Controlled study on the therapeutic efficacy of propionyl-L-carnitine in patients with congestive heart failure.

A double-blind phase II study of propionyl-L-carnitine (CAS 17298-37-2) versus placebo was carried out on a group of 60 patients with mild to moderate (II and III NYHA class) congestive heart failure. The group was made up of men and women aged between 48 and 73 years in chronic treatment with digitalis and diuretics for at least 3 months and who still displayed symptoms. Thirty of these patients were chosen randomly and for 180 days, 500 mg of propionyl-L-carnitine was orally administered, 3 times a day in addition to their usual treatment. At basal conditions and after 30, 90 and 180 days the maximum exercise time was evaluated using an exercise tolerance test performed on an ergometer bicycle and the left ventricular ejection fraction was tested by means of bidimensional echocardiography. After one month of treatment, the patients treated with propionyl-L-carnitine, compared to the control group, showed significant increases in the values of both tests, increases which became even more evident after 90 and 180 days. At the stated times the increases in the maximum exercise time were 16.4%, 22.9%, and 25.9%, respectively. The ventricular ejection fraction increased by 8.4%, 11.6% and 13.6%, respectively. On the basis of these results, having studied the particular mechanism of action of propionyl-L-carnitine the authors conclude that it represents a drug of undoubted therapeutic interest in patients with congestive heart failure, in whom it could be efficaciously administered along with a standard pharmacological therapy.


Pharmacokinetics and antihypertensive effect of oral pelanserin in renal hypertensive dogs.

The pharmacokinetics and antihypertensive effect of pelanserin (CAS 2208-51-7), a 5-HT2- and alpha 1-antagonist, were studied during repetitive administration (0.5 mg/kg, p.o., b.i.d.) in renal hypertensive dogs. After the first dose, pelanserin was absorbed reaching a Cmax value of 39.6 +/- 9.01 ng/ml at a tmax of 2.58 +/- 0.74 h. The steady state of plasma levels was reached between the 3rd and 15th doses of pelanserin. Pharmacokinetic parameters calculated after the 47th dose of pelanserin were Cmax(ss) of 147.15 +/- 35.88 ng/ml at a tmax(ss) of 3.17 +/- 1.02 h, AUC(0-12 h) of 593.80 +/- 106.96 ng.h/ml and a terminal half-life of 18.02 +/- 2.94 h. The accumulation ratio determined as Cmin(ss)/Cmin1 was 2.36 +/- 0.43 and was similar to that calculated in basis to the terminal half-life 2.67 +/- 0.37. On the other hand, pelanserin produced blood pressure decrease with two different profiles. After the first dose an acute antihypertensive effect was observed which reached a maximum of 20 mmHg in about 3 h; then blood pressure recovered gradually arriving to basal values at 12 h. When administered repetitively, pelanserin produced a gradual reduction in blood pressure which reached its maximum at 15 days. After the last dose, blood pressure basal values were about 20 mmHg lower than pretreatment levels and remained almost unchanged during 48 h after the last dose. It is concluded that pelanserin pharmacokinetic and pharmacodynamic profiles in dogs are adequate for an antihypertensive agent, therefore this drug possesses potential therapeutic usefulness in the treatment of hypertension.


Relative efficacy and safety of loratadine, hydroxyzine, and placebo in chronic idiopathic urticaria.

The efficacy and safety of a new non-sedating antihistamine, loratadine (Clarityn, CAS 79794-75-5) 10 mg q.d., was compared to the classical antihistamine, hydroxyzine 25 mg t.i.d. and placebo in a 4-week (optional 12 week) randomized, double-blind, multi-center study in 203 patients with chronic idiopathic urticaria. Efficacy evaluations included weekly physician and patient assessments of pruritus, overall disease condition, and therapeutic response to treatment. Loratadine and hydroxyzine were significantly more effective than placebo and clinically comparable to each other as measured by all efficacy evaluations at each visit. Loratadine was safe and well tolerated with sedation and dry mouth similar to placebo and significantly less than hydroxyzine.


Percutaneous absorption of methylprednisolone aceponate after single and multiple dermal application as ointment in male volunteers.

Six healthy, elderly volunteers were treated once daily with Advantan ointment containing 0.1% of methylprednisolone aceponate (MPA, CAS 86401-95-8) in an area dose of 5 mg ointment/cm2 on a marked area of 80 cm2 of intact skin on the back for 14 days. The ointments used for treatment on days 1 and 8 contained 14C-MPA with a specific radioactivity of 2.5 MBq/mg MPA. Following the radioactive pulse doses, the concentrations of 3H-radioactivity in plasma and urine were monitored up to 48 h and 7 days, respectively. The concentration of 14C-radioactivity in the plasma did not exceed the limit of detection of 0.3 ng MPA-equiv./ml. Percutaneous absorption of MPA through intact skin was small (les than 1%) and did not change during repeated application, indicating that the penetration barrier is not influenced by the drug or the vehicle.


Hypolipidaemic activity of a novel acyclic ansamycin derivative. Synthesis and pharmacokinetic and pharmacodynamic studies in rodents.

Certain classes of the antibacterial agent rifamycin SV have recently been shown to possess marked hypolipidaemic activity. An acyclic oxazolylrifamycin has been prepared and its hypolipidaemic properties evaluated; it was found to be significantly more potent when administered orally to Wistar and Sprague-Dawley rats than other previously described rifamycin hypolipidaemics. The plasma decay rate of a bolus of intravenously administered 125I-LDL (low density lipoprotein) was significantly greater in treated rats than in rats receiving vehicle alone, compatible with a drug-induced increase in LDL catabolism. A bolus of radiolabelled drug was rapidly removed from the circulation by the liver, the presumed target organ. Compound 3 constitutes the first example of a new class of acyclic hypolipidaemic ansamycins.


Influence of protein binding on the metabolic clearance rate of synthetic progestins in the rat liver perfusion model.

Levonorgestrel (LN), 3-Keto-desogestrel (KDG), norethisterone (NET), and gestodene (GST) were investigated in the recirculating rat liver perfusion model. Progestins were dissolved in buffered salt solution (MI), BSA containing (MII) or HSA and sex hormone binding globulin (SHBG) containing medium (MIII) at a concentration of about 60 ng/ml. Each 3-5 female rat livers were perfused with MI, MII, and MIII for 1 h. Perfusion medium, liver biopsies and total bile were analyzed for progestin levels by specific radioimmunoassays. Protein binding characteristics were determined in media and tissue. In all experiments bile (remaining liver) contained less than 1% (3%) of respective progestin dose demonstrating an almost complete biotransformation of all drugs by rat livers, irrespective of used medium. With MI, metabolic clearance rates (MCRs) and half-lives (t1/2) were not different for the four progestins. With MII, the actual progestin levels were generally higher than with MI, but half-lives were not changed. MCRs were close to the perfusion rate at the start of experiments but decreased to about 50%. MCRs of free and total drug levels were identical. Protein binding of 70-80% did not change with time. With MIII, the half-lives increased 1.5 fold (NET), 2.8 fold (KDG), 3.1 fold (GST) and 3.2 fold (LN) and MCRs accounted for 50-70% of perfusion rate at the beginning. The time courses of further MCR decreases were different for the various progestins and can be attributed to differences in specific binding of drugs to SHBG. Clearly, the presence of SHBG in MIII induced a shift of drug from liver tissue into the perfusion medium.(ABSTRACT TRUNCATED AT 250 WORDS)


Pharmacokinetics and serum protein binding of gestodene and 3-keto-desogestrel in women after single oral administration of two different contraceptive formulations.

Two low-dose oral contraceptives, both containing the same dose of ethinyl estradiol (EE2, CAS 57-63-6) but different progestins--gestodene (CAS 60282-87-3) and desogestrel (CAS 54024-22-5), respectively--were administered to 18 women in a single dose, cross-over study. The serum concentrations of gestodene (GEST, one of the components of Femovan) and 3-keto-desogestrel (KDG) have been measured by specific radioimmuno-assays and the pharmacokinetics of both progestins were assessed. The serum protein binding of both compounds was also investigated and although the free fraction was the same for GEST and KDG, the distribution with respect to the binding proteins albumin and sex hormone binding globulin (SHBG) was slightly different. GEST was mainly bound to SHBG, while KDG was predominantly bound to albumin. Maximum concentrations of GEST were observed after 0.7 +/- 0.2 h and amounted to 4.9 +/- 2.4 ng/ml. A biphasic pattern of disposition was observed, with half lives of 0.13 +/- 0.06 h and 14.6 +/- 4.2 h, respectively. The AUC was 32.9 +/- 18.3 ng.ml-1.h. For KDG, maximum serum levels of 1.7 +/- 0.8 ng/ml were observed 1.5 +/- 0.8 h post administration. Drug levels declined with half-lives of 0.5 +/- 0.2 h and 17.0 +/- 9.3 h, respectively, and the AUC was 15.2 +/- 10.9 ng.ml-1.h.


Pharmacokinetics and serum protein binding of 3-keto-desogestrel in women during three cycles of treatment with a low-dose combination oral contraceptive.

The serum concentrations of 3-keto-desogestrel have been measured in 43 women who took a low-dose oral contraceptive containing 30 micrograms ethinyl estradiol (CAS 57-63-6) together with 150 micrograms desogestrel (CAS 54024-22-5) for a period of 3 months. Basic pharmacokinetic parameters, like Cmax, tmax and AUC, as well as the serum protein binding of 3-keto-desogestrel were determined on days 1, 10 and 21 of the first and the third treatment cycle, respectively. During cycle one, Cmax, AUC(0-4h) and AUC(0-24h) values on day 1 were 1.9 +/- 0.7 ng/ml, 3.9 +/- 1.3 ng.ml-1.h and 12.4 +/- 5.7 ng.ml-1.h, respectively. These values increased to 4.7 +/- 2.0 ng/ml, 12.1 +/- 5.6 ng.ml-1.h and 47.3 +/- 26.0 ng.ml-1.h on day 21. Within cycle 3, a similar, although less steep increase was observed for these parameters and there was practically no difference in the values of corresponding parameters on day 21 of both cycles. Throughout treatment, there was a redistribution of 3-keto-desogestrel with respect to the binding proteins albumin and sex hormone binding globulin (SHBG). During cycle 1, the free fraction decreased from 1.8% on day 1 to 1.1% on day 21, and the SHBG-bound fraction increased at the same time from 40% to 62%, mainly at the expense of the albumin-bound fraction. During cycle 3, there were only minor changes as compared to cycle one. The observed changes in the serum protein binding were related to an increase in SHBG levels during the treatment period.


Pharmacokinetics and protein binding of gestodene under treatment with a low-dose combination oral contraceptive for three months.

