Methylprednisolone improves pulmonary function and hemodynamics in experimental gram-positive septicemia.

It has been suggested that the effects of high-dose corticosteroid therapy (HDC) in gram-positive (G+) and gram-negative (G-) septicemia differ. As few data are available on HDC in G+ septicemia, pulmonary and cardiovascular function was studied for 44 hr in five anesthetized pigs subjected to brief infusion of live Staphylococcus aureus (approximately 10(11) cfu) followed by intravenous methylprednisolone (MP, 30 mg/kg) administered as a bolus every 8 hr. Comparisons were made with six septic pigs given no MP but otherwise identically managed. Six control pigs received no bacteria or MP. Infusion of bacteria induced identical transient pulmonary hypertension in both septic groups (52 +/- 7 mm Hg, mean +/- SD), but MPAP remained significantly lower in the pigs with MP (18 +/- 1 mm Hg vs. 30 +/- 9 mm Hg at 8 hr, P less than 0.05). MAP was better maintained in the MP group (107 +/- 9 mm Hg vs. 80 +/- 16 mm Hg at 8 hr, P less than 0.05). Pulmonary function also was less affected in the MP group at 8 hr, with significantly better maintenance of arterial oxygenation (13.5 +/- 1.2 kPa vs. 9.4 +/- 2.2 kPa, P less than 0.05) less venous admixture (11 +/- 6% vs. 34 +/- 23%, P less than 0.05) and superior lung-thorax compliance (29 +/- 5 ml/cm H2O vs. 15 +/- 5 ml/cm H2O, P less than 0.05). Five of five with MP survived, whereas two of six without MP survived (P = 0.045). MP thus attenuated pulmonary and hemodynamic abnormalities induced by S. aureus septicemia.(ABSTRACT TRUNCATED AT 250 WORDS)


Increased plasma concentrations of hyaluronan after major thermal injury in the rat.

Hyaluronan (HYA) is an ubiquitous polysaccharide in connective tissue interstitium; its normal plasma concentration is in the nanogram/ml range. Following major burn injury in sheep, plasma HYA can increase to levels tenfold greater than normal. The present study aimed to determine the effects of major cutaneous burns on plasma HYA concentration in rat, since in this species, the HYA elimination kinetics may better resemble those in man. Thermal injury did not alter the weight-average molecular weight of HYA in skin. HYA concentration in plasma was 46 +/- 4 ng/ml (mean +/- SEM) in controls. Three hours after scald burns to 40% of the body surface area, plasma HYA was 61 +/- 10 ng/ml in unresuscitated animals (P less than 0.1 vs. controls). After fluid replacement by lactated Ringer's plasma HYA was 75 +/- 8 ng/ml (P less than 0.01 vs. control), whereas plasma infusion prevented the elevation of plasma HYA. HYA also increased significantly after lactated Ringer's infusion in noninjured animals. The increased plasma concentration of HYA after major burns is probably a consequence of increased lymph flow, increasing its transport from skin interstitium. Possibly, plasma concentrations of connective tissue components may be used as indicators of the severity and extent of burn injuries.


Differential contractile responses of mesenteric and pulmonary artery segments to norepinephrine and phorbol ester in the septic pig.

The contractile response of isolated vascular segments was studied in Yucatan miniature swine approximately 48 hr after induction of sepsis by intraperitoneal injection of live Escherichia coli. Compared to non-septic controls, segments of the cranial mesenteric artery from septic animals showed a significantly attenuated contractile response to the adrenergic receptor agonist norepinephrine (NE). The EC50 for NE increased from 1.1 +/- 0.3 to 6.3 +/- 2.0 microM and the Emax decreased from 1,010 +/- 179 to 387 +/- 75 mg tension/mg tissue. In contrast, segments of the pulmonary artery showed no significant difference in contractility to NE between sham-operated and septic animals. Mesenteric and pulmonary artery segments from both septic and control animals exhibited similar contraction to the protein kinase C activator phorbol-12, 13-dibutyrate. This suggests that the observed hyporeactivity to NE in porcine mesenteric artery segments is not simply due to cellular damage by toxins associated with the septic state. The results also indicate that the impact of gram-negative sepsis on vascular contractile function varies between tissue from the systemic and pulmonary circulation in pigs.


Urokinase in conditioned medium from phorbol ester-pretreated endothelial cells promotes polymorphonuclear leukocyte migration.

Serum-free conditioned medium (CM) generated by human umbilical vein endothelial cell monolayers following pretreatment with 100 ng/ml of phorbol myristate acetate (PMA) promoted human polymorphonuclear leukocyte (PMNL) migration as assayed in blindwell chambers. Stimulation of PMNL migration in response to CM was dependent on the dose of PMA used to pretreat the endothelial cells as well as the duration of incubation time to generate CM. Phorbol esters have been previously shown to release plasminogen activators from vascular endothelial cells. In the present study, pretreatment of endothelial cells with PMA also increased plasminogen activator activity in CM at a time course similar to the generation of PMNL chemoattractant activity. Treatment of CM with a polyclonal antibody against human urokinase-type plasminogen activator (uPA) not only inhibited uPA activity, but also significantly reduced PMNL chemoattractant activity when compared with untreated CM. In contrast, treatment of CM with an antibody directed against tissue-type plasminogen activator (tPA) did not affect PMNL migratory activity. Furthermore, when CM was passed over an anti-uPA immunoaffinity column, plasminogen activator activity was reduced 90% and chemoattractant activities was reduced 68%. Both plasminogen activator and chemoattractant activities were reconstituted in the eluate from the anti-uPA column. These data demonstrate that uPA present in the CM from PMA-pretreated endothelial cells stimulates PMNL chemoattractant activity and suggests a possible role for endothelial cell-derived uPA in stimulating migration of peripheral blood leukocytes at an inflammatory locus.


Fundamentals of receptor theory: basics for shock research.

