Search

Context: Obesity prevalence is persistently increasing worldwide. Among surgical therapeutic procedures, bypass surgery and sleeve gastrectomy have shown the best results regarding weight loss, prevention, and treatment of secondary complications. However, these surgeries are associated with an increased risk of malabsorption and metabolic changes that could further affect the pharmacokinetics of drugs. On the other hand, patients with a history of such surgeries are more likely to experience pain and request analgesic initiation or adaptation. The question of how to manage pain medication in these patients is challenging due to their narrow therapeutic indexes., Objectives: To summarize the current literature on the impact of bariatric surgery on the subsequent pharmacokinetics of analgesics and propose a multidisciplinary therapeutic attitude to optimize pain management in these patients., Methods: We conducted a systematic review that included all pharmacological studies published after 2000., Results: Unexpectedly, these surgeries seem to increase the bioavailability of drugs by long-term improvement of hepatic function. Yet, the medical community drastically lacks robust guidelines for pain management in those patients. This systematic review aims to bring together pharmacological studies related to the use of pain treatments in patients who underwent bypass surgery or sleeve gastrectomy., Conclusions: Caution should be exercised regarding the risk of overdose in every circumstance: treatment initiation, change of doses, or change of molecule. More prospective trials comparing the pharmacokinetics of medications in obese patients with and without prior bariatric surgery are needed., (Copyright © 2024 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Radiation-induced lymphopenia (RIL) is characterized by a significant decrease in the absolute number of lymphocytes circulating in the blood after radiotherapy. With the major shift in cancer management initiated by cancer immunotherapy (IT), the reduction of incidence of RIL appears today as an extremely promising way of potentiating the synergy between radiotherapy and immunotherapy. However, the causes of RIL and mechanisms involved are still poorly understood. Improving our knowledge on RIL is therefore essential to limit it and thus improve the quality of care delivered to patients. The objective of this review is to provide a global view of RIL from a clinical point of view, with particular emphasis on recent knowledge and avenues explored to explain RIL and especially its depletion and remission kinetics. An opening on treatment concepts to be rethought is conducted in the context of combined RT/IT treatments., (Copyright © 2023 Elsevier Inc. All rights reserved.)

PD-L1 and tumor-infiltrating lymphocytes play a key role in the immune escape of cancer, although their prognostic value remains unknown in patients with refractory solid cancer compared to other known prognostic estimation methods. In this ancillary study, we assessed the prognostic value of previously-defined prognostic scores (such as the Royal Marsden Hospital (RMH) score) and of PD-L1, CD3, CD8 and FOXP3 expressions based on immunohistochemistry (IHC) and RNA sequencing (RNAseq) of tumor samples from patients included in the personalized-medicine MOSCATO-02 trial. We collected biopsies with successful IHC analysis from 266 patients treated between April 2016 and September 2017, among whom 170 (63.9%) also had a matched RNAseq. We used a Random Forest model to identify the best prognostic factor, and a Lasso-penalized Cox model to validate the findings. We found that the RMH score was the strongest prognostic factor, with high scores associated with a higher risk of death (Hazard Ratio (HR)=1.29; CI95%[1.19-1.21]). The PD-L1 expression score obtained from IHC analyses was the second-best performing predictor, with the 1+ score (low expression) linked to a lower risk of death (HR=0.564; CI95%[0.539-0.580]). Other tested variables, including primary tumor type and subsequent treatments received following biopsy, were not found significantly linked to prognosis. We found modest correlation between IHC and RNAseq expressions of immune genes, but RNAseq related better to prognosis. Overall, our study supports the use of the RMH score and the assessment of PD-L1 expression in IHC to estimate prognosis in patients with advanced cancer., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Immune therapies have revolutionized cancer treatment over the last few years by allowing improvements in overall survival. However, the majority of patients is still primary or secondary resistant to such therapies, and enhancing sensitivity to immune therapies is therefore crucial to improve patient outcome. Several recent lines of evidence suggest that epigenetic modifiers have intrinsic immunomodulatory properties, which could be of therapeutic interest., Material and Methods: We reviewed preclinical evidence and clinical studies which describe or exploit immunomodulatory properties of epigenetic agents. Experimental approaches, clinical applicability and corresponding ongoing clinical trials are described., Results: Several epigenetic modifiers, such as histone deacetylase inhibitors, DNA methyl transferase inhibitors, bromodomain inhibitors, lysine-specific histone demethylase 1 inhibitors and enhancer of zeste homolog 2 inhibitors, display intrinsic immunomodulatory properties. The latter can be achieved through the action of these drugs either on cancer cells (e.g. presentation and generation of neoantigens, induction of immunogenic cell death, modulation of cytokine secretion), on immune cells (e.g. linage, differentiation, activation status and antitumor capability), or on components of the microenvironment (e.g. regulatory T cells and macrophages). Several promising combinations, notably with immune checkpoint blockers or adoptive T-cell therapy, can be envisioned. Dedicated clinically relevant approaches for patient selection and trial design will be required to optimally develop such combinations., Conclusion: In an era where immune therapies are becoming a treatment backbone in many tumour types, epigenetic modifiers could play a crucial role in modulating tumours' immunogenicity and sensitivity to immune agents. Optimal trial design, including window of opportunity trials, will be key in the success of this approach, and clinical evaluation is ongoing.

