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Invasive pneumococcal disease due to Streptococcus pneumoniae can cause mortality and severe morbidity due to sepsis, meningitis and pneumonia, particularly in young children and the elderly. Recurrent invasive pneumococcal disease is rare yet serious sequelae of invasive pneumococcal disease that is associated with the immunocompromised and leads to a high mortality rate.This retrospective study reviewed recurrent invasive pneumococcal disease cases from the Canadian Immunization Monitoring Program, ACTive (IMPACT) between 1991 and 2019, an active network for surveillance of vaccine-preventable diseases and adverse events following immunization for children ages 0-16 years. Data were collected from 12 pediatric tertiary care hospitals across all 3 eras of public pneumococcal conjugate vaccine implementation in Canada.The survival rate within our cohort of 180 recurrent invasive pneumococcal disease cases was 98.3%. A decrease of 26.4% in recurrent invasive pneumococcal disease due to vaccine serotypes was observed with pneumococcal vaccine introduction. There was also a 69.0% increase in the rate of vaccination in children with preexisting medical conditions compared with their healthy peers.The decrease in recurrent invasive pneumococcal disease due to vaccine-covered serotypes has been offset by an increase of non-vaccine serotypes in this sample of Canadian children.

Measuring optical density (OD) is a very common technique in biological laboratories to determine the concentration of a substance in solution or of bacteria (or microscopic particles) in suspension. For example, bacterial cultures engineered to produce (express) a protein or compound of interest are a workhorse of modern molecular biology laboratories. Commonly, the expression of the product is triggered (induced) by a chemical signal added to the culture at the proper time in the growth curve of the culture (typically in the middle of the exponential growth phase, at an OD value of ∼0.6). The most common tool for measuring OD is a spectrophotometer. However, most spectrophotometers are sophisticated, non-portable and expensive laboratory instruments, costing tens of thousands of dollars. Even a very low cost spectrophotometer for educational use costs at least US$1,000. Because of the cost, even well resourced labs have only one instrument, which becomes a bottleneck when multiple bacterial cultures need to be monitored simultaneously. The problem is more acute in developing countries, where multiple labs have to share a single spectrophotometer, or there’s no such instrument at all. Having a cheap and simple device to measure OD would enable multiple people in a laboratory to monitor their bacterial cultures independently, even in resource-limited settings. At the same time, a portable OD meter could be useful for field work. Here we present the detailed build instructions and characterization of a very simple OD meter that costs only US$60, and can measure OD values from ∼0.05 to 2.0.Specifications table

3051 Background: ctDNA levels in plasma samples permits temporal assessment of tumor mutational status and tumor burden during therapy. Poziotinib is an oral HER2 TKI in development for NSCLC patients harboring HER2 exon 20 insertion mutations. We assessed serial plasma samples for changes in HER2 exon 20 insertion mutations and other driver mutations in first- and second-line patients comparing to clinical response per RECIST1.1. Methods: NSCLC patients harboring HER2 exon 20 insertion mutations were enrolled into the poziotinib ZENITH20 using tumor tissue based NGS. Serial plasma samples were collected at baseline, at C3D1, at Day 1 of every other cycle until disease progression. The Guardant360â 74-gene liquid biopsy assay was used to assess changes in tumor-associated somatic variants including the target variant HER2 exon20 insertion as well as other emergent driver mutations in ctDNA as expressed as percent variant allele frequency (%VAF). Results: 23 first- and second-line NSCLC patients were evaluable with tumor tissue confirmation of HER2 exon 20 insertion mutations. 22 of 23 (96%) had baseline plasma samples with detectable ctDNA. 21 of 22 samples had detectable HER2 exon 20 insertion mutations (mean % VAF 20±5) resulting in a concordance of 95% versus tissue based NGS. 7 patients had serial testing through C7D1 permitting assessment of ctDNA dynamics and comparison to clinical responses. 5 of 7 (71%) serially tested patients treated with poziotinib at 16mg QD had undetectable HER2 exon 20 insertion at C3D1 which was associated with a tumor response PR. Tumor escape (PD) was observed in 2 of the 5 patients which correlated with increases in target HER2 exon 20 insertion VAF in the plasma with the remaining 3 patients ≥PR. Notably, the rise in HER2 exon 20 in ctDNA occurred prior to tumor escape. In one patient treated with poziotinib at 16 mg QD we observed undetectable levels of the HER2 exon 20 insertion in ctDNA at C3D1 which continued through C16. This patient’s responses correlated with patient tumor response of SD at C2 which then became PR through C9 and CR through C17. Conclusions: Poziotinib treatment resulted in reductions in HER2 exon 20 insertion mutations in ctDNA preceded and correlated with the clinical tumor response. Increases in ctDNA HER2 exon 20 insertion mutations were observed prior to confirmation of tumor escape. Serial monitoring of ctDNA is a potential predictive biomarker for treatment response and disease progression. Future evaluation in a larger population is required to confirm the impact of these findings.