A variety of inflammatory mediators [e.g., tumor necrosis factor-alpha (TNF alpha)], endogenous hormones (e.g., epinephrine), and neurotransmitters (e.g., norepinephrine) are elevated as either a cause or a consequence of circulatory shock. The pathophysiologic responses observed during circulatory shock are the direct result of a complex interplay between the individual responses produced by the various mediators that interact with specific receptors. For example, as part of a compensatory response in circulatory shock, sympathetic outflow increases, which results in elevated synaptic levels of norepinephrine, which will activate alpha- and beta-adrenoceptors in the synaptic cleft. Additionally, plasma epinephrine and norepinephrine concentrations are elevated to a level sufficient to stimulate alpha- and beta-adrenoceptors in the heart, vasculature, and kidney, leading to profound changes in heart rate, cardiac output, peripheral vascular resistance, renal blood flow, and urine output. As such, the nature of the interaction between inflammatory mediators, hormones, and neurotransmitters with specific receptors in the cardiovascular system is fundamental to understanding the changes in circulatory status that occur during the shock state.


1,1,3 Tricyano-2-amino-1-propene (Triap) stimulates choline acetyltransferase activity in vitro and in vivo.

1,1,3 Tricyano-2-amino-1-propene (Triap) is a small molecule that has neurotrophic properties similar to nerve growth factor (NGF). Studies have shown that NGF increases choline acetyltransferase (ChAT) activity, the enzyme responsible for the synthesis of acetylcholine, in several cell lines and in the CNS of adult animals. To investigate whether Triap can cause similar increases in ChAT enzyme activity, we used the PC12 cell line and primary cultures of rat fetal brain tissue to examine Triap's effects. Nanomolar concentrations of Triap produced a 4.2- and 2.1-fold increase in the ChAT activity of PC12 cells and cultured rat fetal brain cells, respectively. This stimulation reached a plateau within 4 days of treatment in the primary fetal brain cultures with the first increases evident within 24 h. In the PC12 cell line, Triap's stimulation of ChAT activity was significantly greater than increases produced by optimal concentrations of NGF. Triap also matched NGF's stimulation of ChAT activity in primary neuronal culture. Triap also potentiated NGF's actions on ChAT activity in the PC12 cell line and in primary fetal neuronal cultures. These increases in enzyme activity correlated with increases in cellular enzyme levels as assessed using immunochemical identification of the ChAT enzyme. We also conducted experiments to determine if Triap also induced these same increases in ChAT activity in adult animals. Ten-day chronic injections of Triap in mice resulted in significant increases in specific ChAT enzyme activity in the cortex and septal-hippocampal area. Similar increases in ChAT enzyme levels were also detected using western blotting techniques.(ABSTRACT TRUNCATED AT 250 WORDS)


Age dependency of the susceptibility of rats to aminooxyacetic acid seizures.

Immature rats are more susceptible to clonic seizures induced by aminooxyacetic acid (AOAA) than mature and senile rats. Highest susceptibility to AOAA seizures was observed in 7-14-day-old rat pups. The lowest susceptibility was recorded in 10-20 month-old rats. AOAA seizures in 14-day-old rats were blocked by clonazepam and valproate, but not by phenobarbital, carbamazepine, diphenylhydantoin, trimethadione or ethosuximide. Morphological analysis of brains from 14-day- and 3-month-old rats which experienced AOAA seizures did not reveal epilepsy-related damage. These observations suggest that immature rat brain is highly prone to convulsions induced by AOAA and that such convulsions are difficult to control by available antiepileptic treatment.


Neuronal cell loss in heterozygous staggerer mutant mice: a model for genetic contributions to the aging process.

Staggerer is a neurological mutation of mice that causes a severe ataxia correlated with digenesis of the cerebellar cortex. The Purkinje cell population in the homozygous mutant is reduced in size with a near total atrophy of dendritic structure. Further, the cells are ectopic and are reduced in number by about 75%. All of these phenotypes have been shown to be direct effects of the staggerer gene on the Purkinje cell itself. As an indirect consequence of gene action, virtually all of the cerebellar granule cells die as do 60% of the cells of the inferior olive. The mutation is described as recessive because of the heterozygote, +/sg, is behaviorally normal and the mature cerebellum shows none of the defects described in the homozygous mutant. We report here that, as the +/sg mouse advances in age, a syndrome of cell losses is observed. While these losses are not as severe as in the homozygote, by 12 months of age 35% of the Purkinje cells are gone, as are 35% of the granule cells and 40% of the cells in the inferior olive. We propose that these results illustrate a synergy between the aging process and the heterozygous genotype. Neither alone is sufficient to cause the cell loss. This interaction suggests that the +/sg represents a new model for the genetic contribution to regressive CNS changes during aging.


Development of AChE-positive neuronal projections from basal forebrain to cerebral cortex in organotypic tissue slice cultures.

Development of the innervation of the cerebral cortex by acetylcholinesterase (AChE)-stained basal forebrain neurons was studied in vitro using the roller tube technique. Slice cultures were maintained from 3 days to 4 weeks either in serum based medium or in chemically defined medium, each supplemented in some cases with nerve growth factor (NGF). The distribution of AChE and choline acetyltransferase (CAT)-containing neurons was investigated using histo- and immunocytochemical techniques. Slice cultures of basal forebrain revealed the presence of large and medium sized AChE-positive neurons. Within one week of cultivation, numerous AChE-labeled fibers could be seen growing out from the basal forebrain toward the cortex. After entering cortical tissue most of the afferent basal forebrain fibers projected either radially or obliquely into the cortical layers. Many afferent axons initially also travelled tangentially within the white matter, and turned then to grow into the cortical layers. Cerebral cortex tissue maintained a coarse laminar organization. Ramifications of basal forebrain fibers were visible within the subplate region, the deep and superficial cortical layers, and within the marginal zone; greatest density occurred in the subplate region and in marginal zones. Many of these processes exhibited branching patterns markedly similar to those observed during cortical development in vivo. Cortex slices placed with the pial surface adjacent to the basal forebrain revealed AChE-stained fibers that entered the cortical tissue through the marginal surface and gave off ramifications within the superficial layers and, less frequently, the deeper cortical layers. CAT-immunostaining revealed labeled cell bodies and neurites only in the basal forebrain, not in the cortex tissue. Control experiments with co-cultures of basal forebrain and cerebellum slices showed no AChE-positive fiber ingrowth into the cerebellum tissue. The results of these studies demonstrate that basal forebrain projections to cerebral cortex in vitro appear similar to the projections that develop in vivo, and indicate that organotypic co-cultures provide a valuable model for studies of developing cortical afferents.