Background: Automation in microbiology laboratories impacts management, workflow, productivity and quality. Further improvements will be driven by the development of intelligent image analysis allowing automated detection of microbial growth, release of sterile samples, identification and quantification of bacterial colonies and reading of AST disk diffusion assays. We investigated the potential benefit of intelligent imaging analysis by developing algorithms allowing automated detection, semi-quantification and identification of bacterial colonies., Methods: Defined monomicrobial and clinical urine samples were inoculated by the BD Kiestra™ InoqulA™ BT module. Image acquisition of plates was performed with the BD Kiestra™ ImagA BT digital imaging module using the BD Kiestra™ Optis™ imaging software. The algorithms were developed and trained using defined data sets and their performance evaluated on both defined and clinical samples., Results: The detection algorithms exhibited 97.1% sensitivity and 93.6% specificity for microbial growth detection. Moreover, quantification accuracy of 80.2% and of 98.6% when accepting a 1 log tolerance was obtained with both defined monomicrobial and clinical urine samples, despite the presence of multiple species in the clinical samples. Automated identification accuracy of microbial colonies growing on chromogenic agar from defined isolates or clinical urine samples ranged from 98.3% to 99.7%, depending on the bacterial species tested., Conclusion: The development of intelligent algorithm represents a major innovation that has the potential to significantly increase laboratory quality and productivity while reducing turn-around-times. Further development and validation with larger numbers of defined and clinical samples should be performed before transferring intelligent imaging analysis into diagnostic laboratories., (Copyright © 2017 Chang Gung University. Published by Elsevier B.V. All rights reserved.)

Background: Although the role of epigenetic abnormalities has been studied for several years in cancer genesis and development, epigenetic-targeting drugs have historically failed to demonstrate efficacy in solid malignancies. However, successful targeting of chromatin remodeling deficiencies, histone writers and histone reader alterations has been achieved very recently using biomarker-driven and mechanism-based approaches. Epigenetic targeting is now one of the most active areas in drug development and could represent novel therapeutic opportunity for up to 25% of all solid tumors., Material and Methods: We reviewed preclinical and clinical studies that described epigenetic oncogenic addictions, synthetic lethal relationships or epigenetic antagonisms in chromatin regulators. Experimental approaches, their clinical relevance and applicability, as well as corresponding on-going studies are described., Results: The most successful approaches that have been clinically validated so far include the targeting of the BRD4-NUT fusion transcript in NUT-midline carcinoma by BET (Bromodomain Extra-Terminal) inhibitors, and the use of EZH2 (Enhancer of Zest Homolog 2) inhibitors in SMARCB1-deficient malignant rhabdoid tumors and SMARCA4-deficient ovarian small cell carcinomas. Clinical validation is still required for other synthetic lethal relationships or epigenetic antagonisms, including those described between EZH2 inhibitors and deficiencies in components of the Polycomb or SWI/SNF chromatin-remodeling complexes (including BAP1, ARID1A and PBRM1 subunits), as well as between the CREBBP and EP300 histone acetylases. Further, interplays between epigenetic modifiers and non-epigenetic cellular processes might be therapeutically exploited, and combinatorial strategies could be envisioned to overcome resistance or to sensitize cells to already approved drugs., Conclusion: Epigenetic-targeting drugs have historically failed proving efficacy in solid malignancies when used broadly, but novel mechanism-based approaches in molecularly selected patient populations have facilitated recent successes in proof-of-concept studies in solid tumors. Appropriate clinical trial design and molecular patient selection will be key for the success of epigenetic modifiers in solid tumours., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Anti-cytomegalovirus (CMV) prophylaxis is recommended in D+R- kidney transplant recipients (KTR), but is associated with a theoretical increased risk of developing anti-CMV drug resistance. This hypothesis was retested in this study by comparing 32 D+R- KTR who received 3 months prophylaxis (valganciclovir) with 80 D+R- KTR who received preemptive treatment. The incidence of CMV infections was higher in the preemptive group than in the prophylactic group (60% vs. 34%, respectively; p = 0.02). Treatment failure (i.e. a positive DNAemia 8 weeks after the initiation of anti-CMV treatment) was more frequent in the preemptive group (31% vs. 3% in the prophylactic group; p = 0.001). Similarly, anti-CMV drug resistance (UL97 or UL54 mutations) was also more frequent in the preemptive group (16% vs. 3% in the prophylactic group; p = 0.05). Antiviral treatment failures were associated with anti-CMV drug resistance (p = 0.0001). Patients with a CMV load over 5.25 log(10) copies/mL displayed the highest risk of developing anti-CMV drug resistance (OR = 16.91, p = 0.0008). Finally, the 1-year estimated glomerular filtration rate was reduced in patients with anti-CMV drug resistance (p = 0.02). In summary, preemptive therapy in D+R- KTR with high CMV loads and antiviral treatment failure was associated with a high incidence of anti-CMV drug resistance., (©Copyright 2011 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: GPVI is a major platelet collagen signaling receptor. In rare cases of immune thrombocytopenic purpura (ITP), autoantibodies to GPVI result in receptor shedding., Objectives: To investigate a possible pathogenic role of plasma anti-GPVI antibody located in a woman with lupus nephritis., Methods: Measured were (i) platelet aggregation to collagen and convulxin, (ii) platelet GPVI expression (flow cytometry and western blotting), (iii) plasma soluble GPVI (sGPVI, dual antibody ELISA), and (iv) plasma anti-GPVI antibody (ELISA using recombinant sGPVI)., Results: In 2006 and early 2007, the patient had a normal platelet count but a virtual absence of platelet aggregation to collagen and convulxin. Her platelets responded normally to other agonists including cross-linking ITAM-dependent FcgammaRIIA by monoclonal antibody, IV.3. Flow cytometry and western blotting showed a platelet deficiency of GPVI. Plasma sGPVI levels were undetectable whereas ELISA confirmed the presence of anti-GPVI antibody. Sequencing revealed a normal GPVI cDNA structure. The patient's plasma and the isolated IgG3 fraction activated and induced GPVI shedding from normal platelets. A deteriorating clinical condition led to increasingly strict immunosuppressive therapy. This was globally associated with a fall in plasma anti-GPVI titres, the restoration of platelet GPVI and the convulxin response, and the loss of her nephrotic syndrome., Conclusions: Our results show that this patient acquired a potent anti-GPVI IgG3 antibody with loss of GPVI and collagen-related platelet function. Further studies are required to determine whether anti-GPVI antibodies occur in other lupus patients with nephritis.

