[High-pressure liquid chromatography versus a radiometric method in the identification of aminoglycoside-acetylating enzymes]. High Pressure Liquid Chromatography and a radiometric method for detecting and iso-enzyme identification of aminoglycoside-acetylation enzymes were compared. HPLC determines the acetylating activity of an enzyme by using its reaction product. Three reference strains that produce AAC (3)-I, AAC (6')-IV and AAC (2') and 15 strains isolated from patients. Identification was performed using radiometric and HPLC method in all cases. References strains: The enzymes produced by these strains were correctly identified with HPLC. Patient's strains: All give positive acetylase screening results with the chromatographic method, with holding time peaks that allows the identification of at least three different compounds. Identification at isozyme level was possible in all cases. In 14 out of 15 strains the results were the same using either technique. Radiometric method could not identify the enzyme of one strain. HPLC is a useful technique for isoenzyme identification of aminoglycoside-acetylation enzymes. The results were easily interpreted when compared to those of radiometric method. The group identification was possible with sisomycin.


[Effect of chemotherapy on the antibody response to A60 antigen]. Study of the serologic response in two groups of patients with pulmonary tuberculosis: with and without treatment. Antibodies (type IgG) against the A60 antigen were studied in 103 patients with pulmonary tuberculosis: 46 without specific treatment and 57 after the application of the chemotherapy. 81.6% of the patients showed antibodies against the A60 antigen and 60.2% were strongly positive; 32.6% and 41.3% of the patients without treatment were negative and strongly positive respectively. In the patients with treatment this results were 7% and 75.4%. The differences found between both groups were statistically significant (p less than 0.001). It is concluded that the application of the specific treatment modify in a high percentage the response of antibody against A60 antigen and which reduced the false negatives response, this fact could condition the clinic utility of the test.


[Endocarditis caused by Lactobacillus].

[Endocarditis caused by Lactobacillus]. Endocarditis due to Lactobacillus is rare. Its main features were a subacute course and greater difficulties for achieving a complete recovery even using appropriate antimicrobial therapy with serum levels above MIC. We present one case of Lactobacillus endocarditis in a patient with allergy to penicillin, due to a vancomycin-resistant strain. She was successfully treated with clindamycin and gentamicin. We emphasize the need and importance of sensitivity tests and antibiotic tolerance when choosing an optimal treatment for this infection.


[Bacteriology of mucoviscidosis during a 5-year period]. We have studied the bacteriology of mucoviscidosis cases from 1985 to 1989. A total of 336 samples from 50 patients (median age: 7 year, range: 1 day-18 years) with mucoviscidosis were studied. The most frequently isolated microorganisms was Pseudomonas aeruginosa (59.2%), followed by Staphylococcus aureus (19%) and Haemophilus influenzae (18.4%). In patients younger than 1 year of age other different microorganisms were identified in 61.1% of cases, but S. aureus (11.1%) and Pseudomonas aeruginosa (5.5%) were also isolated. The incidence of Pseudomonas cepacia (0.6%) is low in our environment. We did not isolate any Legionella sp. strain.


[Evaluation of an immunoenzyme technique for the detection in feces of the Giardia intestinalis antigen]. An evaluation is made of the utility for the diagnosis of giardiasis of an enzyme immunoassay (EIA) that detects the GSA65 specific antigen in feces, as compared with the formalin-ether sedimentation test. Within the context of a longitudinal study on intestinal parasitization, 147 fecal samples from children attending 7 day care centres in the city of Salamanca were studied. The feces were examined a few hours after collection by the sedimentation technique and conserved in 10% formol. They were later studied by the EIA method. G. intestinalis was detected by microscopy and/or EIA in 26 of the 147 fecal samples (17.7%). Both assays were positive in 22 of the 26 cases detected (84.6%) and the remaining 4 cases were positive only by EIA (4/26; 15.4%). The EIA assay, using visual reading and very simple to implement, showed sensitivity, specificity, positive predictive and negative predictive values of 100, 96.9, 84.6 and 100%, respectively.


[Surgical bacteremia. Analysis of 210 episodes with special attention to factors influencing prognosis]. From January 1984 to April 1987, we have prospectively studied 210 consecutive episodes of bacteremia recorded in patients who underwent major surgical procedures. The incidence rate was 6.4 episodes/1000 surgical procedures. Men were responsible of 73.8% of episodes. The highest incidence was recorded in general surgery patients and the lowest in Ob & Gyn patients. Bacteremia-related mortality was 15.2% (overall mortality 29.5%). The five most common microorganisms isolated were: Staphylococcus epidermidis (17.7%), Staphylococcus aureus (14.7%), polymicrobial flora (13.3%), Escherichia coli (11.4%) and Pseudomonas sp. (9.5%). The common sources of bacteremia were intravascular devices (34.7%), surgical wound infection (28.5%) and urinary tract infection (12.8%). Multivariant analysis identified six variables that influence an adverse prognosis: complications, source of sepsis in a joint or unknown, admission in trauma or vascular surgery department, development of sepsis between the second and eight postoperative day, chronic illness or fatal underlying disease and sepsis after clean surgical procedures.


Universality in neural networks: the importance of the 'mean firing rate'. We present a general analysis of highly connected recurrent neural networks which are able to learn and retrieve a finite number of static patterns. The arguments are based on spike trains and their interval distribution and require no specific model of a neuron. In particular, they apply to formal two-state neurons as well as to more refined models like the integrate-and-fire neuron or the Hodgkin-Huxley equations. We show that the mean firing rate defined as the inverse of the mean interval length is the only relevant parameter (apart from the synaptic weights) that determines the existence of retrieval solutions with a large overlap with one of the learnt patterns. The statistics of the spiking noise (Gaussian, Poisson or other) and hence the shape of the interval distribution does not matter. Thus our unifying approach explains why, and when, all the different associative networks which treat static patterns yield basically the same results, i.e., belong to the same universality class.


Human cone-pigment spectral sensitivities and the reflectances of natural surfaces. The evolution of visual pigment spectral sensitivities is probably influenced by the reflectance spectra of surfaces in the animal's environment. These reflectances, we conjecture, fall into three main classes: i. Most inorganic and many organic surfaces, including tree bark, dead leaves and animal melanin pigmentation, whose reflectance increases gradually as a function of wavelength. ii. Living leaves, which contain chlorophyll, have a sharp reflectance peak at about 555 nm. iii. Flowers, fruit and other signaling colours that have co-evolved with animal vision typically do not reflect strongly at the same wavelength as leaves, and present a colour contrast against a leafy background. These three spectral functions we call 'grey-red', 'leaf-green' and 'leaf-contrast' respectively. This simple categorisation allows us to interpret the spectral tuning of human cone pigments in a way that might not seem possible given the wide variety of colours present in nature. In particular L-(red) cones will capture the highest possible proportion of photons reflected by leaves, and M-(green) cones will capture about 10% fewer photons both from leaves and from 'grey-red' surfaces. These observations have some clear implications for our understanding of the evolution of trichomacy and the trade-off between chromatic and luminance vision in Old-World Primates.


Average phase difference theory and 1:1 phase entrainment in interlimb coordination. The dynamics of coupled biological oscillators can be modeled by averaging the effects of coupling over each oscillatory cycle so that the coupling depends on the phase difference phi between the two oscillators and not on their specific states. Average phase difference theory claims that mode locking phenomena can be predicted by the average effects of the coupling influences. As a starting point for both empirical and theoretical investigations, Rand et al. (1988) have proposed d phi/dt = delta omega--K sin phi, with phase-locked solutions phi = arcsin(delta omega/K), where delta omega is the difference between the uncoupled frequencies and K is the coupling strength. Phase-locking was evaluated in three experiments using an interlimb coordination paradigm in which a person oscillates hand-held pendulums. Delta omega was controlled through length differences in the left and right pendulums. The coupled frequency omega c was varied by a metronome, and scaled to the eigenfrequency omega v of the coupled system; K was assumed to vary inversely with omega c. The results indicate that: (1) delta omega and K contribute multiplicatively to phi; (2) phi = 0 or phi = pi regardless of K when delta omega = 0; (3) phi approximately 0 or phi approximately pi regardless of delta omega when K is large (relative to delta omega); (4) results (1) to (3) hold identically for both in phase and antiphase coordination. The results also indicate that the relevant frequency is omega c/omega v rather than omega c.(ABSTRACT TRUNCATED AT 250 WORDS)


Sensory segmentation with coupled neural oscillators. We present a model of sensory segmentation that is based on the generation and processing of temporal tags in the form of oscillations, as suggested by the Dynamic Link Architecture. The model forms the basis for a natural solution to the sensory segmentation problem. It can deal with multiple segments, can integrate different cues and has the potential for processing hierarchical structures. Temporally tagged segments can easily be utilized in neural systems and form a natural basis for object recognition and learning. The model consists of a "cortical" circuit, an array of units that act as local feature detectors. Units are formulated as neural oscillators. Knowledge relevant to segmentation is encoded by connections. In accord with simple Gestalt laws, our concrete model has intracolumnar connections, between all units with overlapping receptive fields, and intercolumnar connections, between units responding to the same quality in different positions. An inhibitory connection system prevents total correlation and controls the grain of the segmentation. In simulations with synthetic input data we show the performance of the circuit, which produces signal correlation within segments and anticorrelation between segments.


The emergence of long-lasting transients of activity in simple neural networks. The question was investigated whether long-lasting transients of activity, observed to occur in the intact cerebral cortex (EEG slow (delta) waves and 'K' complexes) as well as in isolated tissues cultured in vitro, can also emerge in a model network of excitatory and inhibitory cells. We show that such transients can indeed occur even if the cells do not have built-in slow kinetics. For certain parameter settings, the network is in a bistable state in which periods of increased activity (long-lasting transients) alternate with minimal activity. Transients are triggered by spontaneously firing cells ('noise'), which, rather than via a build-up of recurrent synaptic inhibition, also initiate their termination. During a transient, the network continually makes transitions from one equilibrium to another as a result of spontaneous firing until it is switched back to the quiescent state, i.e., after a variable period of time of noise-induced transitions the transient is terminated. If the network is small, activity can terminate even without inhibition. In large networks, inhibition keeps the network sensitive to spontaneously firing cells by holding it in the neighbourhood of a critical point between active and quiescent state.