Actin-binding proteins in the growth cone particles (GCP) from fetal rat brain: a 44 kDa actin-binding protein is enriched in the fetal GCP fraction.

Neuronal growth cones, the motile tips of growing neurites, are thought to play a significant role in nerve growth. To study the role of actin in their motility, we examined actin-binding proteins in growth cone particles (GCP) isolated from fetal rat brain, using a blot-overlay method with biotinylated actin. Among the more than ten species of actin-binding proteins in the GCP, a 44 kDa protein was found specifically in growth cones and was enriched in the cytoskeletal and the membrane skeletal subfractions from the GCP. This protein binds to actin in a Ca(2+)- and Mg(2+)-dependent manner, and ATP enhances its binding to actin. The protein was predominantly present in the fetal GCP, but it is expressed at a much lower level in the neonatal GCP and not detected in adult synaptosomes. The protein also bound to a deoxyribonuclease I column and was eluted by EGTA-containing buffer. The 44 kDa protein appears to be a novel actin-binding protein, since none of the known actin-binding proteins exhibit this combination of properties. Our results suggest that the protein may be involved with the early stages of neurite extension.


Sexual dimorphism of the dopamine-beta-hydroxylase-immunoreactive neurons in the rat locus ceruleus.

Sex differences in the noradrenaline synthesizing neurons of the locus ceruleus (LC) in rat brain were investigated immunocytochemically using an antibody to dopamine-beta-hydroxylase. Female adult rats contained a greater structural volume and average somatic area in the anterior intermediate region of the nucleus compared with males. Whether this difference is related to the endocrine status of the animals, and consequently a functionally distinct population of neurons, is yet to be determined.


Pre- and postnatal development of noradrenergic projections to the rat spinal cord: an immunocytochemical study.

Using immunocytochemistry with a specific antiserum against noradrenaline, the pre- and postnatal development of noradrenergic (NA) projections to the rat spinal cord was studied from embryonic day 16 (E16) to adulthood (the day following nocturnal mating being considered as E0). In this study, pregnant animals were pre-treated with the MAO inhibitor pargyline (200 mg/kg i.p.), whereas postnatal animals received 100 mg/kg. In vibratome sections, noradrenaline-immunoreactive (NA-IR) axons were seen to invade the spinal cord at E16, at cervical and upper thoracic levels, from the ventral funiculus. At E18, small caliber NA-IR fibers were present in the ventral horn at all cord levels, and some fibers were seen in the intermediolateral cell column (IML) at thoracic level. The growth of axons towards the dorsal horn became noticeable by postnatal day 0 (P0). At P3, fine beaded and radially orientated NA-IR fibers were observed at all levels. The pattern of NA innervation of the dorsal horn was similar to that of the adult by P7. The segregation of noradrenaline immunoreactivity in the ventral and dorsal horns, the IML and the periependymal area was more obvious at all levels by P14 and P20. From P30 the NA innervation was similar to that found in the adult spinal cord. Thus, noradrenaline, like serotonin, was present early in the spinal cord before the onset of specific functions. In addition to and prior to its transmitter function, it might play a trophic role in the neurogenesis of the spinal cord.


On the ontogenetic and sequential characteristics of bombesin-induced grooming in the infant rat.

This paper examined the grooming effects of central injections of the tetradecapeptide bombesin (BN) in the infant rat. Anaesthetized rat pups of 1-20 days of age (n = 7/dose/age) were injected intracerebroventricularly (i.c.v.) with either BN (0.01-1.0 micrograms) or saline (control condition) and placed in heated test cages. Following recovery from the anaesthetic, the subsequent behaviour displayed by the pups was videotaped for the next 60 min. These videotaped responses were then scored for a variety of grooming and other behaviours. Pups of all ages (1-20 days) groomed in response to BN with the 1-day-old pups the least and 20-day-olds the most sensitive to BN. In the 10-day-olds, scratching, in an immature, non-contact form, was elicited by BN. This was replaced by mature, contact type scratching in the sequence of grooming behaviour at 20 days of age. Scratching activities appeared to form a subsystem connected to but nonetheless separate from washing behaviours and this was particularly distinguishable at 20 days of age. Changes in BN-induced grooming appeared to reflect the maturation of the motor capabilities of the developing rat. In conclusion, these results indicate that BN binding sites in the developing rat central nervous system (CNS) are pharmacologically functional from an early stage in ontogeny when there is little or no measurable amount of the peptide itself present in the CNS.


Carbonic anhydrase in distinct precursors of astrocytes and oligodendrocytes in the forebrains of neonatal and young rats.

Carbonic anhydrase is present in oligodendrocytes and astrocytes in the mature rat brain. Whereas carbonic anhydrase-positive oligodendrocyte precursors had been identified during the first postnatal week, no information was available about the earliest occurrence of carbonic anhydrase in the astrocytic cell line, nor had carbonic anhydrase been detected in astrocytes in neonatal rat brains. Beginning on the first postnatal day, rat brains were double immunostained with anti-carbonic anhydrase II and respective 'markers' for immature and mature astrocytes and oligodendrocytes. During the first postnatal week there were intensely carbonic anhydrase-positive cells which were ovoid or had broad processes. On the basis of their shapes and antigen contents these were considered to be precursors of oligodendrocytes. Beginning on the first postnatal day carbonic anhydrase II was also observed in some vimentin-positive radial glia and in other vimentin-positive cells that differed in their appearance from the immature oligodendrocytes. The vimentin-positive, carbonic anhydrase-positive cells were less smooth-surfaced, and had much finer processes, than the oligodendrocyte precursors. By the third postnatal day there appeared carbonic anhydrase-positive, glial fibrillary acidic protein (GFAP)-positive cells that resembled the vimentin-positive cells. It is concluded that the latter are immature astrocytes and that carbonic anhydrase is in distinct precursors of oligodendrocytes and astrocytes as early as the first postnatal day.


A developmentally regulated plasmalemmal antigen present in synaptosomes but not in growth cones.