The presence of circulating villous lymphocytes (VLs) in lymphoma patients usually points to splenic marginal zone B-cell lymphoma (SMZL), even if the VLs can be found occasionally in other small B-cell lymphomas. However, those cells are variably described, and detailed cytologic characterization is often lacking. We identified lymphoma cases with numerous basophilic VLs among the large group of splenic lymphoma with VLs, and for further delineation, 37 cases with this particular cytology were analyzed. Patients, predominantly older men, presented with moderate lymphocytosis and splenomegaly without pancytopenia. The monoclonal B cells expressed IgM + D, IgM + G, IgM or IgG, as well as CD76 and CD11c, frequently CD103, and rarely CD123. Spleen sections were peculiar, with atrophic white pulp and a monomorphic diffuse lymphoma infiltration in a congested red pulp. Bone marrow infiltration was interstitial and intrasinusoidal without extensive fibrosis. Cytogenetic analysis showed a frequent absence of clonal aberrations (68%). Most cases (79%) were IgH mutated, with an overrepresentation of V(H)3 and V(H)4 gene families. These results, as well as the clinical evolution, show that those lymphoma cases represent a homogeneous group distinct from SMZL and reminiscent of hairy cell leukemia variant, perhaps corresponding to a separate lymphoma entity.

Study Objectives: We hypothesized that lowering blood viscosity with acute normovolemic hemodilution (ANH) would confer additional cardioprotection in patients undergoing coronary artery bypass surgery (CABG) with aortic cross-clamping., Design: In a prospective, randomized controlled trial, we studied the efficacy of ANH in anesthetized patients prior to cardiopulmonary bypass for the prevention of myocardial injuries., Setting: Cardiac surgical center in a university hospital., Patients and Methods: Patients scheduled to undergo elective CABG entered the study protocol and were randomly allocated to one of two groups: ANH (n = 43 patients) or standard care management (n = 41 patients). In the ANH group, the whole-blood/colloid exchange was aimed to achieve a hematocrit value of 28%. All patients were managed with standard myocardial preservation techniques including cold-blood cardioplegia and anesthetic preconditioning. The outcome measures included the release of myocardial enzymes (plasma troponin I and creatinine phosphokinase), perioperative hemodynamic changes, need for pharmacologic cardiovascular support, and cardiac complications., Results: In the hemodilution group, the postoperative release of troponin I (mean peak plasma concentration, 1.4 ng/mL; 95% confidence interval, 1.0 to 1.8) and myocardial fraction of creatine kinase (mean, 29 U/L; 95% confidence interval, 23 to 35) were significantly lower than in the control group (mean, 3.8 ng/mL; 95% confidence interval, 3.2 to 4.5; and 71 U/L; 95% confidence interval, 53 to 89). Requirement for inotropic support was significantly lower in the protocol patients (7 of 41 patients vs 15 of 39 patients), and fewer patients presented with either atrial fibrillation, atrioventricular conduction blockade, or combined disorders (12 of 41 patients vs 26 of 39 patients, p < 0.05)., Conclusions: In addition to conventional myocardial preservation techniques, preoperative ANH achieved further cardiac protection in patients undergoing on-pump myocardial revascularization.

Chronic allograft nephropathy (CAN) is the main cause of graft failure after the first year of transplantation. This prospective, centrally randomized, open-label study was conducted to examine the possibility that mycophenolate mofetil (MMF) can prevent the emergence of CAN. The incidence of biopsy-proven CAN at 1 year was compared between two cyclosporine-based regimens comprising either mycophenolate mofetil (MMF) or azathioprine (AZA). The AZA group (n = 34) and the MMF group (n = 37) were balanced for all baseline characteristics of donors and recipients, the pre-existence of renal lesions on donor biopsy, the incidence of delayed graft function and acute rejection. Based on an intent-to-treat analysis, the number of patients with CAN at 1 year post-transplantation was significantly reduced in the MMF group (17/37-46%) compared with the AZA group (24/34-71%) (p = 0.03). When observed data were considered, 56/71 (78.8%) patients had a 1-year biopsy, and the number of patients with CAN was significantly lowered in the MMF group (9/29-31%) compared with the AZA group (17/27-63%) (p = 0.01). These results suggest a beneficial effect of MMF on the incidence of CAN at 1 year post-transplantation.

Objective: to investigate the affect of reduced aortic compliance on cardiovascular hemodynamics., Materials and Method: fourteen Yucatan miniature swine were divided into two equal groups, a Sham Operated Group and a Banding Group. A Teflon prosthesis was wrapped around the aortic arc in order to limit proximal aortic compliance (Banding Group). Data were recorded operatively (after implantation of a pressure sensor and a flow probe in the ascending aorta), after banding (only in the Banding Group) and at 2 days postoperatively., Results: after banding, compliance decreased by 52 +/- 13% ((-)X +/- SEM) (p < 0.01) while systolic and pulse pressure increased by 37 +/- 8% (p < 0.05) and 87 +/- 31% (p < 0.01), respectively. Diastolic pressure, mean blood pressure, cardiac output and systemic vascular resistance did not change significantly. Aortic characteristic impedance increased nearly 2.5 times. Amplitudes of forward and reflected pressure waves (derived from the aortic pressure wave) increased by 96 +/- 41% and 174 +/- 46%, respectively (p < 0.05), while the time delay between the two decreased by 36 +/- 7% (p < 0.05)., Conclusions: about half of the total arterial compliance is located in the proximal thoracic aorta. Arterial reconstruction of the proximal aorta with a non-compliant graft results in a significant decrease in systemic arterial compliance, which in turn increases systolic and pulse pressure. The development of more compliant prosthesis, which matches the host artery compliance, is expected to reduce the hemodynamic changes induced after their implantation.