Concomitant gradient fields are transverse magnetic field components that are necessarily present to satisfy Maxwell's equations when magnetic field gradients are utilized in magnetic resonance imaging. They can have deleterious effects that are more prominent at lower static fields and/or higher gradient strengths. In diffusion tensor imaging schemes that employ large gradients that are not symmetric about a refocusing radiofrequency pulse (unlike Stejskal–Tanner, which is symmetric), concomitant fields may cause phase accrual that could corrupt the diffusion measurement. Theory predicting the error from this dephasing is described and experimentally validated for both Reese twice-refocused and split gradient single spin-echo diffusion gradient schemes. Bias in apparent diffusion coefficient values was experimentally found to worsen with distance from isocenter and with increasing duration of gradient asymmetry in both a phantom and in the brain. The amount of error from concomitant gradient fields depends on many variables, including the diffusion gradient pattern, pulse sequence timing, maximum effective gradient amplitude, static magnetic field strength, voxel size, slice distance from isocenter, and partial Fourier fraction. A prospective correction scheme that can reduce concomitant gradient errors is proposed and verified for diffusion imaging. Magn Reson Med, 2012. © 2011 Wiley Periodicals, Inc.

Improved neuroscientific understanding of high-risk behaviours such as alcohol binging, drug use, and unsafe sex will lead to therapeutic advances for high-risk groups. High-risk behaviour often occurs in an emotionally-charged context, and behavioural inhibition and emotion regulation play important roles in risk-related decision making. High impulsivity is an important potential contributor to high-risk behaviour tendencies. We explored the relationships between high-risk behaviour tendencies, impulsivity, and fMRI brain activations in an emotional Go/NoGo task. This task presented emotional distractor pictures (aversive vs. neutral) simultaneously with Go/NoGo stimuli (square vs. circle) that required a button press or withholding of the press, respectively. Participants' risk behaviour tendencies were assessed with the Cognitive Appraisal of Risky Events (CARE) scale. The Barratt Impulsivity Scale 11 (BIS) was used to assess participant impulsivity. Individuals with higher CARE risk scores exhibited reduced activation related to response inhibition (NoGo-Go) in right orbital frontal cortex (OFC) and ventromedial prefrontal cortex. These regions did not show a significant relationship with impulsivity scores. Conversely, more impulsive individuals showed reduced emotion-related activity (aversive-neutral distractors) in dorsomedial prefrontal cortex, perigenual anterior cingulate cortex, and right posterior OFC. There were distinct neural correlates of high-risk behaviour tendency and impulsivity in terms of brain activity in the emotional Go/NoGo task. This dissociation supports the conception of high-risk behaviour tendency as a distinct construct from that of impulsivity. Our results suggest that treatment for high-risk behaviour may be more effective with a nuanced approach that does not conflate high impulsivity necessarily with high-risk behaviour tendencies.

Endothelin 1 (ET-1) is a potent vasoactive and mitogenic peptide that is thought to participate in the hemodynamic effects elicited by drugs that block the biosynthesis and release of endothelium-derived nitric oxide (NO), such as NO synthase inhibitors. Using the nonpeptide endothelin receptor antagonists bosentan and LU-135252, we tested the hypothesis that endothelins contribute to the pressor activity of diaspirin-crosslinked hemoglobin (DCLHb), a hemoglobin-based oxygen carrier, whose pressor activity in mammals is attributed primarily to a scavenging action towards NO. The NO synthase inhibitor nitro-L-arginine methyl ester (L-NAME), ET-1, and noradrenaline (NA) were used as reference drugs. Bosentan markedly reduced the pressor effects elicited by DCLHb, L-NAME, and ET-1, but not those evoked by NA. LU-135252 attenuated the pressor effect elicited by DCLHb and ET-1, but not that produced by L-NAME or NA. The decreases in heart rate associated with the pressor effect of DCLHb and L-NAME were reduced by LU-135252, whereas only those elicited by DCLHb were attenuated by bosentan. In contrast with bosentan, LU-135252 caused a decrease in the baseline blood pressure and heart rate. These results suggest that endothelins may participate in the pressor activity of DCLHb. They suggest also that nonpeptide endothelin receptor antagonists such as bosentan or LU-135252 may be useful to counteract endothelin-mediated undesirable hemodynamic effects of drugs that inhibit the activity of the NO system.Key words: hemoglobin, endothelin, nitric oxide, blood pressure, diaspirin-crosslinked hemoglobin (DCLHb).

