Ripening of mature avocado fruit was accelerated by 18-and 24-hr ethylene treatments which were a... more Ripening of mature avocado fruit was accelerated by 18-and 24-hr ethylene treatments which were applied beginning 1 hr after harvest. Exposure to ethylene for 12 hr or less, starting 1 hr after harvest, did not accelerate the respiration rate, ethylene evolution, or fruit softening. Ethylene treatment for 6 hr starting at 1, 6, 12, or 18 hr after harvest did not accelerate the onset of the ripening process. It is suggested that ethylene does not just "trigger" the ripening of avocado fruit but rather is involved in a relatively long (18 to 24 hr) process which requires its continuous presence.
The aim of this study was to establish the sensitive, specific and clinically acceptable method f... more The aim of this study was to establish the sensitive, specific and clinically acceptable method for detection of tumor cells (TCs) circulating in peripheral blood (PB) of cervical cancer patients without the clinically detectable risk of disease progression. The 7.5 ml of PB of healthy donor was spiked with 5 to 100 cells from SiHa or HeLa cell lines. The spiked tumor cells were collected without gradient centrifugation, by standard gradient centrifugation or by modified gradient centrifugation combined with immunomagnetic separation using EpCAM antibody with affinity for epithelial cell adhesion molecule. The number of collected TCs was determined by EpCAM-FITC-staining and their viability was detected by nested RT-PCR amplifying E6/E7 HR-HPV 16 or HR-HPV 18 oncogenes. For the technical validation of this approach the TCs separation and RT-PCRs were repeated several times. The recovery of viable TCs was reproducibly higher using modified gradient centrifugation combined with immunomagnetic separation in comparison with standard approach. The recovery of TCs in low number of spiked TCs (range from 5 - 20 TCs in 7.5 ml of PB) using modified gradient centrifugation was not reproducible. The recovery of TCs in higher number of spiked TCs (25 TCs and more in 7.5 ml of PB) was reproducible with average recovery about 50 %. The sensitivity of nested RT-PCR amplifying E6/E7 oncogenes was decisively influenced by the number of recovered TCs and the amount of cDNA introduced to RT-PCR, as well. Using this approach we were allowed to detect circulating TCs (CTCs) in cervical cancer patients without metastases, thus this procedure might become a tool to early estimation of disease progression. According to our knowledge, this is the first report describing the use of EpCAM antibody for CTCs detection in cervical cancer patients.
Background This study was performed within the scope of two multi-center European Commission-fund... more Background This study was performed within the scope of two multi-center European Commission-funded projects (HEPMEAP and PAMCHAR) concerning source-composition-toxicity relationship for particulate matter (PM) sampled in Europe. The present study aimed to optimize the design for PM in vivo toxicity screening studies in terms of dose and time between a single exposure and the determination of the biological responses in a rat model mimicking human disease resulting in susceptibility to ambient PM. Dust in thoracic PM size-range (aerodynamic diameter <10 μm) was sampled nearby a road tunnel (RTD) using a high volume cascade impactor. Spontaneously hypertensive rats were exposed to urban dust collected in Ottawa, Canada (EHC-93 10 mg/kg of body weight; reference PM) or different RTD doses (0.3, 1, 3, 10 mg/kg of body weight) by intratracheal instillation. Necropsy was performed at 4, 24, or 48 hr after exposure. Results The neutrophil numbers in bronchoalveolar lavage fluid increased tremendously after exposure to the highest RTD doses or EHC-93. Furthermore, PM exposure slightly affected blood coagulation since there was a small but significant increase in the plasma fibrinogen levels (factor 1.2). Pulmonary inflammation and oxidative stress as well as changes in blood coagulation factors and circulating blood cell populations were observed within the range of 3 to 10 mg PM/kg of body weight without significant pulmonary injury. Conclusion The optimal dose for determining the toxicity ranking of ambient derived PM samples in spontaneously hypertensive rats is suggested to be between 3 and 10 mg PM/kg of body weight under the conditions used in the present study. At a lower dose only some inflammatory effects were detected, which will probably be too few to be able to discriminate between PM samples while a completely different response pattern was observed with the highest dose. In addition to the dose, a 24-hr interval from exposure to sacrifice seemed appropriate to assess the relative toxic potency of PM since the majority of the health effects were observed one day after PM exposure compared to the other times examined. The aforementioned considerations provide a good basis for conducting PM toxicity screening studies in spontaneously hypertensive rats.
Isolating a sexually mature Aplysia fasciata for either 1 or 24 hr immediately after training tha... more Isolating a sexually mature Aplysia fasciata for either 1 or 24 hr immediately after training that a food is inedible blocks the subsequent expression of memory measured 24 hr later. Isolation that is delayed for 1 hr after training, but not for 12 hr after training, is also effective in blocking memory. Isolation affects memory because of a specific effect caused by the absence of pheromones secreted by conspecifics rather than by a nonspecific change in the chemical environment, because transferring animals to a novel environment (120% seawater) that contains a conspecific does not affect memory. Isolation also does not affect memory in sexually immature Aplysia, even though immature animals are able to sense one another&amp;amp;#39;s presence. Isolation may affect memory because social (and sexual) isolation is a form of stress in mature A. fasciata, and stress after training affects retention in many animals.