The inappropriate use of antihypertensive medications may cause hypotensive responses associated with organ failure. We describe a patient who developed nonocclusive splanchnic ischemia leading to death following the administration of enalapril to treat postoperative hypertension. The mechanisms and consequences of refractory hypotension induced by angiotensin-converting enzyme inhibitors are discussed.

Patients undergoing cardiac surgery with moderate hypothermic cardiopulmonary bypass (CPB) were allocated randomly to receive either saline (control group, n = 29) or a high-dose regimen of aprotinin (aprotinin group, n = 28). In both groups, CPB was associated with similar and transient increases in effective renal plasma flow (+54% in controls and +48% in aprotinin-treated patients) and in fractional excretion of sodium and potassium, but glomerular filtration rate remained unchanged. Plasma and urinary ratios of 6-keto-PGF1 alpha to thromboxane B2 (TxB2) increased significantly, indicating systemic and renal release of vasodilatory prostaglandins. Osmolar clearance correlated with urinary excretion of cyclic GMP (r = 0.79 and 0.86 in the control and aprotinin groups, respectively) and 6-keto-PGF1 alpha (r = 0.63 and 0.69 in the control and aprotinin groups, respectively). Compared with preoperative values, plasma atrial natriuretic peptide increased after weaning from CPB (+71% and +93% in the control and aprotinin groups, respectively). Aprotinin had no apparent adverse effect on renal function and it did not alter mechanisms involving prostanoids and atrial natriuretic peptide during cardiac surgery.

Background: Chronic uremia is responsible for secondary hyperparathyroidism (HPT II). Parathyroid secretion usually tends to normalize after kidney transplantation (KT), but the parameters of the reversibility of HPT II remain poorly defined, particularly the intrinsic mechanisms underlying the improvement of parathyroid function., Methods: The kinetic functional parameters of the ionized calcium (iCa)/parathormone (PTH) relationship curve were studied in 11 patients with mild to moderate HPT II one and six months after successful KT. Hypercalcemia and hypocalcemia were induced, respectively, by CaCl2 and Na2-ethylenediaminetetraacetic acid (Na2-EDTA) infusions., Results: The mean glomerular filtration rate remained stable during follow-up. Basal PTH decreased from 195 +/- 54 pg/ml before KT to 70 +/- 12 pg/ml six months later (P < 0. 005). During the tests, mean PTH levels decreased significantly between the two measured times for all iCa levels, indicating an improved parathyroid function. An analysis of the kinetic parameters of the curves showed significant decreases of the mean maximal and minimal PTH levels, respectively, from 340 +/- 91 to 220 +/- 30 pg/ml (P = 0.03) and from 25 +/- 6 to 15 +/- 5 pg/ml (P = 0.005). On the other hand, no change was noted in the parathyroid-cell calcium-sensitivity parameters (slope, set point) assessed using two different approaches, either the entire curve or the limited calcium-mediated suppression curve., Conclusion: Improvement of the parathyroid function between the first and sixth months post-KT seems mainly attributable to a reduction of the parathyroid functional mass.

Carotenoids and alpha-tocopherol are dietary, lipophilic antioxidants that may protect plasma lipoproteins from oxidation, a process believed to contribute to atherogenesis. Previous work demonstrated that after the Cu(II)-initiated oxidation of human low density lipoprotein (LDL) in vitro, carotenoids and alpha-tocopherol were destroyed before significant lipid peroxidation took place, and that alpha-tocopherol was destroyed at a much faster rate than were the carotenoids. Additionally, in vitro enrichment of LDL with beta-carotene, but not with lutein or lycopene, inhibited LDL oxidation. In the present studies the impact of LDL carotenoid and alpha-tocopherol content on LDL oxidation by human endothelial cells (EaHy-1) in culture was assessed. LDL isolated from 11 individual donors was incubated at 0.25 mg protein/mL with EaHy-1 cells in Ham's F-10 medium for up to 48 h. Formation of lipid hydroperoxides was assessed by chemical analysis and the contents of lutein, beta-cryptoxanthin, lycopene, beta-carotene and alpha-tocopherol were determined by high performance liquid chromatography. The extent of lipid peroxidation correlated with the endogenous alpha-tocopherol content of the LDL but not with its content of carotenoids. As in the Cu(II)-initiated system, carotenoids and alpha-tocopherol were destroyed before significant peroxidation took place, but, in the cell-mediated system, alpha-tocopherol and the carotenoids were destroyed at comparable rates. Also, like the Cu(II)-initiated oxidation, enrichment of the LDL with beta-carotene protected it from oxidation by the endothelial cells. However, enrichment with either lutein or lycopene actually enhanced the cell-mediated oxidation of the LDL. Thus, the specific content of carotenoids in low density lipoprotein (LDL) clearly modulates its susceptibility to oxidation, but individual carotenoids may either inhibit or promote LDL oxidation.