Concomitant gradient fields are transverse magnetic field components that are necessarily present to satisfy Maxwell's equations when magnetic field gradients are utilized in magnetic resonance imaging. They can have deleterious effects that are more prominent at lower static fields and/or higher gradient strengths. In diffusion tensor imaging schemes that employ large gradients that are not symmetric about a refocusing radiofrequency pulse (unlike Stejskal-Tanner, which is symmetric), concomitant fields may cause phase accrual that could corrupt the diffusion measurement. Theory predicting the error from this dephasing is described and experimentally validated for both Reese twice-refocused and split gradient single spin-echo diffusion gradient schemes. Bias in apparent diffusion coefficient values was experimentally found to worsen with distance from isocenter and with increasing duration of gradient asymmetry in both a phantom and in the brain. The amount of error from concomitant gradient fields depends on many variables, including the diffusion gradient pattern, pulse sequence timing, maximum effective gradient amplitude, static magnetic field strength, voxel size, slice distance from isocenter, and partial Fourier fraction. A prospective correction scheme that can reduce concomitant gradient errors is proposed and verified for diffusion imaging.

Our experience has shown that determining an effective daily dose of theophylline means considering such factors as: age, patient's ideal weight, available pharmaceutical format, cost, frequency of administration, nicotine intake, coffee intake, diet and lifestyle. Cardiac and/or renal insufficiency and hepatic disorder are also factors affecting treatment with theophylline. We have therefore created a guide to daily dosage, taking all these factors into account. This helps both prescriber and pharmacist on instituting or evaluating theophylline treatment in an otherwise normal individual. This article presents the guide and explains the adjustment of dose in adult smokers, those with cardiac or renal insufficiency, and those with hepatic disorders.

We develop an adaptive active contour tracing algorithm for extraction of spinal cord from MRI that is fully automatic, unlike existing approaches that need manually chosen seeds. We can accurately extract the target spinal cord and construct the volume of interest to provide visual guidance for strategic rehabilitation surgery planning.

The reflex changes of systemic blood pressure (BP) and heart rate (HR) induced by intraperitoneal (IP) injections of neurotensin-containing solutions (NTCS) were measured in anesthetized guinea pigs whose BP was raised up by intravenous (IV) infusions of either angiotensin II (ATII) or noradrenaline (NA), and compared to those observed in control animals (i.e., saline-infused guinea pigs with low initial BP level). The amplitudes of reflex pressor and tachycardic responses to IP NTCS were either not affected or reduced in animals whose BP was raised with ATII or NA. However, no hypotensive effect was observed, following IP NTCS, in any of the animals tested. The results indicate that high initial BP levels tend to attenuate the reflex increases of BP and HR caused by IP NTCS, the level of inhibition being largely determined by the type of vasopressor agent utilized to raise up the BP. They also suggest that the initial BP level is unlikely to be an important factor in determining whether the activation of capsaicin-sensitive visceral afferents will produce hypotensive or hypertensive effects in this animal model.

Two forms of the same commercial product (SORBIAL, Allonnes, France), one with live bacteria (PSA) and the other with heat-inactivated bacteria (PSI), containing a mixture of 2 strains of lactobacilli and their growth medium were tested as a diet complement for juvenile sea bass (Dicentrarchus labrax) during a 103-day experiment. In addition to zootechnical parameters (survival, growth, conformation), some effects on digestive metabolism were studied, including enzymatic, ultrastructural and microbial aspects. Microbial preparations improved survival rate. The ventral, dorsal and operculum malformations which usually occur in juveniles did not appear in those receiving PSA and PSI. Furthermore, they stimulated, but not constantly, trypsin and acid phosphatase activities. Intestinal ultrastructure showed an increase in the number of endocytosis vesicles at the apical pole of enterocytes in fishes receiving enrichments. Bacterial flora was not modified in terms of quantity, especially the lactic acid bacteria counts, which were not changed in fishes receiving live lactobacilli (PSA). The mode of action of these multiple beneficial effects appears complex and could be caused by different molecules inside the bacterial cell or excreted into their medium.

