A stochastic evolutionary model of molecular sequences.

A stochastic evolutionary model of molecular sequences is proposed. The basic forces in evolution are supposed to be mutation and selection. The concept is somewhat similar to Kauffman-Levin's concept of adaptive walks and corresponding analytical expressions have been developed. The selective force is divided into two parts: a slowly-varying part and a rapidly-changing fluctuation. The latter influences the distribution of sequences and results in an equation of motion along the flow line. The former plays a more important role in the emergence of evolutionary order. It is demonstrated that the asymmetry of selective forces would lead to a definite order of the system.


Intron evolution: a statistical comparison of two models.

The two most frequently occurring explanations for the existence and distribution of introns in the genes of different species are: (1) introns are remnants of the original genetic material. (2) Introns were introduced during evolution. We construct mathematical models corresponding to these two explanations, and calculate the probabilities that the intron distribution in genes from different species coding for actin, alpha-tubulin, triosephosphate isomerase and superoxide dismutase are described by these models. In both models, the branch lengths as well as the structure of the corresponding evolutionary tree is taken into account. Every branch in the evolutionary tree is assumed to have its own individual rate of loss of introns for the first model and rate of gain of introns for the second model. These rate constants are estimated from the actual number of introns. Using the rate constants we stimulate the intron evolution and calculate the probabilities that the actual intron arrangements are produced. The results for actin and alpha-tubulin, which are the two genes we have the most data for, favor the model corresponding conjecture (1), i.e. the idea that introns are old. This contradicts the results from an earlier attempt to model intron evolution where almost the same data was used (Dibb & Newman, 1989, EMBO J. 8, 2015-2021).


A comprehensive multiple matrix model representing the life cycle of the tick that transmits the agent of Lyme disease.

An extension of Leslie matrix methodology was developed to describe the life cycle of Ixodes dammini, the tick that transmits the agent of Lyme disease in eastern North America. Thereby, we described the seasonally changing pattern of interactions of the tick with its various hosts in a well-studied site on Nantucket Island, Massachusetts. Particular numerical values representing the site were estimated mainly on the basis of published values and interpreted on the basis of experience. The model was used to predict seasonal abundance and annual rate of increase of this vector tick. Although these ticks quest for hosts during two consecutive feeding seasons, all but a few feed during the first such season. The relative distribution of developmental stages of the tick stabilized after 35 years. Abundance of the simulated population increased exponentially and doubled every 6 years. The simulations produced realistic seasonal feeding distributions of the ticks in its various developmental stages.


Evolutionarily stable age at first reproduction in a density-dependent model.

We develop a new model of life history evolution to investigate the evolution of age at first reproduction. Density dependence is taken into account. For a given "species", age of maturity, offspring survival, immature survival, adult survival, fecundity, immature age-classes entering in competition with adults and immature competitive ability are traits adjustable by natural selection, and constitute a particular strategy. On the contrary, the type of intraspecific competition (scramble or contest), strength of competition and inherent net reproductive rate Ro(inh) are fixed (specific) characteristics. As a consequence of fixing Ro(inh), the evolution of any trait will affect trade-offs between others. Evolutionarily stable strategies are determined numerically by using the mathematical concept of Lyapunov exponents. Altogether, we consider 960 different hypothetical "species" (i.e. different combinations of fixed traits). Corresponding ESSs are analyzed with respect to their age at first reproduction, adult survival and immature competitive ability components. They appear to be gathered in three groups. One is intuitive and characterized by a reduction of immature competitive ability and a correlation of age of maturity with adult survival; populations reach mainly equilibria. The two other groups respectively include "species" with low age of maturity but high adult survival, and "species" close to semelparity with delayed maturity; immature competitive ability may not be minimized, and populations possibly exhibit complex dynamics. In conclusion, the hypothesis that the evolution of a demographic parameter modifies trade-offs between others turns out to have important consequences. We argue that life history theory cannot ignore the source and mode-of-operation of density dependence and must regard potential short-term instability as essential.


South African traditional herbal medicines used during pregnancy and childbirth.

Many black South African women use traditional herbal remedies as antenatal medications or to induce or augment labour. Very little is known about the pharmacology and potential toxicity of the plants used in these herbal remedies. The ethnic background and traditional usage of these remedies was researched and a literature survey revealed that 57 different plants were used in herbal remedies during pregnancy and childbirth. Several of these plants are poisonous and details of their toxicity are given.


Headache treatments by native peoples of the Ecuadorian Amazon: a preliminary cross-disciplinary assessment.

Headache, specifically migraine, is an extremely frequent and debilitating syndrome with worldwide prevalence, including indigenous cultures of Amazonia. This paper considers headache as perceived within the medical philosophy of 5 Indian tribes of the Ecuadorian Amazon Basin. Their ethnobotanical treatments for headache are examined, along with the limited available biochemical assay data. This information is analyzed by means of an Ethnopharmacology Rating Scale. Suggestions are offered as to methods of biochemical analysis that may be fruitful in assessment of potential clinical headache remedies. Key among these is the screening of ethnobotanical samples for serotonin receptor activity. The potential may exist for the discovery of more effective, less toxic headache drugs, as well as for the development of a new industry for the local economy that could promote conservation of an endangered ecosystem.


Essential oils and antimicrobial activity of two varieties of Cedronella canariensis (L.) W. et B.

The qualitative and quantitative determination of the essential oils of the aerial part of two varieties of Cedronella canariensis (L.) W. et B., namely, C. canariensis var. canariensis and C. canariensis var. anisata have been performed, together with the study of the antimicrobial activity of both oils. The noteworthy inhibition exhibited against Bordetella bronchiseptica and Cryptococcus albidus may justify the popular use of the these plants in the treatment of certain diseases of the respiratory tract.


Stevioside effect on renal function of normal and hypertensive rats.

Physiological and pharmacological experiments have suggested that stevioside from the leaves of Stevia rebaudiana acts as a typical systemic vasodilator. The effect of stevioside on renal function in both normal and with experimental renal hypertension rats (GII) was evaluated using clearance techniques. Stevioside provoked hypotension, diuresis and natriuresis in both the normal and hypertensive rats. Normal rats presented an increase in renal plasma flow (RPF) and glomerular filtration rate (GFR) constant following stevioside administration. The last effect is in part due to vasodilation of both the afferent and efferent arterioles. Moreover, stevioside infusion in hypertensive rats caused an increase in RPF and GFR. These data are consistent with impairment of a renal autoregulation mechanism in this experimental hypertensive model.


Cardiovascular responses in the normotensive rat produced by intravenous injection of gambirine isolated from Uncaria callophylla B1. ex Korth.

Among several alkaloids, including dimeric indoles, isolated from Uncaria callophylla, gambirine which is an alkaloid unique to this plant, has been found to be another hypotensive principle from the plant. Intravenous injections of gambirine in the dose range of 0.2 to 10.0 mg/kg caused a dose-related fall in both systolic and diastolic blood pressures as well as heart rate. At all doses gambirine showed a prompt onset of action and at the higher doses (5.0-10 mg/kg), marked persistence of hypotension accompanied by severe bradycardia were observed. In addition, higher doses of gambirine produced a more marked decrease in diastolic than systolic pressure while at lower doses both decreased equally. It is suggested that the hypotensive effect of gambirine may be peripheral in origin and is associated, at least in part, with a cardiac action.


Studies on the individual and combined diuretic effects of four Vietnamese traditional herbal remedies (Zea mays, Imperata cylindrica, Plantago major and Orthosiphon stamineus).

Herbal remedies are widely used in Vietnam alongside modern drugs. We assessed the diuretic effect of four traditional Vietnamese herbal remedies from Zea mays, Imperata cylindrica, Plantago major and Orthosiphon stamineus, all claimed to produce an increase of diuresis. No influence was recorded for the 12- and 24-h urine output or on the sodium excretion for any of the drugs when tested under standardized conditions in a placebo controlled double-blind crossover model. The present study indicates the need for critical review of the present recommendations regarding therapy with plant materials in countries relying on empiric traditions.


Pharmacologic properties of Moringa oleifera. 2: Screening for antispasmodic, antiinflammatory and diuretic activity.

Hot water infusions of flowers, leaves, roots, seeds and stalks or bark of Moringa oleifera were screened to detect three pharmacologic activities in experimental models in rats. The antispasmodic activity was demonstrated using isolated duodenum, oral anti-inflammatory activity by carrageenan-induced hindpaw edema and oral diuretic activity by urine output in metabolic cages. The seed infusion showed a significant inhibition of acetylcholine-induced contraction with an ED50 of 65.6 mg/ml bath concentration, inhibition of carrageenan-induced edema at 1000 mg/kg and diuretic activity at 1000 mg/kg. Some activity was also demonstrated in the roots. All doses expressed here are as equivalents of dried starting plant material.


Evaluation of xanthotoxol for central nervous system activity.

Xanthotoxol (XT), 8-hydroxypsoralen, exhibited dose-graded sedative activity in dogs, cats, rats, mice and hamsters. At doses of 5-20 mg/kg intraperitoneally (i.p.) in cats and 3-100 mg/kg orally (p.o.) in dogs, XT blocked predatory mouse/rat killing behavior. In mice, XT (10-300 mg/kg i.p.) exhibited a dose-dependent reduction in locomotor activity but was less potent in this regard than reference diazepam (10-100 mg/kg i.p.). XT in mice (0.1-10.0 mg/kg i.p.) and in hamsters (0.1-10.0 mg/kg p.o.) antagonized amphetamine-induced hypermobility but was less potent than diazepam. XT elevated the electrical threshold in foot-shock-induced fighting behavior in rats. XT (0.1-30.0 mg/kg p.o.) potentiated pentobarbital-induced narcosis in hamsters at otherwise subeffective doses of pentobarbital. Conditioned avoidance responses in rats were not significantly altered with 1-3 mg/kg i.p. and 30-100 mg/kg p.o. doses of XT but 300 mg/kg p.o. blocked both conditioned and unconditioned response. Doses of 100-1000 mg/kg i.p. of XT in mice were used to study 48-h acute toxicity of XT and its LD50 was estimated to be 468 mg/kg. Doses of 10, 40 and 80 mg/kg p.o. were used to study the chronic toxicity of XT in rats for 6 months and no side effects or abnormalities in reproductive activity or endocrine integrity were noted. The F1 generation of rats from 6-month XT-treated parents were free of teratogenic effects.


Anti-granuloma activity of Iraqi Withania somnifera.

The granuloma-tissue formation inhibiting activity of various fractions of an extract of the aerial parts of Withania somnifera were established using subcutaneous cotton-pellet implantation in rats. Antiinflammatory activity was retained in the methanolic fractions of the plant extract and was comparable to that of a 5 mg/kg dose of hydrocortisone sodium succinate. Activity was attributed to the high content of biologically active steroids in the plant, of which withaferin A is known to be a major component.


