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Biomedical subjects

J M Mayer

Publications and source records attributed to J M Mayer.

At least 19 recordsLinked to original sources
PubMed2006

Antiproliferative and overadditive effects of everolimus and mycophenolate mofetil in pancreas and lung cancer cells in vitro.

BACKGROUND: Everolimus inhibits the growth of several tumor cell lines in vitro as well as tumor growth in a rat model. Mycophenolate mofetil (MMF) inhibits growth of a Walker sarcoma in a rat model in vivo. Herein we tested the in vitro antiproliferative capacity of everolimus and MMF on a pancreatic tumor cell line Panc-1 and on a small cell lung cancer cell line ScLc. MATERIALS AND METHODS: Cells were cultured under standardized conditions. Everolimus was added in increasing doses from 0.005 to 500 microg/mL; MMF was used from 0.05 to 5000 microg/mL. For co-incubation experiments, we combined everolimus (0.005 microg/mL and 0.05 microg/mL) with five concentrations of MMF; and MMF (0.5 microg/mL and 5 microg/mL) with five concentrations of everolimus. The antiproliferative capacity was assessed by a BrdU incorporation assay. RESULTS: Everolimus and MMF inhibited BrdU incorporation into Panc-1 and ScLc in a dose-dependent fashion. A 50% inhibition was seen in Panc-1 only at 50 microg/mL everolimus, but in ScLc at 5 microg/mL everolimus. MMF was clearly more potent in Panc-1: 50% inhibition was observed at 5 microg/L. In ScLc, 40% inhibition of BrdU incorporation was seen only at 50 microg/L MMF. In co-incubation, an effective combination for both Panc-1 and ScLc was 5 microg/mL MMF with 0.005 microg/mL everolimus resulting in 50% inhibition of BrdU incorporation (P < .001). CONCLUSIONS: Everolimus and MMF showed dose-dependent antiproliferative effects in tumor cell lines in vitro both alone and in combination. The combined use of everolimus and MMF showed supra-additive effects at concentrations used for therapeutic immunosuppression in patients.

Animals↗
PubMed2004

Pseudo-thermosetting chitosan hydrogels for biomedical application.

To prepare transparent chitosan/beta-glycerophosphate (betaGP) pseudo-thermosetting hydrogels, the deacetylation degree (DD) of chitosan has been modified by reacetylation with acetic anhydride. Two methods (I and II) of reacetylation have been compared and have shown that the use of previously filtered chitosan, dilution of acetic anhydride and reduction of temperature in method II improves efficiency and reproducibility. Chitosans with DD ranging from 35.0 to 83.2% have been prepared according to method II under homogeneous and non-homogeneous reacetylation conditions and the turbidity of chitosan/betaGP hydrogels containing homogeneously or non-homogeneously reacetylated chitosan has been investigated. Turbidity is shown to be modulated by the DD of chitosan and by the homogeneity of the medium during reacetylation, which influences the distribution mode of the chitosan monomers. The preparation of transparent chitosan/betaGP hydrogels requires a homogeneously reacetylated chitosan with a DD between 35 and 50%.

Biomedical Technology↗
PubMed2004

Pseudo-thermosetting chitosan hydrogels for biomedical application.

To prepare transparent chitosan/beta-glycerophosphate (betaGP) pseudo-thermosetting hydrogels, the deacetylation degree (DD) of chitosan has been modified by reacetylation with acetic anhydride. Two methods (I and II) of reacetylation have been compared and have shown that the use of previously filtered chitosan, dilution of acetic anhydride and reduction of temperature in method II improves efficiency and reproducibility. Chitosans with DD ranging from 35.0 to 83.2% have been prepared according to method II under homogeneous and non-homogeneous reacetylation conditions and the turbidity of chitosan/betaGP hydrogels containing homogeneously or non-homogeneously reacetylated chitosan has been investigated. Turbidity is shown to be modulated by the DD of chitosan and by the homogeneity of the medium during reacetylation, which influences the distribution mode of the chitosan monomers. The preparation of transparent chitosan/betaGP hydrogels requires a homogeneously reacetylated chitosan with a DD between 35 and 50%.

