Clavispora opuntiae and other yeasts associated with the moth Sigelgaita sp. in the cactus Pilosocereus arrabidae of Rio de Janeiro, Brazil. Clavispora opuntiae was the prevalent yeast associated with the feeding sites of Sigelgaita sp. larvae in the cactus Pilosocereus arrabidae. Also associated with this habitat were Candida sonorensis, Pichia cactophila, Pichia barkeri, Candida sp. A, Geotrichum sp., Geotrichum sericeum and the yeast like organisms Prototheca zopfii and Acremonium sp. Atypical yeast biotypes that may represent new species of Pichia, Sporopachydermia and Candida were isolated. Mating types of Clavispora opuntiae were at a ratio 70 h- to 3 h- and reduced levels of sporulation suggested low pressure for sexual reproduction in this habitat. Sigelgaita sp. probably was not an important vector for Clavispora opuntiae because it was not isolated from an adult or eggs of this moth.


Evaluation of two unstructured mathematical models for the penicillin G fed-batch fermentation. The mathematical model for the penicillin G fed-batch fermentation proposed by Heijnen et al. (1979) is compared with the model of Bajpai & Reuss (1980). Although the general structure of these models is similar, the difference in metabolic assumptions and specific growth and production kinetics results in a completely different behaviour towards product optimization. A detailed analysis of both models reveals some physical and biochemical shortcomings. It is shown that it is impossible to make a reliable estimation of the model parameters, only using experimental data of simple constant glucose feed rate fermentations with low initial substrate amount. However, it is demonstrated that some model parameters might be key factors in concluding whether or not altering the substrate feeding strategy has an important influence on the final amount of product. It is illustrated that feeding strategy optimization studies can be a tool in designing experiments for parameter estimation purposes.


Characterization of a novel enzyme, N6-acetyl-L-lysine: 2-oxoglutarate aminotransferase, which catalyses the second step of lysine catabolism in Candida maltosa. A novel aminotransferase catalyzing the second step of lysine catabolism, the oxidative transamination of the alpha-group of N6-acetyllysine, was identified and characterized in the yeast Candida maltosa. The enzyme was strongly induced in cells grown on L-lysine as sole carbon source. Its activity was specific for both N6-acetyllysine and 2-oxoglutarate. The Km values were 14 mM for the donor, 4 mM for the acceptor and 1.7 microM for pyridoxal-5-phosphate. The enzyme had a maximum activity at pH 8.1 and 32 degrees C. Its molecular mass estimated by sodium dodecyl sulphate-polyacrylamide gel electrophoresis was 55 kDa. Since the native molecular mass determined by gel filtration was 120 kDa, the enzyme is probably a homodimer.


High-affinity oxygen uptake by Bifidobacterium bifidum. Oxygen uptake by washed cell suspensions of Bifidobacterium bifidum DSM 20082 was studied by using spectrophotometric measurements of the degree of oxygenation of added myoglobin as a measure of the concentration of dissolved O2. The absorbance changes during consumption of O2 in a closed reaction vessel were analysed by computer to obtain estimates of the changes in dissolved O2 concentration with time. These were then used to calculate the rate of O2 uptake as a function of the dissolved O2 concentration. The cell suspensions showed Michaelis-Menten kinetics with an apparent Km value of 0.06 microM O2. Cell-free extracts contained a soluble NADH oxidase activity with a stoichiometry corresponding to the reduction of O2 to H2O and with a high affinity for O2.


Dimorphism in Benjaminiella poitrasii: cell wall chemistry of parent and two stable yeast mutants. In the dimorphic zygomycetous fungus Benjaminiella poitrasii, the cell wall compositions of mycelial phase (M), yeast phase (Y) and its yeast form mutants (Y-2 and Y-5) were studied. Chitosan was abundant in M-phase (26.6%) whereas lesser amounts were present in Y-phase (17.3%) and in mutants Y-2 (19.6%) or Y-5 (17.3%). Although chitin was present as a smaller fraction of the total glucosaminoglycan in each of different cell wall preparations, it was almost 3 times more prevalent in M-phase than the Y-phase cells. Cross-linking studies among the various cell wall components in B. poitrasii, suggest linkages among mannans and proteins and glucans and glucosaminoglycans.


Mechanism of chlorpromazine binding by gram-positive and gram-negative bacteria. Chlorpromazine forms charge-transfer complexes with xanthene dyes in bacteria. These complexes permit the differentiation of Gram-positive and Gram-negative bacteria in both light and polarization microscopy. The birefringence induced by the charge-transfer complex might explain the molecular basis of bacterial staining. The charge-transfer complexes formed between chlorpromazine and xanthene dyes accumulate in the bacterial cell, mainly inside the bacterial cell wall. The complexes give the cells a color, which depends on the chemical composition of the staining structure, and in particular the polysaccharides of the cell wall in bacteria. Metachromatic granules were seen inside Gram-positive bacteria after chlorpromazine and rose bengal staining. Although the nature of these granules remains unclear, this type of binding may have a role in the inhibition of biochemical processes in the bacterial cells.


Effects of some tricyclic psychopharmacons and structurally related compounds on motility of Proteus vulgaris. A simple test for the evaluation of drugs interfering with bacterial motility was established with Proteus vulgaris. With this model, promethazine, 7-hydroxy-chlorpromazine, imipramine, 7,8-dioxochlorpromazine and acridine orange were shown to exert significant motility and swarming inhibitory action on Proteus vulgaris strains at subinhibitory concentrations. Quinidine enhanced the antimotility effect of promethazine. The antimotility effect of promethazine was synergized by proton pump inhibitors omeprazole and abscissic acid, but antagonized by extracellular potassium and sodium ions.


Pathophysiology of cutaneous inflammation. For the better part of the past century, dermatologists have regarded the skin primarily as a large protective coat. Epidermal keratinocytes were highlighted for their production of keratins and lipids, which contributed to the structural integrity and barrier formation of skin. This "saran-wrap" perspective of skin mentioned keratinocytes only in cutaneous inflammatory reactions as passive targets for damaging diffusion products of infiltrating leukocytes. However, sufficient compelling in vitro and in vivo evidence is rapidly accumulating to support the novel perspective that epidermal keratinocytes can initiate and actively participate in the perpetuation of numerous cutaneous inflammatory reactions that involve a highly diverse array of inciting agents. This presentation emphasizes the keratinocyte and highlights the dynamic immunomodulatory capacity of this overlooked epidermal cell.


The role of complement-derived mediators in inflammatory skin diseases. The complement system represents an important nonspecific skin defense mechanism. Its activation leads to the generation of products that not only help to maintain normal host defenses but also mediate inflammation and tissue injury. Proinflammatory products of complement include large fragments of C3 with opsonic and cell-stimulatory activities (C3b and C3bi), low molecular weight anaphylatoxins (C3a, C4a, and C5a), and membrane attack complex. Among them C5a or its degradation product C5a des Arg seems to be the most important mediator because it exerts a potent chemotactic effect on inflammatory cells. Intradermal administration of C5a anaphylatoxin induces skin changes quite similar to those observed in cutaneous hypersensitivity vasculitis that occurs through immune complex-mediated complement activation. Complement activation is involved in the pathogenesis of the inflammatory changes in autoimmune bullous dermatoses. In pemphigus complement activation by pemphigus antibody in the epidermis seems to be responsible for the development of characteristic inflammatory changes termed eosinophilic spongiosis. In bullous pemphigoid (BP) interaction of basement membrane zone antigen and BP antibody leads to complement activation that seems to be related to leukocytes lining the dermoepidermal junction. Resultant anaphylatoxins not only activate the infiltrating leukocytes but also induce mast cell degranulation which facilitates dermoepidermal separation and eosinophil infiltration. Similar complement activation seems to play a more direct role in the dermoepidermal separation noted in epidermolysis bullosa acquisita and herpes gestationis. Anaphylatoxin generation via the alternative pathway activation under light irradiation is implicated in the development of the immediate erythematous phototoxic reactions induced by such well-known chemicals as porphyrin, chlorothiazide, demethylchlortetracycline, and chlorpromazine.(ABSTRACT TRUNCATED AT 250 WORDS)


Peptides and cytokines.

Peptides and cytokines. In the last decade a number of proteinaceous inflammatory mediators have been structurally characterized. Two of these mediators, tumor necrosis factor alpha (TNF alpha) and Interleukin 1 alpha and beta (IL-1), have pleiotropic properties. Both cytokines are now known to be potent inducers of a number of cell-selective chemotactic cytokines, which belong to a novel superfamily of structurally related low-molecular-weight proteins. One of the most prominent members is termed "IL-8" and represents a neutrophil-selective attractant, whereas another one called "monocyte chemotactic protein 1 (MCP-1)" is a monocyte-selective chemotaxin. Other members seem to be selective chemotaxins for other leukocyte types and subsets. These chemotactic cytokines are produced by a variety of different cells under appropriate stimulation conditions. Large amounts of IL-8 have been detected in scales of psoriatic lesions and may be of importance in explaining predominant neutrophil infiltration in psoriatic lesions. Regulation of gene expression and/or release of these chemotactic cytokines may occur by IL-1 receptor antagonists or soluble TNF-alpha-receptors. So far, natural antagonists to these chemotactic cytokines have not been described; however, pharmacological inhibition of its gene expression and/or release is possible.


Therapy with topical corticosteroids.

Therapy with topical corticosteroids. Therapy with topical corticosteroids has improved greatly in recent years due to both advanced understanding of their mode of action and awareness of their side effects, as well as newly developed derivatives with specifically designed pharmacological properties. Paradoxically, the fear of using corticosteroids has increased on the part of the public during the same period. Treatment of inflammatory or neoplastic skin disorders with topical corticosteroids can be both successful and safe only if certain points are clarified before it is begun. These include (a) specific diagnosis, (b) choice of strength of the compound needed for control of the disease, (c) time schedule for length of therapy and planned patient visits, and (d) choice of vehicle adequate to the skin lesion. Topical corticosteroids of different potency are available today; one can classify these into four groups (weak, medium, strong, very strong) and use them in a patient-tailored treatment. When large areas are to be treated, systemic side effects must be taken into consideration, and compounds that are degraded quickly after absorption are recommended. Finally, the corticophobia of many patients must be addressed by careful information to ensure compliance. Using these guidelines, treatment with corticosteroids is highly effective, easy to use by the patient, and allows a maximum of safety.