The serum concentrations of gestodene (CAS 60282-87-3) as well as the binding of this progestin to serum proteins were studied in 40 women who took a low-dose oral contraceptive (Femovan, Femodene) containing 30 micrograms ethinyl estradiol (CAS 57-63-6) and 75 micrograms gestodene for 3 months. On days 1, 10, and 21 of the first and the third treatment cycle, respectively, 7 blood samples were drawn before and up to 4 h after pill intake; additional samples were taken prior to morning ingestion of pill on days 2, 5, 11, 15 and 22 of these cycles. Gestodene levels were measured by means of a specific radioimmunoassay and were evaluated for Cmax, tmax, and AUC up to 4 and 24 h. Independent of the test day and the treatment cycle studied, mean maximum gestodene serum levels were found about 0.8 to 0.9 h after pill intake. During the first treatment cycle, mean values of Cmax, AUC(0-4h), and AUC(0-24h) amounted to 4.3 ng.ml-1, 9.3 ng.ml-1.h, and 27.3 ng.ml-1.h on test day 1; these values increased by 250-400% and by 300-500%, respectively, when days 10 and 21 were compared to day 1. On day 1 of the third treatment cycle, these pharmacokinetic parameters were higher by almost a factor of two as compared to the corresponding data obtained on the beginning of the first cycle whereas the increase of these values between day 1 and the subsequent test days (200-300%) was slightly lower in cycle 3 as compared to cycle 1.(ABSTRACT TRUNCATED AT 250 WORDS)


Synthesis of the orally macrofilaricidal and stable glycerolipidic prodrug of melphalan, 1,3-dipalmitoyl-2-(4'(bis(2''-chloroethyl)amino)phenylalaninoyl)gl ycerol.

A new strategy is presented to develop macrofilaricidal compounds orally administered and able to concentrate in the lymphatic system. A diglyceride derivative of melphalan, 1,3-dipalmitoyl-2-(4'(bis(2''-chloroethyl)amino)phenylalaninoyl)gl y cerol, was synthesized. The esterification of melphalan by 1,3-dipalmitin allowed chemical stabilization of the alkylating agent in aqueous dispersion. No degradation of this prodrug was observed after a 3-month storage of an aqueous dispersion at 4 degrees C. The filaricidal activity of the prodrug was compared with those of melphalan in vitro against adults, infective larvae and microfilariae of Molinema dessetae, and evaluated in vivo on Molinema dessetae infected Proechimy oris. In vitro, melphalan and the glycerolipidic prodrug were inactive against microfilariae but active at 1 mmol/l against infective larvae and adults. In vivo studies were performed with rodents subcutaneously inoculated with infective larvae from Aedes aegypti. The number of macrofilariae was significantly reduced following treatment with a single oral dose of the alkylating agent prodrug (0.082 mmol/kg).


In vitro activity of taurolidine, chlorophenol-camphor-menthol and chlorhexidine against oral pathogenic microorganisms.

The antimicrobial activity of taurolidine (Taurolin, CAS 19388-87-5), a synthetic broad-spectrum antimicrobial agent and anti-toxin, and two conventional antiseptics, chlorophenol-camphor-menthol (CCM) and chlorhexidine digluconate (CHX) were compared using the serial dilution test on 10 potential oral pathogenic bacterial species. The minimum inhibitory and minimum bactericidal concentrations were lowest for CHX (MIC 0.03-0.12 mg/ml), followed by taurolidine (MIC 0.12-0.5 mg/ml) and CCM (MIC 0.5-2.0 mg/ml). However, if both bacterial efficacy and cytotoxicity are considered, only taurolidine achieves extensive bactericidal activity with tissue tolerability.


Pharmacokinetics of nicotine and cotinine after application of two different nicotine patches under steady state conditions.

Tobacco use has resulted in major health related problems world-wide. Transdermal nicotine replacement therapy is one of the most promising strategies in smoking cessation. In the present trial the pharmacokinetic properties of two matrix patches (A and B) were characterized and compared after daily application on day 4. Predose nicotine concentrations on day 4 with patch B were higher than with patch A (12.7 +/- 9.5 ng/ml vs. 8.3 +/- 5.3 ng/ml). With patch A there was a steeper increase up to the peak level, followed by a decline gradually up to 24 h. 24 h after application predose levels were reached again, demonstrating absence of significant accumulation of nicotine. The calculated elimination half-lives of nicotine (3.4 +/- 1.8 h after patch A and 3.3 +/- 2.0 h after patch B) were longer than after i.v. application (published values range from 40 to 120 min). Under steady state cotinine concentrations remained constant.


Resistance mechanisms in murine tumors with acquired multidrug resistance.

Mechanisms of multidrug resistance were studied in murine leukemia (L 1210) and sarcoma (Sa 180) tumors after pretreatment with anthracyclines in vivo. Despite identical pretreatment protocols, a considerable difference in the level of resistance between L 1210 and Sa 180 tumors was noted (for doxorubicin: 45-fold versus 340-fold; for daunorubicin: 51-fold versus 275-fold). However, no difference in mdr 1 gene-amplification and the overexpression of mdr 1-RNA or P-glycoprotein was demonstrated. None of these parameters did increase by further treatment with a higher concentration of anthracyclines. Resistant sublines of Sa 180 revealed an overexpression of glutathione S-transferase-pi (GST-pi) in comparison to the parental line, whereas in sensitive and resistant sublines of L 1210 tumors the expression of GST-pi was similar. In order to study whether trifluoperazine can reverse the P-glycoprotein mediated component of multidrug resistance, trifluoperazine and doxorubicin were tested in vitro in L 1210 and Sa 180 cells. In contrast to the complete reversal of resistance in L 1210 tumors, resistance in Sa 180 was only partly circumvented. However, by buthionine sulfoximine treatment, the toxicity of multidrug resistant Sa 180 tumors could be increased. It was possible to reverse the resistance of Sa 180 tumors completely by trifluoperazine plus buthionine sulfoximine. Thus, multidrug-resistant Sa 180 tumors express different defense mechanisms whereas L 1210 tumors express only one defense mechanism (P-glycoprotein).


Distribution of low density lipoprotein in the branch and non-branch regions of the aorta.

Atherosclerosis occurs focally in branch segments of the artery. Understanding why these segments are more susceptible to the development of the disease is at the root of understanding atherogenesis. We investigated accumulation of low density lipoprotein (LDL) in the branch and non-branch regions of the aorta to determine why the disease develops in branch regions. Abdominal aortas and their major branches were harvested from 36 rabbits. Rabbit LDL was prepared from whole blood and radiolabeled with 125I. The aorta was incubated with radiolabeled LDL in the lumen at 37 degrees C, under intraluminal pressure of 2-3 mmHg, for 1 h. Disks of 1.8 mm diameter were punched from the branch and non-branch regions of the aorta, cryosectioned and the sections counted in a gamma counter. Protein bound radioactivity was determined by TCA precipitation. LDL accumulation was highest towards the aortic intima and declined sharply towards the media. LDL accumulation at any given depth was higher in the branch than non-branch region. LDL accumulation in the intimal-medial sections was 87% higher in the branch than non-branch region. Total LDL accumulation in the branch was almost twice that in the non-branch region. Mean LDL accumulation was also greater in the branch than non-branch region. The aorta was significantly thicker at the branch. LDL distribution profiles indicate that LDL is present in a greater concentration and over a greater depth in the branch than non-branch region. The tendency of the branch region to accumulate LDL in greater amounts may explain its susceptibility to atherosclerotic lesion development.


Effect of low-dose probucol therapy on LDL oxidation and the plasma lipoprotein profile in male volunteers.

The effect of 4 months of low-dose probucol treatment (250 mg/day) on LDL oxidation and on plasma-HDL cholesterol was studied in a prospective, double-blind, randomized, placebo-controlled trial involving 26 male volunteers. LDL samples isolated at baseline and at 4 months were subjected to in vitro tests of LDL oxidation, involving copper-catalyzed, time-course experiments. For the placebo group, LDL oxidation did not significantly change over the 4-month period. However, in the probucol group, LDL oxidation was significantly inhibited at 4 months, as evidenced by assays measuring conjugated diene formation, lipid peroxide production and altered electrophoretic mobility of oxidized LDL. In fact, in the probucol group the 'lag-phase' of oxidation was prolonged 2.7-fold. Neither probucol nor placebo had a significant effect on plasma HDL-cholesterol: in the probucol group HDL-cholesterol fell from 37.7 +/- 7.4 mg/dl to 34.2 +/- 8.3 mg/dl (percentage decrease -8.9), while in the placebo group plasma HDL-cholesterol levels were 42.4 +/- 8.3 mg/dl and 40.9 +/- 7.0 mg/dl at baseline and 4 months (percentage decrease -2.7). Therefore, a low dose of probucol (250 mg/day) given daily seems to afford protection against the oxidative modification of LDL, and does not appear to exert any substantial effect on the plasma lipoprotein profile.


Transforming growth factor-beta 1 and interleukin-1 beta stimulate LDL receptor activity in Hep G2 cells.

The effect of transforming growth factor-beta 1 (TGF-beta 1) and interleukin-1 beta (IL-1 beta) on LDL receptor in Hep G2 cells was investigated. A greater than two-fold stimulation of the binding and internalisation of [125I]-labelled LDL at 37 degrees C was observed after an 18-h incubation of the cells with TGF-beta 1 at 50 ng/ml and IL-1 beta at 11,700 units/ml compared with control cells. Scatchard analysis of the binding of [125I]-labelled LDL at 4 degrees C after an 18-h incubation of the cells with 1170 units/ml IL-1 beta and 5 ng/ml TGF-beta 1 showed that they were both acting primarily by increasing LDL receptor number. The increase in LDL receptor activity could not be attributed to an increase in cell proliferation as TGF-beta 1 at concentrations from 0.05 ng/ml to 50 ng/ml had no significant effect on either cell number or [3H]thymidine incorporation into DNA whilst IL-1 beta inhibited DNA synthesis by more than 80% at a concentration of 11,700 units/ml but had significant effect on cell number. Cholesterol biosynthesis from [14C]acetate, in contrast to the stimulation of LDL receptor activity, was inhibited by approximately two-fold by incubation with TGF-beta 1 at 50 ng/ml and IL-1 beta at 11,700 units/ml.


Paradoxical response of plasma lipoprotein(a) in patients undergoing cardiopulmonary bypass.

