Recent advances: oncology.
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Biomedical subjects
Publications and source records attributed to H Thomas.
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Stereospecific N-methylation of the tetrahydroisoquinoline alkaloids isosalsoline (7-hydroxy-6-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline) and salsolidine (6,7-dimethoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline) by amine N-methyltransferase A isolated from bovine liver is reported. Incubation with S-adenosylmethionine as cosubstrate revealed that in case of isosalsoline, an endogenous tetrahydroisoquinoline alkaloid, the (+)-(R)-enantiomer, is preferentially methylated, whereas in the case of salsolidine the (-)-(S)-enantiomer is preferentially methylated. The results were obtained by using two independent methods, namely a radioassay and HPLC following separate incubation experiments.
STUDY OBJECTIVE: To determine antibody titers to hepatitis B surface antigen (anti-HBsAg) among previously vaccinated emergency physicians and to assess the degree of compliance with Centers for Disease Control and Prevention (CDC) postvaccination guidelines. METHODS: A descriptive analysis was performed of anti-HBsAg titer determinations and vaccination surveys among a self-selected group of emergency physicians attending the annual scientific assembly of the American College of Emergency Physicians in 1995, 1996, or 1997. RESULTS: Of 943 participants, titer levels were found to be protective in 768 (81%), borderline in 45 (5%), and nonreactive in 130 (14%). A total of 337 participants (36%) had not obtained postvaccination titer determinations, as advised by the CDC. More than 50% reported an occupational exposure to blood products within the previous 2 years. CONCLUSION: Despite their high risk for exposure to blood products, many previously vaccinated emergency physicians were not in compliance with CDC postvaccination guidelines.
IL-12 treatment of a murine transplantable breast carcinoma (HTH-K) led to tumour regression and cure which was related to the duration of treatment. We studied the sequential molecular and phenotypic changes in IL-12-treated tumours. IFN-gamma mRNA was detected 8 hr after the first treatment. mRNA expression for the IFN-gamma-inducible genes beta 2-microglobulin and indoleamine dioxygenase (IDO) was induced subsequently, together with the chemokine IP-10. IL-12-treated tumours had an abundant cellular infiltrate, consisting mainly of CD8+ T cells. mRNA for granzyme B and perforin also could be detected, suggesting that those cells were activated. After 7 days of daily therapy, tumours in IL-12-treated mice had a significant reduction in vasculature. Finally, the number of apoptotic tumour cells increased throughout IL-12 treatment. We compared the anti-tumour effects of IL-12 to those induced by IFN-gamma therapy, which caused initial tumour stasis but subsequent tumour progression. IFN-gamma induced beta 2-microglobulin and IDO over a 7-day period, but IP-10 was induced only transiently. IFN-gamma caused a lesser cellular infiltrate, a minor anti-angiogenic effect and a transient apoptotic effect. The success of IL-12 may be due to its ability to produce a distinct sequence of molecular and phenotypic changes in tumours, leading to an anti-tumour immune response, toxicity against tumour cells and an anti-angiogenic effect. Other cytokines, such as IFN-gamma, induce some, but not all, of these actions. Comparison of IL-12 and IFN-gamma suggests that sustained induction of IP-10 and activation of a resulting cellular infiltrate may be key changes in regressing tumours.
The low blood/gas solubility, the rapid uptake and nonpungent odor permits mask induction with sevoflurane in adults. Depending on the induction techniques (tidal breathing, deep breaths or single-breath induction), the use of nitrous oxide and the concentration of inspired sevoflurane anesthesia can rapidly be induced within 41-178 s. Adverse effects like coughing, breath-holding or increased secretions occur with a low incidence of 2%-20%. Some 88 to 100% of the volunteers or patients would accept a mask induction again. Clinical experience shows that sevoflurane is well indicated for mask induction in adults. Acute severe bronchospasm is a feared complication of anesthesia with an incidence of 1.7%. Although halothane is often recommended as the agent of choice in patients with reactive airways, there is little evidence in humans that it is more effective than other volatile agents. The bronchodilating effects of sevoflurane are comparable to those of other volatile anesthetics, it produces minimal airway irritation and allows rapid adjustment of anesthetic depth. These properties and our clinical experience suggest that sevoflurane is a useful choice for patients with reactive airways. Hypoxemia during one-lung ventilation (OLV) occurs in 9-27% of patients and remains a clinical problem. Although hypoxic pulmonary vasoconstriction is directly inhibited by volatile anesthetics in in vitro studies, this effect is usually of minor clinical consequence. The use of volatile anesthetics may be advocated because of their salutory effects on bronchomotor tone, high potency (allowing high inspired concentration of oxygen while avoiding awareness) and rapid adjustment of anesthetic depth. Sevoflurane possesses these attributes and may be useful for OLV.
