposure to family-related content. Family assessment and intervention were identified as the areas of highest priority for development of training materials and curricula. The results of this study provide direction for the design of infant- and family-focused training materials and curricula in physical therapy.

The medical device industry and the biomedical engineer: current status and future trends.

The role of new and existing technology in the development of medical devices is examined. The impact of competition and economic and regulatory pressures is assessed. The identification of clinical needs is discussed. These include the needs to reduce liability, find less invasive alternatives to surgery, improve the quality of life, and prevent disease. Career opportunities are considered in some detail.

The effect of region of interest variations on morphologic operations data and gray-level values extracted from digitized dental radiographs.

OBJECTIVE: To determine the correlations among morphologic operations (MO) values and the correlations among gray-level values for regions of interest (ROIs) placed at various locations on digital images of alveolar bone for 45 patients. STUDY DESIGN: As part of a larger study, up to 7 vertical bite-wing radiographs were taken and digitized for each of 45 patients. Sets of 2 rectangular ROIs were placed on the digitized images of interdental alveolar bone at 4 locations for each patient. The ROIs (1 crestal and 1 apical) were placed between second premolars and first molars in all 4 dental quadrants. Gray-level values were measured, and MO analysis was performed on each ROI. Descriptive statistics were calculated and correlations determined. RESULTS: Paired correlations (such as apical vs crestal, left vs right, maxillary apical vs mandibular apical) of MO values were weak (r = 0.01-0.21), but corresponding correlations for gray-level values were relatively strong (r = 0. 60-0.92). CONCLUSION: MO values varied with ROI location considerably more than did gray-level values. Additionally, ROI size and shape apparently affected MO data. Accurate placement and documentation of ROIs appear to be critical considerations in analyses that use MOs.

Retrofitting an esthetic post and core to salvage a six-unit fixed partial denture.

Teeth restored with post and core restorations present a clinical dilemma if they fracture. An individual with a maxillary anterior six-unit fixed partial denture had one of the canine abutment teeth fracture. The other abutment debonded and the post separated from the core. The fixed partial denture was salvaged by retrofitting a porcelain-fused-to-metal post and core restoration in the fractured abutment.

Exercise and neuroplasticity in persons living with Parkinson's disease.

For many years, exercise was not a recommended rehabilitation strategy for persons with a diagnosis of idiopathic Parkinson's disease (PD). Since it was believed that exercise had no measurable effect on PD, or might worsen the underlying pathology, it was to be avoided. A rich vein of bench and translational research now suggest non-pharmacological approaches, such as exercise or physiotherapy, have a far greater effect on the cardinal features of PD than previously believed. In particular, recent studies utilizing animal models of PD have begun to explore the molecular mechanisms of exercise-induced changes in the pathophysiology of PD. Yet, many clinicians and communities remain unaware of the scientific literature underlying exercise-induced brain repair or reorganization (neuroplasticity) and accompanying behavioral recovery in animal models of PD. The authors will summarize some noteworthy preliminary studies suggesting that continuous, deficit targeted, intensive training may confer neuroprotection and thereby, slow, stop or reverse the progression of the disease or promote neurorestoration through adaptation of compromised signaling pathways. While much work remains and these preliminary results await replication in larger prospective human trials, we believe a major challenge in the field of non-pharmacological, rehabilitative intervention for PD will be the extent to which healthcare providers are able to translate the science of exercise and PD to the level of the community.

Trunk muscle activity during the simultaneous performance of two motor tasks.

A unique feature of trunk muscles is that they can be activated to meet functional requirements for combined behaviors, including those related to posture and breathing. Trunk muscles therefore may have developed mechanisms for dealing with simultaneous inputs for different task requirements. This study was designed to test the hypothesis that a linear addition in trunk muscle activities would occur when an isometric trunk task and a pulsed expiration task was performed simultaneously. Surface electromyograms (EMG) were recorded from four trunk regions (medial and lateral back, upper and lower lateral abdomen) in sitting during the performance of the individual isometric trunk task, the individual pressure task, and the combined task (isometric trunk and pressure task). The direction of static holding for the isometric trunk task was varied between flexion and extension positions. For the pressure task subjects produced two consecutive pressure pulses (2/s) to a target oral pressure. For each muscle recording, a linear prediction was calculated from the mathematical addition of the EMG recorded from the individual trunk and pressure tasks. This linear prediction was compared to the actual muscle activity recorded during the combined task. Typically the EMG from two muscles showed linear addition, such that the relative contribution of muscle activity did not change for the combined task. This suggests that the motor commands for each task reached these motor neuron pools essentially unmodified. The other two muscles showed nonlinear combination of two EMG patterns. That is, qualitatively both EMG patterns, specific to each command, were evident in the measured EMG traces for the combined task, but quantitatively the muscle did not meet all criteria for linear addition. Linear addition may provide a simple mechanism for combining breathing-related behaviors (expiratory efforts) with other trunk behaviors (holding against gravity). This suggests that some muscles can be shared for two different voluntary tasks without changing their contribution to either component task. At the same time, nonlinear combination suggests that some muscles are shared, but their contribution to either component task may be modulated, thus avoiding the construction of a third new and unique plan.