High-affinity binding of [125I]RTI-55 to dopamine and serotonin transporters in rat brain. RTI-55 (3 beta-(4-iodophenyl)tropan-2 beta-carboxylic acid methyl ester), one of the most potent inhibitors of dopamine uptake reported to date, was radioiodinated and tested as a probe for the cocaine receptor in Sprague-Dawley rat brain. Saturation and kinetic studies in the striatum revealed that [125I]RTI-55 bound to both a high- and low-affinity site. The Kd for the high-affinity site was 0.2 nM, while the Kd for the low-affinity site was 5.8 nM. The corresponding number of binding sites in the striatum was 37 and 415 pmol/g protein. The pharmacological profile of specific [125I]RTI-55 binding in the striatum was consistent with that of the dopamine transporter. Additionally, [125I]RTI-55 was found to bind with high affinity to the cerebral cortex. Scatchard analysis revealed a single high-affinity component of 0.2 nM with a density of 2.5 pmol/g protein. The pharmacological profile demonstrated by [125I]RTI-55 in the cerebral cortex matched that of the serotonin transporter. Autoradiographic analysis of sagittal brain sections with [125I]RTI-55 binding was consistent with these findings. Specific binding of [125I]RTI-55 was blocked by dopamine uptake inhibitors in areas rich in dopaminergic nerve terminals. Conversely, serotonin uptake inhibitors blocked the binding of [125I]RTI-55 in brain areas rich in serotonergic neurons. These results demonstrate that [125I]RTI-55 may be a very useful ligand for the dopamine and serotonin transporters.


In vivo binding of [125I]RTI-55 to dopamine transporters: pharmacology and regional distribution with autoradiography. Previous studies have demonstrated that para-substituted WIN 35,065-2 analogs of cocaine show high binding affinity for dopamine uptake sites both in vitro and in vivo, and inhibit DA uptake in vitro. These analogs also produce potent cocaine-like behavioral effects in various procedures. The purpose of the present studies was to evaluate the iodinated WIN 35,065-2 analog [125I]RTI-55 as an in vivo ligand for the DA transporter. Following intravenous injection in mice, [125I]RTI-55 showed highest accumulation in areas with high densities of dopamine uptake sites. Light microscopic autoradiography was used to examine binding with higher resolution. Displacement studies demonstrated that [125I]RTI-55 binding in dopamine containing regions, striatum and olfactory tubercles, was saturable and inhibited by other cocaine analogs. GBR 12909 and WIN 35,428 significantly inhibited [125I]RTI-55 binding in striatum, while paroxetine significantly inhibited hypothalamic binding but had little effect in striatum. The latter finding suggests that [125I]RTI-55 also binds to the serotonin transporter. Haloperidol had no effect on [125I]RTI-55 binding in any brain region measured. In addition, treatment of animals with the dopamine neurotoxin MPTP caused significant reductions in striatal [125I]RTI-55 binding. The results of these studies indicate that [125I]RTI-55 binds primarily to the dopamine transporter in the mouse striatum in vivo.


Quantitation of carbon-11-labeled raclopride in rat striatum using positron emission tomography. Using conventional autoradiographic and tissue counting techniques, the experimental quantitation of in vivo kinetics of prospective or established radioligands for PET is animal and labour intensive. The present study tested the feasibility of using PET itself to quantitate the specific binding of [11C]raclopride to rat striatum and to study the effects of experimental manipulation of endogenous dopamine on binding parameters. Carbon-11-labeled raclopride was given i.v. to anaesthetised rats, positioned in a PET camera and dynamic emission scans acquired over 60 min. Time-activity curves were generated for selected regions of interest, representing striatum and cerebellum and the striatal data fitted to a compartmental model, using cerebellum as the input function, thus circumventing the need for individual metabolite-corrected plasma curves. In control rats, the binding potential (BP), defined as the ratio of the rate constants for transfer from "free to bound" and "bound to free" compartments, was of the order of 0.6. This was reduced threefold by predosing with nonradioactive raclopride. Increasing extracellular dopamine levels by predosing with d-amphetamine resulted in a significant decrease in BP whereas reducing extracellular dopamine by predosing with gamma-butyrolactone caused a significant increase. Thus, despite the limitation in spatial resolution of PET, specific binding of raclopride could be assessed from regional time-activity curves from individual rats. The system was sufficiently sensitive that changes in BP could be detected following modulation of endogenous dopamine levels, a finding of potential relevance to the interpretation of clinical PET data.


[Allergy and other skin reactions as a result of rubber gloves]. Protective latex surgical gloves and examination gloves may cause allergic contact dermatitis, mainly due to rubber chemicals used in the manufacturing process. Latex proteins in the gloves may cause contact urticaria and even anaphylactoid reactions. Eighty-eight dentists and other members of the dental team were tested for contact allergy to thiuram- and mercapto-derivatives, and for contact-urticaria to latex proteins. All but 5 persons used gloves at least periodically. Fifty-one of 87 of the persons who answered a questionnaire had or had had symptoms from the skin on the hands, but in only 3 cases could allergy to the gloves be proved. Women had more often symptoms than men, and female dentists with symptoms used gloves more often and for longer periods than female dentists without symptoms. It can be concluded that redness of the skin, itching, vesicles and eczema are common symptoms reported in connection with use of gloves, but proved allergy to the gloves is rare. Most symptoms are supposed to be due to skin irritation from the gloves in addition to irritative exposure from handwashing and other chemical irritants in dental work. The nature of the irritative effect from gloves is only partly known and should be studied further.


[Permeability of protective gloves to (di)methacrylates in resinous dental materials]. Dentists may develop contact allergy induced by handling resinous dental materials. Vinyl and latex gloves may provide protection against the monomers of these materials during the time it takes for a monomer to permeate the glove. The passage times and rates of penetration of four commonly used (di)methacrylates, HEMA, TEGDMA, BISGMA and UEDMA for 11 protective gloves were measured. The passage time in vinyl gloves for HEMA and TEGDMA was about 2 min, and around 20 min for BISGMA and UEDMA. The rates of penetration of HEMA and TEGDMA in vinyl gloves were between 1 and 4 mumol.min-1.cm-2. The passage times of HEMA and TEGDMA through most of the latex and modified latex gloves were between 5 and 8 min and the rates of penetration between 0.5 and 1 mumol.min-1.cm-2. Latex and modified latex gloves provide protection against BISGMA and UEDMA in 80 min or more with one exception (Elastyrene), which burst after about 50 min in contact with the resins. Of the tested gloves Ansell, Neutralon, Mediglove and Biogel D provide protection against HEMA and TEGDMA for at least 5 min.


[Necrotizing sialometaplasia].

[Necrotizing sialometaplasia]. Necrotizing sialometaplasia is a benign, self-limiting disease that requires no treatment. It is often confused with malignancy, resulting in unnecessary, extensive surgery. Clinicians need to be aware of this lesion and include it in a differential diagnosis of ulcerated lesions, especially in the hard palate. Correct diagnosis depends upon histological diagnosis by a pathologist who is familiar with the characteristics of this disease. One case is presented and the total number in our department from 1985-1991 is summarized.


[Results after short- and long-term observations of bone transplantation to vertical, marginal bone defects]. The effect of autologue bone transplantation to 26 vertical, marginal bone defects has been investigated on a long-term scale ranging from 2 to 26 years. The operation technique included excision of gingival pocket epithelium, removal of granulation tissue, and cleansing of the root surface with scalers. The bone cavities were filled preferably with cancellous bone chips, usually from the patients' upper third molar region. After suturing, the area was covered with a wound paste for 12-14 days. Loosened teeth were splinted for at least 2 months. In 25 of 26 teeth (96%) a bone regeneration was observed radiographically. The maximum healing of 22 cases occurred 2-12 months (median 6 months) postoperatively (Table 1). The maximum healing was maintained for more than half of the teeth (56%) at the last control, median 16 years (range 2-26 years), and none of these teeth were extracted of periodontal causes. They might therefore be expected to function for still a long time. Eight teeth (32%) showed more or less recurrence when controlled 5 to 15 years (median 10 years) after operation and 6 of the 8 teeth with recurrence were extracted. Three teeth (12%) developed root resorption and were extracted 6, 10 and 14 years postoperatively. As most of the complications occurred after extended observation periods, this factor has to be taken into account when prognosis of periodontal treatment procedure is considered.


[Effect of irradiation with dental polymerized lamps on human Langerhans cells: a study made on human skin transplanted to nude mice]. Light polymerized composite resin materials are now widely used in dentistry. Most resins are polymerized by light sources which have a powerful emission of visible light and a small emission in the ultraviolet light A spectrum (UV-A 320-400 mm). Possible eye damage, induced by such light, has been investigated, but the effects on the oral mucosa, which is directly exposed to the light, have been examined in only one animal study. Langerhans cells (LC) are dendritic non-epithelial cells which form a network within stratified epithelia. LC have features of macrophages, functions as antigen-presenting cells, and play an important role in the immune system associated with skin and oral mucosa. Pilot studies on human skin transplanted to nude mice showed that radiation with small therapeutic doses from a dental light curing unit (DLU) having only a small fraction of UV-light can reduce or deplete the OKT6 surface marker of LC in human epithelium. Further investigation of the photobiologic mechanisms involved spectral analyses of the emmission from the lamps and construction of a suitable light source for establishing an action spectrum for LC in the UV-A range. The action spectrum for LC in the UV-A range was obtained by exposing human skin, grafted to nude mice, to monochromatic light with a band pass of 5-10 nm. Criterion for threshold doses was total depletion of LC, visualized by staining with known LC-markers, monoclonal antibodies OKT6, DAKO-Vimentin, DAKO-HLA-DR and DAKO-S-100. The action spectrum for LC consisted of a biphasic curve, with a non-linear, strong wave-length dependency.(ABSTRACT TRUNCATED AT 250 WORDS)


[A comparison of two methods for pre-operative radiographic examination in treatment with oral implants in the anterior mandibular area]. Insertion of osseointegrated implants in the anterior mandibular region for retaining a removable denture represents a treatment, which is cheap for the patient and surgically uncomplicated. Bone height measures from two radiographic examinations 1) panoramic radiographs and 2) lateral tangential views, were compared. Radiographs from 20 patients were analyzed. The vertical height of the mandible was measured in the midline as well as in the cuspid region on the panoramic radiographs and the tangential views ("maximum" bone heights). The mean maximum bone heights were higher on tangential views in both regions. On the tangential views the inclinations of the future implants were estimated and the part of the alveolar ridge having a width less than 5 mm, which is the minimum width for housing an implant, was compiled. The resulting height ("effective bone height") was calculated. In 10% of the cases the effective bone height was equal to the maximum height, and in 90% it was smaller. The over-estimation varied between 0 mm and 15.3 mm. It is concluded that panoramic radiographs are unreliable for evaluating bone height in planning insertion of oral implants in the anterior mandibular region. They give no information about form and width of the bone. Tangential views reveal the true morphology of the mandible as seen in a cross-section, and offer an opportunity for calculating the effective bone height at disposal for oral implants.