Plasma lipid, lipoprotein and apolipoprotein levels are known to decrease after major surgery. Coronary artery bypass surgery additionally involves use of extracorporeal circulation by use of a cardiopulmonary bypass pump, which necessitates hemodilution due to saline dextrose infusion to prime the pump. To investigate changes in lipids, lipoproteins and apolipoproteins as well as changes in C-reactive protein and albumin we conducted a study on 22 patients undergoing cardiac surgery involving cardiopulmonary bypass. Timed arterial blood samples were taken before, during and after cardiopulmonary bypass. At the onset and during cardiopulmonary bypass a rapid and significant fall was observed in all lipids and lipoproteins except lipoprotein(a) with recovery to near basal levels by 72 h for cholesterol, triglycerides, high density lipoprotein cholesterol and albumin, while apolipoproteins AI and B remained below basal levels during the postoperative period up to 72 h. In contrast, lipoprotein(a) levels increased at the onset, doubled during cardiopulmonary bypass and remained elevated postoperatively. On the other hand, C-reactive protein levels fell at the onset and during cardiopulmonary bypass but they became markedly elevated postoperatively. When results were corrected for hemodilution, the response patterns remained unchanged. As lipoprotein(a) is both atherogenic and thrombogenic, its elevation during cardiopulmonary bypass may be clinically important.


Acute physical exercise alters apolipoprotein E and C-III concentrations of apo E-rich very low density lipoprotein fraction.

To evaluate the influence of exercise on the apolipoprotein (apo) composition of very low density lipoprotein (VLDL) subfractions, we exercised 6 sedentary men for 30 min, 1 h after a fatty meal. VLDL fractions from samples drawn 4, 6 and 8 h post-prandially were separated from pre-stained plasma by high performance liquid chromatography and fractionated to apo E-poor (heparin-unbound) and apo E-rich (heparin-bound) fractions. The postprandial peak area (volts) and apo E, C-II and C-III concentrations (mg/dl) of post-exercise VLDL fractions were compared with corresponding postprandial values obtained at rest. Plasma triglycerides (TG) levels (mg/dl) were significantly lower 4 (P < 0.05), 6 (P < 0.02) and 8 h (p < 0.05) postprandially; the apo E-poor VLDL fraction was not modified by exercise and its apo concentrations were in the low range of detection; the apo E-rich VLDL peak area significantly decreased 4 (P < 0.01), 6 (P < 0.01) and 8 h (P < 0.05) postprandially; the apo E concentration of apo E-rich VLDL was significantly lower 4 (P < 0.02) and 6 h (P < 0.05) postprandially; the apo C-III concentration of apo E-rich VLDL significantly increased, 4 and 6 h postprandially (P < 0.05). Apo E-rich VLDL is, presumably, the metabolically active fraction of the particle and may regulate plasma TG level following exercise. The metabolic role of apo E-poor VLDL remains to be defined.


Probucol reduces plasma lipid peroxides in man.

Although primarily used as a lipid lowering drug, probucol also possesses anti-oxidant activity and has been shown in animal models to inhibit or delay the progression of atherosclerosis. It has been suggested that this anti-atherosclerotic effect may occur through inhibition of free radical oxidation of low density lipoprotein. The aim of this study was to investigate the effects of probucol on free radical activity in hyperlipidaemic patients. Plasma lipid peroxides were measured before probucol treatment, at 4 and 12 weeks treatment and then 4 weeks after stopping probucol. Lipid peroxide concentrations were significantly reduced during and 4 weeks after stopping treatment with probucol, when compared with baseline values. There were no changes in plasma vitamin E concentrations. The results of this study indicate that probucol reduces lipid peroxidation in patients, an effect which may occur through a free radical scavenging action.


Hageman factor and risk of myocardial infarction in middle-aged men.

In order to evaluate whether Hageman factor (XII) is increased in survivors of myocardial infarction and whether this in turn influences factor VII coagulant activity (VIIc), we examined the coagulation and lipoprotein profiles in 82 subjects, 51 of whom had a definite history of myocardial infarction and 31 healthy volunteers invited from a local general practice register for a cardiovascular screen. Both serum cholesterol (P = 0.03) and plasma fibrinogen levels (P = 0.02) were significantly elevated in cases compared with controls. There were no significant differences in coagulant activities, and in particular factor XII concentration was not significantly different between groups. Furthermore, in 47 of the subjects, 28 of whom had a history of myocardial infarction, a more detailed analysis, including measurement of VIIc after overnight incubation of plasma at 4 degrees C, was undertaken. Approximately half the subjects in either group showed some evidence of activation, though history of myocardial infarction was not in itself a significant predictor of this. All measures of XII concentration related positively to VIIc after cold activation, the strongest being the measure of amidolytic activity following activation of factor XII (XIIAm) (r = 0.5, P < 0.01). In addition, XIIa, a measure of activity due to enzymes derived from factor XII, related strongly to many of the measured lipoprotein variables, particularly VLDL cholesterol and triglycerides, supporting the hypothesis that negatively charged molecules such as free fatty acids on larger lipoprotein particles provide the contact surface necessary to activate factor XII. The findings confirm the importance of this alternative pathway in leading to activation of factor VII.


Interferon-gamma suppresses PDGF production from THP-1 cells and blood monocyte-derived macrophages.

Involvement of the immunological mechanisms in atherogenesis has recently been suggested by immunohistological detection of macrophages and T lymphocytes in atherosclerotic lesions. In the present study, we have investigated the regulatory effect of interferon-gamma (IFN-gamma), a cytokine secreted by activated T cells, on the production and secretion of platelet-derived growth factor (PDGF) from macrophages in culture. The human monocytic leukemia cell line, THP-1, was treated with phorbol 12-myristate 13-acetate (PMA) for 24 h to induce macrophage differentiation and PDGF production, and then various doses of recombinant human IFN-gamma (0-1000 I.U./ml) were added to the culture. After 48 h, the conditioned medium and the cells were harvested and analyzed for PDGF production. PDGF-dependent mitogenic activity in the conditioned medium, estimated by neutralization of mitogenic activity with anti-PDGF antibody, was suppressed by IFN-gamma treatment. Radioimmunoassays for PDGF also revealed a decrease in both PDGF-AA and -BB in the conditioned medium with IFN-gamma treatment, whereas neither total cell DNA as an indication of cell number nor overall protein synthesis based on [3H]leucine incorporation were decreased. Northern analysis of total RNA extracted from the cells demonstrated that IFN-gamma suppressed the level of PDGF mRNA. Analysis of mRNA degradation in the presence of actinomycin D demonstrated that the decrease in PDGF mRNA was not due to enhanced degradation of mRNA. A similar inhibitory effect of IFN-gamma on PDGF mRNA levels was also found in monocyte-derived macrophages cultured in the presence of granulocyte-macrophage colony stimulating factor. These results suggest that IFN-gamma modulates production and secretion of PDGF from macrophages and that the functions of macrophages in atherogenesis may be regulated by the cellular interactions between T cells and macrophages through the action of cytokines such as IFN-gamma.


An oxidative mechanism is involved in high glucose-induced serum protein modification causing inhibition of endothelial cell proliferation.

In order to investigate the role of hyperglycemia on the development of atherosclerosis in diabetics, the effects of high glucose-induced modification of serum factors on the proliferation of bovine carotid artery endothelial cells were studied. Dialysates of high glucose-treated serum inhibit cell growth in a time- and glucose concentration-dependent manner. With 6 weeks of pretreatment, 16.7 mM glucose causes a 47.2% inhibition in cell growth compared to 5.6 mM glucose (P < 0.001). Pretreatment of serum in the presence of reduced glutathione (0.5-1.0 mM), an antioxidant, significantly prevents the high glucose-induced inhibition without inhibiting the formation of early non-enzymatic glycosylation products. Dithiothreitol (7.5 mM) treatment after preincubation with glucose fully restores the glucose-induced inhibition. When the dialysates are fractionated according to molecular mass, the high glucose-induced inhibition is maximal in the MW fraction above 100 kDa. These data suggest that high glucose conditions facilitate the susceptibility of serum proteins to sulfhydryl oxidation forming disulfide crosslinks and this oxidative process may contribute to the inhibition of endothelial cell proliferation.


Homocysteine catabolism: levels of 3 enzymes in cultured human vascular endothelium and their relevance to vascular disease.

Elevated plasma homocysteine enhances the risk of thrombosis and premature arteriosclerosis. We have assessed the activity of the 3 prime enzymes of homocysteine metabolism in cultured human venous endothelial cells, in a study of their possible protective roles. In cells from 4 individuals, cultured in Dulbecco's modified Eagle medium, the mean activity +/- S.D. of cystathionine beta-synthase (nmol of product/h per mg of cell protein, at 37 degrees C) was 3.58 +/- 3.11 at pH 8.6. The assay used was our newly developed amino acid analyser-based procedure. The activity of 5-methyltetrahydrofolate:homocysteine methyltransferase at pH 7.4 was 4.12 +/- 1.25 and betaine:homocysteine methyltransferase (BHMT) was undetectable (< 1.4 nmol/h per mg protein). Cells were also cultured in a medium aimed at stimulating methionine biosynthesis, containing methionine-deficient Dulbecco's modified Eagle medium to which L-homocystine (100 mumol/l) and methylcobalamin (1 mumol/l) had been added. In these cells 5-methyltetrahydrofolate:homocysteine methyltransferase activity increased to 7.95 +/- 1.45, P < 0.001, there was a non-significant decrease in cystathionine beta-synthase activity to 2.16 +/- 1.52 and BHMT activity was still undetectable. These cells were more resistant to in vitro homocysteine-induced detachment than were cells from the same line cultured in Dulbecco's modified Eagle medium alone. Our findings establish that human endothelial cells express 2 of the 3 primary enzymes of homocysteine catabolism. They suggest that persons who are deficient in cystathionine beta-synthase or 5-methyltetrahydrofolate:homocysteine methyltransferase activity may not only develop homocysteinemia, but also have vascular endothelium which is more susceptible to damage by homocysteine than persons with normal enzyme levels.


Results of a randomized trial of partner notification in cases of HIV infection in North Carolina.

We sought to compare two methods of notifying sex partners of subjects infected with the human immunodeficiency virus (HIV) or persons who had shared needles with them (needle-sharing partners): "patient referral," in which the responsibility for notifying partners was left to the patient, and "provider referral," in which providers attempted to notify partners. Names of sex partners and needle-sharing partners and information on how to locate them were obtained from consenting HIV-infected subjects identified in the HIV-testing programs at three public health departments in North Carolina. The subjects were randomly assigned to a patient-referral group (in which patients had the initial responsibility for notifying their partners) or a provider-referral group (in which the study counselor notified the partners). The success of attempts to notify partners was monitored by means of interviews with counselors conducted both in the field and at the health department. Of 534 HIV-positive persons identified at the health departments, 247 (46 percent) did not return for counseling after the test, 8 were counseled outside the study, and 117 (22 percent) were ineligible. Of the 162 invited to participate, 88 (54 percent) declined and 74 (46 percent) agreed. The subjects were mostly male (69 percent), black (87 percent), homosexual or bisexual (76 percent of the men), and had a median age of 30 years. Thirty-nine were assigned to the provider-referral group and 35 to the patient-referral group. In the provider-referral group 78 of 157 partners (50 percent) were successfully notified, whereas in the patient-referral group only 10 of 153 (7 percent) were notified. Of the partners notified by the counselors, 94 percent were not aware that they had been exposed to HIV. Overall, 23 percent of the partners notified and tested were HIV-positive. In this trial, leaving the notification of partners up to the subjects (patient referral) was quite ineffective, despite the North Carolina law requiring that partners be notified. Partner notification by public health counselors (provider referral) was significantly more effective. Although the effectiveness of notification procedures is constrained by the accuracy of the information provided by HIV-infected patients, counselors who notify the partners of an infected patient can refer them to educational, medical, and support services targeted to persons at high risk for HIV infection and may encourage the adoption of less risky behavior.


