A repeating fast radio burst source in a globular cluster.

Fast radio bursts (FRBs) are flashes of unknown physical origin1. The majority of FRBs have been seen only once, although some are known to generate multiple flashes2,3. Many models invoke magnetically powered neutron stars (magnetars) as the source of the emission4,5. Recently, the discovery6 of another repeater (FRB 20200120E) was announced, in the direction of the nearby galaxy M81, with four potential counterparts at other wavelengths6. Here we report observations that localized the FRB to a globular cluster associated with M81, where it is 2 parsecs away from the optical centre of the cluster. Globular clusters host old stellar populations, challenging FRB models that invoke young magnetars formed in a core-collapse supernova. We propose instead that FRB 20200120E originates from a highly magnetized neutron star formed either through the accretion-induced collapse of a white dwarf, or the merger of compact stars in a binary system7. Compact binaries are efficiently formed inside globular clusters, so a model invoking them could also be responsible for the observed bursts.

Chronic pain after open inguinal hernia repair: expertise-based randomized clinical trial of heavyweight or lightweight mesh.

BACKGROUND: There is a shortage of high-quality studies regarding choice of mesh in open anterior inguinal hernia repair in relation to long-term chronic pain. The authors hypothesized that heavyweight compared with lightweight mesh causes increased postoperative pain. METHODS: An RCT was undertaken between 2007 and 2009 at two sites in Sweden. Men aged 25 years or older with an inguinal hernia evaluated in the outpatient clinic were randomized in an unblinded fashion to heavyweight or lightweight mesh for open anterior inguinal hernia repair. Data on pain affecting daily activities, as measured by the Short-Form Inguinal Pain Questionnaire 9-12 years after surgery, were collected as the primary outcome. Differences between groups were evaluated by generalized odds and numbers needed to treat. RESULTS: A total of 412 patients were randomized; 363 were analysed with 320 questionnaires sent out. A total of 271 questionnaires (84.7 per cent) were returned; of these, 121 and 150 patients were in the heavyweight and lightweight mesh groups respectively. Pain affecting daily activities was more pronounced in patients randomized to heavyweight versus lightweight mesh (generalized odds 1.33, 95 per cent c.i. 1.10 to 1.61). This translated into a number needed to treat of 7.06 (95 per cent c.i. 4.28 to 21.44). Two reoperations for recurrence were noted in the heavyweight mesh group, and one in the lightweight mesh group. CONCLUSION: A large-pore lightweight mesh causes significantly less pain affecting daily activities a decade after open anterior inguinal hernia repair. Registration number: NCT00451893 (http://www.clinicaltrials.gov).

Unexpectedly large mass loss during the thermal pulse cycle of the red giant star R Sculptoris.

The asymptotic-giant-branch star R Sculptoris is surrounded by a detached shell of dust and gas. The shell originates from a thermal pulse during which the star underwent a brief period of increased mass loss. It has hitherto been impossible to constrain observationally the timescales and mass-loss properties during and after a thermal pulse--parameters that determine the lifetime of the asymptotic giant branch and the amount of elements returned by the star. Here we report observations of CO emission from the circumstellar envelope and shell around R Sculptoris with an angular resolution of 1.3″. What was previously thought to be only a thin, spherical shell with a clumpy structure is revealed to also contain a spiral structure. Spiral structures associated with circumstellar envelopes have been previously seen, leading to the conclusion that the systems must be binaries. Combining the observational data with hydrodynamic simulations, we conclude that R Sculptoris is a binary system that underwent a thermal pulse about 1,800 years ago, lasting approximately 200 years. About 3 × 10(-3) solar masses of material were ejected at a velocity of 14.3 km s(-1) and at a rate around 30 times higher than the pre-pulse mass-loss rate. This shows that about three times more mass was returned to the interstellar medium during and immediately after the pulse than previously thought.

A systematic review of working conditions and occupational health among immigrants in Europe and Canada.