[Lymphangioma of the tongue: case report and review of the literature]. A case of lymphangioma in the tongue is discussed with special reference to diagnosis, treatment and prognosis. The patient is a boy, aged 13, with a congenital malformation in the right half of the tongue. The lesion was removed by surgery. Histologic examination showed lymphangioma. In cases of minor, localized lymphangiomas the clinical diagnosis may be difficult. A past history information of recurring swellings can be regarded as almost diagnostic. The treatment of choice is surgery, if necessary in several settings. Recurrences are often seen.


[Hemangioma of the maxilla].

[Hemangioma of the maxilla]. A patient with a cavernous hemangioma of the maxilla is presented. The tumor had caused resorption of the roots af adjacent teeth. After enucleation, the area healed without complications, and the pulpal tissues of the teeth remained vital.


Conjoined twins: theoretical embryologic basis. A theoretical basis for the embryology of conjoined twins was formulated from clinical experience with ten cases and extensive review of pertinent embryologic and clinical literature, including over 500 cases. Regarding the age old question of fusion or fission, it is concluded that there is no known embryologic process by which conjoined twins can be formed by fission but firm evidence to support fusion in all cases. Whether the fusion occurs between embryos on one embryonic disc or on two is of no consequence since they are all monovular. Intact ectoderm will not fuse to intact ectoderm, and all seven types of conjoined twins are explained by seven possible sites of union in the early embryo. One new term is proposed: parapagus, from the Greek para, meaning "side," combined with pagus, meaning "fixed"; this is the group formerly called dicephalus or diprosopos. These anterolaterally united parapagus twins must result from two nearly parallel notochords in close proximity; craniopagi and pygopagi from fusion at the cranial and caudal neuropores, respectively; cephalopagi and ischiopagi from union at the pharyngeal and cloacal membranes, respectively; thoracopagi from merging of the cardiac anlage; and omphalopagi from fusion of the umbilicus or of the edges of two embryonic discs in any area not including the above sites. Parasitic twins result from embryonic death of one twin, leaving various portions of the body vascularized by the surviving autosite. The rarity of cases (2) not easily explained by the above theories, and the nearly 6% of twins with two umbilical cords arising from the placenta would seem to support these conclusions. Should one wish to learn the methods of a conjurer, he might vainly watch the latter's customary repertoire, and, so long as everything went smoothly, might never obtain a clue to the mysterious performance, baffled by the precision of the manipulations and the complexity of the apparatus; if, however, a single error were made in any part or if a single deviation from the customary method should force the manipulator along an unaccustomed path, it would give the investigator an opportunity to obtain a part or the whole of the secret.(ABSTRACT TRUNCATED AT 400 WORDS)


Extraembryonic tissue changes induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin and 2,3,4,7,8-pentachlorodibenzofuran with a note on direction of maternal blood flow in the labyrinth of C57BL/6N mice. Histologic changes in extraembryonic and embryonic tissues induced by 3 or 6 micrograms 2,3,7,8-tetrachlorodibenzo-p-dioxin/kg (TCDD) or 80 micrograms 2,3,4,7,8-pentachlorodibenzofuran/kg/day (4-PeCDF) were studied 24 h after the last of four daily doses administered orally to C57BL/6N mice on days 10-13 of pregnancy. Both test compounds ruptured (1) the embryo-maternal vascular barrier in the labyrinth, which resulted in hemorrhage of embryonic blood into the maternal circulation, (2) the visceral yolk sac membrane with the embryonic blood from the vitelline vessels escaping into the uterine, exocelomic and amniotic cavities, and (3) the maternal vascular spaces of the placental periphery resulting in hemorrhages into the interconceptal space. The role of the hemorrhagic lesions in the induction of cleft palate and hydronephrosis by the two compounds remains to be investigated. The presence of embryonic nucleated erythroblasts that hemorrhaged into the maternal lacunar network allowed the identification of maternal venous channels in the placenta. It revealed that (1) the labyrinth could be tentatively divided into two caudocranially oriented zones, an arterial and a venous zone; (2) the maternal blood in the labyrinthine lacunae circulated from the arterial to the venous zone, somewhat parallel to the uterine axis; and (3) the largest maternal vessels in the center of the placenta hitherto named the "central maternal artery," was in fact, venous.


Axial skeletal malformations induced by acetazolamide in rabbits. In order to evaluate the teratogenic potential of acetazolamide in rabbits, three groups of 18 artificially inseminated females were treated orally with 50, 100, or 150 mg/kg/day of acetazolamide on days 6-18 of gestation. These doses induced maternal acidosis and electrolyte changes, consistent with those reported in rats and considered to be a result of carbonic anhydrase inhibition, as well as reductions in maternal body weight gain. At cesarean sections, average fetal body weights in the acetazolamide groups were dose-dependently decreased compared with controls. There were no effects of acetazolamide on embryonic survival or external morphology of live fetuses. In the fetal skeletal examination, thoracic and lumbar vertebral malformations occurred in 0.7%, 3.9%, and 6.1% of fetuses in the 50, 100, and 150 mg/kg/day groups, respectively, compared with none in the control group. In addition, missing vertebra was seen in a small number of fetuses in the 100 and 150 mg/kg/day groups. These axial skeletal malformations were, in some cases, associated with costal malformations. These results indicate that acetazolamide at maternotoxic doses can produce axial skeletal malformations in the rabbit.


Analysis of high dysmorphogenic activity of Ro 13-6307, a tetramethylated tetralin analog of retinoic acid. Certain synthetic retinoids differ widely from retinoic acid (RA) in teratogenic potency, being much more or much less effective than RA. It is assumed that the potency of a retinoid may depend on the nature of its interaction with cellular binding components (nuclear retinoic acid receptors or cytoplasmic binding proteins) and, as in the case of retinoids that are mammalian teratogens, on factors that determine its accessibility to the embryo. To investigate some of the factors that contribute to potency, we used a new synthetic retinoid Ro 13-6307 that differs in structure from RA in having an aromatic ring inserted in its side chain along with gem dimethyl modification of the natural cyclohexenyl ring. Pregnant ICR mice were given a single oral dose (0, 1, or 10 mg/kg) on day 11 of gestation, and the resultant teratogenic outcome was monitored on day 17. Direct effects on cell differentiation were obtained by exposing high density cultures of limb bud mesenchymal cells to a range of concentrations (0.3 ng/ml-3 micrograms/ml) of Ro 13-6307 and scoring for chondrogenic suppression. Concentrations reaching the embryo after maternal administration of Ro 13-6307 were measured by HPLC to quantify the analog for a period of 4 h after administration of the oral dose. We found that this retinoid was 40-fold as active as RA in both inducing teratogenesis and suppressing chondrogenesis, yet its concentration in the affected embryo was only a fraction of that achieved after an equivalent dose of RA was employed in a similar protocol.(ABSTRACT TRUNCATED AT 250 WORDS)


Trends in rates of multiple vascular disruption defects, Atlanta, 1968-1989: is there evidence of a cocaine teratogenic epidemic? Research suggests that, perhaps through mechanisms initiated by vasoconstriction and leading to vessel thrombosis or embolism, cocaine causes vascular disruption defects, and that frequent cocaine use during early pregnancy could disrupt multiple organ systems in the fetus. We hypothesized that if cocaine is an important cause of multiple vascular disruption defects, a rising prevalence of cocaine use by mothers during pregnancy should be accompanied by rising rates of these defects in their offspring. Using data from the Metropolitan Atlanta Congenital Defects Program, we identified all infants born in Atlanta from 1968 through 1989 who had nonsyndromic, provisional vascular disruption defects affecting more than one organ system: 61 infants (78%) had gastrointestinal and genitourinary defects, 7 (9%) had gastrointestinal and abdominal wall defects, 2 (3%) had gastrointestinal and limb reduction defects, 2 (3%) had limb reduction and abdominal wall defects, 2 (3%) had central nervous system and gastrointestinal defects, 2 (3%) had genitourinary and limb reduction defects, 1 (1%) had genitourinary and abdominal wall defects, and 1 (1%) had central nervous system and genitourinary defects. The prevalence of Atlanta infants with more than one vascular disruption defect is 0.13 per 1,000 live births. Chi-square analysis for trends showed no increase in prevalence during the study period. Our data are from one of the first population-based studies in which trends for defects potentially caused by maternal cocaine use are examined; the results of our study show no significant change in the prevalence of multiple vascular disruption defects over time.(ABSTRACT TRUNCATED AT 250 WORDS)


Growth and differentiation schedule of mouse embryos obtained from delayed matings. We previously showed that digit formation in mouse embryos from early morning mating seemed to progress faster than those from overnight mating. In this study, to confirm this phenomenon, we examine whether the embryos from normal (0 hr from ovulation to fertilization) and delayed matings (3, 6, or 9 hr from ovulation to fertilization) respond differently to some acute teratogens when they are treated at the same time point from mating. Five mg/kg of cytosine arabinoside (Ara-C) was given to pregnant mice intraperitoneally at 246, 249, or 252 hr (day of gestation (dg) 10) after mating. The patterns of Ara-C induced digit malformations in embryos from the delayed mating groups were those of more advanced stages, when compared with normal mating groups with the same time intervals from mating to Ara-C treatment. In other words, oocytes fertilized up to 9 hr after the presumed time of ovulation could grow similarly to those of normally fertilized oocytes. This catch-up phenomenon suggests that the ovulation clock should be used for the startpoint of the time scale of the growth and differentiation of embryos rather than fertilization clock.


