Circulating tumour cells to drive the use of neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer.

BACKGROUND: Guidelines recommend neoadjuvant chemotherapy (NAC) for the treatment of nonmetastatic muscle-invasive bladder cancer (MIBC). NAC is, however, underutilized in practice because of its associated limited overall survival (OS) benefit and significant treatment-related toxicity. We hypothesized that the absence of circulating tumour cells (CTCs) identifies MIBC patients with such a favourable prognosis that NAC may be withheld. PATIENTS AND METHODS: The CirGuidance study was an open-label, multicentre trial that included patients with clinical stage T2-T4aN0-N1M0 MIBC, scheduled for radical cystectomy. CTC-negative patients (no CTCs detectable using the CELLSEARCH system) underwent radical surgery without NAC; CTC-positive patients (≥1 detectable CTCs) were advised to receive NAC, followed by radical surgery. The primary endpoint was the 2-year OS in the CTC-negative group with a prespecified criterion for trial success of ≥75% (95% confidence interval (CI) ±5%). RESULTS: A total of 273 patients were enrolled. Median age was 69 years; median follow-up was 36 months. The primary endpoint of 2-year OS in the CTC-negative group was 69.5% (N = 203; 95% CI 62.6%-75.5%). Two-year OS was 58.2% in the CTC-positive group (N = 70; 95% CI 45.5%-68.9%). CTC-positive patients had a higher rate of cancer-related mortality [hazard ratio (HR) 1.61, 95% CI 1.05-2.45, P = 0.03] and disease relapse (HR 1.87, 95% CI 1.28-2.73, P = 0.001) than CTC-negative patients. Explorative analyses suggested that CTC-positive patients who had received NAC (n = 22) survived longer than CTC-positive patients who had not (n = 48). CONCLUSION: The absence of CTCs in MIBC patients was associated with improved cancer-related mortality and a lower risk of disease relapse after cystectomy; however, their absence alone does not justify to withhold NAC. Exploratory analyses suggested that CTC-positive MIBC patients might derive more benefit from NAC. TRIAL REGISTRATION: Netherlands Trial Register NL3954; https://www.trialregister.nl/trial/3954.

Exercise training increases skeletal muscle mitochondrial volume density by enlargement of existing mitochondria and not de novo biogenesis.

AIMS: (i) To determine whether exercise-induced increases in muscle mitochondrial volume density (MitoVD ) are related to enlargement of existing mitochondria or de novo biogenesis and (ii) to establish whether measures of mitochondrial-specific enzymatic activities are valid biomarkers for exercise-induced increases in MitoVD . METHOD: Skeletal muscle samples were collected from 21 healthy males prior to and following 6 weeks of endurance training. Transmission electron microscopy was used for the estimation of mitochondrial densities and profiles. Biochemical assays, western blotting and high-resolution respirometry were applied to detect changes in specific mitochondrial functions. RESULT: MitoVD increased with 55 ± 9% (P < 0.001), whereas the number of mitochondrial profiles per area of skeletal muscle remained unchanged following training. Citrate synthase activity (CS) increased (44 ± 12%, P < 0.001); however, there were no functional changes in oxidative phosphorylation capacity (OXPHOS, CI+IIP ) or cytochrome c oxidase (COX) activity. Correlations were found between MitoVD and CS (P = 0.01; r = 0.58), OXPHOS, CI+CIIP (P = 0.01; R = 0.58) and COX (P = 0.02; R = 0.52) before training; after training, a correlation was found between MitoVD and CS activity only (P = 0.04; R = 0.49). Intrinsic respiratory capacities decreased (P < 0.05) with training when respiration was normalized to MitoVD. This was not the case when normalized to CS activity although the percentage change was comparable. CONCLUSIONS: MitoVD was increased by inducing mitochondrial enlargement rather than de novo biogenesis. CS activity may be appropriate to track training-induced changes in MitoVD.

Milestones and controversies in maternal and child health: examining a brief history of micronutrient fortification in the US.

Fortification of our food and drinking supply has decreased morbidity rates related to micronutrient deficiencies among mothers and their children, particularly during the perinatal and neonatal periods of development. The purpose of this historical review is to examine the impact of public policy changes related to micronutrient fortification. We provide a historical investigation of achievements and controversies related to iodine, vitamin D, fluoride and folic acid fortifications in our food and drinking supply. We also discuss the current status of fortification recommendations and their significance to maternal and child health.

