Plasma pituitary hormone levels in severe trauma with or without head injury.

In order to evaluate the effect of head injury in severely traumatized patients on the response of ACTH, GH, PRL, and TSH plasma levels, 36 patients were prospectively studied over 5 consecutive days following injury. They were divided into three groups: Group I, severe isolated head injury (n = 14); Group II, multiple injury combined with severe head injury (n = 12); Group III, multiple injury without head injury (n = 10). No significant trend was observed during the 5 consecutive days. The following changes in plasma levels were observed, compared to normal reference value (median values): ACTH was normal in the three groups; PRL was elevated in Group II and normal in the other groups; GH was elevated in all groups; TSH was elevated in Group III and reduced in Groups I and II. Intergroup comparisons showed significantly lower plasma levels for PRL (p less than 0.05) and TSH (p less than 0.01) in Groups I and II, i.e., head-injured patients, compared to Group III, i.e., traumatized patients without head injury. A relationship was observed between the severity of head injury, as expressed by Glasgow Coma Score, intracranial pressure levels, outcome, and TSH and PRL levels.

A single LC-tandem mass spectrometry method for the simultaneous determination of 14 antimalarial drugs and their metabolites in human plasma.

Among the various determinants of treatment response, the achievement of sufficient blood levels is essential for curing malaria. For helping us at improving our current understanding of antimalarial drugs pharmacokinetics, efficacy and toxicity, we have developed a liquid chromatography-tandem mass spectrometry method (LC-MS/MS) requiring 200mul of plasma for the simultaneous determination of 14 antimalarial drugs and their metabolites which are the components of the current first-line combination treatments for malaria (artemether, artesunate, dihydroartemisinin, amodiaquine, N-desethyl-amodiaquine, lumefantrine, desbutyl-lumefantrine, piperaquine, pyronaridine, mefloquine, chloroquine, quinine, pyrimethamine and sulfadoxine). Plasma is purified by a combination of protein precipitation, evaporation and reconstitution in methanol/ammonium formate 20mM (pH 4.0) 1:1. Reverse-phase chromatographic separation of antimalarial drugs is obtained using a gradient elution of 20mM ammonium formate and acetonitrile both containing 0.5% formic acid, followed by rinsing and re-equilibration to the initial solvent composition up to 21min. Analyte quantification, using matrix-matched calibration samples, is performed by electro-spray ionization-triple quadrupole mass spectrometry by selected reaction monitoring detection in the positive mode. The method was validated according to FDA recommendations, including assessment of extraction yield, matrix effect variability, overall process efficiency, standard addition experiments as well as antimalarials short- and long-term stability in plasma. The reactivity of endoperoxide-containing antimalarials in the presence of hemolysis was tested both in vitro and on malaria patients samples. With this method, signal intensity of artemisinin decreased by about 20% in the presence of 0.2% hemolysed red-blood cells in plasma, whereas its derivatives were essentially not affected. The method is precise (inter-day CV%: 3.1-12.6%) and sensitive (lower limits of quantification 0.15-3.0 and 0.75-5ng/ml for basic/neutral antimalarials and artemisinin derivatives, respectively). This is the first broad-range LC-MS/MS assay covering the currently in-use antimalarials. It is an improvement over previous methods in terms of convenience (a single extraction procedure for 14 major antimalarials and metabolites reducing significantly the analytical time), sensitivity, selectivity and throughput. While its main limitation is investment costs for the equipment, plasma samples can be collected in the field and kept at 4 degrees C for up to 48h before storage at -80 degrees C. It is suited to detecting the presence of drug in subjects for screening purposes and quantifying drug exposure after treatment. It may contribute to filling the current knowledge gaps in the pharmacokinetics/pharmacodynamics relationships of antimalarials and better define the therapeutic dose ranges in different patient populations.

Promising survival for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide.