Variation in development of rat embryos at the presomite period. Rat embryos at a single gestational time in the presomite period were studied for their variation in development and their fate after culture. They were explanted at 8 A.M. on day 9 of gestation from timed-pregnant Sprague-Dawley rats which were obtained by mating between 8 and 10 A.M. (plug day = day 0). In the first experiment, a total of 203 embryos from 20 litters were examined for their variation in development. Several dimensions of embryo/egg cylinder were measured and development of various embryonic/extraembryonic structures were assessed using a scoring system that we developed for the present study. Embryos were then divided into different stages of development based on their scores using the staging system that we developed previously. A large variation in developmental stage was demonstrated; the youngest embryo was at the early primitive streak stage with no signs of amniotic folds and the oldest one was at the late neural plate stage with a foregut pocket but without visible somites. No strong correlation was demonstrated between developmental stage and size of embryo/egg cylinder, nor between developmental stage and development of the proamniotic tube, ectoplacental cavity, or allantois. In the second experiment, embryos were explanted at the same time and those at different stages were cultured separately in rotating bottles and their outcomes were compared after 49 hours. The difference in mean somites number of embryos cultured from the mid primitive streak and late neural plate stages was 6.1. This difference corresponds to approximately 10 hours based on the known linear increase of somites number on day 11 of approximately 0.6 somites per hour. These results indicate a large variation in development of presomite period embryos supposedly of the same gestational age and suggest the importance of careful staging at the time of explantation if precision is needed for whole embryo culture experiments.


Increased postimplantation loss and malformations among the F2 progeny of male rats chronically treated with cyclophosphamide. Cyclophosphamide, administered to the male rat, produces increased pre- and postimplantation loss in the progeny as well as an increase in the numbers of malformed and growth retarded fetuses. The purpose of this study was to determine whether the adverse effects of chronic paternal cyclophosphamide exposure are transmissible to the next generation, the F2 progeny. Adult male rats were treated by gavage daily with saline or with cyclophosphamide (3.4 or 5.1 mg/kg) for 4 or 18 weeks and mated. The male and female offspring in each treatment group (F1 generation) were randomly mated. The resulting pregnant females were killed on day 20 of gestation to evaluate progeny outcome in the F2 generation. There was a significant increase in postimplantation loss among the offspring of the group whose fathers had been treated with cyclophosphamide at a dose of 5.1 mg/kg/day. Exposure to a dose of 5.1 mg/kg/day of cyclophosphamide also resulted in an F2 generation with a significantly decreased mean fetal weight per litter and a significant increase in the number of malformed fetuses. The malformations observed among the F2 progeny included open eyes, omphalocele, generalized edema, syndactyly, gigantism, and dwarfism. Thus, exposure of the father to cyclophosphamide does result in a specific and heritable alteration in the fertility of the surviving "apparently normal" F1 progeny. Interestingly, the adverse consequences of exposure of male rats to cyclophosphamide are similar in the F2 generation to those previously reported for the F1 progeny.


Further genetic studies of the cause of exencephaly in SELH mice. We have developed an inbred stock of mice called SELH that has a high frequency of the neural tube defect exencephaly at birth. A previous genetic study indicated that the exencephaly is due to two to three additive loci differing between SELH and a closely related normal strain, ICR/Bc, but this analysis was not designed to detect genetic maternal effects. Recently, we demonstrated that there is genetic polymorphism among normal mouse strains leading to differences in site of initiation of closure of the cranial neural tube. In the present study, an inbred substrain of SELH mice, with 24% exencephaly among embryos, was crossed with an unrelated normal strain, SWV/Bc, and the frequency of exencephaly in subsequent generations used to extend our understanding of the genetic cause of exencephaly in SELH mice. The purposes of the genetic studies reported here were twofold. First, based on the influence of genetic maternal effects on other genetically complex birth defects in mice, we hypothesized that the exencephaly of SELH mice would exhibit strong genetic maternal effects. This hypothesis was tested by comparisons among the four possible reciprocal backcrosses to SELH. The result was an overall frequency of 2.3% exencephaly in first backcross embryos with no difference among the four crosses and no evidence of genetic maternal effects. Second, the frequency of exencephaly recovered in the backcross and F1 embryos was compared with the previous genetic study and with various genetic models. The frequencies were similar to those obtained from the cross to ICR/Bc mice and were compatible with a hypothesis of additive gene action at a few loci.(ABSTRACT TRUNCATED AT 250 WORDS)


Effect of ACE inhibition on the fetal kidney: decreased renal blood flow. The kidneys of nine fetuses whose mothers were chronically hypertensive were examined microscopically. Three of these mothers used antihypertensive agents throughout pregnancy including one who used an angiotensin-converting enzyme (ACE) inhibitor. The tubular defects found in these kidneys were compared to the kidneys of 20 normal controls, 13 fetuses with various multiple malformation syndromes and six cases of the twin to twin transfusion syndrome. Evidence from these cases as well as the literature suggest that the primary mechanism by which ACE inhibitors affect development of the fetal kidney is through decreased renal blood flow.


Pathogenesis of ethanol-induced limb reduction defects in mice. Acute administration of dosages of 2.5, 2.8, or 2.9 g/kg of ethanol to pregnant C57BL/6J mice on gestational day 9 1/4 resulted in major malformations of the forelimb including postaxial ectrodactyly, preaxial syndactyly, and reduction defects involving intermediate digits. The incidence and severity of these defects was positively correlated with dosage. Sidedness of the defects was also dose-dependent. In affected embryos, excessive amounts of cell death were notable within 5-9 hr of treatment initiation in selected cell populations. Cell death was primarily distributed in two regions of the developing limb bud--a ventrodistal ectodermal cell population (apical ectodermal ridge) and a proximal mesenchymal cell population. The patterns of cell death observed appear to be pathogenically related to the limb defects noted at later stages. In particular, it would appear that the deficiencies in the apical ectodermal ridge resulting from ethanol-induced cell death can account for virtually all the subsequent limb defects.


A decade of rabbit fertility data: study of historical control animals. Reproductive data for 1795 artificially inseminated Hra: (NZW)SPF control rabbits in 93 developmental toxicity studies conducted from 1980 through 1989 were summarized. Data were obtained during terminal Caesarean-sectioning procedures performed on animals which survived to day 29 of gestation and during postmortem evaluation of does which aborted, delivered prematurely, or were found dead. Significant seasonal variation was not observed. Average pregnancy rate, percentage of rabbits that aborted, and percentage of rabbits that delivered prematurely throughout the decade were 86, 2.0, and 1.6%, respectively. Average numbers of corpora lutea, implantations, live fetuses, dead fetuses, early resorptions, and late resorptions for each doe that survived to scheduled termination were 10.8, 7.8, 7.1, 0.02, 0.49, and 0.15, respectively. The various vehicles used, routes of administration, and a variety of maternal and paternal factors were compared with the fertility data, and no correlations were observed. Rabbits that aborted earlier in gestation had fewer implantations than does which aborted late or delivered prematurely. Does which resorbed 100% of their conceptuses had fewer corpora lutea and implantations when compared with rabbits in the remainder of the population. Rabbits pregnant at scheduled termination which had a low number of corpora lutea or implantation sites had higher than expected pre- and postimplantation losses relative to the population as a whole. Does with a high number of corpora lutea had significantly higher preimplantation loss relative to the general population. This may indicate the presence of a "ceiling value" for the number of ova that can become fertilized and/or implant when the ovulation rate is high and which probably varies according to strain as well as a number of factors related to the individual rabbit. Based upon the results of this study and the work of a previous author, a minimum of four corpora lutea may be necessary for the successful maintenance of pregnancy in the New Zealand white rabbit. The minimum number of corpora lutea required may be strain dependent and may bear a relationship to the normal litter size of the strain.


Serotonin as a regulator of craniofacial morphogenesis: site specific malformations following exposure to serotonin uptake inhibitors. During craniofacial development in the mouse embryo (days 9-12 of gestation; plug day = day 1), transient expression of serotonin (5-HT) uptake in epithelial structures of this region correlates with critical morphogenetic events (Lauder et al., '88; Shuey, '91; Shuey et al., '89, '92). The purpose of the present investigation was to assess the possible functional significance of these uptake sites by examination of patterns of dysmorphology following exposure of embryos to selective 5-HT uptake inhibitors. Exposure of mouse embryos in whole embryo culture to sertraline, at a concentration (10 microM) which produced no evidence of general embryotoxicity, caused craniofacial malformations consistent with direct action at 5-HT uptake sites. Two other 5-HT uptake inhibitors, fluoxetine and amitriptyline, produced similar defects. The critical period of sertraline exposure occurred on days 10-11. The observed craniofacial defects were associated with decreased proliferation and extensive cell death in mesenchyme located 5-6 cell layers deep from the overlying epithelium. In contrast, the subepithelial mesenchymal layers showed normal or elevated levels of proliferation. From these results it appears that inhibition of 5-HT uptake into craniofacial epithelia may produce developmental defects by interference with serotonergic regulation of epithelial-mesenchymal interactions important for normal craniofacial morphogenesis.


The warfarin embryopathy: a rat model showing maxillonasal hypoplasia and other skeletal disturbances. Sprague-Dawley rats were given daily subcutaneous doses of sodium warfarin (100 mg/kg) and vitamin K1 (10 mg/kg) for up to 12 weeks, starting on the day after birth. This dosing regimen creates an extrahepatic vitamin K deficiency while preserving the vitamin K-dependent processes of the liver. Control rats received either vitamin K1 only or were untreated. All rats survived without any signs of hemorrhage. The warfarin-treated rats developed a marked maxillonasal hypoplasia associated with a 11-13% reduction in the length of the nasal bones compared with controls. The length of the posterior part of the skull was not significantly different from controls. In the warfarin-treated rats, the septal cartilage of the nasal septum showed large areas of calcification, not present in controls, and abnormal calcium bridges in the epiphyseal cartilages of the vertebrae and long bones. The ectopic calcification in the septal cartilage may have been the cause of the reduced longitudinal growth of the nasal septum and the associated maxillonasal hypoplasia. It is proposed that (1) the facial features of the human warfarin embryopathy are caused by reduced growth of the embryonic nasal septum, and (2) the septal growth retardation occurs because the warfarin-induced extrahepatic vitamin K deficiency prevents the normal formation of the vitamin K-dependent matrix gla protein in the embryo.


