Inhibition of vasopressin-sensitive cAMP accumulation by alpha 2-adrenoceptor agonists in collecting tubules is species dependent.

The ability of alpha 2-adrenoceptor agonists to inhibit vasopressin (VP)-stimulated cAMP accumulation in collecting tubules and to inhibit the antidiuretic effect of VP in rats is clearly established. However, in other species, such as the dog, alpha 2-adrenoceptor-induced inhibition of VP action has not been convincingly demonstrated. In the present study, we examined the effects of epinephrine and other alpha 2-adrenoceptor agonists on VP-stimulated cAMP accumulation in inner medullary collecting tubule cells and/or cortical collecting tubules from a number of species. Epinephrine, oxymetazoline, clonidine, and guanabenz inhibited VP-induced cAMP formation in rat inner medullary collecting tubule cells with IC50s ranging from 10 to 30 nM. However, epinephrine or guanabenz had no effect on VP-stimulated cAMP formation in cells from dog, pig, rhesus monkey, or human inner medulla. Similarly, epinephrine inhibited VP-induced cAMP accumulation in cortical collecting tubules dissected from rat kidneys but not from dog or rabbit kidneys. We conclude that there is a marked species difference in the ability of alpha 2-adrenoceptor agonists to inhibit VP-induced cAMP formation at the tubular level. This may explain the difficulty in demonstrating an alpha 2-adrenoceptor agonist-induced inhibition of VP action in other species such as dog and man.


Muscarinic regulation of somatostatin release from primary cultures of human antral epithelial cells.

A newly developed, primary culture of human antral epithelial cells has been utilized to examine the effect of parasympathomimetics on somatostatin release. The cholinergic agonists, carbachol and methacholine, stimulated somatostatin secretion in a concentration-dependent manner. Maximal release in response to carbachol was observed at 0.1 mmol/l. Methacholine was 10 times more potent with a significant release being observed at 1 mumol/l, maximal secretion was observed at 10 mumol/l. Somatostatin release, stimulated by the mixed nicotinic and muscarinic agonist, carbachol, was attenuated by the addition of atropine at 0.1 mumol/l but was unaffected by the same concentration of pirenzepine. Methacholine-stimulated release was attenuated by addition of 0.1 mumol/l atropine and unaffected by the same concentration of pirenzepine. The response to methacholine was reversed by the addition of 0.1 mumol/l 4-diphenylacetoxy-n-methylpiperidine methiodide (4-DAMP) and attenuated by 1 nmol/l 4-DAMP indicating that the effect was mediated by an M3 receptor. In conclusion, human antral D cells are stimulated by parasympathomimetics acting at an M3 receptor.


Chronic nicotine intake increases the responses to muscarinic receptor stimulation.

Chronic nicotine administration depresses the autonomic ganglia, but its effects on the muscarinic receptors at the neuroeffector sites remain unclear. The present study, using rats, examines the influence of chronic treatment with nicotine (25 micrograms/ml drinking water) for 10 or 15 days on muscarinic receptor responses, as reflected by bethanechol-evoked gastric secretion or by acetylcholine-induced decreases in mean blood pressure. Bethanechol, 0.4, 0.8, 1.6 or 3.2 mg/kg injected subcutaneously, dose-dependently increased the basal gastric secretory volume and acid output in pylorus-ligated control animals which normally drank tap water. Rats given nicotine in their drinking water for 10 or 15 days showed a further marked increase in both the volume of gastric secretion and acid output in response to bethanechol injections. Although bethanechol dose-dependently increased acid secretion, the ulcer index was very small and there was no significant difference between the control and nicotine-treated groups. The basal mean blood pressure remained normal after the 10-day nicotine treatment. Acetylcholine, 0.1, 0.3, 1 or 3 micrograms/kg given intravenously, decreased the mean blood pressure; this acetylcholine-evoked blood pressure fall was intensified by nicotine pretreatment. The findings suggest that the responses to muscarinic receptor stimulation are increased by chronic nicotine treatment for 10 or 15 days. These exaggerated effects are possibly the consequence of persistent autonomic ganglion blockade by chronic nicotine treatment.


The development of face processing skills.

An early orientation to faces is followed by a gradual development of face processing skills. During the course of maturation, children acquire the ability to learn new faces and to deal with facial transformations. Some skills are achieved more quickly than others. Moreover, encoding ability in young children is somewhat different from that shown by older children. The younger groups fail to take advantage of increased inspection time and stimulus characteristics such as facial distinctiveness. They are also more likely to be confused by alterations in background context. Although with familiar faces they reveal very similar identity priming effects to older children and adults, younger children display a relative inefficiency in categorizing faces as being that of a target unless it is noticeably dissimilar. Young children are more likely than older people to prefer positive caricatures of certain faces, which is not consistent with the view that caricature effects are simple reflections of a general expertise with faces.


Neurophysiological mechanisms underlying face processing within and beyond the temporal cortical visual areas.

The ways in which information about faces is represented and stored in the temporal lobe visual areas of primates, as shown by recordings from single neurons in macaques, are considered. Some neurons that respond primarily to faces are found in the cortex in the anterior part of the superior temporal sulcus (in which neurons are especially likely to be tuned to facial expression and to face movement involved in gesture), and in the TE areas more ventrally forming the inferior temporal gyrus (in which neurons are more likely to have responses related to the identity of faces). Quantitative studies of the responses of the neurons that respond differently to the faces of different individuals show that information about the identity of the individual is represented by the responses of a population of neurons, that is, ensemble encoding rather than 'grandmother cell' encoding is used. It is argued that this type of tuning is a delicate compromise between very fine tuning, which has the advantage of low interference in neuronal network operations but the disadvantage of losing the useful properties (such as generalization, completion and graceful degradation) of storage in neuronal networks, and broad tuning, which has the advantage of allowing these properties of neuronal networks to be realized but the disadvantage of leading to interference between the different memories stored in an associative network. There is evidence that the responses of some of these neurons are altered by experience so that new stimuli become incorporated in the network. It is shown that the representation that is built in temporal cortical areas shows considerable invariance for size, contrast, spatial frequency and translation. Thus the representation is in a form which is particularly useful for storage and as an output from the visual system. It is also shown that one of the representations that is built is object based, which is suitable for recognition and as an input to associative memory, and that another is viewer centred, which is appropriate for conveying information about gesture. Ways are considered in which such cortical representations might be built by competitive self-organization aided by back projections in the multi-stage cortical processing hierarchy which has convergence from stage to stage.


Cognitive mechanisms of face processing.

Evidence from natural and induced errors of face recognition, from the effects of different cues on resolving errors, and from the latencies to make different decisions about seen faces, all suggest that familiar face recognition involves a fixed, invariant sequence of stages. To recognize a familiar face, a perceptual description of a seen face must first activate a long-standing representation of the appearance of the face of the familiar person. 'Semantic' knowledge about such things as the person's occupation and personality are accessed next, followed, in the final stage, by the name. Certain factors affect the ease of familiar face recognition. Faces seen in the recent past are recognized more readily (repetition priming), as are distinctive faces, and faces preceded by those of related individuals (associative priming). Our knowledge of these phenomena is reviewed for the light it can shed upon the mechanisms of face recognition. Four aspects of face recognition--graded similarity effects and part-to-whole completion in repetition priming, prototype extraction with simultaneous retention of information about individual exemplars, and distinctiveness effects in classification and identification--are proposed as being compatible with distributed memory accounts of cognitive representations.


Modelling face recognition.

Much early work in the psychology of face processing was hampered by a failure to think carefully about task demands. Recently our understanding of the processes involved in the recognition of familiar faces has been both encapsulated in, and guided by, functional models of the processes involved in processing and recognizing faces. The specification and predictive power of such theory has been increased with the development of an implemented model, based upon an 'interactive activation and competition' architecture. However, a major deficiency in most accounts of face processing is their failure to spell out the perceptual primitives that form the basis of our representations for faces. Possible representational schemes are discussed, and the potential role of three-dimensional representations of the face is emphasized.


Organization and functions of cells responsive to faces in the temporal cortex.

Cells selectively responsive to the face have been found in several visual sub-areas of temporal cortex in the macaque brain. These include the lateral and ventral surfaces of inferior temporal cortex and the upper bank, lower bank and fundus of the superior temporal sulcus (STS). Cells in the different regions may contribute in different ways to the processing of the facial image. Within the upper bank of the STS different populations of cells are selective for different views of the face and head. These cells occur in functionally discrete patches (3-5 mm across) within the STS cortex. Studies of output connections from the STS also reveal a modular anatomical organization of repeating 3-5 mm patches connected to the parietal cortex, an area thought to be involved in spatial awareness and in the control of attention. The properties of some cells suggest a role in the discrimination of heads from other objects, and in the recognition of familiar individuals. The selectivity for view suggests that the neural operations underlying face or head recognition rely on parallel analyses of different characteristic views of the head, the outputs of these view-specific analyses being subsequently combined to support view-independent (object-centred) recognition. An alternative functional interpretation of the sensitivity to head view is that the cells enable an analysis of 'social attention', i.e. they signal where other individuals are directing their attention. A cell maximally responsive to the left profile thus provides a signal that the attention (of another individual) is directed to the observer's left. Such information is useful for analysing social interactions between other individuals.(ABSTRACT TRUNCATED AT 250 WORDS)


Representation of visual stimuli in inferior temporal cortex.

In primates, inferior temporal (IT) cortex is crucial for the processing and storage of visual information about form and colour. This article reviews the properties of IT neurons and considers how these properties may underlie the perceptual and mnemonic functions of IT cortex. The available evidence suggests that the processing of the facial image by IT cortex is similar to its processing of other visual patterns. Faces and other complex visual stimuli appear to be represented by the pattern of responses over a population of IT neurons rather than by the responses of specific 'feature detectors' or 'grandmother' cells. IT neurons with adult-like stimulus properties are present in monkeys as young as six weeks old.


The role of the 'face-cell' area in the discrimination and recognition of faces by monkeys.

Cortical neurons that are selectively sensitive to faces, parts of faces and particular facial expressions are concentrated in the banks and floor of the superior temporal sulcus in macaque monkeys. Their existence has prompted suggestions that it is damage to such a region in the human brain that leads to prosopagnosia: the inability to recognize faces or to discriminate between faces. This was tested by removing the face-cell area in a group of monkeys. The animals learned to discriminate between pictures of faces or inanimate objects, to select the odd face from a group, to inspect a face then select the matching face from a pair of faces after a variable delay, to discriminate between novel and familiar faces, and to identify specific faces. Removing the face-cell area produced no or little impairment which in the latter case was not specific for faces. In contrast, several prosopagnosic patients were impaired at several of these tasks. The animals were less able than before to discern the angle of regard in pictures of faces, suggesting that this area of the brain may be concerned with the perception of facial expression and bearing, which are important social signals in primates.