ABSTRACT There is considerable academic interest in the consequences of European integration for ... more ABSTRACT There is considerable academic interest in the consequences of European integration for human resource (HR) management within multinational companies. In the context of this debate discusses the implications of changes in the organisation of production and markets for the management of HR in the banking sector. Frames the analysis with special reference to British and Spanish banks, and draws implications regarding the impact of such changes for the most prominent development in terms of European legislation at company level, European Works Councils (EWCs). Argues that deregulation and European integration have facilitated restructuring and consolidation within national boundaries, which in turn have facilitated cross-border mergers and acquisitions. As a result, the number of banks with operations in two or more countries of the European Union has increased. While business continues to be geographically segmented according to countries, affording EWCs a relatively limited role, growing similarities in work organisation and processes in banks across countries offers potential for change.
Journal of Pharmacological and Toxicological Methods, 2007
The objective of this study was to define the normal LVdP/dt (an index of myocardial contractilit... more The objective of this study was to define the normal LVdP/dt (an index of myocardial contractility)-heart rate relationship in telemetered conscious dogs, primates and mini-pigs in our laboratory and to use these data as the basis for an additional parameter useful in drug safety evaluation. Trained dogs, Rhesus monkeys, Cynomolgus monkeys and mini-pigs (Goettinger) were equipped with radiotelemetry transmitters (ITS). Aortic pressure (AP), left ventricular pressure (LVP), a lead II ECG and body temperature could be continuously monitored. The contractility index LVdP/dtmax was derived from the LVP signal. Notocord HEM 4.1 software was used for data acquisition. For each species an LVdP/dt-heart rate relationship was evaluated using spontaneous heart rates (HR) throughout the observation period. A validation compound with positive inotropic effects (pimobendan) was then used to investigate the LVdP/dt-heart rate relationship. There was a clear LVdP/dt-HR relationship in the animals tested. The inotropic agent pimobendan demonstrated the expected shift in this relationship. Contractility of the myocardium is regulated by autonomic input activating primarily myocardial beta1-adrenoceptors, but it is also affected by the &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;force-frequency&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; relationship. Compounds can therefore either directly or indirectly affect the contractility of the heart. The chronotropic effects are routinely measured in preclinical studies; however, the inotropic effects are not routinely analysed in cardiovascular safety studies. Our experience strongly recommends including this evaluation for drug candidate selection. The evaluation of LVdP/dtmax, as an index of myocardial contractile state must, however, take into account its HR-dependency.
Ambulatory blood pressure monitoring (ABPM) has demonstrated a high prevalence of white coat hype... more Ambulatory blood pressure monitoring (ABPM) has demonstrated a high prevalence of white coat hypertension (WCH) in adults, but few studies exist in obese and overweight children and adolescents. We can define WCH as elevated casual blood pressure (BP) with normal 24-hr mean BP, but ABPM in adults has shown that BP load( % of BP readings Ͼ 95th percentile) is better to predict hypertensive end-organ injury than mean BP. Our objective was to evaluate the prevalence of hypertension (HTN) and WCH in overweight and obese children and adolescents by both mean BP criteria and BP load criteria. From January 1999 to June 2000, 39 patients ( 22M/17F) from 10 to 17 years old were evaluated and in all, ABPM were performed. They were evaluated by two cardiologists and the BP was measured two times by each one, with 5 minutes interval. HTN were considered when the average of these 4 measures (systolic or diastolic) Ͼ 95th percentile. In relation to ABPM, BP was measured 3 times/hr from 8 am to 10 pm and 2 times/hr from 10 pm to 8 am. Wake and sleep period were defined by patient self-report. WCH was defined by mean BP criteria as wake systolic BP (SBP) and diastolic BP (DBP) Ͻ 95th percentile (Task Force for HTN Control in Children and Adolescent) and by BP load criteria as 24-hr SBP and DBP load Ͻ 30% (using 24-hr 95th percentile normative pediatric ABPM data). The criteria used for overweight and obesity were defined by body mass index (BMI) according to Expert Committee on Clinical Guidelines for Overweight in Adolescent Preventive Service. The prevalence of HTN was 28.2% (11/39), being 54.6% females (6/11) and 90.9% (10/11) were obese. The prevalence of WCH defined by mean BP criteria was 45.4% (5/11) and 80% were girls (4/5) and 80% (4/5) were obese. BP load was normal (Ͻ 30%) in 27.2% (3/11) for SBP and 81.8% (9/11) for DBP. The prevalence of WCH by BP load criteria (SBP and DBP Ͻ 30%) was 27.2% (3/11), being 66.6% girls (2/3) and 66.6% obese (2/3); 27.2 % (3/11) of patients had WCH by both criteria (mean BP and BP load). The HTN and WCH in obese and overweight children and adolescents are common and they occur more often in girls and obese. ABPM should be used in hypertensive obese and overweight children to avoid mistaken for casual HTN that may lead to unnecessary use of medication and expensive diagnostic approaches.
mediators with the capacity to recruit marrow-derived stromal cells. To test this, primary murine... more mediators with the capacity to recruit marrow-derived stromal cells. To test this, primary murine tracheal epithelial cells (MTEC) were cultured on a supported semi-permeable membrane (Transwell) under air-liquid interface conditions. When cells developed tight junctions, stromal marrow cells derived from adult transgenic GFPexpressing mice, cultured on glass cover slips, were placed in the lower Transwell chamber. After 1 week, a small number of stromal cells were observed to have migrated to the permeable membrane. The number of migrating cells substantially increased after MTEC were stimulated with endotoxin (25 µg/well, 1 hr). Media from naïve and endotoxin-stimulated MTEC and from the stromal marrow cells were assayed for multiple chemokines. Stromal-derived factor (SDF-1), a chemokine implicated in stem cell mobilization was produced in higher amounts by stromal cells than by MTEC (908 vs 100 pg/ml), suggesting that SDF-1 release by epithelial cells may not drive stromal cell migration in the lung. In contrast, IL-17 was released in higher amounts by both naïve and endotoxin-stimulated MTEC than by stromal cells. Adding neutralizing anti IL-17 antibody (1 µg/ml) to the culture media blocked migration of stromal cells to the transwell membrane. These data provide a functional model for assay of airway epithelial cell-marrow derived stromal cell interactions that are important for repair in lung injury and implicate a critical role of IL-17 in migration of adult marrow-derived stromal cells to lung epithelium.