Steroids versus nonsteroids in the treatment of cutaneous inflammation: therapeutic modalities for office use. Inflammatory skin diseases are often treated successfully with topical substances alone. The basic prerequisites for proper treatment are that the specialist has a good knowledge of the products available, their active substances and bases and their relative properties and actions, as well as precise indications for and effects of long-term use. Treatment should be individualized, and best results are usually achieved with a two-phase schedule, beginning mainly with administration of steroids followed by application of nonsteroid products, such as, in psoriasis, anthralin, coal tar, and calcipotriol.


[The dynamic morphology of the endothelial cells of aortocoronary vessels cultured in vitro]. The morphologic and functional meaning of the endothelial cell, as the first cellular element between blood and tissues, has been investigated since the earliest histological knowledge of the vascular tree. Although there have been multiple attempts for its study, through different biological branches, very little has been comprehended in its dynamic biology, due to technical difficulties and to the apparent simplicity of this extraordinary cellular type. In this research we pretend to establish a morphodynamic pattern of the endothelial cells from the aortocoronary segment, using the particular advantages of tissue culture. Our results, have been obtained through careful observations with light microscopy under different optical systems and the help provided by spaced microcinematography. Our results showed the reality of the images in the different cellular phenomena, particularly, endocytotic pinocytosis, the dynamic of the cellular membrane, and the cell-cell linkages established in vitro.


[The primary outcome in transluminal coronary angioplasty: the recent experience of the Instituto Nacional de Cardiología (1991-1992)]. Percutaneous balloon coronary angioplasty had a slow start in Mexico, and until recently only a relatively small number of procedures have been performed. Since March 1991, the Instituto Nacional de Cardiología has state-of-the-art fluoroscopic imaging and easy access to a variety of balloon coronary angioplasty catheters and accessories. Under these conditions, an increasing number of PTCAs have been performed (221 procedures in an initial 15 month period). The primary results of PTCA in this patient population is presented as a reference source for results of PTCA in our population. Indication for PTCA was stable angina in 31%, unstable angina in 64% and AMI in 5%. Forty-two percent of the procedures were for multivessel PTCA, with a total of 355 lesions approached (1.6 segments per patient). There were 34% type A, 51% type B and 15% type C lesions. Mean percent stenosis was reduced from 81% to 29% (p < 0.001). There was a 94% success rate in type A lesions, 89% in type B and 77% in type C lesions. Six patients required urgent CABG (2.7%), thirteen had a myocardial infarction (5.9%) and mortality was 1.35% (including one patient with cardiogenic shock who had a noncomplicated failure and had a late in-hospital death). We conclude that with adequate support and equipment, angioplasty results compare favorably to those reported by more experienced groups in developed nations. Also, the necessary number of procedures for the maintenance of competence in PTCA can be done in our country.


[The usefulness of electrophysiology in a patient undergoing cardiomyoplasty]. The cardiomyoplasty is a new surgical procedure that uses a skeletal muscle electrostimulated in order to reinforce or even substitute partially the cardiac muscle. We present the electrophysiology aspects in a patient with dilated cardiomyopathy that underwent cardiomyoplasty. First the latissimus dorsi muscle was prepared with a neurostimulant ITREL II. During the surgical procedure a dual-chamber pacemaker mode DDD brand CPI was placed. After three months, ablation radiofrequency of the AV node was performed in order to control the atrial fibrillation that caused heart failure. By means of the AV block we obtained synchrony between the ventricular stimulation and the latissimus dorsi muscle, and by this the patient improved. Using the modern pacemakers and radiofrequency we can control the bradyarrhythmias as well as the tachyarrhythmias frequent in patients with dilated cardiomyopathy, increasing the success rate of cardiomyoplasty.


[The long-term follow-up of 1000 patients with a valve replacement by the prosthesis of the Instituto Nacional de Cardiología Ignacio Chávez]. The long-term follow-up of patients with bioprosthetic valves manufactured at the Instituto Nacional de Cardiología Ignacio Chávez is presented. From February 1983 to May 1990, 1068 patients were operated and 1252 valves were replaced. Eighty two percent had rheumatic heart disease with one or more injured valves. In 17% it was a replacement of a failing valve. Seventy three percent of the patients had a low or medium-low socioeconomical status. There were 176 perioperative deaths in the first month after the operation and 150 patients were lost to follow-up. The rest (740) are the subject of this report. Mortality associated with valve related complications had a probability of 0.74 +/- 0.05, it had a significative increase after month 70th, with a 88% survival at that time. The functional class in the whole group improved 90%, with confidence limits for binomial distribution between 85 and 97%. There was also a significant reduction in heart enlargement. There were 161 prosthesis dysfunctions due to valve calcification or rupture, 50 were replaced. Twenty-three patients had hemolysis, and 19 infective endocarditis. There were 6.5% with systemic embolism in spite that only one half of those in which there was an indication, different of the valve replacement, received anticoagulant medication. The use of this prosthesis is on economical and medical satisfactory solution for the problem of a great number of our population of patients.


[The thickness/radius ratio (h/r) of the left ventricle in pure mitral insufficiency]. We studied 11 patients with severe mitral regurgitation (MR). With 2-D echocardiogram we could obtain the septal and posterior wall thickness, left ventricular internal dimensions and ventricular function. With parasternal short axis view we calculate the h/r ratio (left ventricular thickness/radius). The results were compared with normal values: we found important left atrial and ventricle dilatation with significative difference from the normal values (P < 0.001), the diastolic and systolic h/r ratio was significative lower than the normal values (P < 0.005): the systolic wall stress was significative higher in relation to normal values (P < 0.001). We conclude that patients with severe (MR) initially have an important ventricular dilatation but no hypertrophy despite volume overload. The possible explanation is that in early stages of the disease, the afterload of the left ventricle is low and does not trigger the development of hypertrophy. The hypertrophy appears only when the systolic stress is high secondary to myocardial failure. The excessive dilatation of the left ventricle probably damages the myocardial fibers by excessive stretch. This mechanism probably explains the poor late surgical evolution of patients with mitral prosthesis. This we propose that the optimal surgical timing for such patients is when the systolic wall stress elevates over the normal limits, because this is an early sign of myocardial failure.


[Percutaneous valvuloplasty in tricuspid valve stenosis]. This report describes the first successful case of tricuspid valve stenosis by percutaneous double balloon valvuloplasty in Mexico. The gradient decreased from 5 to 0 mmHg, with an increase in valve area by echocardiography and improvement of the jugular vein pulse and disappearance of symptoms. The feasibility of the balloon percutaneous valvuloplasty was demonstrated unequivocally.


[The prevention of postinfarction left ventricular dilatation by captopril]. Thirty patients admitted to the ICCU with a first myocardial infarction (MI) of any localization, with left ventricular dysfunction revealed by echo-Doppler ejection fraction (EF) < 40%, where randomly divided in three groups of ten: GROUP 1 who was treated with captopril 25 mg orally between the 5th and 7th day post MI, and sustained until the end of the study. GROUP 2 received nifedipine, 10 mg capsules t.i.d. also started between days 5 and 7 post MI. GROUP 3 as a control group was treated conventionally, according to the ICCU routine. The treatment was maintained during 12 months. All patients had a second echo-Doppler at the 5th day post MI to confirm the EF criteria. Also left ventricular end-systolic and end-diastolic diameters were measured. At the 5th day post MI and before the drug administration, a low level treadmill stress test was performed in all patients. Subsequently a maximal stress test (Bruce protocol) was done at the first month and at 6 and 12 months of the study. The results showed a significant increase EF in patients of GROUP 1 from an average basal value of 38 +/- 2 to 54 +/- 5 at six months (p < 0.01) and to 60 +/- 3 at 12 months (p < 0.005). The increments observed in patients of GROUP 2 and 3 were more modest; only the 12 month value in GROUP 3, from a basal figure of 41 +/- 3 to 50 +/- 4, had a p < 0.05.(ABSTRACT TRUNCATED AT 250 WORDS)


[The incidence of Trypanosoma cruzi antibodies in patients with dilated myocardiopathy at the Instituto Nacional de Cardiología Ignacio Chávez]. Our objective was to measure the incidence of humoral immune response against Trypanosoma cruzi among patients with a definitive diagnosis of dilated cardiomyopathy at the Instituto Nacional de Cardiología "I. Chávez" over a year. Thirty seven patients were collected, 15 of them (40%) had antibodies against T. cruzi in two different tests, indirect immunofluorescence and ELISA, the presence of IgG antibody was confirmed through Western blot. There was not differences in clinical picture of cardiomyopathy nor on paraclinical studies. However, there was a significant difference in regard socio economical indexes between the group with positive anti T. cruzi antibodies. They had a predominant rural origin, poor housing and were aware of the vector bug. Also they recalled primary infection in their childhood--American trypanosomiasis could be on important etiologic factor for dilated cardiomyopathy in our country.


[Transesophageal atrial stimulation: a technic with the pentapolar catheter electrode]. The objective of the present study was to employ a transesophageal atrial pacing (TAP) technique that would permit the use of the lowest possible currents for consistent atrial capture (CAC) and a more accurate recording system. An electrode catheter containing five poles (E1 to E5) spaced 22 mm apart was constructed, with pole E1 being the most cranial one. The catheter was introduced nasally into the esophagus of eleven adult healthy volunteers, and five unipolar intraesophageal leads were recorded and analyzed until the tracings obtained with E2, E3 and E4 showed P waves of the highest potentials, when the catheter was fixed in place. An electric generator specially constructed for TAP was used. CAC was attempted with each of the 20 stimulating bipoles formed by the permutations of the five poles of the fixed catheter. The least voltage needed for CAC in each individual was always detected in at least one of the six stimulating bipoles formed by the permutations involving poles E2, E3 and E4. Thus, in the population studied as a whole, the minimum voltage range needed to obtain TAP was between 5 and 15 V (mean 11.2 +/- 3.0 V), which was tolerated quite well by the individuals. Pulse durations of more than 10 ms did not lead to use of significantly lower voltages for CAC. Six simultaneous tracings were used during and after TAP, and at least one of them recorded intraesophageal or esophago-thoracic bipolar leads.