We have investigated patients undergoing cardiac surgery with hypothermic bypass to see if the addition of skin surface warming during systemic rewarming on bypass (heated group, n = 43) would improve perioperative thermal balance compared with conventional management without skin warming (control group, n = 43) in an open, randomized, controlled study. Intraoperative skin warming with a water mattress and forced warm air over the face, neck and shoulders attenuated the afterdrop in nasopharyngeal temperature after weaning from bypass (2.3 (1.2) degrees C and 1.3 (0.5) degrees C in the control and heated groups, respectively) (P < 0.05) and resulted in higher rectal temperature 4 h after surgery. Despite similar standard coagulation tests, heated patients had lower blood loss via the chest tubes (600 (264) ml vs 956 (448) ml in control patients) (P < 0.05) and less requirements for i.v. colloid infusion (1662 (404) ml vs 1994 (389) ml) (P < 0.05). There was a significant inverse correlation between rectal temperature on arrival in the ICU and postoperative blood loss (r = 0.57, P < 0.001). These data suggest that additional skin surface warming with a water mattress and forced warm air helped to preserve perioperative thermal balance and may contribute to reduced bleeding after cardiac surgery.

Oxysterols arising from the diet or through lipid peroxidation may be important in the modulation of cellular cholesterol metabolism. In this study, the metabolism of one of the oxysterols, 25-hydroxycholesterol (25OHC), was examined in J774 and mouse peritoneal macrophages. Uptake of 25OHC from serum was rapid and substantial. Esterification of the cellular 25OHC was also rapid as was hydrolysis of pre-formed esters. Like cholesterol, 25OHC was removed from cells by an extracellular acceptor such as high density lipoprotein. Unlike cholesterol, 25OHC was also rapidly and extensively removed from cells by serum albumin, but not by ovalbumin. The differential removal of oxysterols and cholesterol from cells by albumin allows separation of cellular effects due to oxysterols and cholesterol. In order to understand more about this differential efflux of sterols, a computer model for sterol mass transport in cells was used to compare intracellular trafficking of cholesterol and 25OHC. The rate constants determined by this model for movement of sterols between cytoplasm and plasma membrane were similar for both cholesterol and 25OHC, whereas those for esterification and ester hydrolysis as well as those for bidirectional movement between plasma membrane and extracellular medium were greater for 25OHC than for cholesterol. For both sterols, the rate-limiting step for removal of cellular esters appeared to be the rate of cytoplasmic ester hydrolysis. As 25OHC and cholesterol differ significantly in aqueous solubility, the similarity in their rate constants for movement between cytoplasm and plasma membrane is consistent with facilitation of transport between these two loci.

We studied 22 patients undergoing aortic surgery, allocated randomly to receive, before induction of anaesthesia, a single i.v. dose of enalapril 50 micrograms kg-1 or saline. During infrarenal aortic cross-clamping, we observed similar reductions in oxygen uptake in the two groups, despite greater systemic oxygen delivery in enalapril-treated patients; angiotensin-converting enzyme inhibition prevented the reduction in cardiac output and attenuated the decrease in glomerular filtration. Changes in glomerular filtration secondary to aortic clamping were related positively to changes in renal plasma flow (r = 0.83 (saline group) and r = 0.65 (enalapril group)). Creatinine clearance on the first day after operation was significantly higher in the enalapril compared with the saline group. We conclude that enalapril pretreatment is effective in improving systemic oxygen delivery, renal plasma flow and glomerular filtration during aortic abdominal surgery.

Oxysterols, oxidized derivatives of cholesterol, may enter the circulation as contaminants of cholesterol-containing food, arise through peroxidation of lipoproteins, or be generated by enzymatic reactions. They are found in serum associated either with lipoproteins or with albumin. In these studies, 25-hydroxycholesterol (25OHC) was used as a model oxysterol to investigate the effect of esterification on the association of oxysterols with serum components and their delivery to cultured cells. 25OHC added in vitro to fresh human serum was readily esterified during incubation at 37 degrees C, most likely by serum lecithin:cholesterol acyltransferase (LCAT) as it was blocked by known inhibitors of LCAT. The 25OHC-esters formed were identified as monoesters by comparing their elution on high performance liquid chromatography and thin-layer chromatography with that of chemically synthesized 25OHC mono- and diesters. Esterification doubled the percentage of 25OHC associated with lipoproteins, concomitantly decreasing the amount associated with albumin. Whereas unesterified 25OHC readily transferred between isolated lipoproteins, 25OHC-esters remained associated with donor lipoproteins unless human lipoprotein-deficient serum was added. That cholesteryl ester transfer protein (CETP) mediated transfer of 25OHC-esters was demonstrated by the ineffectiveness of rat lipoprotein-deficient serum as well as by the ability of IC-4, an anti-CETP monoclonal antibody, to suppress the transfer. Esterification of 25OHC in serum limited its entry into human erythrocytes and fibroblasts (GM 3468A cells) in vitro. Up-regulation of fibroblast low density lipoprotein (LDL)-receptors enhanced the uptake of esterified 25OHC from medium, but did little to enhance the total uptake of 25OHC. Thus, esterification of oxysterols in serum shifts their distribution away from albumin into LDL and high density lipoprotein (HDL) and limits their availability to cells in culture.

A 52 year-old man was hospitalised for acute renal failure with thrombocytopenia and hemolytic anemia without oliguria. A haemolytic-uremic syndrome was diagnosed and prostacyclin infusion was started. Twenty-four hours later, the renal function improved as well as thrombocytopenia and anemia. Recovery occurred after 11 days of treatment. Haemolytic-uremic syndrome treatment is not well codified: plasmaphoresis, fresh frozen plasma, transfusions showed inconstant efficiency and data about prostacycline treatment are rare and often contradictory. Multicentric studies must be started in order to determine the precise benefit of this treatment.