Osservatorio Innovazione Sifo web www.osservatorioinnovazione.org mail [email protected] SCHEDA... more Osservatorio Innovazione Sifo web www.osservatorioinnovazione.org mail [email protected] SCHEDA PRODOTTO con valutazione economica semplificata I dati originali riportati nella scheda sono proprietà del Laboratorio SIFO di Farmacoeconomia, Firenze Il prodotto innovativo preso in esame determina un beneficio clinico incrementale; la VES viene perciò impostata come analisi del rapporto tra costo incrementale ed efficacia incrementale (CEA). Data di aggiornamento della scheda: 30/12/2008 Nome commerciale del prodotto: Zevalin® radiomarcato con [ 90 Y (Ytracis®)] Descrizione del prodotto: [ 90 Y]-ibritumomab tiuxetano Indicazione terapeutica:
Monthly Notices of The Royal Astronomical Society, 1979
Infrared observations are presented which reinforce the conclusion reached from optical data that... more Infrared observations are presented which reinforce the conclusion reached from optical data that the variability of HR 5999, sometimes being misidentified as HR 6000, is due to ejected dust grains. A simple model is proposed for the existing dust shell. This simple model fits the colors reasonably well. Visible and IR observations planned at a number of observatories for 1978 are expected to give a much more complete picture of this interesting system.
Splanchnic and systemic arteriolar vasodilationplays an important role in ascites formation incir... more Splanchnic and systemic arteriolar vasodilationplays an important role in ascites formation incirrhosis. Octreotide produces splanchnicvasoconstriction, but the effects on systemichemodynamics and renal function are controversial. This studyevaluated the effect of subcutaneous octreotideadministration on systemic hemodynamics, endogenousvasoactive systems, and renal function in cirrhoticpatients with ascites. Twenty patients were included: 10received octreotide 250 μg/12 hr subcutaneously (forfive days), and 10 did not. No statistically significantchanges were found in mean arterial pressure and cardiac rate. Octreotide induced astatistically significant decrease in plasma reninactivity (P < 0.01), plasma aldosterone (P = 0.01)and plasma glucagon (P < 0.05). No significantvariations were observed in other systemic vasoactivesubstances (nitric oxide and prostacyclin). Renalfunction was not modified in either group. Inconclusion, in cirrhotic patients with ascites,subcutaneous octreotide administration decreases plasma glucagon, reninactivity, and aldosterone without changing in systemichemodynamics or renal function.
Splanchnic and systemic arteriolar vasodilationplays an important role in ascites formation incir... more Splanchnic and systemic arteriolar vasodilationplays an important role in ascites formation incirrhosis. Octreotide produces splanchnicvasoconstriction, but the effects on systemichemodynamics and renal function are controversial. This studyevaluated the effect of subcutaneous octreotideadministration on systemic hemodynamics, endogenousvasoactive systems, and renal function in cirrhoticpatients with ascites. Twenty patients were included: 10received octreotide 250 μg/12 hr subcutaneously (forfive days), and 10 did not. No statistically significantchanges were found in mean arterial pressure and cardiac rate. Octreotide induced astatistically significant decrease in plasma reninactivity (P < 0.01), plasma aldosterone (P = 0.01)and plasma glucagon (P < 0.05). No significantvariations were observed in other systemic vasoactivesubstances (nitric oxide and prostacyclin). Renalfunction was not modified in either group. Inconclusion, in cirrhotic patients with ascites,subcutaneous octreotide administration decreases plasma glucagon, reninactivity, and aldosterone without changing in systemichemodynamics or renal function.
Proceedings of The National Academy of Sciences, 1985
The GO/Gj to S transition in quiescent BALB/c 3T3 cells stimulated by serum growth factors can be... more The GO/Gj to S transition in quiescent BALB/c 3T3 cells stimulated by serum growth factors can be specifically blocked by the administration ofinterferon (IFN) to the system. In the present communication, we studied whether IFN inhibits the early events in the Go/G1 phase that are initiated by the platelet-derived growth factor (PDGF). The results show that IFN inhibits most of the PDGF-mediated increase of c-myc, ornithine decarboxylase, and j3-actin mRNAs measured 3 hr after stimulation. c-fos mRNA levels are reduced by IFN as early as 20 min after exposure of the quiescent cells to PDGF. The expression of several genes that belong to the competence gene family is, therefore, inhibited by IFN and this could account for the failure of the IFN-treated cells to enter into the S phase when growth factors present in the platelet-poor plasma are added. We also report that the PDGF-mediated increase in the uptake of deoxyglucose is not impaired by IFN, thus suggesting that the early effects of IFN on gene expression do not result from inhibition of binding of PDGF to its cell-surface receptors. Unlike the direct stimulatory effect ofPDGF, which is not sensitive to cycloheximide, the inhibitory effect of IFN on c-myc mRNA levels depends in part on protein synthesis. We propose that a putative product of one of the IFN-induced genes could mediate the decrease in expression of the PDGF-regulated gene family.