Propranolol-induced hyperreactivity in guinea-pig lung parenchyma strips: possible role of histamine. In vivo and in vitro studies have demonstrated that beta-adrenoceptor blockers enhance the airway smooth muscle contraction to antigen, but the mechanisms are not fully understood. In the present work, we corroborated that propranolol (3.9 x 10(-6) M, 30 min incubation) induces hyperreactivity to antigenic challenge (cumulative concentration-response curve to ovalbumin, 0.01 to 100 micrograms/ml) in lung parenchyma strips from sensitized guinea-pigs. This hyperreactivity was enhanced by indomethacin (3.2 x 10(-5) M) and was unaffected by the lipoxygenase/cyclooxygenase inhibitor phenidone (1 x 10(-4) M). However, the histamine H1 receptor antagonist pyrilamine (1 x 10(-6) M) reduced the potentiation effect of propranolol. These results suggest that bronchoconstrictor prostaglandins, thromboxane A2 and leukotrienes, are not involved in the propranolol-induced lung parenchyma strips hyperreactivity to antigen in vitro, and that histamine may account, at least in part, for such propranolol effect.


Pharmacological profile of a new 5-hydroxytryptamine2 receptor antagonist, DV-7028. The pharmacological profile of DV-7028, a pyrido triazine derivative, showed that it is a potent and selective 5-hydroxytryptamine (5-HT)2 receptor antagonist. DV-7028 bound to 5-HT2 receptors in rat brain membranes with a Ki value of 22 nM and caused shifts to the right of the concentration-contraction curves to 5-HT in rat thoracic aorta and canine femoral arteries, which are attributed to activation of 5-HT2 receptors. The compound was highly active by oral administration (0.1-10 mg/kg) based on blockade of the 5-HT-induced pressor responses in pithed rats. In contrast, DV-7028 had no affinity for 5-HT1A, 5-HT1B and 5-HT1D receptors. The affinity of the compound was 14-26 times greater for the 5-HT2 receptors when compared to 5-HT1C, adrenergic alpha 1, dopamine D2 and histamine H1 receptors. In human platelets, DV-7028 attenuated the aggregation induced by collagen and inhibited the amplifying effect of 5-HT with collagen on platelet aggregation. Furthermore, a 10-day toxicity study revealed that DV-7028 was a safe compound which did not produce lethality at repeated oral doses of 800 mg/kg/day in rats. These results indicate that DV-7028 is a selective and potent 5-HT2 receptor antagonist which is orally active and safe.


Spiperone-induced endothelium-dependent relaxation of porcine coronary artery: an investigation into the underlying mechanism. In pig coronary artery rings contracted by the thromboxane analogue U 46619 (9,11-dideoxy-11 alpha, 9 alpha-epoxy-methano-prostaglandin F 2 alpha), spiperone induced a relaxation which, at 30 mumol/l, corresponded to a complete reversal of the U 46619-induced contraction. The concentration-response curve for spiperone was bell-shaped. The second phase, i.e. the reduction of the relaxant effect (at concentrations above 30 mumol/l) was due to a contractile effect which was the only response in (1) endothelium-denuded arteries, (2) arteries treated with gossypol or methylene blue, or (3) arteries not precontracted with U 46619. Suramin and reactive blue 2 antagonized the relaxing effect, whereas metitepine, spiroxatrine, propranolol, idazoxan, flupenthixol, atropine and 8-phenyltheophylline did not. The endothelium-independent contraction was not reduced by metitepine. In strips of arteries with intact endothelium, incubated with [3H]adenosine and subsequently superfused with physiological salt solution containing dipyridamole, spiperone evoked an increase in tritium overflow above basal efflux. The present results are compatible with the hypothesis that spiperone releases ATP from the pig coronary artery. ATP, in turn, seems to activate endothelial P2 purinoceptors, leading to the release of endothelium-derived relaxing factor (NO) with a subsequent vascular relaxation.


Effects of nilvadipine on regional cerebral blood flow and skin blood flow in anesthetized cats. The effects of an intravenous injection of the novel calcium channel blocker, nilvadipine, on the relative regional cerebral blood flow and relative regional skin blood flow were studied in anesthetized cats using the laser-Doppler method. The effects of nilvadipine were compared with those of nicardipine hydrochloride (nicardipine). Nilvadipine and nicardipine both increased the relative regional cerebral blood flow dose-dependently, in spite of their hypotensive effect. At a dose of 32 micrograms/kg, nilvadipine and nicardipine increased the relative regional cerebral blood flow by 61 +/- 8% and 25 +/- 10% of the predrug value, respectively, 15 min after administration. At this time, both drugs induced a comparable degree of hypotension: -18 +/- 3% of the predrug value for nilvadipine and -25 +/- 2% for nicardipine. After nilvadipine, the relative regional cerebral blood flow enhanced by 45 +/- 10% 180 min after drug administration, whereas after nicardipine, it returned to the predrug value within 60 min. In contrast, the increase in relative regional skin blood flow produced by nilvadipine (32 micrograms/kg) and nicardipine (32 micrograms/kg) was 23 +/- 15% and 32 +/- 8% of the predrug value, respectively, 5 min after drug administration. The effect of nicardipine on the relative regional skin blood flow, compared with that of control, was significantly higher. These results indicate that nilvadipine exhibits a pronounced and longer-lasting effect on the relative regional cerebral blood flow, compared with the relative regional skin blood flow, and that its action on the relative regional cerebral blood flow is more potent than that of nicardipine.


Effects of buprenorphine on respiratory and cardiovascular functions during hypoxia in anaesthetized rabbits. Respiratory and cardiovascular variables were studied in 10 anaesthetized rabbits, before and after buprenorphine i.v. injections (cumulative doses of 5 to 100 micrograms/kg). In normoxic conditions, buprenorphine induced hypoventilation, due to a decrease in respiratory rate, and bradycardia: mean maximum modifications in ventilation (-17%) and heart rate (-7%) were obtained with buprenorphine 10 and 100 micrograms/kg, respectively. Isocapnic hypoxia, produced by the inhalation of a gas mixture containing 10% O2 in nitrogen for 5 min, provoked a mean 44% increase in base line ventilation and a mean 15% decrease in heart rate. The ventilatory response to hypoxia was not significantly modified by buprenorphine on an average; large decreases in hypoxic drive could still be observed in 3 out of 10 animals with buprenorphine 5 and 10 micrograms/kg. Buprenorphine enhanced hypoxia-induced bradycardia: a mean maximum decrease in heart rate (-29%) was reached with 10 micrograms/kg of this opioid.


Cardiotoxic effects of high doses of cyclophosphamide in albino rats. A histopathological study of cyclophosphamide-induced cardiotoxicity has been conducted in 43 Swiss albino rats. Multiple interstitial myocardial haemorrhage, multifocal myofibre necrosis, inflammatory reaction, vascular changes, pericarditis and valvulitis, mainly in the heart ventricles, have been observed. Previous results have suggested that cyclophosphamide directly damages the vascular endothelium, followed by the extravasation of blood containing high levels of the drug, and resulting into a toxic damage of the muscle cells. Our results are in favor of this hypothesis.


Studies on mercury-induced myotonia in the mouse diaphragm. Muscle contracture and myotonia of mouse diaphragm, induced by HgCl2, were studied. HgCl2 induced myotonia of mouse diaphragm only on condition that the Hg2+ contracture was inhibited by 0.005-0.01 mM NaCN. A higher concentration of 0.05 mM NaCN abolished both the Hg2+ contracture and Hg2+ myotonia. This finding suggests that the Hg2+ contracture masked the Hg2+ myotonia which was less sensitive to the inhibitory action of NaCN. This differential inhibitory action of NaCN on Hg2+ contracture from Hg2+ myotonia implies a possibility that NaCN antagonized the actions of HgCl2 not only through a simple chemical interaction. Hg2+ myotonia was characterized by an increase in contractile amplitude and a prolongation of contractile duration which were associated with stimulus-bound repetitive action potentials and an increase in membrane input resistance. A low Cl- medium as well as a Cl- channel blocker (9-anthracene carboxylic acid) not only by themselves induced myotonia, but also antagonized Hg2+ myotonia. Thus, Hg2+ appeared to mimic the Cl- channel blocker in inducing myotonia through a blockade of the Cl- channel. K+ channel blockers (4-aminopyridine, uranyl nitrate and tetraethylammonium chloride), as well as low (0.25 mM) Ca2+ Krebs, augmented Hg2+ myotonia while ATP-sensitive K+ channel blockers (tolbutamide and glibenclamide) antagonized Hg2+ myotonia (in the presence of NaCN). Since glibenclamide did not affect myotonia induced by a Cl- channel blocker, it was suggested that glibenclamide inhibited the Hg2+ myotonia through an interaction either directly or indirectly with NaCN on the sarcolemma. All of these findings suggest that K+ channels (delayed rectifier and Ca(2+)-activated K+ channel) functionally cooperated with the Cl- channel of the sarcolemma in the regulation of the skeletal muscle contraction. In this study, K+ channel blockers synergistically cooperated with Cl- channel blockers in inducing myotonia of the mouse diaphragm, while an ATP-sensitive K+ channel blocker exerted only an opposite effect on NaCN. Ca2+ appeared to play an important role in regulating the ionic channel activities, especially the Cl- channel, since low Ca2+ markedly potentiated not only Hg2+ but also low Cl- in inducing myotonia.