Monoclonal antibody 2L4 was generated against rat synaptosomes but does not cross-react with nerve growth cones. Expression of the 2L4 antigen is developmentally regulated in a manner that is, in part, the opposite of the expression of the 5B4-CAM antigen, a marker of neuronal outgrowth belonging to the N-CAM family. While 5B4-CAM appears and increases during sprouting and then decreases to reach low levels in the adult, the 2L4 antigen appears only late in development, when neuronal outgrowth ceases, at or around the time of synaptogenesis. Once expressed, the antigen is found on the entire plasmalemmal surface of the neuron, but seems to be enriched at synaptic endings, at least of some neuron types. Biochemical analyses involving blotting of non-denaturing gels and immunoaffinity chromatography identify the antigen as a pair of polypeptides with similar, basic isoelectric points. These polypeptides form a somewhat diffuse, probably glycosylated band at 67 kDa and may be part of a hetero-oligomeric complex. The localization, biochemical, and developmental results suggest that the 2L4 antigen is a plasmalemmal marker of maturing and/or mature neurons whose expression may be triggered by synaptogenesis.


The organization of radial glial fibers in spontaneous neocortical ectopias of newborn New Zealand black mice.

Forty percent of New Zealand Black (NZB) mice, a strain that develops severe autoimmune disease, have ectopic collections of neurons in layer I of the neocortex. This strain is used as a model for similar anomalies seen in the dyslexic brain. In the present study we immunohistochemically stained radical glial fibers and their anchoring processes (which form the glial external limiting membrane) in the region of ectopias in NZB mice. The organization of glial fibers was abnormal in and around the ectopic region. Radial glial fibers underlying the ectopia were denser than in the surrounding cortex, and within the ectopia there was a disorganized matrix of glial fibers. Most glial fibers, however, did not enter the ectopia, but instead curved towards the edge of the ectopia and attached there. The glial limiting membrane was breached in the area of the ectopia, indicating that an insult to this membrane may have allowed neurons to migrate into layer I and the overlying subarachnoid space. This finding along with the results of the accompanying paper on puncture wounds of the cortex of newborn rodents supports the view that rupture of the external limiting glial membrane is responsible for the inappropriate migration of neurons into the molecular layer.


Development of tone response thresholds, latencies and tuning in the mouse inferior colliculus.

The development of tone response thresholds, latencies and tuning of neurons in the inferior colliculus (IC) of the mouse has been investigated between postnatal days 10 (first responses) and 20. As in adults, response thresholds of neurons are lowest in the center of the IC compared with other areas right from the beginning of responsiveness at day 10. Thresholds decrease rapidly until at days 16-20 (depending on the characteristic frequency of the neurons) adult levels are reached. Response latencies decrease rapidly to adult levels at days 16-18. Broad frequency tuning curves can be measured at days 10 and 11. From day 12 onwards, tuning curve shapes differentiate and adult diversity occurs which indicates presence of inhibition and summation in the pathway to or within the IC at that early age. The tip lengths of the tuning curves increase faster than the sharpness of the tips (Q10 dB values). The developmental courses of the measured parameters are expressed by power functions. The time constants of these functions are used in the discussion of processes underlying the functional maturation in the auditory system of the mouse. The general course of the development of all the here investigated response properties of single neurons in the IC, except tuning curve shape, appears to be determined by maturation at or peripheral to the cochlear level.


Dendritic morphology of interstitial amacrine cells with monostratified dendrites in different-sized carp retinas.

The dendritic morphology of a class of interstitial (IS) amacrine cells in retinas of different-sized carp (body length, 9.1-32.3 cm) was investigated by identifying their fluorescent nuclei pre-loaded with 4,6-diamidino-2-phenylindole (DAPI), followed by iontophoretic injection of Lucifer yellow (LY) in isolated and formaldehyde-fixed flat-mounts under microscopic control. The LY-injected fusiform or pyriform cell bodies were found to locate at the middle of the inner plexiform layer (IPL) or immediately beneath the amacrine cell layer, and their dendrites monostratified in sublamina b of the IPL. The pyriform cells had a short stem from which extended 4-5 stout dendrites, while the fusiform cells extended similar dendrites from the soma. The dendrites of both types of cell were decorated with spines and a few long axon-like processes. The pyriform cells were found more frequently in smaller retinas than in larger retinas, suggesting that the former may migrate proximally during retinal growth. The dendritic field sizes of these IS amacrine cells were wider as the fish became larger, while the dendritic morphology, analyzed by the Sholl's branching model, was very similar in smaller and larger retinas. The results indicate that the IS amacrine cells do not add dendrites, but that their dendritic trees simply expand during retinal growth.


Delayed changes of chromogranin A immunoreactivity (CgA ir) in human striate cortex during postnatal development.

The changes in chromogranin A expression in the human striate cortex from birth till 67 years were studied by immunohistochemical method in 18 autopsied patients. The first chromogranin A immunoreactivity (CgA ir) was identified at birth in layer IV (especially IVc) mainly as fine nerve terminals. By 6 months, the first perikaryal reactivity was noted in the large pyramidal neurons of layer V. The smaller neurons in layers IV, V and VI showed a progressive increase in CgA ir from 15 months to about 17 years. At approximately 9 years, immunoreactivity began to be noted in supragranular neurons in layers II and III. The final laminar distribution of CgA ir seemed to be attained at about 25 years with relatively little change thereafter. The CgA ir in the striate cortex demonstrates a prolonged period of developmental changes, lasting from birth to about 25 years.


The development of neuropeptide Y immunoreactive neurons in cat visual cortical areas.