The class III histone deacetylase (HDAC) SIRT1 plays a role in the metabolism, aging, and carcino... more The class III histone deacetylase (HDAC) SIRT1 plays a role in the metabolism, aging, and carcinogenesis of organisms and regulates senescence and apoptosis in cells. Recent reports revealed that SIRT1 also deacetylates several DNA double-strand break (DSB) repair proteins. However, its exact functions in DNA repair remained elusive. Using nuclear foci analysis and fluorescence-based, chromosomal DSB repair reporter, we find that SIRT1 activity promotes homologous recombination (HR) in human cells. Importantly, this effect is unrelated to functions of poly(ADP-ribose) polymerase 1 (PARP1), another NAD(+)-catabolic protein, and does not correlate with cell cycle changes or apoptosis. Interestingly, we demonstrate that inactivation of Rad51 does not eliminate the effect of SIRT1 on HR. By epistasis-like analysis through knockdown and use of mutant cells of distinct SIRT1 target proteins, we show that the non-homologous end joining (NHEJ) factor Ku70 as well as the Nijmegen Breakage Syndrome protein (nibrin) are not needed for this SIRT1-mediated effect, even though a partial contribution of nibrin cannot be excluded. Strikingly however, the Werner helicase (WRN), which in its mutated form causes premature aging and cancer and which was linked to the Rad51-independent single-strand annealing (SSA) DSB repair pathway, is required for SIRT1-mediated HR. These results provide first evidence that links SIRT1's functions to HR with possible implications for genomic stability during aging and tumorigenesis.
Background: WR1065 is the free-thiol metabolite of the cytoprotective aminothiol amifostine, whic... more Background: WR1065 is the free-thiol metabolite of the cytoprotective aminothiol amifostine, which is used clinically at very high doses to protect patients against toxicity induced by radiation and chemotherapy. In an earlier study we briefly reported that the aminothiol WR1065 also inhibits HIV-1 replication in phytohemagglutinin (PHA)-stimulated human T-cell blasts (TCBs) infected in culture for 2 hr before WR1065 exposure. In this study we expanded the original observations to define the dose-response curve for that inhibition, and address the question of additive effects for the combination of WR1065 plus Zidovudine (AZT). Here we also explored the effect of WR1065 on SIV by examining TCBs taken from macaques with well-established infections several months with SIV.
ABSTRACT Previous,studies,have,shown,that,cells,in the,6-day old,embryonic,chick,lens,epithelium ... more ABSTRACT Previous,studies,have,shown,that,cells,in the,6-day old,embryonic,chick,lens,epithelium elongate in tissue culture . In the present study, the time course of elongation during the 1st day,of cultivation,has,been,examined,histologically . Cultured,epithelia,were,also,treated with,cycloheximide,or colchicine in order,to determine,if cell,elongation,depends,on new protein synthesis and on the utilization of microtubules,respectively . In the first 5 hr of culture, the mean cell length increased from I 1 µ to 21 µ
The previous publications of this series described the expected grain distributions around model ... more The previous publications of this series described the expected grain distributions around model radioactive structures in EM autoradiographs as a function of the specimen resolution. This family of expected distributions was called the "universal curves". In the present study, experiments on ~4C-labeled specimens refine our information regarding the tails of the universal curves. When the expected grain distributions from 125I-, all-, and ~4C-sources were compared, significant differences were found depending on the energy of the isotope. These differences were primarily in the tails of the distributions, and are therefore important in correcting for cross-scatter when analyzing electron microscope autoradiographs.
Background: Salt-sensitive normotensive men exhibit an enhanced pressor and heart rate (HR) respo... more Background: Salt-sensitive normotensive men exhibit an enhanced pressor and heart rate (HR) response to mental stress. Stress-induced HR acceleration may result from sympathetic activation or vagal withdrawal. We studied the importance of vagal withdrawal for the increased stress responsiveness of salt-sensitive subjects.
Background-Inspired CO 2 is a potent ventilatory stimulant exhibiting a paradoxical inhibitory eV... more Background-Inspired CO 2 is a potent ventilatory stimulant exhibiting a paradoxical inhibitory eVect on breathing at high concentrations. Severe respiratory depression as a result of CO 2 rebreathing during sleep has been implicated as a possible trigger factor in sudden infant death syndrome (SIDS). Objective-To investigate the ventilatory and heart rate (HR) responses to inhaled CO 2 in infants with apnoea of infancy, a group believed to be at increased risk of SIDS. Study design-Thirty one infants with severe sleep related apnoea, 31 infants with mild recurrent apnoea, and 31 age and sex matched controls for the infants with severe sleep related apnoea were studied. HR was computed from digitised RR intervals, "ventilation" was recorded by inductance plethysmography, and PCO 2 and PO 2 were monitored by transcutaneous electrodes. The ventilatory and HR responses to CO 2 were expressed as percentage increase in ventilation and change in HR/unit change in transcutaneous PCO 2 . Results-The mean increase in transcutaneous PCO 2 during CO 2 challenge (0.45 kPa = 3.4 mm Hg) resulted in a mean increase in ventilation of 291%/1 kPa (7.3 mm Hg) increase in transcutaneous PCO 2 , with no diVerence between the groups. A significant diVerence between infants with severe sleep related apnoea and mild recurrent apnoea versus controls (p < 0.02, p < 0.01, respectively) was found in their HR response to CO 2 challenge: HR decreased in 12 severe sleep related apnoea infants and 10 infants with mild recurrent apnoea, but only in two controls. Conclusion-Infants with apnoea of infancy frequently show a paradoxical decrease in HR during CO 2 challenge, possibly because of an insuYcient ability to mobilise cardiovascular defence mechanisms when challenged with hypercapnia.