BACKGROUND: A systematic attempt to summarize the literature that examines working conditions and occupational health among immigrant in Europe and Canada. METHODS: We established inclusion criteria, searched systematically for articles included in the Medline, Embase and Social Sciences Citation Index databases in the period 2000-2016 and checked the reference lists of all included papers. RESULTS: Eighty-two studies were included in this review; 90% were cross-sectional and 80% were based on self-report. Work injuries were consistently found to be more prevalent among immigrants in studies from different countries and in studies with different designs. The prevalence of perceived discrimination or bullying was found to be consistently higher among immigrant workers than among natives. In general, however, we found that the evidence that immigrant workers are more likely to be exposed to physical or chemical hazards and poor psychosocial working conditions is very limited. A few Scandinavian studies support the idea that occupational factors may partly contribute to the higher risk of sick leave or disability pension observed among immigrants. However, the evidence for working conditions as a potential mediator of the associations between immigrant status and poor general health and mental distress was very limited. CONCLUSION: Some indicators suggest that immigrant workers in Europe and Canada experience poorer working conditions and occupational health than do native workers. However, the ability to draw conclusions is limited by the large gaps in the available data, heterogeneity of immigrant working populations, and the lack of prospectively designed cohort studies.

From population genomics to conservation and management: a workflow for targeted analysis of markers identified using genome-wide approaches in Atlantic salmon Salmo salar.

A genotyping assay for the Ion Torrent Ion PGM platform was developed for fast and cost-effective targeted genotyping of key single nucleotide polymorphisms (SNPs) earlier identified using a genome-wide SNP array in Atlantic salmon Salmo salar. The method comprised a simple primer design step for multiplex-polymerase chain reaction (PCR), followed by two rounds of Ion Torrent Ion PGM sequencing to empirically evaluate marker efficiency in large multiplexes and to optimise or exclude them when necessary. Of 282 primer pairs initially tested, 217 were successfully amplified, indicating good amplification success (>75%). These markers included the sdy partial gene product to determine genetic sex, as well as three additional modules comprising SNPs for assessing neutral genetic variation (NSNP = 150), examining functional genetic variation associated with sea age at maturity (NSNP = 5), and for performing genetic subpopulation assignment (NSNP = 61). The assay was primarily developed to monitor long-term genetic changes in S. salar from the Teno River, but modules are likely suitable for application in a wide range of S. salar populations. Furthermore, the fast and versatile assay development pipeline offers a strategy for developing targeted sequencing assays in any species.

Long-term persistence of a multi-resistant methicillin-susceptible Staphylococcus aureus (MR-MSSA) clone at a university hospital in southeast Sweden, without further transmission within the region.

The objective of this study was to characterise isolates of methicillin-susceptible Staphylococcus aureus (MSSA) with resistance to clindamycin and/or tobramycin in southeast Sweden, including the previously described ECT-R clone (t002) found in Östergötland County, focusing on clonal relatedness, virulence determinants and existence of staphylococcal cassette chromosome (SCC) mec remnants. MSSA isolates with resistance to clindamycin and/or tobramycin were collected from the three county councils in southeast Sweden and investigated with spa typing, polymerase chain reaction (PCR) targeting the SCCmec right extremity junction (MREJ) and DNA microarray technology. The 98 isolates were divided into 40 spa types, and by microarray clustered in 17 multi-locus sequence typing (MLST) clonal complexes (MLST-CCs). All isolates with combined resistance to clindamycin and tobramycin (n = 12) from Östergötland County and two additional isolates (clindamycin-R) were designated as spa type t002, MREJ type ii and were clustered in CC5, together with a representative isolate of the ECT-R clone, indicating the clone's persistence. These isolates also carried several genes encoding exotoxins, Q9XB68-dcs and qacC. Of the isolates in CC15, 83% (25/30) were tobramycin-resistant and were designated spa type t084. Of these, 68% (17/25) were isolated from new-borns in all three counties. The persistence of the ECT-R clone in Östergötland County, although not found in any other county in the region, carrying certain virulence factors that possibly enhance its survival in the hospital environment, highlights the fact that basic hygiene guidelines must be maintained even when MRSA prevalence is low.

Cognitive testing with the Post-Operative Quality of Recovery Scale in pre-surgery cancer patients--a controlled study.

