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Biomedical subjects

M Paul

Publications and source records attributed to M Paul.

At least 73 records · Page 4Linked to original sources
PubMed2003

Pharmacological characteristics and side effects of a new galenic formulation of propofol without soyabean oil.

We compared the pharmacokinetics, pharmacodynamics and safety profile of a new galenic formulation of propofol (AM149 1%), which does not contain soyabean oil, with a standard formulation of propofol (Disoprivan 1%). In a randomised, double-blind, cross-over study, 30 healthy volunteers received a single intravenous bolus injection of 2.5 mg.kg-1 propofol. Plasma propofol levels were measured for 48 h following drug administration and evaluated according to a three-compartment model. The pharmacodynamic parameters assessed included induction and emergence times, respiratory and cardiovascular effects, and pain on injection. Patients were monitored for side effects over 48 h. Owing to a high incidence of thrombophlebitis, the study was terminated prematurely and only the data of the two parallel treatment groups (15 patients in each group) were analysed. Plasma concentrations did not differ significantly between the two formulations. Anaesthesia induction and emergence times, respiratory and cardiovascular variables showed no significant differences between the two treatment groups. Pain on injection (80 vs. 20%, p < 0.01) and thrombophlebitis (93.3 vs. 6.6%, p < 0.001) occurred more frequently with AM149 than with Disoprivan. Although both formulations had similar pharmacokinetic and pharmacodynamic profiles the new formulation is not suitable for clinical use due to the high incidence of thrombophlebitis produced.

Adult↗
PubMed2003

The concomitant occurrence of multiple epidermal cysts, osteomas and thyroid gland nodules is not diagnostic for Gardner syndrome in the absence of intestinal polyposis: a clinical and genetic report.

Gardner syndrome, a phenotypic variant of familial adenomatous polyposis, is characterized by the classical clinical triad of skin and soft tissue tumours, osteomas and intestinal polyposis, but disease patterns with pairs of these findings have also been reported. Different mutations in the adenomatous polyposis coli (APC) gene have been shown to be associated with Gardner syndrome disease phenotypes. A 36-year-old patient presented with multiple epidermal cysts on the face, left ear lobe and neck, and the possible diagnosis of Gardner syndrome was based on the additional findings of two classical osteomas in the left radius and ulna and a cold non-malignant nodule of the thyroid gland. Intestinal polyposis was lacking at the time of examination. Major deletions but not microdeletions were excluded by a cytogenetic analysis with 650 chromosomal bands per haploid set. Systematic sequencing of the entire coding region of the APC gene (> 8500 bp) of the patient and five healthy controls was also performed. As a results, new APC gene polymorphisms were identified in exons 13 [A545A (A/G)] and 15 [G1678G (A/G), S1756S (G/T), P1960P (A/G)]. We also detected D1822V (A/T) which has recently been reported to be potentially related to colorectal carcinoma, and genotyped 194 randomly chosen healthy individuals from the Glasgow area for this as well as for the above variants in exons 13 and 15. Interestingly, of the 194 controls, 112 carried the DD (57.7%), 71 the DV (36.6%), and the remaining 11 (5.7%), including our patient, the VV genotype. It is therefore unlikely that APC D1822V serves as an important marker for colorectal carcinoma. In conclusion, we failed to identify obvious germline candidate mutations in > 8500 bp of the coding region of the APC gene in a patient with multiple epidermal cysts, osteomas and a thyroid gland nodule; major chromosomal deletions were excluded. Therefore, we assume that only the presence of intestinal polyposis is a marker for Gardner syndrome.

Adult↗
PubMed2003

[Severe ethanol-intoxication mimics symptoms of intracranial hypertension].