Carotenoids and alpha-tocopherol are dietary, lipophilic antioxidants which may protect plasma lipoproteins from oxidation, a process believed to contribute to atherogenesis. In this study, the quantities and distributions of carotenoids, alpha-tocopherol and major lipids in the plasma and lipoproteins of seven normolipidemic humans were determined. Experiments were also conducted to determine if these antioxidants redistribute among lipoproteins when plasma is incubated in vitro. Virtually all of the total carotenoid in plasma associated with lipoproteins, primarily LDL [73 +/- 10% (mean +/- SD)], as did the more non-polar individual carotenoids, beta-cryptoxanthin (68 +/- 9%); lycopene (79 +/- 9%), and beta-carotene (72 +/- 12%), in patterns which closely resembled the distribution of total cholesterol. Xanthophyll, the most polar carotenoid examined, distributed equally between LDL (44 +/- 11%) and HDL (38 +/- 14%), whereas alpha-tocopherol associated with LDL (43 +/- 12%), HDL (26 +/- 10%), and VLDL (27 +/- 13%). These patterns closely resembled that of phospholipid. Approximately four carotenoid molecules associated with each VLDL and one with each LDL particle, whereas only 25 of every 1000 HDL particles contained carotenoid. Approximately 145 molecules of alpha-tocopherol associated with VLDL, 12 with LDL, and one with each HDL particle. Unlike triglyceride and cholesteryl ester, known to transfer among lipoproteins through the action of cholesteryl ester transfer protein, net transfer of carotenoids and alpha-tocopherol among lipoproteins did not occur.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of oxysterols on efflux of cholesterol from mouse L-cell fibroblasts, rat Fu5AH hepatoma cells, J774 macrophages, and human EA.hy 926 endothelial cells was studied. Cells were preincubated with 25-hydroxycholesterol (25-OHC) either during labeling of the cells with [3H]cholesterol or during equilibration after labeling. Subsequently, the release of [3H]cholesterol into medium containing 0.2 mg HDL3/ml was measured and the fractional release of cellular [3H]cholesterol was calculated. Pretreatment with 25-OHC (1 microgram/ml) caused a 30% reduction in [3H]cholesterol efflux from L-cells during 8 h of incubation with HDL3. 25-OHC also inhibited cholesterol efflux from Fu5AH and J774 cells, but the effect was less marked. There was only a small, nonsignificant reduction of efflux from EA.hy 926 cells. The mechanisms of 25-OHC-induced inhibition of cellular cholesterol efflux was further studied in L-cells, because of their sensitivity to 25-OHC treatment. The effect of 25-OHC on cholesterol efflux was dose-dependent, with significant effects seen at 25-OHC concentrations as low as 50 ng/ml. The half-time for cholesterol efflux from 25-OHC-treated cells (5 micrograms/ml) was 13.0 +/- 3.3 h compared to 5.7 +/- 1.0 in control cells, corresponding to a 55% reduction in the rate of cholesterol release. Other oxysterols, including 7-ketocholesterol, 7 alpha- and 7 beta-hydroxycholesterol, and 22(S)-hydroxycholesterol also inhibited [3H]cholesterol efflux from L-cells significantly, but to a lesser degree. 25-Hydroxycholesterol (5 micrograms/ml) reduced efflux from both normal and cholesterol-enriched cells by 31 and 14%, respectively. Inhibition of efflux was similar when reconstituted HDL3-apolipoprotein/phosphatidylcholine particles or small unilamellar phosphatidylcholine vesicles were used as cholesterol acceptors instead of HDL3. The content of phospholipids, cholesterol and the FC/PL ratio of intact cells and from isolated plasma membrane vesicles were the same for control and 25-OHC-treated cells. Efflux of [3H]cholesterol from plasma membranes isolated from 25-OHC-treated cells was 20% less than efflux from membranes from control cells. The difference in efflux observed in intact cells is partially explained by the reduction in efflux from the plasma membrane. In conclusion, our studies suggest that oxysterols, especially 25-hydroxycholesterol, can reduce cellular cholesterol efflux in vitro. Therefore oxysterols, either endogenous or derived from the diet, may influence cellular cholesterol efflux in vivo, the first step in reverse cholesterol transport.

New Zealand White rabbits were made hypercholesterolemic by feeding a high cholesterol diet (10 g/kg diet) with or without added antioxidants. The antioxidants used were either probucol (10 g/kg) or vitamin E (10 g/kg) plus vitamin C (0.6 g/kg). Serum cholesterol concentrations were monitored as a function of time. At the end of 10 wk, serum and lipoprotein vitamin E concentrations, the extent of oxidation of lipoprotein fractions (thiobarbituric acid reacting substances), the susceptibility of lipoprotein to oxidation in vitro (conjugated diene formation) and the extent of atherosclerosis (aortic area stained by Sudan IV and plaque thickness) were measured. Rabbits fed diets supplemented with vitamins E and C had markedly higher serum vitamin E concentrations, marked vitamin E enrichment in all lipoprotein fractions, less oxidation in VLDL and LDL and enhanced resistance of LDL to further in vitro oxidation, but did not have significantly less aortic atherosclerosis. Rabbits given supplemental probucol likewise exhibited reduced oxidation of lipoproteins. However, aortic atherosclerosis in these animals was significantly lower, as were serum cholesterol concentrations. Inhibition of lipoprotein oxidation itself was not sufficient to reduce atherosclerosis in cholesterol-fed New Zealand White rabbits.

