Sick leave due to SARS-CoV-2 infection.

BACKGROUND: Coronavirus disease 2019 (COVID-19) caused a high burden of sick leave worldwide. Long-term sick leave for COVID-19 may be longer than for other influenza-like syndromes. The real impact of long COVID on absenteeism remains uncertain. AIMS: To investigate the burden of sick leave, especially >12 weeks, in Belgian workers with a positive polymerase chain reaction (PCR) test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from July 2020 to September 2021 and to compare these figures with sick leave for other infectious diseases. METHODS: We coupled a database of SARS-CoV-2-positive workers and workers who were absent for other infections with objective absence data. Predictors of prolonged sickness were evaluated by negative binomial regression, Cox proportional hazards regression and ordinal logistic regression. RESULTS: The study population involved 2569 workers who tested positive for SARS-CoV-2 and 392 workers who were absent for other infectious diseases. In total, 16% (95% CI 14-17%) of workers with a positive SARS-CoV-2 test had no sick leave registered. Fourteen out of 1000 (95% CI 9-20‰) workers with absenteeism for COVID-19 experienced sick leave >12 weeks as compared to 43 out of 1000 workers (95% CI 3-69‰) with absenteeism due to other infections. When including PCR-positive workers without sick leave, the prevalence of long-term sick leave decreased to 12 per 1000 (95% CI8-17‰). Long-term sick leave was associated with older age, high previous sick leave and low educational level. CONCLUSIONS: The prevalence of long-term sick leave was lower than estimated in earlier investigations regardless of worrying reports about post-COVID-19 syndrome.

Beta blockers and improved progression-free survival in patients with advanced HER2 negative breast cancer: a retrospective analysis of the ROSE/TRIO-012 study.

BACKGROUND: Recent retrospective studies suggest that beta-adrenergic blocking drugs (BB) are associated with improved outcomes in patients with a range of cancers. Although limited and discordant data suggest that BB may increase overall survival (OS) in localized breast cancer (BC), there is no information on the effects of BB in women with advanced BC. PATIENTS AND METHODS: To explore the association between BB use and BC outcomes, we retrospectively reviewed ROSE/TRIO-012, a double-blinded, multinational phase III trial that randomized 1144 patients with HER2-negative advanced BC to first-line docetaxel in combination with ramucirumab or placebo. We compared progression-free survival (PFS), OS, overall response rate, and clinical benefit rate in patients who received BB to those who did not. RESULTS: 153/1144 (13%) patients received BB; 62% prior to enrolment and 38% began after enrolment. Median PFS in BB treated patients was longer than in patients who did not receive them (10.3 versus 8.3 months; HR 0.81; 95% CI 0.66-0.99; P = 0.038). Patients treated with BB only after enrolment had even higher median PFS (15.5 versus 8.3 months, P < 0.001). In the TNBC subset, median PFS was 13.0 months with BB, compared to 5.2 months without BB (HR 0.52; 95% CI 0.34-0.79; P = 0.002). The benefit of BB intake in PFS was independent of treatment-emergent hypertension (P = 0.476) but associated with treatment arm (P = 0.037). The test for interactions between BB and treatment arm was not significant (P = 0.276). No differences were seen in OS, overall response rate, or clinical benefit rate. A validation dataset analysis had consistent but less substantial improved outcomes for women with node positive operable breast cancer receiving BB in the BCIRG-005 trial. CONCLUSIONS: In this exploratory analysis, BB intake was associated with significant improvement in PFS, particularly in patients with TNBC and patients not previously exposed to BB. CLINICAL TRIAL NUMBER: NCT00703326.

Successful Semi-Ambulatory Veno-Arterial Extracorporeal Membrane Oxygenation Bridge to Heart-Lung Transplantation in a Very Small Child.