We report on a patient intoxicated with ethanol, who was found unconscious with fixed dilated pupils, deviation of eyes, absent cough and corneal reflexes, with her arms in decerebrate posture. Because of an orbital haematoma a traumatic intracranial hemorrhage with elevated intracranial pressure and compression or concussion of the brain stem was suspected. A CT-scan of the head did not reveal an intracranial mass or any radiographic signs of intracranial hypertension. Drug screening, blood gas analysis and other laboratory tests as well anamnestic data were not indicative of other intoxications or a metabolic decompensation. These unusual neurological findings were caused by a life-threatening ethanol intoxication with a blood-alcohol concentration of 700 mg/dl (151.8 mmol/l). The patient was extubated after several hours of mechanical ventilation in the intensive care unit and was discharged to a regular ward on the following day.

Adult↗
PubMed2003

Antibiotic prophylaxis of bacterial infections in cirrhotic inpatients: a meta-analysis of randomized controlled trials.

BACKGROUND: Antibiotic prophylaxis has been reported to decrease bacterial infections and fatality rates in inpatients with cirrhosis. We performed a systematic review to evaluate the efficacy of antibiotic prophylaxis in inpatients with cirrhosis, regardless of the underlying risk factors that led to hospital admission. METHODS: A comprehensive literature search strategy was performed including the Cochrane Library, Embase, Medline, a manual search of bibliographic references, and contacting the authors of each included trial. We included any randomized clinical trial comparing different types of antibiotic prophylaxis with placebo or no intervention in inpatients with cirrhosis. Two reviewers independently applied the selection criteria to all identified references, appraised the methodological quality of each trial and extracted the relevant data. Relative risks and 95% confidence intervals were estimated using the fixed effect model. A test of heterogeneity and a funnel plot were performed and an intention-to-treat approach was used for the outcome measures. RESULTS: Nineteen randomized trials were identified, 13 of which were included in the review. A significant beneficial effect on mortality (RR: 0.70; 95% CI: 0.56, 0.89) and prevention of bacterial infections (RR: 0.39; 95% CI: 0.32, 0.48) was observed, regardless of the underlying risk factors. Few adverse events were reported and there was no heterogeneity between studies. We identified a funnel plot asymmetry for the included trials. CONCLUSIONS: Antibiotic prophylaxis for inpatients with cirrhosis is efficacious in reducing the number of deaths and bacterial infections regardless of the underlying risk factors.

Antibiotic Prophylaxis↗
PubMed2003

Intracranial placement of a nasotracheal tube after transnasal trans-sphenoidal surgery.

Intracranial misplacement of a tracheal tube during attempted nasotracheal intubation is a rare, usually lethal complication. Such incidents are associated with fractures of the face and base of the skull. We report inadvertent intracranial placement of a nasotracheal tube in a patient who had 2 weeks previously undergone transnasal trans-sphenoidal surgery for a pituitary tumour. One should be aware that transnasal trans-sphenoidal surgery leaves a bony defect in the skull, which is susceptible to perforation by nasally introduced tubes.

Adenoma↗
PubMed2003

Therapeutic evaluation of free and nanocapsule-encapsulated atovaquone in the treatment of murine visceral leishmaniasis.

The activities of free atovaquone (ATV) and of poly(D,L-lactide) nanocapsules loaded with the drug, in the treatment of mice with visceral leishmaniasis caused by Leishmania infantum, were compared. Each mouse was infected intravenously with 2x10(7) promastigotes, on day 0. On days 15, 17 and 19, most of the infected mice were treated either with free ATV, in a dimethylsulphoxide/cremophor/water mixture, or with the ATV-loaded nanocapsules (at, respectively, 0.2-1.6 and 0.125-1.0 mg ATV/kg, on each treatment day). The rest of the mice were left untreated, as controls. All the mice were killed on day 21 and dissected so that their livers and spleens could be weighed. The liver parasite burdens, evaluated using the Stauber method, indicated that the ATV-loaded nanocapsules were significantly more effective than the free drug. In nanocapsules, for example, a total dose of 3.0 mg ATV/kg reduced liver burdens by 71.3%, whereas treatment with a higher total dose of the free drug (4.8 mg/kg) only cut the number of liver parasites by 34.4%. The dose-response data indicated that livers would have been cleared of parasites if the nanocapsule preparation had been given as three doses each equivalent to 3 mg ATV/kg, whereas the maximum suppression possible with the free drug would have been about 61%, whatever the dose.