The neuropsychology of lipreading.

Lipreading presents a unique glimpse of the intersection of sensory processes with modular, cognitive ones. It presents speech to the eye in an automatic and natural way, whether performed silently or in conjunction with heard speech. It therefore allows us to examine closely claims concerning the relation between input modality and cognitive function. In this paper I consider some of the ways in which the investigation of single neuropsychological cases casts light on this; such cases show us that lipreading can dissociate from other aspects of face perception and recognition, and from auditory speech perception and reading, too. Furthermore, different cognitive components of lipreading itself can be inferred from dissociations on different lipreading tasks. This leads to closer consideration of the boundaries of the necessary cognitive (and possibly anatomical) structures that subserve these functions.


Face recognition impairments.

Face recognition impairments are often found in the context of brain injury involving the right cerebral hemisphere. Recognition impairments can be dissociated from impairments affecting the processing of other types of information carried by the face, such as expression. The face recognition impairments themselves take different forms, corresponding to idealized stages or levels of recognition. These types of error can also arise as transitory phenomena in normal everyday life. From these observations, psychologists have proposed functional models that characterize the organization of the face processing system in schematic form. Such models provide useful ways of summarizing what is known. More importantly, they also allow new findings to act as tests of each model's usefulness by the extent to which they can be readily accommodated or force revision. Examples of this are briefly considered, including delusional misidentification, impaired learning of new faces, disordered attention to faces, 'covert' recognition in prosopagnosia, and unawareness of impaired face recognition.


Functional and anatomical decomposition of face processing: evidence from prosopagnosia and PET study of normal subjects.

Studies of brain-damaged patients have revealed the existence of a selective impairment of face processing, prosopagnosia, resulting from lesions at different loci in the occipital and temporal lobes. The lesions are often extensive, and it is unclear what functional aspects of face processing are normally served by the damaged areas, and whether they are uniquely devoted to the processing of faces. These issues are further addressed through a combined magnetic resonance imaging (MRI) and positron emission tomography (PET) study of regional cerebral blood flow (rCBF) in normal subjects performing different tasks of face and object processing. The results indicate different patterns of cerebral activation depending on the requirements of the tasks within the processing of faces, as well as a clear dissociation of the neural substrates underlying face and object processing. These results are compared with radiological data from prosopagnosic patients, and are put in relation with the patterns of deficits observed in the patients as a function of the location of their lesions. Together, the findings offer new evidence regarding the functional neuroanatomy of face and object processing.


Facial expressions of emotion: an old controversy and new findings.

Evidence on universals in facial expression of emotion and renewed controversy about how to interpret that evidence is discussed. New findings on the capability of voluntary facial action to generate changes in both autonomic and central nervous system activity are presented, as well as a discussion of the possible mechanisms relevant to this phenomenon. Finally, new work on the nature of smiling is reviewed which shows that it is possible to distinguish the smile when enjoyment is occurring from other types of smiling. Implications for the differences between voluntary and involuntary expression are considered.


Lipreading and audio-visual speech perception.

This paper reviews progress in understanding the psychology of lipreading and audio-visual speech perception. It considers four questions. What distinguishes better from poorer lipreaders? What are the effects of introducing a delay between the acoustical and optical speech signals? What have attempts to produce computer animations of talking faces contributed to our understanding of the visual cues that distinguish consonants and vowels? Finally, how should the process of audio-visual integration in speech perception be described; that is, how are the sights and sounds of talking faces represented at their conflux?


The extraction and use of facial features in low bit-rate visual communication.

A review is given of experimental investigations by the author and his collaborators into methods of extracting binary features from images of the face and hands. The aim of the research has been to enable deaf people to communicate by sign language over the telephone network. Other applications include model-based image coding and facial-recognition systems. The paper deals with the theoretical postulates underlying the successful experimental extraction of facial features. The basic philosophy has been to treat the face as an illuminated three-dimensional object and to identify features from characteristics of their Gaussian maps. It can be shown that in general a composite image operator linked to a directional-illumination estimator is required to accomplish this, although the latter can often be omitted in practice.


The computer synthesis of expressive faces.

This paper presents a methodology for the computer synthesis of realistic faces capable of expressive articulations. A sophisticated three-dimensional model of the human face is developed that incorporates a physical model of facial tissue with an anatomical model of facial muscles. The tissue and muscle models are generic, in that their structures are independent of specific facial geometries. To synthesize specific faces, these models are automatically mapped onto geometrically accurate polygonal facial representations constructed by photogrammetry of stereo facial images or by non-uniform meshing of detailed facial topographies acquired by using range sensors. The methodology offers superior realism by utilizing physical modelling to emulate complex tissue deformations in response to coordinated facial muscle activity. To provide realistic muscle actions to the face model, a performance driven animation technique is developed which estimates the dynamic contractions of a performer's facial muscles from video imagery.


Becoming a face expert.

Young children do not form representations of newly encountered faces as efficiently as do adults. A first step in explaining this difference, like any age-related change, is locating its source. A major source of the improvement is acquisition of knowledge of faces per se, as opposed to age-related changes in general pattern encoding or memorial skills. Two consequences of expertise at individualizing members of classes that share a basic configuration are known: a large inversion effect and a caricature advantage. It is possible that both of these effects reflect increased reliance, with expertise, on configuration distinguishing features. Several phenomena that indicate that inversion interferes with the encoding of configural aspects of faces are reviewed. Finally, developmental data are presented that confirm the suspicion that there are at least two distinct sources of the vulnerability of face encoding to inversion, perhaps reflecting two distinct senses of 'configural encoding' of faces, only one of which is implicated in adult expertise at face encoding.


Contribution of amino acid transmitters to epileptiform activity and reflex suppression in electrically head stunned sheep.

In sheep, administration of a combination of zolazepam and tiletamine hydrochloride resulted in a dose dependent reduction in the duration of epileptic activity induced by an electric stun applied to the head. The compound also lengthened the normal period of reflex suppression that occurs after a stun. Excitatory amino acid receptor antagonists (2-amino-7-phosphonoheptanoic and 2-amino-5-phosphonovaleric acids) also reduced the duration of epileptic activity following an electric stun. These drugs did not alter the time of pedal and ear pinch reflex suppression. Administration of bicuculline (a gamma amino-4-butyric acid [GABA] receptor antagonist) reduced the period of stun induced reflex suppression and increased seizure duration. Administration of a GABA receptor agonist, baclofen, increased the duration of reflex suppression. The results suggest that the development of epileptiform-like activity following application of an electric current to the head is dependent upon excitatory amino acid receptors. The reflex suppression that also arises following an electric stun is contributed to by the activation of GABA receptor mechanisms.


Mediation of contraction and relaxation by alpha- and beta-adrenoceptors in the ureterovesical junction of the sheep.

The effects of alpha- and beta-adrenoceptor agonists and antagonists were studied in the sheep ureterovesical junction. Non-specific adrenergic agonists such as adrenaline and noradrenaline induced contraction in the sheep ureterovesical junction, suggesting a predominance of alpha-over beta-adrenoceptors in this functional unity. An inhibition of the noradrenaline-induced contraction was observed after prior blocking with prazosin (10(-7) M) and yohimbine (10(-7) M), the effect of prazosin being more potent than that of yohimbine. The effect of phenylephrine on alpha 1-adrenoceptors was more potent than that of B-HT 920 on alpha 2-adrenoceptors. Isoproterenol caused a concentration-dependent relaxation that was inhibited by propranolol (10(-6) M), pafenolol (10(-5) M) and butoxamine (10(-5) M). These results suggest that ureterovesical junction contraction is mediated by both alpha 1 and alpha 2-adrenoceptors, alpha 1 predominating over alpha 2. Relaxation is mediated by beta-adrenoceptors of the beta 1 and beta 2 subtypes.


Effects of prostaglandin E2 on ganglionic transmission in the guinea pig trachea.

We studied the effects of prostaglandin E2 (PGE2) on the contractile responses of in vitro guinea pig tracheal preparations with intact vagal innervation. The preparation was stimulated either through the vagal nerves (NS) or with an electrical field (EFS) and trachealis response was assessed from the pressure change inside the tracheal tube. Ganglionic blockade by hexamethonium inhibited responses to NS but did not affect EFS while both responses to NS and EFS were abolished by atropine or tetrodotoxin. This indicates that responses to both stimulation modalities were mediated by cholinergic nerves but that NS involved a ganglionic relay whereas EFS did not. Within the frequency range of 0.1-20 Hz, there was a gradual increase in the pressure generated by the trachealis muscle with increasing frequency of stimulation. The frequency-response relationship was similar for NS and EFS. Thus, the ganglion does not appear to play an important filtering or amplifying role under those conditions. PGE2 (1-50 mM) produced a concentration-dependent inhibition of NS and EFS without affecting responses to exogenous acetylcholine (ACh). This suggests that the main action of PGE2 is to reduce ACh release from post-ganglionic nerve terminals. PGE2 inhibited EFS to a larger extent than NS; we postulate a possible excitatory effect of PGE2 on neurotransmission in the airway ganglia.


Evidence of a role for heterotrimeric GTP-binding proteins in endosome fusion.

Guanosine triphosphate (GTP)-binding proteins are required for intracellular vesicular transport. Mastoparan is a peptide component of wasp venom that increases nucleotide exchange in some classes of G alpha subunits of regulatory heterotrimeric GTP-binding proteins (G proteins). Mastoparan and other compounds that increase nucleotide exchange by G proteins inhibited endosome fusion in vitro and reversed the effects of guanosine 5'-O-(3-thiotriphosphate) (GTP-gamma-S), a nonhydrolyzable GTP analog. Addition of beta gamma subunits of G proteins to the fusion assay antagonized the stimulatory effect of GTP-gamma-S, confirming the participation of G proteins. These results indicate that GTP-binding proteins are required for endosome fusion and in particular that a G protein is involved. Given the function of G proteins in signal transduction, these findings may provide insight into the mechanism by which endosomal vesicles become competent for fusion after their formation at the cell surface.


Racial differences in the relaxation response of hypertensives.