Biomedical Technology↗
PubMed2004

Structure and interactions in chitosan hydrogels formed by complexation or aggregation for biomedical applications.

The aim of this review was to provide a detailed overview of physical chitosan hydrogels and related networks formed by aggregation or complexation, which are intended for biomedical applications. The structural basis of these systems is discussed with particular emphasis on the network-forming interactions, the principles governing their formation and their physicochemical properties. An earlier review discussing crosslinked chitosan hydrogels highlighted the potential negative influence on biocompatibility of covalent crosslinkers and emphasised the need for alternative hydrogel systems. A possible means to avoid the use of covalent crosslinkers is to prepare physical chitosan hydrogels by direct interactions between polymeric chains, i.e. by complexation, e.g. polyelectrolyte complexes (PEC) and chitosan/poly (vinyl alcohol) (PVA) complexes, or by aggregation, e.g. grafted chitosan hydrogels. PEC exhibit a higher swelling sensitivity towards pH changes compared to covalently crosslinked chitosan hydrogels, which extends their potential application. Certain complexed polymers, such as glycosaminoglycans, can exhibit interesting intrinsic properties. Since PEC are formed by non-permanent networks, dissolution can occur. Chitosan/PVA complexes represent an interesting alternative for preparing biocompatible drug delivery systems if pH-controlled release is n/ot required. Grafted chitosan hydrogels are more complex to prepare and do not always improve biocompatibility compared to covalently crosslinked hydrogels, but can enhance certain intrinsic properties of chitosan such as bacteriostatic and wound-healing activity.

Biocompatible Materials↗
PubMed2004

Structure and interactions in covalently and ionically crosslinked chitosan hydrogels for biomedical applications.

This review presents a critical analysis of covalently and ionically crosslinked chitosan hydrogels and related networks for medical or pharmaceutical applications. The structural basis of these hydrogels is discussed with reference to the specific chemical interactions, which dictate gel formation. The synthesis and chemistry of these hydrogels is discussed using specific pharmaceutical examples. Covalent crosslinking leads to formation of hydrogels with a permanent network structure, since irreversible chemical links are formed. This type of linkage allows absorption of water and/or bioactive compounds without dissolution and permits drug release by diffusion. pH-controlled drug delivery is made possible by the addition of another polymer. Ionically crosslinked hydrogels are generally considered as biocompatible and well-tolerated. Their non-permanent network is formed by reversible links. Ionically crosslinked chitosan hydrogels exhibit a higher swelling sensitivity to pH changes compared to covalently crosslinked chitosan hydrogels. This extends their potential application, since dissolution can occur in extreme acidic or basic pH conditions.

Biomedical Technology↗
PubMed2004

Pancreas graft thrombosis: is there a role for trypsin.

PURPOSE: Thrombosis of the pancreas graft is the main cause of early graft loss in pancreas transplantation. We investigated whether hypercoagulability develops locally in the pancreas and contributes to thrombosis formation because of ischemia or reperfusion injury. It was further hypothesized that this might be induced by excessive intravascular trypsin activity. METHODS: Ten Patients undergoing pancreas transplantation were studied. In addition to the standard operation a 14 French catheter was inserted in the distal part of the splenic vein of the pancreas graft. After reperfusion blood samples were drawn simultaneously from the splenic vein of the pancreas graft (local samples) and the radial artery (systemic samples) at 0,1,2,5,10,30, and 60 minutes after reperfusion. RESULTS: After reperfusion a progressive hypercoagulability developed locally in the pancreas as seen by an increase of thrombin-antithrombin complexes and only a transient increase of plasmin-antiplasmin complexes. In addition antithrombin 3 and protein c decreased systemically. The alterations seem not to be triggered by trypsin because trypsin activity locally remained low despite trypsinogen release and activation as assessed by trypsinogen activation peptides. CONCLUSION: Local hypercoagulability might contribute to the development of graft thrombosis, however, the mechanism seems not to be related to ectopic trypsin activation.