Animals↗
PubMed2002

Large angle elastic alpha scattering on a N=Z nucleus above A=40.

Scattering of alpha particles from 44Ti, the lightest unstable alpha-particle nucleus above A=40, has been measured at backward angles. The "anomalous" order-of-magnitude enhancement that is characteristic of 40Ca and other light alpha-particle nuclei is not observed. Instead, the backward yield is similar to that observed for other nuclei heavier than 40Ca, and is well described with average optical model parameters.

Journal Article↗
PubMed2002

Beta-lactam versus beta-lactam-aminoglycoside combination therapy in cancer patients with neutropaenia.

BACKGROUND: Chemotherapy treated cancer patients are prone to neutropaenia and life-threatening infections. Early, empirical antibiotic treatment is therefore administered routinely to febrile neutropaenic patients. Currently, either beta-lactam-aminoglycoside combination treatment or beta-lactam monotherapy are recommended. OBJECTIVES: We compared beta-lactam monotherapy versus beta-lactam-aminoglycoside combination therapy for cancer patients with fever and neutroepaenia. SEARCH STRATEGY: Cochrane Library (Issue 4,2001), the Cochrane Cancer Network Register of trials (July 2000), EMBASE (January 1980-2000), MEDLINE (1966-8/2001), and ICAAC conference proceedings (1995 onwards). We scanned references of all included studies, pertinent reviews, and contacted the first author of each included trial and the pharmaceutical companies. SELECTION CRITERIA: Randomised controlled trials comparing any beta-lactam antibiotic monotherapy to any combination of a beta-lactam and an aminoglycoside antibiotic, for the initial, empirical treatment of febrile neutropaenic cancer patients. DATA COLLECTION AND ANALYSIS: Data concerning mortality, treatment failure (including treatment modifications), superinfections, adverse effects and study quality measures were extracted independently by two reviewers. Relative risks with their 95% confidence intervals (CI) were estimated. Outcomes were extracted by intention-to-treat analysis whenever possible. MAIN RESULTS: Forty-six trials and 7642 patients were included. All cause mortality was the primary outcome assessed. For all mortality comparisons, no significant difference between monotherapy and combination therapy was seen, relative risk 0.85 (95% CI 0.72-1.02) for all studies combined. Treatment failure was the outcome reported in all included trials. No significant difference between study groups was shown for studies comparing the same beta-lactam, relative risk 1.12 (95% CI 0.96-1.29). A significant advantage to monotherapy was observed for studies comparing different beta-lactams, relative risk 0.86 (95% CI 0.80-0.93). Bacterial and fungal superinfections developed with similar frequencies in the monotherapy and combination treatment groups. Adverse events were significantly more common in the combination treatment group, relative risk 0.83, (95% CI 0.72-0.97). These included events associated with significant morbidity, primarily renal toxicity. Results were consistent for subgroup and sensitivity analyses. REVIEWER'S CONCLUSIONS: We have shown an advantage to broad-spectrum beta-lactam monotherapy over beta-lactam-aminoglycoside combination therapy for febrile neutropaenia. This advantage comprises of 1) a similar, if not better, survival, 2) a significantly lower treatment failure rate, 3) comparable probability for secondary infections and, 4) most importantly, a lower rate of adverse events associated with significant morbidity. Monotherapy can be regarded, therefore, as the standard of care for febrile neutropaenic patients.

Aminoglycosides↗
PubMed2002

Characterisation of atovaquone resistance in Leishmania infantum promastigotes.