To provide updated, evidence-based recommendations for the diagnosis and assessment of high blood pressure in adults.For people with high blood pressure, the assignment of a diagnosis of hypertension depends on the appropriate measurement of blood pressure, the level of the blood pressure elevation, the duration of follow-up and the presence of concomitant vascular risk factors, target organ damage and established atherosclerotic diseases. For people diagnosed with hypertension, defining the overall risk of adverse cardiovascular outcomes requires laboratory testing, a search for target organ damage and an assessment of the modifiable causes of hypertension. Out-of-clinic blood pressure assessment and echocardiography are options for selected patients.People at increased risk of adverse cardiovascular outcomes and were identified and quantified.Medline searches were conducted from the period of the last revision of the Canadian recommendations for the management of hypertension (May 1998 to October 2000). Reference lists were scanned, experts were polled, and the personal files of the subgroup members and authors were used to identify other studies. All relevant articles were reviewed and appraised, using prespecified levels of evidence, by content experts and methodological experts.A high value was placed on the identification of people at increased risk of cardiovascular morbidity and mortality.The identification of people at higher risk of cardiovascular disease will permit counselling for lifestyle manoeuvres and the introduction of antihypertensive drugs to reduce blood pressure for patients with sustained hypertension. In certain settings, and for specific classes of drugs, blood pressure lowering has been associated with reduced cardiovascular morbidity and/or mortality.The present document contains detailed recommendations pertaining to aspects of the diagnosis and assessment of patients with hypertension, including the accurate measurement of blood pressure, criteria for the diagnosis of hypertension and recommendations for follow-up, routine and optional laboratory testing, assessment for renovascular hypertension, home and ambulatory blood pressure monitoring, and the role of echocardiography in hypertension.All recommendations were graded according to strength of the evidence and voted on by the Canadian Hypertension Recommendations Working Group. Only the recommendations achieving high levels of consensus are reported here. These guidelines will be updated annually.These recommendations are endorsed by the Canadian Hypertension Society, The Canadian Coalition for High Blood Pressure Prevention and Control, The College of Family Physicians of Canada, The Heart and Stroke Foundation of Canada, The Adult Disease Division and Bureau of Cardio-Respiratory Diseases and Diabetes at the Centre for Chronic Disease Prevention and Control of Health Canada.

Werner syndrome (WS) is a rare autosomal recessive disorder characterized by genomic instability and by the premature onset of a number of age-related diseases, including cancers. The gene responsible for WS encodes a protein that has an exonuclease domain and a domain similar to DNA helicases of the RecQ-like subfamily. Accumulating evidence indicates that the WS gene product is involved in resolving aberrant DNA structures that may arise during the process of DNA replication and transcription. Such processes generate regions of single-stranded DNA that may inadvertently provide a substrate for the initiation of recombination. Various mechanisms have evolved to ensure that recombination does not occur promiscuously during these events, and results are consistent with a model in which the WS protein is part of one such mechanism.

Tyrosine hydroxylase (TH) is the rate-limiting enzyme of dopamine and (nor)adrenaline biosynthesis. Regulation of its gene expression is complex and different regulatory mechanisms appear to be operative in various neuronal lineages. Pitx3, a homeodomain-containing transcription factor, has been cloned from neuronal tissues and, in the CNS, mouse Pitx3 is exclusively expressed in midbrain dopaminergic (MesDA) neurons from embryonic day 11 (E11). TH appears in these neurons at E11.5, consistent with a putative role of Pitx3 in TH transcription. We show that Pitx3 activates the TH promoter through direct interaction with a single high-affinity binding site within the promoter and that this site is sufficient for Pitx3 responsiveness. In contrast, we did not observe an effect of Nurr1, an orphan nuclear receptor essential for normal development of MesDA neurons, on TH promoter activity. Pitx3 activation of TH promoter activity appears to be cell-dependent suggesting that Pitx3 action may be modulated by other(s) regulatory mechanism(s) and factor(s).

Werner syndrome is an autosomal recessive disorder characterized by genomic instability and by the premature onset of a number of age-related diseases, including malignancy. To assess a potential collaboration between p21 or p53 cell cycle regulators and Wrn proteins, Wrn mutant mice were created and mated with p21 or p53 null mice to generate double mutants. The p21 null/Wrn mutant mice did not show an acceleration of tumorigenesis during the first year of life, suggesting that the p53-dependent G1-S cell cycle checkpoint (which operates via p21) is not involved in Wrn-abetted tumor suppression. In contrast, the p53 null/Wrn mutant mice were particularly remarkable with respect to the rapidity with which they developed tumors. These mice were also distinguished by the variety of tumors they developed compared to those that developed in p53 null mice. Such data suggest a genetic interaction between p53 and Wrn in which loss of Wrn provokes a more variable p53 response unrelated to its role in the G1-S cell cycle checkpoint.