Lung transplantation (LTx) may be denied for children on extracorporeal membrane oxygenation (ECMO) due to high risk of cerebral hemorrhage. Rarely has successful LTx been reported in children over 10 years of age receiving awake or ambulatory veno-venous ECMO. LTx following support with ambulatory veno-arterial ECMO (VA ECMO) in children has never been reported to our knowledge. We present the case of a 4-year-old, 12-kg child with heritable pulmonary artery hypertension and refractory right ventricular failure. She was successfully bridged to heart-lung transplantation (HLTx) using ambulatory VA ECMO. Initial resuscitation with standard VA ECMO was converted to an ambulatory circuit using Berlin heart cannulae. She was extubated and ambulating around her bed while on VA ECMO for 40 days. She received an HLTx from an oversized marginal lung donor. Despite a cardiac arrest and Grade 3 primary graft dysfunction, she made a full recovery without neurological deficits. She achieved 104% force expiratory volume in 1 s 33 months post-HLTx. Ambulatory VA ECMO may be a useful strategy to bridge very young children to LTx or HLTx. Patient tailored ECMO cannulation, minimization of hemorrhage, and thrombosis risks while on ECMO contributed to a successful HLTx in our patient.

Cardiac-specific adipose triglyceride lipase overexpression protects from cardiac steatosis and dilated cardiomyopathy following diet-induced obesity.

BACKGROUND: Although obesity increases the risk of developing cardiomyopathy, the mechanisms underlying the development of this cardiomyopathy are incompletely understood. As obesity is also associated with increased intramyocardial triacylglycerol (TAG) deposition, also referred to as cardiac steatosis, we hypothesized that alterations in myocardial TAG metabolism and excess TAG accumulation contribute to obesity-induced cardiomyopathy. OBJECTIVE AND DESIGN: To test if increased TAG catabolism could ameliorate obesity-induced cardiac steatosis and dysfunction, we utilized wild-type (WT) mice and mice with cardiomyocyte-specific overexpression of adipose triglyceride lipase (MHC-ATGL mice), which regulates cardiac TAG hydrolysis. WT and MHC-ATGL mice were fed either regular chow (13.5 kcal% fat) or high fat-high sucrose (HFHS; 45 kcal% fat and 17 kcal% sucrose) diet for 16 weeks to induce obesity and mice were subsequently studied at the physiological, biochemical and molecular level. RESULTS: Obese MHC-ATGL mice were protected from increased intramyocardial TAG accumulation, despite similar increases in body weight and systemic insulin resistance as obese WT mice. Importantly, analysis of in vivo cardiac function using transthoracic echocardiography showed that ATGL overexpression protected from obesity-induced systolic and diastolic dysfunction and ventricular dilatation. Ex vivo working heart perfusions revealed impaired cardiac glucose oxidation following obesity in both WT and MHC-ATGL mice, which was consistent with similar impaired cardiac insulin signaling between genotypes. However, hearts from obese MHC-ATGL mice exhibited reduced reliance on palmitate oxidation when compared with the obese WT, which was accompanied by decreased expression of proteins involved in fatty acid uptake, storage and oxidation in MHC-ATGL hearts. CONCLUSION: These findings suggest that cardiomyocyte-specific ATGL overexpression was sufficient to prevent cardiac steatosis and decrease fatty acid utilization following HFHS diet feeding, leading to protection against obesity-induced cardiac dysfunction.

Are users of sulphonylureas at the time of an acute coronary syndrome at risk of poorer outcomes?

AIMS: Adenosine triphosphate sensitive potassium (K(ATP)) channel activity is cardioprotective during ischaemia. One of the purported mechanisms for sulphonylurea adverse effects is through inhibition of these channels. The purpose of this study is to examine whether patients using K(ATP) channel inhibitors at the time of an acute coronary syndrome are at greater risk of death or heart failure (HF) than those not exposed. METHODS: Using linked administrative databases we identified all adults who had an acute coronary syndrome between April 2002 and October 2006 (n = 21 023). RESULTS: Within 30 days of acute coronary syndrome, 5.3% of our cohort died and 15.6% were diagnosed with HF. Individuals with diabetes exhibited significantly higher risk of death (adjusted OR: 1.20, 95% CI: 1.03-1.40) and death or HF (aOR: 1.73, 95% CI: 1.59-1.89) than individuals without diabetes. However, there was no significantly increased risk of death (aOR: 1.00, 95% CI: 0.76-1.33) or death/HF (aOR: 1.06, 95% CI: 0.89-1.26) in patients exposed to K(ATP) channel inhibitors versus patients not exposed to K(ATP) channel inhibitors prior to their acute coronary syndrome. CONCLUSIONS: Diabetes is associated with an increased risk of death or HF within 30 days of an acute coronary syndrome. However, we did not find any excess risk of death or HF associated with use of K(ATP) channel inhibitors at the time of an acute coronary syndrome, raising doubts about the hypothesis that sulphonylureas inhibit the cardioprotective effects of myocardial K(ATP) channels.