The relationship between a neuronal cross-correlogram and the underlying postsynaptic current. Cross-correlations between stimuli and neuronal discharges yield information about synaptic events at the investigated neuron. In this paper it is shown that the time course estimated by a cross-correlogram, the cross-correlation function (ccf), represents the input current that upon injection into the perfect integrator model evokes spike sequences that are (almost) identical to those used for estimation of the ccf. Thus, the shape of a ccf may be regarded as an estimate of the underlying postsynaptic current, if the neuron investigated behaves, at least to a first approximation, like a perfect integrator model.


The diagnostic and therapeutic approach to chest trauma. The diagnosis of thoracic injuries is now accomplished by a combination of time-honored techniques and new modalities such as echocardiography, CT, and thoracoscopy. Operative approaches are reserved for exsanguination, significant false aneurysms, tamponade, and perforation of the main aerodigestive tracts.


The multi-injured patient: the Maryland shock trauma protocol approach. Thoracic trauma will continue to be a major cause of morbidity and mortality in our population. Improvement in ambulance transport systems and prehospital care has improved the salvage rate. It is hoped that earlier recognition, better understanding of the pathophysiology, and improvement in management will further reduce the number of deaths due to thoracic injuries.


Blunt cardiac trauma: clinical manifestations and management. In conclusion, blunt cardiac trauma is the leading cause of fatalities following motor vehicle accidents. Although many of the patients with anatomic cardiac injuries die at the scene, with improved prehospital care these patients have more likelihood of surviving the first hour and presenting to an emergency room alive for definitive treatment. Prompt recognition of the injury based on the mechanism and a high index of suspicion must lead to immediate surgical intervention in order for these patients to survive. Patients with functional cardiac injuries (myocardial contusion/concussion) usually present a much less urgent scenario. They should be triaged early on the basis of admission ECG and severity of pre-existing or associated injuries to appropriately monitored units. This will allow better allocation of scarce hospital resources rather than blindly pursuing "routine" (expensive) work-ups. The sequelae of these injuries are generally nonfatal. If serious sequelae do arise in the ICU or in the OR, prompt treatment with inotropic support is usually successful.


Pediatric thoracic trauma.

Pediatric thoracic trauma. The majority of chest injuries in children may be effectively diagnosed and treated in the emergency room area, if an organized plan is followed and a high index of suspicion for specific injuries is maintained. Unique features of pediatric anatomy and physiology require innovative adaptation to provide maximal effective resuscitation. Children in this sense are not merely "little adults." Of those few blunt and penetrating injuries that require operative management, operative techniques do not differ from those employed in adult trauma patients.


Effects of green light on biological systems. Green light (510-565 nm) constitutes a significant portion of the visible spectrum impinging on biological systems. It plays many different roles in the biochemistry, physiology and structure of plants and animals. In only a relatively small number of responses to green light is the photoreceptor known with certainty or even provisionally and in even fewer systems has the chain of events leading from perception to response been examined experimentally. This review provides a detailed view of those biological systems shown to respond to green light, an evaluation of possible photoreceptors and a review of the known and postulated mechanisms leading to the responses.


[The use of digoxin in primary care].

[The use of digoxin in primary care]. A study aimed at a population attended at the Primary Health level was designed, in order to reach a greater understanding of the use of Digoxin by doctors and patients. A crossover observational study, carried out wholly at the Primary Care level. 205 patients under long-term Digoxin treatment were studied. 94 (46%) were men and 111 (54%) women. The average age (SD) was 67 (13). The indication was considered adequate in 62.9% of patients. The average dose (AD) of Digoxin was 0.163 mg a day (0.04): the age of the patients is not taken into account on working out the dose of Digoxin. 52 patients (25.4%) recognised they had not properly carried out the prescription. In this group the view that Digoxin was unnecessary was more common (X = 10.63; p = 0.001). The average Digoxinemia (AD) was 0.85 (0.46) ng/ml. 57% of patients had plasmatic levels below a therapeutic level. The variables related to plasmatic level were: daily dosage (r = 0.4, p = 0.001); age (r = 0.2, p = 0.001; plasmatic creatinine (r = 0.3, p = 0.001); clearing of creatinine (r = -0.4, p = 0.001) and compliance (t = 2.42, p = 0.01). The same independent variables were identified as significant in the multivariant analysis. The week-end break from dosage supposed a fall in the plasmatic levels of 67.7%. In spite of being a widely-used drug, the dosage of Digoxin is not adequately worked out and compliance is a long way from the optimum. Digoxinemia correlates to the dosage, renal function and compliance with the prescription.


[Evaluation of a rapid technique for detecting the type A Streptococcus antigen (Test Pack Strep A)]. To test a rapid technique of Antigen Detection (TAD) of Type A Betahemolitic Streptococci (BHSA) in Acute Tonsillitis (AT), comparing it with and using as a point of reference traditional Blood Agar Cultivation (BAC). Additionally, the use of Clinical Data as a method of supposed Diagnosis was studied. Prospective observational study. SITE. Health Primary Care (Maspalomas Health Centre). 118 patients between the ages of 1 and 71 affected by AT. There was a proportion of 13.56% BHSA in the AT of our sample, with a Confidence Interval (CI) of 95% (7.38-19.74) using the BAC; and 17.80% with a CI of 95% (10.90-24.70) using the TAD. The following values were obtained for the TAD: Sensitivity (S) of 93.75%, Specificity (Sp) of 94.12%, Positive Predictive Value (PPV) of 71.43% and Negative Predictive Value (NPV) of 98.9%. Of the clinical variables studied, only the presence/absence of Exudate and Adenopathies were linked to the presence of BHSA in the Cultivations (p less than 0.05 and p less than 0.01 respectively); with, however, inconclusive S, Sp, PPV and PNV values. We found insufficient correlation between clinical findings and the presence of BHSA to consider it a valid method of supposed diagnosis. There was however a statistical link between the presence of Exudate and local Adenopathies, and a positive result in the cultivation. The TAD is shown to be a rapid method, easy to use, and highly reliable for the discovery of the presence of BHSA in AT.


[Follow-up of the patient with HIV infection: a hospital task?]. To assess how often patients with HIV infection abandon treatment. Longitudinal, prospective and observational study. SITE. Out-patient Hospital Clinic. The total number of patients with HIV infection treated between September 1989 and December 1990. Assessment of the level of out-patient follow-up. The rate of abandonment of out-patient follow-up was determined, with "abandonment" defined as unexplained non-attendance for at least two consecutive appointments. Its possible correlations with sex, age and HIV risk behaviour was calculated. 182 patients (143 men and 39 women) with an average age of 30.1 (ds 8.62) were surveyed. The abandonment rate for the sample as a whole was 44%, with no difference as to sex. However the abandonment rate was higher in the group of patients addicted to drugs (DDA) (69%) than in non-DDA (25%) or in ex-DDA patients (6.5%). These figures reached high statistical significance (p less than 0.01 and 0.001 respectively. The abandonment rate of out-patient hospital follow-up by HIV-infected patients appears extremely high, especially among drug addicts (DDA).


[Evaluation of the school health program for the detection of vertebral deformities]. To evaluate the prevalence of deformities of the vertebral column in the child population of a rural area; the index of false positives that diagnoses in the School Health programme generate; and the percentage of children where the diagnosis is confirmed and the treatment is then followed. Descriptive observational study. SITE. Public and private Schools of the Basic Areas of Sanlúcar la Mayor and Olivares, and the Rehabilitation Unit of Sanlúcar la Mayor Health Centre. 4120 children from the first, fifth and eighth years of EGB, in 1989 and 1990. Pathology was suspected in 5% of the children examined. 64.59% attended Rehabilitation and anomalies were confirmed in 51.85%. The level of false positives in the screening was about 48%. In 54% of the confirmed cases, Physiotherapy was indicated; in one case, Surgery; and in one case orthesis. There were no important differences as to the prevalence of Pathology among the three age groups studied. (p = 0.05). In spite of the small number of anomalies confirmed, their detection by means of a simple method allowed evolution to be watched and early treatment started when necessary. The low productivity of the examination was due to the high number of children that did not attend for the confirmation of the diagnosis (35%), and the false positives that the screening generated (48%).


[Difficulties in carrying out the treatment as seen by the tuberculous patient]. To identify the obstacles, as seen by the patient, to adequately carrying through anti-Tuberculosis treatment. Crossover study. SITE. At Community level, in the city of Barcelona. Each patient was responsible for filling in a survey at home. It was considered that a patient did not adequately carry out the treatment if he/she failed to take the medication for a period longer than three consecutive days. We discounted 66 exitus or losses and were left with 308 surveys. Out of these, the failure rate was 13.5%. The only variable statistically linked to failure was Dangerous Drug Addiction (DDA) (OR = 6.1; CI:2.3-15.8). The most common cause of failure was forgetfulness, followed by deliberate abandonment. The greatest problems in obtaining prescriptions were the opening hours or location of the dispensary. In spite of the seriousness of the illness, patients do not illness, patients do not usually give up their toxic habits. 68.8% were followed up in hospitals and only 8.8% in Primary Care Centres. Failure is linked to forgetfulness and deliberate abandonment. Patients have problems in obtaining prescriptions because of the opening hours and location of the prescriptions dispensary. Corrective measures should be taken for these latter problems.


[An evaluation of growth tables].

[An evaluation of growth tables]. To establish how suitable the growth tables we usually use are. A descriptive crossover study. SITE. Primary Care. Casalduch Health Centre in Castellón. 120 boys and 158 girls, aged 6, who attended the Health Centre for routine School Health examinations. The weight and height of the children was analysed. The percentil corresponding to each value was assigned in line with the growth tables in the Child Health Booklet. It was found that values higher than those expected were obtained, in both sexes and for weight and height. On comparing the proportion of girls with percentils above 5 and 75 with the theoretical proportions of 50 and 25% respectively, significant differences were obtained in all cases. Despite our only having studied exclusively 6 year old children in an extremely restricted geographical area, we can claim that this survey contributes to the revision and updating of the growth tables.


[Pink pityriasis in primary care. Review of 46 cases]. We pretend to improve the knowledge and management of pityriasis rosea by family practitioners. A retrospective qualitative study by the review of the registry in a outpatient Dermatology clinic. This work is made in the Dermatology clinic attending to San Sebastián de los Reyes population (Madrid) that's situated in the V Centenario Center. 46 patients (28 females) were diagnosticated (mean age 25 +/- 13). Incidence was 85/100,000 hab; 12 patients were derivated urgently; 38 cases showed herald patch (82.6%). Lesions had characteristical distribution in 36 patients (78.3%); 43 cases had a clinic diagnosis (93.5%). Treatment wasn't necessary in 20 patients (43.5%). Most usual General Practitioner's presumption diagnosis was pityriasis rosea (21.7%); there was no diagnosis in 36.9%. We find inexperience in general practitioners about pityriasis rosea. It's necessary a correct knowledge and management of this pathology in Primary Care.