Ripening of mature avocado fruit was accelerated by 18-and 24-hr ethylene treatments which were a... more Ripening of mature avocado fruit was accelerated by 18-and 24-hr ethylene treatments which were applied beginning 1 hr after harvest. Exposure to ethylene for 12 hr or less, starting 1 hr after harvest, did not accelerate the respiration rate, ethylene evolution, or fruit softening. Ethylene treatment for 6 hr starting at 1, 6, 12, or 18 hr after harvest did not accelerate the onset of the ripening process. It is suggested that ethylene does not just "trigger" the ripening of avocado fruit but rather is involved in a relatively long (18 to 24 hr) process which requires its continuous presence.
The aim of this study was to establish the sensitive, specific and clinically acceptable method f... more The aim of this study was to establish the sensitive, specific and clinically acceptable method for detection of tumor cells (TCs) circulating in peripheral blood (PB) of cervical cancer patients without the clinically detectable risk of disease progression. The 7.5 ml of PB of healthy donor was spiked with 5 to 100 cells from SiHa or HeLa cell lines. The spiked tumor cells were collected without gradient centrifugation, by standard gradient centrifugation or by modified gradient centrifugation combined with immunomagnetic separation using EpCAM antibody with affinity for epithelial cell adhesion molecule. The number of collected TCs was determined by EpCAM-FITC-staining and their viability was detected by nested RT-PCR amplifying E6/E7 HR-HPV 16 or HR-HPV 18 oncogenes. For the technical validation of this approach the TCs separation and RT-PCRs were repeated several times. The recovery of viable TCs was reproducibly higher using modified gradient centrifugation combined with immunomagnetic separation in comparison with standard approach. The recovery of TCs in low number of spiked TCs (range from 5 - 20 TCs in 7.5 ml of PB) using modified gradient centrifugation was not reproducible. The recovery of TCs in higher number of spiked TCs (25 TCs and more in 7.5 ml of PB) was reproducible with average recovery about 50 %. The sensitivity of nested RT-PCR amplifying E6/E7 oncogenes was decisively influenced by the number of recovered TCs and the amount of cDNA introduced to RT-PCR, as well. Using this approach we were allowed to detect circulating TCs (CTCs) in cervical cancer patients without metastases, thus this procedure might become a tool to early estimation of disease progression. According to our knowledge, this is the first report describing the use of EpCAM antibody for CTCs detection in cervical cancer patients.
Background This study was performed within the scope of two multi-center European Commission-fund... more Background This study was performed within the scope of two multi-center European Commission-funded projects (HEPMEAP and PAMCHAR) concerning source-composition-toxicity relationship for particulate matter (PM) sampled in Europe. The present study aimed to optimize the design for PM in vivo toxicity screening studies in terms of dose and time between a single exposure and the determination of the biological responses in a rat model mimicking human disease resulting in susceptibility to ambient PM. Dust in thoracic PM size-range (aerodynamic diameter <10 μm) was sampled nearby a road tunnel (RTD) using a high volume cascade impactor. Spontaneously hypertensive rats were exposed to urban dust collected in Ottawa, Canada (EHC-93 10 mg/kg of body weight; reference PM) or different RTD doses (0.3, 1, 3, 10 mg/kg of body weight) by intratracheal instillation. Necropsy was performed at 4, 24, or 48 hr after exposure. Results The neutrophil numbers in bronchoalveolar lavage fluid increased tremendously after exposure to the highest RTD doses or EHC-93. Furthermore, PM exposure slightly affected blood coagulation since there was a small but significant increase in the plasma fibrinogen levels (factor 1.2). Pulmonary inflammation and oxidative stress as well as changes in blood coagulation factors and circulating blood cell populations were observed within the range of 3 to 10 mg PM/kg of body weight without significant pulmonary injury. Conclusion The optimal dose for determining the toxicity ranking of ambient derived PM samples in spontaneously hypertensive rats is suggested to be between 3 and 10 mg PM/kg of body weight under the conditions used in the present study. At a lower dose only some inflammatory effects were detected, which will probably be too few to be able to discriminate between PM samples while a completely different response pattern was observed with the highest dose. In addition to the dose, a 24-hr interval from exposure to sacrifice seemed appropriate to assess the relative toxic potency of PM since the majority of the health effects were observed one day after PM exposure compared to the other times examined. The aforementioned considerations provide a good basis for conducting PM toxicity screening studies in spontaneously hypertensive rats.
Isolating a sexually mature Aplysia fasciata for either 1 or 24 hr immediately after training tha... more Isolating a sexually mature Aplysia fasciata for either 1 or 24 hr immediately after training that a food is inedible blocks the subsequent expression of memory measured 24 hr later. Isolation that is delayed for 1 hr after training, but not for 12 hr after training, is also effective in blocking memory. Isolation affects memory because of a specific effect caused by the absence of pheromones secreted by conspecifics rather than by a nonspecific change in the chemical environment, because transferring animals to a novel environment (120% seawater) that contains a conspecific does not affect memory. Isolation also does not affect memory in sexually immature Aplysia, even though immature animals are able to sense one another&amp;amp;#39;s presence. Isolation may affect memory because social (and sexual) isolation is a form of stress in mature A. fasciata, and stress after training affects retention in many animals.
