Digit displacement, not object compliance, underlies task dependent modulations in human corticomuscular coherence

Human sensorimotor EEG shows oscillatory activity at approximately 10 and approximately 20 Hz; the latter frequency is coherent with contralateral EMG. The functional significance of this activity is obscure. A recent study found that corticomuscular coherence varied systematically with increasing lever compliance during a precision grip task. However, since subjects exerted the same force in all conditions, changes in lever compliance also produced changes in how far the digits moved. In this study, we disambiguated whether corticomuscular coherence modulates with object compliance or digit displacement. Subjects performed a precision grip task. Under computer control, the manipulandum could simulate a load of arbitrary compliance (spring constant). Subjects were required to produce a hold-ramp-hold profile of lever displacement, under visual feedback. Subjects first performed tasks with different sized lever movements, against an isotonic load (zero spring constant). Corticomuscular coherence was calculated between left sensorimotor EEG and EMG from five right hand and forearm muscles during the hold phase of the task. Coherence magnitude showed a clear dependence on the extent of digit displacement. In the next task, lever compliance instantaneously changed at the onset of the second hold phase of the task. Corticomuscular coherence modulated not with lever compliance during the analysed hold phase, but with digit displacement during the preceding ramp movement. These data suggest that human corticomuscular coherence is directly related to digit displacement during the preceding movement and not to object compliance. We speculate that corticomuscular coherence may reflect a sensorimotor recalibration, providing updated information about system state following movement.     

DNA damage is a novel response to sublytic complement C5b-9-induced injury in podocytes

In response to Ab-complement-mediated injury, podocytes can undergo lysis, apoptosis, or, when exposed to sublytic (<5% lysis) amounts of C5b-9, become activated. Following the insertion of sublytic quantities of C5b-9, there is an increase in signaling pathways and growth factor synthesis and release of proteases, oxidants, and other molecules. Despite an increase in DNA synthesis, however, sublytic C5b-9 is associated with a delay in G(2)/M phase progression in podocytes. Here we induced sublytic C5b-9 injury in vitro by exposing cultured rat podocytes or differentiated postmitotic mouse podocytes to Ab and a complement source; we also studied the passive Heymann nephritis model of experimental membranous nephropathy in rats. A major finding was that sublytic C5b-9-induced injury caused an increase in DNA damage in podocytes both in vitro and in vivo. This was associated with an increase in protein levels for p53, the CDK inhibitor p21, growth-arrest DNA damage-45 (GADD45), and the checkpoint kinases-1 and -2. Sublytic C5b-9 increased extracellular signal-regulated kinase-1 and -2 (ERK-1 and -2), and inhibiting ERK-1 and -2 reduced the increase in p21 and GADD45 and augmented the DNA damage response to sublytic C5b-9-induced injury. These results show that sublytic C5b-9 induces DNA damage in vitro and in vivo and may explain why podocyte proliferation is limited following immune-mediated injury.     

RSV604, a novel inhibitor of respiratory syncytial virus replication

Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infections worldwide, yet no effective vaccine or antiviral treatment is available. Here we report the discovery and initial development of RSV604, a novel benzodiazepine with submicromolar anti-RSV activity. It proved to be equipotent against all clinical isolates tested of both the A and B subtypes of the virus. The compound has a low rate of in vitro resistance development. Sequencing revealed that the resistant virus had mutations within the nucleocapsid protein. This is a novel mechanism of action for anti-RSV compounds. In a three-dimensional human airway epithelial cell model, RSV604 was able to pass from the basolateral side of the epithelium effectively to inhibit virus replication after mucosal inoculation. RSV604, which is currently in phase II clinical trials, represents the first in a new class of RSV inhibitors and may have significant potential for the effective treatment of RSV disease.     

Quantifying normal 3D hip ROM in healthy young adult males with clinical and laboratory tools: hip mobility restrictions appear to be plane-specific

Background

Hip mobility is known to affect lumbar spine motion, yet the literature is unclear as to what constitutes normal, limited or excessive motion, given differences in methods, postures, age, etc. The purpose of this study was to establish normative and percentile data for hip rotation and extension, in a young adult male population, using varying methods of quantification.