Atovaquone, an antiparasitic agent, could possibly represent an alternative therapy after relapse following classical treatment for visceral leishmaniasis. Atovaquone-resistant strains were selected in vitro by stepwise drug pressure to study the mechanism of resistance in Leishmania. Characteristics of a promastigote strain resistant to 250 microg/ml of atovaquone were compared with those of the wild type (WT) strain. Resistant strains were shown to have a high level of resistance (45 times). They were stable in drug-free medium for 6 months, and showed no cross-resistance with other antileishmanial drugs. Rhodamine uptake and efflux were studied. They were not modified in the resistant strain, indicating the absence of P-glycoprotein overexpession. The effect of atovaquone on membrane lipidic composition was determined in both WT and atovaquone-resistant promastigotes. Analysis of lipid composition of the atovaquone-resistant strain showed that sterol biosynthesis was decreased in atovaquone-resistant parasites. Cholesterol was found to be the major membrane sterol as opposed to the WT strain. Cholesterol, due to its ordering effect, could decrease membrane fluidity and subsequently block the passage of atovaquone through the membrane. Increased membrane cholesterol content and altered drug membrane fluidity resulted from possible decrease of ergosterol biosynthesis by atovaquone, incorporation of cholesterol by promastigotes in the culture medium, solubilisation of atovaquone by cholesterol and co-passage of the two compounds or influence of dimethylsulfoxide. These results indicate that different cellular alterations may participate in the resistant phenotype, by altering drug membrane permeability.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Predictors of complications in acute type B aortic dissection.

OBJECTIVES: Medical treatment is generally advocated for patients with acute type B aortic dissection without complications. The objective of this retrospective analysis was to determine whether there are any initial findings that can help predict the long-term course of the disease. METHODS: Case records of the 130 patients treated for type B aortic dissection between 1988 and 1997 were reviewed; 41 (31%) were operated on in the acute phase (<14 days), 31 (24%) were operated on in the chronic phase and 58 (45%) were treated medically. RESULTS: Overall acute mortality was 10.8%; 22% for patients operated on in the early phase and 5.6% for medically treated patients. Age (P=0.002), persistent pain (P=0.01) and malperfusion (P=0.001) were significant independent predictors of the need for surgery. Paraplegia/para paresis (P=0.0001), leg ischaemia (P=0.003), pleural effusion (P=0.003), rupture (P=0.0001), shock (P=0.0001), age (P=0.003), cardiac failure (P=0.002) and aortic diameter >4.5 cm (P=0.002) were significant predictors of poor survival. Age and shock also emerged as independent risk factors. Patients without malperfusion (P=0.0001), pleural effusion (P=0.003), rupture (P=0.0001) and shock (P=0.0001) had a significantly better event-free survival (freedom from repeat surgery and death). The actuarial survival rate for high-risk patients (malperfusion, rupture, shock) was 62% at 1 year and 40% at 5 years; the corresponding values for low-risk patients were 94 and 84%, respectively. CONCLUSIONS: Rupture, shock and malperfusion are significant predictors of poor survival in patients with acute type B aortic dissection.

Adult↗
PubMed2002

[Anti-C. pneumoniae IgG, IgA and IgM antibodies in patients undergoing coronary artery bypass grafting].

The aim of the study was to analyse the prevalence of anti-C. pneumoniae specific IgG, IgA and IgM antibodies in patients undergoing coronary artery bypass engraftment. Sera of forty-six patients aged from 40 to 74 years (mean 57.3) were examined just before the time of operation. Serum samples taken from 21 young healthy blood donors aged from 19 to 28 years (mean 22.4) and 23 sera taken from older blood donors aged 44-60 years (mean 54.7), were used as controls. Specific IgG, IgA and IgM serum antibodies were tested by the enzyme immunoassay kits (Lab-systems, Helsinki). The prevalence of anti-C. pneumoniae IgG was determined within the studied groups, to be independent of their age. On the contrary, the level and seropositivity rate of specific IgA (63.0%), as well as a co-existence of IgA and IgG (60.9%) were significantly higher in coronary patients when compared to healthy blood donors. The presence of specific IgM (positive or borderline values) were detected in 23.9% of patients, whereas they were rarer found in healthy population. In the majority of coronary patients immunological markers of C. pneumoniae infection were found.