Antithrombins↗
PubMed2002

Serum amyloid A is a better early predictor of severity than C-reactive protein in acute pancreatitis.

BACKGROUND: Serum amyloid A (SAA) is an early and sensitive marker of the extent of tissue trauma and inflammation. The aim of this study was to compare the early prognostic accuracy of SAA with that of serum C-reactive protein (CRP) in acute pancreatitis. METHODS: In a prospective multicentre trial, plasma SAA and CRP levels were measured in patients with severe and mild acute pancreatitis, and in a control group with acute abdominal pain. Plasma samples were collected on admission and at 6-h intervals for 48 h, every 12 h between 48 and 72 h, then daily for 5 days. Plasma SAA was measured by a new enzyme-linked immunosorbent assay and CRP was measured by immunoturbidometry. RESULTS: There were 137 patients with mild and 35 with severe acute pancreatitis, and 74 control patients. SAA levels were significantly higher in patients with severe acute pancreatitis than in those with mild acute pancreatitis, on admission, at 24 h or less after symptom onset, and subsequently. Whereas plasma CRP concentration was also significantly higher in patients with severe acute pancreatitis on admission, it failed to distinguish mild from severe acute pancreatitis until 30-36 h after symptom onset. SAA levels predicted severity (sensitivity 67 per cent, specificity 70 per cent, negative predictive value 89 per cent, mean(s.d.) area under curve 0.7(0.05)) significantly better than CRP (57 per cent, 60 per cent, 84 per cent, 0.59(0.06) respectively) on admission (P = 0.02) and at 24 h following symptom onset (area under curve 0.65(0.09) versus 0.58(0.09) respectively; P < or = 0.02). CONCLUSION: Plasma SAA concentration is an early marker of severity in acute pancreatitis and is superior to CRP estimation on hospital admission and at 24 h or less after symptom onset. This study suggests that plasma SAA concentration is clinically useful, with the potential to replace CRP in the management of acute pancreatitis.

Abdominal Pain↗
PubMed2001

Application of the Marcus cross relation to hydrogen atom transfer reactions.

The transfer of a hydrogen atom-a proton and an electron-is a fundamental process in chemistry and biology. A variety of hydrogen atom transfer reactions, involving iron complexes, phenols, hydroxylamines, tBuOOH, toluene, and related radicals, are shown to follow the Marcus cross relation. Thus, the Marcus theory formalism based on ground-state energetics and self-exchange rates, originally developed for electron transfer processes, is also valuable for hydrogen atom transfer. Compounds that undergo slow proton transfer (C-H bonds) or slow electron transfer (cobalt complexes) also undergo slow hydrogen atom transfer. Limitations of this approach are also discussed.

Chemical Phenomena↗
PubMed2001

Protonation and deprotonation of TpOs(NHPh)Cl(2): an unusually inert amido ligand.

Protonation of the Os(IV) amido complex TpOs(NHPh)Cl(2) (1) to give the aniline complex [TpOs(NH(2)Ph)Cl(2)]OTf (2) requires excess triflic acid (HOTf). Complex 1 is unreactive with HCl and other moderately strong acids. Consistent with the low basicity of 1, the aniline complex 2 is extremely acidic and is deprotonated by stoichiometric addition of weak bases such as Cl(-) or H(2)O. No reaction is observed between 1 and methyl triflate (CH(3)OTf) at ambient temperatures. Upon heating, CH(3)OTf removes the chloride ligands from 1 to give CH(3)Cl and the amidobis(triflate) complex TpOs(NHPh)(OTf)(2) (3). Attack at the amido nitrogen is not observed. Complex 1 is thus very inert to protonation and electrophilic attack at nitrogen. A deprotonated form of 1, TpOs[NPh(MgBr)]Cl(2) (4), is generated on reaction of PhMgBr with TpOs(N)Cl(2). Complex 4 is extremely basic and will protonate to 1 with weak acids such as CH(3)CN, DMSO, and acetic anhydride. Thus, 1 has a low acidity as well as a low basicity; it is both less acidic and less basic than aniline. The inertness of 1 is ascribed to partial Os-N pi bonding and to the oxidizing nature of the Os(IV) center.