The development of NPY-ir neurons and fibers in cat striate and extrastriate cortex was studied to determine whether temporal changes in the morphology, distribution and density of NPY-ir neurons during development would provide clues to the emergence of specific cortical areas. No differences in the number or distribution of NPY-ir neurons were observed at any age among the five visual cortical areas examined, area 17, 18, 19, posteromedial lateral suprasylvian and posterolateral lateral suprasylvian cortex. The number of NPY-ir neurons in cat visual cortical areas was higher in adult animals than in kittens. The proportion of NPY-ir neurons found in layer VIb was constant throughout life, suggesting that NPY immunoreactivity is not a marker for the transient neurons of the subplate. NPY-ir neuronal morphology was seen to 'flatten' in older animals with the development of sulci and increasing density of the brain. In contrast to the pattern observed with NPY-ir neurons, NPY-ir processes exhibited area-dependent differences during development. NPY-ir fibers grew into area 17 earlier and with a radial orientation which was not consistently observed laterally. This radial orientation was still apparent in adult brains in layer IV of area 17, though there was no orientation of fibers in the other laminae or other visual areas of the adult.


Age-related anticonvulsant activity of NMDA in the rat caudate-putamen.

Striatal pathways are important for modulating the threshold for seizures in the rat forebrain. N-Methyl-D-aspartate (NMDA), an excitatory amino acid derivative and powerful anticonvulsant agent, when injected into the brain, has been shown to protect adult rats against kindling and pilocarpine-induced seizures when injected into the caudate-putamen. The present study examines whether the anticonvulsant action of NMDA in the caudate-putamen varies with age. Bilateral striatal administration of NMDA was effective in suppressing bicuculline-induced seizures in rats older than 23 days of age. The results suggest that striatal pathways involved in the anticonvulsant activity of NMDA in the caudate-putamen are not functionally active in developing rats before the 4th week of life.


Use of [3H]-GBR12935 to measure dopaminergic nerve terminal growth into the developing rat striatum.

In this study we determined the temporal association between the appearance of the dopamine transporter, measured by 1-[2-(diphenyl-methoxy)ethyl]-4-(3- phenylpropyl)-piperazine ([3H]-GBR12935), a potent and selective inhibitor of dopamine uptake, and other biochemical markers of dopaminergic nerve terminal growth into the developing striatum. [3H]-GBR12935 binding was minimally detected in the rudimentary striatum of embryonic day 14 rat brains, increased to 23% of the adult level by birth, and reached the adult level during the fifth postnatal week. This finding contrasts with a slower developmental increase in [3H]-dopamine uptake, a functional measure of the transporter. Tyrosine hydroxylase activity levels followed a developmental curve similar to that of [3H]-GBR12935 binding but did not reach adult levels until the 7th postnatal week. Dopamine content increased at a slower rate, being only 10% and 92% of the adult level at birth and postnatal week 8, respectively. These results indicate that the appearance of a structural, but not optimally functional, dopamine transporter may be the earliest detectable biochemical index of dopaminergic nerve terminal growth into the striatum during development.


Pharmacokinetic drug interactions of macrolides.

The macrolide antibiotics include natural members, prodrugs and semisynthetic derivatives. These drugs are indicated in a variety of infections and are often combined with other drug therapies, thus creating the potential for pharmacokinetic interactions. Macrolides can both inhibit drug metabolism in the liver by complex formation and inactivation of microsomal drug oxidising enzymes and also interfere with microorganisms of the enteric flora through their antibiotic effects. Over the past 20 years, a number of reports have incriminated macrolides as a potential source of clinically severe drug interactions. However, differences have been found between the various macrolides in this regard and not all macrolides are responsible for drug interactions. With the recent advent of many semisynthetic macrolide antibiotics it is now evident that they may be classified into 3 different groups in causing drug interactions. The first group (e.g. troleandomycin, erythromycins) are those prone to forming nitrosoalkanes and the consequent formation of inactive cytochrome P450-metabolite complexes. The second group (e.g. josamycin, flurithromycin, roxithromycin, clarithromycin, miocamycin and midecamycin) form complexes to a lesser extent and rarely produce drug interactions. The last group (e.g. spiramycin, rokitamycin, dirithromycin and azithromycin) do not inactivate cytochrome P450 and are unable to modify the pharmacokinetics of other compounds. It appears that 2 structural factors are important for a macrolide antibiotic to lead to the induction of cytochrome P450 and the formation in vivo or in vitro of an inhibitory cytochrome P450-iron-nitrosoalkane metabolite complex: the presence in the macrolide molecules of a non-hindered readily accessible N-dimethylamino group and the hydrophobic character of the drug. Troleandomycin ranks first as a potent inhibitor of microsomal liver enzymes, causing a significant decrease of the metabolism of methylprednisolone, theophylline, carbamazepine, phenazone (antipyrine) and triazolam. Troleandomycin can cause ergotism in patients receiving ergot alkaloids and cholestatic jaundice in those taking oral contraceptives. Erythromycin and its different prodrugs appear to be less potent inhibitors of drug metabolism. Case reports and controlled studies have, however, shown that erythromycins may interact with theophylline, carbamazepine, methylprednisolone, warfarin, cyclosporin, triazolam, midazolam, alfentanil, disopyramide and bromocriptine, decreasing drug clearance. The bioavailability of digoxin appears also to be increased by erythromycin in patients excreting high amounts of reduced digoxin metabolites, probably due to destruction of enteric flora responsible for the formation of these compounds. These incriminated macrolide antibiotics should not be administered concomitantly with other drugs known to be affected metabolically by them, or at the very least, combined administration should be carried out only with careful patient monitoring.(ABSTRACT TRUNCATED AT 400 WORDS)


P450 enzymes. Inhibition mechanisms, genetic regulation and effects of liver disease.

Multiple hepatic P450 enzymes play an important role in the oxidative biotransformation of a vast number of structurally diverse drugs. As such, these enzymes are a major determinant of the pharmacokinetic behaviour of most therapeutic agents. There are several factors that influence P450 activity, either directly or at the level of enzyme regulation. Drug elimination is decreased and the incidence of drug interactions is increased when there is competition between 2 or more drugs for oxidation by the same P450 enzyme. The available knowledge concerning the relationship between the presence of certain functional groups within the drug structure and inhibition of P450 activity is increasing. In many instances, it is possible to associate inhibition with certain drug classes, e.g. antimycotic imidazoles and macrolide antibiotics. Disease states, especially those with hepatic involvement, and the genetic makeup of the individual are conditions in which some P450s may be downregulated (that is, the enzyme concentrations in liver are decreased), with associated slower rates of drug elimination. In these individuals, dosages of drugs that are substrates for downregulated P450s should be decreased. Exposure to environmental pollutants as well as a large number of lipophilic drugs can result in induction (upregulation) of P450 enzyme activity. This raises the issue of previous approaches to the study of P450 induction in vivo. The use of human hepatocyte preparations in culture is a promising new direction that could assist the determination of modifications to drug therapy necessitated by exposure to inducing agents. Until such information is obtained, however, the use of drugs known to increase the microsomal expression of particular P450s, and increase associated drug oxidation capacity in humans, should be used with caution.