Four weeks of normobaric "live high-train low" do not alter muscular or systemic capacity for maintaining pH and K⁺ homeostasis during intense exercise.

It was investigated if athletes subjected to 4 wk of living in normobaric hypoxia (3,000 m; 16 h/day) while training at 800-1,300 m ["live high-train low" (LHTL)] increase muscular and systemic capacity for maintaining pH and K(+) homeostasis as well as intense exercise performance. The design was double-blind and placebo controlled. Mean power during 30-s all-out cycling was similar before and immediately after LHTL (650 ± 31 vs. 628 ± 32 W; n = 10) and placebo exposure (658 ± 22 vs. 660 ± 23 W; n = 6). Supporting the performance data, arterial plasma pH, lactate, and K(+) during submaximal and maximal exercise were also unaffected by the intervention in both groups. In addition, muscle buffer capacity (in mmol H(+)·kg dry wt(-1)·pH(-1)) was similar before and after in both the LHTL (140 ± 12 vs. 140 ± 16) and placebo group (145 ± 2 vs. 140 ± 3). The expression of sarcolemmal H(+) transporters (Na(+)/H(+) exchanger 1, monocarboxylate transporters 1 and 4), as well as expression of Na(+)-K(+) pump subunits-α(1), -α(2), and -ß(1) was also similar before and after the intervention. In conclusion, muscular and systemic capacity for maintaining pH and K(+) balance during exercise is similar before and after 4 wk of placebo-controlled normobaric LHTL. In accordance, 30-s all-out sprint ability was similar before and after LHTL.

Determinants of time trial performance and maximal incremental exercise in highly trained endurance athletes.

Human endurance performance can be predicted from maximal oxygen consumption (Vo(2max)), lactate threshold, and exercise efficiency. These physiological parameters, however, are not wholly exclusive from one another, and their interplay is complex. Accordingly, we sought to identify more specific measurements explaining the range of performance among athletes. Out of 150 separate variables we identified 10 principal factors responsible for hematological, cardiovascular, respiratory, musculoskeletal, and neurological variation in 16 highly trained cyclists. These principal factors were then correlated with a 26-km time trial and test of maximal incremental power output. Average power output during the 26-km time trial was attributed to, in order of importance, oxidative phosphorylation capacity of the vastus lateralis muscle (P = 0.0005), steady-state submaximal blood lactate concentrations (P = 0.0017), and maximal leg oxygenation (sO(2LEG)) (P = 0.0295), accounting for 78% of the variation in time trial performance. Variability in maximal power output, on the other hand, was attributed to total body hemoglobin mass (Hb(mass); P = 0.0038), Vo(2max) (P = 0.0213), and sO(2LEG) (P = 0.0463). In conclusion, 1) skeletal muscle oxidative capacity is the primary predictor of time trial performance in highly trained cyclists; 2) the strongest predictor for maximal incremental power output is Hb(mass); and 3) overall exercise performance (time trial performance + maximal incremental power output) correlates most strongly to measures regarding the capability for oxygen transport, high Vo(2max) and Hb(mass), in addition to measures of oxygen utilization, maximal oxidative phosphorylation, and electron transport system capacities in the skeletal muscle.

Reticulocyte and haemoglobin profiles in elite triathletes over four consecutive seasons.

INTRODUCTION: The World Anti-Doping Agency has implemented the Blood Passport in attempt to detect blood doping in athletes. The Blood Passport looks for uncommon changes overtime in reticulocytes percentage (Ret %), as a variable of the OFF-hr score, and haemoglobin concentration ([Hb]) reflecting potential doping violations. Few studies, however, have actually investigated the concurrent stability of Ret % and [Hb] in athletes over extended periods of time, none of which were measured in athletes who undergo strenuous and prolonged physical exercise. METHODS: Measurements of Ret % and [Hb] were assessed over the course of four competitive seasons in elite triathletes (10 males and seven female). Blood was obtained at the start of the season, precompetitive period, competitive period and at the end of the competitive period. RESULTS: Differences (P<0.001) were observed in both [Hb] and Ret % between genders and there was a high variability between subjects. Neither males nor females exhibited differences in [Hb] across all periods within one season. Within gender, analysis revealed that Ret % varied significantly (P=0.0018) between periods only in female athletes. CONCLUSION: We conclude that Ret % and [Hb] remain stable over four consecutive seasons in elite triathletes, confirming that both parameters are valid for antidoping purposes based on the Blood Passport. In addition, Ret % fluctuations within one season require further investigation in females.