Medicinal plants used to treat malaria in Madagascar.

Two-hundred thirty-nine Madagascan medicinal plants have been either retrieved from computerized ethnobotany information or identified in our own ethnomedicine work as having antimalarial properties. Such a high rate percent of plants compared to those used empirically to treat other diseases reflects the importance and the complication of this major tropical disease in Madagascar.


The Moraceae-based dart poisons of South America. Cardiac glycosides of Maquira and Naucleopsis species.

The use of cardenolide-containing Moraceae in the dart poisons of South America is reviewed. Those prepared by the Chocó Indians of western Colombia--called niaará or kieratchi--have probably been made from the latex of Naucleopsis amara and N. glabra. In Ecuador, the Colorado Indians used N. chiguila, while the Coaiquer Indians still derive a poison from the latex of N. naga and the Cayapá Indians occasionally make use of a blowgun poison, hambi, which probably also comes from a Naucleopsis species. The Kaborí (Rio Uneiuxi Makú) Indians of north-western Brazil may have utilized Maquira coriacea, but a more recent collection documents N. mello-barretoi latex as a source of their poison. The Tikuna Indians of western Brazil included leaves and bark of N. stipularis in one of their poisons. The principal cardiac glycosides present in Maquira species are strophanthidin-based and the main ones occurring in Naucleopsis species are antiarigenin- as well as strophanthidin-based. The structures of two new glycosides, isolated from dart-poison samples, have been established as strophanthidin beta-D-glucomethylosido-D-alloside and beta-D-digitoxosido-D-alloside. The former is a major component of pakurin, the crystalline glycoside mixture prepared by Santesson in 1928 from a Chocó Indian poison.


Experimental cardiovascular depressant effects of garlic (Allium sativum) dialysate.

The objectives of this work were to investigate the effects of a garlic dialysate on diastolic blood pressure (DBP), heart rate (HR) and electrocardiogram (ECG) of anaesthetized dogs and its effects on frequency and tension of isolated rat atria. Garlic dialysate led to a drop in DBP (from 112.5 +/- 3.67 to 70 +/- 3.16 mmHg) and a decrease in HR (from 198 +/- 9.81 to 164 +/- 16.59 beats/min) in a dose-dependent manner. The ECG showed a regular sinus bradycardic rhythm. The addition of garlic dialysate to isolated left rat atria evoked a decrease in tension development. Frequency, measured by spontaneous beating of the right atria, was also reduced. Both effects were dose-dependent. In addition to these effects, the positive inotropism and chronotropism induced by addition of isoproterenol 10(-9) M, were partially antagonized by preincubation of the rat atria with the garlic dialysate. The above findings can be explained by a depressant effect on automaticity and tension development in the heart, suggesting a beta-adrenoceptor blocking action produced by the garlic dialysate.


Inhibition of Microlax-induced experimental diarrhoea with narcotic-like extracts of Psidium guajava leaf in rats.

Measurement of rates of propulsion in the small intestine in control and experimental groups of male Sprague-Dawley rats (200-250 g) were carried out as a means of assessing antidiarrhoeal activity of aqueous extracts of the leaf of Psidium guajava (L.), using morphine as the standard drug of reference. Hyperpropulsion (diarrhoea) was induced by gavaging rats in a control group with Microlax, using phenol red mixed into it as a marker in the intestine, and the mean rate of the hyperpropulsion was determined. The normal rate of propulsion, defined as the percentage of the length of the ileum traversed by the front of the dye in 1 h after gavaging animals with a liquid paraffin-phenol red meal, was also determined in another control group. In experimental groups pretreated with enteral administration of either morphine or aqueous extracts, 1 h before the challenge with Microlax, the percentage inhibition to the hyperpropulsive rate (antidiarrhoeal activity) was calculated. Both morphine and the extracts produced a dose-response relationship in their antidiarrhoeal effects. A dose of 0.2 ml/kg fresh leaf extract produced 65% inhibition of propulsion. This dose is equiactive with 0.2 mg/kg of morphine sulphate. The antidiarrhoeal action of the extract may be due, in part, to the inhibition of the increased watery secretions that occur commonly in all acute diarrhoeal diseases and cholera.


Biological and chemical studies of Pera benensis, a Bolivian plant used in folk medicine as a treatment of cutaneous leishmaniasis.

The stem barks of Pera benensis are employed by the Chimane Indians in the Bolivian Amazonia as treatment of cutaneous leishmaniasis caused by the protozoan Leishmania braziliensis. The chloroform extracts containing quinones were found active against the promastigote forms of Leishmania and the epimastigote forms of Trypanosoma cruzi at 10 micrograms ml-1. The activity guided fractionation of the extract by chromatography afforded active compounds. Their structures were elucidated, by spectral and chemical studies, as known naphthoquinones, plumbagin, 3,3'-biplumbagin, 8-8'-biplumbagin, and triterpene, lupeol. The activity in vitro of each compound was evaluated against 5 strains of Leishmania (promastigote), 6 strains of Trypanosoma cruzi (epimastigote) and the intracellular form (amastigote) of Leishmania amazonensis. The baseline drugs used were Glucantime and pentamidine (Leishmania spp.), nifurtimox and benznidazole (T. cruzi). Plumbagin was the most active compound in vitro. This study has demonstrated that Pera benensis, a medicinal plant used in folk medicine, is an efficient treatment of cutaneous leishmaniasis.


Medicinal plants used by the Fang traditional healers in Equatorial Guinea.

This work is an ethnobotanical study of some medicinal plants used by the Fang traditional healers of two regions of Equatorial Guinea in Central Africa: Malabo and Bata. For each species listed, the family, the botanical name, the voucher specimen number, the vernacular name, the pharmacological and therapeutical properties are given.


An Ayurvedic formulation 'Trikatu' and its constituents.

'Trikatu' is an Ayurvedic preparation containing black pepper, long pepper and ginger, which is prescribed routinely for a variety of diseases as part of a multidrug prescription. These herbs along with piperine (alkaloid of peppers) have been shown to possess diverse biological activities in mammalian systems. A review is presented of these studies and it has been suggested that their use in the Indian system of medicine could be due to their bioavailability enhancing action on other medicaments.


Inventory of plants used in traditional medicine in Somalia. III. Plants of the families Lauraceae-Papilionaceae.

Thirty-five plants are listed, which are used by traditional healers in the central and southern parts of Somalia. For each species are listed: the botanical name with synonyms, collection number, vernacular name, medicinal use, preparation of remedy and dosage. Results of a literature survey are also reported including medicinal use, substances isolated and pharmacological effects.


Operative treatment of Ebstein's anomaly.

From April 1972 to February 12, 1991, 189 patients with Ebstein's anomaly underwent repair. Ages ranged from 11 months to 64 years (median 16 years, mean 19.1 years). In 58.2%, tricuspid valve reconstruction was possible, and in 36.5%, a prosthetic valve, usually a bioprosthesis, was inserted. In 5.3%, a modified Fontan or other procedure was performed. There were 12 hospital deaths (6.3%). All 28 patients who had accessory conduction pathways (Wolff-Parkinson-White syndrome) underwent successful ablation of the pathways as part of the operative treatment. Follow-up was obtained in 151 (85.3%) patients. Of those patients followed up more than 1 year after operation, 92.9% were in New York Heart Association class I or II. There were 10 late deaths: seven cardiac (four sudden), two noncardiac, and one of an unknown cause. Postoperative Doppler echocardiographic assessment showed the atrial septum was intact in all patients and tricuspid valve function was good to excellent in most patients. Four of the 110 patients (3.6%) who underwent valve reconstruction required reoperation 1.4 to 14.1 years later. Postoperative reduction in heart size was usual, atrial arrhythmias were reduced, and late postoperative exercise testing showed a significant improvement in performance: Maximal oxygen consumption increased from a mean of 47% of predicted value before the operation to a mean of 72% after the operation. Nine patients had a total of 12 successful pregnancies with deliveries of normal children.


Morphology of ventricular septal defects in complete transposition. Surgical implications.

Postmortem examination of 62 hearts with complete transposition (concordant atrioventricular and discordant ventriculoarterial connections) and an accompanying ventricular septal defect was performed to determine the morphologic variability of ventricular septal defects and to explore the surgical implications of these defects. Particular attention was directed toward assessing alignment of the outlet septum relative to the muscular septum. Coronary arterial distributions were also evaluated, but specific patterns of distribution did not correlate with morphology of the defect. Of 49 hearts with a normally aligned outlet septum, there were 24 perimembranous, 21 muscular, and 2 doubly committed and juxtaarterial defects. Two hearts had both perimembranous and muscular defects. Twelve of the 21 muscular defects were "central," being surrounded entirely by muscle and located just below the leaflets of the pulmonary valve, and 9 were located in the inlet or apical trabecular septum. There were 13 hearts with malalignment of the outlet septum, anteriorly in 11 and posteriorly in 2. All with anterior malalignment had a subpulmonary defect that was perimembranous in 7 and muscular in 4. Both defects with posterior malalignment had a subaortic perimembranous defect. Because variations in morphology of a ventricular septal defect have a direct impact on selection of the most suitable surgical repair, specific operative approaches are discussed.


Role of the septal leaflet in tricuspid valve closure. Consideration for treatment of complete atrioventricular canal.

A septal leaflet of the tricuspid valve is thought to work differently from other anterior and posterior leaflets. We studied its role in valve closure in dogs by means of a dynamic area meter. During the control state, the tricuspid valve orifice area increased twice in diastole coincidentally with either atrial systole or rapid ventricular filling. We observed several findings after the septal leaflet resection: (1) two peak area patterns of the tricuspid valve orifice in diastole, (2) no elevation of right atrial pressure on ventricular systole (there was no V wave), (3) no tricuspid valve regurgitation on right ventriculography. These findings suggest that a complete valve closure occurred without the septal leaflet in regular sinus rhythm. An elevation of the right ventricular pressure produced by pulmonary artery stenosis without septal leaflet, however, easily caused tricuspid valve regurgitation in contrast to the same pressure of the right ventricle with the normal tricuspid valve. The right ventricular pacing caused severe valve regurgitation without the septal leaflet. Results indicate that in the repair of the complete atrioventricular canal defect and other tricuspid valve lesions, the septal leaflet of the tricuspid valve rarely requires attention. An atrioventricular block should be avoided, however, because electrical cardiac pacing on the right ventricle causes severe valve regurgitation without the septal leaflet.


The Mustard procedure for correction of simple transposition of the great arteries before 1 month of age.