BACKGROUND: Post-Operative Quality of Recovery Scale (PQRS) has been revised to allow for the normal variation in cognitive performance seen in healthy volunteers. This modification could result in exclusion of test subjects because of poor baseline performance. Our aim was to investigate the impact of severe disease and waiting for cancer surgery on PQRS baseline cognitive performance and exclusion rate, and also on variation in cognitive performance at test re-test. METHODS: Sixty-one subjects, 31 women diagnosed with breast cancer and waiting for surgery and 30 healthy women, performed the PQRS cognitive, nociceptive and emotional domains three times in 48 h. Exclusion rate, change in score and the proportion fulfilling 'recovery' criteria at re-tests were assessed. RESULTS: Nine out of 31 patients (29%) and two out of 30 controls (7%) had too low baseline score to be further assessed (P = 0.043). The change in score at re-tests was similar between the groups. Sixty-four per cent and 83% at 20 h and 79% and 86% at 48 h in the patient and control groups respectively fulfilled the 'recovery' criteria (P = 0.45). The 'recovery' for nociceptive and emotional distress was similar between the groups, but anxiety and sadness absolute scores were significantly higher in the patient group. CONCLUSION: Women with breast cancer waiting for surgery expressed a higher level of emotional distress, performed lower at baseline but showed no difference in test re-test variability in cognitive performance according to the PQRS when compared with controls. The considerable exclusion rate among patients waiting for cancer surgery should be acknowledged.

Cognitive recovery after ambulatory anaesthesia based on desflurane or propofol: a prospective randomised study.

BACKGROUND: The impact of anaesthetic agents on cognitive recovery during the first post-operative week in a middle-aged population undergoing general anaesthesia is insufficiently studied. We hypothesised that patients receiving anaesthesia based on desflurane would have a quicker recovery and regain cognitive capacity faster than patients receiving anaesthesia based on propofol. METHODS: We performed a prospective, randomised, single-blinded study comparing the effects of desflurane and propofol as primary anaesthetic agents on cognitive recovery in 59 American Society of Anesthesiologists Physical Status Classification System I-II women undergoing breast surgery. Cognitive recovery was evaluated using the Cognitive Failure Questionnaire and a modified version of the Post-operative Quality of Recovery Scale. RESULTS: Post-operative cognitive recovery according to Cognitive Failure Questionnaire was 65% and 66% at 72 h, and 71% and 72% at 1 week for the desflurane and the propofol groups, respectively. Recovery according to Post-operative Quality of Recovery Scale was 52% and 50% at 2 h, increasing to 71% and 87% at 48 h for the desflurane and the propofol groups, respectively. At the final point of measurement (Cognitive Failure Questionnaire 1 week, Post-operative Quality of Recovery Scale 48 h), many of the patients had still not reached their baseline cognitive performance. There was no difference in overall cognitive recovery between the desflurane and propofol groups. CONCLUSION: Cognitive recovery was not complete 1 week after surgery in any of the groups. There was no difference in the rate of cognitive recovery in middle-aged patients receiving desflurane or propofol anaesthesia during ambulatory breast surgery.

Post-operative Quality of Recovery Scale: the impact of assessment method on cognitive recovery.

BACKGROUND: We measured cognitive performance and recovery with the Post-operative Quality of Recovery Scale (PQRS) at 30 and 90 min after elective ambulatory or short-stay surgery under general anaesthesia. The aim was to study the impact of the assessment algorithm, comparing the original and modified more liberal score assessment. METHOD: One hundred and ten ASA 1-2 patients scheduled for elective surgery in general anaesthesia responded to the five cognitive performance questions in the PQRS; pre-operatively, 30 and 90 min after end of anaesthesia. Assessment of cognitive recovered was performed according to the original and modified definition which includes a tolerance factor to account for performance variability. RESULTS: Cognitive recovery improved from 30 to 90 min. The modified score assessment decreased number of patients that were evaluated low because it excluded initial low scoring subjects and also dramatically increased number of patients assessed as cognitively recovered; original 9% at 30 min and 28% at 90 min vs. 54% at 30 min and 81% at 90 min, P < 0.001. There were no other significant differences identified when using either the original or modified scoring method for age > 50 years, orthopaedic vs. abdominal surgery, premedication or gender. CONCLUSIONS: The modified definition which includes a tolerance factor to account for performance variability has dramatic effects in increasing the number of patients assessed as recovered. It is from the present study not possible to comment on whether the more liberal assessment provides more or less accurate description of cognitive performance.

Detection and characterisation of SCCmec remnants in multiresistant methicillin-susceptible Staphylococcus aureus causing a clonal outbreak in a Swedish county.