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UNLABELLED: We studied the effects of the beta2-adrenoceptor and DA1-receptor agonist dopexamine on ventilation perfusion (V(A)/Q) distribution in anesthetized, paralyzed patients (n = 17) undergoing major abdominal surgery. Intrapulmonary shunt (Q(S)/Q(T)) (percentage of cardiac output [CO]), perfusion of low V(A)/Q areas (percentage of CO), ventilation of high V(A)/Q areas (percentage of total ventilation [V(E)]), and dead space ventilation [percentage of V(E)]) were calculated from the retention/excretion data of six inert gases. In the control state, Q(S)/Q(T) was 11% +/- 9% (mean +/- SD) and little perfusion of low V(A)/Q areas (3% +/- 4%) was observed. Infusion of 1.0 microg kg(-1) x min(-1) dopexamine had no effect on Q(S)/Q(T) and low V(A)/Q areas despite an increased CO (7.7 +/- 2.2 L/min versus 6.2 +/- 1.2 L/min; P < 0.01). Pao2 increased from 15.5 +/- 5.6 kPa (116 +/- 42 mm Hg) to 17.3 +/- 6.3 kPa (130 +/- 47 mm Hg) (P < 0.05). Infusion of 2.0 microg x kg(-1) x min(-1) dopexamine further increased CO to 8.4 +/- 2.7 L/min (P < 0.01) without alterations of Q(S)/Q(T), perfusion of low V(A)/Q areas, and Pao2. We concluded that dopexamine (1.0 microg x kg(-1) x min(-1) and 2.0 microg x kg(-1) x min(-1)) has no adverse effects on V(A)/Q relationships and Q(S)/Q(T) in anesthetized, paralyzed patients. IMPLICATIONS: The I.V. administration of vasoactive drugs can improve oxygen delivery to different organ systems but may impair pulmonary gas exchange. In anesthetized, paralyzed patients, we studied the effects of beta2-adrenoceptor and DA1-receptor agonist dopexamine on ventilation perfusion distribution. Dopexamine (1.0 microg x kg(-1) x min(-1) and 2.0 microg x kg(-1) min(-1)) improved cardiac output and oxygenation without alterations of intrapulmonary shunt.
UNLABELLED: Acetyl starch (ACS) is a new synthetic colloid solution for plasma volume expansion and is now undergoing phase 2 clinical trials. We compared the pharmacokinetics of ACS with those of hydroxyethyl starch (HES) in 32 patients (ASA physical status I and II) undergoing elective surgery. In this randomized, double-blind trial, patients received either 15 mL/kg ACS 6% (average molecular weight [Mw] 200,000/molar substitution [MS] 0.5) or HES 6% (Mw 200,000/MS 0.5) i.v. up to a maximal dose of 1000 mL. Plasma colloid concentrations were measured by repetitive arterial blood sampling over 24.5 h. Plasma colloid concentrations were detected using a high-pressure liquid chromatography controlled enzymatic test. Standard pharmacokinetics were calculated, including initial half-life (t(1/2init)), i.e., the time required for a 50% decline of the maximal plasma colloid concentration at the end of drug infusion. Whereas HES was eliminated by second-order kinetics, ACS followed first-order characteristics. In the first hours after i.v. administration, t(1/2init) and clearances were similar in both groups. However, the terminal half-life of HES was significantly longer than that of ACS (9.29 +/- 1.43 h vs 4.37 +/- 1.06 h). After 16.5 and 24.5 h, ACS showed significantly lower plasma concentrations than HES, which indicates that the final degradation of ACS by esterases and amylase was significantly more rapid. ACS might be an alternative plasma volume expander, which avoids the accumulation of persisting macromolecules. IMPLICATIONS: We studied the pharmacokinetics of acetyl starch, a newly developed colloid solution for plasma volume substitution, compared with hydroxyethyl starch in 32 surgical patients undergoing elective major general surgical procedures. In contrast to hydroxyethyl starch, this new agent undergoes rapid and nearly complete enzymatic degradation.
BACKGROUND: Induction of CO2-pneumoperitoneum may have significant effects on systemic and pulmonary haemodynamics. We hypothesized that intrathoracic (ITBV) and pulmonary blood volume (PBV) are affected during intra-abdominal CO2-insufflation, which may be pronounced by positional changes of the patient. METHODS: Sixteen anaesthetized patients were studied before, during and after CO2-pneumoperitoneum for laparoscopic cholecystectomy. A dye indicator technique was used to assess ITBV and PBV. In addition, gas exchange and haemodynamics were recorded. RESULTS: In the supine position, induction of CO2-pneumoperitoneum had no effects on ITBV, PBV and cardiac output. Mean systemic arterial pressure increased from 10.9 +/- 1.5 kPa (82 +/- 11 mmHg) to 12.7 +/- 1.5 kPa (95 +/- 11 mmHg, P < 0.01). In the reverse Trendelenburg position ITBV decreased from 19.8 +/- 5.1 ml.kg-1 to 16.7 +/- 3.7 ml.kg-1 (P < 0.05) during CO2-insufflation, but increased to control values after 20 min. PBV decreased from 4.2 +/- 1.2 ml.kg-1 to 3.4 +/- 1.1 ml.kg (P < 0.05) and remained decreased during CO2-pneumoperitoneum. Calculated venous admixture was unchanged throughout the study. Deflation of CO2-pneumoperitoneum increased ITBV (22.4 +/- 5.2 ml.kg-1, P < 0.05) and cardiac output above control values. CONCLUSIONS: In anaesthetized-paralyzed patients in the reverse Trendelenburg position intra-abdominal CO2-insufflation is associated with significant alterations of ITBV and PBV. The release of CO2-pneumoperitoneum is associated with a re-distribution of blood into the thorax.
