Arterial H+ regulation during exercise in humans.

Resting arterial H+ concentration ([H+]a) is in the nanomolar range (40±2 nm/L) while its production is in the millimolar range/min, with little variation from subject to subject. To determine the precision with which [H(+)]a is regulated during exercise, [H+]a, PaCO2 and ventilation (V˙(E)) were measured during progressively increasing work rate exercise in 16 normal subjects. (V˙(E)) increased with [H+]a, the latter attributable to PaCO2 increase below the lactic acidosis threshold (LAT) (ΔV˙(E)/Δ[H+]a ≈ 15   L   min(-1)   nanomol(-1)). [H+]a and PaCO2 increased, simultaneously, as work rate was increased below LAT. PaCO2 reversed direction of change between LAT and ventilatory compensation point (VCP). Above LAT, [H+]a increase relative to (V˙(E)) increase was greater than below LAT. PaCO2 decreased above the LAT, while [H+]a continued to increase. Thus the exercise acidosis was converted from respiratory, below, to a metabolic, above the LAT. We conclude that [H+]a is increased and regulated over the full range of exercise, but with less sensitivity above the LAT.

Visualization of individual Scr mRNAs during Drosophila embryogenesis yields evidence for transcriptional bursting.

The detection and counting of transcripts within single cells via fluorescent in situ hybridization (FISH) has allowed researchers to ask quantitative questions about gene expression at the level of individual cells. This method is often preferable to quantitative RT-PCR, because it does not necessitate destruction of the cells being probed and maintains spatial information that may be of interest. Until now, studies using FISH at single-molecule resolution have only been rigorously carried out in isolated cells (e.g., yeast cells or mammalian cell culture). Here, we describe the detection and counting of transcripts within single cells of fixed, whole-mount Drosophila embryos via a combination of FISH, immunohistochemistry, and image segmentation. Our method takes advantage of inexpensive, long RNA probes detected with antibodies, and we present novel evidence to show that we can robustly detect single mRNA molecules. We use this method to characterize transcription at the endogenous locus of the Hox gene Sex combs reduced (Scr), by comparing a stably expressing group of cells to a group that only transiently expresses the gene. Our data provide evidence for transcriptional bursting, as well for divergent "accumulation" and "maintenance" phases of gene activity at the Scr locus.

Lamellipodial actin mechanically links myosin activity with adhesion-site formation.

Cell motility proceeds by cycles of edge protrusion, adhesion, and retraction. Whether these functions are coordinated by biochemical or biomechanical processes is unknown. We find that myosin II pulls the rear of the lamellipodial actin network, causing upward bending, edge retraction, and initiation of new adhesion sites. The network then separates from the edge and condenses over the myosin. Protrusion resumes as lamellipodial actin regenerates from the front and extends rearward until it reaches newly assembled myosin, initiating the next cycle. Upward bending, observed by evanescence and electron microscopy, results in ruffle formation when adhesion strength is low. Correlative fluorescence and electron microscopy shows that the regenerating lamellipodium forms a cohesive, separable layer of actin above the lamellum. Thus, actin polymerization periodically builds a mechanical link, the lamellipodium, connecting myosin motors with the initiation of adhesion sites, suggesting that the major functions driving motility are coordinated by a biomechanical process.

Review of the analgesic efficacy of ibuprofen.

There is a clear relationship between single doses of ibuprofen over the range 50-400 mg and the peak analgesic effect and the duration of analgesia. The smallest clinically useful dose of ibuprofen is 200 mg. Ibuprofen 400 mg has been shown to be as effective as aspirin 600 or 900 mg/day in models of moderate pain but superior to aspirin or paracetamol in more sensitive models such as dental pain. The duration of action of ibuprofen 400 mg is at least 6 hours compared with 4-6 hours for ibuprofen 200 mg or paracetamol. In patients undergoing oral surgery, ibuprofen 200 mg was broadly comparable with naproxen 220 mg and ibuprofen 400 mg comparable with ketoprofen 25 mg. The combination of ibuprofen and hydrocodone is more effective than either drug alone in patients undergoing abdominal and gynaecological surgery. The absorption of ibuprofen acid is influenced by formulation, and certain salts of ibuprofen (lysine, arginine, potassium) and solubilised formulations have an enhanced onset of activity. These differences are clinically important, offering a shorter time to onset of relief of tension headache compared with paracetamol.

A 12-Hour Evaluation of the Analgesic Efficacy of Diflunisal, Acetaminophen, an Acetaminophen-Codeine Combination, and Placebo in Postoperative Pain.

The analgesic efficacy of single 500 and 1,000 mg doses of diflunisal, a new nonsteroidal antiinflammatory analgesic, was compared in a double-blind study with acetaminophen 600 mg, the combination of acetaminophen 600 mg with codeine 60 mg, and placebo in 132 inpatients with postoperative pain. Using a self-rating record, patients rated their pain and its relief hourly for up to 12 hours after medication. Diflunisal 500 and 1,000 mg were significantly superior to placebo for every measure of total and peak analgesia, and a significant analgesic effect persisted for 8 hours. Acetaminophen alone and the acetaminophen-codeine combination were significantly superior to placebo for most measures of analgesia, and their effects were significant for 4 and 5 hours respectively. Differences among the active medications were not statistically significant for measures of total or peak analgesia.

A Method for the 12-Hour Evaluation of Analgesic Efficacy in Outpatients with Postoperative Oral Surgery Pain: Three Studies of Diflunisal.

We have developed a method for measuring the efficacy of a single dose of an analgesic for 12 hours after administration to outpatients with postoperative oral surgery pain. Using a self-rating record, patients evaluate their pain and its relief for 12 hours after medication. We have used this method successfully in a series of three studies to compare diflunisal, a new nonsteroidal antiinflammatory analgesic, with placebo and aspirin 650 mg, acetaminophen 600 mg, propoxyphene napsylate 100 mg, or a combination of acetaminophen with either codeine 60 mg or propoxyphene 100 mg. Diflunisal evinced an unusually long duration of analgesic effect. In each study, all doses of diflunisal were significantly superior to placebo through the end of the 12-hour observation period, while the standards were superior for periods ranging from 2 to 7 hours. In terms of peak analgesia, diflunisal 1,000 mg was comparable to the acetaminophen-codeine combination and was significantly superior to all the other analgesic standards.

A 12-Hour Evaluation of the Analgesic Efficacy of Diflunisal, Zomepirac Sodium, Aspirin, and Placebo in Postoperative Oral Surgery Pain.

One hundred ninety-nine outpatients with pain following oral surgery were randomly assigned, on a double-blind basis, a single oral dose of diflunisal (500 or 1,000 mg), zomepirac sodium 100 mg, aspirin 650 mg, or placebo. Using a self-rating record, subjects rated their pain and its relief hourly for 12 hours after medication. Measures of total and peak analgesia were derived from these patients' subjective reports. Diflunisal (500 and 1,000 mg) and zomepirac were significantly superior to aspirin and placebo for every measure of total and peak analgesia. Based upon the first 4 hours of observation, aspirin was superior to placebo for every measure of analgesia. Diflunisal 500 and 1,000 mg were comparable to zomepirac in peak analgesia and significantly superior to zomepirac for all measures of total analgesia. The onset of analgesia was comparable for 1,000 mg diflunisal, zomepirac, and aspirin, but more rapid for these treatments than for 500 mg diflunisal. The duration of analgesia was 12 hours for diflunisal, 9 hours for zomepirac, and 3 hours for aspirin.