The drug titration paradox: more drug does not correlate with more effect in individual clinical data.

BACKGROUND A fundamental concept in pharmacology is that increasing dose increases drug effect. This is the basis of anaesthetic titration: the dose is increased when increased drug effect is desired and decreased when reduced drug effect is desired. In the setting of titration, the correlation of doses and observed drug effects can be negative, for example increasing dose reduces drug effect. We have termed this the drug titration paradox. We hypothesised that this could be explained, at least in part, by intrasubject variability. If the drug titration paradox is simply an artifact of pooling population data, then a mixed-effects analysis that accounts for interindividual variability in drug sensitivity should 'flip' the observed correlation, such that increasing dose increases drug effect. METHODS We tested whether a mixed-effects analysis could correctly reveal the underlying pharmacology using previously published data obtained during automatic feedback control of mean arterial pressure (MAP) with alfentanil (effect site concentration, CeAlf) during surgery. The relationship between MAP and CeAlf was explored with linear regression and a linear mixed-effects model. RESULTS A linear mixed-effects model did not identify the correct underlying pharmacology because of the presence of the titration paradox in the individual data. CONCLUSIONS The relationship between drug dose and drug effect must be determined under carefully controlled experimental conditions. In routine care, where the effect is profoundly influenced by varying clinical conditions and drugs are titrated to achieve the desired effect, it is nearly impossible to draw meaningful conclusions about the relationship between dose and effect

Searching for dark clouds in the outer galactic plane I -- A statistical approach for identifying extended red(dened) regions in 2MASS

[Abridged] Though the exact role of infrared dark clouds in the formation process is still somewhat unclear, they seem to provide useful laboratories to study the very early stages of clustered star formation. Infrared dark clouds have been identified predominantly toward the bright inner parts of the galactic plane. The low background emission makes it more difficult to identify similar objects in mid-infrared absorption in the outer parts. This is unfortunate, because the outer Galaxy represents the only nearby region where we can study effects of different (external) conditions on the star formation process. The aim of this paper is to identify extended red regions in the outer galactic plane based on reddening of stars in the near-infrared. We argue that these regions appear reddened mainly due to extinction caused by molecular clouds and young stellar objects. The work presented here is used as a basis for identifying star forming regions and in particular the very early stages. We use the Mann-Whitney U-test, in combination with a friends-of-friends algorithm, to identify extended reddened regions in the 2MASS all-sky JHK survey. We process the data on a regular grid using two different resolutions, 60" and 90". The two resolutions have been chosen because the stellar surface density varies between the crowded spiral arm regions and the sparsely populated galactic anti-center region. We identify 1320 extended red regions at the higher resolution and 1589 at the lower resolution run. The majority of regions are associated with major molecular cloud complexes, supporting our hypothesis that the reddening is mostly due to foreground clouds and embedded objects.Comment: Accepted for publication in A&A -- 9 pages, 5 figures (+ on-line only tables

The Arecibo Methanol Maser Galactic Plane Survey - II: Statistical and Multi-wavelength Counterpart Analysis

We present an analysis of the properties of the 6.7 GHz methanol maser sample detected in the Arecibo Methanol Maser Galactic Plane Survey. The distribution of the masers in the Galaxy, and statistics of their multi-wavelength counterparts is consistent with the hypothesis of 6.7 GHz maser emission being associated with massive young stellar objects. Using the detection statistics of our survey, we estimate the minimum number of methanol masers in the Galaxy to be 1275. The l-v diagram of the sample shows the tangent point of the Carina-Sagittarius spiral arm to be around 49.6 degrees, and suggests occurrence of massive star formation along the extension of the Crux-Scutum arm. A Gaussian component analysis of the maser spectra shows the mean line-width to be 0.38 km/s which is more than a factor of two larger than what has been reported in the literature. We also find no evidence that faint methanol masers have different properties than those of their bright counterparts.Comment: Accepted by ApJ; Revised footnote number 3 on page 8 based on private communicatio

Increase on the Initial Soluble Heme Levels in Acidic Conditions Is an Important Mechanism for Spontaneous Heme Crystallization In Vitro