Clinical pharmacokinetics of alpha 1-antitrypsin in homozygous PiZ deficient patients.

A pharmacokinetic study of alpha 1-antitrypsin (ATT) was performed in 2 groups of homozygous PiZ-deficient patients (treated and untreated) and 1 group of healthy volunteers. The distribution of the 131I-labelled protein corresponds to a 3-compartment model. The intravenously administered protein diffused quickly to the extravascular compartment where some retention occurred. No significant difference in AAT metabolism was observed between the 3 groups. The half-life of the injected protein is slightly longer than 2.5 days. The AAT protein was not stored. These results confirm the observations collected during the clinical trials. That is, a weekly infusion is necessary to obtain stable serum AAT concentrations. Monthly infusions are unable to maintain a 'plateau' phase. The periodicity may be limited to every 2 weeks.


Pharmacokinetics of drugs in overdose.

The pharmacokinetics of drugs may be altered following an overdose. The degree of absorption depends on the physical characteristics of the drug; the rate of dissolution may delay or broaden peak serum concentrations. The pathophysiological effects of a drug may also limit or augment absorption. Altered distribution of drugs in overdose results from changes in the extent of protein binding and size of the volume of distribution. Saturation of hepatic enzyme systems in overdose is manifested by delayed metabolism or elimination of many drugs; renal elimination of unchanged drug may take on greater importance in this instance. Familiarity with the toxicokinetic profile of a given drug enables the physician to exploit these principles in order to limit toxicity. Delayed or prolonged absorption allows for late decontamination. Multiple doses of activated charcoal are effective in interrupting both entero-enteric and enterohepatic recirculation. Alkalinisation-induced ion trapping enhances renal elimination of unchanged drugs which normally undergo hepatic transformation. For several drugs, chronic overdose due to altered distribution is associated with a greater severity of toxic manifestations despite relatively low serum drug concentrations. Conversely, with some drugs, induction of metabolic pathways may lead to more rapid drug elimination in chronic overdose. Knowledge of the pharmacokinetic alterations which occur in drug overdose enables the physician to predict toxicity with greater accuracy and to institute optimum therapy in a timely manner.


A review of assay methods for cyclosporin. Clinical implications.

Cyclosporin is a unique immunosuppressive agent with a narrow therapeutic range. The pharmacokinetics of the drug present substantial within- and between-patient variability and drug interactions can significantly alter blood cyclosporin concentrations. Monitoring of cyclosporin concentrations in blood is an invaluable and essential aid in adjusting dosage to ensure adequate immunosuppression while minimising toxicity. The principal rationale behind therapeutic monitoring of cyclosporin is the fact that the incidence of rejection is higher at low cyclosporin concentrations and toxicity occurs more often at high concentrations. In renal transplant recipients, cyclosporin concentrations help to discriminate between insufficient immunosuppression and cyclosporin-induced nephrotoxicity. There are several methods available, both specific and nonspecific, for the routine measurement of cyclosporin. Radioimmunoassay and fluorescence polarisation immunoassay are most widely employed, while high performance liquid chromatography remains the reference procedure. The allegedly specific immunoassays tend to slightly overestimate the actual blood cyclosporin concentrations. There is a need for assay systems capable of measuring the biological activity of cyclosporin. Cyclosporin concentrations should be determined by a specific method, using whole blood as the sample matrix. The routine monitoring of individual cyclosporin metabolites is not warranted, but characterising the metabolite pattern of cyclosporin by concomitant use of a nonspecific and a specific assay can be clinically useful in patients with cyclosporin-associated toxicity or impaired liver function. In organ transplantation, measurement of blood cyclosporin concentration should be continued periodically as long as the therapy continues, whereas monitoring is only indicated in special circumstances in patients with autoimmune and other nontransplant diseases. The assessment of a 'therapeutic window' for cyclosporin is complicated for several reasons and definite target ranges cannot be given. Cyclosporin concentrations should always be interpreted in conjunction with the recent blood concentration history and other relevant clinical and laboratory data.


Electroencephalogram effect measures and relationships between pharmacokinetics and pharmacodynamics of centrally acting drugs.

Electroencephalogram (EEG) effect parameters may be useful in pharmacokinetic-pharmacodynamic modelling studies of drug effects on the central nervous system (CNS). Effect parameters derived from a quantitative analysis of the EEG appear to be perfectly suited to characterise the relationships between pharmacokinetics and pharmacodynamics of benzodiazepines and intravenous anaesthetics. EEG parameters represent many of the characteristics of ideal pharmacodynamic measures, being continuous, objective, sensitive and reproducible. These features provide the opportunity to derive concentration-effect relationships for these drugs in individuals, which yield important quantitative information on the potency and intrinsic efficacy of these drugs. The EEG techniques presented can be used to study the influences of factors such as age, disease, chronic drug use and drug interactions on the concentration-effect relationships of psychotropic drugs. An important issue is the choice of the EEG parameter to characterise the CNS effects of the compounds. More attention must be paid to evaluating the relevance of EEG parameters to the pharmacological effects of the drugs. Knowledge of the relationship between EEG effect parameters and clinical effects of drugs under different physiological and pathophysiological conditions is crucial to determining the value of EEG parameters in drug effect monitoring. Pharmacodynamic parameters derived from the concentration-EEG effect relationship may be correlated to pharmacodynamic parameters obtained from other in vitro and in vivo effect measurements. These comparisons revealed that changes in the amplitudes in the beta frequency band of EEG signals is a relevant measure of pharmacological effect intensity of benzodiazepines, which reflects their affinity and intrinsic efficacy at the central gamma-aminobutyric acid (GABA) benzodiazepine receptor complex. The exact EEG correlates of the anxiolytic, anticonvulsant, sedative and hypnotic actions of benzodiazepines have not yet clearly been elucidated. For intravenous anaesthetics, close correlations between the potency determined with EEG measurements and clinical measures of anaesthetic depth have been established, suggesting that, in principle, EEG parameters can adequately reflect depth of anaesthesia. However, more study is required to further substantiate these findings.