The effects of continuous exposure to 20-kHz sawtooth magnetic fields on the litters of CD-1 mice. Mated CD-1 mice were exposed to 20-kHz sawtooth magnetic fields similar to those associated with video display terminals (VDT). Four groups of animals were continuously exposed from day 1 to day 18 of pregnancy to field strengths of 0, 3.6, 17, or 200 microT. There were no less than 185 mated dams in each exposure group. On day 18, the dams were sacrificed and assessed for weight gain and pregnancy. The litters were evaluated for numbers of implantations, fetal deaths and resorptions, gross external, visceral and skeletal malformations, and fetal weights. There were no less than 140 pregnant females in each group, and there were no significant differences between any of the exposure groups and the sham group (0 microT) for any of the end points. The results of this study do not support the hypothesis that the 20-kHz VLF magnetic fields associated with video display terminals are teratogenic in mammals.


Niche breadth in parasites: an evolutionarily stable strategy model, with special reference to the protozoan parasite Leishmania. A parasite's host range essentially defines its niche breadth, which, as foraging theory predicts, is influenced by resource availability. For parasites, the interaction of infection and transmission characteristics with host population dynamics determines host availability. An epidemiological model, involving two host types and describing competition between a "generalist" parasite strain and a related "specialist" strain, is used to examine the interplay among host range, relative host availabilities, and adaptational compromises engendered by increased host range. Results show that the generalist can predominate even when it cannot maintain itself in either host alone, but that the specialist can persist if its reproductive rate attains some threshold relative to either of the generalist's respective rates in its two hosts. The model is in rough, qualitative agreement with observed dynamics of two Leishmania parasite-host systems, and overall results suggest that infection of two species with a common parasite can lead to complex, indirect coevolutionary dynamics.


Of Nobel class: a citation perspective on high impact research authors. The purpose of this paper was to determine if quantitative rankings of highly cited research authors confirm Nobel prize awards. Six studies covering different time periods and author sample sizes were reviewed. The number of Nobel laureates at the time each study was published was tabulated, as was the number of high impact authors who later became laureates. The Nobelists and laureates-to-be were also compared with non-Nobelists to see if they differed in terms of impact and productivity. The results indicate that high rankings by citation frequency identify researchers of Nobel class--that is, a small set of authors that includes a high proportion of actual Nobelists and laureates-to-be. Also, the average impact (citations per author) of Nobelists and laureates-to-be is sufficiently high to distinguish them from non-Nobelists in these rankings. In conclusion, a simple, quantitative, and objective algorithm based on citation data can effectively corroborate--and even forecast--a complex, qualitative, and subjective selection process based on human judgement.


Arrhenius vs. Ehrlich on immunochemistry: decisions about scientific progress in the context of the Nobel Prize. This study forms part of a larger research project examining the election process for the Nobel prizes for Physiology or Medicine at the Karolinska Institute in Stockholm, and the role and function of the prizes in early 20th century Swedish and international medicine. The purpose of the study is to clarify the decision-making process which led to the Nobel prize for Paul Ehrlich in 1908, 'for work on immunity'. His award was preceded by the most dramatic conflict within the prize authority concerning any prizewinner prior to World War I, and thus is apt to illuminate both the implicit and explicit criteria and the strategies used in the prize deliberations. Ehrlich's chemical ideas on the immune response were criticized by the physical chemist Svante Arrhenius who recommended the application of his disciplines's methods and principles on immunological problems. This criticisms were brought into the Nobel prize debate by J.E. Johansson, a physiologist who asserted that Ehrlich's research was of little scientific value and therefore not worthy of a prize. Yet the majority of the Institute, led by its chairman, the chemist K.A.H. Mörner, succeeded in awarding Ehrlich. An analysis of the controversy shows it to be primarily based upon (1) a difference of scientific styles between the antagonists, resulting in incongruous definitions of immunology as a research field, and of the proper aims and methods of immunological studies. Other factors influencing the final decision were (2) the Institute's negative reaction to what was considered an intrusion in medical Nobel prize matters by a chemist, (3) Arrhenius' and Johansson's diverging views on what kind of work should be awarded a prize, and (4) Johansson's position as a non-conformist at the Karolinska.


Theory change in immunology. Part I: Extended theories and scientific progress. This two-part article examines the competition between the clonal selection theory and the instructive theory of the immune response from 1957-1967. In Part I the concept of a temporally 'extended theory' is introduced, which requires attention to the hitherto largely ignored issue of theory individuation. Factors which influence the acceptability of such an extended theory at different temporal points are also embedded in a Bayesian framework, which is shown to provide a rational account of belief change in science. In Part II these factors, as elaborated in the Bayesian framework, are applied to the case of the success of the clonal selection theory and the failure of the instructive theory.


Theory change in immunology. Part II: The clonal selection theory. This two-part article examines the competition between the clonal selection theory and the instructive theory of the immune response from 1957-1967. In Part I the concept of a temporally 'extended theory' is introduced, which requires attention to the hitherto largely ignored issue of theory individuation. Factors which influence the acceptability of such an extended theory at different temporal points are also embedded in a Bayesian framework, which is shown to provide a rational account of belief change in science. In Part II these factors, as elaborated in the Bayesian framework, are applied to the case of the success of the clonal selection theory and the failure of the instructive theory.


The proliferation of prizes: Nobel complements and Nobel surrogates in the reward system of science. In the last two decades, prizes in the sciences have proliferated and, in particular, rich prizes with large honoraria. These developments raise several questions: Why have rich prizes proliferated? Have they greatly changed the reward system of science? What effects will such prizes have on scientists and on science? The proliferation of such prizes derives from marked limitations on the numbers and types of scientists eligible for Nobel prizes and consequent increases in the number of uncrowned laureate-equivalents. These would-be surrogates for Nobel prizes extend the reward system of science in its upper reaches but this change is not fundamental. The spread of rich prizes to new fields provides added incentives to potential winners, which has its own disutilities; it reinforces competitiveness, concern for priority and attendant secrecy, all this amplifying ambivalence toward the reward system in science. There may also be modest positive effects of such new awards in the form of heightened popular esteem for science and interest in it.


[Basic considerations in the rehabilitation of foreign workers]. Rehabilitation involves executive duties, the patient must actively cooperate with the rehabilitation team, and both sides must set clear goals. In the case of rehabilitation of foreigners, it is difficult to set goals because of language and cultural differences. The rehabilitation clinic in Bellikon hospitalizes so many foreigners that it decided to comply with their demands by choosing a specific personnel. In fact, with the purpose of improving the basis for communication, the clinic employs therapists and nursing staff that come from other countries and cultures, offering them further vocational training, too. Not only should misunderstandings and feelings of frustration be avoided as far as possible, but interactive therapy should become the foundation stone for a successful treatment and rehabilitation. The conference on rehabilitation that was organized by the SAR in autumn 1991 made up a part of these efforts.


[Immigrants in Switzerland: possibilities and difficulties of integration]. Immigrants find it hard--although not all in the same way--to adapt to the language, the social structure and the way of life of their host country. Different factors overlap: the foreigners' social and cultural background, their education and their adaptability to a foreign environment, their plans for the future, the political and legal situation in the host country as well as the local population's acceptance of and tolerance and respect for a foreign culture. The fact that 75% of all foreigners in Switzerland possess a residence permit can be considered as rather positive; however, this does not necessarily mean that these people are familiar with the local language and way of life. Isolation and a continuously postponed return to the home country are conditions well known even among resident foreigners. Seasonal workers, on the other hand, feel great uncertainty and concern. In critical life situations, for instance caused by illness, accidents or unemployment, the process of rehabilitation can strongly be influenced by earlier living conditions. The Swiss legislation on foreigners as well as the legislation on social security can often bring about fundamental fateful questions. In order to find efficient solutions to the wide range of possible difficulties, a whole-hearted interdisciplinary cooperation is extremely important.


[Sinistrosis: cultural approach to understanding chronicity and its economic aspects]. Migration-related health problems can be acute and/or chronic. The chronization is a characteristic of sinistrosis, a multi-institutional phenomenon in which the patient-clinician relationship is trapped in a dead end. To unlock this situation, the author proposes an explorative methodology for case-history making that focuses on the economic aspect of sinistrosis.


[Prevalence and persistence of back pain in foreign workers: class or culture-induced?]. Physically working people are more likely to suffer from backache. Not only is their work hard and menial but usually also degrading. Unpleasant circumstances such as an offensive environment, the monotony of work, poor qualifications or unsatisfactory work generally influence the persistence of pain. The course of an illness such as a lingering backache, is hardly ever determined by somatic factors. A prognosis is rather based upon the attitude and behaviour of the single patient and his social surroundings, as well as upon the pathological process. Medication might even worsen rather than improve the patient's condition. The typical foreign worker, who generally merely has an elementary education and whom we therefore assign unqualified work, does not only risk to suffer from backache. His personal strength and his circumstances can seriously hinder his rehabilitation, more than it would be the case with native patients. The accumulation of negative factors is closely connected to his role of a foreign worker, whereas cultural aspects do not seem to be determining. Therefore, the foreign patient's rehabilitation can be fostered and improved by adopting the same methods used with Swiss patients against the chronicisation of backache. Nevertheless, the mentioned unfavourable factors and additional language problems considerably foil all efforts to a successful rehabilitation.


[Experiences in family therapy with immigrants]. By emigrating, the foreigner has to meet with various expectations and therefore stands under pressure. On one hand, his decision is closely linked to his wish for new achievements and prosperity--his relatives and friends attentively watch over him to make sure that he succeeds. On the other hand, the new environment requires him to adapt to new ways of thinking and behaving. His own values are neither followed anymore nor considered as general guideline through everyday life. In a relatively short time, therefore, the emigrant has to make the strenuous effort to change his views, even if it involves neglecting old family traditions. For the emigrant these demands are often too excessive, so that he becomes insecure and sceptical, finally desperately but subconsciously clinging to his traditional values. Furthermore, he might feel to be surrounded by enemies. All that makes the integration become sluggish if not impossible. Mechanisms of thought and behaviour such as these, are the starting point in family therapy with emigrants. The goal is to make the foreigner more aware of his life in emigration. The experience acquired in family therapy is certainly useful in the rehabilitation of foreign workers who have fallen victim to an accident or an illness.