SRPK2: a differentially expressed SR protein-specific kinase involved in mediating the interaction and localization of pre-mRNA splicing factors in mammalian cells.

Reversible phosphorylation plays an important role in pre-mRNA splicing in mammalian cells. Two kinases, SR protein-specific kinase (SRPK1) and Clk/Sty, have been shown to phosphorylate the SR family of splicing factors. We report here the cloning and characterization of SRPK2, which is highly related to SRPK1 in sequence, kinase activity, and substrate specificity. Random peptide selection for preferred phosphorylation sites revealed a stringent preference of SRPK2 for SR dipeptides, and the consensus derived may be used to predict potential phosphorylation sites in candidate arginine and serine-rich (RS) domain-containing proteins. Phosphorylation of an SR protein (ASF/SF2) by either SRPK1 or 2 enhanced its interaction with another RS domain-containing protein (U1 70K), and overexpression of either kinase induced specific redistribution of splicing factors in the nucleus. These observations likely reflect the function of the SRPK family of kinases in spliceosome assembly and in mediating the trafficking of splicing factors in mammalian cells. The biochemical and functional similarities between SRPK1 and 2, however, are in contrast to their differences in expression. SRPK1 is highly expressed in pancreas, whereas SRPK2 is highly expressed in brain, although both are coexpressed in other human tissues and in many experimental cell lines. Interestingly, SRPK2 also contains a proline-rich sequence at its NH2 terminus, and a recent study showed that this NH2-terminal sequence has the capacity to interact with a WW domain protein in vitro. Together, our studies suggest that different SRPK family members may be uniquely regulated and targeted, thereby contributing to splicing regulation in different tissues, during development, or in response to signaling.

Phosphorylation regulates in vivo interaction and molecular targeting of serine/arginine-rich pre-mRNA splicing factors.

The SR superfamily of splicing factors and regulators is characterized by arginine/serine (RS)-rich domains, which are extensively modified by phosphorylation in cells. In vitro binding studies revealed that RS domain-mediated protein interactions can be differentially affected by phosphorylation. Taking advantage of the single nonessential SR protein-specific kinase Sky1p in Saccharomyces cerevisiae, we investigated RS domain interactions in vivo using the two-hybrid assay. Strikingly, all RS domain-mediated interactions were abolished by SKY1 deletion and were rescuable by yeast or mammalian SR protein-specific kinases, indicating that phosphorylation has a far greater impact on RS domain interactions in vivo than in vitro. To understand this dramatic effect, we examined the localization of SR proteins and found that SC35 was shifted to the cytoplasm in sky1Delta yeast, although this phenomenon was not obvious with ASF/SF2, indicating that nuclear import of SR proteins may be differentially regulated by phosphorylation. Using a transcriptional repression assay, we further showed that most LexA-SR fusion proteins depend on Sky1p to efficiently recognize the LexA binding site in a reporter, suggesting that molecular targeting of RS domain-containing proteins within the nucleus was also affected. Together, these results reveal multiple phosphorylation-dependent steps for SR proteins to interact with one another efficiently and specifically, which may ultimately determine the splicing activity and specificity of these factors in mammalian cells.

Host-Microbe Interplay in the Cardiometabolic Benefits of Dietary Polyphenols.

Polyphenols are nonessential phytonutrients abundantly found in fruits and vegetables. A wealth of data from preclinical models and clinical trials consistently supports cardiometabolic benefits associated with dietary polyphenols in murine models and humans. Furthermore, a growing number of studies have shown that specific classes of polyphenols, such as proanthocyanidins (PACs) and ellagitannins, as well as the stilbenoid resveratrol, can alleviate several features of the metabolic syndrome. Moreover, mounting evidence points to the gut microbiota as a key mediator of the health benefits of polyphenols. In this review we summarize recent findings supporting the beneficial potential of polyphenols against cardiometabolic diseases, with a focus on the role of host-microbe interactions.