Serous cutaneous glands of the western spade-foot toad Pelobates cultripes (Amphibia, Anura): an ultrastructural study on adults and juveniles. The venom glands of the western spade-foot toad Pelobates cultripes were studied under light and electron microscopes. The glands exhibit the structural patterns usual in anurans, including the typical secretory syncytium. The peripheral cytoplasm contains a single row of nuclei and secretory organelles related to proteosynthesis. The inner cytoplasm is filled with large vesicles holding a thin product which originates from the merging of smaller ones containing a thicker material derived from the Golgi apparatus. The appearance and maturation of P. cultripes venom have been compared with patterns of biosynthesis and secretory evolution described in serous cutaneous glands of several anuran species. Following these criteria, the traditional trends in the terminology and classification of serous glands in anuran skin are discussed and reviewed.


Morphological observations on the glands of the oesophagus and stomach of adult Rana esculenta and Bombina variegata. Examination of serial sections of the oesophagus and stomach of Rana esculenta and Bombina variegata revealed that oesophageal peptic glands were only present in Rana, where gastric glandular cells performed only one functional role, represented by HCl production. In contrast, in Bombina the gastric glands were mainly of oxynticopeptic cells with dual oxyntic and peptic roles, reflected morphologically by distinct different areas of their cytoplasm. During activity of the oxynticopeptic cells cytoplasmic differences were reduced because the tubular profiles, carrying HCl, and zymogen granules emerged at the cell apex.


The development of the caeca in the chick embryo. Morphometric and morphological remarks. Quantitative aspects of the organogenesis of the chick embryo caecum (proximal and distal tracts) were investigated from the 8th to the 15th day of incubation. Histological sections were studied by means of a computerized morphometric system and a semiautomatic digital system (Videoplan 2). The total area of sections, of the lumen, the caecal wall and its components (subserous stratum, muscle layer, lamina propria, epithelium) and the thickness of the epithelium and muscle layer were measured. The mean +/- S.E.M. of the obtained values was calculated. The percentage of shrinkage, due to histological procedures, was calculated for each day considered. The mean values for each day of incubation were modified on the basis of the shrinkage percentage. The differences between the mean values of the areas of the proximal and distal tract were statistically evaluated. Exponential curves and the r coefficient were determined in order to evaluate the general growing pattern of the mean area of the caecal wall components as a function of age. The obtained results demonstrate that there are some differences between the proximal and distal tract of the caecal anlage in the growth pattern of the wall components. In the proximal caecal tract, the lamina propria showed the highest growth rate, while in the distal tract, the caecal wall component the subserous stratum did. Moreover, the caecal anlage showed different developmental behaviour from the ileum, duodenum and colon in the same chick embryo.


The innervation of the lingual papillae of the buffalo. A histochemical and immunohistochemical study. The neural structures of the lingual papillae of the buffalo tongue were studied by means of neurohistological and immunohistochemical techniques and by the Ruffini gold chloride impregnation method. The circumvallate papillae were found to be richly innervated; the conical and filiform papillae were poorly innervated; and the innervation of the fungiform and lenticular papillae was intermediate. The following neural structures were identified: myelinated and non-myelinated fibers, free nerve endings and encapsulated end organs, lamellated corpuscles, Ruffini-like endings, and ganglia containing few cell bodies. Brain-derived neurofilament and the S-100 proteins were found in the majority of these structures. These findings indicate that the innervation of the lingual papillae of the buffalo is fairly well developed. It appears to be similar to that of cattle.


History of the anatomy of the funiculus umbilicalis in mammals. The authors, based on a bibliographic search, present a brief survey of the history of the anatomical aspects of the funiculus in mammals, including the evolution of their interpretation and their relationship with the evolution of scientific and technological approaches to their study.


Comparative anatomical and ultrastructural features of the sensory papillae in the tongue of hibernating bats. The papillae of the tongue dorsal surface of the insectivorous, hibernating bats (Vespertilionidae and Rhinolophidae), whose function is mainly sensorial, consist of two circumvallate papillae, two foliate papillae, located at the side edges at the glossopalatine arch, and numerous fungiform papillae. The circumvallate and foliate papillae are characterized not only by their position, but also by presence of several taste buds which open through the external orifice of the gustatory canal into the cavity of the vallum, or furrow, which divides the two folds of the lingual mucosa. The fungiform papillae (extremely numerous on the whole dorsal surface) are characterized by an unusual arrangement (along 3 oblique lines on the anterior two-thirds and predominantly on the middle line of the tongue body) and by the presence of only one to three taste buds which open on the heavily keratinized dorsal epithelial surface. The taste buds are made up of sensory cells with a light or dark matrix; their apical cytoplasmic expansions are not found beyond the middle part of the gustatory canal, in contrast with the circumvallate and foliate papillae which protrude from the orifice of the gustatory pore. Comparisons with the papillae of other types of bats and Insectivora and evaluations of the morphological characteristics and their functional values (unusual areas of distribution of the papillae, apical cytoplasmic expansions and behaviour of microfolds observed under SEM) have been made in different environmental conditions and nutritional habits, with attention to the mechanical events in the course of feeding.


The microvasculature of the lingual mucosa in Capra hircus. The microvasculature of the lingual mucosa of the goat was studied by SEM using microvascular corrosion casts. A complex microcirculatory system was observed to supply the large number of papillae, which had a wide structural variety. Generally, the organization of the vascular network in the lingual papillae was found to be influenced by the nature of the microcirculation in the lamina propria. Another characteristic feature noted was the presence of numerous valves in the venules situated in the lamina propria. They were oriented toward the broader side of the venules and probably control the rapid outflow of blood. This in turn most probably leads to an increased mucosal blood supply, which might sustain both mechanical and gustatory functions.


[Meta-analysis of therapeutic trials of primary prevention in ischemic cardiopathies by hypocholesteremic treatment]. The prevention of lipid-related coronary risk by lipid lowering drugs or diet has been the object of several therapeutic trials. This meta-analysis comprises the 6 available primary prevention trials (representing 30,695 subjects). There was an overall reduction of non-lethal infarcts (-26%) and coronary events (-18%) in the treatment groups. There was a tendency to less coronary deaths (-10%), though not statistically significant, and no difference in mortality due to all causes was observed. Some questions remain unanswered about the fact that the reduced incidence of ischaemic heart disease did not affect global mortality. This fact could be explained by an inadequate duration of treatment or follow-up, to an effect limited to chronic infarction or to eventual unidentified adverse effects (the meta-analysis does not show any significant differences in mortality due to cancer or accidental death).


[Mechanism of action of antilipemic drugs]. The study of the modes of action of lipid lowering drugs is important in order to evaluate their effects on the different lipid fractions and their possible secondary effects. These studies include: direct and indirect measurements of cholesterol absorption, the measurement of the principal enzymatic activities implicated in lipoprotein metabolism, especially those of lipases which play a fundamental role in the metabolism of particles rich in triglycerides and the inverse transport of cholesterol, and, finally, the measurement of intracellular enzyme activities. These last analyses are generally much more complex. Despite recent advances in all these investigative techniques, the mechanisms of action of many lipid lowering drugs remain obscure. Many have indirect modes of action like the inhibition of hydroxymethyl-glutaryl CoA by the fibrates and the mechanisms of action of the most recently introduced drugs are more complex than usually described. All these factors are important because the development of atherosclerosis depends on qualitative variations of the lipoproteins.


On the presence and ultrastructure of valves in the lymphatic vessels of the canine ovary. The origin and course of the intraovarian lymphatic vessels were examined by means of histologic studies of the gonads of pubertal female dogs. The small vessels that were present in the cortex near the follicles and corpora lutea flowed into an anastomotic network located at the margins of the medulla. Vessels of larger caliber were found to originate from the medulla and to reach the hilum by an approximately rectilinear pathway. In concordance with their previous findings in other species, the authors identified numerous semilunar valves in the lymphatic vessels of the cortex. Their ultrastructure is described.


Microscopical aspects of root resorption of human deciduous teeth. In order to obtain detailed information on the tissue changes which occur during physiological root resorption, 52 human deciduous teeth at various stages of resorption were studied under light microscopy. The early stage of root resorption was defined as resorption of not more than one third of the root length; the late stage was defined as resorption of more than one third. A close topographical interrelationship was found among che sites of pressure of the permanent tooth, the extent of root resorption and the types of tissue changes. Linear resorption (which reflects suspension or marked slowing down of resorption) and redeposition of hard tissue were more pronounced at the early stage of resorption, while lacunar resorption was more pronounced at the late stage. There were pronounced haemorrhagic and inflammatory infiltrates within the pulp at the late stage of resorption and the subodontoblastic cells disappeared as the infiltrates took over the tooth. False denticles were found frequently, especially at the early stage of resorption. Unexpectedly, acellular cementum was found to be deposited against secondary dentine at the cuspidal tip of the pulp chamber of seven teeth, independently of any sign of resorption nearby. These data indicate that: 1) the pressure exerted by a permanent tooth is the most important factor in the differentiation of odontoclasts. 2) the extent of lacunar (i.e., active) resorption correlates directly with the resorption rate, which is higher at the late stage of root resorption. 3) inflammation is a consequence, rather than a cause, of resorption; it may lead to the loss of subodontoblastic cells and a consequent decrease in the ability of the pulp cells to replace damaged odontoblasts. 4) the pulp of the deciduous tooth might be cementogenic in some way, given that about 13% of the samples were found to be so.


[The "duration of administration" factor in studies of clinical pharmacology of hypolipemic drugs]. Clinical pharmacological trials of lipid lowering drugs should first of all indicate the duration of interruption of previously used lipid lowering drugs. The duration of interruption should be at least 4 weeks for inhibitors of HMG CoA reductase, 6 weeks for a second generation fibrate or a resin and over 6 months for probucol. In order to obtain the maximum therapeutic effect, a 4 week treatment period is sufficient for a HMG CoA reductase inhibitor or a resin. On the other hand, this period is longer for a fibrate and a 6 week treatment period is to be preferred with this family of drugs. The efficacy of probucol on the lipid fractions can only be assessed after several months' therapy. In future, a more accurate classification of patients with respect to their physiopathology should provide a better evaluation of the comparative efficacy of the different lipid lowering drugs.