[Rehabilitation of foreign workers: myths and reality]. In terms of chances for a successful professional reintegration of a worker who has fallen victim of an accident or an illness, there are no significant differences between Swiss workers and foreign workers. This viewpoint is based on a survey of limited representation. Two groups of 65 and 50 patients from the French speaking part of Switzerland were questioned. The results clearly warn against generalizations, prejudices and clichés. It is wrong to rashly judge a whole cultural or ethnic group only upon one negative experience made with a single person of that group. On the other hand, it is rather significant that the chances for a successful reintegration become smaller for Swiss and foreign workers, the longer it takes to introduce the necessary measures after the beginning of an illness or a handicap. The causes of chronification and interdependence between complex circumstances and conflict situations must be taken appropriately into account with interdisciplinary cooperation. If cases with serious problems can be singled out early, the risk of total disability of the patient can be avoided.


[Social counseling for immigrants--practical experiences exemplified by Portugese immigrants]. The basis for an adequate communication being insufficient, it is very hard to offer foreigners in difficult situations efficient advisory assistance and care. The reason is not only the difference in language but also the difference in culture. Not everything can be expressed properly with a literal translation. The statements must be interpreted in connection with the way of thinking and behaving as well as with the cultural, social and religious environment of those seeking advice. According to the Portuguese community as well as all other emigrants, intermediaries of their mother tongue and culture should stand in more frequently. This way, there would be a better chance of success for all people involved.


[Rehabilitation of foreign workers from the viewpoint of the foreign police authorities]. When speaking of rehabilitation of a foreign worker who has fallen victim to an accident or an illness, it is important to ask one fundamental question: Should he be reintegrated in the society of his host country or in his home country? The Swiss foreign police authorities play a decisive role in answering this question. Whether a residence permit should be granted, extended or denied depends on their considerations. For this purpose, all decisions taken by the cantonal authorities are based on particularly significant discretionary powers guaranteed by the Swiss legislation on foreigners. Numerous factors are determining for the evaluation of a case. Often, it is difficult to find the appropriate overview for circumstances, so that a sound and farsighted approach is essential, which-for its part-requires a constructive cooperation of all parties involved.


[Practical experiences in legal counseling of foreign workers]. When foreign workers ask for legal advice, very often their questions concern primarily insurance rights for disability. Most uncertainties exist about specific clauses in the legislation on disability insurance and about the measurings of disability. Primarily, discussions arise from controversy about claims made to the state disability insurance. The legislation on disability insurance establishes strict requirements for foreigners asking for insurance rights for disability. However, the Agreement on Social Security signed worldwide by over 20 nations being more tolerant in terms of disability insurance, Swiss legislation can be applied only to a minority of foreigners. That is why the system of legislation has become so complex. There are two major points that are rigidly to be observed: On one hand, the process of reintegration measures can start only if the prescribed minimum duration of contributions is guaranteed. On the other, proceedings for disability pensions can be initiated only after the currently valid waiting period. In both cases, it is considerably important that the patient has a domicile in Switzerland or a valid residence permit. Numerous disagreements can possibly result during the evaluation of the degree of disability, as certain factors-such as language problems, lack of education or the labour market situation-, which are not directly linked to the disability, are not taken into consideration.


Endoscopy assisted microthoracotomy: initial experience. Although thoracoscopy has been used for diagnostic and minor therapeutic procedures for many years, there have been few reports of its use in performing major intrathoracic procedures, which have traditionally required formal thoracotomy. Twenty one patients (M:F 1.2:1; mean (SD) age 47.1 (18.8), range 17-75 years) underwent endoscopic intrathoracic surgery. Eight had unidentified peripheral masses on the chest radiograph, eight required lung biopsy, and five had recurrent or persisting pneumothoraces. Under general anaesthesia a laparoscope attached to a video monitor was introduced into the chest. One or two additional stab incisions were made as needed for the introduction of standard surgical or endoscopic instruments and staplers. There were no complications or deaths, though one patient developed a second pneumothorax seven days after endoscopic pleurectomy, necessitating open pleurodesis. All patients were discharged home from two to six days after surgery (mean (SD) 3.7 (1.2) days). Endoscopic thoracic surgery is a safe and useful technique for certain cases. It merits further investigation and assessment.


Clinicopathological correlations in cor pulmonale. The relation between pulmonary disease and physiological abnormality in patients with hypoxic cor pulmonale is controversial and the association between arterial hypoxaemia and right ventricular hypertrophy has been challenged. To address these problems matched patients treated with and without domiciliary oxygen were studied. Necropsy data were obtained on 19 patients (14 male), 10 of whom had been treated with domiciliary oxygen. Pulmonary artery pressure and total pulmonary vascular resistance as well as blood gas tensions during the breathing of air and oxygen were available for the six months before death. Formalin fixed lung slices were assessed for panacinar and centriacinar emphysema. Right and left ventricular weights were measured and their ratio (LV&S/RV) was used as an index of right ventricular hypertrophy. Carotid body weights were available in 14 cases. Fourteen patients died of respiratory failure and antemortem thrombus was found in the pulmonary arteries of eight cases. Physiological measurements were unrelated to the degree of macroscopic emphysema, pulmonary hypertension, or daytime blood gas tensions. When allowance was made for the higher "ambient" arterial oxygen tension (PaO2) of those who had oxygen, PaO2 was correlated with LV&S/RV (r = 0.79), absolute right ventricular weight (r = -0.53), and carotid body weight (r = 0.68). These data show that in hypoxic cor pulmonale in vivo physiological disturbances are poor indicators of the underlying disease process. The relation of "ambient" PaO2 to right ventricular hypertrophy and carotid body weight suggests that domiciliary oxygen therapy might lead to regression of such established disease.


The site of disruption of the bronchial epithelium in asthmatic and non-asthmatic subjects. Attention has recently been focused on the basal cells of the tracheobronchial epithelium as the mechanism of anchorage of the tall columnar cells, which themselves do not appear to form hemidesmosomes with the basement membrane of the epithelium. Residual basal cells have been described as remaining attached to the basement membrane after epithelial denudation. This led this group to formulate the hypothesis that there may be a potential plane of cleavage between the basal cells and the overlying columnar cell layer within the bronchial epithelium, which becomes disrupted in asthma. Bronchoalveolar lavage samples were obtained during bronchoscopy from eight patients with atopic asthma and four normal controls. Ultrathin sections of lavage cell pellets were examined by electron microscopy and the number of columnar and basal cells found in each epithelial cell cluster was counted. Cytocentrifuge preparations of the lavage samples from the same subjects were also examined for free epithelial cells and epithelial cell clusters. Electron microscopic examination of the cell pellets showed that basal cells were present in very small numbers in the epithelial clusters in all subjects (mean 0.03 (SE 0.02)/cluster) and the ratio of columnar cells to basal cells was far greater than was encountered in the intact bronchial epithelium (167 nu 4). The cytocentrifuge preparations showed an increased number of epithelial cell clusters and epithelial cells in the asthmatic patients. Although these clusters were similar in size in the two groups of subjects (6.3 nu 5.1 cells/cluster) the ratio of free epithelial cells to cells within the cluster was higher in the non-asthmatic subjects. It is proposed that shedding of epithelial cells occurs along a suprabasal plane and that there is a potential plane of cleavage between the suprabasal and the basal cell layers, which might be more vulnerable to the various insults.


Quantitative morphology and water distribution of bronchial biopsy samples. An approach to the study of the pharmacokinetics of drugs in the lung is to measure their concentrations in bronchial biopsy specimens. The main criticism of this technique is that bronchial biopsy specimens consist of more than one tissue type and that drugs are often not distributed evenly. The morphology of bronchial biopsy specimens and the distribution of water between the extracellular and the intracellular compartments is therefore important. Fifteen subjects undergoing fibreoptic bronchoscopy each had four bronchial biopsy samples taken. Thirty sections from 10 patients were examined and the proportion of tissue types noted, a morphometric analysis computer being used. The water distribution was investigated in the other biopsy specimens with radiolabelled markers. There was pronounced variation in the relative proportions of tissue types. Ciliated epithelium occupied a mean of 22.3% of the biopsy sample, submucosa 53.4%, muscle 17.6%, and glandular tissue 7.0%. There were no differences between second and the fourth generation subcarinae and macroscopic normality of the mucosa was a good predictor of histological normality. The extracellular water content was 40% of the total weight of the specimen and the total water content was 70%. These data provide the basis for pharmacokinetic study of drugs in bronchial mucosa. They show for pharmacokinetic study that macroscopically normal mucosa may be assumed to be histologically normal; that multiple biopsy specimens should be taken for any study, as there is considerable variation in the proportion of tissue types; that specimens from second and fourth generation subcarinae are the same; and that extracellular water contributes 40% to the total weight of the biopsy specimen.


Lymphocyte and lymphocyte subset numbers in blood and in bronchoalveolar lavage and pleural fluid in various forms of human pulmonary tuberculosis at presentation and during recovery. Lymphocytes have a central role in human defences against mycobacteria. A study was designed to assess the relation between lymphocyte responses and clinical pattern of disease, nutrition and recovery during treatment in patients with tuberculosis. Lymphocyte numbers and subsets (on the basis of CD3, CD4, and CD8 monoclonal antibodies) were measured in peripheral blood and, where appropriate, bronchoalveolar lavage or pleural fluid of patients with different forms of pulmonary tuberculosis. Eleven had localised pulmonary tuberculosis, 18 miliary tuberculosis and seven a tuberculous pleural effusion. CD4 lymphocytes were found in greatly increased numbers in pleural fluid and were relatively depleted in the blood. Lymphocyte numbers in bronchoalveolar lavage fluid varied widely in localised pulmonary and miliary tuberculosis but were highest in lavage fluid from patients with miliary tuberculosis. This was due to an increase in CD8 lymphocytes, which were also increased in the blood. Lymphocyte numbers bore no relation to nutrition, symptom duration, or radiographic profusion scores. In miliary tuberculosis the time taken for the chest radiograph to clear (mean (SD) 17.6 (7.8) weeks) correlated with lymphocyte numbers in lavage fluid, especially CD8 cells (r = 0.74), but not with the patients' age or nutrition. After 8 weeks' treatment, total and CD4 lymphocyte numbers in lavage fluid showed a substantial increase. The association of CD8 cells with delayed recovery is compatible with suppression of the antimycobacterial action of macrophages. The switch to predominance of CD4 cells in lavage fluid during successful treatment supports the view that they may have a role in eliminating mycobacteria.