Characterisation of the Selective Reduced Uteroplacental Perfusion (sRUPP) Model of Preeclampsia.

Preeclampsia is a complication of pregnancy characterised by gestational hypertension, proteinuria and/or end organ disease. The reduced uteroplacental perfusion (RUPP) model, via partial occlusion of the lower abdominal aorta, mimics insufficient placental perfusion as a primary causal characteristic of preeclampsia. However, a major limitation of the RUPP model is that perfusion is reduced to the entire hindquarters of the rat resulting in hindlimb ischemia. We hypothesised that clipping the uterine and ovarian arteries in the selective (s)RUPP model would provoke signs of preeclampsia while avoiding systemic ischemia. Sham, RUPP or sRUPP procedures were performed in pregnant Sprague Dawley rats on gestational day (GD)14. On GD21 uterine blood flow was significantly reduced in both the RUPP and sRUPP models while aortic flow was reduced only in RUPP. Both models resulted in increased MAP, increased vascular oxidative stress (superoxide generation), increased pro-inflammatory (RANTES) and reduced pro-angiogenic (endoglin) mediators. Vascular compliance and constriction were unaltered in either RUPP or sRUPP groups. In summary, refinements to the RUPP model simultaneously maintain the characteristic phenotype of preeclampsia and avoid peripheral ischemia; providing a useful tool which may be used to increase our knowledge and bring us closer to a solution for women affected by preeclampsia.

Phase II feasibility study of concurrent radiotherapy and gemcitabine in chemonaive patients with squamous cell carcinoma of the head and neck: long-term follow up data.

BACKGROUND: Radiotherapy (RT) with concurrent chemotherapy is the current standard of care for patients with unresectable locally advanced squamous cell carcinoma of the head and neck (SCCHN). Gemcitabine (GEM) is a potent radiosensitizer and in addition has activity as an anticancer agent in SCCHN. PATIENTS AND METHODS: Twenty-six patients with locally far advanced SCCHN were enrolled in a chemoradiation feasibility study between November 1998 and September 2003. Use was made of conventionally fractionated RT and GEM 100 mg/m(2), which was given within 2 h prior to radiotherapy on a weekly basis starting on day 1 of RT. Response was assessed according to WHO criteria, toxicity according to NCI-CTC version 2. RESULTS: The patients received a median of 7 (2-8) weekly cycles of gemcitabine and a median cumulative RT dose of 70 Gy (66-84.75). Hematologic toxicity was mild, but non-hematologic toxicity was severe: grade 3-4 stomatitis occurred in 85% of patients, dermatitis in 69%, pharyngitis/esophagitis in 81% and 80% of the patients needed a feeding tube during treatment. All 22 evaluable patients responded (50% complete, 50% partial). Median follow up of the surviving patients is 46 months. Median disease-free and overall survival is 13 months and 19 months, respectively; 27% of the patients are alive without evidence of recurrence beyond 3 years. CONCLUSIONS: Conventionally fractionated RT in combination with GEM 100 mg/m(2) weekly is feasible and highly active in the treatment of locally advanced SCCHN. In particular, long-term local control rate is promising. Acute mucosal toxicities are significant but manageable. Long-term toxicity interferes with normal food intake.

Regulation of NHE1 expression in L6 muscle cells.

We examined regulation of expression of the NHE1 promoter on rat L6 cells. Transient transfection of these cells showed that there are two regions critical for basal expression in this cell type. One is from bp -155 to -171 and second more proximal region is between bp -92 and -125. When cells were induced to differentiate by serum withdrawal, mRNA levels rose 2-3-fold. To investigate the mechanisms of this phenomenon a series of stable transfectants were made of the NHE1 promoter in L6 cells. Muscle differentiation caused a significant stimulation of transcriptional activity in the stable cells containing the more distal regions of the promoter. The results show that basal expression of the NHE1 promoter is mediated largely by two proximal regions of the gene. However, during the process of differentiation more distal regions of the gene are involved in elevation of the level of expression.

Ambulatory blood pressure monitoring and left ventricular mass and function after successful surgical repair of coarctation of the aorta.