ABSTRACT There is considerable academic interest in the consequences of European integration for ... more ABSTRACT There is considerable academic interest in the consequences of European integration for human resource (HR) management within multinational companies. In the context of this debate discusses the implications of changes in the organisation of production and markets for the management of HR in the banking sector. Frames the analysis with special reference to British and Spanish banks, and draws implications regarding the impact of such changes for the most prominent development in terms of European legislation at company level, European Works Councils (EWCs). Argues that deregulation and European integration have facilitated restructuring and consolidation within national boundaries, which in turn have facilitated cross-border mergers and acquisitions. As a result, the number of banks with operations in two or more countries of the European Union has increased. While business continues to be geographically segmented according to countries, affording EWCs a relatively limited role, growing similarities in work organisation and processes in banks across countries offers potential for change.
Journal of Pharmacological and Toxicological Methods, 2007
The objective of this study was to define the normal LVdP/dt (an index of myocardial contractilit... more The objective of this study was to define the normal LVdP/dt (an index of myocardial contractility)-heart rate relationship in telemetered conscious dogs, primates and mini-pigs in our laboratory and to use these data as the basis for an additional parameter useful in drug safety evaluation. Trained dogs, Rhesus monkeys, Cynomolgus monkeys and mini-pigs (Goettinger) were equipped with radiotelemetry transmitters (ITS). Aortic pressure (AP), left ventricular pressure (LVP), a lead II ECG and body temperature could be continuously monitored. The contractility index LVdP/dtmax was derived from the LVP signal. Notocord HEM 4.1 software was used for data acquisition. For each species an LVdP/dt-heart rate relationship was evaluated using spontaneous heart rates (HR) throughout the observation period. A validation compound with positive inotropic effects (pimobendan) was then used to investigate the LVdP/dt-heart rate relationship. There was a clear LVdP/dt-HR relationship in the animals tested. The inotropic agent pimobendan demonstrated the expected shift in this relationship. Contractility of the myocardium is regulated by autonomic input activating primarily myocardial beta1-adrenoceptors, but it is also affected by the &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;force-frequency&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; relationship. Compounds can therefore either directly or indirectly affect the contractility of the heart. The chronotropic effects are routinely measured in preclinical studies; however, the inotropic effects are not routinely analysed in cardiovascular safety studies. Our experience strongly recommends including this evaluation for drug candidate selection. The evaluation of LVdP/dtmax, as an index of myocardial contractile state must, however, take into account its HR-dependency.
Ambulatory blood pressure monitoring (ABPM) has demonstrated a high prevalence of white coat hype... more Ambulatory blood pressure monitoring (ABPM) has demonstrated a high prevalence of white coat hypertension (WCH) in adults, but few studies exist in obese and overweight children and adolescents. We can define WCH as elevated casual blood pressure (BP) with normal 24-hr mean BP, but ABPM in adults has shown that BP load( % of BP readings Ͼ 95th percentile) is better to predict hypertensive end-organ injury than mean BP. Our objective was to evaluate the prevalence of hypertension (HTN) and WCH in overweight and obese children and adolescents by both mean BP criteria and BP load criteria. From January 1999 to June 2000, 39 patients ( 22M/17F) from 10 to 17 years old were evaluated and in all, ABPM were performed. They were evaluated by two cardiologists and the BP was measured two times by each one, with 5 minutes interval. HTN were considered when the average of these 4 measures (systolic or diastolic) Ͼ 95th percentile. In relation to ABPM, BP was measured 3 times/hr from 8 am to 10 pm and 2 times/hr from 10 pm to 8 am. Wake and sleep period were defined by patient self-report. WCH was defined by mean BP criteria as wake systolic BP (SBP) and diastolic BP (DBP) Ͻ 95th percentile (Task Force for HTN Control in Children and Adolescent) and by BP load criteria as 24-hr SBP and DBP load Ͻ 30% (using 24-hr 95th percentile normative pediatric ABPM data). The criteria used for overweight and obesity were defined by body mass index (BMI) according to Expert Committee on Clinical Guidelines for Overweight in Adolescent Preventive Service. The prevalence of HTN was 28.2% (11/39), being 54.6% females (6/11) and 90.9% (10/11) were obese. The prevalence of WCH defined by mean BP criteria was 45.4% (5/11) and 80% were girls (4/5) and 80% (4/5) were obese. BP load was normal (Ͻ 30%) in 27.2% (3/11) for SBP and 81.8% (9/11) for DBP. The prevalence of WCH by BP load criteria (SBP and DBP Ͻ 30%) was 27.2% (3/11), being 66.6% girls (2/3) and 66.6% obese (2/3); 27.2 % (3/11) of patients had WCH by both criteria (mean BP and BP load). The HTN and WCH in obese and overweight children and adolescents are common and they occur more often in girls and obese. ABPM should be used in hypertensive obese and overweight children to avoid mistaken for casual HTN that may lead to unnecessary use of medication and expensive diagnostic approaches.
mediators with the capacity to recruit marrow-derived stromal cells. To test this, primary murine... more mediators with the capacity to recruit marrow-derived stromal cells. To test this, primary murine tracheal epithelial cells (MTEC) were cultured on a supported semi-permeable membrane (Transwell) under air-liquid interface conditions. When cells developed tight junctions, stromal marrow cells derived from adult transgenic GFPexpressing mice, cultured on glass cover slips, were placed in the lower Transwell chamber. After 1 week, a small number of stromal cells were observed to have migrated to the permeable membrane. The number of migrating cells substantially increased after MTEC were stimulated with endotoxin (25 µg/well, 1 hr). Media from naïve and endotoxin-stimulated MTEC and from the stromal marrow cells were assayed for multiple chemokines. Stromal-derived factor (SDF-1), a chemokine implicated in stem cell mobilization was produced in higher amounts by stromal cells than by MTEC (908 vs 100 pg/ml), suggesting that SDF-1 release by epithelial cells may not drive stromal cell migration in the lung. In contrast, IL-17 was released in higher amounts by both naïve and endotoxin-stimulated MTEC than by stromal cells. Adding neutralizing anti IL-17 antibody (1 µg/ml) to the culture media blocked migration of stromal cells to the transwell membrane. These data provide a functional model for assay of airway epithelial cell-marrow derived stromal cell interactions that are important for repair in lung injury and implicate a critical role of IL-17 in migration of adult marrow-derived stromal cells to lung epithelium.