Nicotine enhances 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity.

Epidemiologic evidence of an inverse relationship between cigarette smoking and Parkinson's disease suggests that a component of cigarette smoke protects against nigrostriatal degeneration. Nicotine, a major component of cigarette smoke, is similar in chemical structure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and is metabolized in part by the same enzymes that detoxify MPTP. We investigated the effect of chronic nicotine on MPTP neurotoxicity in two strains of mice and found that nicotine increases rather than decreases MPTP toxicity. These results are not compatible with the hypothesis that nicotine is that component of cigarette smoke that protects against nigrostriatal degeneration, at least in the MPTP experimental model of Parkinson's disease.


Endoscopic transanal resection of large villous tumours of the rectum.

Endoscopic transanal resection (ETAR) is an innovative approach in the management of low lying tumours of the rectum. We report our experience of this technique in six elderly patients (mean age 74 years) with large villous adenomas, situated between 2 and 12 cm from the anal verge. There were no complications. One patient with a circumferential tumour has been spared the more conventional operation of abdominoperineal excision. Follow-up ranged from 6 to 30 months (mean 16 months) during which two recurrences were detected. These were adequately treated by further ETARs. It is concluded that ETAR is a simple and well-tolerated procedure and is a useful addition to the surgeon's armamentarium.


Clonal origin of bladder cancer.

Patients with cancer of the urinary bladder often present with metachronous tumors, appearing at different times and at different sites in the bladder. This observation has been attributed to a "field defect" in the bladder that allows the independent transformation of epithelial cells at a number of sites. We tested this hypothesis using molecular genetic techniques. We examined 13 tumors from cystectomy specimens from four women, using a method that analyzes the pattern of X-chromosome inactivation to determine whether the tumors were derived from the same precursor cell. In addition, we analyzed allelic loss on autosomes to determine whether different tumors had the same genetic alterations. The alterations evaluated included the loss of chromosome 9q sequences (commonly found in superficial bladder tumors) and the loss of 17p and 18q sequences (usually found only in advanced tumors). For each patient studied, all the tumors had inactivation of the same X chromosome, whereas normal bladder mucosa cells had random patterns of inactivation. Moreover, each tumor that could be evaluated from a given patient had lost the same allele on chromosome 9q, suggesting that the loss of this allele preceded the spread of neoplastic cells elsewhere in the bladder. The losses of chromosome 17p and 18q alleles, which are late events in tumor progression, were not common to different tumors from the same patient. A number of bladder tumors can arise from the uncontrolled spread of a single transformed cell. These tumors can then grow independently with variable subsequent genetic alterations.


Factors influencing cosmetic outcome and complication risk after conservative surgery and radiotherapy for early-stage breast carcinoma.

The study was undertaken to assess the relationship among cosmesis and complications to factors related to disease presentation, surgical and radiotherapeutic technique, and adjuvant systemic therapy in conservative treatment for early-stage breast carcinoma. Between 1982 and 1988, 234 women with stage I/II breast carcinoma were treated with conservation therapy by a highly standardized protocol of limited excision and radiotherapy. Radiation boost and/or reexcision were determined by careful quantitation of the normal tissue margin around the primary tumor. Boosts to 20 Gy were preferentially performed with interstitial iridium-192 (192Ir) implants. Axillary node dissections were performed in all patients aged less than 70 years. Adjuvant therapy consisted of cyclophosphamide, methotrexate, (doxorubicin), and fluorouracil (CM[A]F) six to eight times for node-positive premenopausal women and tamoxifen for node-positive or -negative postmenopausal women. Median follow-up was 50 months (range, 20 to 80 months). Cosmesis was graded by defined criteria, and complications were individually scored. Factors found to impact cosmesis adversely were palpable tumors (P = .046), volume of breast tissue resected (P = .027), reexcision of the tumor bed (P = .01), number of radiation fields (P = .03), radiation boost (P = .01), and chest wall separation (P = .01). There was a trend toward worse cosmesis (P = .062) in patients receiving tamoxifen. Cosmesis was not adversely affected by interstitial implant in spite of a higher prescribed dose. Factors influencing complication risk were axillary node dissection (P = .02), number of lymph nodes harvested (P = .05), and chemotherapy (P = .03). Optimal cosmesis and minimal complication risk require careful attention to the technical details of surgery and radiotherapy. The impact of systemic therapies needs to be more thoroughly examined.


The centre thought to control sensory and motor activity in the early history of medicine.

In Ancient Greek medicine the heart instead of the brain was sometimes thought to be the organ co-ordinating sensory and motor activity. The history of the origin of this erroneous idea is outlined. The relative importance of observations and theory in early medical investigations is discussed, and the anatomical dissections leading to the establishment of the brain as the centre of sensory and motor function are described.


Meatoscopy: a simple technique to examine the distal anterior urethra in men.

A common problem is to determine the site of the base of meatal warts in men and if the lesions will be suitable for the treatments available in genitourinary medicine (GUM) or sexually transmitted diseases (STD) clinics. Formal endoscopy requires sterile conditions and is therefore an expensive procedure. A simple safe cheap alternative is meatoscopy using an auroscope with inflation. This allows inspection of the anterior urethra to a depth of 5 or 6 cm. With this technique 175 examinations were performed on 153 patients. Warts were confined to the lips in 27 (56%) of 48 patients with meatal warts; in an additional 5 patients with meatal warts the warts arose from deep in the fossa navicularis and in 16 patients with meatal warts there were additional warts in the fossa navicularis invisible on clinical examination. No urethral warts were seen in 103 patients without meatal warts, comprising 47 patients with external genital warts and 56 without any warts. It is concluded that meatoscopy should be undertaken in all patients with meatal warts to determine the site of their base and to assess if there are any more proximal warts. This should be done as soon as the meatal warts are seen, and urethritis has been excluded, so that appropriate treatment can be planned.


Medical Research Council trial of treatment of hypertension in older adults: principal results. MRC Working Party.

To establish whether treatment with diuretic or beta blocker in hypertensive older adults reduces risk of stroke, coronary heart disease, and death. Randomised, placebo controlled, single blind trial. 226 general practices in the MRC general practice research framework. 4396 patients aged 65-74 randomised to receive diuretic, beta blocker, or placebo. Patients had mean systolic pressures of 160-209 mm Hg and mean diastolic pressures less than 115 mm Hg during an eight week run in and were not taking antihypertensive treatment. Patients were randomised to atenolol 50 mg daily; hydrochlorothiazide 25 mg or 50 mg plus amiloride 2.5 mg or 5 mg daily; or placebo. The regimens were adjusted to achieve specified target pressures. Mean follow up was 5.8 years. Strokes, coronary events, and deaths from all causes. Both treatments reduced blood pressure below the level in the placebo group. Compared with the placebo group, actively treated subjects (diuretic and beta blocker groups combined) had a 25% (95% confidence interval 3% to 42%) reduction in stroke (p = 0.04), 19% (-2% to 36%) reduction in coronary events (p = 0.08), and 17% (2% to 29%) reduction in all cardiovascular events (p = 0.03). After adjusting for baseline characteristics the diuretic group had significantly reduced risks of stroke (31% (3% to 51%) p = 0.04), coronary events (44% (21% to 60%), p = 0.0009), and all cardiovascular events (35% (17% to 49%), p = 0.0005) compared with the placebo group. The beta blocker group showed no significant reductions in these end points. The reduction in strokes was mainly in non-smokers taking the diuretic. Hydrochlorothiazide and amiloride reduce the risk of stroke, coronary events, and all cardiovascular events in older hypertensive adults.


Surgery for stroke: an update.

Carotid endarterectomy was the most common vascular procedure in the USA in the 1980s. The last decade has witnessed a much-needed critical reappraisal of its role. Results from recent large-scale trials are now reported and will have a great influence on patient management.


Advanced Chinese NiTi alloy wire and clinical observations.

Chinese NiTi wire was studied on the bench with six other nickel-titanium-alloy wires. Bending and torsional tests were conducted and temperatures of phase transformation compared. The Chinese NiTi wire was found to have a low stiffness, high springback and constant bending and torsional moments on unloading, in a very large deformation region. It can produce a gentle, nearly constant force. These factors make it desirable for clinical application. Included in this paper are clinical observations of case selected from over 100 patients in current treatment with Chinese NiTi wires. Chinese NiTi wire reduced the leveling and alignment phase of treatment without discomfort to the patient. Chinese NiTi wire can be used in both children and adults.


Bacteremia and fungemia of unknown origin in adults.

Two hundred fifteen (23%) of 955 episodes of bacteremia (defined as including fungemia) detected in adult patients during 2 years were of unknown origin. Sixty-six percent of episodes of unknown origin were hospital acquired. The median age of patients with bacteremia of unknown origin was 65 years, and their most common underlying disorders were solid malignancy (28% of patients) and diabetes mellitus (18%). Only three factors were associated with bacteremia of unknown origin (as opposed to episodes with a known source): peripheral venous catheterization, hemodialysis, and plasmapheresis. Gram-negative bacteria were isolated from the blood in 62% of episodes of unknown origin; 10% of episodes were polymicrobial. Staphylococci were isolated from 67% of patients undergoing hemodialysis and from 37% of those with diabetes; Pseudomonas species from 15% of patients with hospital-acquired episodes; and Candida species from 21% of patients with a central venous catheter. Fifteen percent of episodes in cancer patients were polymicrobial. Empirical antibiotic treatment was inappropriate in 49% of episodes of unknown origin and in 35% of episodes with a known source (P less than .001). Death rates were 44% and 25% in episodes of unknown and known origin, respectively. An unknown source of bacteremia was independently associated with a fatal outcome.


Trying times for human insulin.

The introduction of human insulin to treat diabetics seemed straightforward. What can account for the problems that have followed?


The comparative strengths of commercial glass-ionomer cements with and without metal additions.