Since April 1976, 34 infants (25 male and 9 female) less than 1 month of age underwent a Mustard intraatrial baffle procedure for repair of simple transposition of the great arteries. Thirty patients were less than 2 weeks old and 19 patients less than 1 week (mean 7.8 +/- 6 days). The weights ranged from 2.6 to 4.4 kg (mean 3.4 +/- 0.4 kg). Rashkind balloon atrial septostomy was performed in the first hours or days of life in 29 patients. The average interval from balloon atrial septostomy to baffle repair was 3.9 days (range 2 hours to 14 days). Mechanical ventilation was required in eight patients preoperatively and prostaglandin E1 was infused in 17 patients to maintain ductal patency. In all patients, the Mustard procedure was performed with the use of deep hypothermic circulatory arrest, averaging 53 minutes (range 37 to 82 minutes). The duration of postoperative intubation and ventilatory support averaged 1.7 +/- 1.0 days (range 1 to 5 days). Inotropic drugs were used in 24 patients during a period of 1.4 +/- 1.3 days (range 1 to 6 days) postoperatively. There were no hospital deaths. Follow-up evaluation has extended from 1 month to 14 years (mean 3 +/- 3 years). One infant died 2 months postoperatively as a result of milk aspiration; no cardiac defects were found at the autopsy. A second infant died at 1 year with right ventricular and tricuspid valve dysfunction. Baffle complications occurred in 6 of the 32 survivors, including superior vena caval stenosis in 4, inferior vena caval stenosis in 1, and pulmonary venous obstruction in 3. Reoperations for baffle obstructions were performed in three patients (8.8%) and balloon angioplasties in two. One patient required permanent pacemaker implantation. Results with the Mustard procedure before 1 month of age show that it can be performed with negligible mortality and a low incidence of late complications at an age comparable to when arterial switching would be performed. Until long-term studies demonstrate superiority of arterial operations, the low operative mortality favors continued evaluation of the neonatal Mustard repair as a valid alternative to the arterial switch.


Continuous arteriovenous hemofiltration after cardiac operations in infants and children.

Acute renal insufficiency after cardiopulmonary bypass can lead to a significant morbidity from fluid overload and electrolyte disturbance, impede pulmonary gas exchange, and postpone weaning from mechanical ventilation. The limitations placed on free water intake result in severe restriction of nutrition while diuretic therapy causes electrolyte imbalance. Artificial renal support either in the form of peritoneal dialysis or hemodialysis may be complicated by sepsis and hemodynamic instability. We reviewed our experience with the use of continuous arteriovenous hemofiltration, an extracorporeal technique for removal of solutes, toxins, and water in critically ill patients with cardiac failure complicated by acute renal insufficiency and hemodynamic instability after cardiopulmonary bypass. Ten infants and children with renal insufficiency caused by low cardiac output had continuous arteriovenous hemofiltration instituted for indications including sepsis, volume overload, oliguria for more than 24 hours nonresponsive to diuretic therapy, and the need for hyperalimentation. All were supported by mechanical ventilation and receiving high-dose inotropic support. Arterial and venous vascular access was successfully obtained by cannulation of the femoral artery and vein in nine patients. Anticoagulation of the circuit was achieved with heparin infusion (6 to 20 micrograms/kg/hr) and monitored by measurement of activated clotting time. The continuous arteriovenous hemofiltration circuit was replaced if there was clot formation, or at 3 days after placement. Dialysis solution (Dianeal) 1.5% or 0.5% was infused as prefilter dilution. With the use of continuous arteriovenous hemofiltration, 20 to 100 m/hr of ultrafiltrate was removed, which allowed correction of hypervolemia, and caloric intake increased from 13.5 kcal/kg/day to 79.5 kcal/kg/day. Continuous arteriovenous hemofiltration was maintained between 5 hours and 8 days and was well tolerated in all patients. Serum urea and creatinine levels declined during continuous arteriovenous hemofiltration. We conclude that continuous arteriovenous hemofiltration is a safe and effective method for fluid and electrolyte homeostasis and that it thus allows hyperalimentation in infants and children after cardiac operations.


Combined mustard and Rastelli operations. An alternative approach for repair of associated anomalies in congenitally corrected transposition in situs inversus [I,D,D].

We report on two patients with congenitally corrected transposition of the great arteries in situs inversus who underwent successful anatomic repair of associated cardiac anomalies--ventricular septal defect and pulmonary outflow tract obstruction. Surgical intervention was influenced by the recently introduced technique of Ilbawi and colleagues in cases of congenitally corrected transposition in situs solitus. Principles of the correction are as follows: (1) patch redirection of venous flows at the atrial level through an incision in the left-sided right atrium; (2) patch closure of the ventricular septal defect through a right ventriculotomy, baffling the left ventricle to the aorta; and (3) valved conduit interposition between the right ventricle and the pulmonary artery. If the ventricular septal defect is restrictive, it can be safely enlarged by extensive resection of the anterosuperior border, because of the posteroinferior location of the bundle of His in this anomaly. With this technique, the left ventricle and the native mitral and aortic valves are recruited for systemic work, with intrinsic long-term advantages. It is, however, a complex procedure involving substantial use of prosthetic material. More experience is necessary to establish whether this approach is superior to currently available physiologic repairs.


The Björk-Shiley valve prosthesis. Analysis of long-term evolution.

The long-term follow-up of 831 patients who underwent valve replacement with Björk-Shiley Delrin and standard Pyrolyte prostheses (341 aortic, 345 mitral, and 145 mitroaortic) between 1971 and 1980 is reviewed. The follow-up concluded in 1985. Cumulative follow-up amounted to 4724 years, with a mean of 5.68 years per patient. Data on survival were obtained in 754 patients (complete follow-up in 90.8% of cases). Perivalvular leak was the most frequent complication in aortic valve replacement, whether isolated or combined, with values significantly higher than those registered in isolated mitral replacement (p < 0.001 in both cases). No correlation was found between this complication and valve calcification, but it was statistically correlated with the size 19 model (p < 0.05). Prosthetic stenosis was more common in mitral than in aortic replacement (p < 0.001), and of the former, size 23 was that most often affected (p < 0.001). The earliest case of mitral pannus was diagnosed 20 months postsurgery, and from 45 months on this pathology was the cause of every case of stenosis. The risk of thromboembolism was similar in aortic, mitral, and double prostheses, while it was the single most frequent complication in isolated mitral replacement. Prosthetic thrombosis was triggered in all cases in which it occurred by discontinuance of anticoagulant therapy. Anticoagulant-induced hemorrhages were more frequent in double replacement than in mitral (p < 0.05) and aortic valve replacement. Endocarditis was the complication that produced the highest mortality rate in all groups; the frequency of this infection was higher among patients with double prostheses when compared with either aortic replacement (p < 0.05) or mitral replacement (p < 0.001). The risk of suffering endocarditis was correlated with the existence of active preoperative infection in patients with mitral prostheses and double prostheses (p < 0.001 in both cases). Overall morbidity was higher in the double replacement group with respect to the mitral group (p < 0.01). The rate of mortality was also higher among the double valve replacement patients when compared with both the aortic (p = 0.0002) and mitral (p = 0.006) groups.


Eleven-year follow-up study of aortic or aortic-mitral anulus-enlarging procedure by Manouguian's technique.

Although Manouguian's operation is well established, there have been little long-term data published on its outcome. From January 1980 to June 1988, 15 patients underwent patch enlargement of the small aortic anulus by Manouguian's approach, either with aortic single valve replacement (7 patients) or with aortic-mitral double valve replacement (8 patients). Follow-up ranged from 3.0 to 11.4 years (mean 8.5) and was completed with a cumulative total of 102 patient-years. One patient died of fulminant hemolysis, probably related to turbulent jet flow and Dacron patch material (operative mortality 6.7%). There were four late deaths, and the actuarial survival, including operative death at 10 years, was 62% +/- 14%. Reoperations were performed seven times in six patients. Most of these complications were not considered to be caused by the anulus-enlarging procedure. Actuarial freedom rate from reoperation at 10 years was 65% +/- 15%. Four patients underwent rereplacement of prostheses for Hancock valve failure during 2.9 to 11.3 years (mean 8.2 years). The anulus enlargement was found to be well healed and presented no problem during reoperation. Surgically induced mitral regurgitation by Manouguian's procedure was observed in two patients. The regurgitation did not progress during follow-up duration of 1.9 to 10.0 years, nor did it cause congestive heart failure. Annular enlargement by Manouguian's procedure with use of mechanical valves is one of the good selections in patients with the narrow aortic valve ring.


Comparison of immediate hemodynamic response to closed mitral commissurotomy, single-balloon, and double-balloon mitral valvuloplasty in rheumatic mitral stenosis.

The hemodynamic response to closed mitral commissurotomy, single-balloon, and double-balloon mitral valvuloplasty was compared using 20 patients in each group. All patients had symptomatic rheumatic mitral stenosis with a mitral valve area < 1 cm2, without any left atrial clot, mitral valve calcification, or mitral regurgitation. There was a significant improvement in hemodynamics following intervention in all three groups. The mean pulmonary artery pressure decreased from 49.1 +/- 17.5 to 28.6 +/- 8.3 mm Hg (p < 0.001), 48.8 +/- 12.3 to 34.0 +/- 13.9 mm Hg (p < 0.001), and 46.7 +/- 18.0 to 26.3 +/- 13.7 mm Hg (p < 0.001) in the closed mitral commissurotomy, single-balloon, and double-balloon mitral valvuloplasty groups, respectively. The mitral valve area increased from 0.62 +/- 0.27 to 1.5 +/- 0.5 cm2 (p < 0.001), 0.68 +/- 0.24 to 1.5 +/- 0.4 cm2 (p < 0.001), and 0.68 +/- 0.25 to 1.9 +/- 0.8 cm2 (p < 0.001) in the closed mitral commissurotomy, single-balloon, and double-balloon mitral valvuloplasty groups, respectively. The increase in the mitral valve area was maximum in the group with double-balloon mitral valvuloplasty. In the closed mitral commissurotomy group there was a significant rise in left ventricular end-diastolic pressure, from 6.8 +/- 3.9 to 9.3 +/- 3.1 mm Hg (p < 0.001), but this remained unchanged in the single-balloon and double-balloon mitral valvuloplasty groups. Our study shows that single-balloon and double-balloon mitral valvuloplasty are comparable to closed mitral commissurotomy in the immediate hemodynamic response, with a larger valve area in the double-balloon mitral valvuloplasty group.


Correction of anterior mitral prolapse. Results of chordal transposition.