Pharmacokinetic optimisation of anticonvulsant therapy.

Changing attitudes towards the use of antiepileptic drugs have led to an emphasis on monotherapy with serum concentration measurement coupled with standard, weight-adjusted starting and maintenance regimens to guide initial therapy and subsequent dosage titration. Currently, the established anticonvulsants are carbamazepine, valproic acid (sodium valproate) and phenytoin. Phenobarbital is now less commonly prescribed due to its propensity to produce sedation and impair cognitive function. The value of pharmacokinetic optimisation with valproic acid is limited by its wide therapeutic index, large fluctuations in the concentration-time profile and concentration-dependent protein binding. Thus, although serum concentrations are often measured, they are rarely subjected to pharmacokinetic interpretation. Carbamazepine has a flatter concentration-time profile than valproic acid. Its target range is more clearly defined and it undergoes autoinduction of metabolism and interacts with other drugs. Pharmacokinetic principles can, therefore, be more readily applied to carbamazepine, although, in general, a simple clinical approach to its use is usually satisfactory. Phenytoin has required the greatest pharmacokinetic input due to its nonlinear pharmacokinetics and narrow target range. Many different graphical methods, equations and computer programs have been reported, some of which demand 2 steady-state, dose-concentration pairs; others function satisfactorily with only 1. Recent attempts have been made to interpret non-steady-state data. In addition, a number of workers have demonstrated the value of altering the population parameter estimates to account for ethnic differences. A pharmacokinetic approach can also be used to tailor the use of phenytoin in the treatment of status epilepticus. Dosage alterations may be needed for specific patient groups. In particular, children generally require higher dosages on a weight-for-weight basis than adults, while equivalently lower dosages should be given to neonates. Most anticonvulsants are principally cleared by hepatic mechanisms, so dosage adjustment is not usually required in renal disease, although care must be taken in interpreting serum concentrations because of changes in protein binding. Close monitoring is required in the elderly and patients with hepatic impairment, while increased dosages may be needed in critically ill patients and during pregnancy. Pharmacokinetic principles can be used in the treatment of treat self-poisoning with anticonvulsants. There are few data available on the pharmacokinetics of vigabatrin, lamotrigine, oxcarbazepine and gabapentin in patients. Due to its mode of action in binding irreversibly to its target enzyme, serum concentration monitoring of vigabatrin plays no role in optimising therapy. The value of applying pharmacokinetic principles with the other 3 drugs remains to be investigated.(ABSTRACT TRUNCATED AT 400 WORDS)


Pravastatin: a new drug for the treatment of hypercholesterolemia.

The chemistry, pharmacology, pharmacokinetics, clinical trials, adverse effects, role in lipid-lowering therapy, and dosage and administration of pravastatin are reviewed. Pravastatin sodium is a new 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor for the treatment of hypercholesterolemia. Its structural formula is similar to those of lovastatin and simvastatin, but it is active in the parent form. It competitively inhibits HMG-CoA reductase, reduces hepatic cellular cholesterol synthesis, increases the expression of hepatic low-density lipoprotein (LDL) receptors, and reduces hepatic very low-density lipoprotein (VLDL) synthesis. Pravastatin has been demonstrated to reduce cholesterol in patients with familial and nonfamilial polygenic hypercholesterolemia and patients with diabetes mellitus. In doses of 10-40 mg/day, pravastatin has been shown to reduce total cholesterol by 15-30% and LDL cholesterol by 15-40%. It also increases high-density lipoprotein cholesterol by 2-20% and reduces triglycerides. It is generally well tolerated, with few adverse effects reported in clinical trials. Pravastatin reduces LDL cholesterol and increases HDL cholesterol comparably to lovastatin but possibly with fewer adverse effects. Further studies and clinical use will be needed to confirm potential differences in adverse effect profiles between the two drugs.


Treatment of nonsteroidal anti-inflammatory drug-induced gastropathy.

The etiology, natural history, epidemiology, prevention, and treatment of nonsteroidal anti-inflammatory drug (NSAID)-induced gastrointestinal (GI) effects are reviewed. Current evidence suggests that NSAIDs cause acute cellular damage by a topical effect that is exacerbated by impaired healing. Although acute gastric injury from NSAIDs is rapid and almost uniform from patient to patient, not all patients develop serious chronic injury. Some adaptation to the effects of NSAIDs does occur. Endoscopic studies have found that 14-31% of long-term NSAID users have gastric or duodenal ulcers. Data on individual drugs are inconsistent, but they suggest that enteric-coated aspirin, salsalate, and ibuprofen cause the lowest incidence of GI hemorrhage. Preventive measures tested to date include reduction in gastric acid production (histamine H2-receptor antagonists) and attempts to increase mucosal defenses (sucralfate or misoprostol). Misoprostol is the only drug with FDA-approved labeling for prevention of NSAID-induced gastropathy. NSAID-related ulcers heal in most patients within two to three months when they are treated with H2-receptor antagonists with or without antacid, omeprazole, or misoprostol. In patients with multiple risk factors, prophylaxis with misoprostol would be appropriate unless the clinician is concerned solely about reactivation of a duodenal ulcer, in which case an H2-receptor antagonist would also be appropriate. Full-dose treatment with H2-receptor antagonists, omeprazole, or misoprostol will heal NSAID-induced ulcers, even when NSAID therapy is continued.


Endocrine complications associated with human immunodeficiency virus infection.