Metal reinforced glass-ionomer cements are said to possess superior mechanical properties when compared to non-metal reinforced glass-ionomer cements. However, the literature to date does not always support this view, owing to the variety of materials and test methods employed. In this study the mechanical properties of three reinforced and three standard materials were tested using the standard specification tests of compressive and diametral strength in addition to tensile strength using the four point bend test. The tensile strength was also measured using the shell test in order that this test, which on theoretical grounds is more suited to these materials, may be evaluated. Six specimens of each material were prepared for each of the test modalities resulting in the conclusion that the addition of metal to glass-ionomer cements can markedly increase the strength of the materials. However, the method of fusing the metal to the glass rather than by simple addition does not produce any advantages in strength. In this evaluation one reinforced material was significantly stronger than all other materials in all four test modalities. The compressive strength test which appears in most standards does not appear to be very discriminatory. Of the tensile tests, which have more clinical significance, the results of the diametral strength tests, which are included in some standards, appear to be at variance with the other two tensile tests, suggesting that the flexural or shell test would be more appropriate.


Study of diagnostic accord between general practitioners and an ophthalmologist.

To identify diagnostic accord and disagreement between general practitioners and an ophthalmologist and thereby determine how undergraduate and non-specialist postgraduate ophthalmic training could be improved. Comparison of diagnosis of presenting conditions by general practitioners and one ophthalmologist in patients consulting general practitioners for ophthalmic problems during March 1989 to February 1990. 12 general practices in west Nottingham. 1474 patients presenting to the study general practitioners with new ophthalmic conditions or new episodes of recurrent conditions. Diagnoses of general practitioners and ophthalmologist. 1121 (76%) of patients with eye problems agreed to see the ophthalmologist and most were seen within three days. Sufficient data for comparison were available on 1103 patients. Diagnostic agreement was found in 638 cases (58%), but potentially serious misdiagnosis was found in only 15 cases; management in three of these cases would have ensured later identification. Most commonly confused conditions were infective and allergic conjunctivitis, blepharitis, and dry eyes. General practitioners assessed visual acuity in only 114 cases yet eight of the 15 patients seriously misdiagnosed had reduced acuity, an important diagnostic sign. Most ophthalmic disease seen in general practice does not require specialised equipment for diagnosis. Most cases of misdiagnosis have no serious consequences for the patient. Undergraduate and postgraduate training in ophthalmology should ensure that common conditions can be easily differentiated and more serious conditions identified and referred.


Nucleotide sequence analysis and serologic characterization of the Mycobacterium intracellulare homologue of the Mycobacterium tuberculosis 19 kDa antigen.

Disseminated Mycobacterium avium/Mycobacterium intracellulare complex (MAC) disease is a frequent complication in patients with the acquired immune deficiency syndrome (AIDS). In this report, we present the nucleotide sequence of the M. intracellulare MI22 gene. Computer sequence comparisons reveal that the MI22 gene, which encodes a serologically active protein, has 78% DNA sequence identity and 77% protein sequence identity with the seroreactive 19 kDa Mycobacterium tuberculosis lipoprotein antigen. Southern blot hybridizations indicate that an MI22 gene probe binds similar-sized restriction fragments in M. tuberculosis and M. intracellular genomic DNA. In addition, immunoblot analyses demonstrate that MI22 is recognized by sera from tuberculosis patients. These data further support the existence of 19 kDa MAC and M. tuberculosis protein homologues. Phase partitioning experiments and the presence of a consensus lipid modification site in the deduced MI22 protein sequence strongly suggest that M122 is also a lipoprotein. Comparative analyses of these mycobacterial antigenic homologues may provide the basis for the design of species-specific diagnostic reagents.


Transdifferentiation of macrophages into fibroblasts as a result of Schistosoma mansoni infection.

The possibility of transdifferentiation of macrophages into fibroblasts which could be at the origin of fibrotic tissue in schistosome-infected mice was studied using immunocytochemical techniques. Macrophage cell samples extracted from the peritoneal cavity of schistosome-infected mice were fractionated on a Percoll gradient. The cultures were purified by treatment with a trypsin solution to eliminate any fibroblasts possibly collected along with the macrophages. Immunocytochemical methods were then used to characterize the cells at different points in time. The fibroblastic property of the morphologically transformed cells was confirmed by their positive labeling with the anti-procollagen antibody. However, these cells still possessed the mac-1 and mac-2 antigens which characterize the monomacrophage line.


Flow cytometry in the study of the interaction between murine macrophages and the protozoan parasite Leishmania amazonensis.

A flow cytometry method was adapted to study interaction between murine macrophages and Leishmania amazonensis. Using this method it was possible to detect internalization of parasites through an increase in macrophage granularity (side scatter), with the latter indicating the presence of parasites inside parasitophorus vacuoles. A quenching technique was used to confirm the feasibility of the method and to distinguish between internalized and externally attached parasites. Experiments using fixed-labeled and killed-unlabeled parasites gave similar results, demonstrating that granularity was an adequate parameter in the study of parasite-macrophage interaction, when compared with labeling methods. Experiments that measured internalization using only the increase in macrophage granularity as an indicator showed that living L. amazonensis was internalized to a greater extent than killed-unlabeled parasites. This finding suggests that the parasite has an active role in the process of internalization. The 2 methods in combination, flow cytometry and labeling, can be used to study murine peritoneal cell-L. amazonensis interactions and to sort phagocytosing and nonphagocytosing subpopulations of macrophages for further studies.


Sleep disturbance in children with growth hormone deficiency.

We examined the effects of growth hormone (GH) deficiency on sleep development by performing all-night polysomnography in three female children with GH deficiency (GHD). The percentage of REM sleep seemed to be reduced before the treatment in 2 cases, and human GH (hGH) compensation slightly increased it. Submental twitch movements (mTMs), i.e., body movements during sleep localized in the submental muscle and lasting less than 0.5 seconds, were commonly disturbed in the three patients. Rapid eye movements in REM sleep (REMs) were reduced before the therapy in one case, this decrease being reversed on hGH compensation. REMs also seemed to increase after hGH treatment in the other two cases. Dopamines and cholinergic muscarinic agonists can cause GH release, while mTMs and REMs might be related to dopaminergic and cholinergic systems in the human brain. It is intriguing that GHD, and the disturbance of mTMs and REMs coexisted in children with GHD. Since a relatively poor social outcome in patients with GHD has been reported, even after hGH compensation, it is important to monitor their neurological development by means of evaluation of their sleep disturbance.


Inhibition of rat tissue kallikrein gene family members by rat kallikrein-binding protein and alpha 1-proteinase inhibitor.

The regulation of tissue kallikrein activity by plasma serine proteinase inhibitors (serpins) was investigated by measuring the association rate constants of six tissue-kallikrein family members isolated from the rat submandibular gland, with rat kallikrein-binding protein (rKBP) and alpha 1-proteinase inhibitor (alpha 1-PI). Both these serpins inhibited kallikreins rK2, rK7, rK8, rK9 and rK10 with association rate constants in the 10(3)-10(4) M-1.s-1 range, whereas only 'true' tissue kallikrein rK1 was not susceptible to alpha 1-PI. This results in slow inhibition of rK1 by plasma serpins, which could explain why this kallikrein is the only member of the gene family identified so far that induces a transient decrease in blood pressure when injected in minute amounts into the circulation.


Mother-to-infant transmission of human immunodeficiency virus by breast milk: presumed innocent or presumed guilty?

This article reviews the virological and epidemiological data available on transmission of the human immunodeficiency virus type 1 (HIV-1) by breast milk. Colostrum and breast milk are considered major modes of transmission for many animal retroviruses as well as human T-cell leukemia virus, mainly as the consequence of ingestion of infected cells. Several cases that strongly suggest transmission of HIV-1 through breast-feeding have now been reported. In addition, recent evidence suggests that postpartum HIV-1 seroconversion of a mother may be associated with a high risk of postnatal transmission to offspring via breast milk. Preventive measures such as pasteurization of breast milk have not been fully examined. While the World Health Organization continues to promote breast-feeding in areas where no safe alternative exists, the Centers for Disease Control recommends that American women who are infected by HIV-1 not practice breast-feeding if a safe alternative is available. Large-scale, carefully controlled, prospective studies of the risk of HIV-1 infection associated with breast-feeding are of the utmost priority. Feasible and ethically acceptable feeding alternatives should be developed for countries where formula feeding has a strong negative effect on child morbidity and mortality.


Clinical breast cancer, new developments in selection and endocrine treatment of patients.

Breast cancer is the most common malignant tumor among women, comprising an estimated 24% of all cancer cases and 18% of all cancer deaths. At least half of the patients with primary breast cancer will ultimately die by metastatic disease. The tumor characteristics, the natural course of the disease and the response to therapy vary strongly. A number of recently detected cell biological parameters such as oncogenes/suppressor genes, growth factors and secretory proteins are more or less important prognostic factors, because they influence the characteristics and behavior of a tumor with respect to metastatic pattern, extent of cellular differentiation, growth rate and response to treatment. However, there is no clear consensus how best to identify patients at high or low risk. In our experience c-myc amplification and pS2 protein are strong prognosticators for relapse rate, while in advanced disease (apart from a negative estrogen/progesterone receptor/pS2 status) amplification of HER2/neu is a good prognosticator for failure to endocrine therapy. In the diagnosis of breast cancer, in vivo imaging of tumors by labeled hormones or other factors also forms a new development which might have implications for treatment too. With respect to treatment both endocrine and chemotherapy can cure a minority of patients with micrometastases, but in patients with advanced disease only a prolongation of (progression-free) survival can be reached. Response rates decrease with increasing tumor load. In the past decade a number of interesting new endocrine agents has been developed such as new (pure) (anti)steroidal agents, vitamins, aromatase inhibitors, analogs of peptide hormones, prolactin inhibitors and growth factor antagonists. However, less is known on the (potential) interaction between hormones, chemotherapeutic agents, retinoids, cytokins, growth factor antagonists and irradiation. Rapid detection of new powerful combination therapies are needed to improve treatment results during the nineties.


Postantibiotic effect of amikacin and rifapentine against Mycobacterium avium complex.

Postantibiotic effect (PAE) has received little attention in the therapy of chronic intracellular infections, such as those caused by mycobacteria. Amikacin is active therapeutically against Mycobacterium avium complex, even though serum levels exceed the MIC for only a few hours. To determine the PAE of amikacin and rifapentine for M. avium, bacteria were exposed to concentrations of 1x, 4x, and 10x the MIC of each drug for up to 120 min. Regrowth of M. avium was compared with similarly diluted untreated cultures. No PAE was observed on an inoculum of 10(4) bacteria when rifapentine was used at 5x MIC, although a slight inhibition of growth was obtained at 10x MIC for 2 h. For amikacin, PAE was observed up to 48 h at concentrations of 4x and 8x MIC and exposure times of 30-120 min. A PAE of 22 h was seen with 10(7) cfu of M. avium during incubation for 30 min with amikacin at 4x MIC. These results show that amikacin, unlike rifapentine, has a long PAE against M. avium.


Cloning of a subunit of yeast RNA polymerase II transcription factor b and CTD kinase.