From 1986 to 1992 102 mitral valve repairs were done for mitral regurgitation due to a degenerative disease. Forty-eight patients had an anterior prolapse or prolapse of both leaflets at initial presentation and underwent chordal transposition from the mural leaflet to the anterior leaflet. The corrective procedure was completed by polytetrafluoroethylene or pericardial posterior annuloplasty. Operative mortality was 2.9%, and follow-up (average 22 months) was 100% complete. There were three postreconstruction valve replacements (one earlier and two later) for a probability of freedom from reoperation of 91.5% +/- 5.2% at 3 years. Freedom from all morbidity was 85.5% +/- 5.5% at 3 years. Postoperative echocardiographic studies demonstrated a good mitral valve function: (1) Eighty-seven percent of patients presented no or mild residual regurgitation; (2) transmitral flow indexes were within the norm; (3) left ventricular outflow tract flow was normal in all patients. This study shows that chordal transposition is a safe and effective technique for prolapse of anterior or both leaflets and improves the chances of repair in patients with mitral degenerative disease.


Partial replacement of mitral valve by homograft. An experimental study.

Satisfactory long-term clinical results with heart valves have renewed the interest in the use of mitral homografts, despite the technical difficulties with their surgical implantation. This report describes the behavior and viability of the partial mitral homograft in the ortotopic position in a chronic sheep model (n = 25). The 20 surviving animals were studied hemodynamically and were anesthetized and electively put to death 3, 6, 9, and 12 months after the operation. All specimens had a normal mitral valve without signs of infection or thrombosis. Light, scanning, and transmission electron microscopy showed the presence of viable endothelial cells from the recipient covering the graft, signs of reendothelialization, and organized dense collagen tissue. The structural integrity was more evident in the fresh mitral homografts. This method may provide consider improvement in the viability of the mitral homograft, and it could be a valid alternative for repair of mitral valve localized pathology.


Tolerance to glyceryl trinitrate in isolated human internal mammary arteries.

The purpose of this study was to examine the vascular reactivity of segments of internal mammary artery removed from patients undergoing coronary artery bypass operations. Responses to relaxant and contractile agents were compared in arteries removed from patients who had or had not been treated with glyceryl trinitrate after admission to the hospital until operation. Segments of mammary artery were removed from 13 patients who underwent coronary artery bypass grafting. Endothelium-containing rings of artery, 3 to 5 mm long, were suspended in physiologic saline solution in 20 ml organ baths. Responses to the endothelium-dependent relaxant acetylcholine and the endothelium-independent relaxants glyceryl trinitrate and sodium nitroprusside were compared. In addition, contractile responses to phenylephrine and 9,11-dideoxy-9 alpha,11 alpha-methanoepoxy prostaglandin F2 alpha (U46619) were examined. Glyceryl trinitrate-induced relaxation was significantly impaired in mammary artery segments from patients treated with that nitrate before operation; the responses to acetylcholine and sodium nitroprusside were not affected. Previous treatment with glyceryl trinitrate also reduced the contractile responses to both phenylephrine and U46619. These studies indicate that treatment of patients with glyceryl trinitrate before operation induces significant tolerance to this agent in the mammary artery; however, there was no evidence of cross tolerance to sodium nitroprusside or the endothelium-dependent vasodilator acetylcholine. Glyceryl trinitrate may therefore not always be effective in dilating mammary artery grafts and sodium nitroprusside may be a more effective dilator of the internal mammary artery in patients who have been treated with glyceryl trinitrate before operation.


Antimineralization treatments for bioprosthetic heart valves. Assessment of efficacy and safety.

Since calcification limits the durability of contemporary bioprosthetic heart valves, antimineralization treatments are being widely investigated. Potential antimineralization treatments must have sustained prevention of mineralization without adverse effects. The preclinical investigation of efficacy and safety of antimineralization treatments comprises four essential steps: (1) subcutaneous implantation in small animals, (2) in vitro biomechanical studies of hemodynamics and durability, (3) morphology of unimplanted valves, and (4) circulatory implants in large animals.


The effect of ambient temperature on papaverine-induced relaxations in canine saphenous veins.

This study was designed to measure the effect of ambient temperature (25 degrees C) on papaverine-induced relaxations in canine saphenous veins. Segments of vein were suspended in water-jacketed tissue baths at 37 degrees C, and isometric tension was recorded. After equilibration, veins were preconstricted by a median effective dose of norepinephrine 2 x 10(-6) mol/L at either 25 degrees C or 37 degrees C. Consequent dose-dependent relaxations showed that papaverine (10(-7) to 10(-3) mol/L was three times more potent as a dilator at 37 degrees C than at 25 degrees C, with half-maximal relaxations occurring at 2.2 x 10(-5) mol/L and 6.4 x 10(-5) mol/L, respectively. A 10(-4) mol/L dose of papaverine completely relaxed veins at 37 degrees C, whereas veins at 25 degrees C never fully relaxed even at ten times the standard concentration. In addition, the time for half-maximal relaxation with a 10(-4) mol/L dose of papaverine averaged 40 minutes at 25 degrees C compared with 22 minutes at 37 degrees C; this is indicative of a reduced relaxation rate at the lower temperature. These data show that papaverine is a slower and less potent dilator of canine saphenous veins at 25 degrees C than at 37 degrees C. This may have implications for the use of papaverine in the operating room, where it is usually applied at ambient temperature to reduce vasospasm of the saphenous vein during coronary artery bypass procedures.


Different effects of activated platelets in the right gastroepiploic and internal mammary arteries. Implications for coronary artery grafting.

The right gastroepiploic artery is increasingly utilized as an alternative coronary bypass conduit, although postoperative spasm can represent a problem. Platelet-vessel wall interactions are important determinants of graft function and patency. We studied the effects of activated platelets in porcine and human gastroepiploic and mammary arteries. Arterial rings were suspended in organ chambers for isometric tension recording. In the porcine and human gastroepiploic arteries with or without endothelium contracted with norepinephrine, activated platelets evoked only further and strong contraction. In contrast, in the porcine and human mammary arteries, endothelium-dependent relaxations to platelets mediated by nitric oxide were noted, particularly in rings preincubated with the thromboxane A2 receptor antagonist SQ-30741 and the 5-hydroxytryptamine (5HT2)-serotonergic receptor antagonist ketanserin. Although endothelium-dependent and endothelium-independent relaxation to bradykinin and the nitrovasodilator 3-morpholino sydnonimine were more pronounced in the gastroepiploic than in the mammary artery, norepinephrine, serotonin, and potassium chloride evoked much stronger contractions in the former than in the latter. Thus activated platelets induce pronounced contraction of the gastroepiploic artery that may contribute to postoperative spasm. The administration of antiplatelet drugs and vasodilators that prevent the effects of thromboxane A2 and serotonin may be beneficial for gastroepiploic graft function.


The effects of different techniques of internal mammary artery harvesting on sternal blood flow.

We investigated chest wall blood flow in a canine model to determine if the technique used to harvest the mammary artery has a differential effect on residual chest wall blood flow. Eight dogs underwent bilateral internal mammary artery mobilization; one artery was harvested as a pedicle and the other was harvested as a skeletonized vessel. Residual blood flow to the chest wall distribution of each artery was measured with radioactive microspheres. Chest wall blood flow was significantly decreased from preharvest levels after internal mammary artery mobilization regardless of the technique used. Tissue blood flows decreased to 46.9%, 22.1%, and 41.2% of baseline values for the manubrium (p < 0.01), sternum (p < 0.001), and ribs (p < 0.05), respectively. Residual sternal blood flow on the side of the skeletonized vessel was significantly greater than on the side of the pedicle graft (2.60 +/- 0.68 versus 1.27 +/- 0.27 cm3/min/100 gm, p < 0.001). We conclude that minimization of tissue mobilization during internal mammary artery harvesting may reduce sternal devascularization. This finding may have clinical significance with respect to lowering the incidence of sternal wound complications in coronary bypass surgery using the internal mammary artery as a bypass conduit.


Evaluation of surgical procedures. Changing patterns of patient selection and costs in heart transplantation.

During the past 4 years we have observed a marked increase in costs of heart transplantation in our center. This trend coincides with a shift in our recipient population toward the more severely ill patients. The percentage of patients bound for the intensive care unit has doubled. In analyzing the components of cost, we find that the length of stay, both in special care and regular nursing units, accounts for most of the cost increase. In our study of outcomes we find no significant difference in survival, at 1 month and 1 year, between recipients operated on from the intensive care unit and those not in intensive care. We find that at 1 year after transplantation, approximately 80% of patients are rehabilitated, which we define as the ability to work or to go to school. Only 20% of patients are off disability rolls, however, primarily because of problems related to insurance and the cost of continuing care, including drugs. We conclude that the comprehensive evaluation of surgical procedures requires an approach that balances costs with results on a continuing and long-term basis.


The effects of donor-recipient size disparity in infant and pediatric heart transplantation.

To determine the effect of heart donor and recipient size mismatches in infant and pediatric heart transplantation, we studied all 69 patients (age 1 day to 11 years) having 71 orthotopic heart transplants from 1985 to 1989. Patients were divided into three groups based on donor to recipient weight ratios. Group I comprised 13 heart transplants with a donor to recipient weight ratio less than 0.95 (mean 0.81, range 0.48 to 0.94); group II comprised 29 heart transplants with a weight ratio between 0.95 and 1.60 (mean 1.28); and group III had 27 heart transplants with weight ratios greater than 1.60 (mean 2.2, range 1.61 to 3.09). All chests were closed primarily. The cardiothoracic ratio by chest radiography was significantly larger in group III (p = 0.0002); 75% of group III patients had periods of lobar or complete lung collapse by chest radiography compared with 28% of group II and 19% of group I patients (p < 0.05). Despite this, there was no difference in the number of days of ventilator support for any group (p = 0.92). There was no difference in graft ischemic time or inotropic drug use among groups, nor were differences found in the cardiac systolic function parameters of left ventricular preejection time (p = 0.975), left ventricular ejection time (p = 0.975), left ventricular fiber shortening (p = 0.97), and left ventricular fractional shortening (p = 0.596). Thus despite a high incidence of transient lobar or complete lung collapse in high donor to recipient weight ratio transplants, large donor heart size produces very little clinical impairment in recipient lung function. Size mismatches do not influence cardiac systolic function. Overall, large size mismatches appear to be very well tolerated in infant and pediatric heart transplantation.


The myocardial recovery mode after cold storage for transplantation with Collins' solution and cardioplegic solution. A functional and metabolic study in the rat heart.