Late cardiovascular morbidity and mortality remain significant despite apparently successful surgical repair of aortic coarctation. Alterations in cardiac function have been reported in normotensive patients who have had successful repair, the reasons for which remain unclear. This study addresses the relation between ambulatory blood pressure measurements and alterations in left ventricular performance in 20 patients with normotension at rest after successful repair of aortic coarctation. Exercise testing, ambulatory blood pressure monitoring and two-dimensional echocardiographic studies in 13 boys and 7 girls (mean age 14.2 +/- 2.31 and 14.7 +/- 3 years, respectively) who had no evidence of recoarctation were compared with the findings in 20 matched control subjects. No difference was found in systolic blood pressure at rest or peak exercise between patients and control subjects. Male patients developed a significant arm/leg gradient at peak exercise. Systolic ambulatory blood pressure was higher throughout the day in the male group. In the female group, systolic blood pressure was higher only during sleep. No difference was found in diastolic blood pressure or heart rate. The transverse aortic arch was smaller and the left ventricular mass greater in all patients. The relation of wall stress to rate-corrected velocity of shortening was 2 SD above normal in 8 of the 20 patients, suggesting that some have enhanced contractility. The E/A ratio on the atrial echocardiogram was significantly reduced in the patient group. Successfully treated patients who are normotensive at rest after operation are still at risk for developing end organ damage, which is probably explained by incipient mild hypertension documented by ambulatory blood pressure monitoring.

A "whole-blood" technique for the quantitation of canine "T-lymphocyte" progenitors using a semisolid culture system.

A whole blood technique is described for the growth of concanavalin A (Con A) stimulated canine lymphocyte colonies in semisolid medium. By eliminating the routine Ficoll-Paque (F-P) gradient lymphocyte isolation, this method avoids potential problems of growth modulation due to elimination of non-lymphoid accessory cells and the influences on colony formation associated with the selective effects of F-P on lymphocyte subpopulations. Thus, the technique more closely approximates the in vivo milieu. The whole-blood method also produces higher cloning efficiencies than methods using gradient isolation of lymphocytes. Studies over a wide range of blood concentration produced a linear response of in vitro colony formation although extrapolation of the cell-dose colony-response curve did not intersect zero. Mitogen titration data indicates that a relatively large dose of Con A is required for whole blood colony formation compared to the standard F-P method. The colonies ultrastructurally were composed of lymphoblastic and lymphocytic elements which were negative for non-specific esterase activity. Characterization of cells retrieved from the colonies using rosetting techniques indicates a high percentage of the colony cells relative to canine peripheral blood cells form rosettes with human erythrocytes.

The formation of human lymphocyte colonies in semisolid cultures in response to allogeneic mixed-lymphocyte stimulation.

A technique is described for the growth of human lymphocyte colonies in semisolid culture systems in response to allogeneic lymphocyte stimulation. Colonies did not form to any major extent using autologous lymphocyte stimulation. Both one-way and two-way mixed-lymphocyte reactions were investigated. Ultrastructurally, such colonies are composed of cells with lymphoblastic and lymphocytic morphology. The majority of the lymphoid elements composing the colonies were T-cells based on their ability to rosette with sheep red blood cells. Our studies suggest that the colonies are clonogenic in origin and therefore the technique offers the potential for isolation of specific clones, or subpopulations of lymphocytes involved in allogeneic reactions and characterization of their function. Studies directly comparing the stimulation indices achieved with standard mixed lymphocyte cultures utilizing 3HTdr-incorporation to the colony-forming assay indicate that the cloning technique produces higher stimulation indices for allogeneic/autologous reactions and produces less autologous (background) response than the 3HTdr incorporation technique. In addition to lymphocyte colonies, we also observed colonies of surface-adherent populations of macrophages, including multinucleated giant cells. Thus, the technique appears to provide a new and potentially more sensitive method for the study of transplantation immunology and cell-mediated immunity in humans.

Growth of canine T-lymphocyte colonies in vitro.