PURPOSE: Temozolomide is a novel oral alkylating agent with demonstrated efficacy as second-line therapy for patients with recurrent anaplastic astrocytoma and glioblastoma multiforme (GBM). This phase II study was performed to determine the safety, tolerability, and efficacy of concomitant radiation plus temozolomide therapy followed by adjuvant temozolomide therapy in patients with newly diagnosed GBM. PATIENTS AND METHODS: Sixty-four patients were enrolled onto this open-label, phase II trial. Temozolomide (75 mg/m(2)/d x 7 d/wk for 6 weeks) was administered orally concomitant with fractionated radiotherapy (60 Gy total dose: 2 Gy x 5 d/wk for 6 weeks) followed by temozolomide monotherapy (200 mg/m(2)/d x 5 days, every 28 days for six cycles). The primary end points were safety and tolerability, and the secondary end point was overall survival. RESULTS: Concomitant radiation plus temozolomide therapy was safe and well tolerated. Nonhematologic toxicities were rare and mild to moderate in severity. During the concomitant treatment phase, grade 3 or 4 neutropenia, thrombocytopenia, or both were observed in 6% of patients, including two severe infections with Pneumocystis carinii. During adjuvant temozolomide, 2% and 6% of cycles were associated with grade 3 and 4 neutropenia or thrombocytopenia, respectively. Median survival was 16 months, and the 1- and 2-year survival rates were 58% and 31%, respectively. Patients younger than 50 years old and patients who underwent debulking surgery had the best survival outcome. CONCLUSION: Continuous daily temozolomide and concomitant radiation is safe. This regimen of concomitant chemoradiotherapy followed by adjuvant chemotherapy may prolong the survival of patients with glioblastoma. Further investigation is warranted, and a randomized trial is ongoing.

Effects of neuropeptide Y on intrarenal hemodynamics, plasma renin activity and urinary sodium excretion in rats.

Neuropeptide Y (NPY) is a vasoconstrictor peptide possibly involved in the regulation of renal sodium handling and renin release. This investigation was undertaken to assess in conscious normotensive rats the acute effects of a non-pressor dose of NPY on renal plasma flow, glomerular filtration rate, sodium excretion and plasma renin activity. Experiments were also performed during concomitant beta-adrenoceptor stimulation with isoproterenol. NPY per se had no effect on the studied parameters. Renal plasma flow was increased by isoproterenol and was significantly higher when the beta-adrenoceptor stimulant was infused alone (13.4 +/- 2.1 ml/min, p < 0.05, mean +/- SEM) that when administered together with NPY (7.2 +/- 2.0 ml/min). This was also true for glomerular filtration rate (3.3 +/- 0.3 vs. 1.8 +/- 0.3 ml/min, p < 0.01) and plasma renin activity (6.3 +/- 1.7 vs. 2.1 +/- 0.4 ng Ang I/ml/h, p < 0.05). Our data however do not allow to deduce whether the inhibitory effect of NPY on isoproterenol-induced renin release is mediated by changes in intrarenal hemodynamics or a direct effect on juxtaglomerular cells.

Helical tomotherapy or intensity-modulated radiation therapy in the treatment of anal cancer: experience of Geneva and Lausanne

Background: To assess the early clinical outcomes and toxicities in patients treated with high precision radiation therapy (RT) consisting of helical tomotherapy (HT) or intensity-modulated radiation therapy (IMRT) for anal cancer. Materials and Methods: Since March 2006, 30 patients with stage I-IIIB anal squamous-cell carcinoma were treated curatively by IMRT or HT alone (n = 2) or by concomitant chemotherapy and IMRT or HT (n = 28). Median age was 59 years (range, 36−83 years) and the female/male ratio was 2.3 (21/9). Primary tumor site was anal canal, anal margin, or both in 26, 1, and 3 patients, respectively. Anal tumor, pelvic and inguinal nodes were irradiated with a median dose of 36 Gy using HT, or 5- or 7-field IMRT in 18 and 12 patients, respectively; After a planned gap of 1−2 weeks (median 1 week), a median boost dose of 23.4 Gwas delivered to the tumor and/or involved nodes using 3DRT (n = 24) or HT/IMRT (n = 6). The total delivered dose ranged between 59.4 and 64.8 Gy (median, 59.4 Gy). Concomitant chemotherapy consisted of mitomycin C alone (n = 1), mitomycin C and 5-fluorouracil (n = 17) or capecitabin (n = 10) in 28 patients. Common Terminology Criteria for Adverse Events v3.0 scale was used to score acute and late toxicities. Results: All but one patient, who developed progressive local and distant disease at the end of RT, achieved a complete response. Twelve months following RT, one patient had a recurrence at the primary tumor site, salvaged with brachytherapy. After a median follow-up of 7.5 months (range, 1−35 months), no deaths were observed. The 2-year actuarial locoregional control and probability of disease control without colostomy rates were 82% and 79%, respectively. RT was well tolerated without any unplanned treatment interruptions. Grade 1 or 2 acute adverse events consisted of skin toxicity in 8 and 22 patients, diarrhea in 18 and 3 patients, and cystitis in 9 and 2 patients; respectively. Only one patient developed grade 3 mucosal necrosis at the end of the treatment, requiring diverting colostomy. No difference in terms of acute toxicity was observed between patients treated with HT or IMRT. None of the 22 patients with a follow-up of more than 3 months developed grade 3 or more late toxicity. Conclusions: Our preliminary results suggest that HT or IMRT combined with concomitant chemotherapy for anal cancer is effective, and associated with favorable rates of toxicity compared with historical series. Further follow-up is warranted to assess late toxicity.