Racial differences in the relaxation response of hypertensives maintained on diuretic were investigated by comparing blood pressure, muscle tension, and hand temperature changes occurring with biofeedback assisted relaxation. Resting blood pressures were not different in blacks compared with whites. Both black and white subjects decreased diastolic blood pressure significantly from baseline values, but only whites significantly decreased systolic blood pressure. Though both blacks and whites significantly decreased forehead muscle tension, black subjects showed no changes in finger temperature while whites increased temperature significantly. The lack of change in finger temperature in blacks may be a reflection of the increased peripheral resistance previously associated with the greater incidence of hypertension in the American black population.


[Fracture lines of the foot].

In follow-up examinations of 112 patients who had been diagnosed as having a sprained foot, bony lesions, confirmed by X-ray films, were found in 96 (85.7%) patients. Up to this time the fractures had not been found in 58 of them. The fractures were found to be distributed in a point-specific location, i.e., a precisely defined anatomical area in 43 cases (44.8%) and a linear presentation in 53 (55.2%). This linear grouping of bony injuries is seen to develop along the path of joints, bones and ligamental insertions that anatomically follow one another in a functional manner. The line-like pattern to these presentation permitted us to develop 3 line sets that could be attributed to specific mechanisms of injury. The lateral line (56.6%) specially follows a supination sprain to the foot. The medial line (20.8%) is seen to follow injuries that involved a blow along the longitudinal axis. The transverse line (22.6%) follows trauma involving the Chopart joint. Six diagrams are presented to illustrate the mechanisms of foot trauma, with their vectors of force and the corresponding injuries that may result. Radiological examples of several clinical cases are given to demonstrate these three fracture lines.


Protection of pancreatic and biliary anastomosis after partial duodenopancreatectomy by external drainage.

The pancreaticojejunostomy after duodenopancreatectomy is the "Achilles' heel" of the procedure. Herein we describe a technique for percutaneous drainage of the efferent limb of the Roux-en-Y loop relieving tension from the anastomosis. Seventy-six Whipple procedures, using this technique, have been done. The operative mortality rate was 1.3 per cent and anastomosis leakage occurred in two instances. In addition, one patient had to be reoperated upon for biliary fistula. Our technique for external Roux-en-Y loop drainage after partial duodenopancreatectomy is safe and efficient and permits rapid diagnosis of anastomotic complications.


[Primary decontamination: vomiting, gastric irrigation or only medicinal charcoal?].

Procedures to reduce the absorption of ingested poisons have been employed widely for decades in the management of intoxicated patients. However, evidence of substantial clinical benefit to the majority of patients undergoing such treatments is lacking. Volunteer studies suggest that activated charcoal is generally more effective than either syrup of ipecacuanha or gastric lavage, though lavage may be more effective than syrup of ipecacuanha. Studies in poisoned patients have shown that although lavage is more effective than syrup of ipecacuanha, it led to a better outcome in comatose patients only if performed less than one hour after overdose. Syrup of ipecacuanha did not alter the outcome beneficially in those who were alert on presentation and is known to produce significantly more complications than charcoal alone even in patients who are awake with a gag reflex. A recent study suggests that activated charcoal may be superior both to lavage and syrup of ipecacuanha. Based on these studies it would seem reasonable to recommend that 50 to 100 g activated charcoal be administered to patients who have taken a substantial amount of a toxic substance less than one hour previously. This may be done conveniently by using an orogastric tube, which would also allow lavage to be undertaken with possible additional benefit.


An immunohistological demonstration of c-erbB-2 oncoprotein expression in primary urothelial bladder cancer.

Sections of formalin-fixed, paraffin-blocked tissue from 116 primary transitional cell carcinomas were stained immunohistochemically using a polyclonal antibody against the c-erbB-2 oncoprotein. Positive staining of cell membranes, known to correlate with gene amplification, was seen in 22 (19%) of the 116, with variable staining from tumour to tumour and within tumours themselves. Consistent with its mooted value as a prognosticator in bladder cancer, the c-erbB-2 oncoprotein was detected in 13 (of 40) grade III and 9 of the 26 muscle-invasive tumours examined compared to 1 (of 25) grade I and 6 (of 66) mucosa only (pTa) lesions. These results support further examination of c-erbB-2 expression in bladder cancer.


Factor-XIIIa-expressing dermal dendrocytes in Kaposi's sarcoma. A comparison between classical and immunosuppression-associated types.

The histogenetic origin of Kaposi's sarcoma is a matter of controversy, with recent reports claiming it to derive from the factor-XIIIa-positive dermal dendrocyte rather than endothelial cells. We investigated the potential role of factor-XIIIa-positive dermal dendrocytes in the genesis of both classical (endemic) and immunosuppression-associated Kaposi's sarcoma. Thirteen cases of classical and 16 cases of immunosuppression (mostly AIDS)-associated Kaposi's sarcoma were immunostained with antibodies to factor XIIIa and to the blood-group antigen H, recognizing endothelial cells. Factor-XIIIa-positive cells were consistently antigen-H-negative and represented only a small percentage (usually less than 10%) of the proliferative cells. Their relative density tended to be decreased in immunosuppression-associated Kaposi's sarcoma when compared with that of the classical form. These results do not support the view that dermal dendrocytes may be the cells of origin of Kaposi's sarcoma; conversely, their decreased density in cases of immunosuppression-associated Kaposi's sarcoma could be related to immunosuppression and may account for more rapid tumour growth.


[Localization of somatostatin mRNA in the rat retina detected by in situ hybridization histochemistry].

In order to determine the localization of the mRNA encoding somatostatin in the rat retina, we studied Sprague-Dawley rats by in situ hybridization histochemistry. Radiolabelled oligodeoxyribonucleotides complementary for rat somatostatin mRNA were used in this study. Among the layers of the retina, we found specific labelling in the soma of some cells in the innermost and outermost laminae of the inner-nuclear layer and in the ganglion cell layer. These results indicate the major site of somatostatin synthesis within the rat retina.


Relapse-preventing effect and safety of sulfasalazine and olsalazine in patients with ulcerative colitis in remission: a prospective, double-blind, randomized multicenter study. The Ulcerative Colitis Multicenter Study Group.

Forty-nine patients with ulcerative colitis in remission were entered into a prospective, double-blind, multicenter trial comparing the relapse-preventing effect and safety of 4 g sulfasalazine and 2 g olsalazine daily during 48 wk. Of the 46 evaluable patients, 23 were assigned to sulfasalazine and 23 to olsalazine. Seven of 23 patients (30.4%) relapsed on sulfasalazine and six of 23 patients (26.1%) on olsalazine (95% confidence interval of the difference -22.0% to 30.3%). The relapse-free survival curves did not differ significantly at any time during the trial period. In both treatment groups, three patients dropped out because of adverse effects. Four patients on sulfasalazine and six patients on olsalazine experienced minor adverse effects. One patient on sulfasalazine had mild leukopenia, and four patients on sulfasalazine and one patient on olsalazine had decreased levels of haptoglobin. Thus, sulfasalazine and olsalazine are equally effective in maintaining remission of ulcerative colitis and are accompanied by a similar incidence of adverse effects.


Familial association of autoimmune thrombocytopenia and hyperthyroidism.

An association between thrombocytopenia and thyrotoxicosis in a single individual is well documented, and the theories for this event include a common immunologic cause or a thyrotoxic-induced decrease in platelet survival. We report the first description of the coexistence of autoimmune thrombocytopenic purpura (AITP) and Graves' disease in several members of the same family, in which four females were thrombocytopenic and two of these were also hyperthyroid. All four patients had high titers of antiplatelet antibodies, and the two hyperthyroid cases were positive for thyroid-stimulating immunoglobulins (TSI). The familial occurrence of two autoimmune disorders is very uncommon, and suggests a genetic etiology. The HLA phenotype was determined and the antigens B8 and DR3, which are reported with high frequency in both diseases, were present in three patients. Although the etiologic cause is still unknown, our findings further support the theory that a genetic predisposition underlies autoimmune disease.


Alprazolam as a neuroleptic adjunct in the emergency treatment of schizophrenia.

While neuroleptics remain the mainstay of drug intervention in the emergency management of psychosis, a variety of agents have received study as alternatives or adjuncts to these drugs in an attempt to improve the safety and efficacy of acute treatment. The purposes of this study were to investigate the efficacy and safety of alprazolam as a neuroleptic adjunct for schizophrenic patients in psychotic relapse and to clarify the effects of combination treatment on specific aspects of the psychotic process. Twenty-eight acutely psychotic patients with schizophrenia who were admitted to an emergency psychiatric service were randomly assigned to treatment with either haloperidol and alprazolam or haloperidol with placebo under double-blind conditions. Drug administration lasted 72 hours. Both groups improved significantly. The combination-treated group required significantly less medication and had 56% fewer dystonic reactions. The addition of alprazolam was most effective for symptoms of excitement and uncooperativeness, particularly in the initial hours of treatment. The combination of alprazolam and haloperidol seems to be the most effective for agitated patients, particularly in the first 48 hours of treatment. It may also result in fewer dystonic reactions.


Prospective study of neuroleptic-induced dystonia in mania and schizophrenia.

The authors' goal was to conduct a prospective study comparing the rate of occurrence of neuroleptic-induced dystonia in a group of consecutively admitted manic and schizophrenic patients receiving typical inpatient treatment from several clinicians. All patients met the following criteria: 1) male sex, 2) age between 17 and 45 years, 3) definite diagnosis of mania or schizophrenia according to Research Diagnostic Criteria, 4) no exposure to neuroleptics during the past month, 5) absence of past or family history of a neurodegenerative disorder with extrapyramidal symptoms. All treatment decisions were left to the treating clinicians. Fifty patients with mania and 33 with schizophrenia were included in the study. Most of these patients received high-potency neuroleptics, but the specific neuroleptic used varied in the two groups. Twelve (24%) of the patients with mania and five (15%) of the patients with schizophrenia developed acute dystonia. Manic patients received significantly higher peak doses of neuroleptics during the risk period for dystonia. Stepwise multiple regression analysis revealed that the peak neuroleptic dose and age were most strongly related to the occurrence of dystonia. This prospective study failed to support the retrospective finding of another study that acute dystonia occurred more often in manic patients than in patients with nonparanoid schizophrenia. The authors conclude that there is a need for carefully controlled prospective studies with larger groups of patients.


Comorbidity in mania at first hospitalization.