Methods

77 males (age 18–35) were recruited. Position data was captured using the Vicon Motion capture system, as participants were passively positioned in hip extension (using the Modified Thomas test) and prone hip rotation. 22 of these participants also had measurements obtained with a goniometer. 3D hip extension angles were calculated using Euler angles, and compared to those calculated in 2D. Goniometric results were compared to 2D measurements.

Findings

Normal distribution of hip extension and rotation range of motion was established, as were average values for the 5th through 95th percentiles. No significant differences existed between hip extension angles measured with the 2D and 3D approaches. Goniometric measurements of hip extension averaged 3.9° less than 2D, less than 1° different for external rotation, and not different for internal rotation.

Interpretation

The normative and percentile data documented here for hip rotation and extension appear to be validly quantified with goniometric techniques when compared to more objective techniques. Further, hip restriction in one plane may not predict restrictions in other planes.     

Glucose plus insulin regulate fat oxidation by controlling the rate of fatty acid entry into the mitochondria.

We tested the hypothesis that glucose plus insulin determine the rate of fat oxidation in humans by controlling the rate of fatty acid entrance into the mitochondria. We gave constant infusions of [1-13C]oleate, a long-chain fatty acid, and [1-14C]octanoate, a medium-chain fatty acid, for 3 h in seven volunteers (basal). Immediately after the basal period, a hyperinsulinemic (insulin infusion = 120 mU x m(-2) min(-1)), hyperglycemic (plasma glucose = 140 mg/dl) clamp was started and continued for 5 h. During the last 3 h of the clamp, the infusions of [1-13C]oleate and [1-14C]octanoate were repeated. Intracellular acylcarnitine concentrations were measured in muscle biopsies obtained before and after the clamp. Plasma oleate enrichment and FFA concentration were kept constant by means of variable infusions of lipids and heparin. Oleate, but not octanoate, requires carnitine binding to gain access to the mitochondrial matrix; hence, if glucose and/or insulin limit long-chain fatty acid entrance into the mitochondria, then, during the clamp, long-chain acylcarnitine formation should be decreased, causing a decrease in oleate, but not octanoate, oxidation. Oleate oxidation decreased from the basal value of 0.7+/-0.1 to 0.4+/-0.1 micromol x kg(-1) x min(-1) (P < 0.05). In contrast, octanoate oxidation remained unchanged. Long-chain acylcarnitine concentration decreased from 855+/-271 in the basal state to 376+/-83 nmol/gram dry weight during the clamp (P < 0.05). We conclude that glucose and/or insulin determine fatty acid oxidation by controlling the rate of long-chain fatty acid entrance into the mitochondria.     

Nature and specificity of the immune response to collagen in type II collagen-induced arthritis in mice.

Autopsy findings suggest that lung surfactant is damaged in the adult respiratory distress syndrome. In the present study 225 bronchoalveolar lavage specimens (78 from 36 patients, 1-78 yr old with respiratory failure, 135 from another 128 patients with other respiratory disease, and 12 from healthy controls) were assayed for the lung profile [lecithin/sphingomyelin (L/S) ratio, saturated lecithin, phosphatidylinositol, and phosphatidylglycerol]. Bronchoalveolar lavage fluid was further analyzed for phospholipids and for phosphatidic acid phosphohydrolase, phospholipase A2, and phosphatidylinositol phosphodiesterase activities. A lipid-protein complex was isolated and analyzed for surface activity, and plasma was measured for myoinositol. There were only small differences seen in the recovery of total phospholipid between respiratory failure patients and normal controls. However, in respiratory failure, phospholipids in bronchoalveolar lavage were qualitatively different from those recovered either from normal controls or from patients with other lung disease: the LO/S ratio, phosphatidylglycerol, and disaturated lecithin were low, whereas sphingomyelin and phosphatidylserine were prominent. These abnormalities were present early in respiratory failure and tended to normalize during recovery. Low L/S ratio (less than 2), and low phosphatidylglycerol (1% or less of glycerophospholipids) in bronchoalveolar lavage was always associated with respiratory failure. Abnormal lavage phospholipids were not due to plasma contamination. The phospholipase studies revealed little evidence of increased catabolism of phospholipids. In respiratory failure, the lipid-protein complexes from lung lavage were not surface active, whereas that from healthy controls had surface properties similar to lung surfactant. Phospholipids from patients with respiratory failure were similar to those from respiratory distress syndrome in the newborn. However, the latter condition is characterized by fast recovery of surfactant deficiency and by high plasma myoinositol that suppresses the synthesis of surfactant phosphatidylglycerol and increases phosphatidylinositol (Pediatr. Res. 1981. 15: 720). On the other hand, in adult respiratory distress syndrome, the abnormality in surfactant phospholipids may last for weeks and in most cases is associated with low phosphatidylinositol, low phosphatidylglycerol, and low plasma myoinositol.     