[Suitability of the practice of recording only the main health problem in primary care]. To analyse if recording only the main health problem (P) can reflect in a valid way the totality of health problems (P+S) cared for and all the actions generated by a consultation. Using a representative sample of the patients seen at the centre over a three-month period, information on P+S was gathered, P was identified and the actions generated by each one of the problems were recorded. Health problems were codified through CIPSAP-2-D and grouping diagnoses. SITE. General Medicine service in a Primary Care Centre. All the General Medical physicians at the Centre took part in the study by collecting data on the consultations established by the sampling. Frequency and order among the first 25 P+S and P problems were compared, as was the percentage of secondary problems encountered. Out of 559 consultations examined, Diabetes, Dislepemia and an irritated? Colon stood out as under-represented. Acute infections of the Upper Respiratory Tract, Conjunctivitis and ??Queratitis were over-represented. As for the activity generated, 83.1% corresponded to P, although there was great variability among the problems according to the percentage of secondary problems according to the percentage of secondary problems. Recording only the main health problem can be a valid instrument for providing an initial view of problems seen.


[The use of role-playing with actors and video in teaching clinical interviews to medical students]. To describe the use of the technique of role-play, using actors and recorded on video, in teaching clinical interviews to medical students; and the latters' evaluation of the methodology used. Prospective and observational controlled study. SITE. The Faculty of Medicine in Granada. The study was carried out with a group of 32 students doing the last year of Medicine. Two actors, ten students as interviewers and two teachers were involved. The programme consisted of: a theoretical setting-out of the contents of the clinical interview; a description of the group analysis method; filming simulated interviews on video; group analysis of the material filmed; and evaluation by means of a questionnaire. The choice of interviews gave rise to no problems. The actors assumed with ease the roles they had to play. In the group work, students actively participated and made constructive contributions all the time. In the assessment the items referring to Interest, Teaching Method and Relevance and Originality were high (4.49 out of 5 points). Only that referring to documentation obtained a lower score (3.87 out of 5). Role-play technique, using actors and video, are excellent educational methods for teaching the clinical interview in undergraduate training.


[Q fever: epidemic outbreak of the pure febrile form]. To describe an epidemic of 30 cases of Q fever, none of which had respiratory manifestations. Descriptive study. SITE. General medicine practices in the Billabona Health Centre, which covers the populations of Billabona and Zizurkil. Thirty patients, 27 men and 3 women, were diagnosed by serology as having Q fever, during and epidemic of a type of fever in Spring 1990. They were treated with Doxiciclin, taken orally. A general analysis and thoracic x-ray were carried out. The respiratory mechanism was not affected in any case. Transaminases were extremely high in 86% of cases. Other findings were: fever 100%, shivering 83.3%, sweating 96.6%, severe headache 86.7% and myalgia 73.4%. Faced with pseudoinfluenza symptoms, and in areas with high occurrence of Q fever, we should consider that we could be dealing with cases of Q fever, even when there are no respiratory manifestations.


[The authors and the bibliographic references of the original articles published in the journal Atención Primaria (1984-1990)]. The main aim of the study is to assess the developing situation of the articles published in the journal Atención Primaria in relation to the original articles included in the same journal. There are secondary aims of describing the amount of self-quotation, the profession of the authors, their geographical distribution and their use of bibliographic references. A descriptive analysis of the authors and bibliographic references in the original articles. SITE. Publications and research in Primary Care. All the original articles published in the journal Atención Primaria during its first seven years (1984-1990). Gathering of data from the original articles (the number of authors, province of their place of work, titles, total number of references, references from Atención Primaria, the number of self-quotations, etc.) In the seven years studied, 295 original articles have been published by 1467 authors, 44% of whom are family doctors. The average number of authors per article was 5. There are twelve Spanish provinces from which no-one has published. Altogether 4,908 bibliographic references, an average of 16.6 per article, have been used. The number of references from the journal itself rose steadily from 1% in 1984 to 11.7% in 1988, but went down to 10.3% in 1990. 52% of the bibliographic references were in Castilian and 42.6% in English. The journal Atención Primaria is often quoted in original articles published in the same journal. The number of authors and references per original article is high but stable.


[Sarcoidosis: retrospective analysis of 14 cases]. A clinical evaluation of Sarcoidosis in our environment. A retrospective and descriptive analysis of 14 cases encountered between 1988 and 1990. SITE. In-hospital patients studied within a catchment area of 200,000 people. 13 women and 1 man ranging in age from 24 to 63 (X = 37. DS 13). All of them were confirmed histologically. Six patients received V.O. steroid treatment. 28.5% started as Nodose Erythema, 28.5% as Respiratory Syndrome, 21% as general Toxic Syndrome. 35% were without clinical symptoms; 25% Arthralgias, 21% cough. Thoracic X-ray with bilateral hiliar adenopathies 78%; interstitial pattern 28.5%. Analytically, Monocitosis was presented in 43%; Anaemia, Hypergammaglobulinemia, rise in Transaminases in 35%; a normal ACE in 50% and raised ACE in 35%. There was a positive pulmonary Cammagraphy (Galio) in 50%. Diagnostic confirmation was made by means of transbronchial B (28%), Mediastinoscopy (14%), open Pulmonary B. (14%), Hepatic B (14%), osseous B. and Daniels (14%) and peripheric adenopathy B (14%). Pulmonary circulatory capacity (DLCO-KCO) was decreased in 3 cases. Statistic 1, 71%; 11, 14%, 111, 14%. Sarcoidosis is not so rare in our environment as had been thought. Factors such as a Northerly geographical situation, low temperatures, the long duration of the disease, improvement in diagnostic methods and a high level of awareness have all influenced this high number of cases found in an area of 200,000 inhabitants. The disease's clinical behaviour in our environment does not differ from that described by other spanish and foreign authors.


[Pigmented basocellular epithelioma. Presentation of 7 cases]. To review the clinical, histological, evolutive and therapeutical characteristics of basal cell carcinoma and the pigmented subtype. Descriptive transversal study. Primary Care; Clinic of Dermatology in a Primary Care of Madrid. Seven patients (4 males, 3 females) over 60 years old with pigmented lesions and skin little pigmented. Medical records and the histological examination were reviewed in all the cases. The clinical evolution had been the same in all the patients starting with an asymptomatic papular lesion of dark pigmentation growing slowly. Finally the lesions were transformed to a plaque or a shining nodule. Prolonged exposure to sunlight was present in five cases. All the patients were referred to the Dermatology Clinic with the presumptive diagnosis of melanoma. The lesion histological examination was diagnostic. It is very important the knowledge of basal cell carcinoma in Primary Care due the elevated incidence mainly among the geriatric population and the immunosupressed subjects. We must think in this type of neoplasia, doing the differential diagnosis with the other pigmented lesions. It is necessary to perform the histological examination of the suspects lesions.


[Care for women: where and how].

[Care for women: where and how]. To analyse the demand for family planning, gynecological cancer tests and pregnancy supervision in an area with no public resources devoted specifically to these questions. To evaluate users' level of satisfaction and their readiness or otherwise to be visited at the Health Centre (HC), with a view to planning out a specific programme. Descriptive study. SITE. Health Centre at Castelldefels. (Barcelona). Random stratified sample of 595 women over 14, living within the centre's catchment area. The age distribution was selected in line with the town's population pyramid. We undertook a self-administered, anonymous survey of 437 women. 4.9% of those sexually active between the ages of 14 and 20 and 13.2% of women aged between 21 and 45 use no contraceptive method. The greater attendance at private rather than public centres for contraception (73% as against 23.8/1000 p less than 0.001) and for regular check-ups (63.8% as against 32.1/1000 p less than 0.001) was notable. But for pregnancy care it was the other way round (29.3% as against 61.2/1000 p less than 0.001). 64.1% have regular check-ups; 48.8% annually. A higher level of satisfaction is shown by women seen at private (95.2%) than at public centres (75.1/1000 p = 0.0159). 68.9% would use a special care services for women if offered by the HC. Existing services offer scant cover to sections of the population more at risk and tend to make everything a medical problem. The public centres give little user-satisfaction. The Primary Care teams could cover these deficiencies with their services and would be welcome by the public.


Solvent damping of internal processes in myoglobin studied by specific heat spectroscopy and flash photolysis. We address the question of dynamic coupling between protein and solvent by comparing the enthalpy relaxation of the solvent (75% v/v glycerol-water) to internal ligand binding in myoglobin. When the solvent relaxation is slow compared to intramolecular events we observe decoupling of protein motions from the solvent. In the opposite limit there is a significant contribution of the solvent to internal friction. The solvent enhances the apparent activation energy of transitions in myoglobin. This result is discussed in terms of a generalized Kramer's law involving a dynamic friction coefficient.


Reaction rate enhancement by surface diffusion of adsorbates. Ligands can be captured by a surface target through either direct bulk diffusion or surface diffusion following reversible adsorption to the surface. We have solved a steady state boundary value problem for a perfect sink disk target in the surface, taking into account bulk and surface diffusion coefficients D and Ds and adsorption/desorption kinetic rate constants ka and kd at non-target regions. Solutions have been successfully found by numerical computation. The results show that the rate of capture from the surface depends non-linearly on Ds, D, ka, kd and geometrical dimensions. In particular, we demonstrate that not only is the non-target region equilibrium constant Keq (= ka/kd) important in determining the rate of capture from the surface, but so are the kinetic rate constants ka and kd separately. In all cases, the surface adsorption/diffusion combination enhances the total rate of capture. The results should be useful for predicting reaction rates of biological membrane bound receptor clusters and substrate-immobilized enzymes.


Isoelectric point of an ion-penetrable membrane. The surface potential of an ion-penetrable planar membrane is calculated for the case in which acidic and basic groups are present in the membrane. It is found that when both acidic and basic groups are not uniformly distributed in the direction normal to the membrane, the isoelectric point (the pH value at which the surface potential becomes zero) of the membrane varies with the electrolyte concentration, whereas if both groups are uniformly distributed, the isoelectric point is independent of the electrolyte concentration. As a simple example, we treat a membrane consisting of two layers, in which acidic groups are distributed in the outer layer and basic groups are in the inner layer. Simple equations determining the membrane surface potential as a function of pH and electrolyte concentration and the dependence of the isoelectric point on the electrolyte concentration are presented.