Yeast RNA polymerase II initiation factor b copurifies with three polypeptides of 85, 73, and 50 kilodaltons and with a protein kinase that phosphorylates the carboxyl-terminal repeat domain (CTD) of the largest polymerase subunit. The gene that encodes the 73-kilodalton polypeptide, designated TFB1, was cloned and found to be essential for cell growth. The deduced protein sequence exhibits no similarity to those of protein kinases. However, the sequence is similar to that of the 62-kilodalton subunit of the HeLa transcription factor BFT2, suggesting that this factor is the human counterpart of yeast factor b. Immunoprecipitation experiments using antibodies to the TFB1 gene product demonstrate that the transcriptional and CTD kinase activities of factor b are closely associated with an oligomer of the three polypeptides. Photoaffinity labeling with 3'-O-(4-benzoyl)benzoyl-ATP (adenosine triphosphate) identified an ATP-binding site in the 85-kilodalton polypeptide, suggesting that the 85-kilodalton subunit contains the catalytic domain of the kinase.


Pharmacological profile of TCV-309--a potent PAF antagonist.

TCV-309 potently and specifically inhibited the diverse biological actions of PAF such as platelet aggregation, hypotension, increased vascular permeability, bronchoconstriction and death. TCV-309 did not cause hemolysis or vascular irritation. TCV-309 showed beneficial effects on experimental endotoxic shock, anaphylactic shock and disseminated intravascular coagulation.


[Nursing care of the elderly. Moral and ethical problems].

The article deals with moral and ethical issues involved in nursing care of the elderly during their hospitalization. Nursing interventions resulted in iatrogenic complications as well as nursing dilemmas are also discussed.


[The present status of interpleural analgesia].

Since the introduction of interpleural administration of local anaesthetics by Kvalheim and Reiestad in 1984, this technique has been applied to treat postoperative pain after cholecystectomy, renal, thoracic and unilateral abdominal surgery. Other indications are pain control in patients who suffered multiple rib fractures and in patients with chronic pain due to pathological processes in the pancreas. Due to the fact that interpleural analgesia is considered a new anaesthetic procedure, a number of questions still have to be answered regarding the mechanism of action, the appropriate local anaesthetic solution to be employed and, most importantly, the benefit/risk ratio associated with this technique. The purpose of this review article is to give a detailed account of the knowledge and obtained clinical experiences present to date regarding interpleural analgesia, and to give a critical evaluation of this method.


[Anaphylactoid reactions to muscle relaxants].

Anaphylactoid (i. e. anaphylactic-like) reactions have been estimated to occur in between one in 600 and one in 1,000 general anaesthesias. Two thirds of these reactions are caused by neuromuscular blocking drugs used during anaesthesia. An anaphylactoid potential is inherent in all muscle relaxants, albeit to a varied extent, reflecting an obligatory feature of their molecular structure (quaternary ammonium groups) and common physicochemical characteristics. Hence, also newer relaxants are not void of anaphylactoid risk. In Britain, the recent availability of drug-specific radioallergosorbent tests (RAST) has initiated much controversy on preanaesthetic antibody screening and possible medicolegal consequences. Since every anaesthetist must expect to be faced with such an unforeseen and occasionally life-threatening reaction, the characteristic clinical manifestations, basic therapeutic strategies and current opinion on underlying pathophysiological mechanisms are summarized in this review article. Based on the recommendations of the British National Adverse Anaesthetic Reaction Advisory Service (NAARAS), essential diagnostic procedures during and after anaphylactoid events are discussed. Finally, prophylactic precautions including the preoperative administration of H1- and H2-antihistamines are recommended.


[Chronic hemodialysis treatment of patients older than 74 years. An epidemiological study in 16 renal units in Northern Greece].

In a review of 1057 patients who started receiving chronic haemodialysis treatment during the last decade in 16 renal units of Northern Greece only 25 patients (2.36%) were found to be older than 74 years at start of haemodialysis treatment. The most common cardiovascular problems in these elderly patients were angina pectoris in 9 and difficulties in fistula creation in 10 patients. Arterial hypertension was present in 7 patients. The first year survival rate was 55.5%. Cardiovascular episodes were the commonest cause of death among the 14 patients who died. We conclude that during the last decade in Northern Greece, among patients receiving chronic haemodialysis treatment, only a few started treatment after the age of 74 years and although they had significant cardiac and vascular problems their first year survival rate was acceptable.


[Effects of acute myocardial infarction on the patient's and the family's way of life].

During the last decade, the relation between psychosocial factors and patient's personality in front of the risk of an acute myocardial infarction and his health progress after the infarction has fully been investigated. The patient's personality and a number of factors related to his job-carrier and family environment have been proved to be very important. The effect of patient's behaviour, educational level, social and psychological status in the progress of coronary heart disease have especially pointed out. The myocardial infarction is a serious disease which can alter the patient and his close family's way of life due to its financial among the other consequences. This influences the members of the family as an entity and alters their life in many ways. The present study aims to investigate how the myocardial infarction as an expected or unexpected event affects differently and at which degree the behaviour of patient's family.


[Nifedipine prolongs a neuromuscular blockade caused by atracurium].

Calcium entry blockers are now widely employed in the treatment of cardiovascular diseases and perioperative hypertension. In patients with coronary heart disease nifedipine therapy should be continued perioperatively to avoid coronary artery spasm. Animal experiments have demonstrated that calcium entry blockers potentiate the neuromuscular blockade induced by nondepolarizing blocking agents. In patients, an atracurium-induced neuromuscular depression is prolonged by intravenous nifedipine. In this prospective clinical study we evaluated the effect of chronic oral nifedipine therapy on the duration of neuromuscular block by atracurium. Sixty patients anaesthetized with isoflurane in nitrous oxide/oxygen were recruited for this study. Thirty of these were on chronic oral nifedipine therapy and received their normal morning dose before premedication. The control consisted of 30 patients of similar age and status but not taking any calcium entry blockers. Monitoring included noninvasive blood pressure, heart rate, pharyngeal temperature, physical breathing parameters and neuromuscular transmission with a Datex Relaxograph TM ("train of four"-principle). After inducing hypnosis 0.5 mg/kg atracurium were administered for muscular relaxation. The duration of block from administration of the relaxant to recovery of first twitch height (T1) to 25% of control twitch height was registered as duration of initial block. When T1 reached 25% a repetition dose of 0.2 mg/kg atracurium was injected. The time till recovery of T1 to 25% was recorded as the duration of the repetition dose. Results were compared using Student's t-test for unpaired data. There was a significant prolongation of the duration of initial block from 38 min +/- 10 min in the control group to 46 min +/- 8 min in the therapy group (P < 0.01). The duration of the repetition dose rose from 30 min +/- 8 min in the control group to 38 min +/- 7 min in the therapy group (P < 0.001). Daily nifedipine doses varied from 10 mg in the morning to 40 mg divided into single doses with no influence on the prolongation of neuromuscular block. Our results confirm previous assumptions of synergistic effects of nifedipine and neuromuscular blocking drugs in patients. Chronic oral nifedipine therapy potentiates neuromuscular blockade by atracurium as does nifedipine intravenously. This effect should be considered in the treatment of cardiovascular diseases with nifedipine in the perioperative period.


[Study of clean versus aseptic technique of tracheotomy care based on the level of pulmonary infection].

The purpose of this research study was to determine whether the clean technique of tracheotomy care is the same, or more, secure from the aseptic, by testing the difference in the level of postoperative pulmonary infection between tracheotomized patients receiving aseptic and those receiving clean tracheotomy care. The sample consisted of 103 patients with tracheotomy (transient or permanent) from ENT or IC units of four big hospitals of Athens. The level of the patient's pulmonary infection was defined using the Weighted Level of Pulmonary Infection Tool, which was constructed especially for this research study. The data were analysed using the x2 statistical test, and the coefficients phi, Cramer's V and Kendall's, while, with the same statistics, the relationship between certain important external variables and the dependent variable was examined. The findings indicated that no statistically significant difference exists between clean and aseptic technique as to the level of pulmonary infection when used for tracheotomy postoperative care of tracheotomized patients.


[Nursing care research on the evaluation of elderly patients].

Research in nursing of elderly patients refers to the investigation of their special needs as well as the context and methods for this kind of care to be provided. Reports published on nursing needs are rare. Clinical nursing evaluation of elderly patients and relevant research studies are briefly reviewed.


Pyrazolo[3,4-d][1,2,3]triazole-1-carboxamides and 5-alkylaminopyrazolo[3,4-d]oxazoles: synthesis and evaluation of the in vitro antifungal activity.

A series of N-alkyl-N'-(4-diazo-5-pyrazolyl)-ureas (4) was thermally and photochemically converted into pyrazolo [3,4-d][1,2,3]triazole derivatives (5,6) and 5-alkylaminopyrazolo[3,4-d]oxazoles (7) respectively. The products were tested for in vitro antifungal activity against Fusarium culmorum, Botrytis cinerea, Phoma betae, Pythium ultimum, Sclerotinia minor and Rhizoctonia solani. The MIC and ED50 values of compound (6) against some of the test fungi were comparable to those of the reference fungicides iprodione and mancozeb.


Studies on anti-Candida agents with a pyrrole moiety. Synthesis and microbiological activity of some [(1-alkyl),(1-aryl) and (1-benzyl)-5-aryl-3-carboxamido-2-methyl]pyrrole derivatives.

The synthesis of some [(1-alkyl),(1-aryl) and (1-benzyl)-5-aryl-3-carboxamido-2-methyl]pyrrole derivatives is reported. Their activity against Candida strains has been assessed and the structure-activity relationships for these compounds are discussed.


Pyrimidoacridine derivatives as potential antitumor agents.

A series of some N-alkylaminoalkyl derivatives of pyrimido[5,6,1-d,e]acridine-1,3,7-trione (3) was synthesized as new potential antitumor drugs, starting from the suitable 9,10-dihydro-9-oxo-4-acridinecarboxamides and using phosgene as cyclizing agent. 1-(9,10-dihydro-9-oxo-4-acridinecarbonyl)-3-alkyl-2-imidazolido nes were also obtained as side products. The final products 3 and some carboxamides were tested "in vitro" against L 1210 leukemia and "in vivo" against P388 leukemia. Of the tested compounds, one is active "in vivo", another shows significant cytotoxic activity "in vitro", but is inactive or toxic "in vivo".


Synthesis and antimycobacterial activity of some 2-pyridinecarboxyamidrazone derivatives.

A series of N1-aryliden-2-pyridincarboxyamidrazone derivatives was prepared. Some of the synthesized compounds showed interesting in vitro antimycobacterial activity against some strains of Mycobacterium and clinical isolates of Mycobacterium tuberculosis.


Simultaneous determination of amiodarone and desethylamiodarone in human plasma by high performance liquid chromatography.