Electrophysiologic latency to the external obliques of the laryngeal cough expiration reflex in humans

OBJECTIVE: The purpose of this study was to trigger the laryngeal cough expiration reflex using inhaled tartaric acid aerosol and to record the latency between the time of initiation of the laryngeal cough expiration reflex component of the laryngeal cough reflex and the onset of electromyographically recorded responses in the external abdominal oblique in humans. DESIGN: Five male subjects were tested in the seated position, and four latencies were recorded for each subject. The latencies were recorded from laryngeal stimulation to an electromyogram in the muscle belly of the left external abdominal oblique. The time line was activated by a microswitch attached to a breath-activated nebulizer. Data were analyzed using SPSS for mean latency and standard deviation. RESULTS: The mean (standard deviation) latency to the external abdominal oblique muscle was 17.6 +/- 10.6 msec. No adverse events to inhalation were reported. CONCLUSION: SIn humans, nebulized tartaric acid stimulates primarily rapid adapting receptors in the supraglottic larynx rather than C-fiber receptors. This receptor location in humans evolved neurologically to protect the airway during speech and swallowing, making the laryngeal cough expiration reflex an inseparable component of the laryngeal cough reflex, thus making it clinically significant when assessing airway protection.     

"This food may contain ..." What nurses should know about genetically engineered foods

Genetic engineering has been in existence since 1973. The process involves placing genetic DNA from one organism into another. Genetically engineered organisms (GEOs) are the name given to such new species of plants created through this process. Proponents of GEOs assert that foods we are now able to produce have greater nutritional value, longer shelf life, better appearance, taste and smell. There are positive benefits to genetic engineering of plants and animals. A growing concern for the health safety of genetically engineered plants and foods is developing among the cautious. The purpose of this article is to define genetic engineering, present benefits and risks, describe the impact on human health, and address implications for nursing.     

Susceptibilities of Genotype 1a, 1b,and 3 Hepatitis C Virus Variants to the NS5A Inhibitor Elbasvir

Elbasvir is an investigational NS5A inhibitor with in vitro activity against multiple HCV genotypes. Antiviral activity of elbasvir was measured in replicons derived from wild-type or resistant variants of genotypes 1a, 1b, and 3. The barrier to resistance was assessed by the number of resistant colonies selected by exposure to various elbasvir concentrations. In a phase 1b dose-escalating study, virologic responses were determined in 48 noncirrhotic adult men with chronic genotype 1 or 3 infections randomized to placebo or elbasvir from 5 to 50 mg (genotype 1) or 10 to 100 mg (genotype 3) once daily for 5 days. The NS5A gene was sequenced from plasma specimens obtained before, during, and after treatment. Elbasvir suppressed the emergence of resistance-associated variants (RAVs) in vitro in a dose-dependent manner. Variants selected by exposure to high elbasvir concentrations typically encoded multiple amino acid substitutions (most commonly involving loci 30, 31, and 93), conferring high-level elbasvir resistance. In the monotherapy study, patients with genotype 1b had greater reductions in HCV RNA levels than patients with genotype 1a at all elbasvir doses; responses in patients with genotype 3 were generally less pronounced than for genotype 1, particularly at lower elbasvir doses. M28T, Q30R, L31V, and Y93H in genotype 1a, L31V and Y93H in genotype 1b, and A30K, L31F, and Y93H in genotype 3 were the predominant RAVs selected by elbasvir monotherapy. Virologic findings in patients were consistent with the preclinical observations. NS5A-RAVs emerged most often at amino acid positions 28, 30, 31, and 93 in both the laboratory and clinical trial. (The MK-8742 P002 trial has been registered at ClinicalTrials.gov under identifier {"type":"clinical-trial","attrs":{"text":"NCT01532973","term_id":"NCT01532973"}}NCT01532973.)