Tuberculous meningoencephalitis in a pregnant woman presenting 7 years after removal of a cerebral granuloma.

We describe the unusual case of a young woman with a history of seizures and a granulomatous, likely tuberculous brain lesion that was surgically removed. She had an uneventful recovery without any additional therapy other than anti-epileptics. Seven years later, she presented during pregnancy with culture-confirmed tuberculous meningoencephalitis. This case highlights the spectrum of tuberculous central nervous system disease and the challenges in diagnosis.

Chemosensitive serotonergic neurons are closely associated with large medullary arteries.

We have previously shown that serotonergic neurons of the medulla are strongly stimulated by an increase in CO(2), suggesting that they are central respiratory chemoreceptors. Here we used confocal imaging and electron microscopy to show that neurons immunoreactive for tryptophan hydroxylase (TpOH) are tightly apposed to large arteries in the rat medulla. We used patch-clamp recordings from brain slices to confirm that neurons with this anatomical specialization are chemosensitive. Serotonergic neurons are ideally situated for sensing arterial blood CO(2), and may help maintain pH homeostasis via wide-ranging effects on brain function. The results reported here support a recent proposal that sudden infant death syndrome (SIDS) results from a developmental abnormality of medullary serotonergic neurons.

Characterization of emissions of dioxins and furans from ethylene dichloride, vinyl chloride monomer and polyvinyl chloride facilities in the United States. Consolidated report.

This is the consolidated report of emissions of PCDD/F from facilities in the organic chemical manufacturing chain leading to polyvinyl chloride. Data have been gathered from facilities in the US and Canada from a number of manufacturers and at various steps in the manufacturing process. Estimates of US emissions or transfers of PCDD/F were generated on an "Upper Bound" and "Most Likely" basis. The Most Likely estimate of US emissions of PCDD/F to the open environment, that is, air, water and land surface by facilities in this chain, based on evaluation of non-detects at one-half the detection limit is about 12 g I-TEQ per year. On this same basis, an estimated 19 g is disposed of in secure landfills.

Impact of an intravenous fluconazole restriction policy on patient outcomes.

OBJECTIVE: To evaluate both the economic and clinical impact of an intravenous fluconazole restriction policy in a university teaching hospital. METHODS: Intravenous fluconazole was restricted to patients unable to take oral medications due to significant nausea or to patients whose oral intake was restricted. A retrospective chart review and computerized record review was conducted in patients receiving intravenous or oral fluconazole from January 1 to June 30, 1997, and again from January 1 to June 30, 1998, after implementation of the policy. RESULTS: Six-month institutional expenditures for intravenous fluconazole decreased following policy implementation, from $81,900 to $45,400, an estimated annual institutional savings of $73,000. A 47% reduction in the number of patients treated with intravenous fluconazole was observed over the six-month period after policy implementation. During this time, the rate of successful clinical outcomes for documented or suspected disseminated Candida albicans infection or febrile neutropenia remained the same (66.6% prepolicy and 65.9% postpolicy; p = 0.95). Similarly, the number of deaths in patients receiving fluconazole remained unchanged (p = 0.31). CONCLUSIONS: A restriction policy for intravenous fluconazole results in significant cost savings, with no significant decrease in successful outcomes or change in mortality.

Experience-dependent visual cue integration based on consistencies between visual and haptic percepts.

