Phosphodiesterase-5 inhibitors have distinct effects on the hemodynamics of the liver

<p>Abstract</p> <p>Background</p> <p>The NO - cGMP system plays a key role in the regulation of sinusoidal tonus and liver blood flow with phosphodiesterase-5 (PDE-5) terminating the dilatory action of cGMP. We, therefore, investigated the effects of PDE-5 inhibitors on hepatic and systemic hemodynamics in rats.</p> <p>Methods</p> <p>Hemodynamic parameters were monitored for 60 min. after intravenous injection of sildenafil and vardenafil [1, 10 and 100 μg/kg (sil1, sil10, sil100, var1, var10, var100)] in anesthetized rats.</p> <p>Results</p> <p>Cardiac output and heart rate remained constant. After a short dip, mean arterial blood pressure again increased. Systemic vascular resistance transiently decreased slightly. Changes in hepatic hemodynamic parameters started after few minutes and continued for at least 60 min. Portal (var10 -31%, sil10 -34%) and hepatic arterial resistance (var10 -30%, sil10 -32%) decreased significantly (p < 0.05). At the same time portal venous (var10 +29%, sil10 +24%), hepatic arterial (var10 +34%, sil10 +48%), and hepatic parenchymal blood flow (var10 +15%, sil10 +15%) increased significantly (p < 0.05). The fractional liver blood flow (total liver flow/cardiac output) increased significantly (var10 26%, sil10 23%). Portal pressure remained constant or tended to decrease. 10 μg/kg was the most effective dose for both PDE-5 inhibitors.</p> <p>Conclusion</p> <p>Low doses of phosphodiesterase-5 inhibitors have distinct effects on hepatic hemodynamic parameters. Their therapeutic use in portal hypertension should therefore be evaluated.</p

Effect of remote ischemic conditioning on atrial fibrillation and outcome after coronary artery bypass grafting (RICO-trial)

Background: Pre- and postconditioning describe mechanisms whereby short ischemic periods protect an organ against a longer period of ischemia. Interestingly, short ischemic periods of a limb, in itself harmless, may increase the ischemia tolerance of remote organs, e.g. the heart (remote conditioning, RC). Although several studies have shown reduced biomarker release by RC, a reduction of complications and improvement of patient outcome still has to be demonstrated. Atrial fibrillation (AF) is one of the most common complications after coronary artery bypass graft surgery (CABG), affecting 27-46% of patients. It is associated with increased mortality, adverse cardiovascular events, and prolonged in-hospital stay. We hypothesize that remote ischemic pre- and/or post-conditioning reduce the incidence of AF following CABG, and improve patient outcome.Methods/design: This study is a randomized, controlled, patient and investigator blinded multicenter trial. Elective CABG patients are randomized to one of the following four groups: 1) control, 2) remote ischemic preconditioning, 3) remote ischemic postconditioning, or 4) remote ischemic pre- and postconditioning. Remote conditio

Epidemiology, practice of ventilation and outcome for patients at increased risk of postoperative pulmonary complications

BACKGROUND Limited information exists about the epidemiology and outcome of surgical patients at increased risk of postoperative pulmonary complications (PPCs), and how intraoperative ventilation was managed in these patients. OBJECTIVES To determine the incidence of surgical patients at increased risk of PPCs, and to compare the intraoperative ventilation management and postoperative outcomes with patients at low risk of PPCs. DESIGN This was a prospective international 1-week observational study using the ‘Assess Respiratory Risk in Surgical Patients in Catalonia risk score’ (ARISCAT score) for PPC for risk stratification. PATIENTS AND SETTING Adult patients requiring intraoperative ventilation during general anaesthesia for surgery in 146 hospitals across 29 countries. MAIN OUTCOME MEASURES The primary outcome was the incidence of patients at increased risk of PPCs based on the ARISCAT score. Secondary outcomes included intraoperative ventilatory management and clinical outcomes. RESULTS A total of 9864 patients fulfilled the inclusion criteria. The incidence of patients at increased risk was 28.4%. The most frequently chosen tidal volume (VT) size was 500 ml, or 7 to 9 ml kg1 predicted body weight, slightly lower in patients at increased risk of PPCs. Levels of positive end-expiratory pressure (PEEP) were slightly higher in patients at increased risk of PPCs, with 14.3% receiving more than 5 cmH2O PEEP compared with 7.6% in patients at low risk of PPCs (P < 0.001). Patients with a predicted preoperative increased risk of PPCs developed PPCs more frequently: 19 versus 7%, relative risk (RR) 3.16 (95% confidence interval 2.76 to 3.61), P < 0.001) and had longer hospital stays. The only ventilatory factor associated with the occurrence of PPCs was the peak pressure. CONCLUSION The incidence of patients with a predicted increased risk of PPCs is high. A large proportion of patients receive high VT and low PEEP levels. PPCs occur frequently in patients at increased risk, with worse clinical outcome