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PURPOSE: Pulmonary infection is one of the most feared complications in patients receiving long-term ventilation. We evaluated prospectively the diagnostic value of daily bedside chest radiography performed as digital luminescence radiography (DLR) in comparison to clinical findings and quantitative microbial culture. MATERIAL AND METHODS: Prospective evaluation of daily bedside chest radiography (DLR) and clinical parameters such as blood count, body temperature, and microbiological monitoring (quantitative culturing, microscopy) of 20 patients receiving long-term ventilation was undertaken. Altogether 325 chest radiographs were evaluated. RESULTS: 96% of the routine radiographs showed abnormal findings. Nosocomial pneumonia was suspected in 31% of all 330 days of observation by means of clinical and microbiological findings. DLR showed correct findings in 80% of this days (right-positive interpretation); a false-positive interpretation was resulted in 16 radiographs. Most common finding in nosocomial pneumonia was an alveolar pattern with air bronchogram. Fever and leucocytosis often precede radiological evidence of pneumonia. CONCLUSION: Daily bedside chest radiography performed as DLR shows abnormal finding in a high percentage. Bedside chest radiograph is in accordance to clinical and microbiological finding of nosocomial pneumonia in 80%.
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(+)-(R)- and (-)-(S)-salsolinol, dopamine-derived tetrahydroisoquinolines, were tested as substrates of pig brain soluble and membrane-bound catechol-O-methyltransferase (COMT) and as inhibitors of O-methylation of dopamine by soluble COMT in vitro. Methylation products were separated by high-performance liquid chromatography with electrochemical detection. Quantification of the products showed that O-methylation of (+)-(R)-salsolinol by soluble COMT afforded the 7-O-methylated product salsoline preferentially, whereas (-)-(s)-salsolinol yielded almost equivalent amounts of the 6- and 7-methyl ethers. Unlike O-methylation by soluble COMT, 7-O/6-O-methylation ratio produced by membrane-bound COMT varied with (+)-(R)-salsolinol concentration. As to the O-methylation of dopamine by soluble COMT, comparable competitive inhibition was observed with both (+)-(R)- and (-)-(S)-salsolinol.
We combined a newly developed ambulatory fiberoptic system for detecting intragastric bilirubin (Bilitec 2000, Synectics Medical Inc., Sweden) with prolonged measurement of gastroduodenal motility in 10 healthy volunteers and 10 patients followed BI resection. Circadian intragastric bilirubin exposure and the total number of tremendous changes of bilirubin absorption (more than 20%, over a period of at least 5 min) were significantly increased in the BI-resected patients (P < 0.05). In patients the interdigestive motility cycle (IMC) was characterized by the appearance of several types of abnormally propagated phase III activity fronts. Of the tremendous increases of bilirubin absorption in the patient group, 90.1% were associated with abnormally propagated phase III activity fronts. In cases of increased duodenogastric reflux, the combination of ambulatory intragastric bilirubin measurement and long-term manometry seems to be feasible to assess motility and reflux simultaneously.
BACKGROUND/AIMS: Vagal dysfunction is reported in about 70% of patients with cirrhosis, irrespective of aetiology, as detected by cardiovascular reflex tests. We have previously shown that RR-variability on 24-h ECG is a more sensitive marker of vagal dysfunction in cirrhosis. Angiotensin II inhibits vagal function in animals, and it is elevated in cirrhosis and may be the cause of the vagal dysfunction. Our aim was to observe the effect of captopril on vagal dysfunction in cirrhosis. METHODS: Eight patients with cirrhosis (biopsy proven, male two, female six, mean age 54.25) had 24-h ECG RR-variability performed. They then received captopril 25 mg t.d.s. for 48 h. The 24-h ECG was repeated on therapy. RESULTS: Mean blood pressure remained unchanged: baseline 89.8 +/- 4.8 mmHg (mean +/- sem) versus 91.8 +/- 5.9 mmHg, p = not significant. Median baseline RR-variability was 791 (range 18-5344) counts/24 h and increased in all but one patient, with captopril, to 1548 (56-4824) p = 0.008. Three increased into the normal range. CONCLUSION: The vagal dysfunction of cirrhosis is caused by neuromodulation by angiotensin II and is not due to a neuropathy.