We study the hypothesis that observers can use haptic percepts as a standard against which the relative reliabilities of visual cues can be judged, and that these reliabilities determine how observers combine depth information provided by these cues. Using a novel visuo-haptic virtual reality environment, subjects viewed and grasped virtual objects. In Experiment 1, subjects were trained under motion relevant conditions, during which haptic and visual motion cues were consistent whereas haptic and visual texture cues were uncorrelated, and texture relevant conditions, during which haptic and texture cues were consistent whereas haptic and motion cues were uncorrelated. Subjects relied more on the motion cue after motion relevant training than after texture relevant training, and more on the texture cue after texture relevant training than after motion relevant training. Experiment 2 studied whether or not subjects could adapt their visual cue combination strategies in a context-dependent manner based on context-dependent consistencies between haptic and visual cues. Subjects successfully learned two cue combination strategies in parallel, and correctly applied each strategy in its appropriate context. Experiment 3, which was similar to Experiment 1 except that it used a more naturalistic experimental task, yielded the same pattern of results as Experiment 1 indicating that the findings do not depend on the precise nature of the experimental task. Overall, the results suggest that observers can involuntarily compare visual and haptic percepts in order to evaluate the relative reliabilities of visual cues, and that these reliabilities determine how cues are combined during three-dimensional visual perception.

Perceptual learning for a pattern discrimination task.

Our goal was to differentiate low and mid level perceptual learning. We used a complex grating discrimination task that required observers to combine information across wide ranges of spatial frequency and orientation. Stimuli were 'wicker'-like textures containing two orthogonal signal components of 3 and 9 c/deg. Observers discriminated a 15% spatial frequency shift in these components. Stimuli also contained four noise components, separated from the signal components by at least 45 degrees of orientation or approximately 2 octaves in spatial frequency. In Experiment 1 naive observers were trained for eight sessions with a four-alternative same-different forced choice judgment with feedback. Observers showed significant learning, thresholds dropped to approximately 1/3 of their original value. In Experiment 2 we found that observers showed far less learning when the noise components were not present. Experiment 3 found, unlike many other studies, almost complete transfer of learning across orientation. The results of Experiments 2 and 3 suggest that, unlike many other perceptual learning studies, most learning in Experiment 1 occurs at mid to high levels of processing rather than within low level analyzers tuned for spatial frequency and orientation. Experiment 4 found that performance was more severely impaired by spatial frequency shifts in noise components of the same spatial frequency or orientation as the signal components (though there was significant variability between observers). This suggests that after training observers based their responses on mechanisms tuned for selective regions of Fourier space. Experiment 5 examined transfer of learning from a same-sign task (the two signal components both increased/decreased in spatial frequency) to an opposite-sign task (signal components shifted in opposite directions in frequency space). Transfer of learning from same-sign to opposite-sign tasks and vice versa was complete suggesting that observers combined information from the two signal components independently.

Motor timing learned without motor training.

Improvements due to perceptual training are often specific to the trained task and do not generalize to similar perceptual tasks. Surprisingly, given this history of highly constrained, context-specific perceptual learning, we found that training on a perceptual task showed significant transfer to a motor task. This result provides evidence for a common neural architecture underlying analysis of sensory input and control of motor output, and suggests a potential role for perception in motor development and rehabilitation.

Ceftriaxone therapy for staphylococcal osteomyelitis: a review.

Ceftriaxone, although less active than standard antistaphylococcal agents, is potentially useful in the treatment of osteomyelitis. Thirty-one patients with osteomyelitis due to Staphylococcus aureus were identified, 22 of whom were treated with ceftriaxone and 9 with other agents. Of those patients treated with ceftriaxone, 17 were cured; all treatment failures were associated with chronic osteomyelitis and continued presence of necrotic bone or infected hardware. It is concluded that ceftriaxone is effective in the ambulatory treatment of S. aureus osteomyelitis.

Prevention of adverse events in hospitalized patients using an antimicrobial review program.

OBJECTIVE: To evaluate whether an antimicrobial review system is associated with a reduction in antimicrobial-associated adverse events. DESIGN: All antimicrobial medication orders for patients hospitalized over a two-year period were evaluated. High-level interventions intended to prevent adverse antimicrobial events were collated. Based on literature estimates of adverse antimicrobial events, potential reduction of high-level adverse antimicrobial events was estimated. SETTING: Department of Clinical Pharmacy and Division of Infectious Diseases at a tertiary care teaching hospital. RESULTS: A total of 452 interventions were classified as "high-level." The incidence of preventable adverse antimicrobial events requiring intervention was 16 per 1000 antimicrobial orders. The incidence of high-level errors necessitating intervention was 4.4 per 1000 antimicrobial orders. An estimated 125 to 198 high-level adverse events were avoided. CONCLUSION: An antimicrobial review program has the potential to reduce significant adverse events in hospitalized patients.