A rapid, sensitive and specific reversed phase HPLC method for the simultaneous assay of amiodarone and its major metabolite desethylamiodarone in human serum has been developed. This method is suitable for pharmacokinetic studies and for monitoring of the drug and metabolite concentrations in serum of patients on both short and long-term therapy with amiodarone.


Mutational analysis of a dominant oncogene (c-Ki-ras-2) and a tumor suppressor gene (p53) in hamster lung tumorigenesis.

In human lung cancers, alterations of both a dominant oncogene (ras) and a tumor suppressor gene (p53) have been identified. Polymerase chain reaction (PCR) analysis of mRNA was used to amplify the c-Ki-ras-2 and p53 genes from Syrian golden hamsters. The PCR products were confirmed by predicted-size analysis, probing with nonradioactive (biotin-labeled) oligonucleotides, and direct sequencing. Lung tumors were produced in hamsters by repeated injections of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Of six tumors examined, three (50%) had mutations in codon 12 of Ki-ras. Examination of the conserved regions of p53 revealed no mutations. We conclude that NNK-induced carcinogenesis in the hamster results in characteristic alterations of Ki-ras but may not necessarily involve the p53 gene.


Stability study of cloxacillin in an oily suspension, by high performance liquid chromatography.

A high performance liquid chromatography method, using spectrophotometric detection (254 nm) has been developed for the analysis of cloxacillin in an oily suspension. Analysis was performed by isocratic elution with 0.02M potassium dihydrogen phosphate solution, methanol, 50/50 (V/V). The method was specific, linear, accurate (99.8 +/- 1.4%) and precise (less than 1.0%). A stability study of cloxacillin in the formulation, showed that about 10% degradation occurred for 6 months storage at room temperature, when lyophilized sodium cloxacillin was used. On the contrary, when sodium cloxacillin obtained by precipitation from non aqueous solvent was used, about 6% degradation appeared in the drug for 3 years storage in the same conditions.


Role of activator protein-1 and methylation function in 12-O-tetradecanoylphorbol-13-acetate--mediated inhibition of differentiation of Friend erythroleukemia cells.

Friend erythroleukemia cells (FELCs) differentiate after hexamethylene-bis-acetamide treatment. This differentiation is characterized by an increase in beta-globin gene expression that is followed by appearance of the hemoglobin. Phorbol-ester tumor promoters, such as 12-O-tetradecanoylphorbol-13-acetate (TPA), inhibit differentiation of TPA-sensitive cells but not TPA-resistant cells. We have shown that the increase in beta-globin expression is inhibited by TPA in a TPA-sensitive clone but not in a TPA-resistant clone. To study the molecular mechanisms of regulation of gene expression by TPA, we examined the possible involvement of gene methylation and the TPA-responsive element (TRE). Both clones showed similar patterns of methylation around the beta-globin gene. Moreover, TPA-induced TRE binding and TRE enhancer activity were similar in both variants. These results suggest that the TPA inhibition of induced differentiation may not be explained by regulation of the methylation state. The activator protein-1 also does not play a crucial role in the sensitivity of FELCs to TPA.


12-O-tetradecanoylphorbol-13-acetate--induced levels of AP-1 proteins: a 46-kDa protein immunoprecipitated by anti-fra-1 and induced in promotion-resistant but not promotion-sensitive JB6 cells.

Neoplastic transformation and transcriptional activation by activator protein-1 (AP-1) complex are stimulated by tumor-promoting agents in promotion-sensitive (P+) but not promotion-resistant (P-) mouse epidermal JB6 cells in culture. This implicates AP-1 as a specific regulator of signal transduction pathways in the promotion phase of neoplastic transformation. We therefore hypothesized that the defective P- responsiveness may be due to limiting levels of AP-1 protein components in those cells. In this investigation, steady-state levels of AP-1 protein components were measured by immunoprecipitating proteins from 12-O-tetradecanoylphorbol-13-acetate (TPA)-treated P+ and P- cells to discern what may limit the AP-1 response. Whereas the AP-1 proteins junB, junD, and fosB did not show differential basal or TPA-inducible levels in P+ and P- cells, a 46-kDa species precipitated by anti-fra-1 antibody was TPA-inducible in P- cells but not in P+ cells, and c-jun protein was present at higher levels in TPA-treated and untreated P+ cells than in P- cells. These data raise the possibility that the 46-kDa fra-1-related protein may be a negative modulator of AP-1 activity and suggest that elevated levels of this 46-kDa species and limiting levels of c-jun may significantly impair AP-1 function or transformation response in P- cells or both.


Simultaneous quantitative determination of calcium leucovorin and parabens in lyophilized ampoules by derivative spectroscopy.

A simple and rapid procedure for quantitation of Calcium Leucovorin and parabens simultaneously in lyophilized ampoules formulation by "zero crossing" first-order derivative spectroscopy was developed. The ampoules content was dissolved in a mixture water/ethanol (50/50) and first-derivative spectra were recorded. The absolute values of the derivative at 312 nm for the determination of Calcium Leucovorin and between 244 and 246 nm for the determination of parabens were measured. The method is linear, quantitative and reproducible.


Simplified dosing and monitoring of vancomycin for the burn care clinician.

Vancomycin has excellent activity against Gram-positive bacteria and is often selected for use in the infected burn patient. Because of multiple-compartment pharmacokinetics, vancomycin serum concentrations can decrease dramatically in a short time period following the end of an intravenous infusion. This accounts for the widely divergent recommendations for serum vancomycin peak concentrations, e.g. from 15 mg/l up to 80 mg/l, when the time for blood sampling following the end of intravenous infusion is different. It is in general not necessary to monitor vancomycin peak concentrations, not only because its toxic potential is overrated but also because potential toxicity and therapeutic efficacy are correlated with trough concentrations. Post-distribution 'peak' concentrations are generally only useful for determining the optimal dosing interval for patients with impaired renal function. A dosing and monitoring paradigm for vancomycin therapy in burned adults has been devised for burn care clinicians. It provides suggested dose and dosing intervals based on body weight and creatinine clearance, with specific recommendations for regimen modification based upon the results of trough serum concentration determinations.


HPLC detection of thioperamide from biological samples and its determination in rat blood and brain after systemic administration.

Thioperamide is a potent and selective antagonist on histamine H3 receptors. A method for its isolation and quantitation by HPLC from rat plasma and brain samples has been developed. Using this technique, thioperamide concentrations in rat plasma and brain were measured after systemic administration, in order to evaluate its persistence in blood and its ability to cross the blood-brain barrier. We observed that, at a dose of 60 mg/Kg, thioperamide undergoes a slow elimination from plasma, with a half-life of 10 hours, and can readily cross the blood-brain barrier.


Dynamic balance changes between elastase and antiprotease in the early stages after smoke inhalation injury.

Following the use of a rabbit smoke inhalation injury model established in this institute, there were marked reductions in elastase activities in neutrophils and alveolar macrophages; rapid increases in elastase activity in broncho-alveolar lavage fluid (BALF); reductions of serum trypsin inhibitory capacity; a decrease of Pao2 and an increase of PaCO2, and marked increases of lung water volume. Significant correlations were found between the increased extravascular lung water content and the rising elastase activity in BALF. It seems probable that the imbalance between elastase and antiprotease played an important role in the development of acute lung injury after smoke inhalation.


Predicting survival in burned patients.

Data pertaining to 562 consecutive admissions for burn treatment were analysed to identify factors related to survival. Besides socioeconomic, demographic and burn-related variables, three indices to measure burn severity, were proposed and evaluated with the help of multiple regression and discriminant analyses. The results of multiple regression analysis showed that one of the proposed indices, total burned surface (TBS), based on presence or absence of burn injury on 11 different body sites, turned out to be the best single predictor of survival. TBS alone accounted for 64.5 per cent of the total variance in survival variable. Combined use of TBS with type and severity of burn, age, sex, etc. did not appreciably raise the value of R2. The results of the discriminant analysis yielded a cut-off point of 20 TBS score which provided maximum separation between survivors and fatalities. Using this cut-off point (20 per cent) the TBS index provided the correct prediction of the eventual survival status in about 93 per cent of 562 patients. This cut-off point score of 20 was cross-validated on an independent sample of 924 cases. The prediction in 79 per cent of patients could be made correctly.


Cutaneous copper and zinc losses in burns.

To measure the exudative cutaneous copper (Cu) and zinc (Zn) losses in burns, 10 patients, aged 36 +/- 9 years (mean +/- s.d.) with burns covering 33 +/- 10 per cent of the total body surface area, were studied from the first postburn day (D1) until D7. All intakes and losses were analysed for Cu, Zn and nitrogen (N) content. Cutaneous losses were extracted from textiles surrounding the patients. Urinary excretions were 0.12 +/- 0.06mg/24h for Cu, 0.9 +/- 0.6mg/24h for Zn, and 14.1 +/- 4.4g/24h for N. Mean daily exudative losses through wound seepage from D1 to D7 were 4.7 +/- 2.1mg/24h for Cu, 27.1 +/- 14.4mg/24h for Zn, and 8.7 +/- 3.8g/24h for N. The cumulated mean losses over 7 days were 37mg for Cu, and 212mg for Zn, representing respectively 20-40 per cent and 5-10 per cent of normal body content. Serum Cu and Zn levels were strongly depressed. The urinary Cu/N ratios correlated with clinical improvement. We conclude that the exudative Cu and Zn losses during the first week postburn contribute significantly to the increased nutrient requirements in burns.


Researches on psychotropic agents. IV. Synthesis and neuropsychopharmacological effects of 1,3,4,14 b-tetrahydro-10-methyl-2H,10H- pyrazino[2,1-d] pyrrolo[1,2-b][1,2,5]benzotriazepine and its derivatives.

The synthesis and neuropsychopharmacological properties of new 1,3,4,14b-tetrahydro-2H,10H-pyrazino [2,1-d] pyrrolo [1,2-b] [1,2,5] benzotriazepine derivatives related to antidepressant agent aptazepine are reported. The new derivatives displayed sedative-miorelaxant activity in mice, but no significant antagonist effect on clonidine blockade of phenylquinone-induced abdominal constriction. Among test compounds 4a, 4l and 4n showed high antinociceptive effect on the hot-plate test and compound 4e protected from death and convulsion all the electroshocked animals.


Formation of gastrocnemius [3H]polyinositol phosphates in response to burn trauma.