Mechanisms and kinetics of the effects of the ionic composition of two different storage solutions, an intracellular type and an extracellular type, were analyzed by examining the myocardial functional and metabolic recovery processes during the early reperfusion periods after 3 hours of cold storage using an isolated perfused working rat heart model. The hearts were stored either in our own cardioplegic solution (group 1) or in Collins' solution (group 2) for 3 hours at 4 degrees C and were then reperfused. The electromechanical activity in group 1 was elevated, as indicated by a higher incidence of ventricular fibrillation at 5 minutes of reperfusion (group 1: 5/6; group 2: 0/5; p < 0.05). The coronary flow rate in group 2 was significantly lower, at least for the first 15 minutes after reperfusion, than that of group 1, suggesting the possible existence of vasoconstriction in group 2. Although myocardial oxygen uptake during this period was smaller in group 2, the recovery of myocardial high-energy phosphate levels was better and creatine kinase leakage was less in group 2. The recovery of aortic flow after 30 minutes of reperfusion was significantly better in group 2 (group 1, 59.1 +/- 5.8%; group 2, 71.7 +/- 6.0%; p < 0.01), although the early recovery was somewhat worse in group 2. These data suggest that the heart stored in an intracellular-type solution, compared with one stored in an extracellular-type solution, recovers in an electromechanically suppressed fashion during the early reperfusion phase, associated with a better metabolic recovery and a slower but larger functional recovery. The disadvantage of the intracellular-type solution, however, may be its effect on the increase of coronary vascular resistance during the early reperfusion period.


Growth potential of porcine reduced-size mature pulmonary lobar transplants.

The use of mature pulmonary lobes for pediatric lung transplantation has recently been described. Successful application of this technique could help alleviate the pediatric donor lung shortage. Whether an already mature lobe can grow by forming new alveolar units after transplantation into a developing recipient is not known. We therefore measured functional residual capacity, fixed lung volume and weight, alveolar size and air space volume percent, and total number of alveoli in mature left lower lobe porcine lung transplants 12 weeks after transplantation into growing piglets. Comparisons were made with nontransplanted mature left lower lobes to determine if functional or morphologic growth had occurred after transplantation. The transplanted and control lobes were all taken from 6-month-old animals (mean body weight 105 +/- 4 kg). Recipients of the transplanted lobes were 9 weeks old and weighed 22 +/- 2 kg. By the end of the 12-week holding period, the recipient animals increased their body weight approximately fourfold (85 +/- 4 kg). No significant differences were seen in functional residual capacity or morphologic analysis of total alveolar number and alveolar size between the transplanted and nontransplanted lobes (p = not significant). Although the reduced-size mature porcine lobar transplants did not display a significant increase in either functional residual capacity or total alveolar number, there was significant growth of the transplanted mature lobes as determined by fixed volume and total lobar weight (p < or = 0.05 versus control animals).


Lazaroid U74500A as an additive to University of Wisconsin solution for pulmonary grafts in the rat transplant model.

Lazaroids are a class of novel 21 aminosteroids. They have been reported to be potent inhibitors of lipid peroxidation, which is a major contributing factor to ischemia-reperfusion injury in the lung. A Lewis rat orthotopic left lung isotransplant model was used to investigate the effects of the lazaroid U74500A on pulmonary preservation. The heart-lung blocks of donor rats were flushed with and then stored in either standard University of Wisconsin solution or University of Wisconsin solution with 30 mumol/L of U74500A substituted for the dexamethasone. After 6 or 12 hours of cold storage at 0 degrees C, the left lungs were transplanted into recipient rats and reperfused for 1 hour. Pulmonary function was assessed by measuring oxygen and carbon dioxide tensions in arterial blood after removal of the right lung. Lipid peroxide concentrations were measured as a thiobarbituric acid-reactive substance. Although arterial oxygen and carbon dioxide pressures and water content after 6 hours of preservation followed by reperfusion were similar in both the lazaroid and dexamethasone groups, lipid peroxide concentration was significantly higher in the dexamethasone group (0.88 +/- 0.07 mumol/gm) than in the lazaroid group (0.54 +/- 0.07 mumol/gm) (p < 0.01). After 12 hours of preservation, there were significant differences between the lazaroid and dexamethasone groups in arterial oxygen pressure (339 +/- 70 vs 27 +/- 3 mm Hg, p < 0.01), arterial carbon dioxide pressure (24.3 +/- 2.7 vs 47.7 +/- 7.0 mm Hg, p < 0.001), and lipid peroxide concentrations (0.69 +/- 0.07 vs 1.30 +/- 0.09 mumol/gm, p < 0.001). We conclude that addition of U74500A to the flush and storage solution enhances the preservation of the pulmonary graft in this transplant model.


The use of combined antegrade-retrograde infusion of blood cardioplegic solution in pediatric patients undergoing heart operations.

The benefits of combined antegrade-retrograde infusion of blood cardioplegic solution are becoming well known in adult coronary and valvular heart operations. Many of these advantages relate directly to the pediatric patient. They include prompt arrest and even distribution, particularly with aortic insufficiency or open aortic root, avoiding or limiting ostial cannulation, allowing uninterrupted surgical procedures, and flushing air/debris from the coronary arteries. We therefore report on the first 123 pediatric patients at the University of California, Los Angeles, to receive myocardial protection with antegrade (aortic) infusion in conjunction with retrograde (coronary sinus) infusion of blood cardioplegic solution. We employed a retroplegia catheter with a self-inflating and deflating occlusion balloon on the tip of a pressure-monitored infusion cannula that remains in the coronary sinus during the operation. Induction blood cardioplegic solution, 30 ml/kg in equally divided doses, is administered in the coronary sinus first antegrade at an aortic pressure less than 80 mm Hg, followed by retrograde infusion at less than 40 mm Hg. Maintenance cardioplegic solution (15 ml/kg) is administered every 20 minutes through one or both of the infusion cannulas, depending on the surgical procedure. Patients' ages ranged from 1 week to 16 years with a mean of 4.6 years. The following procedures were included in descending order: Fontan 20, atrioventricular valve repair/replacement (and complete atrioventricular canal) 16, aortic root/Konno/Ross 16, Rastelli 13, aortic valve repair/replacement 13, ventricular septal defect (and double-outlet right ventricle) 13, tetralogy of Fallot 10, coronary artery reimplantation/fistula repair 6, truncus arteriosus 4, arterial switch 3, bidirectional Glenn 2, sinus venosus 2, and aortopulmonary window, Senning, Stansel, interrupted aortic arch, and Ebstein's, 1 each. Aortic crossclamp times ranged from 6 to 219 minutes with a mean of 87 minutes. Myocardial oxygen consumption data for a series of six patients indicated the supplemental benefit for retrograde infusion of cardioplegic solution along with antegrade infusion, particularly in hypertrophied myocardium. Three deaths occurred (2.4% 30-day mortality), in the following patients: the first with truncus arteriosus and interrupted aortic arch, the second with complete atrioventricular canal and pulmonary hypertension, and the third with truncal valve regurgitation and replacement. There were no complications related to the retroplegia catheter. From this initial positive experience, we conclude that (1) combined antegrade-retrograde infusion of blood cardioplegic solution can be safely used in an expanding number of pediatric heart operations in all age groups, and (2) combined antegrade-retrograde infusion of blood cardioplegic solution may provide additional myocardial protection, with excellent surgical outcome, in complex congenital heart repairs.


The effectiveness of University of Wisconsin solution on prolonged myocardial protection as assessed by phosphorus 31-nuclear magnetic resonance spectroscopy and functional recovery.

The effectiveness of the University of Wisconsin solution on extended myocardial preservation was examined in this study using phosphorus 31-nuclear magnetic resonance spectroscopy. Isolated perfused rat hearts were arrested and stored in four preservation solutions: group 1, modified Krebs-Henseleit solution; group 2, modified St. Thomas' Hospital solution; group 3, oxygenated modified St. Thomas' Hospital solution containing 11 mmol/L glucose; and group 4, University of Wisconsin solution. The changes in myocardial high energy phosphate profiles and the intracellular pH values were measured during 12 hours of cold (4 degrees C) global ischemia and 90 minutes of normothermic reperfusion. Following ischemia, the hearts were assessed for hemodynamic recovery and myocardial water content. During ischemia, adenosine triphosphate depletion was observed in all groups; however, after 5 hours of ischemia, the adenosine triphosphate levels were significantly higher in group 3 compared with the other groups (adenosine triphosphate levels at 6 hours in mumol/gm dry weight: group 3, 7.6; group 4, 3.2; group 2, < 1; p < 0.025). The tissue water content at the end of ischemia was lower with the University of Wisconsin solution compared with the modified St. Thomas' Hospital solution or the oxygenated modified St. Thomas' Hospital solution (in ml/gm dry weight: group 4, 3.0; group 2, 4.4; group 3, 3.9; p < 0.05). The adenosine triphosphate repletion during reperfusion was greater with the University of Wisconsin solution compared with the modified St. Thomas' Hospital solution or the oxygenated modified St. Thomas' Hospital solution (12 mumol/gm dry weight in group 4; 8.1 in group 2; 9.0 in group 3; p < 0.05). Similar findings were obtained for the recovery of left ventricular pressure (in percent of preischemic control: group 4, 70%; group 2, 42%; group 3, 52%; p < 0.01) and coronary flow (group 4, 61%; group 2, 49%; group 3, 49%; p < 0.05). These data suggest that preservation with the University of Wisconsin solution affords improved hemodynamic recovery, enhanced adenosine triphosphate repletion, and reduced tissue edema upon reperfusion; however, oxygenated St. Thomas' Hospital solution with glucose is associated with the preservation of higher myocardial adenosine triphosphate levels during prolonged cold global ischemia. In conclusion, these data indicate that the University of Wisconsin solution might improve graft tolerance of ischemia in clinical heart transplantation.


Crystalloid cardioplegia and hypothermia do not impair endothelium-dependent relaxation or damage vascular smooth muscle of epicardial coronary arteries.

Canine hearts were arrested with crystalloid cardioplegic solution (45 minutes at 7 degrees C) to determine whether either cardioplegia or hypothermia impairs the production of endothelium-derived relaxing factor or damages the vascular smooth muscle of epicardial coronary arteries. In addition, isolated coronary artery segments were exposed to either cold (7 degrees C) or warm (37 degrees C) crystalloid cardioplegic solution and physiologic salt solution in vitro for 45 minutes. After cardiac arrest or incubation with the solutions, segments of epicardial coronary artery were prepared and studied in organ chambers. Cardioplegic arrest of the heart or exposure to cardioplegic solution in vitro (7 degrees or 37 degrees C) did not alter endothelium-dependent relaxation of epicardial coronary artery segments in response to adenosine diphosphate or acetylcholine (10(-9) to 10(-4) mol/L). Cardioplegic arrest did not alter G protein-mediated, endothelium-dependent relaxation in response to sodium fluoride. In addition, smooth muscle contraction in response to potassium ions (voltage-dependent) or prostaglandin F2 alpha (receptor-dependent) and relaxation in response to isoproterenol (cyclic adenosine monophosphate-mediated) or sodium nitroprusside (cyclic guanosine monophosphate-mediated) was unaltered after exposure to cardioplegic solution or hypothermia. These experiments demonstrate that hyperkalemic crystalloid cardioplegia does not irreversibly alter function of epicardial coronary arteries. We hypothesize that coronary artery endothelial cell dysfunction identified in previous studies of cardioplegia may have been due to the effects of barotrauma or shear stress on the vasculature and not the effect of cardioplegia per se.