Modeling the combination of motion, stereo, and vergence angle cues to visual depth.

Three models of visual cue combination were simulated: a weak fusion model, a modified weak model, and a strong model. Their relative strengths and weaknesses are evaluated on the basis of their performances on the tasks of judging the depth and shape of an ellipse. The models differ in the amount of interaction that they permit among the cues of stereo, motion, and vergence angle. Results suggest that the constrained nonlinear interaction of the modified weak model allows better performance than either the linear interaction of the weak model or the unconstrained nonlinear interaction of the strong model. Further examination of the modified weak model revealed that its weighting of motion and stereo cues was dependent on the task, the viewing distance, and, to a lesser degree, the noise model. Although the dependencies were sensible from a computational viewpoint, they were sometimes inconsistent with psychophysical experimental data. In a second set of experiments, the modified weak model was given contradictory motion and stereo information. One cue was informative in the sense that it indicated an ellipse, while the other cue indicated a flat surface. The modified weak model rapidly reweighted its use of stereo and motion cues as a function of each cue's informativeness. Overall, the simulation results suggest that relative to the weak and strong models, the modified weak fusion model is a good candidate model of the combination of motion, stereo, and vergence angle cues, although the results also highlight areas in which this model needs modification or further elaboration.

Pineal nitric oxide synthase, but not heme oxygenase, mRNA is suppressed by continuous exposure to light.

We have previously shown that exposure of rats to constant light (LL) induced a decrease in NO synthase (NOS) activity in the pineal gland. We report here that the use of the sensitive technique of RT-PCR has demonstrated that mRNA for neuronal NOS is present in the pineal, and that it is photoneurally regulated. There was a marked decrease in pineal neuronal NOS mRNA levels in continuous light conditions, similar to the changes seen in NOS enzyme activity. Inducible NOS was not present in the pineal, and there was evidence that the photoregulatable form was not endothelial NOS. The mRNA for two isoforms of heme oxygenase, the enzyme responsible for the generation of the putative neuromodulator carbon monoxide, was also present in the pineal, but neither isoform was photoregulated. Using immunodetection, it was not possible to identify the presence of NOS protein, other than to a minimal extent, even though NOS activity was clearly present. NADPH-diaphorase staining and in situ hybridization were carried out in an attempt to identify the precise location of neuronal NOS message. A strong NADPH-diaphorase reaction was present in sympathetic nerve fibers of the pineal, but pinealocytes showed no or only very weak labelling. In situ hybridization was also unable to identify neuronal NOS message in pinealocytes. These data thus also suggest the possible presence of a pineal-specific NOS isoenzyme.

Expression and functional analysis of endothelial nitric oxide synthase (eNOS) in human placenta.

We have investigated the expression and localization of endothelium-derived nitric oxide synthase (eNOS) and the effect of eNOS on placental human chorionic gonadotrophin (HCG) release. eNOS mRNA was found to be expressed in all tissues, with its expression significantly (P<0.05) increased across gestation. Compared to normal term gestation, placentae from term pregnancies with fetal retardation, or maternal diabetes, but not with maternal hypertension, displayed significantly more (P<0.05) eNOS mRNA. By immunocytochemistry, we found staining for eNOS in both the cyto- and syncytiotrophoblasts of first trimester and a loss of cytotrophoblast eNOS staining in term placentae, while syncytiotrophoblasts at term were strongly eNOS positive. Additional staining was found in endothelium surrounding the vascular tree. HCG was found to colocalize with eNOS in trophoblasts, but not in endothelia. When placental explants were perifused, exposure to the NOS substrate, the NO donor, I-arginine and trinitroglycerol evoked a prompt, albeit transient, increase of HCG release. The NOS inhibitor delayed, but did not block arginine-induced HCG release. Thus, eNOS is expressed in the human placenta at increasing levels during gestation with further increases during some pathological conditions. A role for NO in the acute endocrine modulation of the placenta is suggested by the colocalization of eNOS with HCG in human trophoblasts and the prompt secretion of HCG in response to agents which increase NO concentrations.