The purpose of this report was to see if changes in polyinositol phosphates occurred with increasing percentage body surface area (% BSA) burn. Burn injury was applied to predefined areas of the dorsal and ventral skin surface of mice. After a 10-min stimulation period involving muscle twitch, polyinositol phosphate levels at 3 weeks postburn were measured by the incorporation of myo[2-3H]inositol with separation of the phosphates by anion-exchange chromatography. Analysis of variance was used for all statistical evaluations. In gastrocnemius muscle an increase (P < 0.001) occurred for levels of [3H]inositol, inositol-1, phosphate (I1P), and inositol-1,4,5-trisphosphate (I1,4,5P3) for the 50 per cent BSA burn group. However, levels of inositol-1;4,biphosphate (I1,4P2) decreased (P < 0.001). Positive correlations were found between [3H]inositol, I1P and IP3 and 50 per cent BSA burn. A negative correlation between I1,4P2 and percentage BSA burn was found. These data provide evidence that polyinositol phosphate metabolism in skeletal muscle was altered due to large burn size.


Effect of chronic interleukin-2 treatment on RES phagocytic activity in the rat.

The effect of chronic interleukin-2 (IL-2) injection upon reticuloendothelial system (RES) function in the rat has been determined. Seven-day treatments with two doses of human recombinant IL-2 resulted in a dramatic reduction in the phagocytic uptake of the liver and spleen, while increasing the weight of both organs. There were dramatic histological changes in the intestine, liver and spleen as well. These results suggest that the chronic use of IL-2 can result in hepatic dysfunction, which is associated with altered RES phagocytic function.


Microskin grafting of rabbit skin wounds with Biobrane overlay.

Biobrane was used to overlay micrografts and the wound using the microskin grafting technique with an expansion ratio of 10:1 in 16 rabbits. The rabbits were divided randomly into four groups, with four rabbits in each group, for evaluating the wound conditions on days 7, 10, 12 and 14. Histological examination of the removed Biobrane showed a variable degree of entrapment of inflammatory cells within the nylon fabric. Biobrane adhered well to the wounds although many wrinkles containing fluid accumulations were noted on day 7. By 10, 12 and 14 days all the wounds become dry and their Biobrane adhered completely. Histological examination of the grafted wound on day 7 showed active proliferation and spread of micrografts. In the later groups, the neoepidermis increased in thickness and differentiated into skin with a normal texture. On day 10, the wounds were almost completely resurfaced with neoepithelium. The growth of these grafts progressed smoothly as the adherent Biobrane was kept on the wound for 12 or 14 days. In these animal studies, the overlain Biobrane provided favourable conditions for the successful growth of micrografts.


Fibrin glue in the treatment of dorsal hand burns.

This paper analyses two groups of patients with only dorsal hand burns: groups I contains patients with a total of 15 burned hands and group II patients with 12 hand burns. The patients in group I were all treated by full sheet skin grafts using a two-component fibrin glue. Patients in group II underwent the traditional operative treatment without fibrin glue and the same postoperative physical therapy programme. After follow-up periods of 6-11 months (group I) and 12-21 months (group II), we investigated in both groups, grip strength, key pinch, mobility, two-point discrimination and with the Semmes-Weinstein monofilaments. Our results prove that after the respective follow-up periods group I patients developed far better results for two-point discrimination, touch recognition and mobility.


Increased survival rate in patients with massive burns.

A review of 113 patients with massive burns treated in our centre from 1970 to 1989 is presented. There were 57 adults patients with massive burns (> or = 50 per cent TBSA) in 1980-89 who were compared with 56 patients with similar massive burns in the period between 1970 and 1979. The results show a significant improvement (P < 0.01) in survival rate of the more recent patients. The increased survival rate is attributed to improvements in the early treatment of inhalation injury, sepsis and multiorgan failure.


Wound healing of burns in rats treated with a new amino acid copolymer membrane.

A new amino acid copolymer (leucine + methylglutamate) membrane which is moderately permeable to water vapour, impermeable to bacteria, non-biodegradable and stable, has been developed as a burn wound covering. In an experimental model in the rat, excised burn lesions were covered either with the membrane or with conventional petrolatum-impregnated gauze. Morphometric analyses and histological investigations performed on days 7, 14, 21 and 42, suggested a significantly increased rate of healing for wounds covered with the polymeric membrane as compared with those covered with impregnated gauze. No wound dessication, fluid retention or exudate was observed under the membrane due to its moderate permeability to water vapour. The wounds covered with impregnated gauze also showed a marked inflammatory response in the granulation tissue, which remained even at day 42. This appearance was very different from a normal dermis or a polymeric membrane treated dermis.


A technique of haemostasis of the extremities after debridement of burn wounds.

A technique used to achieve prompt haemostasis in burned wounds of the extremities is described. After tangential debridement using a tourniquet, thrombin solution (1000 units in 1 ml of saline solution) is applied on the entire wound. Immediately after removing the tourniquet; the wound is tightly wrapped with a thin plastic film and a pressure bandage over the entire wound. The pressure bandage is kept on for approximately 10 min after removing the tourniquet. With this procedure, haemostasis of the capillary oozing can be promptly and completely achieved. Furthermore, arterial and venous haemostasis can also be achieved, with clots present at the arterial and venous haemorrhagic points. As these clots can be removed easily, ligation or electrocoagulation is necessary. This technique is especially useful for haemostasis in a wound of the extremity after tangential excision leading to decreasing blood loss.


Burns as a result of domestic accidents and their prevention.

Over a 1-year period (October 1990 to October 1991), 100 patients with burns due to domestic accidents have been admitted to our Burn Unit. The total number of burn admissions was 238. There is a relative abundance of data in the burn literature, clearly depicting local characteristics and peculiarities in different countries or societies. Our purpose is to present some statistical, epidemiological and socioeconomic data from Greek society, as well as to compare data from other countries.


Experience of a chemical burn due to 3,5-dichloro 2,4,6-trifluoropyridine.

An example is reported of a burn caused by cutaneous exposure to 3,5-dichloro 2,4,6-trifluoropyridine (DCTFP) involving 25 per cent of the body surface. A striking feature was the development of the appearance of the burn over the first 72h postinjury. Healing was nevertheless spontaneous. The management of the injury is discussed.


Burns of the skull with underlying intracranial meningioma.

A 68-year-old white-skinned male fell head first into a fireplace while having a seizure. Extensive burns of the skull were sustained requiring removal of the necrotic bone. The patient had an underlying meningioma. Healing of the skull was obtained using a latissimus dorsi flap. After the scalp was completely healed, the meningioma was successfully resected with significant improvement in the patient's mental function.


Trapezius myocutaneous flap for reconstruction of a large scalp defect following the excision of postburn scar carcinoma (Marjolin's ulcer).

The successful use of a trapezius myocutaneous flap to cover a large scalp defect resulting from the excision of a postburn Marjolin's ulcer is described. The exposed dura was covered with a good functional and cosmetic result.


[Macrological identification of Chinese drug dangshen (radix Codonopsis)].

Macrological characters of 17 reference crude drugs from Codonopsis and Campanumoea were observed. Identification of 110 samples collected from 18 provinces of China indicated that more than 70 percent of the commercial Dangshen is derived from Codonopsis pilosula.


[Growth regularities of yujin (Curcuma longa L.)].

Based on the characteristics of leaf, root and tuber growth as well as dry matter accumulation, the ontogeny of Yujin is divided into 4 stages. The growth and correlation among the leaf, root and tuber as well as accumulation of essential oils and curcumins have also been studied.


[Determination of magnolol and honokiol in different processed samples of houpo by HPLC method].

HPLC was applied to determine and compare 17 samples of Houpo processed in different ways: sauted with ginger juice, dipped with ginger juice, boiled with ginger juice, and so on. The results provide a scientific basis for screening the best processing technology of Houpo.


[Thin layer chromatography for identification of 9 species of traditional Chinese medicine in baihe gujin tang granules].

Baihe Gujin Tang granules are mainly composed of nine species of traditional Chinese medicine and other admixtures, so the composition is very complex. In order to confirm the presence of each traditional Chinese medicine in the preparation, a thin layer chromatographic method was developed successfully for analysis of Scrophulariae, Platycodon, Paeoniae and Glycyrrhizae.


[Granule-making technology for preparing luohanguo chrysanthemum granule medicine with orthogonal design].

L9 (3(4)) orthogonal design was adopted to inspect the consumption of white sugar, water and ethanol and the duration of raw material mixing in relation to the granule-attaining rate in preparing Luohanguo-Chrysanthemum granule medicine. The result shows that with a consumption of 170 kg of white sugar, 6000 ml of water and 800 ml of ethanol and a duration of 8 minutes, the granule attaining rate reaches about 80%.


[Chemical constituents of Actinidia kolomikta (Rupr. et Maxim.) Planch].

Two crystalline components I and II were isolated from the roots of Actinidia kolomikta. I was identified as delta 7-stigmasterol and II was named alpha-kolomiktriose and elucidated as 2, 3-di-0-beta-D-galactopyranosyl-alpha-D-galactopyranose on the basis of spectral data (13C NMR, 1H NMR, IR and EI-MS).


[Chemical components of the leaves of Pistacia Chinensis Bge].

Six compounds have been isolated from the leaves of Pistacia chinensis, a species of Anacardiaceae family. Their structures were identified on the basis of UV, IR, NMR, and MS as gallic acid, m-digallic acid, quercetin, 6-0-galloyl arbutin-quercitrin and quercetin-3-0(6''-galloyl)-beta-D-glucosides.


[Pharmacokinetics of sinomenine by HPLC].

Pharmacokinetics of sinomenine in rabbit was studied by reverse-phase HPLC method. After i.v. injection of 20 mg/kg of sinomenine to rabbits, the pharmacokinetic characteristics were found to fit a two-compartment open model.


[The effects of dachengqi decoction, shaogan decoction, emodin and sennoside on the histamine level of intestinal mucosa in intestinally obstructed rats].

The experimental intestinal obstruction model was made by partly ligating the ileum in rat. The histamine levels of obstruction groups (8.14 +/- 2.28 micrograms/g) were obviously lower than those of control groups (P < 0.01). After administration of Dachengqi decoction, Shaogan decoction, emodin and sennoside, the levels of histamine were significantly higher than those of obstruction groups, but there were no significant differences as compared with control groups.


[Hypoglycemic effect of fructus Ligustri Lucidi].

The decoction of Fructus Ligustri Lucidi (FLL) 15.30 g/kg ig for 10 days significantly decreased the blood glucose level in normal mice. FLL 30 g/kg before or after the treatment of alloxan also decreased the blood glucose level in alloxan diabetic mice. The elevation of blood glucose level induced by adrenaline or glucose was antagonized by FLL.


A new role for the cerebellum in cognitive operations.

Over the last 2 centuries, the predominant view of the cerebellum has been that it is part of a motor control system. Evidence is now presented that the neocerebellum, the evolutionarily newest region of the cerebellum, may also be involved in a key mental operation: the voluntary shift of selective attention between sensory modalities. It is theorized that this newly recognized function may operate via previously described sensory modulation properties of the cerebellum and its many connections with areas known to be important for selective attention, such as the pulvinar, the superior colliculus, and the parietal and frontal cortices.