Journal Article↗
PubMed2001

C--N bond formation on addition of aryl carbanions to the electrophilic nitrido ligand in TpOs(N)Cl(2).

The osmium(VI) nitrido complex TpOs(N)Cl(2) (1) has been prepared from K[Os(N)O(3)] and KTp in aqueous ethanolic HCl. It reacts rapidly with PhMgCl and related reagents with transfer of a phenyl group to the nitrido ligand. This forms Os(IV) metalla-analido complexes, which are readily protonated to give the analido complex TpOs(NHPh)Cl(2) (4). The nitrido-phenyl derivatives TpOs(N)PhCl and TpOs(N)Ph(2) react more slowly with PhMgCl and are not competent intermediates for the reaction of 1 with PhMgCl. Reactions of 1 with alkyl- and arylboranes similarly result in transfer of one organic group to nitrogen, leading to isolable borylamido complexes such as TpOs[N(Ph)(BPh(2))]Cl(2) (11). This is an unprecedented insertion of a nitrido ligand into a boron--carbon bond. Hydrolysis of 11 gives 4. Mechanistic studies suggest that both the Grignard and borane reactions proceed by initial weak coordination of Mg or B to the nitrido ligand, followed by migration of the carbanion to nitrogen. The hydrocarbyl group does not go to osmium and then move to nitrogen--there is no change in the atoms bound to the osmium during the reactions. It is suggested that there may be a general preference for nucleophiles to add directly to the metal--ligand multiple bond rather than binding to the metal first and migrating. Ab initio calculations show that the unusual reactivity of 1 results from its accessible LUMO and LUMO + 1, which are the Os = N pi* orbitals. The bonding in 1 and its reactivity with organoboranes are reminiscent of CO.

Journal Article↗
PubMed2001

The esterase-like activity of serum albumin may be due to cholinesterase contamination.

PURPOSE: The "esterase-like activity" of human serum albumin (HSA) is described in the literature, but a contamination of commercially available HSA preparations by plasma cholinesterase is conceivable in some cases. The purpose of the present work was to examine this hypothesis. METHODS: The hydrolytic activity of HSA and its inhibition by physostigmine were measured fluorimetrically by monitoring the hydrolysis of the ester substrate moxisylyte. Affinity chromatography was used to separate cholinesterase and HSA. The cholinesterase activity in the eluted fractions was assessed using Ellman's reagent and butyrylthiocholine as substrate. RESULTS: A significant variation in the esterase-like activity of different albumin batches was observed. This activity was strongly inhibited by physostigmine, a well-known inhibitor of cholinesterase. Affinity chromatography led to a complete separation between HSA and the esterase activity, which was found exclusively in the cholinesterase fraction. CONCLUSIONS: The apparent esterase-like activity of HSA toward moxisylyte and butyrylthiocholine was due to a contamination by cholinesterase. With these substrates, HSA showed a total lack of esterase-like activity.

Butyrylcholinesterase↗
PubMed2001

Clinical relevance of caspase-1 activated cytokines in acute pancreatitis: high correlation of serum interleukin-18 with pancreatic necrosis and systemic complications.