[Methodology of phase II clinical trials of hypocholesteremic drugs: which criteria?]. Phase II is crucial in drug trials: during this period the first patients are exposed to the drug and the results influence the continuation of the development and the success of later trials. This stage is fundamental in lipid lowering drugs considering the costs of development and potential benefits for public health. The choice of pertinent criteria for the design of a lipid lowering drug trial depends on the analysis of data acquired during previous large scale trials. These criteria should demonstrate the potential of the tested drug and the best conditions of its administration. It is especially at this stage that the drug dosage optimising the efficacy/tolerance ratio should be determined. Analysis of large scale prevention trials indicates LDL-cholesterol as the principal criterion. It is related to coronary risk in the major trials of lipid lowering drugs. A reduction of LDL-cholesterol gives a good numerical estimate of the expected reduction of cardiovascular risk. It is then possible to formulate the hypotheses required for the design of these trials, in particular to calculate the size of the treatment group required. The total cholesterol should also be measured above all because of the large amount of data correlating it with cardiovascular risk. The HDL-cholesterol and triglycerides should also be taken into account even though some of the data concerning these parameters is controversial. The discrimination obtained by measuring HDL-cholesterol is without any doubt crude, and future criteria should enable more accurate and rapid evaluation of lipid lowering activity.(ABSTRACT TRUNCATED AT 250 WORDS)


[Methodology of phase III clinical trials of hypocholesteremic agents. Do any reliable substitution criteria exist?]. Pathological events such as myocardial infarction or cardiac death due to hypercholesterolaemia are easily quantified and reliable parameters for assessing the value of lowering the serum cholesterol. However, these events are relatively rare during Phase III clinical trials, the duration of which does not exceed 1 year. To solve this problem, intermediary or substitute criteria have to be used which are predictive of cardiovascular complications related to this pathology. Substitute criteria such as total cholesterol LDL-cholesterol and HDL-cholesterol have been validated by epidemiological and/or clinical studies which have established their predictive value. These primary and secondary prevention trials and regression studies have been analysed. The possibility of more sensitive predictive values of certain lipid fractions and particles is discussed.


[Primary prevention trial. Methodological problems]. Primary prevention trials are the best method of demonstrating the true value of medical intervention to correct abnormalities of lipid metabolism. A large number of patients must be followed up for a long period and this explains the complexity of the logistic problems which are encountered. However, these trials must conform to the classical guide lines of all clinical trials: an accurate definition of the study population, a principal criterion of adjustment which satisfies the golden rule "One question, one study".


[Evaluation of acquired data on long-term risk of hypolipidemic treatments]. At present, it is very difficult, if not impossible, to draw reliable conclusions about the long-term risks of lipid lowering therapy. Many so-called "long-term" trials only cover a few years of treatment, comparative studies versus placebo are very rare and the notification of acute events in the context of pharmacovigilance does not provide information about the long-term risk. However, analysis of large scale primary or secondary prevention trials, the Lipid Research Clinics study with cholestyramine, the Helsinki cardiological study with gemfibrozil, the Coronary Drug Project with clofibrate and nicotinic acid, has not shown any significant differences between the treatment and control groups, in particular with regards to the prevalence of malignant disease. These reassuring observations contradict those of the WHO study with clofibrate: a significant increase in the incidence of cancer, especially gastrointestinal, is observed in the treatment group. Therefore, despite the absence of confirmed long-term clinical or biological adverse effects of lipid lowering drugs (apart from the WHO clofibrate study), the physician must remain vigilant, especially as the long-term risks are difficult to assess.


[Mediterranean nutrition: a model for the world?]. The protection of Mediterranean populations against ischaemic heart disease has been recognised ever since the "Seven Countries" Study by Keys. It is probably related to the life style and, in particular, to the dietary habits of these populations. The Mediterranean diet is characterised by a certain frugality, a low intake of saturated animal fats contrasting with a high but reasonable intake of mono or polyunsaturated fatty acids, slow carbohydrates, fresh vegetables rich in antioxidating vitamins, fish and wine. These dietary habits have been shown to improve the lipid profile (not only lowering LDL-cholesterol but also raising the HDL-cholesterol), platelet activity and to reduce the phenomena of lipoperoxidation. The roles played by garlic and onions are controversial. Nevertheless, at pharmacological dosages, they have cholesterol lowering, fibrinolytic and antiaggregant effects. These dietary habits, which have been proved to be beneficial, should therefore be preserved in our country.


[Methodological problems of prevention/regression trials of atherosclerosis]. Animal models of atherosclerosis have improved our understanding of the pathogenic mechanisms involved in the formation of the atherosclerotic plaque. However, extrapolation of these data to the clinical situation is difficult. In addition, evaluation of the prevention or regression of atherosclerosis raises methodological problems. Although improved techniques provide a better evaluation of the extension of the plaques and their functional consequences, a number of points remain undecided: when to intervene, in which patients and how to extrapolate the results. A standardisation of the methods of evaluation of the atherosclerotic plaque is essential as is the fact that the benefit observed should be a reduction in cardiovascular complications and not simply the progression or regression of an angiographic lesion.


[Technique for measuring the atheroma volume in men]. The evaluation of the impact of therapy on the evolution of atherosclerotic lesions or restenosis after angioplasty requires the use of techniques of vascular imaging. The reference invasive method is digital angiography although it does not provide data on the arterial wall thickness. This parameter can be approached however by intravascular ultrasound imaging, a technique which has a number of important practical limitations. Of the non-invasive techniques available, Doppler ultrasonography is the only one that can be used in clinical trials. Nuclear magnetic resonance imaging is the object of much research and is without doubt the technique of the future. The choice of model of atherosclerosis influences that of the imaging technique: cineangiography for coronary arteries, digital angiography or Doppler ultra sonography for lower limb arteries and Doppler ultrasonography for the carotid arteries. Interpretation of angiography is now performed quantitatively by videodensitometry. Interpretation of other techniques should be performed by a second independent observer and "blinded" with respect to the order in which the investigations were performed and to the treatment administered. The criteria of judgment may be qualitative (progression, stabilisation, regression) or quantitative, the latter having a number of advantages over the former. Of the quantitative criteria, the percentage stenosis, though widely used, does not fully answer the question posed, and neither does the diameter of the stenosis. The volume of the arterial lumen calculated from videodensitometric data would seem to be the best, by its sensitivity and additivity, current angiographic parameter.(ABSTRACT TRUNCATED AT 250 WORDS)


[Hypolipidemic treatment after myocardial infarction]. Treatment of hyperlipidaemia is even more important after than before myocardial infarction. Currently available data should be confirmed by larger studies including women and lasting over 10 years. Analysis of the results would be facilitated by studying comparable groups with respect to left ventricular function and severity of the coronary disease. The total serum cholesterol should optimally be under 2 g/l and the LDL-cholesterol under 1.30 g/l. However, coronary artery disease is a multifactorial condition and the correction of only one predisposing factor, albeit a major one, is not sufficient for effective prevention.


[Evaluation of anti-atheromatous properties of calcium channel inhibitors]. Calcium is involved in several biochemical atherogenesis processes and its activity is antagonised in cell and animal experimental models by all classes of slow channel calcium inhibitors. However, the doses required in animals to slow the development of atherosclerotic lesions are above therapeutically acceptable doses in man. The clinical relevance of their anti-atherosclerotic activity in the few clinical studies undertaken is difficult to assess because of the variable criteria of judgment used.


[Inhibitors of angiotensin-converting enzyme and processus of intima proliferation in atherosclerosis]. The renin angiotensin system is a negative feed-back system of blood pressure control. A number of concordant experimental and clinical results indicate that the angiotensin family has a trophic effect on the vessel wall. These properties of the angiotensins favorise the proliferation of the cells which make up the vessel wall and also amplify the vascular dysfunction in the absence of the inhibitory regulations. Angiotensin converting enzyme inhibitors could be a valuable therapeutic method of counteracting these deleterious effects on the composition and function of the vessel wall.


[Atheroma and antithrombotic agents].

[Atheroma and antithrombotic agents]. The clotting factors are thought to play a part in the development of atherothrombosis, not only in the formation of occlusive thrombosis but also in the progression of vessel wall lesions. Activated platelets participate in thrombus formation and stimulate the proliferation of smooth muscle cells via the growth factor that they liberate. Many therapeutic trials have been carried out with different platelet-inhibiting drugs and some have show a preventive effect on occlusive events. The role of platelet anti-aggregants in the prevention of vessel wall lesions is more difficult to demonstrate. Activation of the coagulation system or a defect in the fibrinolytic system result in the accumulation of intravascular and intraparietal fibrin. The increases in plasma concentration of factors such as the fibrinogen, factor VII, a fibrinolytic inhibitor, PAI-1, are considered to be markers of coronary risk. The preventive effect of low-dose vitamin K antagonists which reduce factor VII activity and the effect of metformin which counteracts insulin resistance and reduces PAI-1 concentrations, are at present under trial. Some platelet antiaggregants and lipid lowering drugs reduce fibrinogen, factor VII and PAI-1 concentrations. Results of therapeutic trials of these molecules are eagerly awaited.


[Atheroma and fish oils].

[Atheroma and fish oils]. The reduction in cardiovascular mortality and morbidity observed over the last decade may be considered to be largely the result of the prevention of lipid disorders. The beneficial effects of diet and increased consumption of unsaturated fatty acids on ischaemic heart disease is a generally accepted concept. The low death rate from coronary artery disease amongst Greenland eskimos who eat a lot of fish has been confirmed by epidemiological studies of other large fish eating populations like the Japanese. The results reported by Bang and Dyerberg have been confirmed by the Zutphen study undertaken by Kromhout in the Netherlands. Fish oil act by the intermediary of the omega-3 fatty acids. Fish oil is rich in high unsaturated omega-3 fatty acids, the most important one being eicosapentaenoic (EPA) and docosahexaenoic acids (DHA). On the basis of epidemiological studies and clinical and experimental observations, it would appear that the consumption of marine polyunsaturated fatty acids has at least a preventive effect on phenomena of atherosclerosis and thrombosis. Their efficacy on the regression or stabilisation of the atheromatous plaque has not been demonstrated. The sites of action are multiple: decreased platelet aggregation; inhibition of thromboxane A2 production; reduction of triglyceride and VLDL concentration; improved blood rheology; action on the endothelium and proliferation of the intimal cells, vascular tone and vasomotricity. The importance of cardiovascular mortality and the hopes raised by clinical and epidemiological trials justify the pursuit of complementary studies on the efficacy and modes of action of marine polyunsaturated omega-3 fatty acids.