Mild oxidation (< 6h) of human high density lipoprotein (HDL) induced by incubation with copper ions increased its thiobarbituric acid reactivity, decreased its phospholipid content, increased its free cholesterol to phospholipid ratio and reduced its ability to mediate cholesterol efflux from cells. While protein modification did occur with further oxidation (> 12h), diminished efflux of cell cholesterol was apparent for HDL samples without increased electrophoretic mobility or altered apolipoproteins. Thus, reduced cholesterol efflux to mildly oxidized HDL may reflect changes in its lipids rather than its apoproteins. By limiting cholesterol removal from cells, any mild oxidation of HDL which might occur in vivo could contribute to cellular cholesterol accumulation.

We have studied postoperative analgesia and unwanted side effects of a single dose of a mixture of morphine and sufentanil administered extradurally with the effects produced by extradural injection of each opioid alone in 64 patients after Caesarean delivery. The patients were allocated randomly to receive morphine 4 mg (n = 21), sufentanil 50 micrograms (n = 22) or morphine 2 mg with sufentanil 25 micrograms (n = 21) via an extradural catheter in a double-blind design. Intensity of pain was measured using a linear visual analogue scale. Compared with the effect produced by morphine alone, the morphine-sufentanil combination produced more rapid onset of pain relief (19 (SD 5) min vs 79 (23) min for a 75% reduction of pain; P less than 0.01), whereas the duration and quality of analgesia assessed during 12 h was similar for these two groups. In contrast, patients receiving sufentanil alone required significantly more supplementary analgesia 4 h after administration than with morphine alone or morphine combined with sufentanil. There were no significant changes in cardiorespiratory variables in any group. Side effects consisted mainly of pruritus and nausea and did not differ between groups, with the exception of early and transient dizziness which was observed only in patients given sufentanil either alone or in combination with morphine. We conclude that a single extradural injection of morphine and sufentanil combines the short onset time produced by sufentanil and the long duration of analgesia attributable to morphine, thus providing excellent and prolonged analgesia after Caesarean delivery.

Inadequate tissue oxygenation may occur in critically ill patients with sepsis despite an apparently adequate O2 transport (QO2), and this may contribute to the development of an O2 debt and also to multiple organ failure. It has been shown that increasing QO2 by infusing a vasodilator may reveal this O2 debt in septic patients. To investigate whether the site of action of vasodilators may be of importance in unmasking such an O2 debt, we administered prostacyclin, a prostaglandin with a preferential effect on the microcirculation, and phentolamine, an arteriolar vasodilator, in 11 patients studied during the first 48 hours after the onset of sepsis, and compared their effect on whole body oxygen consumption (VO2) and skin microvascular blood flow. The results demonstrated that increasing QO2 by prostacyclin but not by phentolamine significantly increases VO2 in critically ill patients with sepsis. The site of action of vasodilators may therefore play an important role in their ability to unmask an O2 debt.

We have studied five pigs undergoing bilateral clamping of the renal pedicles, seven pigs undergoing orthotopic liver transplantation and three control animals without surgery in order to examine the roles of the kidney and liver in the plasma clearance of pipecuronium. An i.v. infusion of pipecuronium was controlled to maintain a constant 90-95% twitch depression throughout the investigation. The right sciatic nerve was stimulated continuously with supramaximal stimuli at 0.1 Hz and the force of the corresponding evoked isometric muscle contraction was recorded continuously. Control pigs needed an infusion rate of pipecuronium 8-10.7 micrograms kg-1 min-1. In the renal group, it was necessary to reduce the infusion rate of pipe-curonium by about 25% after clamping both renal vascular pedicles (P less than 0.05 compared with controls); in pigs undergoing liver transplantation, it was necessary to reduce the rate by approximately 80% after clamping hepatic vessels (P less than 0.05 compared with controls and from the period after clamping of renal vessels). After hepatic recirculation, the infusion rate of pipecuronium was increased progressively to a rate which corresponded to 50% of baseline values (P less than 0.05 compared with the anhepatic phase and from controls). Plasma concentrations of pipecuronium were comparable in the three animal groups and did not change significantly during the study. These data suggest that the liver plays a more important role than the kidney in the plasma clearance of pipecuronium in pigs.

To determine if functional residual capacity (FRC), compliance of the respiratory system (C), or underlying pulmonary disease are predictive for the efficacy of high frequency jet ventilation (HFJV) on pulmonary gas exchange, we investigated six adult patients within 4 h of abdominal surgery and six patients with severe adult respiratory distress syndrome. Gas exchange during intermittent positive pressure ventilation (IPPV) was compared with that during HFJV at frequencies of 100 b.p.m. (HFJV100) and 200 b.p.m. (HFJV200), resulting in a minute ventilation of about 400 ml kg-1 with both ventilatory frequencies, and in both groups of patients. Baseline FRC and C were measured during IPPV with the multiple-breath nitrogen washout method and from expiratory pressure-volume curves, respectively. Changes in the alveolar-arterial oxygen difference (PAO2 - PaO2): FIO2 ratio induced by HFJV correlated negatively with C (HFJV100: r = -0.78, P less than 0.005; HFJV200: r = -0.84, P less than 0.005); that is, greater oxygenation was obtained in patients with a better compliance. Similarly, changes in arterial partial pressure of carbon dioxide (PaCO2) induced by HFJV correlated negatively with C (HFJV100: r = -0.77, P less than 0.001; HFJV200: r = -0.61, P less than 0.05). In contrast, there was no significant correlation between FRC measured during IPPV and changes in (PAO2 - PaO2): FIO2 ratio or PaCO2 induced by HFJV, as these changes were influenced more by the patient's pulmonary disease than by baseline FRC. These results should be interpreted in the context of different underlying pathophysiological mechanisms reducing FRC in both groups of patients.