Osservatorio Innovazione Sifo web www.osservatorioinnovazione.org mail [email protected] SCHEDA... more Osservatorio Innovazione Sifo web www.osservatorioinnovazione.org mail [email protected] SCHEDA PRODOTTO con valutazione economica semplificata I dati originali riportati nella scheda sono proprietà del Laboratorio SIFO di Farmacoeconomia, Firenze Il prodotto innovativo preso in esame determina un beneficio clinico incrementale; la VES viene perciò impostata come analisi del rapporto tra costo incrementale ed efficacia incrementale (CEA). Data di aggiornamento della scheda: 30/12/2008 Nome commerciale del prodotto: Zevalin® radiomarcato con [ 90 Y (Ytracis®)] Descrizione del prodotto: [ 90 Y]-ibritumomab tiuxetano Indicazione terapeutica:
Monthly Notices of The Royal Astronomical Society, 1979
Infrared observations are presented which reinforce the conclusion reached from optical data that... more Infrared observations are presented which reinforce the conclusion reached from optical data that the variability of HR 5999, sometimes being misidentified as HR 6000, is due to ejected dust grains. A simple model is proposed for the existing dust shell. This simple model fits the colors reasonably well. Visible and IR observations planned at a number of observatories for 1978 are expected to give a much more complete picture of this interesting system.
Splanchnic and systemic arteriolar vasodilationplays an important role in ascites formation incir... more Splanchnic and systemic arteriolar vasodilationplays an important role in ascites formation incirrhosis. Octreotide produces splanchnicvasoconstriction, but the effects on systemichemodynamics and renal function are controversial. This studyevaluated the effect of subcutaneous octreotideadministration on systemic hemodynamics, endogenousvasoactive systems, and renal function in cirrhoticpatients with ascites. Twenty patients were included: 10received octreotide 250 μg/12 hr subcutaneously (forfive days), and 10 did not. No statistically significantchanges were found in mean arterial pressure and cardiac rate. Octreotide induced astatistically significant decrease in plasma reninactivity (P < 0.01), plasma aldosterone (P = 0.01)and plasma glucagon (P < 0.05). No significantvariations were observed in other systemic vasoactivesubstances (nitric oxide and prostacyclin). Renalfunction was not modified in either group. Inconclusion, in cirrhotic patients with ascites,subcutaneous octreotide administration decreases plasma glucagon, reninactivity, and aldosterone without changing in systemichemodynamics or renal function.
Splanchnic and systemic arteriolar vasodilationplays an important role in ascites formation incir... more Splanchnic and systemic arteriolar vasodilationplays an important role in ascites formation incirrhosis. Octreotide produces splanchnicvasoconstriction, but the effects on systemichemodynamics and renal function are controversial. This studyevaluated the effect of subcutaneous octreotideadministration on systemic hemodynamics, endogenousvasoactive systems, and renal function in cirrhoticpatients with ascites. Twenty patients were included: 10received octreotide 250 μg/12 hr subcutaneously (forfive days), and 10 did not. No statistically significantchanges were found in mean arterial pressure and cardiac rate. Octreotide induced astatistically significant decrease in plasma reninactivity (P < 0.01), plasma aldosterone (P = 0.01)and plasma glucagon (P < 0.05). No significantvariations were observed in other systemic vasoactivesubstances (nitric oxide and prostacyclin). Renalfunction was not modified in either group. Inconclusion, in cirrhotic patients with ascites,subcutaneous octreotide administration decreases plasma glucagon, reninactivity, and aldosterone without changing in systemichemodynamics or renal function.
Proceedings of The National Academy of Sciences, 1985
The GO/Gj to S transition in quiescent BALB/c 3T3 cells stimulated by serum growth factors can be... more The GO/Gj to S transition in quiescent BALB/c 3T3 cells stimulated by serum growth factors can be specifically blocked by the administration ofinterferon (IFN) to the system. In the present communication, we studied whether IFN inhibits the early events in the Go/G1 phase that are initiated by the platelet-derived growth factor (PDGF). The results show that IFN inhibits most of the PDGF-mediated increase of c-myc, ornithine decarboxylase, and j3-actin mRNAs measured 3 hr after stimulation. c-fos mRNA levels are reduced by IFN as early as 20 min after exposure of the quiescent cells to PDGF. The expression of several genes that belong to the competence gene family is, therefore, inhibited by IFN and this could account for the failure of the IFN-treated cells to enter into the S phase when growth factors present in the platelet-poor plasma are added. We also report that the PDGF-mediated increase in the uptake of deoxyglucose is not impaired by IFN, thus suggesting that the early effects of IFN on gene expression do not result from inhibition of binding of PDGF to its cell-surface receptors. Unlike the direct stimulatory effect ofPDGF, which is not sensitive to cycloheximide, the inhibitory effect of IFN on c-myc mRNA levels depends in part on protein synthesis. We propose that a putative product of one of the IFN-induced genes could mediate the decrease in expression of the PDGF-regulated gene family.