Comorbidity was studied in 41 manic and mixed-state bipolar patients at first hospitalization. The lifetime prevalence of comorbidity was high; 21 subjects (51.2%) had at least one other psychiatric diagnosis (N = 16, 39.0%) or medical disorder (N = 9, 22.0%). Nine subjects had multiple comorbid diagnoses. Women were 2.7 times more likely to have a comorbid diagnosis. The presence of comorbidity was not associated with differences in outcome measures.


Pharmacokinetics and pharmacodynamics of vecuronium in the obese surgical patient.

The effect of obesity on the disposition and action of vecuronium was studied in 14 surgical patients. After induction of anesthesia with thiopental and maintenance of anesthesia by inhalation of nitrous oxide and halothane, seven obese patients (93.4 +/- 13.9 kg, 166% +/- 30% of ideal body weight, mean +/- SD) and seven control patients (60.9 +/- 12.3 kg, 93% +/- 6% of ideal body weight) received 0.1 mg/kg of vecuronium. Plasma arterial concentrations of muscle relaxant were determined at 1, 3, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 210, 240, 300, and 360 min by a spectrofluorometric method. Simultaneously, neuromuscular blockade was assessed by stimulation of the ulnar nerve and quantification of thumb adductor response. Times to 50% recovery of twitch were longer in the obese than in the control patients (75 +/- 8 versus 46 +/- 8 min) as were 5%-25% recovery times (14.9 +/- 4.0 versus 10.0 +/- 1.7 min) and 25%-75% recovery times (38.4 +/- 13.8 versus 16.7 +/- 10.3 min). However, vecuronium pharmacokinetics were similar for both groups. When the data were calculated on the basis of ideal body weight (IBW) for obese and control patients, total volume of distribution (791 +/- 303 versus 919 +/- 360 mL/kg IBW), plasma clearance (4.65 +/- 0.89 versus 5.02 +/- 1.13 mL.min-1.kg IBW-1), and elimination half-life (119 +/- 43 versus 133 +/- 57 min) were not different between groups.(ABSTRACT TRUNCATED AT 250 WORDS)


Atracurium and vecuronium: repeated bolus injection versus infusion.

The purpose of this study was to compare the characteristics of recovery from neuromuscular blockade after either atracurium or vecuronium given by intravenous infusion or by repeated injection. Four groups of 10 patients each were studied during nitrous oxide narcotic anesthesia. An initial intravenous dose of 2 x ED95 of either muscle relaxant was followed by an intravenous infusion started at 5% recovery of control twitch tension and adjusted for 95% block or by repeated injection of 0.6 x ED95 administered whenever twitch tension had returned to 25% of control. There were no significant differences between the maintenance doses required based on method of administration: atracurium repeated injection, 1.6 +/- 0.3 x ED95 h-1; atracurium infusion, 1.7 +/- 0.3 x ED95 h-1; vecuronium repeated injection, 1.8 +/- 0.5 x ED95 h-1; and vecuronium infusion, 1.6 +/- 0.4 x ED95 h-1. Nevertheless, differences of up to 20 min were noted in the recovery indices in the following order: atracurium repeated injection = atracurium infusion less than vecuronium repeated injection less than vecuronium infusion. A single dose of neostigmine (7 micrograms/kg) significantly reduced the recovery indices, thereby eliminating their differences.


Subjective, behavioral, and physiologic responses to intravenous dezocine in healthy volunteers.

Dezocine is an agonist-antagonist opiate that acts at the mu receptor, and is used for management of pain. Monkeys will readily press a lever to receive an injection of dezocine, and in former opiate addicts dezocine produces positive subjective effects similar to those of morphine. It is not clear, however, what its subjective effects are in people who do not have a history of opiate abuse. To answer this question, a within-subjects design was used in which 10 normal healthy volunteers (six men, four women) were injected with 0, 2.5, 5.0, and 10 mg/70 kg of dezocine in a double-blind fashion. Subjects completed several questionnaires (e.g., Addiction Research Center Inventory) commonly used in abuse liability testing before and at periodic intervals for up to 5 h after drug injection. We also assessed psychomotor performance (e.g., eye-hand coordination) and several physiologic measures (e.g., pupil size, respiration rate) at these times. Dezocine produced increases in ratings of drug liking (P less than 0.001), as well as other subjective effects that might be considered as pleasant ("good mood," "drunken," "coasting," "happy" ratings) (all P less than 0.05). At the same time, the drug had effects (increased dysphoria and sedation) that typically are not reported by addicts. Dezocine produced psychomotor impairment and miosis (constriction of the pupils) in a dose-dependent fashion. The observation that dezocine produces euphoria and increased drug-liking ratings in individuals without histories of drug abuse suggests that hospitals and surgicenters should have strict accountability procedures with this drug.


Characteristics of the inflammation in biopsies from large airways of subjects with asthma and subjects with chronic airflow limitation.

Although the characteristics of the histopathologic changes present in subjects who die with status asthmaticus are well documented, the structural changes present in subjects with mild to moderately severe asthma are not well described and the inflammatory changes in the large airways of subjects with chronic airflow limitation (CAL) and asthma have not been compared. Ten subjects with asthma, five taking inhaled corticosteroids and five taking beta 2-agonist aerosols, five subjects with CAL, and four subjects with no respiratory illness had four biopsies taken from airways 10 mm in diameter. The length of intact epithelium, thickness of basement membrane, and number of lymphocytes, neutrophils, eosinophils, plasma cells, monocytes, and mast cells in the lamina propria, bronchial smooth muscle, and submucosa were measured. Intact epithelium was present along 56% of the basement membrane in the asthmatic subjects, along 54% in the subjects with CAL, and along 84% in the control subjects. In the asthmatic subjects there was no direct relationship between the severity of asthma and the amount of epithelial cell loss or the number of inflammatory cells. The basement membrane was thickened in all asthmatic subjects but not in normal subjects or subjects with CAL. There was a significant increase in the number of lymphocytes, eosinophils, and mast cells in the asthmatic airways, particularly in the lamina propria, compared with the CAL subjects. There were no eosinophils or mast cells in any of the control subjects. The airways of subjects with CAL contained significantly more inflammatory cells than the control subjects. Subjects with asthma on inhaled corticosteroids had significantly fewer lymphocytes, eosinophils, and mast cells compared with subjects taking only beta 2-agonists.(ABSTRACT TRUNCATED AT 250 WORDS)


Transaortic patch angioplasty for left coronary ostial stenosis in a patient with Takayasu's aortitis.

A 35-year-old woman who had left coronary ostial stenosis and aortic valve regurgitation due to Takayasu's aortitis underwent transaortic patch enlargement of the stenosed left coronary ostium in combination with aortic valve replacement. This technique may be suitable and recommendable as an alternative to aortocoronary bypass grafting or endarterectomy for coronary ostial stenosis in Takayasu's aortitis.


Comparison of the effects of insulin and adrenergic agonists on the phosphorylation of an acid-soluble 22 kDa protein in rat epididymal fat-pads and isolated fat-cells.

1. Earlier studies have shown that exposure of fat-cells to insulin results in the rapid increased phosphorylation of an acid-soluble 22 kDa protein and that increases in phosphorylation were also evident in cells exposed to adrenaline [Belsham & Denton (1980) Biochem. Soc. Trans. 8, 382-383; Belsham, Brownsey, Hughes & Denton (1980) Diabetologia 18, 307-312]. 2. The effects of adrenaline are shown to be brought about through beta-adrenergic receptors and to be mimicked by other agents which increase cell cyclic AMP concentrations. The maximum extent of phosphorylation is about 60% of that observed with insulin. Increased phosphorylation is also observed in fat-cells exposed to vasopressin, oxytocin and phorbol esters, but not to alpha-adrenergic agonists. 3. No changes in the phosphorylation of the protein are evident in epididymal fat-pads from fat-fed, starved or starved/refed animals, despite the large changes in protein composition of fat-cells which accompany these nutritional alterations. This suggests that the protein is not closely involved in lipogenesis or associated metabolic pathways, but rather that it may play a more general regulatory role. 4. The 22 kDa protein migrates as a doublet on SDS/PAGE even after purification to apparent homogeneity by sequential use of Mono Q chromatography, SDS/PAGE and h.p.l.c. The amino acid compositions of the two components are very similar and share features in common with a number of proteins, including inhibitor-1, inhibitor-2, dopamine- and cyclic-AMP-regulated phosphoprotein (DARPP-32), and G-substrate, which may be involved in the regulation of protein phosphatase activity. 5. Phosphopeptide mapping and phosphoamino acid analysis reveals that insulin increases the phosphorylation of two distinct peptides within the protein (in one peptide insulin increases the amount of phosphothreonine, whereas in the other the hormone increases the amounts of phosphothreonine and phosphoserine). Both components of the doublet exhibit similar changes in phosphorylation, and hence the differences in migration are not the result of differences in phosphorylation, as suggested previously [Blackshear, Nemenoff & Avruch (1983) Biochem. J. 214, 11-19]. The pattern of phosphorylation observed with the beta-adrenergic agonist isoprenaline was similar to that observed with insulin. 6. The possible role and regulation of the 22 kDa protein are discussed.


Stabilization of the oxy form of tyrosinase by a single conservative amino acid substitution.

Asp-208 of Streptomyces glaucescens tyrosinase (an invariant residue in the CuB-binding region of tyrosinases and haemocyanins) was conservatively substituted by glutamic acid. Although having little effect on spectroscopic or kinetic properties of the enzyme, the mutation greatly decreased the lability of Cu-bound O2. A rationalization for these results is given, based on the crystal structure of Panuliris interruptus haemocyanin in the conserved CuB-binding region.


Innervation of the endolymphatic sac.

Previous studies suggest that the endolymphatic sac plays an important role in the homeostasis of endolymph. Factors that influence blood flow in the sac may affect its function. This blood flow may be influenced by autonomic innervation; however, no such innervation has been demonstrated. The purpose of this study was to demonstrate catecholaminergic and cholinergic fibers on the endolymphatic sac. Endolymphatic sacs from Hartley guinea pigs were stained either immunocytochemically for tyrosine hydroxylase to reveal catecholaminergic fibers or histochemically for acetylcholinesterase to reveal cholinergic fibers. For tyrosine hydroxylase immunostaining, the endolymphatic sacs were treated with dilute hydrogen peroxide and then incubated in the primary antiserum. The tissue was further processed by the avidin-biotin immunoperoxidase method and reacted with diaminobenzidine. For acetylcholinesterase histochemistry, the tissue was processed by a modification of the direct thiocholine method. Light microscopy of the whole-mounted endolymphatic sacs revealed tyrosine hydroxylase-positive and acetylcholinesterase-positive fibers. Some of the acetylcholinesterase-positive fibers were clearly associated with vessels. This innervation, which has not been described previously, may significantly influence blood flow and function of the endolymphatic sac.