Epidemiology, practice of ventilation and outcome for patients at increased risk of postoperative pulmonary complications: LAS VEGAS - An observational study in 29 countries

BACKGROUND Limited information exists about the epidemiology and outcome of surgical patients at increased risk of postoperative pulmonary complications (PPCs), and how intraoperative ventilation was managed in these patients. OBJECTIVES To determine the incidence of surgical patients at increased risk of PPCs, and to compare the intraoperative ventilation management and postoperative outcomes with patients at low risk of PPCs. DESIGN This was a prospective international 1-week observational study using the ‘Assess Respiratory Risk in Surgical Patients in Catalonia risk score’ (ARISCAT score) for PPC for risk stratification. PATIENTS AND SETTING Adult patients requiring intraoperative ventilation during general anaesthesia for surgery in 146 hospitals across 29 countries. MAIN OUTCOME MEASURES The primary outcome was the incidence of patients at increased risk of PPCs based on the ARISCAT score. Secondary outcomes included intraoperative ventilatory management and clinical outcomes. RESULTS A total of 9864 patients fulfilled the inclusion criteria. The incidence of patients at increased risk was 28.4%. The most frequently chosen tidal volume (V T) size was 500 ml, or 7 to 9 ml kg−1 predicted body weight, slightly lower in patients at increased risk of PPCs. Levels of positive end-expiratory pressure (PEEP) were slightly higher in patients at increased risk of PPCs, with 14.3% receiving more than 5 cmH2O PEEP compared with 7.6% in patients at low risk of PPCs (P ˂ 0.001). Patients with a predicted preoperative increased risk of PPCs developed PPCs more frequently: 19 versus 7%, relative risk (RR) 3.16 (95% confidence interval 2.76 to 3.61), P ˂ 0.001) and had longer hospital stays. The only ventilatory factor associated with the occurrence of PPCs was the peak pressure. CONCLUSION The incidence of patients with a predicted increased risk of PPCs is high. A large proportion of patients receive high V T and low PEEP levels. PPCs occur frequently in patients at increased risk, with worse clinical outcome.</p

Die Behandlungspraxis und Frakturinzidenz bei postmenopausalen Frauen mit manifester Osteoporose und hohem Frakturrisiko: Eine retrospektive Analyse von Krankenkassendaten