The purpose of this study was to investigate if multiresistant methicillin-susceptible Staphylococcus aureus (MR-MSSA) causing a clonal outbreak in Östergötland County, Sweden, were derived from methicillin-resistant S. aureus (MRSA) by carrying remnants of SCCmec, and, if so, to characterise this element. A total of 54 MSSA isolates with concomitant resistance to erythromycin, clindamycin and tobramycin from 49 patients (91% clonally related, spa type t002) were investigated with the BD GeneOhm MRSA assay and real-time polymerase chain reaction (PCR) targeting the SCCmec integration site/SCCmec right extremity junction. DNA sequencing of one isolate representing the MR-MSSA outbreak clone was performed by massive parallel 454 pyrosequencing. All isolates that were part of the clonal outbreak carried SCCmec remnants. The DNA sequencing revealed the carriage of a pseudo-SCC element 12 kb in size, with a genomic organisation identical to an SCCmec type ΙΙ element, except for a 41-kb gap. This study demonstrates the presence of a pseudo-SCC element resembling SCCmec type II among MR-MSSA, suggesting possible derivation from MRSA. The presence of SCCmec remnants should always be considered when SCCmec typing is used for MRSA detection, and may not be suitable in locations with a high prevalence of MR-MSSA, since this might give a high number of false-positive results.

Effect of the New Nordic Diet compared with usual care on glucose control in gestational diabetes mellitus: Study protocol for the randomized controlled trial intervention with new Nordic DIet in women with GestatiOnal diabetes mellitus (iNDIGO).

BACKGROUND: Gestational diabetes mellitus (GDM) is a pregnancy complication associated with short- and long-term health consequences for mother and child. First line treatment is diet and exercise but there is a recognized knowledge gap as to what diet treatment is optimal. A healthy Nordic diet has been associated with improved health but no studies in women with GDM exist. The New Nordic Diet (NND) is an initiative with the purpose to develop a healthy Nordic diet including foods with the potential to grow in Nordic countries; including fruit, berries, vegetables, whole-grain cereal products, nuts, fish, and rapeseed oil. The purpose of the intervention with new Nordic DIet in women with GestatiOnal diabetes mellitus (iNDIGO) is to test if the NND compared with usual care improves glucose control in women with GDM. METHODS: The iNDIGO study is a randomized parallel controlled trial where 50 women with GDM will be randomized to either an NND or usual care for 14 days (30-32 weeks of gestation). Participants in the NND group will receive menus and food bags containing foods to be consumed. Primary outcome is glycemic control (time in target) measured using continuous glucose monitoring. Compliance to the dietary intervention will be tested using dietary biomarkers and adherence questionnaires. CONCLUSION: Diet treatment represents first line treatment in GDM but it remains unclear what type of diets are effective. iNDIGO is an efficacy study and will provide evidence as to whether a healthy Nordic diet can improve glucose control in women with GDM. TRIAL REGISTRATION: ClinicalTrials.gov registration Number: NCT04169243. Registered 19 November 2019, https://clinicaltrials.gov/ct2/show/NCT04169243.

Pharmacogenetics during standardised initiation of thiopurine treatment in inflammatory bowel disease.

BACKGROUND: Firm recommendations about the way thiopurine drugs are introduced and the use of thiopurine methyltransferase (TPMT) and metabolite measurements during treatment in inflammatory bowel disease (IBD) are lacking. AIM: To evaluate pharmacokinetics and tolerance after initiation of thiopurine treatment with a fixed dosing schedule in patients with IBD. PATIENTS: 60 consecutive patients with Crohn's disease (n = 33) or ulcerative colitis (n = 27) were included in a 20 week open, prospective study. METHODS: Thiopurine treatment was introduced using a predefined dose escalation schedule, reaching a daily target dose at week 3 of 2.5 mg azathioprine or 1.25 mg 6-mercaptopurine per kg body weight. TPMT and ITPA genotypes, TPMT activity, TPMT gene expression, and thiopurine metabolites were determined. Clinical outcome and occurrence of adverse events were monitored. RESULTS: 27 patients completed the study per protocol, while 33 were withdrawn (early protocol violation (n = 5), TPMT deficiency (n = 1), thiopurine related adverse events (n = 27)); 67% of patients with adverse events tolerated long term treatment on a lower dose (median 1.32 mg azathioprine/kg body weight). TPMT activity did not change during the 20 week course of the study but a significant decrease in TPMT gene expression was found (TPMT/huCYC ratio; p = 0.02). Patients with meTIMP concentrations >11,450 pmol/8 x 10(8) red blood cells during steady state at week 5 had an increased risk of developing myelotoxicity (odds ratio = 45.0; p = 0.015). CONCLUSIONS: After initiation of thiopurine treatment using a fixed dosing schedule, no general induction of TPMT enzyme activity occurred, though TPMT gene expression decreased. The development of different types of toxicity was unpredictable, but we found that measurement of meTIMP early in the steady state phase helped to identify patients at risk of developing myelotoxicity.