Predictive equations for total lung capacity and residual volume calculated from radiographs in a random sample of the Michigan population. Published predicted values for total lung capacity and residual volume are often based on a small number of subjects and derive from different populations from predicted spirometric values. Equations from the only two large studies gave smaller predicted values for total lung capacity than the smaller studies. A large number of subjects have been studied from a population which has already provided predicted values for spirometry and transfer factor for carbon monoxide. Total lung capacity was measured from standard posteroanterior and lateral chest radiographs and forced vital capacity by spirometry in a population sample of 771 subjects. Prediction equations were developed for total lung capacity (TLC), residual volume (RV) and RV/TLC in two groups--normal and total. Subjects with signs or symptoms of cardiopulmonary disease were combined with the normal subjects and equations for all subjects were also modelled. Prediction equations for TLC and RV in non-smoking normal men and women were square root transformations which included height and weight but not age. They included a coefficient for duration of smoking in current smokers. The predictive equation for RV/TLC included weight, age, age and duration of smoking for current smokers and ex-smokers of both sexes. For the total population the equations took the same form but the height coefficients and constants were slightly different. These population based prediction equations for TLC, RV and RV/TLC provide reference standards in a population that has provided reference standards for spirometry and single breath transfer factor for carbon monoxide.


Effects of posture on flow-volume curves during normocapnia and hypercapnia in patients with obstructive sleep apnoea. A high ratio of forced expiratory to forced inspiratory maximal flow at 50% of vital capacity (FEF50/FIF50) may identify upper airway dysfunction. Since hypercapnia increases the motor activity of airway dilating muscles its effects on the maximum expiratory and inspiratory flow-volume curves (MEIFV) in patients with obstructive sleep apnoea and in normal subjects in different postures was studied. The effects of posture on the maximum expiratory and inspiratory flow-volume curves during the breathing of air and 7% carbon dioxide in 11 patients with obstructive sleep apnoea were compared with those in nine normal subjects. Measurements were made in the sitting, supine, and right lateral recumbent positions. Forced expiratory flow at 50% vital capacity (FEF50), forced inspiratory flow at 50% vital capacity (FIF50) and FEF50/FIF50 were determined. In the normal subjects FEF50, FIF50, and FEF50/FIF50 were not affected by change in posture or by breathing carbon dioxide. In the patients there was a fall in FIF50 and an increase in FEF50/FIF50 when breathing air in the supine position compared with values in the seated and lateral position. While they were breathing carbon dioxide there was a slight increase in FEF50 when patients were seated or in the lateral position compared with values during air breathing. Hypercapnia abolished the effects of posture on FEF50/FIF50. Values for FEF50/FIF50 in the supine position while they were breathing air correlated with the apnoeic index but not with other polysomnographic data. In patients with obstructive sleep apnoea the upper airway is prone to collapse during inspiration when the patient is supine, even when awake; this tendency can be reversed by breathing carbon dioxide.


Comparison of the prevalence of asthma among Asian and European children in Southampton. Primary health care workers have reported an impression that asthma is commoner among Asian than European children, and a cross sectional survey was designed to compare the prevalence in Asian and European children. The survey was carried out in children aged 7-11 in eight primary schools in Southampton. Four schools contained predominantly children of European ancestry, two contained predominantly Asian children, and two contained a mixture of ethnic groups. Data were collected by means of parent completed questionnaire on recent asthma symptoms, diagnosis, morbidity, and treatment from 759 European and 274 Asian children. The prevalence of reported wheeze in the previous 12 months was higher among European (19.6%) than Asian children (11.9%), as was the prevalence of a night cough (European 64.2%, Asian 42.3%). Although the prevalence of diagnosed asthma was higher in European (12%) than Asian (6.2%) children, a slightly higher proportion of Asian than European children with current wheeze had visited their doctor (European 66.9%, Asian 78.1%, not significant) or been admitted to hospital for wheezing (European 4.8%, Asian 6.5%) in the previous 12 months. This study failed to demonstrate a higher prevalence of asthma among Asian than European children in Southampton.


Platelet kinetics in asthmatic patients with and without aspirin intolerance. A reduced platelet survival time has been described in asthmatic patients. There is also good evidence that platelets are involved in aspirin induced asthma. Since aspirin intolerant patients usually suffer from an active disease and often require anti-inflammatory treatment, it has been suggested that platelet survival time may be shorter in aspirin intolerant asthmatic subjects than in aspirin tolerant subjects. The objective of this study was to investigate this hypothesis. Thirteen asthmatic subjects (six aspirin tolerant and seven aspirin intolerant) in a stable clinical condition and ten healthy subjects were studied. Platelet kinetics and survival time were measured with indium-111 labelled autologous platelets. Mean (SD) platelet sequestration ratios in the spleen and liver were lower in asthmatic (2.3 (0.9) and 0.6 (0.2) respectively) than in healthy subjects (3.2 (0.7) and 1.1 (0.4) respectively). However, mean (SD) platelet survival time in asthmatic subjects (8 (2.7) days) did not differ from that in healthy subjects (7.6 (1.1) days). No differences were observed in platelet kinetics between aspirin tolerant and aspirin intolerant patients. These results suggest the existence of an active non-splenic pool of platelets in patients with asthma. However, they failed to show platelet kinetic differences among asthmatic subjects with and without aspirin intolerance and do not support previous studies suggesting an altered platelet survival in stable asthma.


Asthma from birth to age 23: incidence and relation to prior and concurrent atopic disease. Few studies present prospective data on the incidence of asthma. Its associations with sex and with prior and concurrent hay fever and eczema were examined in a nationally representative sample followed from birth to 23 years of age (British 1958 birth cohort). Reports of asthma or wheezy bronchitis, hay fever and eczema were obtained by interview of parents of children at ages 7, 11, and 16 years, and of cohort members at age 23 years. Linked data from all four interviews were available on 7225 subjects (43% of the original birth cohort). The cumulative incidence of asthma or wheezy bronchitis was 18.2%, 21.8%, 24.5%, and 28.6% by the ages of 7, 11, 16, and 23 years respectively. Over the four incidence periods examined (0 to 7 years, 8 to 11 years, 12 to 16 years, 17 to 23 years) the average annual incidence of new cases was 2.6%, 1.1%, 0.71%, and 0.76% respectively. The male:female incidence ratio rose from 1.23 in the 0 to 7 year period to 1.48 at 12 to 16 years but had reversed to 0.59 at 17 to 23 years. A prior report of hay fever or eczema each increased the subsequent incidence of asthma or wheezy bronchitis by a factor of 1.7 to 2.0 independently of sex. This effect of prior atopic illness, however, was largely explained by the strong independent association of incidence of asthma and wheezy bronchitis with atopic disease at the end of each incidence period (odds ratios 2.0 to 2.5 per atopic condition, p < 0.01). Gender differences in the incidence of asthma or wheezy bronchitis vary with age and are not explained by atopy. The incidence of asthma or wheezy bronchitis can be predicted from a clinical history of hay fever or eczema but is more strongly associated with the presence of atopic disease at the time of onset.


Should we judge a mask by its cover?

Should we judge a mask by its cover? A table of the approximate ranges of inspired oxygen delivered at given oxygen flow rates is often given on the packaging of oxygen masks. A study was carried out to check the inspired oxygen concentration given by one of the new masks, which has been designed to be used with or without the Venturi attachment as a result of the proposal to use it without the Venturi attachment as a general purpose mask for emergency use. Measurements were made at resting respiratory rate and 26 breaths/min in 12 normal subjects. Continuous oxygen and carbon dioxide concentrations were recorded at the lips with a mass spectrometer, and inspired oxygen concentrations were calculated from end tidal values by means of the alveolar gas equation. Measurements were made at oxygen flow rates of 2, 4, and 6 l/min for the mask alone and at 2 and 4 l/min with both the 24% and the 28% Venturi attachments. Without the Venturi attachment the mask gave average inspired oxygen concentrations 8-10% greater than are stated on the packaging at oxygen flow rates of 2, 4, and 6 l/min at resting respiratory rates of 8-20 breaths/min, some individuals receiving 30% more than expected. Addition of the interchangeable Venturi attachments designed to give 24% and 28% inspired oxygen delivered average concentrations within 2% of the expected concentrations, no individual receiving more than 5% above the expected concentrations. The labelling on the packaging of oxygen masks may lead to inappropriate use by those not expert in prescribing oxygen therapy. Caution is still needed when a single multipurpose mask is being selected for emergency use, where accurate delivery of low concentrations of oxygen is vital for some patients.


Rapid diagnosis of gram negative pneumonia by assay of endotoxin in bronchoalveolar lavage fluid. Diagnosis of ventilator associated pneumonia can be made by quantitative cultures of bronchoalveolar lavage fluid or of protected specimen brushings, though cultures require 24-48 hours to provide results. In 80% of cases aerobic Gram negative bacteria are the cause. A rapid diagnostic method of assessing the endotoxin content of lavage fluid by Limulus assay is described. Forty samples of lavage fluid were obtained from patients with multiple trauma requiring mechanical ventilation for a prolonged period. Pneumonia was diagnosed on the basis of clinical, radiological, and bacteriological findings, including quantitative cultures of lavage fluid. A relation was observed between the concentration of endotoxin in lavage fluid and the quantity of Gram negative bacteria. The median endotoxin content of lavage fluid in Gram negative bacterial pneumonia was 15 endotoxin units (EU)/ml; the range observed in individual patients was 6 to > 150 EU/ml. In patients with pneumonia due to Gram positive cocci and in non-infected patients the median endotoxin level was 0.17 (range < or = 0.06 to 2) EU/ml. An endotoxin level greater than or equal to 6 EU/ml distinguished patients with Gram negative bacterial pneumonia from colonised patients and from those with pneumonia due to Gram positive cocci. The measurement of endotoxin in lavage fluid is a rapid (less than two hours) and accurate diagnostic method. It should allow specific and early treatment of Gram negative bacterial pneumonia.