[Vascular action of prostaglandins: atheroma, vasoconstriction and ischemia]. Prostaglandins seem to be involved in all stages of the atheromatous process, especially coronary artery disease. This condition is associated with decreased prostacyclin synthesis. Prostacyclin, by the intermediary of cAMP, regulates cholesterol metabolism in the smooth muscle cell by mobilising intracellular cholesterol. Thromboxane is liberated in great quantities in acute coronary syndromes such as myocardial infarction (especially when fibrinolysis is performed) and unstable angina. It is also found in high concentrations in coronary sinus blood during stress tests inducing transient ischaemia in patients with stable angina. There is a relationship between the degree of ischaemia and plasma concentrations of thromboxane whereas prostacyclin levels remain unchanged, causing an imbalance between these two substances during ischaemia. Thromboxane is also responsible for the acute pulmonary vasoconstriction induced by the neutralisation of heparin by protamine. The introduction of molecules modifying the synthesis of these prostaglandins or inhibiting their effects by specifically blocking their receptors should open up new therapeutic possibilities.


[Evaluation of trials on regression of atheromatous lesions with hypolipemic drugs]. Experimental studies have demonstrated regression of atheromatous lesions with diet and lipid lowering drugs. In order to confirm these results clinically, reliable angiographic methods of analysis must be developed along two lines: quantitative by consensus between independent "blinded" experts, qualitative by digitalizing radiological images. Given the reproducibility of these methods, a variation of 17 to 20% in the size of the atheromatous plaques should be required to affirm a change. Five studies have been performed in patients with atherosclerosis associated with variable degrees of hyperlipidaemia and compared with a control group. NHLBI type II: 59 out of 146 patients with type II hyperlipoproteinaemia were treated with cholestyramine for 5 years with reduction of the progression of > 50% stenosis but no evidence of regression (6%). CLAS: 80 out of 160 coronary patients were treated with cholestipol and nicotinic acid for 2 years and a reduction of progression and a regression of lesions were observed in 16% of cases. Nikkila: 28 coronary patients with hyperlipidaemia were given clofibrate or nicotinic acid for a 7 year period, stabilising the evolution but with no signs of regression. FATS: 74 of 120 coronary patients with apolipoprotein B concentrations of over 1.25 g/l were given lovastatine-cholestipol or nicotinic acid-cholestipol for 2.5 years: regression of coronary lesions was observed in 32 to 39% of cases depending on the treatment administered. Olsson: reported the same results for femoral atheroma with treatments associating fenofibrate and nicotinic acid: 20% regression and reduction of progression.(ABSTRACT TRUNCATED AT 250 WORDS)


[Trials of primary prevention by diet or hypolipidemic treatment]. The experimental demonstration of a causal relationship between serum cholesterol and coronary artery disease has been confirmed by primary prevention trials. Four trials have fulfilled the methodological criteria of this type of research. Three of them have involved lipid lowering drugs (clofibrate, cholestyramine and gemfibrozil) and the fourth a diet low in saturated fats. They were undertaken in middle aged hypercholesterolemic men and offered 9 out of 10 chances of demonstrating a significant reduction in the prevalence in ischaemic heart disease if it existed. The serum cholesterol of the treatment groups was on average 8 to 13% lower to that of the control groups. In the 4 trials, the prevalence of severe coronary events, infarction and sudden death, was significantly reduced (relative reduction of 19 to 47%). The reduction in individual risk was proportional to the reduction in serum cholesterol. In 2 trials, this reduction was related to variations in the opposite directions of the LDL and HDL cholesterol: a reduction of 1% in LDL-cholesterol reduced the risk by 2% and an increase of 1% of HDL-cholesterol reduced it by 2 to 4%. None of the trials were designed to evaluate the effect of intervention on mortality. In one of them (clofibrate), all cases of mortality were temporarily increased during the trial.(ABSTRACT TRUNCATED AT 250 WORDS)


Dosimetry Workshop: extremely-low-frequency electric and magnetic fields. A workshop on the dosimetry of extremely-low-frequency fields was held to assess current knowledge in this field and to develop a set of recommendations for new research that meets the needs of health risk assessment, in particular, the assessment of cancer risk. The workshop was sponsored by the Electric Power Research Institute and was held on March 20-22, 1991, in Carmel, California. Major topics of the workshop were microdosimetry of induced electric fields, scaling of induced fields among biological systems from cells to humans, and the problem of defining a biologically effective "dose." A number of research recommendations were developed, the most important of which are to (1) characterize the natural background electric and magnetic fields in tissues and near cells, (2) improve experimental exposure geometries to allow accurate characterization of induced fields in samples, (3) design experiments to distinguish between electric and magnetic field mechanisms, (4) develop standard in vitro biological systems with reproducible and well-established responses to fields, and (5) develop definition of dose with respect to fields at the primary site of interaction.


Magnetite in human tissues: a mechanism for the biological effects of weak ELF magnetic fields. Due to the apparent lack of a biophysical mechanism, the question of whether weak, low-frequency magnetic fields are able to influence living organisms has long been one of the most controversial subjects in any field of science. However, two developments during the past decade have changed this perception dramatically, the first being the discovery that many organisms, including humans, biochemically precipitate the ferrimagnetic mineral magnetite (Fe3O4). In the magnetotactic bacteria, the geomagnetic response is based on either biogenic magnetite or greigite (Fe3S4), and reasonably good evidence exists that this is also the case in higher animals such as the honey bee. Second, the development of simple behavioral conditioning experiments for training honey bees to discriminate magnetic fields demonstrates conclusively that at least one terrestrial animal is capable of detecting earth-strength magnetic fields through a sensory process. In turn, the existence of this ability implies the presence of specialized receptors which interact at the cellular level with weak magnetic fields in a fashion exceeding thermal noise. A simple calculation shows that magnetosomes moving in response to earth-strength ELF fields are capable of opening trans-membrane ion channels, in a fashion similar to those predicted by ionic resonance models. Hence, the presence of trace levels of biogenic magnetite in virtually all human tissues examined suggests that similar biophysical processes may explain a variety of weak field ELF bioeffects.


Estimates for ELF effects: noise-based thresholds and the number of experimental conditions required for empirical searches. Interactions between physical fields and biological systems present difficult conceptual problems. Complete biological systems, even isolated cells, are exceedingly complex. This argues against the pursuit of theoretical models, with the possible consequence that only experimental studies should be considered. In contrast, electromagnetic fields are well understood. Further, some subsystems of cells (viz. cell membranes) can be reasonably represented by physical models. This argues for the pursuit of theoretical models which quantitatively describe interactions of electromagnetic fields with that subsystem. Here we consider the hypothesis that electric fields, not magnetic fields, are the source of interactions, From this it follows that the cell membrane is a relevant subsystem, as the membrane is much more resistive than the intra- or extracellular regions. A general class of interactions is considered: electroconformational changes associated with the membrane. Expected results of such as approach include the dependence of the interaction on key parameters (e.g., cell size, field magnitude, frequency, and exposure time), constraints on threshold exposure conditions, and insight into how experiments might be designed. Further, because it is well established that strong and moderate electric fields interact significantly with cells, estimates of the extrapolated interaction for weaker fields can be sought. By employing signal-to-noise (S/N) ratio criteria, theoretical models can also be used to estimate threshold magnitudes. These estimates are particularly relevant to in vitro conditions, for which most biologically generated background fields are absent. Finally, we argue that if theoretical model predictions are unavailable to guide the selection of experimental conditions, an overwhelmingly large number of different conditions will be needed to find, establish, and characterize bioelectromagnetic effects in an empirical search. This is contrasted with well-established chemical dosimetry, which is much simpler. Because of the large number of possible electromagnetic field conditions, we also conclude that in vitro studies, rather than in vivo studies, should be emphasized in studies aimed at discovering and characterizing mechanisms for bioelectromagnetic effects.


Bioelectric background fields and their implications for ELF dosimetry. Electrically active cells, such as those comprising nerve, muscle, or bone, produce ELF currents not only across themselves but also in the surrounding tissue including the tight extracellular spaces between cells. An analysis based on "cable models" of neurons or muscle cells is herein used to estimate those extracellular (or "pericellular") current densities. In order to explore frequency bands the neural or muscle action potentials are represented by a Fourier series of sine wave components. The results of this analysis suggest that endogenous currents in, or near, nerve and muscle are far stronger (higher density) than currents likely induced by exogenous ELF fields--such as 1 microT, 60 Hz magnetic fields. This holds true even for "higher harmonics" including those at or near 60 Hz.


Endogenous ionic currents and DC electric fields in multicellular animal tissues. Through the use of the non-invasive vibrating probe technique for detecting extracellular ionic currents developed in 1974 [Jaffe and Nuccitelli: J Cell Biol 63:614-628, 1974], embryonic currents have been detected in a wide range of animal systems (recently reviewed in [Nuccitelli, Noninvasive Techniques in Cell Biology. New York: Wiley-Liss, 1990, pp 273-310]. In four of these studies, the corresponding electric field has been measured within the animal tissue. Such measurements of internal electric fields are quite challenging because they involve the insertion of microelectrodes into the developing tissue along specific regions of current flow. This paper reviews the evidence for endogenous transembryonic currents and dc electric fields in animal systems and provides the range of values for such physiological fields. These data should provide a guide to the range of imposed electric field strengths that could influence normal biological functions in living organisms.


Experimental macroscopic dosimetry for extremely-low-frequency electric and magnetic fields. Environmental and laboratory exposure to electric and magnetic fields (EMF) in the extremely-low-frequency range (ELF) produces electrical quantities that interact directly with the exposed biological system on a scale small compared to the size of the human body but large with respect to cellular dimensions. The purpose of this paper is to describe these macroscopic electrical quantities and their characterization through measurements on living systems and experimental models. Electric field exposure results in a total induced current, surface electric fields, internal electric fields, and internal currents. Magnetic field exposure results in internal magnetic field, internal electric fields, and internal currents. Basic properties of fields and matter determine the methods by which these quantities can be measured. Quantification or dosimetry for these parameters on a macroscopic basis can be directed to the whole body, a cross section across the body, a local surface area, or a local volume. Models of varying degrees of sophistication have been used to establish spatial distributions of external fields and internal fields and currents.