The circumstellar envelope around the S-type AGB star W Aql. Effects of an eccentric binary orbit.

CONTEXT: Recent observations at subarcsecond resolution, now possible also at submillimeter wavelengths, have shown intricate circumstellar structures around asymptotic giant branch (AGB) stars, mostly attributed to binary interaction. The results presented here are part of a larger project aimed at investigating the effects of a binary companion on the morphology of circumstellar envelopes (CSEs) of AGB stars. AIMS: AGB stars are characterized by intense stellar winds that build CSEs around the stars. Here, the CO(J = 3→2) emission from the CSE of the binary S-type AGB star W Aql has been observed at subarcsecond resolution using ALMA. The aim of this paper is to investigate the wind properties of the AGB star and to analyse how the known companion has shaped the CSE. METHODS: The average mass-loss rate during the creation of the detected CSE is estimated through modelling, using the ALMA brightness distribution and previously published single-dish measurements as observational constraints. The ALMA observations are presented and compared to the results from a 3D smoothed particle hydrodynamics (SPH) binary interaction model with the same properties as the W Aql system and with two different orbital eccentricities. Three-dimensional radiative transfer modelling is performed and the response of the interferometer is modelled and discussed. RESULTS: The estimated average mass-loss rate of W Aql is M = 3.0×10-6 M⊙ yr-1 and agrees with previous results based on single-dish CO line emission observations. The size of the emitting region is consistent with photodissociation models. The inner 10″ of the CSE is asymmetric with arc-like structures at separations of 2-3″ scattered across the denser sections. Further out, weaker spiral structures at greater separations are found, but this is at the limit of the sensitivity and field of view of the ALMA observations. CONCLUSIONS: The CO(J = 3→2) emission is dominated by a smooth component overlayed with two weak arc patterns with different separations. The larger pattern is predicted by the binary interaction model with separations of ~10″ and therefore likely due to the known companion. It is consistent with a binary orbit with low eccentricity. The smaller separation pattern is asymmetric and coincides with the dust distribution, but the separation timescale (200 yrs) is not consistent with any known process of the system. The separation of the known companions of the system is large enough to not have a very strong effect on the circumstellar morphology. The density contrast across the envelope of a binary with an even larger separation will not be easily detectable, even with ALMA, unless the orbit is strongly asymmetric or the AGB star has a much larger mass-loss rate.

Adverse events leading to modification of therapy in a large cohort of patients with inflammatory bowel disease.

BACKGROUND: Adverse events leading to discontinuation or dose reduction of thiopurine therapy occur in 9-28% of patients with inflammatory bowel disease. AIMS: To evaluate the influence of thiopurine methyltransferase status and thiopurine metabolites in a large patient population for the risk of developing adverse event. METHODS: Three hundred and sixty-four patients with inflammatory bowel disease and present or previous thiopurine therapy were identified from a local database. RESULTS: The adverse event observed in 124 patients (34%) were more common in adults than children (40% vs. 15%; P < 0.001) and in low to intermediate (

Impaired transport as a mechanism of resistance to thiopurines in human T-lymphoblastic leukemia cells.

In order to better understand the mechanisms of resistance to thiopurines, we studied two sublines of the MOLT4 T-lymphoblastic leukemia cell line, resistant to 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG). We found that the underlying mechanism of resistance in both resistant cell lines was a markedly reduction in initial transport of 6-MP (3- and 5-fold, respectively, in 6-MP- and 6-TG-resistant cells). No significant alteration of activities of hypoxanthine-guanine phosphoribosyl transferase, thiopurine methyltransferase or inosine monophosphate dehydrogenase, the key enzymes involved in the metabolism of thiopurines was detected. We conclude that defected initial transport of thiopurines by cells may very well explain their resistance to these drugs.

No induction of thiopurine methyltransferase during thiopurine treatment in inflammatory bowel disease.