Human Plasma-derived Polymeric IgA and IgM Antibodies Associate with Secretory Component to Yield Biologically Active Secretory-like Antibodies.

Immunotherapy with monoclonal and polyclonal immunoglobulin is successfully applied to improve many clinical conditions, including infection, autoimmune diseases, or immunodeficiency. Most immunoglobulin products, recombinant or plasma-derived, are based on IgG antibodies, whereas to date, the use of IgA for therapeutic application has remained anecdotal. In particular, purification or production of large quantities of secretory IgA (SIgA) for potential mucosal application has not been achieved. In this work, we sought to investigate whether polymeric IgA (pIgA) recovered from human plasma is able to associate with secretory component (SC) to generate SIgA-like molecules. We found that ∼15% of plasma pIgA carried J chain and displayed selective SC binding capacity either in a mixture with monomeric IgA (mIgA) or after purification. The recombinant SC associated covalently in a 1:1 stoichiometry with pIgA and with similar efficacy as colostrum-derived SC. In comparison with pIgA, the association with SC delayed degradation of SIgA by intestinal proteases. Similar results were obtained with plasma-derived IgM. In vitro, plasma-derived IgA and SIgA neutralized Shigella flexneri used as a model pathogen, resulting in a delay of bacteria-induced damage targeted to polarized Caco-2 cell monolayers. The sum of these novel data demonstrates that association of plasma-derived IgA or IgM with recombinant/colostrum-derived SC is feasible and yields SIgA- and SIgM-like molecules with similar biochemical and functional characteristics as mucosa-derived immunoglobulins.

Plasma levels of the enantiomers of thioridazine, thioridazine 2-sulfoxide, thioridazine 2-sulfone, and thioridazine 5-sulfoxide in poor and extensive metabolizers of dextromethorphan and mephenytoin.

Concentrations of total (R) + (S) and of the enantiomers (R) and (S) of thioridazine and metabolites were measured in 21 patients who were receiving 100 mg thioridazine for 14 days and who were comedicated with moclobemide (450 mg/day). Two patients were poor metabolizers of dextromethorphan and one was a poor metabolizer of mephenytoin. Cytochrome P450IID6 (CYP2D6) is involved in the formation of thioridazine 2-sulfoxide (2-SO) from thioridazine and also probably partially in the formation of thioridazine 5-sulfoxide (5-SO), but not in the formation of thioridazine 2-sulfone (2-SO2) from thioridazine 2-SO. Significant correlations between the mephenytoin enantiomeric ratio and concentrations of thioridazine and metabolites suggest that cytochrome P450IIC19 could contribute to the biotransformation of thioridazine into yet-unknown metabolites, other than thioridazine 2-SO, thioridazine 2-SO2, or thioridazine 5-SO. An enantioselectivity and a large interindividual variability in the metabolism of thioridazine have been shown: measured (R)/(S) ratios of thioridazine, thioridazine 2-SO fast eluting (FE), thioridazine 2-SO slow eluting (SE), thioridazine 2-SO (FE+SE), thioridazine 2-SO2, thioridazine 5-SO(FE), and thioridazine 5-SO(SE) were (mean +/- SD) 3.48 +/- 0 .93 (range, 2.30 to 5.80), 0.45 +/- 0.22 (range, 0.21 to 1.20), 2.27 +/- 8.1 (range, 6.1 to 40.1), 4.64 +/- 0.68 (range, 2.85 to 5.70), 3.26 +/- 0.58 (range, 2.30 to 4.30), 0.049 +/- 0.019 (range, (0.021 to 0.087), and 67.2 +/- 66.2 (range, 16.8 to 248), respectively. CYP2D6 is apparently involved in the formation of (S)-thioridazine 2-SO(FE), (R)-thioridazine 2-SO(SE), and also probably (S)-thioridazine 5-SO(FE) and (R)-thioridazine 5-SO(SE).