Adult↗
PubMed2001

Upregulation of the vascular NAD(P)H-oxidase isoforms Nox1 and Nox4 by the renin-angiotensin system in vitro and in vivo.

In different cardiovascular disease states, oxidative stress decreases the bioavailability of endothelial NO, resulting in endothelial dysfunction. An important molecular source of reactive oxygen species is the enzyme family of NAD(P)H oxidases (Nox). Here we provide evidence that the vascular Nox isoforms Nox1 and Nox4 appear to be involved in vascular oxidative stress in response to risk factors like angiotensin II (Ang II) in vitro as well as in vivo. Nox mRNA and protein levels were quantified by real-time RT-PCR and Western blotting, respectively. Nox1 and Nox4 were expressed in the vascular smooth muscle cell (VSMC) line A7r5 and aortas and kidneys of rats. Upon exposure of A7r5 cells to Ang II (1 microM, 4 h), Nox1 and Nox4 mRNA levels were increased 6-fold and 4-fold, respectively. Neither the vasoconstrictor endothelin 1 (up to 500 nM, 1-24 h) nor lipopolysaccharide (up to 100 ng/ml, 1-24 h) had any effect on Nox1 and Nox4 expression in these cells. Consistent with these observations made in vitro, aortas and kidneys of transgenic hypertensive rats overexpressing the Ren2 gene [TGR(mRen2)27] had significantly higher amounts of Nox1 and Nox4 mRNA and of Nox4 protein compared to tissues from normotensive wild-type animals. In conclusion, Nox4 and Nox1 are upregulated by the renin-angiotensin system. Increased superoxide production by upregulated vascular Nox isoforms may diminish the effectiveness of NO and thus contribute to the development of vascular diseases. Nox1 and Nox4 could be targeted therapeutically to reduce vascular reactive oxygen species production and thereby increase the bioavailability of NO.

Angiotensin II↗
PubMed2001

Gamma-vinyl GABA (GVG) blocks expression of the conditioned place preference response to heroin in rats.

We examined the effect of gamma-vinyl GABA (GVG) on the expression of the conditioned place preference response to intraperitoneally (i.p.) administered heroin in rats. Heroin, but not vehicle, produced a significant conditioned place preference response. Pretreatment of animals with 300 mg/kg of GVG significantly attenuated the expression of the heroin-induced conditioned place preference response. These results are the first to suggest that systemic GVG may provide an effective alternative to methadone maintenance in the treatment of heroin addiction, since it is without abuse potential and can be used for treatment outside an institutional setting.

Animals↗
PubMed2001

Impaired hyperpolarization in regenerated endothelium after balloon catheter injury.

Ca(2+)-activated K(+) (K(Ca)) channels control endothelial Ca(2+) homeostasis and the formation of vasodilators. After angioplasty, dysfunction of the regenerated endothelium leads to abnormal vasoregulation. In this study, we tested the expression and function of K(Ca) channels in regenerated endothelium at 6 weeks after balloon catheter injury of rat carotid arteries (CAs) by using single-cell reverse transcription-polymerase chain reaction, patch-clamp techniques, and analysis of vasoreactivity. In single regenerated endothelial cells (ECs), the percentage of ECs expressing the K(Ca) genes, rSK3 (12+/-8%) and rIK1 (22+/-9%), was significantly lower compared with the percentage of native ECs expressing these genes (rSK3 58+/-8%, rIK1 64+/-10%). In patch-clamp experiments, K(Ca) currents and acetylcholine-induced hyperpolarization were markedly reduced in regenerated ECs (shift of membrane potential -6+/-3 mV) compared with those in native ECs (shift of membrane potential -21+/-5 mV). In pressure myograph experiments, acetylcholine-induced dilation was impaired in reendothelialized CAs compared with normal CAs. Intraluminal application of the K(Ca) blocker apamin and charybdotoxin inhibited dilation by 30% in normal CAs but was without effect in reendothelialized CAs. Intraluminal application of 1-ethyl-2-benzimidazolinone (100 micromol/L), an opener of K(Ca) channels, evoked dilation by 29% in normal CAs but had no effect in reendothelialized CAs. In conclusion, the impaired expression of K(Ca) channels in regenerated endothelium results in defective hyperpolarization and impaired dilation. Thus, the impaired K(Ca) channel function contributes to functional alterations of regenerated endothelium after angioplasty.