The cardiovascular effects of incremental fixed i.v. doses of labetalol were evaluated in 10 normovolaemic sedated patients presenting with hypertension and tachycardia in the early period after myocardial revascularization. At first dose of 20 mg was sufficient to provoke a significant (P less than 0.01) mean decrease in systolic (-9.3%), diastolic (-8.2%) and mean arterial (-7.9%) pressure (AP) and in the rate-pressure product (RPP) (-13.1%). The mean heart rate (HR) did not change significantly, but a linear correlation could be established between the change at 2 min and the value before injection (r = 0.73). A second dose of labetalol 40 mg given 5 min later did not decrease AP further, but a significant decrease in HR was noted. A marked difference in the individual response among patients was found as the range of effective total doses per kg body weight was 0.6-4.1 mg kg-1 (mean 2.2) Apart from one patient, no patient needed vagolytic or sympathomimetic drugs to oppose the alpha or beta actions of labetalol during the 24-h follow-up period.

Low density lipoprotein (LDL) has been reported to be injurious or toxic to cells in vitro. This injurious effect is, in some instances, due to oxidation of the lipid moiety of the lipoprotein. The objectives of this study were to determine if the oxidation rendering the lipoprotein toxic to human skin fibroblasts occurred by free radical mechanisms, and if so, which of the common free radical oxygen species were involved. The selective free radical blockers or scavengers employed included superoxide dismutase for superoxide, catalase for hydrogen peroxide, dimethylfuran for singlet molecular oxygen, and mannitol for hydroxyl radical. The presence during lipoprotein preparation of general free radical scavengers (vitamin E, butylated hydroxytoluene) or the divalent cation chelator ethylenediamine tetraacetic acid prevented the formation of cytotoxic low density lipoprotein, while the simultaneous presence of superoxide dismutase and catalase partially inhibited its formation. The results indicate that superoxide and/or hydrogen peroxide are involved in the formation of the toxic LDL lipid. The toxic action of oxidized LDL could not be prevented by inclusion of antioxidants in the culture medium, indicating that an oxidized lipid was responsible for cell injury rather than free radicals generated in culture by the action of oxidized LDL. Three separate assays for cell injury (enumeration of attached cells, cell loss of lactate dehydrogenase into the culture medium, and trypan blue uptake) indicated a sequence of events in which the fibroblasts are injured, die, and then detach.

Increased lipid peroxidation products were detected in a lipoprotein fraction containing very low density lipoprotein (VLDL) and low density lipoprotein (LDL) obtained from rats made diabetic by streptozotocin injection. The enhanced oxidation in the diabetic VLDL plus LDL fraction correlated with the in vitro toxicity of this lipoprotein fraction to proliferating fibroblasts. In contrast, high density lipoprotein (HDL) was not cytotoxic. That the increased oxidation and development of cytotoxic activity in the diabetic VLDL + LDL was related to the diabetes was shown by the fact that insulin treatment of diabetic animals inhibited both oxidation and cytotoxicity of VLDL + LDL. In contrast, treatment of diabetic rats with the antioxidants vitamin E or probucol after diabetes was established also inhibited both the in vivo oxidation and in vitro cytotoxicity of diabetic VLDL + LDL, but without altering hyperglycemia. Vitamin E or probucol treatment thus allowed separation of the oxidation process from the hyperglycemia occurring in experimental diabetes. The mechanisms by which diabetes in humans or experimental animals leads to the various manifestations of tissue damage are unknown; however, these studies demonstrate for the first time that a relationship exists between the in vivo oxidation of lipoproteins in diabetes and the potential for tissue damage as monitored by in vitro cytotoxicity. Furthermore, these results suggest that the mechanism for certain aspects of tissue damage accompanying experimental diabetes may be mediated by lipid peroxidation products.

Metal phosphorothioates are titrated in acetone, acetonitrile and dimethylformamide with potassium hydroxide, with potentiometric detection. They can be titrated in the presence of the corresponding phosphorothioic acids in the dimethylformamide.

A study was carried out to see whether the administration of a small dose of midazolam determined a reduction of the dose of fentanyl necessary for induction of anaesthesia. Sixteen patients undergoing coronary artery bypass surgery were randomly allocated to either of two groups. Patients in group M received 0.075 mg.kg-1 midazolam intravenously 3 to 5 min prior to induction with fentanyl (5 micrograms.kg-1.min-1), whereas patients in group P only received placebo. The mean dose of fentanyl administered to obtain complete loss of reaction to a painful stimulus was 20 +/- 3 micrograms.kg-1 in group M and 21.5 +/- 2.5 micrograms.kg-1 in group P (NS). However the small dose of midazolam associated with fentanyl caused a significant drop in blood pressure by 20%. After the administration of pancuronium (0.15 mg.kg-1), the patients in group P showed a significant increase in heart rate (+ 14 b.min-1), accompanied by an increase in cardiac index (+0.45 l.min-1.m-2). Pretreatment with midazolam seemed to protect the patient from this undesirable reaction. It was concluded that induction with a combination of a small dose of midazolam and fentanyl did not lead to a reduction in the dose of fentanyl necessary to obtain profound analgesia. However, it gave rise to a haemodynamic pattern quite distinct from that seen during induction with fentanyl alone.

Assessing pulmonary function in critically ill patients is difficult, mainly because of lack of cooperation, artificial ventilation and jeopardized vital functions. We describe bedside methods and mobile equipment used to measure lung volumes, static pulmonary and thoracic compliance. The analysis of single and multiple-breath nitrogen washout curves allows an estimation of closing volume and an assessment of the inhomogeneity of ventilation. The use of a microcomputer facilitates recording, calculation, reproduction and classification of the data; it also permits the collection of more information in a shorter time, allowing the adjustment of mechanical ventilation to the underlying pulmonary disease.