Strength of family history in predicting levels of blood pressure, plasma glucose and cholesterol.

Objective: Limited information is available on the quantitative relationship between family history and the corresponding underlying traits. We analyzed these associations for blood pressure, fasting blood glucose, and cholesterol levels. Methods: Data were obtained from 6,102 Caucasian participants (2,903 men and 3,199 women) aged 35-75 years using a population-based cross-sectional survey in Switzerland. Cardiovascular disease risk factors were measured, and the corresponding family history was self-reported using a structured questionnaire. Results: The prevalence of a positive family history (in first-degree relatives) was 39.6% for hypertension, 22.3% for diabetes, and 29.0% for hypercholesterolemia. Family history was not known for at least one family member in 41.8% of participants for hypertension, 14.4% for diabetes, and 50.2% for hypercholesterolemia. A positive family history was strongly associated with higher levels of the corresponding trait, but not with the other traits. Participants who reported not to know their family history of hypertension had a higher systolic blood pressure than participants with a negative history. Sibling histories had higher positive predictive values than parental histories. The ability to discriminate, calibrate, and reclassify was best for the family history of hypertension. Conclusions: Family history of hypertension, diabetes, and hypercholesterolemia was strongly associated with the corresponding dichotomized and continuous phenotypes.

Hybridisation and diversification in the adaptive radiation of clownfishes.

BackgroundThe importance of hybridisation during species diversification has long been debated among evolutionary biologists. It is increasingly recognised that hybridisation events occurred during the evolutionary history of numerous species, especially during the early stages of adaptive radiation. We study the effect of hybridisation on diversification in the clownfishes, a clade of coral reef fish that diversified through an adaptive radiation process. While two species of clownfish are likely to have been described from hybrid specimens, the occurrence and effect of hybridisation on the clade diversification is yet unknown.ResultsWe generate sequences of three mitochondrial genes to complete an existing dataset of nuclear sequences and document cytonuclear discordance at a node, which shows a drastic increase of diversification rate. Then, using a tree-based jack-knife method, we identify clownfish species likely stemming from hybridisation events. Finally, we use molecular cloning and identify the putative parental species of four clownfish specimens that display the morphological characteristics of hybrids.ConclusionsOur results show that consistently with the syngameon hypothesis, hybridisation events are linked with a burst of diversification in the clownfishes. Moreover, several recently diverged clownfish lineages likely originated through hybridisation, which indicates that diversification, catalysed by hybridisation events, may still be happening.

EORTC Radiation Oncology Group quality assurance platform: establishment of a digital central review facility.

OBJECTIVE: Quality assurance (QA) in clinical trials is essential to ensure treatment is safely and effectively delivered. As QA requirements have increased in complexity in parallel with evolution of radiation therapy (RT) delivery, a need to facilitate digital data exchange emerged. Our objective is to present the platform developed for the integration and standardization of QART activities across all EORTC trials involving RT. METHODS: The following essential requirements were identified: secure and easy access without on-site software installation; integration within the existing EORTC clinical remote data capture system; and the ability to both customize the platform to specific studies and adapt to future needs. After retrospective testing within several clinical trials, the platform was introduced in phases to participating sites and QART study reviewers. RESULTS: The resulting QA platform, integrating RT analysis software installed at EORTC Headquarters, permits timely, secure, and fully digital central DICOM-RT based data review. Participating sites submit data through a standard secure upload webpage. Supplemental information is submitted in parallel through web-based forms. An internal quality check by the QART office verifies data consistency, formatting, and anonymization. QART reviewers have remote access through a terminal server. Reviewers evaluate submissions for protocol compliance through an online evaluation matrix. Comments are collected by the coordinating centre and institutions are informed of the results. CONCLUSIONS: This web-based central review platform facilitates rapid, extensive, and prospective QART review. This reduces the risk that trial outcomes are compromised through inadequate radiotherapy and facilitates correlation of results with clinical outcomes.

Stereotactic body radiation therapy in stage I inoperable lung cancer: from palliative to curative options.

Surgery has historically been the standard of care for operable stage I non-small cell lung cancer (NSCLC). However, nearly one-quarter of patients with stage I NSCLC will not undergo surgery because of medical comorbidity or other factors. Stereotactic ablative radiotherapy (SABR) is the new standard of care for these patients. SABR offers high local tumour control rates rivalling the historical results of surgery and is generally well tolerated by patients with both peripheral and centrally located tumours. This article reviews the history of SABR for stage I NSCLC, summarises the currently available data on efficacy and toxicity, and describes some of the currently controversial aspects of this treatment.