Enzymuria in neonates receiving continuous intravenous infusion of gentamicin.

Urinary excretion of the tubular enzymes NAG and AAP was investigated during gentamicin treatment of 105 newborn infants. The values found for NAG and AAP show a significant positive correlation. The urinary excretion of NAG was on the average 92% higher during gentamicin treatment as compared with non-treatment periods in the same newborn infant (33 infants). The same tendency applied to AAP. Newborn infants receiving continuous intravenous infusion of gentamicin were not found to be at greater risk of nephrotoxicity than those receiving intermittent gentamicin treatment, using NAG and AAP as an index of nephrotoxicity. The changes in NAg and AAP within treatment periods were studied. During gentamicin treatment an insignificant average increase in the urinary excretion of NAG occurred, whereas a significant decrease was found during non-treatment periods. A significant negative correlation was found between urinary excretion of NAG and birth weight/gestational age. The long-term effect of the higher excretion of NAG and AAP in newborn and adult patients during aminoglycoside treatment is unknown.


Thyrotrophin-blocking antibodies in congenital hypothyroidism.

The role of transplacental transfer of maternal thyrotrophin (TSH)-blocking antibodies causing congenital hypothyroidism in Southern Chinese children was examined in this study. Twenty-two mothers of 24 patients with congenital hypothyroidism were studied 3-5 years after delivery. None of them had thyroid dysfunction at delivery or at the time of study. None had antithyroglobulin or antimicrosomal antibody. Only one mother was found to have TSH-binding inhibitory immunoglobulin (TBII), and her child had agenesis of the thyroid. This women had Graves disease in remission for 2 years before delivery. None had TSH-stimulated cAMP response inhibitory immunoglobulin (TSII). Ten of the 24 congenital hypothyroid children had transient neonatal hypothyroidism, seven had agenesis of the thyroid, six had dyshormonogenesis and one had a sublingual thyroid. As none of the mothers who had children with transient neonatal hypothyroidism had blocking antibodies at the time of study, the aetiology of the transient neonatal hypothyroidism remains unclear. These data suggest that maternal TSH-blocking antibodies do not play a role in most cases of sporadic congenital hypothyroidism.


Sympathetic nerve anatomy in the cavernous sinus and retrobulbar orbit of the cynomolgus monkey.

We present new information regarding the sympathetic nerve anatomy in the cavernous sinus and retrobulbar orbit of the cynomolgus monkey. Postganglionic sympathetic nerves were identified using an immunoperoxidase technique in which the primary antiserum was directed against tyrosine hydroxylase, the rate-limiting enzyme in norepinephrine synthesis. Our work is unique in adapting this staining method to paraffin-embedded tissue. This technique allows sympathetic nerve fibers to be distinguished from other autonomic, sensory, and motor nerves. A large sympathetic nerve bundle lateral to the internal carotid artery in the cavernous sinus gave off one or more branches that leave the artery to encircle the abducens nerve. Further division occurs within the cavernous sinus, but all sympathetic nerve fibers destined for the orbit entered it through the superior orbital fissure. None pass through the optic canal. In the orbit, sympathetics were associated with the ophthalmic artery and some of its branches and with the sensory root to the ciliary ganglion. After entering the ganglion, the sympathetic fibers were lost to detection in most specimens, but they were again seen in a single short ciliary nerve in one instance. Sympathetic nerve fibers were not detected adjacent to several structures identified in the human anatomy literature, such as the intracranial and intracanalicular segments of the ophthalmic artery, the nasociliary nerve, the long ciliary nerves, the nerve to the inferior oblique muscle, or the lacrimal artery and nerve.


Developing in a family way. Transforming Growth Factor Type beta and Related Proteins in Development: the Sixth Molecular, Cellular and Developmental Biology/Iowa State University Symposium, Ames, IA, USA September 20-23, 1991.

We are left with the impression that members of the TGF-beta family are critically positioned in a cascade of events regulating complex developmental processes. Roberts described the TGF-betas as providing the cells with cues to their temporal positions in a developmental program, that is, telling the cells "where they were, where they are, and where they're going." The broad diversity of cellular and tissue responses to TGF-betas and the widespread expression of their receptors suggest the TGF-betas may act as a "common currency," enabling diverse cell types to communicate with each other. Other members of the family are more restricted in their expression and the expression of their receptors, and may have a more limited and well-defined developmental role. The complex regulation of the members of the TGF-beta family is consistent with their importance as directors and coordinators of complicated physiological processes such as those occurring in the development of multicellular organisms. Their expression is highly regulated at the transcriptional and post-transcriptional levels, and their localization and activation can be affected by binding proteins and matrix proteins. We still have much to learn about the receptors for this family of growth factors, but the recent cloning of the activin and TGF-beta receptors and the discovery of their enzymatic nature has dramatically opened the way for future studies to resolve the signal transduction pathway(s) used by members of this family.(ABSTRACT TRUNCATED AT 250 WORDS)


Trans-regulation of homeotic genes in Drosophila.

Homeotic genes of the Antennapedia and bithorax complexes control Drosophila development by encoding DNA-binding proteins that regulate the transcription of target genes. Because either the presence or absence of these DNA-binding proteins alters development, regulation of the spatial patterns of expression is crucial to normal development. Numerous gene products are required for properly regulated expression of Antennapedia and bithorax complex genes, but few (if any) are dedicated solely to the regulation of these genes. One of the pleiotropic activators of homeotic genes in Drosophila, the brahma gene, encodes a protein similar to a yeast protein that is required for transcriptional activation of multiple tightly regulated genes. Other components of this system may be conserved as well, suggesting that the biochemical basis for induced gene expression in single-celled organisms may have more in common with programmed developmental pathways in multicellular organisms than previously thought.


Desensitization of the isolated beta 2-adrenergic receptor by beta-adrenergic receptor kinase, cAMP-dependent protein kinase, and protein kinase C occurs via distinct molecular mechanisms.

Exposure of beta 2-adrenergic receptors (beta 2ARs) to agonists causes a rapid desensitization of the receptor-stimulated adenylyl cyclase response. Phosphorylation of the beta 2AR by several distinct kinases plays an important role in this desensitization phenomenon. In this study, we have utilized purified hamster lung beta 2AR and stimulatory guanine nucleotide binding regulatory protein (Gs), reconstituted in phospholipid vesicles, to investigate the molecular properties of this desensitization response. Purified hamster beta 2AR was phosphorylated by cAMP-dependent protein kinase (PKA), protein kinase C (PKC), or beta AR kinase (beta ARK), and receptor function was determined by measuring the beta 2AR-agonist-promoted Gs-associated GTPase activity. At physiological concentrations of Mg2+ (less than 1 mM), receptor phosphorylation inhibited coupling to Gs by 60% (PKA), 40% (PKC), and 30% (beta ARK). The desensitizing effect of phosphorylation was, however, greatly diminished when assays were performed at concentrations of Mg2+ sufficient to promote receptor-independent activation of Gs (greater than 5 mM). Addition of retinal arrestin, the light transduction component involved in the attenuation of rhodopsin function, did not enhance the uncoupling effect of beta ARK phosphorylation of beta 2AR when assayed in the presence of 0.3 mM free Mg2+. At concentrations of Mg2+ ranging between 0.5 and 5.0 mM, however, significant potentiation of beta ARK-mediated desensitization was observed upon arrestin addition. At a free Mg2+ concentration of 5 mM, arrestin did not potentiate the inhibition of receptor function observed on PKA or PKC phosphorylation. These results suggest that distinct pathways of desensitization exist for the receptor phosphorylated either by PKA or PKC or alternatively by beta ARK.


Structure of a ricin mutant showing rescue of activity by a noncatalytic residue.

Ricin A chain is an N-glycosidase which removes a single adenine base from a conservative loop of 28S rRNA, thereby inactivating eukaryotic ribosomes. The mechanism of action has been proposed to include transition-state stabilization of an oxycarbonium ion on the substrate ribose by interaction with Glu 177. Conversion of Glu 177 to Gln reduces activity nearly 200-fold [Ready, M. P., Kim, Y., & Robertus, J. D. (1991) Proteins: Struct., Funct., Genet. 10, 270-278] while conversion to Ala (E177A) reduces activity only 20-fold [Schlossman, D., Withers, D., Welsh, P., Alexander, A., Robertus, J., & Frankel, A. (1989) Mol. Cell. Biol. 9, 5012-5021]. X-ray analysis of the latter mutant protein shows that a residue at the edge of the active site, Glu 208, rotates into the space left vacant by the mutation. Its rearranged carboxylate partially substitutes for that of Glu 177. This is equivalent to the rescue of enzyme activity by a second-site reversion. Kinetic analysis shows the E177A mutation affects kcat and not Km, consistent with the notion that the carboxylate serves in transition-state stabilization.


Specificity and kinetics of Rhodotorula gracilis D-amino acid oxidase.

D-Amino acid oxidase purified from the yeast Rhodotorula gracilis is a flavoenzyme which does not require exogenous FAD for maximum activity. The enzyme showed temperature and pH activity optima centred between 40 and 45 degrees C and between 8.0 and 8.5, respectively; a broad pH and ionic strength range of stability and a more limited range of thermostability was determined. The enzyme stability was markedly influenced by the presence of 2-mercaptoethanol. Apparent kinetic parameters for a number of substrates were determined: nonpolar and aromatic D-amino acids appeared to be the best substrates. Steady state measurements carried out at different oxygen concentrations indicated that for D-alanine the kinetic pattern is consistent with a Ping Pong Bi Bi mechanism; kcat values on D-alanine and D-valine are 43,250 min-1 and 31,370 min-1, respectively. L-Amino acids did not inhibit enzyme activity; several aromatic and aliphatic carboxylic acids proved to be competitive inhibitors of the enzyme and their ki values were determined. The reported properties of R. gracilis D-amino acid oxidase markedly distinguish it from other characterized D-amino acid oxidases.


Congenital dyserythropoiesis and progressive alopecia in Polled Hereford calves: hematologic, biochemical, bone marrow cytologic, electrophoretic, and flow cytometric findings.