The class III histone deacetylase (HDAC) SIRT1 plays a role in the metabolism, aging, and carcino... more The class III histone deacetylase (HDAC) SIRT1 plays a role in the metabolism, aging, and carcinogenesis of organisms and regulates senescence and apoptosis in cells. Recent reports revealed that SIRT1 also deacetylates several DNA double-strand break (DSB) repair proteins. However, its exact functions in DNA repair remained elusive. Using nuclear foci analysis and fluorescence-based, chromosomal DSB repair reporter, we find that SIRT1 activity promotes homologous recombination (HR) in human cells. Importantly, this effect is unrelated to functions of poly(ADP-ribose) polymerase 1 (PARP1), another NAD(+)-catabolic protein, and does not correlate with cell cycle changes or apoptosis. Interestingly, we demonstrate that inactivation of Rad51 does not eliminate the effect of SIRT1 on HR. By epistasis-like analysis through knockdown and use of mutant cells of distinct SIRT1 target proteins, we show that the non-homologous end joining (NHEJ) factor Ku70 as well as the Nijmegen Breakage Syndrome protein (nibrin) are not needed for this SIRT1-mediated effect, even though a partial contribution of nibrin cannot be excluded. Strikingly however, the Werner helicase (WRN), which in its mutated form causes premature aging and cancer and which was linked to the Rad51-independent single-strand annealing (SSA) DSB repair pathway, is required for SIRT1-mediated HR. These results provide first evidence that links SIRT1's functions to HR with possible implications for genomic stability during aging and tumorigenesis.
Background: WR1065 is the free-thiol metabolite of the cytoprotective aminothiol amifostine, whic... more Background: WR1065 is the free-thiol metabolite of the cytoprotective aminothiol amifostine, which is used clinically at very high doses to protect patients against toxicity induced by radiation and chemotherapy. In an earlier study we briefly reported that the aminothiol WR1065 also inhibits HIV-1 replication in phytohemagglutinin (PHA)-stimulated human T-cell blasts (TCBs) infected in culture for 2 hr before WR1065 exposure. In this study we expanded the original observations to define the dose-response curve for that inhibition, and address the question of additive effects for the combination of WR1065 plus Zidovudine (AZT). Here we also explored the effect of WR1065 on SIV by examining TCBs taken from macaques with well-established infections several months with SIV.
ABSTRACT Previous,studies,have,shown,that,cells,in the,6-day old,embryonic,chick,lens,epithelium ... more ABSTRACT Previous,studies,have,shown,that,cells,in the,6-day old,embryonic,chick,lens,epithelium elongate in tissue culture . In the present study, the time course of elongation during the 1st day,of cultivation,has,been,examined,histologically . Cultured,epithelia,were,also,treated with,cycloheximide,or colchicine in order,to determine,if cell,elongation,depends,on new protein synthesis and on the utilization of microtubules,respectively . In the first 5 hr of culture, the mean cell length increased from I 1 µ to 21 µ
The previous publications of this series described the expected grain distributions around model ... more The previous publications of this series described the expected grain distributions around model radioactive structures in EM autoradiographs as a function of the specimen resolution. This family of expected distributions was called the "universal curves". In the present study, experiments on ~4C-labeled specimens refine our information regarding the tails of the universal curves. When the expected grain distributions from 125I-, all-, and ~4C-sources were compared, significant differences were found depending on the energy of the isotope. These differences were primarily in the tails of the distributions, and are therefore important in correcting for cross-scatter when analyzing electron microscope autoradiographs.
Background: Salt-sensitive normotensive men exhibit an enhanced pressor and heart rate (HR) respo... more Background: Salt-sensitive normotensive men exhibit an enhanced pressor and heart rate (HR) response to mental stress. Stress-induced HR acceleration may result from sympathetic activation or vagal withdrawal. We studied the importance of vagal withdrawal for the increased stress responsiveness of salt-sensitive subjects.
Background-Inspired CO 2 is a potent ventilatory stimulant exhibiting a paradoxical inhibitory eV... more Background-Inspired CO 2 is a potent ventilatory stimulant exhibiting a paradoxical inhibitory eVect on breathing at high concentrations. Severe respiratory depression as a result of CO 2 rebreathing during sleep has been implicated as a possible trigger factor in sudden infant death syndrome (SIDS). Objective-To investigate the ventilatory and heart rate (HR) responses to inhaled CO 2 in infants with apnoea of infancy, a group believed to be at increased risk of SIDS. Study design-Thirty one infants with severe sleep related apnoea, 31 infants with mild recurrent apnoea, and 31 age and sex matched controls for the infants with severe sleep related apnoea were studied. HR was computed from digitised RR intervals, "ventilation" was recorded by inductance plethysmography, and PCO 2 and PO 2 were monitored by transcutaneous electrodes. The ventilatory and HR responses to CO 2 were expressed as percentage increase in ventilation and change in HR/unit change in transcutaneous PCO 2 . Results-The mean increase in transcutaneous PCO 2 during CO 2 challenge (0.45 kPa = 3.4 mm Hg) resulted in a mean increase in ventilation of 291%/1 kPa (7.3 mm Hg) increase in transcutaneous PCO 2 , with no diVerence between the groups. A significant diVerence between infants with severe sleep related apnoea and mild recurrent apnoea versus controls (p < 0.02, p < 0.01, respectively) was found in their HR response to CO 2 challenge: HR decreased in 12 severe sleep related apnoea infants and 10 infants with mild recurrent apnoea, but only in two controls. Conclusion-Infants with apnoea of infancy frequently show a paradoxical decrease in HR during CO 2 challenge, possibly because of an insuYcient ability to mobilise cardiovascular defence mechanisms when challenged with hypercapnia.
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