Microelectrode measurements of low frequency electric field effects in cells and tissues. The average intensities of electric fields induced into tissue can be calculated if the morphology and conductivities of the tissue are known, and such values provide one estimate of dosage for a given field exposure level. However, the microanatomical structures of living tissue, which include gap junctions, tight junctions, highly charged cell coats, and extracellular matrices, as well as complex cell shapes, precludes a detailed characterization of the field and current distribution near the cells which are actually responding to the electric fields. This suggests that a more useful electric field dose metric may be one based on an induced physical effect on the cells. Electric fields have at least three distinct physical effects on cells: the normal plasma membrane potential will be altered; the ionic currents and ion distributions at the extracellular surface will be modified; and mechanical forces will be imposed at the cell surface. Each of these effects can, in principle, be measured through the application of specific microelectrode techniques. Here, the feasibility of using various intracellular and extracellular recording methods to obtain dosimetric values, as well as the contribution these measurements could make to our understanding of electric field interactions with biological tissue, are discussed.


Voltage-sensitive dyes: measurement of membrane potentials induced by DC and AC electric fields. Dye indicators of membrane potential have been available for the past 15 years and have been employed in numerous studies of cell physiology. Since the cell membrane is a likely primary site for the cascade of events resulting in a biological response to electromagnetic fields, methodologies for monitoring the membrane voltage will be critical. This laboratory has developed a series of dyes by using theoretical molecular orbital calculations to predict electrochromic structures. The spectra of electrochromic dyes are altered via a direct coupling of the molecular electronic states with an electric field. This mechanism has the advantage of providing both high temporal and high spatial resolution because the effect is instantaneous and is localized to the level of individual indicator molecules. It therefore can have significant advantages over traditional microelectrode techniques because fast changes in potential can be monitored simultaneously over many different regions of a biological preparation. We have used these dyes to monitor membrane potentials induced by both DC and AC electric fields. In a series of studies with a model membrane system, a spherical lipid bilayer, we showed that the potential develops on the membrane in good agreement with a time-dependent solution to Laplace's equation. Cell membranes can also be stained with voltage sensitive dyes. In experiments with dc fields, we are able to map the variation of the induced membrane potential along the surface of the cell by employing digital video fluorescence microscopy. We can also use the fluorescence microscope to detect membrane potential induced by ac fields by using a phase-sensitive detection scheme to extract the corresponding change in the light intensity from the fluorescent indicator. The technology can be extended to more complex biological preparations and can be used in conjunction with other optical techniques such as those which monitor intracellular ion concentrations. It may, therefore, prove highly valuable for the elucidation of biological responses to electromagnetic fields.


Factors affecting neural stimulation with magnetic fields. High amplitude magnetic field pulses produced by coils external to the body have been used for medical diagnosis since the mid-1980s to stimulate motor neurons in the brain cortex and peripheral nerves. While successful applications have since blossomed, it has only been during the last three years that quantitative dosimetric data have become available. The factors affecting neural stimulation can be divided into three categories broadly related to the characteristics of (i) the stimulus, (ii) the neuron, and (iii) the induced electric field as related to the configuration of the stimulating coil. The stimulus, in the case of magnetic field stimulation, has the form of an exponentially decaying pulse with a small overshoot of the opposite polarity. Physical and electrical properties of a neuron affect its electrical stimulation. Dosimetric considerations are limited to the linear model describing the threshold phenomena, where passive electrical properties and the cable model provide a reasonable approximation of neuron behavior. The electromagnetic variable responsible for stimulation is the spatial derivative of the induced electric field along the neuron axis. This paper examines the factors involved in eliciting threshold excitation of motor neurons by magnetic fields. The description of various factors is largely based on published data except for the analysis of the electromagnetic stimuli induced by various coils.


Dosimetry of extremely-low-frequency magnetic fields. Extrapolation of quantitative measurements across biological systems requires knowledge of field-organism interaction mechanisms. In the absence of such knowledge, one can only indicate which parameters would be important under some plausible assumptions that still lack experimental proof. In the first part of the paper it is assumed that biological effects of low intensity, extremely low frequency magnetic fields are caused by the electric fields which they induce. It is shown that detailed knowledge of electrical properties on a microscale is important to predict effects that may be due to local current density, electric field strength, surface charge distribution, and mechanical forces. In the second part of the paper, it is shown that all proposed mechanisms for direct interaction between alternating magnetic fields and cells involve also the magnitude and direction of a simultaneously present static magnetic field. Reviewed are "cyclotron resonance," quantum mechanical effects on ions weakly bound to proteins, nuclear magnetic resonance, and recent progress in magneto chemistry dealing with effects of magnetic fields of a few hundred microtesla on chemical reactions that involve free radicals.


Dose-response implications of the transient nature of electromagnetic-field-induced bioeffects: theoretical hypotheses and predictions. Data in the literature imply that the relationship between exposure and bio-effect involves more than a simple time integral of the field strength to which the living system has been subjected. Windows--ranges in which the system exhibits enhanced sensitivity--have been reported for power (or field strength), frequency, and the duration of the exposure. In this paper we show that such isolated window effects can be accounted for by recognizing the transient character of the response of the biological system. The principal assumption here is that the direct effect of the field is to increase the rates of production and degradation of mRNA or proteins. In this paper we review and extend the mathematical model that quantifies this. The model predicts that, for a given field strength, certain optimum relatively short duration exposures cause significantly larger bio-effects than exposure for much longer or much shorter times. The thinking embodied in the model should provide a framework for obtaining a meaningful working definition of "effective dose" and for predicting the response of subjects to environmental electromagnetic fields. It should help in deciding the relevant variables in the design and analysis of epidemiological studies.


Regulation of cell cycle and growth control. The potential biological effects of electric and/or magnetic fields on cells and tissues must be addressed systematically within a context of perturbations in cell cycle control. Such studies should not be pursued in an isolated manner but as a component of the fundamental relationship between proliferation and differentiation, the multi-step process by which structural and functional properties of specialized cells, tissues, and organs progressively develop. It is necessary to quantitatively establish the influence of electric and magnetic fields on the integrated signalling mechanisms which transduce regulatory information for 1) control of the proliferative process and 2) down-regulation of proliferation associated with the initiation of gene expression that mediates the development and maintenance of phenotypic properties characteristic of differentiated cells. We will present an overview of our current understanding of regulatory mechanisms that control proliferation and cell specialization in normal diploid cells with emphasis on rate limiting steps that may be the basis for biological perturbations by electric and magnetic fields. Addressing such questions in normal diploid cells is essential since the loss of growth control in transformed and tumor cells is accompanied by an abrogation of developmental regulatory mechanisms that are functionally coupled to proliferation.


Numerical and analytical methods to determine the current density distributions produced in human and rat models by electric and magnetic fields. Some numerical and analytical methods used to estimate the internal electric fields and current densities produced within human and animal models by low-frequency electric and magnetic fields are surveyed. A major goal of such modeling is the design of laboratory experiments on cellular systems or animal models to produce a dosage comparable to that experienced by humans in a particular situation. Specific comparisons are made between the results of ellipsoidal approximations and finite-difference methods applied to irregularly-shaped, homogeneous, human and rat models for applied 60 Hz electric (10 kV/m) and magnetic (10(-4) T) fields. For scaling purposes, the induced current densities in various parts of the body are compared for rat and human models for both types of field. In addition, the current density distribution induced in rectangular culture dishes by applied magnetic fields is also described. The extension of these methods to inhomogeneous models and localized sources may not be simple.


Numerical dosimetry at power-line frequencies using anatomically based models. We have used the finite-difference time-domain (FDTD) method to calculate induced current densities in a 1.31-cm (nominal 1/2 in) resolution anatomically based model of the human body for exposure to purely electric, purely magnetic, and combined electric and magnetic fields at 60 Hz. This model based on anatomic sectional diagrams consists of 45,024 cubic cells of dimension 1.31 cm for which the volume-averaged tissue properties are prescribed. It is recognized that the conductivities of several tissues (skeletal muscle, bone, etc.) are highly anisotropic for power-line frequencies. This has, however, been neglected in the first instance and will be included in future calculations. Because of the quasi-static nature of coupling at the power-line frequencies, a higher quasi-static frequency f' may be used for irradiation of the model, and the internal fields E' thus calculated can be scaled back to the frequency of interest, e.g., 60 Hz. Since in the FDTD method one needs to calculate in the time domain until convergence is obtained (typically 3-4 time periods), this frequency scaling to 5-10 MHz for f' reduces the needed number of iterations by over 5 orders of magnitude. The data calculated for the induced current and its variation as a function of height are in excellent agreement with the data published in the literature. The average current densities calculated for the various sections of the body for the magnetic field component (H) are considerably smaller (by a factor of 20-50) than those due to the vertically polarized electric field component when the ratio E/H is 377 ohms. We have also used the previously described impedance method to calculate the induced current densities for the anatomically based model of the human body for the various orientations of the time-varying magnetic fields, namely from side to side, front to back, or from top to bottom of the model, respectively.


Some engineering models for interactions of electric and magnetic fields with biological systems. The objective of this paper is to review some of the fundamental mechanisms for the interaction of electric and magnetic fields with biological systems at variable levels of field strengths and to examine several possible ways by which weak fields may influence these systems. We begin with a review of the basic equations by which electric or magnetic fields interact with biological fluids and follow it with a look at the effects of inserting a simple cell membrane. The initial starting points are the force equations on charged particles and dipoles. We examine their effects on current flow, the orientation of long-chain molecules, and the forces which can be exerted by particles of magnetite on membranes. This is followed by a very simple model for the effects of a cell membrane on the overall current distribution and a model for current flow through a membrane. Some sources of nonlinearities which might serve as mechanisms for converting weak electrical signals from one frequency to a more biologically significant frequency are described. Additionally, three models by which a biological system may extract weak signals from noise are presented. The first of these is the injection-locking of oscillating processes where the signal-to-noise ratio may be less than unity. The second is parametric amplification which allows the external signal and the biological process to be at different frequencies and where stability requirements on the external pump frequency discriminates against the noise. The third approach is to examine a computer model for a neural network which can be trained to identify a 60 Hz field at signal-to-noise ratios much less than one. The key to each of these models for possible interactions of magnetic fields with biological systems is the long-term coherence of the signal with respect to the noise. Finally, we briefly examine the possibility of using scanning force and tunneling microscopes to give a better description of the characteristics of the cell surface.