Enhancement of low coronary reflow improves postischemic myocardial function.

The effect of reperfusion coronary vasodilatation on postischemic myocardial mechanical function has been investigated in the isolated working rat heart. After a working period to assess control function, all the hearts were subjected to a single infusion (10 ml) of St. Thomas' Hospital cardioplegic solution No. 1 at 4 degrees C and were kept immersed in the same solution for 4 hours at 4 degrees C. Then hearts (six in each group) were initially reperfused at 37 degrees C for 10 minutes, either with ordinary reperfusate (Krebs-Henseleit bicarbonate buffer) or with reperfusate containing additional coronary dilator. After this period, all hearts were subjected to a further 5 minutes of ordinary reperfusate before being put back into the working mode to assess functional recovery. Mean reperfusion coronary flows and the steady coronary flow measured after 10 minutes of reperfusion in ml/min +/- SEM were--Krebs (control): 17.4 +/- 0.39 and 13.4 +/- 0.40; adenosine (3.75 mumol/L): 19.9 +/- 0.6 and 16.7 +/- 0.8; papaverine (0.05 mmol/L): 21.8 +/- 2.3 and 17.3 +/- 1.8; dipyridamole (2 mmol/L): 20.7 +/- 1.7 and 17.9 +/- 1.0; nitroglycerin (15 mg/L): 20.5 +/- 0.45 and 19.9 +/- 1.4; diltiazem (0.05 mmol/L): 19.6 +/- 2.98 and 17.7 +/- 1.8; calcitonin gene-related peptide (0.03 mmol/L): 20.8 +/- 0.69 and 18.0 +/- 1.3; 5-hydroxytryptamine (0.01 mmol/L): 19.2 +/- 0.53 and 16.9 +/- 0.80. Mean postischemic recovery of cardiac output, peak aortic pressure, and differentiation of pressure were expressed as percent of preischemic control +/- SEM were--Krebs: 54.1 +/- 2.8, 69.1 +/- 2.8, and 53.9 +/- 3.0; adenosine: 78.0 +/- 5.6, 89.5 +/- 2.9, and 69.1 +/- 1.9; papaverine: 81.8 +/- 3.9, 91.8 +/- 3.1, and 71.0 +/- 4.1; dipyrdamole: 67.3 +/- 3.3, 84.3 +/- 2.3, and 75.0 +/- 2.7; nitroglycerin: 83.1 +/- 4.8, 79.7 +/- 2.7, and 69.0 +/- 0.5; diltiazem: 76.5 +/- 3.7, 85.9 +/- 2.9, and 73.3 +/- 1.7; calcitonin gene-related peptide: 79.5 +/- 3.6, 90.0 +/- 4.9, and 75.4 +/- 3.9; 5-hydroxytryptamine: 71.6 +/- 3.2, 85.5 +/- 3.5, and 67.9 +/- 4.8. There was a positive correlation between mean reperfusion coronary flow, steady coronary flow, and postischemic recovery of cardiac output, peak aortic pressure, and differentiation of pressure. Mean reperfusion coronary flow, steady coronary flow, and postischemic recovery of cardiac output, peak aortic pressure, and differentiation of pressure were significantly greater in groups reperfused with vasodilators (p < 0.05) compared with control values.(ABSTRACT TRUNCATED AT 400 WORDS)


Continuous warm blood cardioplegia preserves cardiac autonomic function.

We studied in anesthetized dogs, the effects of cardiopulmonary bypass with normothermic whole blood, crossclamping of the aortic root, and continuous warm blood cardioplegia on the ability of the efferent sympathetic nervous system to augment the heart and that of the efferent parasympathetic nervous system to depress the heart. In control states, heart rate, atrial force of contraction, and right and left ventricular wall systolic pressures were augmented by stimulation of the intrathoracic efferent sympathetic nervous system and by administration of isoproterenol into the systemic circulation. After 1 hour of normothermic cardiopulmonary bypass that utilized aortic crossclamping and continuous perfusion of the coronary arteries with normothermic blood (20 mEq/L potassium), cardiac-augmenting effects induced by the efferent sympathetic nervous system and by isoproterenol were similar. Depressive responses elicited by the efferent parasympathetic nervous system were also unaffected by these procedures. Continuous warm blood cardioplegia does not result in impairment of the efferent sympathetic nervous system regulating the heart.


Influence of pH management on hemodynamics and metabolism in moderate hypothermia.

In moderate hypothermia, three different concepts of pH management have been described to date: pH-stat, alpha-stat, and alkalinity. In our study these pH strategies were compared in adult sheep, with animals serving as their own controls for direct comparability. Hemodynamic parameters, such as mean aortic pressure (from 109 +/- 12 to 72 +/- 23 mm Hg), cardiac output (from 5.55 +/- 1.25 to 4.5 +/- 0.82 L/min), and systemic oxygen consumption (from 3.73 +/- 0.8 to 1.81 +/- 0.4 ml/kg/min), decreased significantly with alpha-stat at 28 degrees C from values for normothermia. No marked or even significant differences were found among the three pH strategies in any value, with the exception of body oxygen consumption. The difference of 2% between pH-stat and alpha-stat, at 0.06 ml oxygen/kg/min, was significant (p < or = 0.05), however of no practical relevance because hypothermia itself caused a decrease of nearly 52%. With regard to myocardial parameters, pH-stat impaired myocardial function compared with both alpha-stat and alkalinity. At nearly identical mean aortic pressures and cardiac outputs, myocardial oxygen consumption reached the highest level in pH-stat (7.65 ml oxygen/100 gm/min; alpha-stat, 6.76 ml oxygen/100 gm/min; p < or = 0.05). Myocardial efficiency thus decreased from 21% (alpha-stat) to 17% (pH-stat). No evident changes in hemodynamic and metabolic values were found for alkalinity vs alpha-stat. The best response to continuously infused epinephrine, however, was found with alkalinity. According to our data there was an impairment of myocardial function without any evident further reduction in body metabolism with pH-stat vs alpha-stat. There were, however, no marked metabolic or hemodynamic differences between alkalinity and alpha-stat, with the exception of a better preservation of sensitivity to adrenergic stimuli with alkalinity.


A comparison of the effects on neuronal Golgi morphology, assessed with electron microscopy, of cardiopulmonary bypass, low-flow bypass, and circulatory arrest during profound hypothermia.

Adult swine (n = 18) were studied to compare the effects on neuronal morphology of hypothermic circulatory arrest with hypothermic very-low-flow cardiopulmonary bypass. Animals were anesthetized with halothane and prepared in a standard manner for nonpulsatile cardiopulmonary bypass. Monitored variables included mean arterial pressure, arterial blood gases, the processed electroencephalogram, and subdural brain temperature. Bypass was initiated with pump flows of 100 ml.kg-1.min-1, and mean arterial pressure was kept above 50 mm Hg at all times. Animals were cooled to 18 degrees C, using a heat exchanger, and were randomly assigned to one of three groups. Group 1 animals were control animals who underwent 1 hour of hypothermic cardiopulmonary bypass. Group 2 animals underwent 1 hour of circulatory arrest. Group 3 animals underwent 1 hour of very-low-flow cardiopulmonary bypass (10% of normal). At the end of the 1 hour of hypothermic bypass, very-low-flow bypass, or arrest period, animals were rewarmed to 37 degrees C with normal bypass flows, and normothermic perfusion continued for 1 additional hour. Animals were then perfusion fixed with formalin and the brains were removed for electron microscopic analysis. Electron microscopic analysis was used to determine the effects of treatment and was limited to 20 neurons of the CA1 sector of the hippocampus in each animal. Golgi bodies were identified and classified as normal, mildly affected, or severely affected. Animals subjected to either very-low-flow bypass or circulatory arrest had significantly more severely affected and significantly fewer normal Golgi bodies than control animals (p < 0.001). Animals maintained with very-low-flow bypass, however, had significantly more severely affected and fewer normal Golgi bodies than animals subjected to circulatory arrest (p < 0.001). We conclude that under the conditions of this experiment very-low-flow hypothermic cardiopulmonary bypass is associated with significantly greater neuronal Golgi abnormalities than total circulatory arrest.


Cognitive outcome after cardiac operations. Relationship to intraoperative computerized electroencephalographic data.

Cardiopulmonary bypass frequently causes new postoperative neuropsychologic deficits. To assess whether these deficits could be predicted or limited, we monitored 29 patients receiving bypass intraoperatively with an on-line computerized electroencephalograph. We hypothesized that the 15 patients whose cerebral perfusion pressure was adjusted on the basis of this electroencephalographic data would have fewer postoperative deficits than the 14 patients whose pressure was monitored on the basis of systemic pressure. The results showed that new postoperative cognitive deficits in both groups were less prevalent than in previous studies, but there was not a significant difference in outcomes between the two groups. The intraoperative electroencephalographic records correlated with surgical, but not neuropsychologic, outcome. It is concluded that careful attention to intraoperative cerebral perfusion pressure may decrease the prevalence of postoperative neuropsychologic complications, but that the use of a computerized electroencephalograph does not necessarily contribute to an improved outcome.


Transesophageal echocardiography predicts successful withdrawal of ventricular assist devices.

Transesophageal echocardiography has been found to be an effective technique for the real-time assessment of myocardial and valvular function in postoperative patients. To determine the value of transesophageal echocardiography in patients with mechanical assist devices, we performed daily, bedside transesophageal echocardiography on 16 patients with right (n = 3), left (n = 1), or biventricular assist devices (n = 12). We obtained four-chamber and short-axis views in all patients. Valvular function and the presence of left-to-right shunts were evaluated by means of color flow Doppler imaging. During the echocardiographic study ventricular assist device flow was diminished to less than 1.5 L/min, and inotropic agents (dobutamine or epinephrine) were given to assess ventricular reserve. Changes in day-to-day ventricular function were assessed in comparisons made by two observers (one unaware of the study sequence) using a semiquantitative method for wall motion analysis. The left ventricular wall motion scores in the patients successfully weaned from left or biventricular assist devices (n = 5) improved (14.2 +/- 1.6 versus 8.2 +/- 1.5, p < 0.0001). The scores did not improve in patients who remained dependent on the devices (n = 8). Two patients with only right ventricular assist devices were successfully weaned after documentation of improvement of right ventricular function by transesophageal echocardiography. Transesophageal echocardiography documented a clot compressing the heart in three patients; intracavitary thrombi were seen in two other patients. Marked hemodynamic improvement occurred after surgical decompression. In conclusion, transesophageal echocardiography is a safe, effective method for the assessment of ventricular function of patients on ventricular assist device support. In addition, it allows one to assess valvular function and the presence or absence of impaired ventricular filling.