Plasma ionized magnesium during acute hyperventilation in humans.

1. Respiratory alkalosis accompanies the clinical syndrome of tetany, precipitates cardiac arrhythmias and predisposes to coronary vasoconstriction. Magnesium plays a critical role in the maintenance of membrane function, and magnesium depletion is often associated with cardiac arrhythmias or vasoconstriction. 2. As technology for detecting circulating ionized magnesium (the most interesting form with respect to physiological and biological properties) is now available in the form of new magnesium-selective electrodes, the effect of respiratory alkalosis induced by voluntary overbreathing for 30 min on circulating ionized magnesium was studied in eight healthy subjects. 3. The total plasma magnesium concentration was not modified by hyperventilation. On the contrary, hyperventilation was associated with a significant reduction in the ionized magnesium concentration of 0.05 (0.02-0.15) mmol/l (median and range) and in the free magnesium fraction of 0.06 (0.01-0.19). During hyperventilation the relative intravascular magnesium mass, calculated from changes in total plasma magnesium concentration and haematocrit, decreased significantly. 4. It is concluded that acute overbreathing reduces the circulating ionized magnesium concentration and the intravascular magnesium mass. It is therefore conceivable that extracellular magnesium deficiency is at least a subsidiary cause of the syndrome of tetany and the cardiac complications that are precipitated by hyperventilation.

Treatment of severe infectious purpura in children with human plasma from donors immunized with Escherichia coli J5: a prospective double-blind study. J5 study Group.

To evaluate the efficacy of anti-J5 serum in the treatment of severe infectious purpura, 73 children were randomized to receive either anti-J5 (40) or control (33) plasma. Age, blood pressure, and biologic risk factors were similar in both groups. At admission, however, tumor necrosis factor serum concentrations were 974 +/- 173 pg/ml compared with 473 +/- 85 pg/ml (P = .023) and interleukin-6 serum concentrations were 129 +/- 45 compared with 19 +/- 5 ng/ml (P = .005) in the control and treated groups, respectively. The duration of shock and the occurrence of complications were similar in both groups. The mortality rate was 36% in the control group and 25% in the treated group (P = .317; odds ratio, 0.76; 95% confidence interval, 0.46-1.26). This trend disappeared after correction for unbalances in risk factors at randomization using a logistic regression model. These results suggest that anti-j5 plasma did not affect the course or mortality of severe infectious purpura in children.

Recrystallisation rims in zircon (Valle d'Arbedo, Switzerland): an integrated cathodoluminescence, LA-ICP-MS, SHRIMP, and TEM study

Recrystallization rims are a common feature of zircon crystals that underwent metamorphism. We present a microstructural and microchemical study of partially recrystallized zircon grains collected in polymetamorphic migmatites (Valle d'Arbedo, Ticino, Switzerland). The rims are bright in cathodo-luminescence (CL), with sharp and convex contacts characterized by inward-penetrating embayments transgressing igneous zircon cores. Laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) data and transmission electron microscopy (TEM) imaging indicate that the rims are chemically and microstructurally different from the cores. The rims are strongly depleted in REE, with concentrations up to two orders of magnitude lower than in the cores, indicating a significant loss of REE during zircon recrystallization. Enrichment in non-formula elements, such as Ca, has not been observed in the rims. The microstructure of zircon cores shows a dappled intensity at and below the 100 nm scale, possibly due to radiation damage. Other defects such as pores and dislocations are absent in the core except at healed cracks. Zircon rims are mostly dapple-free, but contain nanoscale pores and strain centers, interpreted as fluid inclusions and chemical residues, respectively. Sensitive high-resolution ion microprobe (SHRIMP) U-Pb ages show that the recrystallization of the rims took place >200 Ma ago when the parent igneous zircon was not metamict. The chemical composition and the low-Ti content of the rims indicate that they form at sub-solidus temperatures (550-650 degrees C). Recrystallization rims in Valle d'Arbedo zircon are interpreted as the result of the migration of chemical reaction fronts in which fluid triggered in situ and contemporaneous interface-coupled dissolution-reprecipitation mechanisms. This study indicates that strong lattice strain resulting from the incorporation of a large amount of impurities and structural defects is not a necessary condition for zircon to recrystallize. Our observations suggest that the early formation of recrystallization rims played a major role in preserving zircon from the more recent Alpine metamorphic overprint.