Congenital dyserythropoiesis with dyskeratosis is a slow, progressive, and often fatal disease in Polled Hereford calves. Affected calves have a macrocytic normochromic anemia with a mild reticulocytosis. Studies indicate that calves are hyperferremic with increased saturation of serum total iron binding capacity, which rules out iron deficiency as a cause. Other secondary causes of dyserythropoiesis, including cobalamin and folate deficiencies, are unlikely because serum cobalamin and folate levels of affected calves were normal. Virus isolation was negative, and failure to identify bovine retroviral antigens or antibodies from several calves suggested that viral agents were not involved. Bone marrow cytologic findings were similar to those in congenital hereditary dyserythropoiesis in humans and included occasional multinucleate cells, internuclear chromatin bridging between nuclei of partially divided cells, and, more frequently, irregular nuclear shapes and chromatin patterns. DNA content and cell cycle distribution of erythroid cells appeared normal, and no electrophoretic abnormalities were detected in erythrocyte membrane proteins. The Polled Hereford syndrome is similar in many ways to type I congenital dyserythropoiesis in humans and may be an appropriate biomedical model for studying erythroid proliferation during dyserythropoiesis.


Parkinsonism treatment: Part III--Update.

The purpose of this review is to update clinicians with recent advances in the management of parkinsonism, including drug therapy, transplantation, and diet. Pertinent articles were obtained from an English-language literature search using MEDLINE (1970-1991), Index Medicus (1987-1991), Current Contents (1990), and bibliographic reviews of review articles. Index terms included parkinsonism, selegiline, pergolide, vitamin E, and transplantation. Fifty-five articles (representing 85 percent of the complete literature search) were selected by multiple reviewers for their contribution to the stated purpose. Emphasis was placed on double-blind, placebo-controlled, and randomized studies. Data from cited articles were examined by multiple reviewers for support of their stated hypothesis and were included as background for justification of major points in this article; critical studies were abstracted in more detail. New therapeutic measures have been added to the treatment of parkinsonism. Selegiline, a monoamine oxidase inhibitor type B, has shown beneficial results, especially in early stages. Pergolide, a dopamine agonist, may be an efficacious alternative to bromocriptine resistance or intolerable adverse effects. Vitamin E may have protective antioxidant properties, but very few clinical data are available. Fetal tissue transplantation needs continued research and remains very controversial. Diet modification may maximize the results of therapy with exogenous dopamine therapy. Clinicians should familiarize themselves with new alternatives for the management of parkinsonism in order to be reliable consultants for both professional and lay persons.


Long-term use of neuroleptics among elderly in a Swedish community.

Analysis of long-term use of neuroleptics among the elderly in a Swedish community. Cohort study, three-year follow-up period. Primary care. All people aged 65 years or older who used neuroleptics in 1984. Neuroleptic use was fairly common among elderly and continued long-term use was relatively frequent. One third of long-term users obtained doses exceeding a recommended dosage range. Prescribed doses were seldom changed during the study period. The high proportion of long-term users and the stability of the prescribed doses indicate that there is a need for more information to be made available to prescribes regarding the risks of long-term use of neuroleptics in primary care.


Improved biocompatibility of bioprosthetic heart valves by L-glutamic acid treatment.

Treatment of glutaraldehyde-fixed pericardium with L-glutamic acid and storage in bacteriostatic preservatives (paraben) stably antagonizes free, reactive aldehyde groups within the fixed bioprosthetic heart valve tissue. In 63-day subcutaneous implants in rats, the calcification rate of this treatment (13.3 +/- 2 mg calcium/g wt tissue) was markedly reduced as compared to conventionally treated tissue (169 +/- 24 mg/g; p less than 0.05). To test the influence of tissue-released toxic aldehydes on spontaneous endothelial cell ingrowth in vivo, vascular grafts (8-cm long, 6-mm diameter) from fixed pericardium treated with L-glutamic acid were interposed into the carotid arteries in ten sheep. They were compared to grafts from conventionally treated pericardium implanted at the contralateral side. Following 3 months of implantation, planimetry revealed 49% +/- 20% of the surface of conventionally preserved pericardium to be covered with red thrombus, but only 12% +/- 5% in L-glutamic acid treated pericardium (p less than 0.05). The ultrastructural findings of a closed endothelial cell layer on the graft surface reveals the new technique to be a promising approach towards increased biocompatibility of aldehyde-fixed bioprosthetic heart valves.


Polymer encapsulated neurotransmitter secreting cells. Potential treatment for Parkinson's disease.

Parkinson's disease, a neurologic disorder characterized by a dopamine deficit within the striatum, may be improved by transplantation of polymer encapsulated neurosecretory cells. Surrounding cells with a selectively permeable barrier offers several advantages, including preventing immune rejection and tumor formation while allowing functional efficacy. Bovine adrenal medullary chromaffin cells, or PC12 cells, a rat-derived pheochromocytoma cell line, were encapsulated within polyelectrolyte-based microcapsules or thermoplastic-based macrocapsules. Histologic and biochemical analyses revealed that both types of cells survived and that neurotransmitter release from capsules was sustained for several months in vitro, irrespective of the encapsulation method employed. Both of the encapsulation systems protected the enclosed cells from an immunologic challenge in vitro, and prevented immune rejection when cell containing capsules were implanted in an immunologically incompatible host. Chromaffin or PC12 cell containing capsules implanted into the dopamine (DA) depleted striatum of rats reduced the lesion associated functional deficit. These results suggest that encapsulated neurosecretory cell implants may be useful in treating various central nervous system (CNS) deficits, particularly in cases involving a specific neurochemical lesion.


Endothelial cell lining of bioprosthetic heart valve material.

In this in vitro study, the growth properties of cultured endothelial cells on conventionally treated pericardial valve material were measured. These data were compared to endothelial cell proliferation on an alternatively treated valve material. This alternative preservation procedure was developed in order to bind free, residual glutaraldehyde in the valve tissue by reaction with L-glutamic acid. In order to optimize endothelial cell attachment and proliferation, fibronectin and fibrillar collagen type I were tested as surface precoating substances. Cell viability of the seeded cells was evaluated by means of proliferation kinetics, antithrombotic activity, and morphological appearance. Endothelial cell death occurred within the first 2 days after seeding on conventionally treated valve tissue, independent of the type of precoating. On alternatively treated tissue, regular endothelial cell proliferation was observed. Precoating with fibrillar collagen markedly increased endothelial cell attachment and proliferation as compared to fibronectin. Maintenance of antithrombotic activity of the seeded cells was proven by regular release of prostacyclin.


A magnetically actuated left ventricular assist device.

Over the past 6 years, research has led to development of a small, lightweight, power-efficient, uniquely simple ventricular assist device driven by a magnetic actuator. Magnetic actuation permits total elimination of all mechanical motion converter components used for pusher plate displacement, resulting in a significant reduction in complexity and resultant increase in reliability. Extensive in vitro mock loop development has resulted in a left ventricular assist device (LVAD), the primary design parameters of which for the clinical prototype actuator and pump are 1) an actuator weight of 312 g, 2) actuator size of 32.5 cm3, 3) power requirements of 7.8 to 11.4 watts (60-100 beats per minute [BPM]), and 4) system efficiency of 24% to 34% and average dynamic stroke volume of 65 ml. Initial in vivo tests assessed this LVAD's performance in four sheep under three acute conditions of ventricular dysfunction. The results demonstrate that, at a pump-rate of 100 BPM, mean aortic pressure increased by 45-50 mmHg during 1) beta blockade, 2) coronary ligation, and 3) ventricular fibrillation. Pump flow ranged from 2.71 L/min to a maximum of 4.6 L/min. Acute test periods were arbitrarily set for 6 hours duration. Of the four sheep, two survived, one lived 5 hours, and the fourth lived 4.5 hours. Global fibrillation was the primary cause of failure. This initial in vivo data demonstrates the pump's ability to maintain satisfactory hemodynamic parameters of flow and pressure under three acute conditions of extreme left ventricular dysfunction in an animal model. These initial LVAD performances were encouraging. Further tests will use calves with a greatly expanded performance evaluation protocol.


New developments in the pharmacological treatment of schizophrenia.

The ability to use pharmacological treatment for schizophrenia is progressing in a most efficacious fashion, while the risk of adverse effects is declining. An important reevaluation of minimal effective antipsychotic drug dosages for both acute and extended treatment has taken place. Clozapine has provided clinical practitioners with a useful new alternative for treatment-refractory patients, and new research has helped clarify the role of different maintenance and prophylactic medication strategies. The author summarizes recent progress in these areas.


Long-term second-line treatment: a prospective drug survival study.

The long-term use of second-line antirheumatic drugs was prospectively studied in a consecutive sample of 245 patients with recently diagnosed rheumatoid arthritis. A survival analysis was done in which treatment termination due to side-effects and to insufficient therapeutic effect were used as index causes. Cumulative drug 'survival' of aurothioglucose with treatment termination due to toxicity was significantly less compared with hydroxychloroquine. With regard to lack of efficacy as index cause, the administration time of hydroxychloroquine was significantly less than that of either aurothioglucose or sulphasalazine. Treatment termination due to lack of efficacy or combined insufficient therapeutic response and toxicity proved to be influenced by the initial disease activity and by the rank order of prescription.


Sulphasalazine therapy in rheumatoid arthritis: qualitative changes in lymphocytes and correlation with clinical response.

Clinical and immunological parameters in 14 patients with rheumatoid arthritis (RA) receiving sulphasalazine (SASP) were evaluated, to determine whether their clinical response was reflected by any quantitative changes in their peripheral blood lymphocytes after 12 weeks. Whilst disease activity markers fell significantly, no such changes were noted in the percentage or absolute numbers of lymphocytes or their subsets. The lymphocytes of a further 21 patients before and after receiving SASP for 12 weeks were then studied qualitatively. The suppression mediated by in vitro SASP on ex vivo PHA stimulated lymphocytes showed a decrease at 12 weeks. This change was more marked and reached statistical significance only in those patients who showed a good clinical response. It is postulated that this may in some way be related to expression of activation markers and concomitant SASP binding.


Pylorus-preserving versus standard pancreatico-duodenectomy: an analysis of 110 pancreatic and periampullary carcinomas.