Acetylcholine↗
PubMed2001

Regulation of Raf by Akt controls growth and differentiation in vascular smooth muscle cells.

The stimulation of platelet-derived growth factor (PDGF) receptors shifts vascular smooth muscle (VSM) cells toward a more proliferative phenotype. Thrombin activates the same signaling cascades in VSM cells, namely the Ras/Raf/MEK/ERK and the phosphatidylinositol 3-kinase (PI 3-kinase)/Akt pathways. Nonetheless, thrombin was not mitogenic, but rather increased the expression of the smooth muscle-specific myosin heavy chain (SM-MHC) indicative of an in vitro re-differentiation of VSM cells. A more detailed analysis of the temporal pattern and relative signal intensities revealed marked differences. The strong and biphasic phosphorylation of ERK1/2 in response to thrombin correlated with its ability to increase the activity of the SM-MHC promoter whereas Akt was only partially and transiently phosphorylated. By contrast, PDGF, a potent mitogen in VSM cells, induced a short-lived ERK1/2 phosphorylation but a complete and sustained phosphorylation of Akt. The phosphorylated form of Akt physically interacted with Raf. Moreover, Akt phosphorylated Raf at Ser(259), resulting in a reduced Raf kinase activity and a termination of MEK and ERK1/2 phosphorylation. Disruption of the PI 3-kinase signaling prevented the PDGF-induced Akt and Raf-Ser(259) phosphorylation. Under these conditions, PDGF elicited a more sustained MEK and ERK phosphorylation and increased SM-MHC promoter activity. Consistently, in cells that express dominant negative Akt, PDGF increased SM-MHC promoter activity. Furthermore, expression of constitutively active Akt blocked the thrombin-stimulated SM-MHC promoter activity. Thus, we present evidence that the balance and cross-regulation between the PI 3-kinase/Akt and Ras/Raf/MEK signaling cascades determine the temporal pattern of ERK1/2 phosphorylation and may thereby guide the phenotypic modulation of vascular smooth muscle cells.

Animals↗
PubMed2001

Gbeta gamma mediate differentiation of vascular smooth muscle cells.

Proliferation and subsequent dedifferentiation of vascular smooth muscle (VSM) cells contribute to the pathogenesis of atherosclerosis and postangioplastic restenosis. The dedifferentiation of VSM cells in vivo or in cell culture is characterized by a loss of contractile proteins such as smooth muscle-specific alpha-actin and myosin heavy chain (SM-MHC). Serum increased the expression of contractile proteins in neonatal rat VSM cells, indicating a redifferentiation process. RNase protection assays defined thrombin as a serum component that increases the abundance of SM-MHC transcripts. Additionally, serum and thrombin transiently elevated cytosolic Ca(2+) concentrations, led to a biphasic extracellular signal-regulated kinase (ERK) phosphorylation, up-regulated a transfected SM-MHC promoter construct, and induced expression of the contractile proteins SM-MHC and alpha-actin. Pertussis toxin, N17-Ras/Raf, and PD98059 prevented both the serum- and thrombin-induced second phase ERK phosphorylation and SM-MHC promoter activation. Constitutively active Galpha(q), Galpha(i), Galpha(12), and Galpha(13) failed to up-regulate SM-MHC transcription, whereas Gbetagamma concentration-dependently increased the SM-MHC promoter activity. Furthermore, the Gbetagamma scavenger beta-adrenergic receptor kinase 1 C-terminal peptide abolished the serum-mediated differentiation. We conclude that receptor-mediated differentiation of VSM cells requires Gbetagamma and an intact Ras/Raf/MEK/ERK signaling.

Actins↗