Background: Osteoporosis (OP) and its associated fractures have a significant impact on patients' quality of life and are impacting their morbidity and mortality. For OP patients at high risk of fracture, guidelines recommend a pharmacological OP treatment. The aim of this study was to describe the real-world medication treatment of postmenopausal women with severe OP at high risk of fracture, their risk to experience a new fracture after having at least one previous fracture, and to assess the associated healthcare resource use (HCRU).Methods: This retrospective cohort study was based on anonymized German claims data (AOK PLUS). All included OP patients were female, >=55 years old, and had a vertebral and/or femoral fracture. We conducted a cross-sectional analysis in 2018 and a longitudinal analysis, starting with an incident vertebral/femoral fracture (after or simultaneously with the first observed OP diagnosis). In both analyses, patient characteristics, rate of new incident fractures, OP treatment patterns, and HCRU associated with the treatment of patients were investigated.Results: In the cross-sectional setting, 12,180 patients with a mean age of 83.59 years were observed. Of these patients, 14.30% sustained at least one new incident fracture and 34.54% received a pharmaceutical OP treatment during 2018. In this year, 58.50% of the patients had at least one OP-related outpatient visit, and 26.35% had a fracture-related visit. In 160 patients (1.31%), at least one OP-related hospitalization was documented, and in 1,293 patients (10.62%) a fracture-related hospitalization in 2018.In the longitudinal setting, 10,323 patients with a mean age of 83.22 years were included. Of these, 18.96% experienced at least one new incident fracture within the first 12 months after the index fracture, and in total 30.85% in the entire follow-up period (mean 2.03 years). During the 12-month baseline period, 22.12% of the patients received an OP treatment. Three months after the index fracture, the proportion of treated patients remained at 22.30%. During the total follow-up time, 35.54% were prescribed with an OP treatment.Conclusion: We observed a considerable proportion of untreated patients and a high rate of subsequent fractures. The awareness for a proper risk assessment and the appropriate use of available treatments should be increased.Hintergrund: Osteoporose (OP) und die damit verbundenen Frakturen haben einen signifikanten Einfluss auf die Lebensqualität von OP-Patienten und beeinflussen ebenso deren Morbidität und Mortalität. Leitlinien empfehlen für OP-Patienten mit hohem Frakturrisiko eine spezifische medikamentöse Therapie. Das Ziel dieser Studie war es, die Behandlungspraxis und das Risiko erneuter Frakturen von postmenopausalen Frauen mit manifester OP mit deutlich erhöhtem Frakturrisiko zu beschreiben sowie die damit verbundenen Ressourcenverbräuche zu ermitteln.Methoden: Diese retrospektive Kohortenstudie basierte auf anonymen Krankenkassendaten (AOK PLUS). Sämtliche eingeschlossenen OP-Patienten waren weiblich, >=55 Jahre alt und erlitten bereits eine vertebrale oder femorale Fraktur. In der Studie wurden zwei verschiedene Analysen durchgeführt: eine Querschnittsanalyse für das Jahr 2018 und eine Längsschnittanalyse beginnend mit der Indexfraktur (nach erster beobachteter OP-Diagnose in 2015-2017). In beiden Analysen wurden die Patientencharakteristika, die Rate neuer Frakturen, die medikamentöse OP-Behandlung sowie die assoziierten Ressourcenverbräuche untersucht.Ergebnisse: In der Querschnittsanalyse wurden 12.180 Patientinnen mit einem durchschnittlichen Alter von 83,59 Jahren beobachtet. Von diesen Patientinnen erlitten in 2018 14,30% mindestens eine neue Fraktur und 34,54% erhielten eine medikamentöse OP-Behandlung. Im Beobachtungszeitraum besuchten 58,50% OP-bezogen einen ambulanten Arzt, 26,35% der Arztbesuche waren frakturbezogen. 160 (1,31%) bzw. 1.293 Patientinnen (10,62%) hatten 2018 einen stationären Aufenthalt mit OP- oder Fraktur-Bezug (primäre Diagnose).In die Längsschnittanalyse wurden 10.323 Patientinnen mit einem Durchschnittsalter von 83,22 Jahren eingeschlossen. Innerhalb der ersten 12 Monate nach der Indexfraktur erlitten 18,96% mindestens eine weitere neue Fraktur, im gesamten Beobachtungszeitraum (Mittelwert 2,03 Jahre) 30,85%. In den 12 Monaten vor der Indexfraktur erhielten 22,12% der Patientinnen eine medikamentöse OP-Behandlung; 3 Monate nach dem Index lag der Anteil der Behandelten fast unverändert bei 22,30%. Während des gesamten Beobachtungszeitraums erhielten insgesamt 35,54% der Patientinnen OP-Medikamente.Schlussfolgerung: In der Studie wurden ein beträchtlicher Anteil unbehandelter Patientinnen und eine hohe Rate an Folgefrakturen beobachtet. Das Bewusstsein für eine leitliniengerechte Risikobewertung und den zweckmäßigen Einsatz der verfügbaren Behandlungsoptionen sollte verbessert werden

Costs of Fractures: A Real-World Evidence Study using German Claims Data

The article of record as published may be located at http://dx.doi.org/10.2514/6.2008-7164AIAA Guidance, Navigation and Control Conference and Exhibit Paper no. AIAA-2008-7164, Honolulu, Hawaii, 2008Shen and Tsiotras considered the case where the ax symmetric rigid body was subject to only two control torques which spanned the plane perpendicular to the axis of symmetry. They used a cascaded computational scheme which involved both direct and indirect methods of optimization. Additionally, their method required initial costate guesses which further complicated numerical results. They concluded that two torques were sufficient to achieve a time-optimal maneuver. In this work the Legendre Pseudospectral method will be used to solve the two-torque problem with only a two-point guess to demonstrate the method's superiority. Additionally, it will be demonstrated that while reorientation of the spin axis is possible with two control torques spanning the plane perpendicular to the spin axis, the addition of a third control torque about the axis of symmetry further reduces the objective function. It will be shown that this new solution has significantly different characteristics form the previously published work.NAApproved for public release; distribution is unlimited