Short term effect of oxygen on renal haemodynamics in patients with hypoxaemic chronic obstructive airways disease. Oxygen therapy is effective in the prevention and treatment of oedematous exacerbations of cor pulmonale. As renal blood flow is reduced in cor pulmonale a study was designed to investigate whether one of the beneficial effects of oxygen was to increase renal blood flow. The effect of oxygen therapy on renal haemodynamics measured noninvasively was examined in patients with chronic obstructive airways disease and previous episodes of oedema. Renal blood flow waveforms were recorded in a single vessel by colour flow Doppler ultrasound in nine hypoxaemic patients (PaO2) (arterial oxygen tension < 8 kPa while they were breathing air) with chronic obstructive airways disease and previous oedema and eight age matched normoxaemic volunteers (arterial oxygen saturation (SaO2) 97% or more when breathing air) while they were breathing air and oxygen. SaO2 and transcutaneous PaO2 (TcPO2) and PaCO2 (TcPCO2) were monitored. Five renal velocity profile recordings were made from the same segmental vessel with the patient breathing room air for one hour followed by oxygen titrated to achieve an oxygen saturation of 95% or more without a rise in TcPCO2 for 15 minutes. Control subjects breathed 35% oxygen. No significant change in the pulsatility index (a measure of distal vascular resistance) or mean height of the waveform (Tamx, a measure of renal blood flow) occurred in the control subjects while they were breathing air or oxygen. The pulsatility index of the patients with chronic obstructive airways disease was significantly greater than that in the control subjects breathing air (1.44 (SD 0.28) v 1.03 (0.14). Breathing oxygen was associated with an increase in TcPO2 in the patients (from 6.9 (1.9) to 11.5 (0.7) kPa), a fall in pulsatility index (from 1.44 (0.28) to 1.26 (0.14) and an increase in Tamx (from 0.187 (0.055) to 0.234 (0.087) m/s). The results suggest that renal vascular resistance is increased in patients with chronic obstructive airways disease and hypoxaemia and that short term oxygen therapy reduces renal vascular resistance and increases blood flow. Some of the benefits of oxygen therapy in cor pulmonale may be due to improvements in renal haemodynamics.


The pulmonary physician and critical care. 2. The injured lung: conventional and novel respiratory therapy. Several alternatives to conventional ventilation in acute lung injury are now available and have been investigated to a varying degree. The assessment of all such techniques is limited by difficulties in designing proper comparative studies and by the time needed to recruit a large number of appropriate patients with acute lung injury. A common theme of lung volume maintenance combined with strategies designed to limit the extent of ventilator induced lung damage has emerged and should encourage reassessment of the conventional approach. The results of several large prospective comparative studies are eagerly awaited. Meanwhile we may reasonably suggest that improvements in respiratory support, together with advances in microbiological and pharmacological treatment, have the potential for improving the persistently disappointing survival rate in acute lung injury.


Endobronchial sonography: feasibility and preliminary results. Endobronchial sonography, a new ultrasound technique, has been evaluated for the assessment of normal lungs and bronchial carcinomas. The procedure was performed with ultrasound catheters, which were introduced into central and peripheral bronchi through the operating channel of fibreoptic bronchoscopes. The bronchial wall is highly echogenic and laminated. The lung parenchyma appears echo rich and patchy. Pulmonary arteries can be identified by the pulsatile changes and floating echoes within the echo free lumen. Echo poor bronchial carcinomas were detected in 69 out of 74 patients with endoscopically visible tumours and in 19 out of 26 patients with peripheral carcinomas. The correct implantation of metallic stents was facilitated by endobronchial sonography in nine patients. The sonographic examination carried no particular risk and caused little discomfort.


Neutrophilic alveolitis in Sweet's syndrome. In a case of Sweet's syndrome (acute febrile neutrophilic dermatosis) neutrophilic alveolitis was found by lung biopsy. Pulmonary disease in this condition may be underrecognised yet, like the dermatological features, it responds rapidly to corticosteroids.


Corticosteroids in acute severe asthma: effectiveness of low doses. Although the need for corticosteroids in acute severe asthma is well established the appropriate dose is not known. The response to intravenous hydrocortisone 50 mg (low dose), 100 mg (medium dose), and 500 mg (high dose), administered every six hours for 48 hours and followed by oral prednisone, was compared in patients with acute asthma in a double blind randomised study. After initial emergency treatment with bronchodilators subjects received oral theophylline or intravenous aminophylline and nebulised salbutamol four hourly. Patients were given low, medium, or high doses of intravenous hydrocortisone and then 20, 40, or 60 mg/day respectively of oral prednisone with a reducing regimen over the following 12 days. Beclomethasone dipropionate, 400 micrograms twice daily by metered dose inhaler, was also started. Peak expiratory flow (PEF), forced expiratory volume in one second (FEV1), and visual analogue dyspnoea scores (VAS) were recorded daily in hospital and PEF and VAS twice daily after discharge for a total of 12 days. The 66 subjects (40 female) who completed the study had a mean (SD) age of 31(14) years. On presentation mean (SD) FEV1% predicted in the low (n = 22), medium (n = 20), and high dose (n = 24) groups was 17(13), 19(12), and 19(11) and after emergency bronchodilator treatment 32(20), 30(12), and 36(13). After 24 hours of treatment the respective post-bronchodilator FEV1% predicted values were 62(22), 62(23), and 65(28) compared with 71(24), 69(22), and 71(24) after 48 hours. No significant difference between the groups was detected. PEF and VAS improved with treatment over the 12 days but was not influenced by steroid dose. Hydrocortisone 50 mg intravenously four times a day for two days followed by low dose oral prednisone is as effective in resolving acute severe asthma as 200 or 500 mg of hydrocortisone followed by higher doses of prednisone.


Controlled trial of intravenous corticosteroids in severe acute asthma. The value of corticosteroids in severe acute asthma continues to be debated. Ninety consecutive patients admitted to the emergency room with severe acute asthma were studied in a randomised, double blind, controlled trial to determine the efficacy of corticosteroids. Eighty two patients completed the study. All received oxygen therapy and intensive bronchodilator treatment. The patients were divided into three groups for steroid treatment, receiving intravenous methylprednisolone 10 mg/kg every four hours for 48 hours (29 patients, group A); intravenous methylprednisolone 2 mg/kg every 4 hours for 48 hours (27 patients, group B); or no intravenous corticosteroids (26 patients, group C). There were no differences on admission among the three groups in forced expiratory volume in one second (FEV1), forced vital capacity (FVC), peak expiratory flow (PEF), or arterial oxygen or carbon dioxide tension; and the rates of recovery in FEV1, FVC, and PEF were similar. Corticosteroids given with bronchodilators have not shown a beneficial effect in the first 48 hours of recovery of severe acute asthma. Only in those patients who failed to respond by the third hour of treatment, and in those who were previously taking oral corticosteroids, does a favourable, though not statistically significant, effect appear to occur.


Attenuation of exercise induced asthma by local hyperthermia. Prior treatment with local hyperthermia has been shown to prevent mast cell degranulation and leucocyte histamine release, and to reduce mortality and cellular infiltrates in a model of acute lung injury. Local hyperthermia is effective in reducing the symptoms of the common cold and perennial and seasonal allergic rhinitis, nasal patency also being improved in rhinitis. It is possible that these effects are mediated by common anti-inflammatory mechanisms, and that this treatment may be effective in the treatment of asthma. The effect of prior local hyperthermia on the response to exercise challenge and histamine bronchoprovocation was therefore examined. In a randomised, double blind, placebo controlled, crossover study, 10 asthmatic subjects with exercise induced asthma used machines delivering 40 1/minute of fully humidified air at either 42 degrees C (active treatment) or 31 degrees C (placebo treatment) for 30 minutes' tidal breathing. For each pretreatment, at two week intervals they underwent exercise challenges starting one and 24 hours after starting the inhalations. After a further two weeks the protocol was repeated with histamine substituted for the exercise challenges. The mean (SE) maximum percentage fall in forced expiratory volume in one second (FEV1) was significantly lower one hour after treatment with air at 42 degrees C (30.8% (3.1%)) than after treatment with air at 31 degrees C (22.3% (2.9%)). There was no significant effect on exercise challenge at 24 hours, or on histamine challenge at either time point, though there were nonsignificant trends towards protection with exercise at 24 hours and with histamine at one hour. In asthmatic subjects the response to exercise challenge is significantly attenuated one hour after treatment with local hyperthermia. This treatment warrants further investigation in the treatment of clinical asthma and other inflammatory disorders.


Controlled trial of respiratory muscle training in chronic airflow limitation. Whether respiratory muscle training is of benefit to patients with chronic airflow limitation is controversial. The objective of the study was to determine the effect of resistance breathing training on physiological and functional measures in patients with chronic airflow obstruction. The design was a randomised, double blind, controlled trial with a six month follow up. Eighty two patients with a forced expiratory volume in one second (FEV1) of less than 70% predicted, and an FEV1/vital capacity ratio of less than 0.7, were randomised to receive training for 10 minutes five times daily with progressively larger resistances through a resistive breathing device (PFLEX) as tolerated or to a sham device which gave minimal resistance. The main outcome measures, respiratory muscle strength and endurance, a progressive exercise test, a six minute walk test and physical and emotional function (chronic respiratory questionnaire) were assessed at monthly intervals. Patients in both groups were also randomised to wear or not wear nose clips during their training. No significant differences were observed between treatment and control groups, with or without nose clips, for any of the outcomes. Confidence intervals on the difference between treatments were narrow, excluding clinically important difference in any major outcome. This training regimen fails to strengthen respiratory muscles or improve exercise or functional capacity in patients with chronic airflow limitation.