OBJECTIVES: There is recent experimental evidence that caspase-1 activation plays an instrumental role in the pathomechanism of severe acute pancreatitis. Besides interleukin-1beta, interleukin-18, a recently described proinflammatory cytokine, is cleaved into its biologically active form by caspase-1 as well. Interleukin-18 is known to have potent properties concerning the activation of the Th1-lymphocyte subset via costimulation of interferon-gamma production. In contrast to interleukin-1beta, little is known about the clinical impact of interleukin-18 in the course of acute pancreatitis. DESIGN: Cohort study comparing patients with mild and severe acute pancreatitis associated with local and systemic complications during the course of the disease. SETTING: Surgical and anesthesiological intensive care unit as well as wards of the department of general surgery. PATIENTS: We included 68 patients with acute pancreatitis in the present study. In terms of local complications, pancreatic necrosis was present in 37 patients, of whom 21 developed pancreatic infections. Systemic complications included pulmonary, renal, or cardiocirculatory insufficiency and were observed in 40, 18, and 25 patients, respectively. Severe multiple-organ dysfunction syndrome involving all three organ systems occurred in 18 patients, all suffering from pancreatic necrosis. INTERVENTIONS: Serum samples were collected over 14 consecutive days after study inclusion. Ascites or peripancreatic exudate was obtained by ultrasound-guided fine needle aspiration in 14 cases. Sera and local aspirates were stored at -70 degrees C until analysis. MEASUREMENTS AND RESULTS: Interleukin-18 and interferon-gamma were measured by commercially available enzyme-linked immunosorbent assays. Interleukin-18 concentrations were significantly increased after the fourth day of disease onset until the end of the observation period in patients who developed pancreatic necrosis and systemic complications such as pulmonary, renal, and cardiocirculatory failure as well as severe multiple-organ dysfunction syndrome. However, no correlation was found between the development of pancreatic infections and interleukin-18 concentrations. In contrast with interleukin-18, interferon-gamma concentrations did not show any significant difference with respect to the presence or absence of either systemic or local complications. Local interleukin-18 concentrations in ascites or peripancreatic exudate were up to 20-fold higher than systemic concentrations, whereas interferon-gamma concentrations did not differ. CONCLUSIONS: Serum interleukin-18 concentrations are significantly elevated in patients with acute pancreatitis complicated by pancreatic necrosis and remote organ failure. The present data suggest an important role of caspase-1 dependent cytokine activation in the pathomechanism of severe acute pancreatitis beyond the experimental setting. In this context, interleukin-18 may serve as a potential target for new therapeutic approaches.

APACHE↗
PubMed2001

Reduced serum total reductive capacity in lethal severe trauma.

BACKGROUND: Risk assessment is a prerequisite for effective treatment and triage in severe injury. A novel substrate-based assay to measure total reductive capacity (TORC) in serum was used to stratify risk of lethal outcome in severe trauma in a clinical trial. METHODS: Serum of patients with severe trauma (Injury Severity Score > 19) was obtained at the accident site, at admission, and at regular intervals thereafter. TORC was determined and correlated to outcome. The TORC assay uses thiol-labeled arachidonic acid as substrate from which free thiols are released by reductive amino acids and the specific activity of phospholipase A2. Free thiols are coupled to monochrombimone, and the resulting fluorescence is proportional to TORC. RESULTS: Eighteen patients with lethal severe trauma and 16 patients who survived were studied. Injury Severity Scores (lethal, 33 (29--43); survival, 31 (25--42); p = NS) and Polytrauma Scores (lethal, 25 [18--32]; survival, 26 [23--31], p = NS) were not significantly different. At the accident site, patients with a lethal course had significantly lower TORC than nonlethal cases (59.2 +/- 5.1 ng/mL vs. 89.5 +/- 6.7 ng/mL; p < 0.001). Values at admission were similar (lethal, 51.2 +/- 7 ng/mL; survival, 73.8 +/- 9 ng/mL; p < 0.01). At the accident site and at admission, TORC < 82.3 ng/mL was prognostic of lethal outcome (sensitivity, 88%; specificity, 65%/73% and 69%, respectively, for admission). CONCLUSION: Serum reductive potential at the site of accident or at admission allows the stratification of trauma patients with respect to lethal outcome in severe trauma when severity scores fail to do so.

Adolescent↗
PubMed2001

[A comparative study of the ocular tolerance of 3 timolol-based preparations: the influence of preservatives on ocular tolerance].