The aim of this study was to follow, during standardized initiation of thiopurine treatment, thiopurine methyltransferase (TPMT) gene expression and enzyme activity and thiopurine metabolite concentrations, and to study the role of TPMT and ITPA 94C > A polymorphisms for the development of adverse drug reactions. Sixty patients with ulcerative colitis or Crohn's disease were included in this open and prospective multi-center study. Thiopurine naïve patients were prescribed azathioprine (AZA), patients previously intolerant to AZA received 6-mercaptopurine (6-MP). The patients followed a predetermined dose escalation schedule, reaching target dose at Week 3; 2.5 and 1.25 mg/kg body weight for AZA and 6-MP, respectively. The patients were followed every week during Weeks 1-8 from baseline and then every 4 weeks until 20 weeks. TPMT activity and thiopurine metabolites were determined in erythrocytes, TPMT and ITPA genotypes, and TPMT gene expression were determined in whole blood. One homozygous TPMT-deficient patient was excluded. Five non compliant patients were withdrawn during the first weeks. Twenty-seven patients completed the study per protocol; 27 patients were withdrawn because of adverse events. Sixty-seven percent of the withdrawn patients tolerated thiopurines at a lower dose at Week 20. There was no difference in baseline TPMT enzyme activity between individuals completing the study and those withdrawn for adverse events (p = 0.45). A significant decrease in TPMT gene expression (TPMT/huCYC ratio, p = 0.02) was found, however TPMT enzyme activity did not change. TPMT heterozygous individuals had a lower probability of remaining in the study on the predetermined dose (p = 0.039). The ITPA 94C > A polymorphism was not predictive of adverse events (p = 0.35).

An FTIR and CD study of the structural effects of G-tract length and sequence context on DNA conformation in solution.

Fourier transform infrared (FTIR) and CD spectroscopy have been used to investigate the structural effects of G-tract length and flanking sequence on the conformation of DNA G-tracts in aqueous solution. Particularly, a possible predisposition for A-form features has been probed, since this may be important for protein-DNA interactions. Five different G-tract-containing DNA duplexes have been studied: d[CATGGCCATG](2), d[CATGGGCCCATG](2), d[CATGGGGCCCCATG](2,) d[AGGGGCCCCT](2), and d[TGGGGCCCCA](2). In addition, a DNA duplex lacking a G-tract center was probed (d[CATATGCATATG](2)). The CD and FTIR results show that the G-tract-containing sequences are all in a dominating B-DNA conformation in solution. However, certain spectral variations reflect structural effects of sequence context and G-tract length. CD spectra and FTIR results in the 1800-1500 cm(-1) region show that the base-stacking pattern is greatly affected by the sequence context. The FTIR backbone 1250-1000 cm(-1) region shows the antisymmetric non-bridging phosphate vibration around 1225 cm(-1) in all sequences, demonstrating the overall B-conformation of the backbone. The FTIR sugar 900-800 cm(-1) region shows variable contributions of two bands around 865 cm(-1) and 840 cm(-1), reflecting the N and S-type of sugar pucker. The relative intensities of the 865 cm(-1) and 840 cm(-1) bands have been proposed in the literature to quantitatively yield the contribution of N and S-type of sugar pucker, respectively. This correlation is supported by the present study. Furthermore, the contributions of N-type sugar in the DNA sequences studied indicate structural propensities that agree with trends in reported crystal structures of the same sequences: (1) d[CATGGCCATG](2), for which FTIR shows the lowest contribution of N-type sugar puckering in solution, crystallizes in a B-like conformation; (2) d[AGGGGCCCCT](2), with the highest degree of N-type sugar puckering of all the sequences studied, crystallizes in an A-like conformation; (3) d[CATGGGCCCATG](2), with an N-type contribution intermediate between that of d[CATGGCCATG](2) and d[AGGGGCCCCT](2), crystallizes in an A/B intermediate conformation.

Platelet-leukocyte cross talk in whole blood.