Solvation effects upon the thermodynamic substrate activity; correlation with the kinetics of enzyme catalyzed reactions. I. Effects of added reagents such as methanol upon alpha-chymotrypsin. Solvents, detergents, etc., have often been added to the medium to study the kinetics of enzyme action and for binding studies. They have been employed for diverse reasons such as solubilization of substrates or to stabilize an enzyme that was originally membrane bound. Thermodynamic considerations dictate that any added substance, such as methanol, which is present in significant quantity must affect the thermodynamic activities of the enzyme, enzyme-substrate complex, substrate and any other intermediates although cancellation effects may occur in this regard. The influence upon substrate activities is the only one that is easily experimentally accessible. These effects are shown, from the data of Bernard and Laidler, to be large in the case of the alpha-chymotrypsin catalyzed hydrolysis of methylhydrocinnamate. The variation of the Michaelis-Menten constant is quantitatively explainable in terms of the alteration of the thermodynamic activity of the substrate by methanol.


Solvation effects upon the thermodynamic substrate activity; correlation with the kinetics of enzyme catalyzed reactions. II. More complex interactions of alpha-chymotrypsin with dioxane and acetone which are also competitive inhibitors. It is shown that the effects of the addition of various amounts of dioxane and acetone (solvent modifiers) upon the alpha-chymotrypsin-catalyzed hydrolysis of methylhippurate can be explained in terms of three factors. (A) The effects of the above modifiers on the chemical potential of the substrate. (B) The solvent modifiers dioxane and acetone also act as classical competitive inhibitors. The means of sorting out these contributions is presented. (C) The alterations of the chemical potentials or for free energies of the enzyme, enzyme-substrate complex, and/or other intermediates by the added modifiers appear to cancel out with the substrate used here.


The transcriptional control of TGF-beta in human osteoblast-like cells is distinct from that of IL-1 beta. Transforming growth factor beta (TGF-beta) and interleukin 1 (IL-1) are among the most potent osteotropic cytokines. The expression of mRNA for both TGF-beta and IL-1 beta was studied in human osteoblast-like cells in vitro. These cells constitutively expressed TGF-beta but not IL-1 beta mRNA. Treatment of the cells with the systemic hormones 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] (10(-8) M) and parathyroid hormone (10(-7) M) induced an increase in TGF-beta mRNA but failed to stimulate the production of IL-1-beta mRNA. Retinoic acid (10(-8) M) had no effect on either mRNA species. The cytokines IL-1 alpha (200 pg/ml), tumour necrosis factor alpha (TNF-alpha) (17 ng/ml) and bacterial lipopolysaccharide (LPS) (500 ng/ml) stimulated the production of IL-1 beta mRNA after 6-8 hours. This was followed by an increase in protein production after 24 hours. In contrast, the production of TGF-beta mRNA remained constant after treatment with these agents. Treatment of the cells with hydrocortisone (10(-8) M) resulted in the suppression of both TGF-beta and IL-1 beta mRNA. However, when the stimulating agent 1,25-(OH)2D3 was added in conjunction with hydrocortisone the mRNA expression of TGF-beta mRNA returned to 70% of the stimulated level. In contrast, the addition of the stimulatory agent IL-1 alpha to hydrocortisone-treated cells resulted in no increase in IL-1 beta mRNA. In-situ hybridization demonstrated both TGF-beta and IL-1 beta mRNA at the cellular level.(ABSTRACT TRUNCATED AT 250 WORDS)


Blood-derived macrophages produce IL-1, but not TNF-alpha, after infection with HIV-1 isolates from patients at different stages of disease. Interleukin 1 (IL-1) and tumor necrosis factor alpha (TNF-alpha) are not constitutively produced by human mononuclear phagocytes. In the present study we have investigated the production of these cytokines in human blood-derived macrophages (BDM) after infection with 16 primary HIV-1 blood isolates obtained from individuals at different stages of disease. In addition, we monitored the replicative capacity of these primary isolates in blood-derived macrophages over a 3-month period. Production of IL-1 alpha was detected in two cultures, IL-beta was positive in two other cultures, and both IL-1 alpha and IL-beta were present in three additional macrophage cultures. IL-1 alpha production was also detected in BDMs infected with the laboratory strain HIV-1 IIIB. In contrast, TNF-alpha was not found in any of the culture supernatants tested. All primary HIV-1 isolates used in these experiments were able to infect BDM productively irrespective of the clinical stage of the patients at the time of virus isolation. The production of IL-1 was mostly found in chronically infected cultures displaying low levels of HIV-1 replication. These results indicate that macrophages tropism is a general feature of all HIV-1 isolates. Furthermore, release of IL-1 by mononuclear phagocytes upon HIV-1 infection may contribute to the pathogenesis of HIV-1 related diseases.


Cytometrically detected specific binding of interleukin 2 to cells. We have developed a new technique for detecting binding of interleukin 2 (IL-2) to cells. This technique involves incubating the cells with IL-2 and then analysing the cell surface with specific anti-IL-2 antibodies and flow cytometry. This binding was only detected on tumor cells that possessed the p55 subunit of the IL-2 receptor. The role of p55 was ascertained by inhibition of the binding with a monoclonal antibody to p55. Although p55 is necessary for cytometrically detected IL-2 binding, further studies demonstrated that p55 is not sufficient. Thus, cytometrically-detected binding is likely to involved the contribution of other IL-2 surface receptors. Interleukin-2 binding to peripheral blood T lymphocytes and to a non-transformed T-cell clone was also detected cytometrically and it was shown that this binding is regulated by the activation status of the cells. Whereas IL-2 binding to quiescent T cells could not be detected, upon activation abundant binding was seen. The functional consequences of this type of cellular binding were studied. Interleukin-2 binding to cells during a short pulse was shown to have significant long-term consequences both for T-cell proliferation and for the enhancement of major histocompatibility complex (MHC)-non-restricted cytotoxicity.


Oxidative tryptophan metabolism in renal allograft recipients: increased kynurenine synthesis is associated with inflammation and OKT3 therapy. Serum concentrations of tryptophan (TRP) and kynurenine (KYN) were determined in renal allograft recipients (RAR) as an index of interferon-gamma-induced, indoleamine-dioxygenase-catalysed TRP degradation. Serum TRP and KYN in RAR during periods of stable graft function were typically within the normal range, however, the median values for serum KYN demonstrated significant increases 5-7 days prior to biopsy-confirmed acute rejection (1.6-fold, P less than 0.01) and on the day of biopsy (1.7-fold, P less than 0.001). Serum KYN was also markedly elevated in patients who contracted viral or Gram-negative bacterial infections in the absence of graft rejection. Serum KYN was not correlated with serum creatinine in RAR nor were serum TRP or KYN affected by antirejection therapy with high dose steroids. Retrospective analysis of intra-patient changes in serum KYN demonstrated that KYN monitoring was a useful adjunct to serum creatinine in the early detection of first acute rejection episodes. The first course of OKT3 therapy was associated with low serum TRP and significant increases in serum KYN (two- to three-fold) following the first three doses. The time course of these abnormalities corresponded to that over which many of the side effects of the OKT3 'first dose reaction' have been reported to occur. Significant changes in serum KYN were not observed in patients receiving repeat courses of OKT3 therapy. Significant decreases in serum TRP and significant increases in serum KYN were both prevalent and frequent in RAR during the first two postoperative months.(ABSTRACT TRUNCATED AT 250 WORDS)


Comparison of the cytostatic and cytolytic activity of tumor necrosis factor-alpha and interleukin 1 alpha in human malignant cell lines. The cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin 1 alpha (IL-1 alpha) share many properties, including in-vitro cytotoxicity. Because cytotoxicity can result from either cytolytic or cytostatic activity, and because differentiating between these activities may have clinical relevance, we determined the cytostatic and cytolytic activity of TNF-alpha and IL-1 alpha for the human cell lines ME-180, SiHa (cervical carcinomas) and A375 (melanoma). Results of these analyses showed that IL-1 alpha mediated cytostatic activity only for A375 cells. IL-1 alpha was not cytolytic in the presence or absence of protein synthesis inhibitors. TNF-alpha was cytostatic for A375 and ME-180 cells, and although TNF-alpha was not cytolytic in the absence of protein synthesis inhibitors, it was cytolytic in the presence of protein synthesis inhibitors. These results suggest that the difference between the cytolytic and cytostatic activities of IL-1 alpha and TNF-alpha may have therapeutic implications for the use of these biological response modifiers in the treatment of gynecological malignancies.


Interleukin 2 treatment of Staphylococcus aureus mastitis. A study was conducted in dairy cows to evaluate the efficacy of recombinant bovine interleukin 2 (rBoIL-2) as an adjunct to antibiotic therapy in Staphylococcus aureus mastitis. In normal, non-mastitic cows, intramammary infusion of rBoIL-2 caused a tenfold increase in somatic cell counts (SCC) in milk. Co-administration of 2 mg of rBoIL-2 and sodium cephapirin in cows with established S. aureus mastitis decreased SCC and shedding of S. aureus compared with values from cows that were given only sodium cephapirin or 10 mg rBoIL-2 with sodium cephapirin. Cows in the 2 mg rBoIL-2 group cleared the infection earlier and at 2 weeks after treatment had not relapsed with staphylococcal mastitis. These data suggest that rBoIL-2 may be useful as an immunotherapeutic agent in controlling mastitis.


Induction of swelling, synovial hyperplasia and cartilage proteoglycan loss upon intra-articular injection of transforming growth factor beta-2 in the rabbit. Transforming growth factor beta (TGF-beta) is a multifunctional homodimeric polypeptide with potent actions upon many target cells, including those of mesenchymal and haemopoietic lineage. The recent reports of high levels of the cytokine in rheumatoid synovium and synovial fluid, prompted this study into the effect of intra-articular injection of TGF beta-2 into rabbit knee-joints. Four daily injections of 1 microgram caused swelling, probably as a consequence of prostaglandin E2 production, synovial fibroblastic hyperplasia and a striking loss of femoral condyle proteoglycan. Using the polymerase chain reaction, no evidence could be obtained for the induction of interleukin-1 alpha gene expression in either synovial tissue or synovial fluid cells. These findings suggest that the TGF-beta present in the rheumatoid joint may contribute directly to the pathogenesis of rheumatoid arthritis.