Pylorus-preserving pancreaticoduodenectomy (PPPD) has received increasing attention as a physiological alternative to the standard pancreaticoduodenectomy (PD) in patients with adenocarcinoma of the pancreatic head or the periampullary region. We evaluated mortality, morbidity and survival in 110 patients with pancreatic carcinoma (n = 53) or periampullary carcinoma (n = 57). In each group 31 patients underwent PD, the remainder PPPD. There were no differences in age, sex and tumour stage (UICC 1987) between patients undergoing PPPD or PD. Median follow-up was 24 months. There were no significant differences in mortality and morbidity rates between procedures. The mode of resection had no influence on survival in patients with periampullary carcinoma. Patients with pancreatic carcinoma who underwent PD had a significantly better survival rate compared with those who underwent PPPD (P less than or equal to 0.05). This was particularly so in patients with stage III tumours (P = 0.007). These data suggest that in patients with ductal carcinoma of the head of the pancreas, PD provides better survival than PPPD. However, PPPD appears to achieve equivalent results to PD in patients with periampullary carcinoma.


Distribution of tyrosine hydroxylase, serotonin, and leu-enkephalin immunoreactive cells in the brainstem of a shark, Squalus acanthias.

The central nervous system location of neurochemicals that are widely distributed among extant animals may give us clues to changes that occurred in the brains of these animals during evolution. We have been studying the brains of cartilaginous fishes, a heterogeneous group whose central nervous system varies considerably. Squalus acanthias, the spiny dogfish shark, was chosen to represent the squalomorphs, a group of living sharks known to possess many primitive characters. The distribution of tyrosine hydroxylase (TH+), serotonin (5-HT+), and leu-enkephalin (LENK+) positive cells within the brainstem of Squalus was determined by use of antibodies to these substances. All the major raphe groups described for mammals were found in Squalus. The 5-HT+ cells in raphe nuclei were more uniformly distributed in Squalus than in Heterodontus, the horn shark. Other nuclei that were 5-HT+ and LENK+, and that have been identified in mammals, included reticularis paragigantocellularis lateralis, a B9 cell group, and reticularis magnocellularis. The postcommissural nucleus and pretectal area contained 5-HT+ and LENK+ cells. These cells have been described in a holocephalian, in teleosts, and in reptiles but not in other elasmobranchs or in mammals. Cells that were TH+ were located in prominent A1/A2, A6 (locus coeruleus), A9 (substantia nigra), and A10 (ventral tegmental area) cell groups, and in a very small A5 group. We conclude that the variation in chondrichthian brainstems exceeds that in mammals, and we suggest that this variation is related to life-style and the long evolutionary history of these fishes.


Evidence for linear extrachromosomal elements mediating gene amplification in the multidrug-resistant J774.2 murine cell line.

Previous studies from our laboratory have demonstrated specific cytogenetic alterations accompanying development of colchicine resistance in the J774.2 murine cell line and in two sublines (J7.Cl-30 and J7.Cl-100). Although gene amplification is not observed in the parental J774.2 cell line, a approximately 35-fold amplification of the gene for p-glycoprotein (mdr) was noted in the J7.Cl-30 subline (770-fold CLCR) and a approximately 70-fold amplification in the J7.Cl-100 subline (2500-fold CLCR). In this study, we analyzed the localization and organization of the mdr gene. In the colchicine-resistant (CLCR) J7.Cl-30 subline, the p-glycoprotein domain was observed to reside on differently sized extrachromosomal elements. Our results indicate not only circular extrachromosomal elements but also linear extrachromosomal elements. By means of pulsed-field gel electrophoresis (PFGE), the sizes of the extrachromosomal elements were shown to be greater than 2,500 kilobase-pairs (kb), 800 kb, and 400 kb. In contrast, the J7.Cl-100 subline was characterized by the presence of homogeneously staining regions (HSRs). We have noted that with increasing colchicine resistance the extrachromosomal elements are replaced by HSRs. Our findings of linear elements that appear to be precursors of HSRs may offer a new way to interpret different theories of extrachromosomal gene amplification. The J7.Cl-30 cell line presents a unique system to analyze further the formation and structure of extrachromosomal elements.


Cytogenetics of multiple endocrine neoplasia syndromes. I. Two different, unique clonal chromosome changes in a medullary thyroid carcinoma and in a C-cell thyroid hyperplasia.

In short-term cultures of tumor tissue from a medullary thyroid carcinoma (MTC), we found a large clone of cells with a balanced translocation t(9;12)(p24;q22). A large clone with a balanced translocation t(10;16)(p11;q24) was also found in cultures from a C-cell thyroid hyperplasia. No clearcut evidence for chromosome instability was observed in the lymphocytes of the two patients. The mother of the first patient died of MTC; two relatives of the second patient had MTC and one of them had pheochromocytoma. These findings classify the two subjects as MEN 2A patients with different phenotypic expression but with the same type of chromosomal abnormality.


Patient tolerance of ioxaglate and iopamidol in internal mammary artery arteriography.

To compare discomfort caused by ioxaglate and iopamidol, 25 patients scheduled for coronary angiography including internal mammary arteriography were studied. Each patient received both agents. Data were available on 22 randomly selected patients who completed the protocol. Two patients were withdrawn because of unsuccessful internal mammary artery cannulation and one because of idiosyncratic reaction to diazepam. After the internal mammary artery injections, the short-form McGill Pain Questionnaire (SF-MPQ) was completed to evaluate the patient response. Ioxaglate caused significantly less discomfort than iopamidol. Word scale (WS) p less than .05; visual analog scale (VAS) p less than .05. We conclude that ioxaglate is much better tolerated than iopamidol in internal mammary arteriography.


Atresia of the left main coronary artery: clinical recognition and surgical treatment.

Atresia of the left main coronary artery is an extremely rare anomaly with very few cases presented in the literature. Even more uncommon are reports of successful surgical repair. This article concerns two cases of atresia of the left main coronary artery treated surgically with a favourable outcome. The two patients (a 16 year-old boy and a 43 year-old woman) had a different clinical presentation but identical angiographic and morphologic features. The authors examine the embryogenetic defect underlying this anomaly. The differential diagnosis involves two congenital malformations (single coronary artery and anomalous origin of the left coronary artery from the pulmonary trunk) and acquired atherosclerotic disease of the left main coronary artery; the distinguishing features of these conditions are reviewed. Surgical management by means of internal mammary artery revascularization is discussed in light of recent reports about adequacy of blood flow in internal mammary artery bypass grafts.


Right internal mammary artery graft angioplasty through a right brachial artery approach using a new custom guide catheter: a case report.

Angioplasty of right internal mammary artery grafts may present problems because of the variable origin of the mammary artery and its angulation from the subclavian artery. We report a case of successful angioplasty using a custom designed guide catheter, after failed attempts using conventional guide catheters.


Developmental defects in Gorlin syndrome related to a putative tumor suppressor gene on chromosome 9.

Gorlin syndrome is an autosomal dominant disorder that predisposes to basal cell carcinomas of the skin, ovarian fibromas, and medulloblastomas. Unlike other hereditary disorders associated with cancer, it features widespread developmental defects. To investigate the possibility that the syndrome is caused by mutation in a tumor suppressor gene, we searched for loss of heterozygosity in 16 sporadic basal cell carcinomas, 2 hereditary basal cell carcinomas, and 1 hereditary ovarian fibroma and performed genetic linkage studies in five Gorlin syndrome kindreds. Eleven sporadic basal cell carcinomas and all 3 hereditary tumors had allelic loss of chromosome 9q31, and all informative kindreds showed tight linkage between the Gorlin syndrome gene and a genetic marker in this region. Loss of heterozygosity at this chromosomal location, particularly in hereditary tumors, implies that the gene is homozygously inactivated and normally functions as a tumor suppressor. In contrast, hemizygous germline mutations lead to multiple congenital anomalies.


The paired box gene pox neuro: a determinant of poly-innervated sense organs in Drosophila.

This study describes the structure and function of pox neuro (poxn), a gene previously isolated by virtue of a conserved domain, the paired box, which it shares with the segmentation genes paired and gooseberry. Its expression pattern has been analyzed, particularly during development of the PNS. We propose that poxn is a "neuroblast identity" gene acting in both the PNS and the CNS on the basis of the following evidence. Its expression is restricted to four neuronal precursors in each hemisegment: two neuronal stem cells (neuroblasts) in the CNS, and two sensory mother cells (SMCs) in the PNS. The SMCs that express poxn produce the poly-innervated external sense organs of the larva. In poxn- embryos, poly-innervated sense organs are transformed into mono-innervated. Conversely, ectopic expression of poxn in embryos transformed with a heat-inducible poxn gene can switch mono-innervated to poly-innervated sense organs. Expression of poxn in the wing disc is restricted to the SMCs of the poly-innervated sense organs, suggesting that poxn also determines the lineage of poly-innervated adult sense organs.


Isolation of the neu/HER-2 stimulatory ligand: a 44 kd glycoprotein that induces differentiation of mammary tumor cells.

The neu/HER-2 proto-oncogene (also called erbB-2) encodes a transmembrane glycoprotein related to the epidermal growth factor receptor. We have purified to homogeneity a 44 kd glycoprotein from the medium of ras-transformed cells that stimulates phosphorylation of the Neu protein and retains activity after elution from the polyacrylamide gel. The protein is active at picomolar concentrations and displays a novel N-terminal sequence. Cross-linking experiments with radiolabeled p44 result in specific labeling of Neu, indicating that p44 is a ligand for Neu or a related receptor. The purified protein induces phenotypic differentiation of cultured human breast cancer cells, including altered morphology and synthesis of milk components. This is accompanied by an increase in nuclear area, inhibition of cell growth (probably by cell cycle arrest at the late S or the G2/M phases), and induction of DNA polyploidy. We propose the name Neu differentiation factor (NDF) for p44.


Effects of beta-2 microglobulin anti-sense oligonucleotides on sensitivity of HER2/neu oncogene-expressing and nonexpressing target cells to lymphocyte-mediated lysis.

The mechanism by which HER2/neu overexpressing tumor cells resist NK, LAK, and LDCC cytotoxic lymphocytes was investigated. Resistance was not explained by a delay in kinetics of lysis, concurrent resistance to TNF, or a diminished expression of the transferrin receptor. HLA-class I expression, however, was markedly elevated compared to HER2 nonexpressing targets suggesting a reason for resistance. To test the role of class I, we selectively decreased expression by incubation of targets with beta-2 microglobulin anti-sense oligonucleotides. Anti-sense-treated HER2+ targets, displaying levels of class I comparable to HER2- targets, were still markedly resistant to cytotoxic effectors. Down-regulation of class I expression in HER2- carcinoma cells also had no effect on sensitivity to cytotoxicity by anti-sense treatment of Raji and U937 targets resulted in enhanced sensitivity to NK and LAK effectors but not to T cells mediating LDCC. These data indicate resistance to cytotoxicity in HER2-expressing targets cannot be solely explained by heightened expression of class I. The data also support the concept that class I expression regulates sensitivity to NK and LAK cells (but not LDCC effectors) in selected targets.