The effect of desmopressin acetate on postoperative hemorrhage in patients receiving aspirin therapy before coronary artery bypass operations.

It has been suggested that desmopressin acetate has been effective in reducing hemorrhage after coronary artery bypass grafting in patients receiving aspirin before operation. We conducted a prospective, randomized, placebo-controlled, double-blind trial to determine the effectiveness and safety of desmopressin in these patients. Sixty-five patients pretreated with aspirin within 7 days before their scheduled elective coronary artery bypass grafting were randomized to receive desmopressin (0.3 micrograms/kg) or placebo after cessation of bypass and reversal of heparin with protamine. The demographic characteristics and last dose of aspirin were similar in both groups. There was a significant reduction in postoperative blood loss noted between groups for both chest tube blood loss (833 +/- 311 ml for the 1-desamino-8-D-arginine vasopressin [desmopressin] group versus 1176 +/- 674 ml for the placebo group; p = 0.016) and total blood loss (1215 +/- 381 ml for the desmopressin group versus 1637 +/- 761 ml for the placebo group; p = 0.0097). Despite the differences in blood loss between the two groups, the red cell transfusions were not significantly different, but the use of platelets was less in the desmopressin group and almost achieved statistical significance (p = 0.053). Neither was there a difference in the occurrence of thrombotic complications between groups. It appears that desmopressin in this specific subgroup of patients receiving preoperative aspirin is effective as a prophylactic agent for reduction of postsurgical hemorrhage.


Comparative study of cefazolin, cefamandole, and vancomycin for surgical prophylaxis in cardiac and vascular operations. A double-blind randomized trial.

Three-hundred twenty-one adults undergoing cardiac or major vascular operations were randomized to receive intravenous cefazolin, cefamandole, or vancomycin for prophylaxis against surgical infection in a double-blind trial. All three regimens provided therapeutic blood levels throughout operation in patients studied undergoing cardiopulmonary bypass. The prevalence of surgical wound infection was lowest with vancomycin (4 infections [3.7%] versus 14 [12.3%] and 13 [11.5%] in the cefazolin and cefamandole groups, respectively; p = 0.05); there were no thoracic wound infections in cardiac operations in the vancomycin group (p = 0.04). The mean duration of postoperative hospitalization was lowest in the vancomycin group (10.1 days; p < 0.01) and highest in the cefazolin group (12.9 days). Prophylaxis with vancomycin or cefamandole, compared with cefazolin, did not prevent nosocomial cutaneous colonization by methicillin-resistant coagulase-negative staphylococci; colonization or infection with vancomycin-resistant staphylococci or enterococci was not detected. Adverse effects attributable to the prophylactic regimen were infrequent in all three groups. Eight patients given vancomycin became hypotensive during administration of a dose, despite infusion during a 1-hour period; however, slowing the rate of administration and pretreating with diphenhydramine allowed vancomycin to be resumed and prophylaxis completed uneventfully in five of the patients. We conclude that administration of vancomycin (approximately 15 mg/kg), immediately preoperatively, provides therapeutic blood levels for surgical prophylaxis throughout most cardiac and vascular operations, resulting in protection against postoperative infection superior to that obtained with cefazolin or cefamandole. Vancomycin deserves consideration for inclusion in the prophylactic regimen (1) for prosthetic valve replacement and prosthetic vascular graft implantation, to reduce the risk of implant infection by methicillin-resistant coagulase-negative staphylococci and enterococci; (2) for any cardiovascular operation if the patient has recently received broad-spectrum antimicrobial therapy; and (3) for all cardiovascular operations in centers with a high prevalence of surgical infection with methicillin-resistant staphylococci or enterococci. Guidelines for dosing and administration of vancomycin for cardiovascular surgical prophylaxis are provided.


Output power and metabolic input power of skeletal muscle contracting linearly to compress a pouch in a mock circulatory system.

Output power and metabolic input power values were determined for unconditioned canine latissimus dorsi (two), gastrocnemius (seven), and triceps (three) muscles contracting linearly to cause compression of a doubly valved pouch in a hydraulic model of the circulation. The motor nerves to the muscles were stimulated tetanically with 450 msec trains of 0.1 msec pulses having a frequency of 50/sec. The muscles were contracted 10, 20, 30, and 40 times per minute and pouch output in milliliters per minute was measured directly for each muscle at each contraction (train) rate. The output power in milliwatts was determined by two methods: (1) by using the pouch output and the pressure rise imparted to the stroke volume (average power) and (2) by using the pressure-volume loop. Metabolic input power in milliwatts was determined from the oxygen consumption in milliliters per minute of the working muscle. It was found that as the pouch output was increased, the pouch output power and the metabolic input power both increased. The average power output was slightly less than that computed from the pressure-volume loop. The mean output power values, when pumping at L liters per minute, were 0.62 L (average) and 0.75 L mW/gm (pressure-volume loop) for the latissimus dorsi muscles; 0.83 L (average) and 1.16 L mW/gm (pressure-volume loop) for the gastrocnemius muscles; and 0.55 L (average) and 0.66 L mW/gm (pressure-volume loop) for the triceps muscles. The percent efficiency of energy conversion ranged from 9.2% to 17.8% for the latissimus dorsi muscles, from 5.1% to 19.5% for the gastrocnemius muscles, and from 10.5% to 27.3% for the triceps muscles. However, it should not be concluded that one muscle type is better than another on the basis of percent efficiency because efficiency does not take endurance into account. An important observation in this study relates to the large output obtained with the three linearly contracting muscle types. All were capable of pumping in excess of 1.5 L/min. A second observation relates to the absence of fatigue, although determination of endurance was not an objective in these studies.


Subglottic tracheal resection and synchronous laryngeal reconstruction.

Postintubation injury of the upper airway commonly results in stenotic lesions of the larynx, subglottis, and adjacent trachea. The traditional approach to surgical correction is laryngofissure for the laryngeal component and staged plastic reconstruction of the subglottic stenosis. Reported results are variable and unpredictable, and permanent extubation is impossible in a significant number of patients. We report experience with 15 patients with combined laryngeal, subglottic, and tracheal stenosis who were managed by a one-stage operation: circumferential resection of the subglottis and trachea with primary thyrotracheal anastomosis, combined with laryngofissure and laryngeal reconstruction. These procedures required the collaboration of the Departments of Otolaryngology and Thoracic Surgery of the Toronto General Hospital. Between 1972 and 1991, our thoracic surgical division did 53 circumferential subglottic tracheal resections with primary thyrotracheal anastomosis for benign disease. There were no operative deaths and 51 of 53 patients were successfully extubated. In 15 of these patients, a concomitant laryngofissure for laryngeal reconstruction was required. Laryngeal repair included excision or incision of interarytenoid scar (n = 13), interarytenoid mucosal graft (n = 6), or mobilization of cricoarytenoid joint (n = 3). A temporary laryngotracheal stent (usually a Montgomery T tube) was maintained after the operation in all cases (duration 3 to 42 months). Thirteen of these 15 patients are now permanently extubated and none has functionally significant restenosis. Vocal function is satisfactory to good in these patients. The approach described for these combined laryngotracheal lesions provides better results than those reported with traditional staged and plastic techniques of reconstruction. The collaboration of the departments of otolaryngology and thoracic surgery was essential to achieve these results.


Second primary lung cancer after bronchial sleeve resection. Treatment and results in eleven patients.

During the years 1960 to 1989, 145 patients underwent sleeve lobectomy or sleeve resection of a main bronchus. Follow-up was complete except for one patient, who was no longer available for follow-up 4 years after operation. Eleven patients (7.6%) had a second primary cancer in the lung; 10 of these patients (90.9%) were men. Mean age at sleeve operation was 61.2 +/- 11.6 years. Mean interval between sleeve operation and development of second primary cancer was 53.8 months (range, 6 to 197 months). All second primary cancers occurred on the contralateral side. In five cases there was squamous cell carcinoma, in two there was adenocarcinoma, in one there was adenosquamous carcinoma, in two there was small cell carcinoma, and in one patient no definite histologic type could be established. Five patients had different histologic type from the initial, resected primary tumor. Seven patients (64%) were operated on: five underwent lobectomy and two underwent segmentectomy. In one patient the tumor was judged to be unresectable. Chemotherapy was given to the two patients with small cell carcinoma and radiotherapy was given to one patient with bone metastases. Follow-up was complete for these 11 patients. Data were calculated from detection of second primary cancer. There was one postoperative death from myocardial infarction. Eight other patients died during follow-up: five died of recurrent tumor or metastases, two died of acute cardiac failure, and one died of a perforated ulcer. The 1- and 4-year actuarial survivals were 41% and 30%, respectively. For the patients operated on, 1- and 4-year survivals were 57% and 43%, respectively. There were no survivors at 5 years. Sleeve resection is a valuable method of preserving functional lung tissue. It offers a chance of subsequent resection in patients who have second primary cancer, with acceptable results.


Bronchopleural fistulas associated with lung cancer operations. Univariate and multivariate analysis of risk factors, management, and outcome.

During a 28-year period, 52 bronchopleural fistulas developed after pulmonary resection of 49 primary and three recurrent lung cancers at the National Cancer Center Hospital, Tokyo. During the same period there were 2359 pulmonary resections for primary lung cancer; the prevalence of bronchopleural fistula was 2.1%. Multivariate analysis on 15 variables in the most recent 1360 resections revealed significant risk factors for bronchopleural fistula: wider resection such as pneumonectomy, residual carcinomatous tissue at the bronchial stump, preoperative irradiation, and diabetes. Univariate analysis further recognized a risk in preoperative bronchial arterial infusion and the postsurgical stage of lung cancer. Six patients were not treated. Apart from chest tube drainage in seven patients, surgical repair was attempted in 39, direct resuture of the stump in 16, wrapping in 25, thoracoplasty in 31, completion pneumonectomy in 6, and other treatments. Despite various treatments, 37 patients (71.2% mortality) died from fistula-related complications (such as regurgitation of infected pleural fluid through the fistula and airway/intrathoracic bleeding). Even for patients whose fistulas were cured and who were discharged, the average hospital stay was 189 days. Further investigation is necessary to answer whether prevention by flap coverage is of any benefit.


A twenty-five-year follow-up of ninety-three resected typical carcinoid tumors of the lung.