Thrombosis and inflammation involve complex platelet-leukocyte interaction, the details of which are not fully elucidated. Therefore, we investigated cross talk between platelets and leukocytes in whole blood, under the following physiological conditions: at 37 degrees C, with normal calcium concentrations, and with shear force. Platelet P-selectin and leukocyte CD11b expression were used to monitor platelet and leukocyte activation, respectively, and platelet-leukocyte aggregation (PLA) was analyzed. The leukocyte-specific agonist N:-formyl-methionyl-leucyl-phenylalanine (10(-6) mol/L) increased P-selectin-positive platelets from 2.5+/-0. 1% to 5.1+/-0.6% (P:<0.05). The increase was inhibited by either the platelet-activating factor (PAF) antagonist SR27417, the superoxide anion scavenger superoxide dismutase, the 5-lipoxygenase inhibitor Zileuton, or the 5-lipoxygenase-activating protein inhibitor MK-886, suggesting the involvement of PAF, superoxide anion, and 5-lipoxygenase products in leukocyte-induced platelet activation. The platelet-specific agonist collagen (1 microg/mL) increased leukocyte CD11b expression from 2.94+/-0.52 to 3.81+/-0.58 (P:<0. 05); this was not inhibited by the thromboxane A(2) receptor antagonist ICI 192.605 or the PAF antagonist SR27417. Platelet P-selectin expression induced by N:-formyl-methionyl-leucyl-phenylalanine and leukocyte CD11b expression induced by collagen could be suppressed by glycoprotein IIb/IIIa blockade or P-selectin blockade. This study documents platelet-leukocyte cross talk under conditions that mimic a physiological state and suggests that this involves multiple mediators and mechanisms. Furthermore, new evidence of integrin and selectin involvement in intracellular and intercellular signaling during platelet-leukocyte cross talk is provided.

Acute and chronic calcium antagonist treatment elevates sympathetic activity in primary hypertension.

Eleven men with mild to moderate primary hypertension were studied at rest and during mental stress before and during intravenous infusion of the calcium antagonist felodipine. Eight of them were restudied during long-term treatment (extended-release felodipine, 10 mg daily). For comparison, 10 normotensive control subjects were studied with the short-term protocol. Heart rate, cardiac output, central cardiovascular pressures, and forearm blood flow were registered. Arterial and venous sampling was performed. Norepinephrine spillovers to arterial plasma and from the forearm were assessed with the use of radiotracer methodology. In the hypertensive patients, felodipine lowered mean arterial blood pressure acutely by 8% (P < .01). Systemic vascular resistance decreased by 22% (P < .001), cardiac output increased by 20% (P < .01), and norepinephrine spillover to arterial plasma increased by 61% (P < .001). Forearm vascular resistance fell by 30% (P < .001), but norepinephrine overflow from the forearm increased by 115% (P < .001). These forearm responses were not seen in normotensive subjects despite similar systemic responses to felodipine infusion. After 8 weeks of treatment, mean arterial pressure decreased to 15% below baseline (P < .001), cardiac output returned toward pretreatment levels, and systemic vascular resistance remained low. Forearm blood flow returned toward basal levels, but forearm vascular resistance remained lowered. Total body and forearm norepinephrine spillover values were as elevated as in the acute situation. The hemodynamic "defense reaction" and the sympathoadrenal response to mental stress were essentially unaffected by felodipine. Stress-induced small elevations of neuropeptide Y-like immunoreactivity persisted during felodipine. Thus, the vasodilatation induced by felodipine elicits sympathetic counterregulation, which persists in the long term with respect to peripheral and total sympathetic activities, despite resetting of the baroreflex control of heart rate.

Positron emission tomographic measurements of cerebral glucose utilization using [1-11C]D-glucose.

Regional CMRglc was measured in seven healthy volunteers with positron emission tomography using [1-11C]D-glucose. Regional CBF was measured using [11C]fluoromethane. The arteriovenous differences of unlabeled glucose and oxygen together with 11C metabolites were also measured. In addition to the loss of [11C]CO2, a loss of acidic 11C metabolites was also detected. A three-compartment model was applied to the tracer data in the time interval 0-24 min. After correction for the loss of 11C metabolites, the tracer method gave an average CMRglc of 26.4 +/- 1.9 (SD) mumol/100 g/min, close to the value obtained with the Fick principle. After correction for the loss of [11C]CO2 only, the tracer method gave 23.6 +/- 2.1 mumol/100 g/min, compatible with (1/6) CMRO2, obtained with the Fick principle. These results and the time course of the loss of acidic 11C metabolites are consistent with the presence of nonoxidative metabolism of glucose that causes an early loss of mainly [11C]lactate after a bolus injection of the tracer. This implies that [1-11C]D-glucose measures the rate of glucose oxidation rather than the total CMRglc. The experiments using [1-11C]D-glucose were compared to five analogous experiments using [U-11C]D-glucose together with [15O]H2O as a flow tracer. After correction for the loss of [11C]CO2, the two glucose tracers gave similar global values of CMRglc and other parameters associated with glucose utilization, but with labeling in the carbon-1 position, the loss of [11C]CO2 was substantially delayed and the contrast between gray and white matter was improved.(ABSTRACT TRUNCATED AT 250 WORDS)