Activation of noradrenergic and nitrergic mechanisms in the rat anococcygeus muscle by nicotine.

1. Nicotine (10 mumol/L) produced rapidly developing but transient contractions of anococcygeus muscle isolated from rats. The magnitude of the response varied considerably between preparations. Tachyphylaxis occurred, such that no response was elicited by the same or a larger concentration in the continued presence of 10 mumol/L nicotine. 2. Contractions produced by nicotine were not affected by atropine, but were abolished by Hexamethonium and the alpha-adrenoceptor antagonists prazosin and phentolamine. Contractions were absent in the anococcygeus muscles of rats pretreated with reserpine. 3. The alpha 2-adrenoceptor agonist UK14304, or guanethidine, raised the tone of the anococcygeus muscle, and converted responses to field stimulation and nicotine to relaxations. Nicotine-induced relaxations were more pronounced in the presence of UK14304 than guanethidine. 4. Relaxations produced by nicotine (1-18 mumol/L) were transient, and tachyphylaxis occurred. When precautions were taken to avoid tachyphylaxis, concentration-response curves could be constructed. The relaxations elicited by nicotine were abolished or greatly reduced by hexamethonium, tetrodotoxin or omega-conotoxin GVIA. 5. The nitric oxide synthase inhibitor L-NG-nitroarginine methyl ester (90 mumol/L) enhanced contractile responses to field stimulation and nicotine, and markedly reduced relaxations elicited by field stimulation and nicotine in the presence of UK14304. These relaxations were restored by L-arginine (270 mumol/L). 6. The results suggest that nicotine acts on nicotinic receptors of noradrenergic and nitrergic nerve terminals in the rat anococcygeus muscle, resulting in the release of noradrenaline and nitric oxide respectively.


Formoterol, a new long-acting beta 2 agonist, inhaled twice daily, in stable asthmatic subjects.

To determine whether formoterol, a new beta 2 agonist with experimentally documented long duration, is clinically more effective than salbutamol in the maintenance treatment of chronic asthma. Randomized double-blind between-patient comparison between treatment with formoterol and with salbutamol during four weeks. Asthma/allergy department in a university hospital. Thirty-seven patients with chronic stable asthma, who during a two-week run-in period with inhaled salbutamol, 4 x 100 micrograms twice a day, used at least four additional doses (100 micrograms each) daily, were randomly assigned to use either formoterol or salbutamol. Thirty-five patients were evaluated for efficacy. One early withdrawal and one dropout were found in the salbutamol group. The groups were similar with respect to demographic data and baseline lung function. During the four-week study period, the patients used either formoterol (4 x 6 micrograms twice a day and as necessary, n = 19) or salbutamol (4 x 100 micrograms twice a day and as necessary, n = 16). Inhaled steroids and orally administered theophylline were allowed if doses were kept constant. The median number of additional doses per 24 h (median of two weeks) of the test aerosols was 0 (range, 0 to 6) for formoterol and 4 (range, 0 to 14) for salbutamol (p less than 0.01). Morning and evening PEFRs were 422 (SEM = 31) and 443 (SEM = 30), respectively, for formoterol, and 335 (SEM = 30) and 360 (SEM = 26), respectively, for salbutamol (p = 0.05 for both). Formoterol was superior (p less than 0.05) to salbutamol with respect to control of asthma symptoms, estimated duration of action and patient preference. Side effects did not differ. Inhaled formoterol administered twice a day and as necessary was clinically more effective than the same regimen of salbutamol.


Sulfasalazine-induced pulmonary disease.

We report the findings in two patients with sulfasalazine-induced pulmonary disease. The first patient developed pulmonary interstitial fibrosis after more than 4 yr of treatment for Crohn's disease. Pulmonary symptoms and chest roentgenographic and pulmonary function abnormalities gradually reversed after stopping the drug. No specific treatment was given. The second patient, who had rheumatoid arthritis without pulmonary disease, received the drug for 1 yr without experiencing any problems. Readministration seven months later resulted in the development of an acute interstitial pulmonary disease. Discontinuing the drug and treatment with corticosteroids produced rapid improvement. We discuss these patients in relation to other reports of sulfasalazine-induced pulmonary toxicity, highlighting their atypical features.


Breath-holding in panic disorder.

In earlier studies, it was found that exogenous carbon dioxide administration provoked high anxiety in panic disorder (PD) patients, whereas healthy normals and patients suffering from other anxiety disorders were hardly affected. Breath-holding provides a simple method to induce endogenous CO2 accumulation. Fourteen PD patients, 14 patients suffering from other anxiety disorders, and 14 healthy controls were asked to hold their breath as long as possible. Apnea times appeared to be longer in the normal control group than in the other two groups. Using a one-tailed t test, a trend for a difference was found between the PD subjects and other anxiety patients, the PD patients having slightly lower values. No differences were found with respect to increase in anxiety during breath-holding or the ratio of apnea times before and after hyperventilation.


Potentiation of bromobenzene-induced pneumotoxicity by phenobarbital as determined by bronchoalveolar lavage fluid analysis.

Bromobenzene produces pulmonary, renal and hepatic damage in the rat. Phenobarbital potentiates bromobenzene-induced hepatotoxicity. Studies were initiated to determine if phenobarbital potentiates the pulmonary damage produced by bromobenzene. In a dose ranging study, adult male rats were treated daily for 4 days with phenobarbital (80 mg/kg, ip) and on the fifth day were dosed with 0, 2, 3, or 4 mmoles/kg, ip, bromobenzene. In a larger study phenobarbital was given for 4 days (80 mg/kg, ip), and bromobenzene (3.3 mmoles/kg, ip) was given on the fifth day. Pulmonary damage was assessed 24 hours later in the first study and 12 hours later in the second study by bronchoalveolar lavage fluid analysis (BALF), microsomal mixed function oxidase measurements and histopathological evaluations. BALF biochemical markers employed were gamma-glutamyl transpeptidase (GGT), lactate dehydrogenase (LDH) and total protein. Phenobarbital treatment greatly enhanced bromobenzene-induced GGT and LDH release into the lavage fluid in a dose-dependent manner. Phenobarbital treatment increased microsomal 7-O-dealkylation of both ethoxy- and pentoxyresorufin in the liver without affecting these activities in the lung. Bromobenzene treatment decreased the hepatic microsomal dealkylation of decreased the hepatic microsomal dealkylation of pentoxyresorufin in a dose-dependent manner. Since known rat pulmonary P450 isozymes have been reported to be insensitive to phenobarbital induction, it may be that the toxicity is due to transport of a reactive metabolite(s) formed in the liver to the lung or bromobenzene is activated by some other pulmonary P450 isozyme responsive to phenobarbital.


Coronary heart disease risk factors before and after bypass surgery: results of a controlled trial on multifactorial rehabilitation.

The effect of a three-phase multifactorial institution-based rehabilitation programme on coronary heart disease (CHD) risk factors was studied in an open randomised trial comprising 228 patients undergoing coronary artery bypass surgery allocated into a rehabilitation (R) group (n = 119) and a hospital (H = control) group (n = 109). Follow-up examinations were performed at 6 and 12 months. Serum total cholesterol and triglyceride levels decreased significantly in both groups during follow-up. These decreases were not significantly different between the R and H groups. Serum high density lipoprotein (HDL) cholesterol level increased significantly at 6 and 12 months in the R group, but not in the H group. The differences in the changes between the groups were not significant. The ratio of serum HDL cholesterol to total cholesterol increased significantly in the R group from the preoperative value of 0.154 to 0.179 (P less than 0.001) at 6 months and to 0.180 (P less than 0.001) at 12 months. In the H group these values were 0.152, 0.166 (P less than 0.001) and 0.168 (P less than 0.001), respectively. The significance of the differences in the changes between the groups were P = 0.01 at 6 months and 0.06 at 12 months. These differences were more obvious in patients aged 55 years or under. There was a significant decrease (P = 0.005) in the proportion of smokers in the R group and a significant increase in the proportion of patients taking regular exercise in both groups as assessed by questionnaire.(ABSTRACT TRUNCATED AT 250 WORDS)


Both beta 1- and beta 2-adrenoceptors are involved in mediating phosphatidylcholine secretion in rat type II pneumocyte cultures.

A primary culture of rat type II pneumocytes was used for the pharmacological and functional characterization of beta-adrenoceptor subtypes. The beta-adrenoceptor agonists, isoprenaline, dobutamine and procaterol concentration dependently increased the secretion of phosphatidylcholine. These effects were attenuated by propranolol. The effect of dobutamine was attenuated by atenolol, and that of procaterol by ICI 118,551. Isoprenaline-induced secretion was attenuated by the combination of the two blockers but not by each one alone. In conclusion, both beta 1- and beta 2-adrenoceptor subtypes mediate phosphatidylcholine secretion in rat type II pneumocytes.


N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, an irreversible receptor inactivator, as a tool for measurement of alpha 2-adrenoceptor occupancy in vivo.

In rats treatment with N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) induces a dose-dependent decrease in the number of alpha 2-adrenoceptors. Prior injection of alpha-adrenergic agents such as yohimbine and clonidine protect alpha 2-adrenoceptors against the effects of EEDQ. The ED50 values for yohimbine and clonidine were 10.27 and 5.83 mumol/kg, respectively.


Na(+)-dependent high-affinity uptake of L-glutamate in cultured fibroblasts.

Uptake of 1 microM [3H]L-glutamate by cultured 3T3 fibroblasts was strongly dependent on extracellular Na+; it was reduced by elevated concentrations of K+ (60 mM) but it was not influenced by variations in the concentration of Ca2+ (0-9.6 mM). D- and L-Asparate, D- and L-threo-3-hydroxyaspartate DL-threo-3-methylaspartate and a few other glutamate derivatives and analogues inhibited the uptake but several close analogues of L-glutamate (including D-glutamate) had no effect, implying that the uptake system is highly structurally selective. The recently identified inhibitor of glutamate uptake in synaptosomal preparations, L-trans-pyrrolidine-2,4-dicarboxylate, was also among the inhibitors. Apparent Km of the uptake was found to be less than 10 microM. The present observations indicate that Na(+)-dependent 'high-affinity' uptake of L-glutamate may appear in structures which are apparently unrelated to glutamatergic synaptic transmission in the CNS.