Canine lymphocytes from peripheral blood, lymph nodes, thymus and bone marrow were stimulated with phytohemagglutinin-P (PHA) or concanavalin-A (CON-A) to form colonies in methylcellulose. Lymphocytes exposed to mitogens in liquid phase formed clumps the size of colonies. Lymphocyte clumping was eliminated by plating cells directly into methylcellulose, but high concentrations of mitogens (CON-A or PHA is greater than 10 mg/10(6) lymphocytes) were required in order to get subsequent colony formation. Thus, in contrast to published reports, exposure of lymphocytes to mitogen prior to plating was not required for cloning of canine peripheral blood lymphocytes. Colonies from thymus, lymph node, or peripheral blood consisted predominantly of T lymphocytes, whereas cultures from bone marrow also produced colonies with macrophage morphology and surface-adherent colonies with mesenchymal morphology.

Production of mesenchymal tumors in nude mice by Ph1 negative fibroblasts obtained from a Ph 1 positive CML patient: a preliminary report.

An experimental model system is presented for the investigation in humans of the role of hematopoietic stromal elements in the regulation of hematopoiesis as well as in the pathogenesis of myelofibrosis in myeloproliferative disorders. The model is based on the simultaneous application of three experimental techniques: (1) growth of bone-marrow derived fibroblastic colonies in vitro, (2) cytogenetic demonstration of marker chromosomes associated with hematopoietic malignancies, and (3) the transplantation of isolated stromal elements into athymic (nude) mice. Using this model, we describe the induction of mesenchymal tumors in nude mice by Ph1 negative fibroblasts obtained from the bone marrow of a patient with a Ph1 positive chronic myelogenous leukemia. Mesenchymal tumors also were induced in nude mice with bone marrow-derived fibroblasts from a patient with aplastic anemia, who was successfully treated with bone marrow transplantation, and from a normal human volunteer. Morphologic, cytogenetic and electron microscopic studies of bone marrow mesenchymal elements in culture and of tumors induced in nude mice from the CML patient indicate the cells composing the tumor are of human origin and are negative for the Ph1 chromosome. The results provide the first in vivo morphological and cytogenetic support using human materials, of the hypothesized relationship of progenitors of in vitro fibroblastic colonies to marrow stromal elements.

Characterization of canine fetal lymphohematopoiesis: studies of CFUGM, CFUL, and CFUF.

We assayed the colony forming units for granulocyte-macrophages (CFUGM), T-lymphocytes (CFUL) and fibroblasts (CFUF) in the blood, bone marrow, liver and spleen of the canine at 45 and 55 days of gestation and 4 and 30 days post partum. As the number of CFUGM per 5 x 10(5) cells increased in the fetal liver, the number of CFUGM increased in circulating blood, whereas when the number of CFUGM decreased in liver and blood, CFUGM increased in both bone marrow and spleen. This suggests that CFUGM are produced in the liver, are released into the circulation and then transported to the spleen and bone marrow. CFUF studies showed that canine fetal bone marrow and spleen are active sites of fibroblast proliferation, whereas the liver is not. Morphologic examination of colonies derived from concanavalin-A stimulated progenitors ("CFUL") demonstrated that these colonies from fetal tissues and adult bone marrow were not exclusively lymphoid but were also made up of significant numbers of precursors of the myeloid and monocytic series. Lymphocyte stimulation tests (LST) showed the presence of a large population of mitogen-independent dividing cells, suggesting that fetal lymphohematopoiesis may be at least partially under the influence of factors other than those of adult cells.

Induction of expression of the sodium-hydrogen exchanger in rat myocardium.

OBJECTIVE: The aim was to examine the regulation of the cardiac Na+/H+ exchanger NHE-1 isoform mRNA in response to ischaemia and acidosis in the mammalian myocardium. METHODS: Male Sprague Dawley rat hearts were perfused in a non-circulated retrograde fashion according to the Langendorff method. Hearts were perfused for 3 h at flow rates of either 10 ml.min-1 (control), or 3, 1, or 0 ml.min-1 (ischaemia) followed by 5 min of reperfusion. Hearts were immediately frozen in liquid N2, and stored at -80 degrees C until ready for RNA isolation. Northern blot analysis was used to examine expression of the NHE-1 isoform of the Na+/H+ exchanger message in these isolated perfused hearts. Activity of the Na+/H+ exchanger was assessed in primary cultures of neonatal rat myocytes under either control conditions or after treatment with chronic, low external pH. RESULTS: A decrease in developed tension and an increase in resting tension was observed which was dependent upon the severity of the ischaemic episode. Low flow ischaemia of 3 ml.min-1 caused increased Na+/H+ exchanger message levels, while perfusion at more reduced flow rates eliminated the increase. Treatment of primary cultures of isolated myocytes with low external pH resulted in increased ability to recover from an acute acid load. CONCLUSIONS: Low flow ischaemia can increase the Na+/H+ exchanger message in the intact mammalian myocardium. More severe ischaemia prevents the increase, suggesting that severely damaged tissue may not be capable of the ischaemic response. Primary cultures of isolated myocytes can respond to chronic low external pH by increasing Na+/H+ exchanger activity.