Direct stimulation of cytokines (IL-1 beta, TNF-alpha, IL-6, IL-2, IFN-gamma and GM-CSF) in whole blood. I. Comparison with isolated PBMC stimulation. Production of interleukin 1 beta (IL-1 beta), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-alpha), interleukin 2 (IL-2), interferon gamma (IFN-gamma) and granulocyte-macrophage colony-stimulating factor (GM-CSF) after stimulation by lipopolysaccharide (LPS) and phytohemagglutinin (PHA) was studied in 1/10 diluted whole blood (WB) culture and in peripheral blood mononuclear cell (PBMC) culture. Cytokines IL-1 beta, TNF-alpha and IL-6 are preferentially stimulated by LPS whereas IL-2, IFN-gamma and GM-CSF are stimulated by PHA. Combination of 5 micrograms/ml PHA and 25 micrograms/ml LPS gave the most reliable production of the six cytokines studied. IL-1 beta, TNF-alpha and IL-6 represent a homogeneous group of early-produced cytokines positively correlated among themselves and with the number of monocytes in the culture (LeuM3). Furthermore, IL-1 beta was negatively correlated with the number of T8 lymphocytes. IL-2, IFN-gamma and GM-CSF represent a group of late-produced cytokines. Kinetics and production levels of IL-6 and GM-CSF are similar in WB and PBMC cultures. In contrast, production levels of TNF-alpha and IFN-gamma are higher in WB than in PBMC whereas production levels of IL-6 and IL-2 are lower in WB than in PBMC. Individual variation in responses to PHA + LPS was always higher in PBMC cultures than in WB cultures. The capacity of cytokine production in relation to the number of mononuclear cells is higher in WB, or in PBMC having the same mononuclear cell concentration as WB, than in conventional cultures of concentrated PBMC (10(6)/ml). Because it mimics the natural environment, diluted WB culture may be the most appropriate milieu in which to study cytokine production in vitro.


Drugs and the liver. Part III: Ageing of the liver and the metabolism of drugs. The clearance of many drugs by the liver is reduced in the elderly, and this accounts, at least in part, for the greater frequency of adverse drug reactions in this population. Ageing in experimental animals is accompanied by a decline in the activities of certain microsomal monooxygenase enzymes; this has been said to be the reason for decreased drug elimination. However, recent data suggests that this is probably not the case in humans. Reduced size and blood flow are important features of the ageing liver, and probably account for most of the age-related changes in drug metabolism. Major decrements in hepatic function do occur in frail elderly individuals, although the mechanisms underlying this are at present unclear. Future studies of drug metabolism and ageing must carefully define patient groups to allow full interpretation of data.


Effect of indomethacin on the pharmacokinetics of methotrexate in rabbits. The interaction between indomethacin (IND) and methotrexate (MTX) was investigated in rabbits. The study was designed so as to evaluate the effect of IND (1 mg h-1) during a continuous MTX infusion (1 x 2 mg kg-1) over 240 min. IND was injected i.v. at hourly intervals after a steady state MTX concentration had been established. Plasma MTX concentration before and after IND did not differ significantly (p greater than 0.05). The elimination half-life (t1/2 beta) calculated during the washout interval (mean +/- SD) was 47 x 4 +/- 21 x 5 min which is close to that calculated in a reference group of rabbits. This excludes the possibility of delayed elimination as responsible for this toxicity. The toxicity of this combination was confirmed despite the absence of significant pharmacokinetic changes. It is possible that the toxic interaction was caused by enhanced cytotoxic effect of MTX.


Effect of food and relative bioavailability following single doses of diclofenac 150 mg hydrogel bead (HGB) capsules in healthy humans. The effect of food on the bioavailability of diclofenac from a 150 mg diclofenac hydrogel bead (HGB) capsule was evaluated in 12 healthy male subjects in a fed and fasted state. Additionally, the fasting bioavailability of diclofenac from a 150 mg diclofenac HGB capsule relative to diclofenac sodium in buffered aqueous solution was evaluated in these same 12 subjects. The study was designed as an open-label, randomized, single-dose, 3 x 3 Latin-square crossover trial balanced for residual effects. A 2-week washout period was maintained between treatments. Blood samples were collected at frequent intervals over a 24-h period with plasma being separated and analyzed for diclofenac using a validated HPLC method. The administration of the 150 mg diclofenac HGB capsule dose within 30 min following a standardized breakfast minimally affected the bioavailability of diclofenac relative to administration under fasted conditions (7 per cent decrease in AUC(0-24), p greater than 0.05). There was, however, a 38 per cent decrease (p less than 0.05) in the Cmax and a three-fold increase (p less than 0.05) in Tmax for the fed HGB capsule administration. Under fasted conditions, significant differences in mean pharmacokinetic parameters were found between the 150 mg diclofenac HGB capsule and diclofenac sodium in buffered aqueous solution. The extent of availability of diclofenac from the HGB capsule was only 59 per cent relative to that from the solution (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)


Pharmacokinetics of ibuprofen enantiomers after single and repeated doses in man. The pharmacokinetic parameters of ibuprofen enantiomers after a single 600 mg dose and repeated 3 x 400 mg doses of Nurofen were determined in 12 healthy volunteers. Terminal half-lives were similar for both enantiomers, but plasma levels of S-ibuprofen were higher than those of R-ibuprofen, due to the chiral inversion and differences in distribution and metabolism. Comparison of maximal concentrations and areas under the concentration vs time curves between the first and last doses for each enantiomer indicated linear pharmacokinetics with no time-dependency. A large inter-individual variability in the ratio of S- to R-ibuprofen average concentrations at steady-state was observed (mean +/- SD 1.89 +/- 0.89) and probably accounts for the known lack of correlation between racemic ibuprofen concentrations and therapeutic efficacy.


Circadian rhythm of soluble interleukin-2 receptor in healthy individuals. The cytokine levels of soluble interleukin-2 receptor (sIL-2R), interleukin-6 (IL-6) and tumor-necrosis-factor alpha (TNF-alpha) were studied in 12 healthy volunteers at 11 different times of day. TNF-alpha levels were below the detection limit, and IL-6 levels were at baseline values of the respective assay used. Interindividual variations were found for the plasma levels of sIL-2R (179-524 U/ml). Shedded IL-2 receptors displayed a pronounced circadian phase-dependency (p less than 0.0001) with a peak value at 12:29 h and a trough at 4:14 h when a complex cosine function (period lengths: 24 h plus 12 h) was fitted to the data. These findings may be of importance when using sIL-2R as a diagnostic tool as well as in controlling efficacy of drug treatment.


Anti-tumor cytotoxic potential and effect on human bone marrow GM-CFU of human LAK cells generated in response to various cytokines. The effects of various recombinant cytokines i.e. IL-1 alpha, IL-3, IL-4, IL-6, IFN-gamma, TNF-alpha and GM-CSF used either alone or in combination with IL-2, were investigated in this study. First, their capacity to induce killer cells from human PBL was examined by evaluating the degree of killing of human NK-sensitive K562 or NK-resistant Daudi cells. Second the effects of these cytokines, LAK cells (at 1/1, 2/1, 4/1 ratio LAK effectors/bone marrow cell targets) and of the supernatants from washed killer cell cultures, were examined on the colony forming ability of human bone marrow for GM-CFU in vitro. Various degrees of NK activity against K562 was observed in PBL stimulated with the cytokines, whereas LAK activity was found only with IL-2 alone. Culture of PBL with IL-2 + IL-1 alpha or IL-2 + IL-6 or IL-2 + GM-CSF resulted in the highest LAK killing. However, addition of TNF-alpha, or IFN-gamma to IL-2 in cultures resulted in a significant suppression of LAK cell activity. Addition of IL-1 alpha, IL-2, IL-3, and IL-4 to BM cultures had little or no effect on day 14 GM-CFU, whereas addition of IL-6 and GM-CSF resulted in a stimulatory effect. LAK cells induced with IL-2 alone had no significant suppressive effects on GM-CFU.(ABSTRACT TRUNCATED AT 250 WORDS)


Plasma disposition and hemodynamic effects of a single oral dose of isosorbide dinitrate in human males and females. The goal of the present work was to determine the plasma disposition and hemodynamic effects of isosorbide dinitrate (ISDN) in human males and females. Fourteen healthy human volunteers took part in the study; seven males, 21.7 +/- 2.5 y (SD), and seven females, 20.7 +/- 3.4 y. Measurements of forearm blood flow (FBF), vascular conductance (FVC), and venous capacitance (Cv) were obtained by venous occlusion plethysmography, whereas blood pressure was measured by automatic sphygmomanometry. Blood samples were taken through a catheter placed in the antecubital vein at 0, 15, 30, 45, 60, 90, 120, 360, 480, 720, and 1440 min following a single 10 mg oral dose of ISDN. Plasma concentrations of ISDN and its mononitrate metabolites, isosorbide-2-mononitrate (2-ISMN) and isosorbide-5-mononitrate (5-ISMN), were determined by large bore capillary column gas-liquid chromatography. Hemodynamic measurements were made at corresponding experimental times up to 480 min. No differences were observed in the disposition of ISDN, 2-ISMN or 5-ISMN between the male and female volunteers. In addition, the plasma concentrations of ISDN and its mononitrate metabolites did not consistently correlate with the hemodynamic changes of the individual subjects. Diastolic blood pressure was significantly decreased for a 0.5 h period starting at 30 min, which was the time at which plasma ISDN concentrations peaked, and which preceded the time when the plasma concentrations of 2-ISMN and 5-ISMN were maximal. These observations indicate that, for a single 10 mg oral dose of ISDN, there were no gender-dependent differences in the plasma disposition of the parent drug or its mononitrate metabolites, and the vascular changes responsible for the decrease in diastolic blood pressure in these volunteers occurred in vascular beds other than those of skeletal muscle as represented by forearm blood flow.


Augmentation of cytostatic effect of recombinant human lymphotoxin and involvement of glutathione redox cycle. The effect of buthionine sulfoximine (BSO), an inhibitor of glutathione biosynthesis, in combined use with a nitrosourea derivative, ACNU, on the cytostatic effect of recombinant human lymphotoxin (rhLT) was studied in vitro. The simultaneous addition of 0.02 mM or 0.5 mM BSO and rhLT slightly augmented the inhibition of Meth A tumor cell proliferation. Similar tendency was observed when the target cells were treated with 0.02 mM or 0.5 mM BSO for 24 hr prior to the addition of rhLT. A marked augmentation of the antiproliferative effect was obtained when the target cells were treated in vitro with 0.005 mM or 0.02 mM BSO prior to the addition of 0.02 mM or 0.1 mM BSO and rhLT. The addition of ACNU simultaneously with rhLT to BSO-treated cells also augmented the antiproliferative effect. These results suggest that the glutathione redox cycle is closely related to the mechanism of LT-induced cytotoxicity.