To evidence a collagen synthesis and identify which type(s) of collagen is present in hemocytes from the mollusc Haliotis tuberculata, we have performed three separate approaches, namely, de novo synthesis by cultured cells, immunological approaches, and northern blot analysis. We demonstrated first that after 40-hr labeling, the de novo synthesis of collagen in the cell layer of cultured hemocytes represents 9.48 +/- 1.25% with respect to the total [(3)H]proline-labeled protein synthesis. In addition, IGF-I elicited a significant stimulation of collagen synthesis in cultured hemocytes in a dose-dependent manner from 10(-10) to 10(-8) M. The maximal stimulation (10(-9) M) induced an increase of 286 +/- 56% with respect to 100% control. By immunocytochemistry and immunoblotting, we showed that hemocytes present immunoreactive molecules to antibodies directed against the type I fibrillar collagen. In addition, using as a probe Hf 677 corresponding to a human pro alpha1(I) collagen cDNA and which encompasses the (Gly-X-Y) repeated sequence found in all Metazoa, four collagen transcripts of approximately 6.4, 5, 2.2, and 2 kb in length have been detected. These data suggest the presence of fibrillar type I collagen in hemocytes and are compatible with the concept that these cells are involved in the extracellular matrix deposition, a cardinal function in tissue repair as well as in developmental processes. Our model may appear as an excellent system to study the role of growth factors on the regulation of collagen synthesis by molluscan hemocytes. J. Exp. Zool. 287:275-284, 2000.

Endothelin 1 (ET-1) is a potent vasoconstrictor implicated in the control of blood pressure and renal function. Its effects can be modulated by nitric oxide (NO), which inhibits ET-1 production and action. Recently, we reported that ET-1 production can also be modulated by angiotensin II (AngII) in vivo. To investigate the interactions between NO, ET-1, and AngII in hypertension and renal dysfunction, we assessed immunoreactive ET-1 (ir-ET-1) concentration in plasma and urine as well as in vascular and renal tissues of rats with chronic inhibition of NO synthesis, in the presence and the absence of the AngII type 1 receptor antagonist losartan. Normal (protocols A and B) and uninephrectomized rats (protocol C) received the L-arginine analog N(G)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthesis, 0.05% (protocol A) or 0.1% (protocols B and C), with or without losartan (20 mg x kg(-1) x day(-1)). After 6 weeks, systolic blood pressure was significantly increased in L-NAME rats compared with the controls (p0.01), while serum creatinine and urea, creatinine clearance, and proteinuria were similar to control values. However, ir-ET-1 concentration in plasma and in the thoracic aorta was augmented in animals receiving 0.1% L-NAME (10.01), while it was unchanged in the mesenteric arterial bed, preglomerular arteries, and glomeruli. In contrast, ir-ET-1 concentration was decreased in the renal papilla (p0.05) as well as in the urine of L-NAME rats (p0.01). Treatment with losartan significantly attenuated the rise in systolic blood pressure induced by L-NAME (p0.01). Losartan also normalized the increased ir-ET-1 concentration in plasma and in the thoracic aorta, but had no effect on tissues with normal or reduced ir-ET-1 levels. These results indicate that chronic inhibition of NO synthase with L-NAME induces hypertension without renal dysfunction. Increased ET-1 production in some blood vessels and elevated circulating ET-1 concentration may contribute to the maintenance of high blood pressure. The reduction of systolic blood pressure by losartan supports a role for AngII in the pathogenesis of this form of hypertension, which may be due, at least in part, to the modulation of ET-1 production.