PURPOSE: Ophthalmic preparations can cause toxic ocular reactions, often associated with the use of preservatives. The aim of this study was to compare the ocular tolerance of three ophthalmic preparations based on timolol: a preservative free ophthalmic preparation (Timabak) and two other commercially available preserved preparations (Timoptol) and Timoptol LP). METHODS: The effect of repeatedly instilling eye drops for 28 days on rabbit eyes was assessed in vivo by mean of a confocal laser scanning ophthalmoscope. The corneal microlesions were selectively marked by fluorescein. RESULTS AND CONCLUSION: The overall results show the good ocular tolerance of the three tested products. However, a closer comparison between the products brought out differences in the extent of lesions among the tested products depending on their composition. Indeed the preservative free eye drops appeared better tolerated than the two preserved preparations.

Adrenergic beta-Antagonists↗
PubMed2000

Application of in vivo confocal microscopy to the objective evaluation of ocular irritation induced by surfactants.

An ocular irritation test using confocal laser scanning ophthalmoscopy has been developed in which corneal lesions subsequent to instillation of surfactants are specifically marked by fluorescein and assessed by digital image processing. The sum of the observed fluorescent corneal areas is taken into account as an endpoint of ocular irritation. Eight currently used nonionic, cationic and anionic surfactants were applied onto the cornea of rabbits and mice, four times per day during 3 days at various concentrations. Benzalkonium chloride, a cationic surfactant, at a concentration range of 0.01-0.5%, was tested in the same manner. The cornea was evaluated in vivo for ocular tolerance by confocal microscopy. In both rabbits and mice, the test revealed following irritation rankings: cationic>anionic>nonionic surfactants. Furthermore, in both animal models, the ocular damage increased with the concentration of benzalkonium. The test was sensitive enough to detect ocular microlesions at concentrations of surfactants as low as 0.01% for benzalkonium. These findings demonstrate the usefulness of confocal microscopy for the non-invasive, in situ evaluation of ocular tolerance.

Animals↗
PubMed2000

Early prediction of severity in acute pancreatitis by urinary trypsinogen activation peptide: a multicentre study.

BACKGROUND: There is a pressing clinical requirement for an early simple test of severity in acute pancreatitis. We investigated the use of an assay of trypsinogen activation peptide (TAP). METHODS: We undertook a multicentre study in 246 patients (172 with acute pancreatitis [35 with severe disease], 74 controls). We assessed the predictive value of urinary TAP concentrations measured by a validated competitive immunoassay. We compared the results with those for plasma C-reactive protein and three clinicobiochemical scoring systems. TAP and C-reactive protein concentrations were analysed at set times after symptom onset and compared with the clinicobiochemical systems scores at key times during hospital stay. FINDINGS: At 24 h after symptom onset, the median urinary TAP concentration was 37 nmol/L (IQR 17-110) for severe and 15 nmol/L (5-35) for mild disease (p<0.001). The respective values for plasma C-reactive protein were 24 mg/L (3-34) and 25 mg/L (6-75; p=0.208). The sensitivity, specificity, positive predictive, and negative predictive values of the test to show severe acute pancreatitis compared with mild acute pancreatitis at 24 h were: for TAP (>35 nmol/L), 58%, 73%, 39%, and 86%, respectively, and for C-reactive protein (>150 mg/L), 0%, 90%, 0%, and 75%. 48 h after admission the values for the clinicobiochemical scoring systems were: APACHE II (> or =8), 56%, 64%, 30%, and 85%; Ranson score (> or =3), 89%, 64%, 38%, and 96%; and Glasgow score (> or =3), 77%, 75%, 44%, and 93%. At 48 h, the values for C-reactive protein were 86%, 61%, 37%, and 94% and for TAP were 83%, 72%, 44%, and 94%. Combined testing of C-reactive protein and TAP was not superior to TAP alone for accuracy. INTERPRETATION: Urinary TAP provided accurate severity prediction 24 h after onset of symptoms. This single marker of severity in acute pancreatitis deserves routine clinical application.

Acute Disease↗