IL-6 mRNA expression in CD25 positive malignant lymphomas. We recently demonstrated that IL-2 is produced by reactive T cells in CD25-positive malignant lymphomas (ML). Using in situ hybridization, we investigated IL-6 mRNA expression in these CD25-positive ML. The ML tested included 9 anaplastic large cell lymphomas and 3 B-diffuse large cell lymphomas. Five CD25-negative ML were studied as controls. We show that IL-6 producing cells are present in all these ML. The density of positive cells was heterogeneous from case to case. However 3 cases of CD25-positive ML showed a dramatically higher density of IL-6 producing cells (70, 50, 43 producing cells per 10,000 cells, respectively) as compared to the other 9 cases of CD25-positive ML (mean 6.03 +/- 2.1 per 10,000). Morphological and topographical data suggested that several types of cells including fibroblasts, lymphocytes, macrophages and endothelial cells may synthesize IL-6. A combination of immunohistochemistry and in situ hybridization showed that reactive T cells and endothelial cells express the IL-6 gene whereas CD30-positive ML cells do not express this gene. Previous studies showed that IL-6 was capable to induce IL-2 receptor expression as well as production of IL-2 and stimulation of lymphomatous cells growth. Our present results indicate that the paracrine production of this cytokine may play a role in the proliferation of malignant lymphomas.


Homer Smith Award. Cellular mechanisms in proximal tubular Pi reabsorption: some answers and more questions. Inorganic phosphate (Pi) is reabsorbed mainly in the proximal tubule, by a second active Na-dependent transport mechanism. Na/Pi cotransport with a stoichiometry exceeding unity mediates uphill flux across the brush border membrane; at the basolateral cell surface, two separate transport systems are involved in equilibrating Pi fluxes. The protein structure of a rabbit renal cortex Na/Pi cotransport system has been identified recently by expression cloning. The regulation of tubular Pi reabsorption involves mainly alterations in the transport rate of the brush border membrane Na/Pi cotransport system. The regulation of this transport step by either parathyroid hormone (PTH) or Pi deprivation is discussed, mostly on the basis of observations made with a tissue culture model, OK cells derived from opossum kidney. In this model, PTH may use a dual signaling cascade to inhibit apical Na/Pi cotransport (phospholipase C/protein kinase C and adenylate cyclase/protein kinase A). PTH action on Na/Pi cotransport may involve an endocytosis mechanism. For the regulation of apical Na/Pi cotransport by chronic Pi deprivation, the number of "Na/Pi cotransporter" molecules seems to be unaffected; the increased transport rate is apparently related to an "unknown" stimulating event at the membrane level (e.g., a change in the lipid microenvironment), which itself is under the control of protein synthesis/degradation. The availability of new tools (cloning of Na/Pi cotransporter(s) and of PTH receptor(s)) will allow us to enter into a new era in the study of cellular mechanisms involved in proximal tubular Pi reabsorption.


Did Mozart die of kidney disease? A review from the bicentennial of his death. There has been a tremendous interest in the circumstances of Mozart's death. Theories of head trauma, poisoning, heart disease, and most prominently, renal failure have all appeared recently in scholarly musicology publications, the lay press, and the medical literature. The purpose of this article is to present the evidence behind each of these theories. Although this review cannot be considered comprehensive, with the overview provided, it will be shown that few conclusions can be drawn.


Experimental tests of three-dimensional model of urinary concentrating mechanism. Recently, a new model of the urinary concentrating process has been proposed that takes into account the three-dimensional architecture of the renal medulla. Under the assumptions of the model, computer simulations predicted significant axial osmolality gradients in the inner medulla without active transport by the inner medullary loop of Henle. Two of the model assumptions (which constitute hypotheses for this study) were: (1) the osmotic water permeability of the initial part of the inner medullary collecting duct (initial IMCD) is very low even in the presence of vasopressin; and (2) there is significant lateral separation of structures such that thin descending limbs are far from the collecting ducts at the same inner medullary level. The first hypothesis was addressed by perfusing rat initial IMCD segments in vitro and measuring osmotic water permeability. With the osmotic gradient oriented as predicted by the model (lumen greater than bath), vasopressin increased the osmotic water permeability from 286 to 852 microns/s. Three additional series of experiments confirmed the high water permeability in the presence of vasopressin. The second hypothesis was addressed by morphometric analysis of histologic cross-sections of the rat renal medulla. Mean distances of descending limbs to the nearest adjacent collecting duct were very small throughout the inner medulla (less than 6 microns) and substantially less than in the outer medulla (28 microns). It was concluded that the data are inconsistent with both hypotheses and therefore do not support the feasibility of the "three-dimensional" model of the renal inner medulla. The axial distributions of loops of Henle and collecting ducts in the rat renal medulla are also reported.


Urinary concentrating ability in patients with Jk(a-b-) blood type who lack carrier-mediated urea transport. Water homeostasis is regulated in large part by the proper operation of the urinary concentrating mechanism. In the renal inner medulla, urea recycling from the inner medullary collecting duct to the inner medullary interstitium is thought to be essential for the production of a concentrated urine; however, it has not been possible to test this hypothesis in humans. Recently, a unique combination of genetic abnormalities has been described: absence of Kidd blood group antigens and absence of carrier-mediated urea transport in erythrocytes. Because animal studies indicate a similarity between urea transport in red blood cells and the nephron, it was postulated that patients without the Kidd antigen might lack facilitated urea transport in their kidneys. Hence, their ability to concentrate urine maximally was measured. Current models of nephron function would predict that in the complete absence of urea transport, the maximal concentrating ability would be around 800 to 900 mosM/kg H2O. Two homozygous patients had a moderate decrease in maximal concentrating ability (UosM,max = 819 mosM/kg H2O); a heterozygote also had some limitation. These studies raise the possibility that the erythrocyte urea transporter and the kidney urea transporter are encoded by a single gene (detected by the mutational loss of the Kidd antigen) and that a lack of facilitated urea transport impairs urea recycling in the kidney and, hence, maximal urinary concentrating ability.


Age-related changes in glomerular volume and hydroxyproline content in rat and human. Total 4-hydroxyproline content and volume were measured in the same sample of microdissected glomeruli obtained fro rat and human outer or inner cortex. Glomerular volume was determined by computer-assisted image analysis, and 4-hydroxyproline was measured by a highly sensitive gas-liquid chromatographic method. Results were expressed as weight of basement membrane material by comparison with the amount of 4-hydroxyproline in purified basement membrane/mesangial matrix preparations. Microanalyses were possible in samples containing as few as eight human glomeruli. Rat glomerular size increased sevenfold between 5 wk and 2 yr of age, with volume being consistently 36 to 45% greater in inner than in outer cortex glomeruli. Basement membrane material content per glomerulus markedly increased with age (12-fold); however, when expressed per unit volume, this change was greatly reduced (2-fold). Expressed per volume, inner and outer cortex glomerular content of basement membrane material was always similar, regardless of age. Therefore, a greater glomerular size, in itself, does not accelerate the rate of basement membrane material deposition. Glomerular size distributions (measured by skewness and kurtosis) did not change, indicating that, although glomerular volume increases with age, aging does not appear to cause the emergence of distinct glomerular populations within an age group. Basement membrane material accumulation is probably a generalized change. Human glomeruli increased sevenfold in size from infancy to adulthood and then declined during senescence. Contrary to that in the rat, glomerular basement membrane material content appeared to closely follow size changes, thus, varying little from infancy to senescence if expressed per unit of glomerular volume.


Altered synthesis and intracellular transport of proteoglycans by cyst-derived cells from human polycystic kidneys. Employing in vitro pulse-chase techniques, we investigated the de novo synthesis and the kinetics of intracellular transport and extracellular matrix incorporation of proteoglycans (PG) by normal human renal epithelial cell and by epithelial cells isolated from cysts of autosomal dominant kidneys (ADPKD). Cell monolayers were pulsed either with (3H)leucine for 15 min and chased for seven intervals between 15 and 270 min or with (35S)sulfate for 150 min and chased for a single interval of 120 min. Total proteins and PG were isolated from cell, media, and matrix fractions and characterized by Sepharose CL-6B and DEAE-Sephacel chromatographies. ADPKD and NK cells synthesized comparable amounts of total proteins; however, the de novo synthesis of PG by ADPKD cells was significantly reduced. ADPKD versus NK cells exhibited a substantial delay in the cellular transport and extracellular release of de novo synthesized PG, indicating an impairment at the level of the Golgi complex and/or secretory vacuoles. PG synthesized by ADPKD versus NK cells had decreased charge density characteristics, probably due to a posttranslational defect in the sulfation of the PG glycosaminoglycan chains. ADPKD versus NK cells synthesized PG of higher molecular weight and had an increased proportion of chondroitin sulfate PG versus heparan sulfate PG. Collectively, these findings suggest a defect in the synthesis and intracellular transport of sulfated PG in human ADPKD cells.


Renal transplantation in the first year of life: the treatment of choice for infants with end-stage renal disease. The treatment of choice for end-stage renal failure within the first year of life is controversial. Between September 1970 and February 1991, we performed 28 kidney transplants (27 primary, 1 retransplant, 23 living donor, 5 cadaver) in infants less than 1 yr of age (mean, 7 +/- 2 months; range, 6 wk to 12 months). The 1-yr patient survival rate for living donor recipients was 100% versus 20% for cadaver recipients (P = 0.0001). The 1-yr graft survival rate for living donor recipients was 96% versus 20% for cadaver recipients (P = 0.001). The 1-yr patient survival rate for cyclosporin A (CSA) recipients (N = 12) was 100% versus 75% for non-CSA recipients (P = 0.03). The 1-yr graft survival rate for CSA recipients was 92% versus 75% for non-CSA recipients (P = 0.08). There was no difference in the number of rejection episodes or serum creatinine levels in CSA versus non-CSA recipients. Compared with pretransplant values, the mean posttransplant standard deviation scores (SDS) for height (N = 18), weight (N = 22), and head circumference (N = 8) improved: height SDS from -1.9 to -1.5 (not significant); weight SDS from -2.5 to 0.6 (P less than 0.0005); head circumference SDS from -2.0 to -0.7 (P = 0.01). Because no other renal replacement therapy can match these results, we conclude that renal transplantation is the treatment of choice for infants with end-stage renal failure.