The aim of the study was to determine the ET-1 concentration in peritoneal dialysate fluid and to investigate the relationship between peritoneal and plasma ET-1 levels and blood pressure in stable continuous ambulatory peritoneal dialysis (CAPD) patients with and without human recombinant erythropoietin (r-HuEPO) replacement therapy. Twenty-seven stable CAPD patients were investigated. They completed their overnight exchange at the Dialysis Centre. Blood pressure was recorded and a blood sample was drawn. Biochemical parameters and ET-1 were measured in plasma and peritoneal dialysate fluid. Mean plasma ET-1 levels were increased by about four-fold in CAPD patients. ET-1 was detectable in peritoneal dialysate fluid and a significant correlation was observed between plasma and peritoneal ET-1 concentrations (r = 0.65, p0.01). The peritoneal clearance of ET-1 was lower than the creatinine clearance (1.69 +/- 0.08 ml/min vs. 3.96 +/- 0.15 ml/min, p0.01). There was also a significant correlation between the time (months) on dialysis and plasma (r = 0.68, p0.01) or peritoneal dialysate ET-1 levels (r = 0.46, p0.05). Mean blood pressure was higher in patients treated with r-HuEPO than in untreated patients (97 +/- 4 mmHg vs. 81 +/- 4 mmHg, p0.01). Plasma and peritoneal dialysate ET-1 concentrations were comparable in the two groups with or without r-HuEPO replacement therapy and plasma ET-1 values correlated significantly with mean blood pressure only in r-HuEPO-treated patients (r = 0.63, p0.05 vs. r = 0.10, N.S. in untreated patients). In conclusion, plasma ET-1 concentrations are elevated in CAPD patients and the levels appear to increase with time on dialysis. ET-1 is cleared by the peritoneal membrane but at a much lower rate than creatinine. Blood pressure is higher in CAPD patients or r-HuEPO replacement therapy and blood pressure correlates with plasma ET-1 levels in these patients.

To evaluate the influence of a high-fat meal on the pharmacokinetics and pharmacodynamics of the novel atypical antipsychotic drug ziprasidone.Open, randomized, three-way crossover study.University-based research facility.Eight healthy male volunteers.Ziprasidone 20 mg was administered under fasting conditions (treatment A), and directly after (treatment B) and 2 hours after (treatment C) a standard high-fat breakfast.Serial blood samples were obtained over 36 hours. Three objective psychometric tests were employed to evaluate daytime vigilance at baseline and 2 hours after each dose. Ziprasidone had a significant effect on area under the curve (AUC0-infinity), maximum serum concentration, and half-life (analysis of variance all p0.05), with the mean AUC0-infinity being significantly greater (627.2 +/- 206.4 vs 371.0 +/- 126.5 ng x hr/ml, ANOVA with Bonferroni's criteria p0.016) and half-life significantly shorter (4.7 +/- 0.8 vs 6.6 +/- 1.3 hrs, ANOVA with Bonferroni's criteria p0.016) after treatment B compared with treatment A. Although similar trends were observed after treatment C compared with treatment A, the differences did not reach statistical significance when Bonferroni's correction criteria were applied (p0.016).These data suggest an increase in systemic exposure to the highly lipophilic compound ziprasidone when taken after fatty foods, possibly due to improved drug dissolution and solubilization. The drug's longer half-life under fasting conditions may reflect dissolution-limited absorption, although this could not be directly assessed. Despite postprandial increases in ziprasidone AUC0-infinity and maximum concentration, daytime vigilance was not affected.

Objective We hypothesized an increase in dorsolateral prefrontal cortex (DLPFC) glutamate levels would occur after three weeks of repetitve transcranial magnetic stimulation (rTMS) treatment and a decrease in major depressive disorder (MDD) symptoms. Method We report six cases (four females) 15–21 years of age with treatment-resistant MDD. Participants had a mean age of 18.7 years and a mean IQ of 102.3. Short echo proton magnetic resonance spectroscopy (H-MRS) was used to quantify glutamate levels in the left DLPFC (4.5cc) before and after rTMS treatment. rTMS was localized to the left DLPFC and applied for 15 consecutive weekdays. Treatment response was defined as a greater than 50% reduction in Hamilton Depression Rating Scale scores (Ham-D).1H-MRS data was analyzed with LCModel to determine glutamate concentration. Results Following rTMS, treatment responders (N=4) showed an increase (relative to baseline) in left DLPFC glutamate levels (11%), which corresponded to an improvement in depressive symptom severity (68% Ham-D score reduction). Treatment non-responders (N=2) had elevated baseline glutamate levels compared to responders in that same region, which decreased with rTMS (−10%). Procedures were generally well tolerated with no adverse events. Conclusions rTMS is feasible and possibly efficacious in adolescents with MDD. In responders, rTMS may act by Induced elevations in elevating DFPLC glutamate levels in the left DLPFC, thereby leading to symptom improvement. Transcranial Magnetic Stimulation for Adolescent Depression (TMSAD)