From 1965 to 1990, 93 patients (57 women and 36 men) with typical bronchopulmonary carcinoids were operated upon. Patient ages ranged from 17 to 78 years, the mean age being 45.5 years. Central carcinoids were symptomatic in 80% of the patients. A correct preoperative diagnosis was made in 54 of 64 (84%) patients. Peripheral carcinoids were usually asymptomatic and a correct diagnosis was established in 4 of 29 patients (14%). The prognosis in the group of patients with bronchopulmonary carcinoids treated surgically was excellent. Seven patients died from nonrelated causes. The 5-, 10-, and 15-year survival rates for the remaining 86 patients are 100%. Only one patient died as a result of the tumor after 17 years and another patient is known to have had distant metastasis 9 years after resection. There was no hospital mortality. In the last decade a lung parenchyma-preserving attitude was adopted. Whenever possible, bronchoplastic surgery was applied for central carcinoids and resection of one segment or less was used for peripheral carcinoids. This approach was possible in 30 of 50 patients (60%). Nine patients were treated with preoperative endobronchial neodymium:yttrium-aluminum-garnet laser resection to facilitate a lung-preserving surgical resection. The prognosis of patients for whom a lung-preserving approach was adopted was as good as that of those with conventional resections. Involvement of regional lymph nodes (nine patients, 9.7%) or positive resection margins (two patients, 2.1%) had no influence on prognosis. We conclude that lung-preserving resections are often facilitated by preoperative neodymium:yttrium-aluminum-garnet laser treatment in central obstructing carcinoids.


Degree of severity of pectus excavatum and pulmonary function in preoperative and postoperative periods.

Pulmonary function was evaluated in 138 patients with pectus excavatum, paying particular attention to the degree of severity of chest deformity. We defined the severity of deformity quantitatively based upon a computed tomographic index obtained from a computed tomogram. We recognized a positive relationship between computed tomographic index (x) and percent vital capacity (y), as follows: y = 137x + 58 (n = 138, r = 0.61, p < 0.05). Pulmonary function tests were performed from 2 to 42 months postoperatively. Vital capacity decreased about 10% from the baseline value during the initial 2 months after surgical treatment and recovered to the preoperative level by 1 year after surgery. At 42 months after surgical correction, the pulmonary function was maintained at the baseline level and the severity of deformity was significantly improved. Surgical procedures for the treatment of pectus excavatum--sternocostal elevation and sternal turnover--resulted in an excellent cosmetic result but did not importantly affect respiratory function.


Relationship of the type of bcr-abl hybrid mRNA to clinical course and transforming activity in Philadelphia-positive chronic myelogenous leukemia.

We studied the type of bcr-abl mRNA for 34 patients with chronic myelogenous leukemia and analyzed for correlations among the mRNA type, the clinical outcome and the transforming activity using the tumorigenicity assay. There was no difference in the distribution of the mRNA-types (b2-a2 and b3-a2) between clinical phases. We found no correlation between the two types of bcr-abl mRNA and the chronic phase duration or survival. The DNA from 12 of 20 chronic phase patients and all five blastic phase patients showed transforming activity. Although there was no difference in the positive rate of transforming activity among the two mRNA-type groups, the blastic phase patients showed a tendency to have higher transforming activity.


Unexpected cytokinetic effects induced by puromycin include a G2-arrest, a metaphase-mitotic-arrest, and apoptosis.

The potent effects of low doses of PM on the cell cycle have to date been obscured by the conventional usage of this drug at high concentrations (5-50 micrograms/ml) to inhibit protein synthesis. In this in vitro study undertaken in a variety of malignant and non-malignant human and murine cell types, we found that low doses of PM (0.1-0.5 microgram/ml) disrupted significant phase-to-phase cell cycle transitions, causing a G2-arrest, a metaphase-mitotic-arrest, and apoptosis. In HL-60 cells these observations were elicited by PM concentrations starting at 0.1 microgram/ml, and were more pronounced at slightly higher PM concentrations, including that (0.5 microgram/ml) which inhibited [14C]leucine incorporation by approximately 20% after one hour, and by approximately 50% after 24 h. A concentration of CHX (0.25 microgram/ml) which was equivalent to 0.5 microgram/ml of PM, both in terms of molarity (0.9 microM) and degree of inhibition of [14C]leucine incorporation, failed to induce similar changes to those induced by PM. This suggests that at these particular concentrations the PM-induced changes were likely to have been related to the different mechanisms of protein synthesis inhibition exerted by these two 'classical' translation inhibitors. PM but not CHX generates nascent peptidyl-PM complexes (PMPs), and we therefore propose that the subsequent intracellular effects exerted by the PMPs may account, in part, for the differential cytokinetic effects elicited by these drugs. The role of PM is currently being evaluated in vivo as a low-dose component of a multidrug chemotherapeutic regimen in which its cell cycle-specific effects could potentially be synergistic with other agents.


Immunological studies of gamma delta T cells in a case of large granular lymphocyte (LGL) leukemia: leukemic gamma delta+ T cells are resistant to growth stimulation in vitro but respond to interferon-alpha treatment in vivo.

Leukemic T cells from patient BU (WBC 22,000/microliter) resembled morphologically large granular lymphocytes, and expressed a V delta 1-encoded gamma delta T-cell receptor (TCR) on their surface. Upon in vitro activation with various mitogens, IL-2-dependent V delta 1+ cell lines were only obtained if V delta 1+ cells had been positively selected on a cell sorter before culture. However, even under these conditions, the V delta 1+ IL-2-dependent cell lines showed a TCR beta and gamma gene-rearrangement different from that of the freshly isolated leukemic cell population, indicating that they were not derived from the leukemic clone. Thus, known T-cell growth factors (IL-2, IL-4, IL-7) in concert with mitogenic signals failed to induce in vitro proliferation of the V delta 1+ leukemic clone. Interestingly, the patient responded to treatment with interferon-alpha 2c (daily dose of 10(6) I.U.). After 2 1/2 years of continuous interferon treatment, the patient is in partial remission with WBC around 8000/microliter.


Modification of the DiSC assay by the incorporation of monoclonal antibody staining.

The use of immunohistochemical staining with the DiSC assay is described. This modified staining procedure allows differentiation of viable human tumor cells from normal cells in biopsy preparations, facilitating the evaluation of slides from chemosensitivity assays. Samples from ALL and CLL patients were processed using both the DiSC and modified MoAb-DiSC procedure. The predictive results were compared and found to be identical. This procedure is advantageous in determining the chemosensitivity of tumor cells in a highly heterogeneous biopsy specimen.


Specific chromosomal translocations and therapy-related leukemia induced by bimolane therapy for psoriasis.

This paper reports for the first time results of cytogenetic studies on 14 consecutive secondary acute non-lymphocytic leukemia (S-ANLL) induced by bimolane therapy. They included 10 males and 4 females with ages ranging from 17 to 54 years. They had all suffered from psoriasis and received bimolane treatment before the occurrence of their leukemia. The total dose of bimolane ranged from 40 to 400 g (mean dose 194 g). The interval between the initiation of bimolane therapy and the diagnosis of leukemia was 12-96 months (median 30 months). A preleukemic phase was only found in one case. No dysplastic features in the hemopoietic series were seen in any patient. Chromosome analysis of bone marrow cells using banding techniques revealed clonal karyotypic abnormalities in all cases: t(15;17) in 8 cases of M3, of which 75% had extra abnormalities, t(8;21) in 4 cases of M2, del(7q) only in one case of M4 and one case of M5. After antileukemic therapy, complete remission was obtained in 10 out of 12 cases with specific translocations and one out of 2 cases with 7q-anomaly, respectively. The former survived 4-58 months (median 12 months), while the latter 1 and 9 months, respectively. This study indicates that: (1) bimolane is a causative factor of leukemia in this series; (2) the leukemia in our series is therapy-related leukemia (TRL) rather than de novo ANLL; (3) there exists, in fact, a new subgroup of TRL characterized by specific rearrangements, whose clinical, hematological and prognostic features and pathogenetic mechanism may be different from classical TRL characterized by chromosome abnormalities involving absence or deletion of parts of chromosome 5 and/or 7.


HTLV-related markers in a Hungarian patient with adult T-cell leukemia.

Monoclonal integration of DNA sequences related to, but not identical to HTLV-I provirus was detected in the peripheral blood lymphocytes of a Hungarian male suffering from ATL. The patient and his parents showed serological cross-reactivity with both HTLV-I and HTLV-II group-specific antigens. Restriction enzyme analysis with EcoRI, PstI, BamHI, HindIII and SacI revealed structural similarity of the provirus integrated in the DNA of ATL cells to HTLV-I but not to HTLV-II. Data suggest that this provirus and HTLV-I are similar to each other along gag and pol regions, but they are different in the env region.


A new method of mounting and directing chronically implanted microdrives.

A new method of mounting a microdrive on the skull and adjusting the trajectories of microelectrodes is described. The key to this system is a swiveling guide tube held in a small, skull-mounted base by a low-melting-point metal alloy. The microelectrode is advanced via a modified, commercially available, miniature microdrive screwed onto the guide tube. To change the trajectory of the electrode, the alloy is melted in place, and the guide tube swiveled to a different angle. The microelectrode or the trajectory of the pass may be changed in a few minutes while easily maintaining aseptic conditions. The entire assembly is small enough so that several can be simultaneously implanted on the skull of a cat. A metal crown is used to fix the head during recording sessions or to hold a fiberglass cap that protects all skull implants between sessions. Since the microdrives need not be removed between recording sessions, an electrode pass may be continued from day to day. Although guide tubes are generally employed only for subcortical structures, this arrangement also works well when recording from cortex in deeper parts of gyri.


Positioning device for magnetically sensitive environments.

Presented in this short communication are design principles for the construction of a positioning apparatus for biological specimens in magnetically sensitive environments. An apparatus with 3 degrees of freedom was built and found to provide position accuracy to within +/- 0.25 mm throughout a cubic volume measuring 9 cm on each side.


Purification of embryonic rat motoneurons by panning on a monoclonal antibody to the low-affinity NGF receptor.

Available methods for purifying motoneurons to homogeneity from rodent spinal cord involve retrograde labelling and fluorescence-activated cell sorting, making them costly and time consuming. Motoneurons are the only neurons within the 15-day embryonic rat spinal cord to express the p75 low-affinity NGF receptor and we show that monoclonal antibody 192-IgG, which binds to the extracellular domain of p75, selectively labels a sub-population of large multipolar ventral spinal cord neurons in vitro. We have developed a bench-top panning method for purifying these motoneurons using antibody 192-IgG. Approximately 10(5) cells/spinal cord are obtained in 2 h by this method; 95% of them express p75 in culture. They rapidly put out neurites on laminin substrata, and their survival is enhanced by extracts of skeletal muscle. Using the panning method in conjunction with centrifugation on a 6.8% metrizamide cushion, separate populations of large and small motoneurons were obtained, each containing more than 90% neurons staining with antibody 192. The large motoneurons had choline acetyltransferase activities/cell approximately 4-fold greater than those of dissociated total spinal cells and 7-fold higher than those of the small motoneurons. These methods should be of considerable use for studies on factors affecting motoneuron survival and development and for transplantation of highly purified neuronal populations.