Dexmedetomidine decreases cerebral blood flow velocity in humans.

This study was designed to determine the effects of dexmedetomidine on CBF velocity as measured by transcranial Doppler sonography in human volunteers. Dexmedetomidine, a potent alpha-2 adrenergic agonist, was administered by computer-driven infusion pump to six male volunteers. Serial measurements of middle cerebral artery blood flow velocity at four steady-state plasma concentrations of dexmedetomidine were made with a 2-MHz transcranial Doppler transducer via the temporal window. The targeted plasma concentrations were 0.49, 0.65, 0.81, and 0.97 ng/ml. These represent 60, 80, 100, and 120%, respectively, of the mean peak concentration following the intramuscular administration of 2 micrograms/kg of dexmedetomidine. Subjects experienced a significant degree of sedation at the highest infusion rates. Mean CBF velocity decreased with each increase in plasma concentration of dexmedetomidine and then began to return to basal levels after termination of the infusion. A trend toward an increase in the pulsatility index at the higher levels of dexmedetomidine suggests that the observed decrement in CBF velocity was due to an increase in cerebral vascular resistance. Upon initiation of the drug infusion, mean arterial pressure decreased from approximately 95 mm Hg to 78 mm Hg. There were no further decreases in arterial pressure with subsequent increases in plasma concentrations of dexmedetomidine. Arterial carbon dioxide tension increased to a maximum of 45 mm Hg during the drug infusion, but this increase from baseline was not statistically significant. These studies are in agreement with previous animal studies which demonstrate a decrease in CBF after administration of dexmedetomidine.

Pharmacokinetic-pharmacodynamic modeling in drug development: application to the investigational opioid trefentanil.

OBJECTIVE: We determined the possible benefits of a new opioid, trefentanil, relative to fentanyl and alfentanil using high-resolution pharmacokinetic-pharmacodynamic modeling and computer simulations of clinical dosing scenarios. METHODS: First, we determined in nine volunteers the electroencephalographic (EEG) effects and the trefentanil infusion rate that gave maximal EEG changes in 3 to 10 minutes. Then, in a crossover fashion in five volunteers, we compared the pharmacokinetics and EEG pharmacodynamics of trefentanil with fentanyl and alfentanil. Finally, we used computer simulations to predict offset of opioid effects of trefentanil, fentanyl, and alfentanil when given in different dosing schemes. RESULTS: The pharmacokinetic-pharmacodynamic profile of trefentanil was similar to alfentanil, except for a higher elimination clearance. Trefentanil versus alfentanil pharmacokinetic parameters were as follows: Elimination clearance, 0.444 +/- 0.073 versus 0.184 +/- 0.031 L/min; steady-state distribution volume, 37 +/- 7 versus 23 +/- 3 L; and elimination half-life, 127 +/- 24 versus 114 +/- 19 minutes. Trefentanil versus alfentanil pharmacodynamics were as follows: the equilibration half-time between EEG effect and arterial drug concentration, 1.2 +/- 0.5 versus 0.6 +/- 0.4 minutes; and the concentration resulting in 50% of maximal EEG effect, 429 +/- 313 versus 577 +/- 273 ng/ml. The pharmacokinetic-pharmacodynamic profile of fentanyl was significantly different from trefentanil and alfentanil. Simulation of effect compartment concentration decay curves after variable-length infusions predicted more rapid recovery from trefentanil than from alfentanil or fentanyl. CONCLUSION: We suggest that high-resolution pharmacokinetic-pharmacodynamic studies and computer simulations of clinical dosing scenarios may have significant usefulness in appreciating differences between new and established drugs in early phase I studies.