MT-PVLT-10 transgenic mice express large T-antigen of polyomavirus under the control of the mouse metallothionein-1 promoter and mates of this transgenic line develop testicular tumors at advanced ages. The differential display technique was employed to compare mRNA expression from immortalized cell lines derived from normal or adenomatous testis from MT-PVLT-10 transgenic males. Using this technique, a complementary DNA fragment corresponding to the mouse Fas antigen receptor was recovered from normal testicular cells but not from tumor cells. RNAse protection assays with the Fas antigen specific fragment confirmed its differential expression. Normal testicular cells from the transgenic animals responded to treatment of interferon-gamma by increasing the expression of Fas antigen specific mRNA and were sensitive to the proliferative inhibitory effect of anti-Fas antibody in vitro. This proliferative inhibition was characterized by an accumulation of cells in S phase of the cell cycle. In contrast, the testicular tumor cells did not respond to either interferon-gamma or to anti-Fas antibody in vitro. These results suggest that the toss of proliferative inhibitory effect mediated by the Fas antigen pathway in tumor cells may be an important step in testicular tumor progression in the MT-PVLT-10 transgenic mice.

Keratin 19 is an intermediate filament protein produced by cells of simple epithelia and basal cells of stratified epithelia of different organs. These cell types are associated with important human cancers. We have used the keratin 19 promoter to target the expression of the polyomavirus (Py) large T-antigen, an immortalizing oncogene known to bind to the tumor suppressor retinoblastoma gene product, to epithelial cells. Individuals of the transgenic mouse line K19PyLT-6 developed one or two nodules in one of their lungs. By histology, the nodules were papillary tumors that consisted of nonciliated epithelial cells of the terminal bronchioles. In addition, infiltrates emanating from the nodules were consistent with the development of pulmonary adenocarcinomas. In situ hybridization techniques demonstrated large T-antigen expression in the tumors. Primary cultures were established from a lung tumor dissected from a K19PyLT-6 transgenic mouse. These large T-antigen-expressing cell lines produced the keratin proteins reminiscent of the epithelial origin of the lung tumor. However, further molecular studies indicated that these cell lines did not express Clara cells or pneumocytes markers. s.c. injection of the cell lines into nontransgenic syngeneic mice produced tumors in 2 weeks that resembled malignant pulmonary adenocarcinomas. These animals, which display tumor progression in situ, and the cell lines derived thereof provide a useful system for the study of lung tumorigenesis.

The literature on the benefits and risks of self-measurement of blood pressure and interpretation of the readings was reviewed. Self-measurement of blood pressure is useful in selected patients with high blood pressure, can be used to monitor blood pressure closely outside health care facilities, and can determine whether patients have white coat hypertension. The involvement of patients in their own blood pressure management is increased and self measurement may result in more rapid achievement of target blood pressure readings, improvement in adherence to antihypertensive therapy and decreased health care utilization. However, some patients may not be suited to monitor their own blood pressure and some may experience an increase in anxiety regarding their health. With careful training and selection of patients, most can accurately assess their blood pressure. Self-measured readings are generally lower than readings in a physician's clinic (or office) and this must be accounted for in assessing response to therapy and usual levels of blood pressure. Self-measured readings are a valuable supplement to clinic readings in many patients.

To provide health care professionals with guidelines on the use of blood pressure self-measurement.Recommendations were devised after consideration of expert reviews and guidelines, personal files, international standards documents, personal communication with investigators and the results of a MEDLINE search (1966-94) using the term 'blood pressure determination'.Self-measurement of blood pressure can be used to detect white coat hypertension, monitor changes in blood pressure closely, more rapidly achieve desired blood pressure goals, increase adherence to antihypertensive therapy and improve patient self-reliance. However, self-measured blood pressure readings may be misleading because there is insufficient normative, prognostic and outcome data and because some patients may not take accurate measurements. The use of self-measurement of blood pressure has a relatively small direct cost and may result in an overall reduction in treatment costs.Self-measured blood pressure readings can be a valuable supplement to clinic (or office) blood pressure readings. However, self-measurement is appropriate neither for patients who are physically or mentally incapable of accurate assessment and interpretation of readings nor for those who do not want to participate. Patients who self-monitor blood pressure require careful training in blood pressure measurement and instruction on the recording and interpretation of blood pressure readings. Advice to patients using monitoring equipment must take into account the needs and abilities of the patient. Although only a few electronic devices for the self-measurement of blood pressure have met recommended performance standards, their use may be more appropriate for some patients and the training requirements fewer than if manual devices are used.The guidelines of several expert groups were examined in the preparation of these recommendations. The recommendations were presented at the World Conference on Hypertension Control in 1995 and were reviewed by the parent societies of the Canadian Coalition for High Blood Pressure Prevention and Control.