Integrity of the alveolar-capillary barrier and alveolar surfactant system in smokers. The permeability of the alveolar-capillary barrier to technetium-99m labelled diethylenetriamine pentaacetate (99mTc DTPA) is known to be greatly increased in smokers, but the underlying mechanism is poorly understood. Abnormal permeability of the alveolar epithelium as well as impaired surfactant function has been suggested. The purpose of this study was to examine transudation of urea and albumin into the alveoli and alveolar surfactant function in smokers and non-smokers and to relate these variables to the rate of alveolar-capillary transfer of 99mTc DTPA. Standardised bronchoalveolar lavage was performed and the yield of urea and albumin measured in the lavage fluid. The integrity of the alveolar surfactant system was assessed by measurement of the surface activity and of the yield of phospholipids in alveolar lavage fluid. The mean decay constant for the pulmonary clearance of 99mTc DTPA was 0.028/min in the smokers and 0.009/min in the non-smokers. The recovery of albumin and urea in alveolar lavage fluid was very similar in the two groups. The surface activity of alveolar lavage fluid was lower in smokers than in non-smokers (minimum surface tension 37.9 versus 28.6 mN/m) and the yield of phospholipids was reduced (2.08 versus 3.86 mg). The rate constant for the pulmonary clearance of 99mTc DTPA correlated with the yield of phospholipids at bronchoalveolar lavage. The study shows that increased alveolar-capillary transfer of 99mTc DTPA in smokers is not accompanied by increased transudation of small or large molecules into the alveoli. The findings support the hypothesis that increased clearance of 99mTc DTPA in smokers is related to surfactant dysfunction.


Variability of inspired oxygen concentration with nasal cannulas. The likely values of inspired oxygen concentration (FIO2) of patients with chronic obstructive pulmonary disease breathing via nasal cannulas have not been assessed previously. Seven patients with chronic obstructive lung disease and seven healthy subjects were studied while breathing oxygen via nasal cannulas or fixed performance (Venturi) or uncontrolled (MC) oxygen masks. Breath to breath values of FIO2 were calculated by extrapolation from expired oxygen and carbon dioxide concentrations on the basis of the oxygen-carbon dioxide relationship and on the assumption of a respiratory exchange ratio (R) of 0.8. In both groups of subjects the average values of FIO2 with nasal cannulas at 1 and 2 l min-1 were of a similar order to those achieved with 24.5% and 28% Venturi masks, but variations within and between subjects in both groups breathing via nasal cannulas were considerable and similar to those found with MC masks. In the seven patients with chronic obstructive lung disease breathing via nasal cannulas at 2 l min-1 the average FIO2 varied from 23.7% to 34.9%. "Typical" values of FIO2 quoted with nasal cannulas can mislead. The results confirm that this mode of oxygen delivery is unsatisfactory if precise control of inspired oxygen is desired.


Induction of sleep apnoea with negative pressure ventilation in patients with chronic obstructive lung disease. Negative pressure ventilation provides intermittent non-invasive ventilatory assistance for patients with advanced chronic obstructive lung disease. Upper airway obstruction during sleep, a reported complication of the technique, may, however, limit its clinical applicability. The effects of nocturnal negative pressure ventilation on ventilation and on indices of sleep quality were investigated in five patients with severe chronic obstructive lung disease (mean (SE) FEV1 31% (3%) predicted) who had completed three months of nightly negative pressure ventilation. Subjects underwent overnight polysomnography on consecutive nights, the first night serving as a control and negative pressure ventilation being provided on the second night. Ventilators were adjusted to result in maximum suppression of the peak phasic electromyogram signal from the diaphragm. Negative pressure ventilation resulted in substantial increases in episodes of obstructive apnoea and hypopnoea (mean (SE)/h 59.3 (19.8) v 3.2 (1.3) on control nights). Most obstructive events, however, were associated with under 3% oxygen desaturation, and the lowest recorded values for overnight oxygen saturation were similar on the two study nights. Negative pressure ventilation was also associated with significant increases in the frequencies of movement arousals and changes in sleep stage. Negative pressure ventilation applied during sleep to patients with advanced chronic obstructive lung disease may result in the development of recurrent episodes of apnoea and hypopnoea as well as altered sleep quality, which could limit its clinical applicability.


Effects of corticosteroids on bronchodilator action in chronic obstructive lung disease. Short term treatment with corticosteroids does not usually reduce airflow limitation and airway responsiveness in patients with chronic obstructive lung disease. We investigated whether corticosteroids modulate the effects of inhaled salbutamol and ipratropium bromide. Ten non-allergic subjects with stable disease were investigated; eight completed the randomised, double blind, three period cross over study. Treatment regimens consisted of 1.6 mg inhaled budesonide a day for three weeks, 40 mg oral prednisone a day for eight days, and placebo. After each period cumulative doubling doses of salbutamol, ipratropium, a combination of salbutamol and ipratropium, and placebo were administered on separate days until a plateau in FEV1 was reached. A histamine challenge was then performed. At the end of placebo treatment mean FEV1 was 55.5% predicted after inhaled placebo, 67.9% predicted after salbutamol and 64.0% predicted after ipratropium. Compared with the results after the placebo period the FEV1 with salbutamol increased by 0.7% predicted after treatment with budesonide and by 0.7% predicted after treatment with prednisone; the FEV1 with ipratropium increased by 0.7% predicted after budesonide and by 4.8% predicted after prednisone; none of these changes was significant. After placebo treatment the geometric mean PC20 was 0.55 mg/ml after placebo, 1.71 mg/ml after salbutamol and 0.97 mg/ml after ipratropium. Compared with the placebo period the PC20 with salbutamol was increased by 0.86 doubling concentrations after treatment with budesonide, and by 0.67 doubling concentrations after prednisone; the PC20 with ipratropium increased by 0.03 and 0.34 doubling concentrations after budesonide and after prednisone respectively compared with placebo; none of these changes was significant. In non-allergic subjects with chronic obstructive lung disease short term treatment with high doses of inhaled or oral corticosteroids does not modify the bronchodilator response to salbutamol or ipratropium or the protection provided by either drug against histamine. Salbutamol produces greater protection from histamine induced bronchoconstriction than ipratropium.


Nilutamide pneumonitis: a report on eight patients. Nilutamide is a new, specific synthetic antiandrogen, released in several countries for the treatment of metastatic carcinoma of the prostate. Eight patients at the University Medical Centre at Dijon and affiliated referring hospitals developed reversible pulmonary opacities and respiratory symptoms while taking the drug. Records of eight patients who developed new, otherwise unexplained chest opacities while taking nilutamide were reviewed. In each patient a careful aetiological search was made for other environmental or endogenous causes. Six patients underwent bronchoalveolar lavage, and lavage fluid was cultured. Corticosteroids were not given, unless gas exchange was compromised (two patients). The eight patients (all male) had had carcinoma of the prostate diagnosed on average 10.2 months earlier. All had improved with nilutamide, with a dramatic decrease of prostate specific antigen levels. Seven had received nilutamide at the recommended dosage of 150 mg/day, and one had received twice that amount. Treatment had lasted on average 113 (range 10-225) days, and the mean cumulated exposure was 21.8 (3-38) grams. The chest radiographs showed bilateral infiltrates, with no consistent topographic predilection. A restrictive lung defect was present in six patients and hypoxia in all (mean arterial oxygen tension (PaO2) 6.6 kPa). Bronchoalveolar lavage showed lymphocytosis in four patients and neutrophilia in two. The outcome was favourable in all patients after they had stopped nilutamide only (five patients), with corticosteroids (two patients) or a simple reduction of nilutamide from 300 to 150 mg/day (one patient). Recovery was associated with improvement of pulmonary function and PaO2. Nilutamide is associated with interstitial pneumonitis in about 1% of patients and appears reversible.


Acute pneumonitis associated with low dose methotrexate treatment for rheumatoid arthritis: report of five cases and review of published reports. Low dose methotrexate has become established in the treatment of refractory rheumatoid arthritis. Until recently it has been considered that the use of a low dose regimen (< 20 mg/week) would avoid the pulmonary toxicity associated with the higher doses prescribed in malignant disease. Although initial experience with low dose methotrexate was encouraging, an increasing number of cases of an acute, life threatening pneumonitis are being reported in patients with refractory rheumatoid arthritis. Since 1984 43 patients with refractory rheumatoid arthritis have been established on low dose methotrexate in the Oxford Health District. Five of these patients have subsequently developed acute methotrexate induced pneumonitis. The clinical and radiological features of these cases are described and previous reports reviewed. Five patients having low dose methotrexate treatment developed acute pneumonitis. Presentation was subacute and dominated by constitutional features. Respiratory symptoms developed insidiously but progressed rapidly with increasing dyspnoea associated with severe hypoxia. Chest radiographs were non-specific, showing diffuse interstitial infiltration and alveolar shadowing. Microbiological investigation gave negative results. In all cases methotrexate was discontinued and high dose corticosteroids started, with rapid clinical and radiological improvement. After withdrawal of steroid both clinical and radiological resolution was maintained at follow up. Acute pneumonitis is an uncommon but serious adverse effect of low dose methotrexate treatment for refractory rheumatoid arthritis. The initial presentation is non-specific and a high index of suspicion is required as respiratory failure may develop rapidly. Management depends on exclusion of infection, withdrawal of methotrexate, and high dose corticosteroid treatment. Full supportive treatment is indicated as the prognosis in such patients is good.


Effect of heparin on pulmonary fibroblasts and vascular cells. There is a large increase in mast cell numbers in fibrotic lung tissue, suggesting that mast cells may play a part in the pathogenesis of pulmonary fibrosis. Glycosaminoglycans, such as heparan sulphate, that are structurally related to heparin (a mast cell product) are part of the extracellular matrix and known to regulate cell growth. Basic fibroblast growth factor is a heparin binding growth factor produced by endothelial cells. A study was carried out to examine the effect of heparin, basic fibroblast growth factor, and mast cell products on the proliferation of normal human lung fibroblasts and the effect of adding heparin on the proliferation of lung fibroblasts and pulmonary vascular cells incubated with basic fibroblast growth factor. Heparin at low concentration (0.03, 0.3-1.0 micrograms/ml) stimulated the proliferation of normal human lung fibroblasts in culture whereas a higher concentration (100 micrograms/ml) had an inhibitory effect. Mast cell products also stimulated the proliferation of fibroblasts, and the effect was decreased by pretreatment with heparinase or protamine. Heparin enhanced the growth of both fibroblasts and pulmonary vascular cells induced by low concentrations of basic fibroblast growth factor. Mast cells in fibrotic lung tissue may regulate fibroblast proliferation by releasing heparin. These results suggest that endothelial cells may interact with mast cells and modulate fibroblast growth by release of basic fibroblast growth factor.