BACKGROUND: Hemozoin (Hz) is a heme crystal that represents a vital pathway for heme disposal in several blood-feeding organisms. Recent evidence demonstrated that β-hematin (βH) (the synthetic counterpart of Hz) formation occurs under physiological conditions near synthetic or biological hydrophilic-hydrophobic interfaces. This seems to require a heme dimer acting as a precursor of Hz crystals that would be formed spontaneously in the absence of the competing water molecules bound to the heme iron. Here, we aimed to investigate the role of medium polarity on spontaneous βH formation in vitro. METHODOLOGY/PRINCIPAL FINDINGS: We assessed the effect of water content on spontaneous βH formation by using the aprotic solvent dimethylsulfoxide (DMSO) and a series of polyethyleneglycols (PEGs). We observed that both DMSO and PEGs (3.350, 6.000, 8.000, and 22.000) increased the levels of soluble heme under acidic conditions. These compounds were able to stimulate the production of βH crystals in the absence of any biological sample. Interestingly, the effects of DMSO and PEGs on βH formation were positively correlated with their capacity to promote previous heme solubilization in acidic conditions. Curiously, a short chain polyethyleneglycol (PEG 300) caused a significant reduction in both soluble heme levels and βH formation. Finally, both heme solubilization and βH formation strongly correlated with reduced medium water activity provided by increased DMSO concentrations. CONCLUSIONS: The data presented here support the notion that reduction of the water activity is an important mechanism to support spontaneous heme crystallization, which depends on the previous increase of soluble heme levels

Spitzer's mid-infrared view on an outer Galaxy Infrared Dark Cloud candidate toward NGC 7538

Infrared Dark Clouds (IRDCs) represent the earliest observed stages of clustered star formation, characterized by large column densities of cold and dense molecular material observed in silhouette against a bright background of mid-IR emission. Up to now, IRDCs were predominantly known toward the inner Galaxy where background infrared emission levels are high. We present Spitzer observations with the Infrared Camera Array toward object G111.80+0.58 (G111) in the outer Galactic Plane, located at a distance of ~3 kpc from us and ~10 kpc from the Galactic center. Earlier results show that G111 is a massive, cold molecular clump very similar to IRDCs. The mid-IR Spitzer observations unambiguously detect object G111 in absorption. We have identified for the first time an IRDC in the outer Galaxy, which confirms the suggestion that cluster-forming clumps are present throughout the Galactic Plane. However, against a low mid-IR back ground such as the outer Galaxy it takes some effort to find them.Comment: Accepted for publication in ApJL -- 11 pages, 2 figures (1 colour

Unsaturated glycerophospholipids mediate heme crystallization: biological implications for hemozoin formation in the kissing bug Rhodnius prolixus

Hemozoin (Hz) is a heme crystal produced by some blood-feeding organisms, as an efficient way to detoxify heme derived from hemoglobin digestion. In the triatomine insect Rhodnius prolixus , Hz is essentially produced by midgut extracellular phospholipid membranes known as perimicrovillar membranes (PMVM). Here, we investigated the role of commercial glycerophospholipids containing serine, choline and ethanolamine as headgroups and R. prolixus midgut lipids (RML) in heme crystallization. All commercial unsaturated forms of phospholipids, as well as RML, mediated fast and efficient β-hematin formation by means of two kinetically distinct mechanisms: an early and fast component, followed by a late and slow one. The fastest reactions observed were induced by unsaturated forms of phosphatidylethanolamine (uPE) and phosphatidylcholine (uPC), with half-lives of 0.04 and 0.7 minutes, respectively. β-hematin crystal morphologies were strikingly distinct among groups, with uPE producing homogeneous regular brick-shaped crystals. Interestingly, uPC-mediated reactions resulted in two morphologically distinct crystal populations: one less representative group of regular crystals, resembling those induced by uPE, and the other largely represented by crystals with numerous sharp edges and tapered ends. Heme crystallization reactions induced by RML were efficient, with a heme to β-hematin conversion rate higher than 70%, but clearly slower (t1/2 of 9.9-17.7 minutes) than those induced by uPC and uPE. Interestingly, crystals produced by RML were homogeneous in shape and quite similar to those mediated by uPE. Thus, β-hematin formation can be rapidly and efficiently induced by unsaturated glycerophospholipids, particularly uPE and uPC, and may play a role on biological heme crystallization in R. prolixus midgut

A third red supergiant rich cluster in the Scutum-Crux arm

Aims. We aim to characterise the properties of a third massive, red supergiant dominated galactic cluster. Methods. To accomplish this we utilised a combination of near/mid-IR photometry and spectroscopy to identify and classify the properties of cluster members, and statistical arguments to determine the mass of the cluster. Results. We found a total of 16 strong candidates for cluster membership, for which formal classification of a subset yields spectral types from K3-M4 Ia and luminosities between log(L/L-circle dot) similar to 4.5-4.8 for an adopted distance of 6 +/- 1 kpc. For an age in the range of 16-20 Myr, the implied mass is 2-4 x 10(4) M-circle dot, making it one of the most massive young clusters in the Galaxy. This discovery supports the hypothesis that a significant burst of star formation occurred at the base of Scutum-Crux arm between 10-20 Myr ago, yielding a stellar complex comprising at least similar to 10(5) M-circle dot of stars (noting that since the cluster identification criteria rely on the presence of RSGs, we suspect that the true stellar yield will be significantly higher). We highlight the apparent absence of X-ray binaries within the star formation complex and finally, given the physical association of at least two pulsars with this region, discuss the implications of this finding for stellar evolution and the production and properties of neutron stars