Introduction Personalized medicine in oncology relies on translational research efforts to identify biomarkers that will influence clinical management. This is a concerted effort requiring an organizational framework that is often underestimated. The Quebec Clinical Research Organization in Cancer (Q-CROC) consortium is a multi-disciplinary and multi-institutional group of scientists and clinicians devoted to integrating and enhancing translational and clinical research capacity in Quebec. We describe here the organizational framework driving a multicenter, prospective study to identify biomarkers of clinical resistance to first-line therapy in metastatic colorectal cancer (NCT00984048, Q-CROC-01). Results The Q-CROC consortium has put in place an organizational infrastructure to support the activities and operations of its translational projects. We identified and addressed several critical issues during the course of the Q-CROC-01 translational project that were also common to our subsequent biomarker-driven trial in lymphoma (Q-CROC-02, NCT01238692) and breast cancer (Q-CROC-03, NCT01276899). Examples of these issues include: (i) feasibility and burden of tissue collection at participating sites, (ii) limiting pre-analytical variability in blood and tissue specimens for functional downstream applications, (iii) verification of tumor content on biopsy specimens, (iv) tracking sample flow, (v) integration of clinical data with discovery platforms, and (vi) engaging participation throughout all steps of the project. A critical element in these projects was a scientific project management team to ensure that objectives were aligned and deliverables were met. This academic framework for translational research may be comparable to that of multicenter clinical trials undertaken by industry, but some challenges, including financial and time constraints, data sharing and IP agreements, and engagement of its members, may be more palpable in the academic setting. Conclusion Infrastructure science is underestimated and under-reported in translational cancer research and is crucial to the success of any large-scale biomarker discovery effort. Our experience with three multi-institutional biomarker-driven trials is that progress hinges upon the availability of an infrastructure that provides a concrete link between each component. The Q-CROC-01 project is funded by a Pfizer-FRSQ Innovation Fund award and by Sanofi-Aventis. Q-CROC-02 is funded by Novartis and Roche, and Q-CROC-03 is funded by a Genome Quebec grant.

To determine the disposition of cefepime in patients with cystic fibrosis compared with healthy controls.Open-label, single-dose study.Laboratoire de Pharmacocinétique Clinique, Université Laval, Québec, Canada.Twelve patients with the confirmed diagnosis of cystic fibrosis (CF) and 12 healthy volunteers. One subject with CF withdrew for personal reasons; the data of another patient were excluded from the evaluation of renal values due to incomplete urine collection.A single 2000-mg dose of cefepime was administered as a 30-minute intravenous infusion. Healthy subjects did not use any other drugs throughout the study. Those with CF refrained from taking prophylactic antibiotics prior to and during the study, but continued to use pancreatic enzymes, multivitamins, and beta-agonist and/or steroid inhalers. One patient continued insulin treatment.Cefepime's maximum concentration was approximately 150 micrograms/ml at the end of the infusion, half-life 2-2.5 hours, and urinary recovery 80% in both groups. No statistically significant difference was seen in any of the pharmacokinetic values between the groups, except for the mean residence time (2.03 +/- 0.26 vs 2.39 +/- 0.37 hrs; p0.02). Total clearance was 19% higher in patients with CF than in healthy volunteers (119.7 +/- 20.1 vs 103.5 +/- 19.8 ml/min), perhaps due to higher renal (95.1 +/- 12.4 vs 85.1 +/- 12.0 ml/min) and/or nonrenal (25.4 +/- 13.1 vs 18.4 +/- 12.0 ml/min) clearances in subjects with CF.The disposition of cefepime is not significantly affected by CF, and dosage adjustment appears not to be necessary in these patients.

The pharmacokinetics and pharmacodynamics of ranitidine and famotidine were studied in 13 healthy elderly volunteers. On 3 mornings separated by a 1-week wash-out period, each subject received a single oral dose of ranitidine 300 mg, famotidine 40 mg, and placebo in a crossover, randomized fashion with double-dummy administration. Plasma and urine concentrations of ranitidine and famotidine were determined by high-performance liquid chromatography. Intragastric pH was measured for 24-hours with an antimony probe. Famotidine's plasma half-life (4.42 hrs) was significantly longer than ranitidine's (3.14 hrs, p0.05, paired t test). The 24-hour, area under the curve of pH profiles of the two drugs were significantly different from placebo (p0.05, analysis of variance and Fisher PLSD test) but not from each other. The duration of effect (defined as median pH4) was similar for ranitidine and famotidine, 10.3 and 9.9 hours, respectively (p = 0.713, paired Student's t test). Thus both agents exhibited a similar duration of 24-hour antisecretory response under these study conditions.