Hepatic heat shock and acute-phase gene expression are induced simultaneously after celiotomy in the anesthetized pig

BACKGROUND: The liver plays a central role in the whole organism's response to injury. Expression of hepatic acute-phase and heat-shock genes likely contributes to the restoration of homeostasis after stressful events. However, after prolonged ischemia, hepatic transcription of heat-shock genes can exclude the simultaneous transcription of acute-phase genes. The issue of whether hepatic 72-kd heat-shock protein (hsp72) gene expression is induced under perioperative conditions that do not result in prolonged liver ischemia and whether this might further affect the expression of the acute-phase reactant inter-alpha-trypsin inhibitor (alpha-Ti) was examined. METHODS: Pigs were anesthetized with sodium pentobarbital and ketamine hydrochloride, tracheally intubated, and their lungs ventilated. After celiotomy, a hepatic biopsy sample was obtained. Arterial blood pressure, cardiac output, and total hepatic blood flow were measured. Subsequent biopsies were obtained at 1, 2, 3, 4, and 6 h after the initial biopsy. Arterial norepinephrine concentrations were measured using high-pressure liquid chromatography. Nuclear runoff (run on) analysis and Northern blotting were applied to estimate changes in hsp72 and alpha-Ti gene transcription rates and RNA levels. Western blotting was used to estimate changes in hsp72 levels. RESULTS: Hemodynamic parameters did not change significantly over time. Arterial norepinephrine concentrations were increased at all time points. Hepatic hsp72 RNA levels increased up to sixfold while nuclear runoff assays did not detect significant changes in hsp72 gene transcription rates. The increases in hsp72 RNA levels correlated with accumulation of hsp72 (up to sevenfold). Increases in alpha-Ti transcription rates up to 42-fold were associated with respective increases in alpha-Ti RNA levels (up to 17-fold). CONCLUSIONS: These data demonstrate that hepatic expression of hsp72 is not confined to conditions that lead to prolonged liver ischemia but is also part of the response of the liver to surgery under general anesthesia. Furthermore, these conditions are permissive for the simultaneous RNA expression of the acute-phase reactant alpha-Ti

Thionamides inhibit the transcription factor nuclear factor-kappaB by suppression of Rac1 and inhibitor of kappaB kinase alpha

Thionamides, inhibitors of the thyroid peroxidase-mediated iodination, are clinically used in the treatment of hyperthyroidism. However, the use of antithyroid drugs is associated with immunomodulatory effects, and recent studies with thionamide-related heterocyclic thioderivates demonstrated direct anti-inflammatory and immunosuppressive properties. Using primary human T-lymphocytes, we show that the heterocyclic thionamides carbimazole and propylthiouracil inhibit synthesis of the proinflammatory cytokines tumor necrosis factor (TNF)alpha and interferon (IFN)gamma. In addition, DNA binding of nuclear factor (NF)-kappaB, a proinflammatory transcription factor that regulates both TNFalpha and IFNgamma synthesis, and NF-kappaB-dependent reporter gene expression were reduced. Abrogation of NF-kappaB activity was accompanied by reduced phosphorylation and proteolytic degradation of inhibitor of kappaB (IkappaB)alpha, the inhibitory subunit of the NF-kappaB complex. Carbimazole inhibited NF-kappaB via the small GTPase Rac-1, whereas propylthiouracil inhibited the phosphorylation of IkappaBalpha by its kinase inhibitor of kappaB kinase alpha. Methimazole had no effect on NF-kappaB induction, demonstrating that drug potency correlated with the chemical reactivity of the thionamide-associated sulfur group. Taken together, our data demonstrate that thioureylenes with a common, heterocyclic structure inhibit inflammation and immune function via the NF-kappaB pathway. Our results may explain the observed remission of proinflammatory diseases upon antithyroid therapy in hyperthyroid patients. The use of related thioureylenes may provide a new therapeutic basis for the development and application of anti-inflammatory compounds