Does human lymphocyte antigen matching improve the outcome in pediatric renal transplants? Adult studies have shown a high renal graft survival if the donor and recipient match for each antigen of the human lymphocyte antigen (HLA)-A, B and DR loci (six-antigen match). The 4 yr of data from the North American Pediatric Renal Transplant Cooperative Study Registry show a statistically beneficial effect of DR matching for cadaver graft outcome. No antigen matching clearly has a worse outcome, 72% at 1 yr versus those with one or more antigen matching at each loci with a 1-yr graft survival of 81% and 2-yr graft survival of 69%. The long-term improved outcome from better antigen matching suggests that cadaver donor allograft organ assignment should address both the need of the center-driven and patient-driven concepts of recipient selection to achieve the best use of this scarce resource and an improved quality of life.


Hyperlipidemia and transplantation: etiologic factors and therapy. Hyperlipidemia is a well-recognized complication of renal transplantation. In long-term survivors of renal transplantation, cardiovascular disease accounts for the majority of patient deaths. In the cyclosporine era, cardiovascular disease has surpassed infection as the number one cause of death. Risk factors in the transplant population for hyperlipidemia include age, male sex, diabetes, prednisone dose, graft impairment, obesity, and antihypertensive therapy. Recently, cyclosporine has been implicated as an aggravating factor in the development of hyperlipidemia after transplantation, although its role has been controversial. Because renal transplant recipients have other significant risk factors for the development of coronary artery disease, the amelioration of hyperlipidemia may improve long-term patient survival. Because most late deaths occur in patients with a functioning graft, long-term graft survival could also be improved. The role of corticosteroids in the development of hyperlipidemia is well established. Recent studies employing corticosteroid withdrawal after transplantation have shown a marked reduction in cholesterol despite the use of cyclosporine. Data on corticosteroid withdrawal in living related transplants at our center show a significant reduction in total cholesterol after steroid withdrawal. Data from heart transplant recipients under corticosteroid-free protocols show a similar reduction in total cholesterol. Other treatments for hyperlipidemia include diet and cholesterol-lowering agents, such as Mevacor (lovastatin; Merck Sharp & Dohme, West Point, PA). The efficacy of lowering cholesterol in this high-risk population is unknown.


Cyclosporine and posttransplant hypertension. Prevalence studies suggest that hypertension is present in more than 50% of kidney transplant patients. It is more prevalent in pediatric patients, and cyclosporine has added to the rates in both children and adults. Hypertension is an important risk factor for cardiovascular disease, which remains the leading cause of death for recipients of renal transplants. Fortunately, posttransplant hypertension is commonly mild to moderate in nature (transplant artery stenosis hypertension being the exception) and can be treated medically. However, the removal of native kidneys and the correction of arterial stenosis are two surgical interventions that are more common in the transplant population than in the general population. In posttransplant hypertension that is primarily due to cyclosporine, one must balance the risks of reduced cyclosporine dosage against the risks of the hypertension. Both diuretic and calcium channel blocker therapy are believed to be useful in cyclosporine-induced hypertension. Other vasodilators also may be effective, although they may have undesired effects on RBF and glomerular filtration.


Long-term results of cyclosporin A therapy in children. In order to assess the long-term effectiveness and tolerability of cyclosporin A (CsA) treatment in children with renal transplantation (Tx), the follow-ups of 32 children (17 boys, 15 girls; age at Tx = 12.2 yr; range, 5.1 to 16.9) with a functioning graft of greater than or equal to 5 yr and continuous treatment with CsA and low-dose prednisolone are analyzed retrospectively. For comparison, data of 34 children (19 boys, 15 girls; age at Tx, 11.0; range, 3.2 to 17.1) are collected who had received a graft before the introduction of CsA, had at least 5 yr of graft function, and were continuously treated with azathioprine (AZA) plus high-dose prednisolone. The mean observation period in the CsA group was 6.5 (range, 5.0 to 8.0) yr, and in the AZA group was 10.4 yr (range, 5.7 to 15.8). CsA dosage remained unchanged in the range of 200 mg/m2/day; CsA whole blood trough level was 120 to 130 ng/mL throughout the years. One patient died in each group. Four more grafts were lost in the CsA group by chronic rejection, which was associated with noncompliance in three, and two grafts were lost in the AZA group by chronic rejection. Late acute reversible rejection episodes occurred more frequent in the CsA (six) than in the AZA group (two). The overall survival rates for patients and grafts were significantly better with CsA. The graft function in CsA-treated recipients was significantly lower than that in AZA patients, but there was no progressive loss over the years.(ABSTRACT TRUNCATED AT 250 WORDS)


Recurrence of primary renal disease on kidney graft: a European pediatric experience. Of the 4,776 first grafts recorded in the pediatric European Dialysis and Transplant Association (EDTA) registry, 2,113 were reported to have failed and 5.6% of graft failures were related to a recurrence of primary renal disease. Nephrotic syndrome with focal and segmental glomerulosclerosis was the main renal disease prone to recur because recurrence represented 20% of the causes of graft failure in these patients; an even higher proportion was reported in a single-center experience in Europe. Other glomerulonephropathies, such as membranoproliferative glomerulonephritis and Berger's disease, were also reported to be the cause of graft failure by means of recurrence in a proportion similar to focal and segmental glomerulosclerosis. The usual recurrence of primary oxaluria was the cause of close to 50% of graft failure in this disease. Finally, hemolytic uremic syndrome recurred rarely with the graft in the EDTA registry, which is the opposite of what was reported in the United States.


Recurrence of focal segmental glomerulosclerosis posttransplantation: a special report of the North American Pediatric Renal Transplant Cooperative Study. Among various forms of glomerulonephritis, focal segmental glomerulosclerosis (FSGS) is the most common cause of end-stage renal disease leading to transplantation in children. Previous reports of the recurrence of FSGS vary widely. The North American Pediatric Renal Transplant Cooperative Study carried out a special study to determine the rate of recurrence and risk factors leading to recurrence in 132 transplants. Fifty-five percent of the patients were white children, and the remaining were black and Hispanic children. Fifty percent of the patients were under 5 yr of age at the time of the diagnosis of FSGS. Twenty-seven (20.5%) of 132 patients (95% confidence interval, 14 to 27) had a biopsy-proven recurrence of FSGS. The median time to recurrence was 14 days. The recurrence rate was similar in white children (23%) when compared with that in Hispanic children (20%) but was lower than that in black children (9%) (3 of 32 children).2+ (20%). The mean serum albumin level of patients with recurrence was 1.7 versus 2.0 g/dL for those without recurrence. The mean serum cholesterol level of patients with recurrence was 525 versus 476 mg/dL for those without recurrence. The duration of dialysis was similar in the two groups. The mean time from diagnosis to end-stage renal disease status was 33 months for patients with recurrence and 52 months for those without recurrence (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)


Opportunistic fungal and bacterial infection in the renal transplant recipient. The risk of opportunistic infection in the renal transplant recipient is determined by the interaction between two factors: the epidemiologic exposures the individual encounters within the community and the hospital and a complex function termed the net state of immunosuppression. There are two general categories of opportunistic fungal infection in this patient population: (1) disseminated primary or reactivation infection with one of the geographically restricted systemic mycoses (histoplasmosis, coccidioidomycosis, blastomycosis, and paracoccidioidomycosis) and (2) opportunistic infection with fungal species that rarely cause invasive infection in the normal host (Aspergillus species, Candida species, Cryptococcus neoformans, and the Mucoraceae), with these last usually being acquired within the hospital environment. Newly available azole compounds, fluconazole and itraconazole, are exciting new alternatives to amphotericin in the treatment of at least some of these infections. The three most important forms of opportunistic bacterial infections are those due to Listeria monocytogenes, Nocardia asteroides, and a variety of mycobacterial species. Clinical diseases with these first two are effectively prevented by low-dose trimethoprim-sulfamethoxazole prophylaxis. There are two cardinal therapeutic rules to be followed by clinicians in dealing with these infections: prevention is better than treatment; when treatment is required, however, the major determinant of the success of therapy is the rapidity with which the diagnosis is made and effective therapy is initiated.


Extended recombinant human growth hormone treatment after renal transplantation in children. Recombinant human growth hormone (rhGH) was administered to 13 pediatric renal allograft recipients, ages 7.6 to 17.7 yr, who were 14 to 92 months posttransplant and growth retarded as manifested by either a standard deviation (SD) more negative than -2.00 or a height velocity index of less than 25%. The rhGH was given either daily or thrice weekly (0.375 mg/kg/wk) for a period of 12 to 36 months. Growth velocity increased from 2.7 +/- 2.1 SD for the 12-month period before the initiation of treatment of 6.3 +/- 2.9 SD (P less than 0.00005) and 5.2 +/- 2.9 SD (P less than 0.02) after 12 and 24 months of treatment, respectively. Although individual recipients had improvement in their SD scores, the mean values did not increase despite the increased growth velocity. Except for a 0.5-yr increase over 24 months in two recipients, the bone age did not increase at a rate greater than the increase in chronologic age. Four rejection episodes occurred in two recipients during rhGH treatment--an incidence not greater than that which occurred during a comparable time interval before the initiation of treatment. The calculated creatinine clearance declined from 66 +/- 26 SD mL/min/1.73 m2 at the initiation of treatment to 55 +/- 30 SD mL/min/1.73 m2 at 24 months and 52 +/- 28 SD mL/min/1.73 m2 (P = not significant).(ABSTRACT TRUNCATED AT 250 WORDS)


Growth hormone in renal transplantation--the mode of action, animal studies, and clinical use. During circulation, growth hormone (GH) is bound to about 50% by the high-affinity, low-capacity GH-binding protein (BP). GHBP represents the extracellular binding domain of the GH receptor and modulates the action of GH. After binding to its receptor, GH induces the local production of insulin-like growth factor 1 (IGF-1) by autocrine and paracrine mechanisms. In uremia, the plasma GH-binding activity is low and does not get up-regulated by recombinant human GH treatment, which is in contrast to the experience in short, normal children. There is evidence that hepatic IGF-1 production is low, whereas the serum concentration of IGF-binding protein 3 (IGF-BP3) and other IGFBPs is increased because of the reduced renal clearance of the low-molecular-weight fragment of IGF-BP. This result in the reduced bioavailability of free IGF-1 and reduced IGF bioactivity. There is a strong interaction between GH and corticosteroids. Corticosteroids suppress growth by reducing the food efficiency ratio (weight gain per food intake), reduce pituitary GH secretion, and decrease the local production of and cell responsiveness for IGF-1. The growth-depressing and catabolic effects of corticosteroids can be counterbalanced dose dependently by recombinant human GH in animal experiments, and growth can be improved in corticosteroid-treated renal allograft recipients with and without normal renal function. It is not clear at this time to what extent GH may induce acute or chronic rejection crises.