Assessment of conduction properties and thermal noise in cell membranes by admittance spectroscopy. Advances in the speed of signal processing enable application of a Fourier-synthesized function as a small perturbation (1 mV) superposed on voltage clamp steps to rapidly (< 1 sec) acquire cell membrane complex driving-point functions (impedance or admittance) in several frequency bands ranging from 1 Hz to 10 kHz. Curve fits of admittance models to these data yield a complete quantitative linear description of membrane conduction systems and their kinetics. Furthermore, the rate constants between microscopic states of an ion channel can be calculated from conductance parameters derived from model curve fits of membrane admittances. Additionally, the power spectrum of membrane thermal noise is obtainable from impedance determinations by use of the Nyquist relation. Consequently, rapid driving-point function determinations provide the most complete macroscopic assessment of membrane conduction properties presently available. Admittance determinations of the potassium conduction system in squid giant axon and the potassium conducting "inward rectifier" in snail neuron are used to illustrate the above points.


Vitamin A levels and severity of measles. New York City. Recent studies show that vitamin A levels decrease during measles and that vitamin A therapy can improve measles outcome in children in the developing world. Vitamin A levels of children with measles have not been studied in developed countries. We therefore measured vitamin A levels in 89 children with measles younger than 2 years and in a reference group in New York City, NY. Vitamin A levels in children with measles ranged from 0.42 to 3.0 mumol/L; 20 (22%) were low. Children with low levels were more likely to have fever at a temperature of 40 degrees C or higher (68% vs 44%), to have fever for 7 days or more (54% vs 23%), and to be hospitalized (55% vs 30%). Children with low vitamin A levels had lower measles-specific antibody levels. No child in the reference group had a low vitamin A level. Our data show that many children younger than 2 years in New York City have low vitamin A levels when ill with measles, and that such children seem to have lower measles-specific antibody levels and increased morbidity. Clinicians may wish to consider vitamin A therapy for children younger than 2 years with severe measles. Additional studies of vitamin A in measles and other infectious diseases, and in vaccine efficacy trials, should be done.


Long-term follow-up of acute partial transverse myelopathy. We carried out a prospective, long-term, combined clinical and MRI follow-up study on 15 patients hospitalized at the Montreal Neurological Institute between 1985 and 1988 with a diagnosis of acute partial transverse myelopathy of unknown etiology. Twelve of the 15 (80%) developed clinically definite or lab-supported definite multiple sclerosis (MS) by the end of a mean follow-up period of 38.5 months. The presence of CNS periventricular white matter lesions by cranial MRI at onset increased the likelihood of development of MS to 93%.


Pelvic pain without pelvic organs.

Pelvic pain without pelvic organs. We report on 4 patients with persistent, severe pelvic pain unresponsive to removal of the bladder, uterus, ovaries and fallopian tubes. Of the patients 3 had a diagnosis of interstitial cystitis and 1 had voiding dysfunction. We conclude that severe pelvic pain may not be responsive to the elimination of pelvic organs and alternative organ-preserving therapies should be considered.


High-dose chemotherapy with autologous bone marrow transplantation for the treatment of metastatic breast cancer. This review was undertaken to examine the evidence of effectiveness of high-dose chemotherapy and autologous bone marrow transplantation (HDC/ABMT) for the treatment of metastatic breast cancer and to compare the magnitudes of the benefits and harms of HDC/ABMT with those of conventional doses of chemotherapy. Published studies were reviewed and analyzed. No randomized controlled trials have been published that evaluate HDC/ABMT. Only one internally controlled study has been conducted; it demonstrated that HDC/ABMT and conventional treatment have virtually identical outcomes. Comparisons of uncontrolled clinical series are confounded by patient selection and other biases. Gross comparisons indicate that, compared with conventional-dose chemotherapy, HDC/ABMT achieves (1) higher complete response rates (36% v 8%), (2) higher overall response rates (70% v 39%), (3) similar median response durations (8 months v 9.6 months), (4) similar median survival durations (16 months v 16.6 months), and (5) similar overall survival rates (eg, 43% 2-year survival v 39%). Observations of cases with longer-term disease-free survival are promising but not conclusive. High-dose chemotherapy with ABMT has a higher treatment-related mortality rate (5% to 15% v 1%), a high rate of nonmortal toxicity (approximately 30%), and a high rate of side effects (approaching 100%). Firm conclusions are not possible because of the lack of controlled studies and the presence of numerous biases. However, the existing evidence does not demonstrate that HDC/ABMT is superior to conventional-dose chemotherapy for the treatment of metastatic breast cancer. Randomized controlled trials are needed.


Disseminated candidiasis due to amphotericin B-resistant Candida albicans. Although development of resistance in Candida albicans to amphotericin B is considered rare, C. albicans was persistently recovered from a 28-year-old man after a prolonged course of broad-spectrum antimicrobial therapy for a pancreatic abscess. Determination of the MICs of drugs for C. albicans in Sabouraud broth revealed MICs of 2.5 mg/l amphotericin B, greater than 40 mg/l ketoconazole, 2.5 mg/l miconazole, and greater than 40 mg/l 5-fluorocytosine. Synergy testing revealed a MIC of 0.3 mg/l amphotericin B in the presence of 2.5 mg/l 5-fluorocytosine. When intravenous 5-fluorocytosine was added to the patient's antifungal regimen, achieving levels of 125 mg/l, negative blood cultures resulted for the first time. This suggests there may be a clinical use for in vitro synergy testing as an adjunct to guide antifungal therapy for fungemia due to amphotericin B-resistant C. albicans.


Prediction of mortality in patients with cystic fibrosis. The majority of patients with cystic fibrosis die in early adulthood of lung disease. Lung transplantation is a treatment option for patients with advanced pulmonary disease, although the waiting period for organs may be as long as two years. Our purpose was to determine whether the risk of death due to respiratory failure could be predicted one or two years in advance on the basis of pulmonary function, blood gas levels, and nutritional status. The study cohort consisted of 673 patients followed between 1977 and 1989. In each patient, pulmonary function, blood gas levels, nutritional status, and vital status were assessed between 1977 and 1987. Cox proportional-hazards regression analysis was used to compute the relative risk of death within one or two years after particular measurements. The effects of age and sex on mortality were also included in the analysis. One hundred ninety patients (28 percent) died during the study period. Overall, patients with a forced expiratory volume in one second (FEV1) less than 30 percent of the predicted value, a partial pressure of arterial oxygen below 55 mm Hg, or a partial pressure of arterial carbon dioxide above 50 mm Hg had two-year mortality rates above 50 percent. Among the laboratory measurements, the FEV1 was the most significant predictor of mortality, but age and sex were also significant in predicting risk. After adjustment for age and sex, the relative risk of death within two years was 2.0 (95 percent confidence interval, 1.9 to 2.2) for each decrement in the FEV1 of 10 percent below the predicted value. Among patients with the same FEV1, the relative risk of death was 2.0 (95 percent confidence interval, 1.5 to 2.6) in patients 10 years younger than other patients, and 2.2 (1.6 to 3.1) in female patients as compared with male patients. Patients with cystic fibrosis should be considered candidates for lung transplantation when the FEV1 falls below 30 percent of the predicted value. Female patients and younger patients may need to be considered for transplantation at an earlier stage.


Angiomyolipoma of the kidney: a clinical enigma in diagnosis and management. Renal angiomyolipomas are uncommon benign tumours which clinically mimic renal cell carcinoma. They have characteristic features on ultrasound and CT scanning which may enable their diagnosis preoperatively. We review our experience of six cases of renal angiomyolipoma. These cases highlight the difficulties in making a preoperative diagnosis despite the use of modern scanning. We advocate conservative resection when the diagnosis is made preoperatively and when technically possible, but radical nephrectomy should be performed if there is a possibility of a carcinoma.


No evidence of acute cardiovascular complications of chemotherapy for testicular cancer: an analysis of the Testicular Cancer Intergroup Study. The purpose of this study is to evaluate the risk of acute vascular events in patients receiving cisplatin-based chemotherapy for testicular cancer. A questionnaire assessing cardiovascular toxicity was distributed to all participants in the Testicular Cancer Intergroup study and details of toxicity from the chemotherapy flow sheets were reviewed. Patients with pathologic stage I testicular cancer were registered on to the study and observed after retroperitoneal lymphadenectomy. Patients with pathologic stage II disease were randomized to receive two postoperative courses of adjuvant cisplatin-based chemotherapy or observation. Any patient who had disease recurrence after observation or adjuvant therapy was given four cycles of cisplatin-based chemotherapy. Review treatment-related toxicity for those patients receiving adjuvant chemotherapy (n = 97) or chemotherapy for recurrent disease (n = 83) showed no cases of acute cardiovascular toxicity. The median follow-up period after study enrollment was 5.1 years; 459 questionnaires were mailed and 270 were returned. The percent return was equal among the observed adjuvant and recurrent groups (59%, 54%, and 64%). There was a significant increase in the incidence of extremity paresthesias in the two groups receiving chemotherapy. Fatal myocardial infarction was reported in two patients in the observation group and one nonfatal infarction was reported in the adjuvant treatment group. No patient in any group reported an incidence of stroke. Three patients in the observation group and one patient in the recurrent group experienced a thromboembolic event. Despite sporadic case reports suggesting a causal association between chemotherapy for testicular cancer and acute vascular events, this retrospective analysis provides no evidence of an increased risk for subsequent cardiovascular disease in this patient population.