Factors affecting growth after renal transplantation. Renal transplantation has been recognized as the treatment of choice for children with chronic renal failure principally because it can normalize their physiologic status and thus provide them with the potential for normal growth. The results of renal transplantation, however, have been mixed with some reports of excellent posttransplant growth and others with less optimistic results. Some of the differences among these studies may be because of the use of multiple methods to assess the success or failure of posttransplant growth. The usual methods have included assessment of the final adult height, growth velocity, presence of accelerated growth rates, change in height standard deviation scores, and growth survival. All of these methods have advantages and disadvantages in the description of the success or failure of growth after renal transplantation, but no single method stands out as the most appropriate to use in all circumstances. Furthermore, growth is dependent on a large number of complex and interrelated factors. At least four of these factors have been shown to affect the growth rates of children after renal transplantation: age at the time of transplant; allograft function; the type, dose, and schedule of immunosuppressive medication; and other endocrinologic factors. Finally, analysis of long-term growth patterns in children after renal transplantation has shown that growth rates frequently decrease over time. Even children who have grown well immediately after the transplant may develop growth failure after several years. We conclude that the majority of children with renal transplants can experience normal or even accelerated growth rates after the procedure. Unfortunately, growth rates subsequently tend to decline in most children.(ABSTRACT TRUNCATED AT 250 WORDS)


Sequential therapy in pediatric cadaveric renal transplantation: a critical analysis. Cadaveric renal transplant survival rates in children are still somewhat inferior to those reported in adults. Sequential therapy, an immunosuppressive program in which a course of antilymphocyte preparation is used immediately postoperatively and followed in sequence by oral maintenance immunosuppression, has a number of features that might be expected to improve pediatric transplant outcome by addressing some of the metabolic and immunologic difficulties encountered in children. This article examines the rationale for sequential therapy in pediatric renal transplantation. It also examines the use of sequential therapy in children. Sequential therapy appears to significantly improve cadaver renal allograft outcome in children without compromising patient survival. There was a slight improvement in 1- and 2-yr graft outcomes when OKT3 was used prophylactically when compared with antithymocyte globulin, but this difference did not reach statistical significance. Almost 60% of patients receiving OKT3 for sequential therapy remained free of rejection. Major drawbacks of sequential therapy include the adverse side effects of the antilymphocyte preparation, infection, and the possibility of lymphoproliferative syndrome. The implications of these problems as well as potential strategies for ameliorating them are discussed.


The effect of the extended (3-year) anesthesia curriculum on anesthesia subspecialty education. The purpose of this study was to determine the effect of lengthening the anesthesia residency by the American Board of Anesthesiology on the education of anesthesia subspecialists. A survey of anesthesia residency programs was conducted from 1987 to 1991. The most frequent subspecialty practice in the clinical anesthesia (CA) 3 year is cardiovascular anesthesia. However, the percentage of CA3 residents spending extended time (greater than or equal to 6 months) in subspecialty education has significantly decreased. For example, the percentage of CA3 residents spending 12 months in subspecialty education has decreased 83%. There appears to be a slight increase in the number of CA4 or PGY5 residents (fellows) electing subspecialty practice. It is concluded that the 3-year curriculum has produced a negative impact on the education of anesthesia subspecialists.


Resident clinical competence in cardiac anesthesia: a case performance-based evaluation study. The purpose of this study was to estimate the minimum number of cases that anesthesiology residents need to complete in order to master the clinical skills required in cardiac anesthesia. In addition, the extent to which the resident's general anesthesia experience and in-training examination scores influence clinical performance was also studied. The data presented were based on observation of 99 actual cases, which were managed by 16 residents. A performance-based evaluation approach was developed, encompassing nine clinical performance skills considered essential to effective and safe cardiac anesthesia management. It was determined that there was consistent improvement in every clinical skill with the number of cardiac cases managed, except for preanesthetic assessment. The minimum number of cardiac cases that residents needed to manage before achieving a satisfactory level of skill ranged from about 10 cases for preoperative assessment to 20 to 30 cases for hemodynamic and coagulation management. It is concluded that residents needed different lengths of time to develop different skills, and it is logical to look at each basic skill independently in the evaluation of resident progress. Based on the findings of this study, it is suggested that a case performance-based evaluation approach might provide a more objective and accurate means for assessing resident progress in cardiac anesthesia.


The relationship among bronchial blocker cuff inflation volume, proximal airway pressure, and seal of the bronchial blocker cuff. The resting volume and diameter of the bronchial blocker cuff (defined as inflation of the cuff to just its natural shape) of the Univent (Fuji Systems Corp, Tokyo, Japan) tube are 2 mL and 5 mm. However, much larger inflation volumes may be required to seal an adult mainstem bronchus and the surface area of contact between the resultant spherical or ellipsoid-shaped cuff and the wall of the mainstem bronchus may be small and susceptible to leak with the application of high proximal airway pressures. This experiment determined the relationship among airway diameter, proximal airway pressure, inflation volume of the bronchial blocker cuff, and leakage of air around the bronchial blocker cuff in an in vitro model. The experimental model consisted of silicon tubing of 12.8-, 16.0-, and 19.2-mm ID as the mainstem bronchus. The main tracheal cuff sealed the Univent tube into the proximal end of the mainstem bronchus and the bronchial blocker cuff was inflated with various volumes near the distal end of the mainstem bronchus. The space between the tracheal cuff and the bronchial blocker cuff was then progressively pressurized in either a static or pulsed manner. The very distal end of the bronchus was functionally submerged under a beaker of water so that a bronchial blocker cuff leak would be indicated by bubbling. It was found that the Univent bronchial blocker cuff sealed the 12.8- and 16.0-mm ID mainstem bronchi against airway pressures as great as 100 cmH2O, with inflation volumes that were within the manufacturer's recommendation of 6 to 7 mL.(ABSTRACT TRUNCATED AT 250 WORDS)


Anesthesia for bilateral lung transplantation without cardiopulmonary bypass: initial experience and review of intraoperative problems. Bilateral lung transplantation (BLT) is a recently described procedure based on two sequential single-lung transplantations (SLT), which are performed by a transverse sternobithoracotomy. It does not require either cardiac arrest or routine use of cardiopulmonary bypass (CPB). The intraoperative management of 10 patients suffering from end-stage pulmonary disease is reported. Implantation of the first graft is quite similar to a SLT. Problems encountered during this procedure (ie, hypoxemia, hypercapnia, or low cardiac output) were due to restricted pulmonary and cardiac reserve. Preoperative and intraoperative assessment of the recipient's respiratory and cardiac status was, therefore, of prime importance. Mild preoperative pulmonary hypertension, well-preserved right ventricular function, and removal of the less well-perfused lung limited these difficulties; no patient required partial CPB at this stage. During the second lung implantation, gas exchange was provided by the first grafted lung. Measurements of pulmonary vascular resistance (PVR), venous admixture (Qva/Qt), and dead space (VD/VT) assessed with the arterial-to-end-tidal CO2 difference were used to confirm the adequacy of perfusion and V/Q matching. In one patient, partial CPB was instituted because of surgical difficulty related to inadequate size matching of the lungs. In the other patients, first graft function was satisfactory and the second graft was implanted without CPB. With chest closure, PVR returned to nearly normal values (range, 57-293, mean 167 dynes.s.cm-5) and Qva/Qt increased (range, 3 to 36, mean 20%). This limited series demonstrates that CPB is optional during this procedure. Good selection of recipients and donors, good lung preservation methods, and a short duration of cold ischemia are essential to success.


Hemodynamic effect of calcium channel blockade during anesthesia for coronary artery surgery. Because the choice of anesthetic technique does not influence the incidence of perioperative myocardial ischemia, reduction of ischemic risk may require specific antianginal therapy. Calcium entry blockers are effective drugs in antianginal therapy. Diltiazem reduces myocardial oxygen demand through decreases in heart rate, inotropy, and systolic function, while increasing myocardial oxygen delivery through coronary vasodilation. These potentially beneficial effects of diltiazem were evaluated in 15 of 29 patients (diltiazem v placebo, double-blind study) scheduled for coronary artery bypass graft surgery. Continuous infusion of diltiazem (0.15 mg/kg bolus followed by 2 micrograms/kg/min), during anesthesia and surgery before cardiopulmonary bypass, significantly reduced the major MVO2 determinants during anesthesia with moderate doses of fentanyl and a benzodiazepine (midazolam in 8 of 14 control patients and 9 of 15 treated patients, or flunitrazepam in the others). Heart rate, mean arterial pressure, and inotropy were decreased during the most stressful events of surgery when plasma diltiazem concentrations were in the therapeutic range (greater than 96 ng/mL). The number of patients with perioperative ischemia was 2 of 15 in the treated group and 4 of 14 in the control group. Provided that diltiazem plasma concentrations are sufficient, it can contribute to lowering the ischemic burden during anesthesia for coronary artery surgery.


Prognostic value of biventricular function in hypotensive patients after cardiac surgery as assessed by transesophageal echocardiography. In patients after cardiac surgery, hypotension, defined as a mean arterial pressure less than 65 mmHg despite adequate filling pressures and positive inotropic medication, poses a problem. In addition, it is often difficult to determine whether these patients have suffered irreversible myocardial injury or if they are likely to recover. In this study, left and right ventricular function, as assessed by transesophageal echocardiography (TEE), was related to mortality both (1) quantitatively, using fractional area change (FAC), and (2) qualitatively, using a segmental wall motion analysis, which assigned a score to myocardial wall segments, in order to determine whether this technique can be used to predict survival. Mortality rate was very high in patients with biventricular and especially right ventricular failure (FAC less than 35%). Left and right ventricular wall motion abnormality indices were significantly better in survivors compared to nonsurvivors, but no distinct cut-off value could be determined. A wall motion index derived from only 6 segments at the mid-papillary muscle level was found to be as reliable as one based on 16 segments of the entire left ventricle. Thus, TEE provided information about the degree of left and right ventricular dysfunction by using a single cross-section at the papillary muscle level. It identified patients at high risk of death, ie, those with compromised right and biventricular function.