The causes and management of endocrine disorders associated with human immunodeficiency virus (HIV) infection are reviewed. Endocrine disorders observed in HIV-positive patients include adrenal abnormalities, hyporeninemic hypoaldosteronism, pituitary insufficiency, pancreatic abnormalities, thyroid and parathyroid disorders, and testicular abnormalities. Opportunistic pathogens implicated in these disorders include cytomegalovirus, Cryptococcus, Toxoplasma, mycobacteria, Candida, and Aspergillus. Neoplasma such as Kaposi's sarcoma and lymphoma can also cause endocrine abnormalities. Several drugs used in patients with the acquired immunodeficiency syndrome (AIDS) are associated with the development of endocrine disorders. These drugs include ketoconazole, itraconazole, rifampin, vidarabine, pentamidine, trimethoprim-sulfamethoxazole, didanosine, and ganciclovir. Severe patient debilitation can contribute to the development of endocrine abnormalities. Monitoring of adrenal gland function may be prudent in HIV-infected patients who have nonspecific symptoms of adrenal insufficiency. If adrenal insufficiency is diagnosed, replacement therapy with oral hydrocortisone is required. Administration of fludrocortisone can rapidly alleviate the signs and symptoms of hyporeninemic hypoaldosteronism. Fluid restriction is the first step in managing the pituitary abnormality known as the syndrome of inappropriate secretion of antidiuretic hormone. Drug-induced endocrine abnormalities often resolve after withdrawal of the offending agent. Endocrine complications in HIV-infected patients may be caused by infection, malignancy, or drugs. Adjusting or instituting drug therapy may be necessary to control symptomatic endocrine abnormalities.


Air measurements of dusts, chemicals, and fumes.

Estimates of exposure in the workplace or in indoor environments begin with the actual sampling and analysis of the airborne contaminant or rely on a reconstruction of past exposures in the workplace. Direct-reading portable field instruments are being used to supplement laboratory-based analytical methods. The lowering of the OSHA permissible exposure limits and the rise of indoor air pollution concerns indicate the need for more innovative methods for detecting lung irritants and pathogens.


Engineering controls for clean air in the office environment.

Supply of adequate amounts of fresh air, properly conditioned, is crucial to maintaining good air quality in the office environment. Building managers frequently attempt to limit the amount of fresh air supplied to offices, because of the energy costs involved. It is important that the amount of fresh air being supplied be evaluated by competent personnel and that substandard conditions be rectified. It is also important that ventilation systems be properly maintained. If these fairly simple steps are taken, many complaints of poor air quality will be eliminated.


Health effects of air pollution. A review of clinical studies.

The database for the acute health effects of common outdoor air pollutants is rapidly increasing but important gaps still exist. Greater technical efforts and innovative studies are required to adequately characterize health effects and understand the underlying mechanisms of toxicity. Controlled human exposures provide relevant data about short-term effects and complement animal and epidemiologic investigations. Except for possibly nitrogen dioxide, the clinical data for ozone, sulfur dioxide, and particulates (H2SO4) at contemporary levels indicate potentially untoward or adverse physiologic or clinical responses in healthy individuals and sensitive groups such as children, adolescents, and asthmatic patients. Exercise, duration, and other exposure factors may potentiate pollutant effects on symptoms, lung function, nonspecific bronchial reactivity, mucociliary clearance, and BAL markers of inflammation. Continued animal, clinical, and epidemiologic research of both short- and long-term health effects is clearly needed to support or limit future regulatory decisions regarding the quality of outdoor air.


Indoor air pollution.

This article summarizes the health effects of indoor air pollutants and the modalities available to control them. The pollutants discussed include active and passive exposure to tobacco smoke; combustion products of carbon monoxide; nitrogen dioxide; products of biofuels, including wood and coal; biologic agents leading to immune responses, such as house dust mites, cockroaches, fungi, animal dander, and urine; biologic agents associated with infection such as Legionella and tuberculosis; formaldehyde; and volatile organic compounds. An approach to assessing building-related illness and "tight building" syndrome is presented. Finally, the article reviews recent data on hospital-related asthma and exposures to potential respiratory hazards such as antineoplastic agents, anesthetic gases, and ethylene oxide.


Asbestos exposure in buildings.

Asbestos-related diseases are dose-related. Among these, asbestosis has occurred only with the heavy exposures of the past, is a disappearing disease, and is of no concern with the very small exposures from building occupancy. A possibly increased incidence of lung cancer has been included in risk analysis, but probably is also related to high exposure in that both epidemiologic and experimental data suggest a link between the process of alveolar inflammation and fibrogenesis and carcinogenesis. The major concern has been mesothelioma in that it has occurred with much lower household and neighborhood exposure. Additionally, anxiety concerning buildings with ACM has been heightened by finding of friable asbestos in about 20% of public buildings, discovery of environmental asbestos fibers and asbestos bodies in autopsies, and demonstration of a linear relationship between exposure and lung cancer risk in occupational groups, inviting extrapolation to a much lower dose. Legislative and regulatory mandates, promotional activities of abatement companies, adverse court decisions placing the onus of repairs on asbestos manufacturers, and a "pandemic of mediagenic disease" all have contributed to panic among building owners, school boards, insurers, and others. In that there is neither clinical nor epidemiologic support for asbestos-related disease from building occupancy, risk estimates have been based on extrapolation from past experience with generally high-dose occupational exposure. However, only a few epidemiologic studies have contained quantitative estimates of exposure, and these have been measured in terms of all particles, with conversion to asbestos fibers uncertain and the fiber type and dimension largely unknown. To these uncertainties must be added the unproved assumption of a linear dose-response down to very low levels of exposure with no threshold. At the other end of the scale extrapolation has required measurements of present building exposure, and these have been revised downward as methods for collection and analysis have improved. Risk estimates in this country and abroad have assumed exposure to 0.001 f/mL, with indicated lifetime risks for cancer ranging from about 2 to 20 per 1 million students. However, these estimates have assumed mixed fiber exposure whereas most building exposure comes from chrysotile, which is much less toxic than the amphiboles.(ABSTRACT TRUNCATED AT 400 WORDS)


Coal workers' pneumoconiosis.

CWP is a disease distinct and separate from silicosis. Simple CWP is clearly related to the amount of dust deposited within the lungs. Complicated CWP (PMF) results from dust deposition plus other factors. Immunologic and local cellular factors may contribute to the development of this form of the disease. Studies of lung cell response and function may further elucidate mechanisms and mediators of lung dust reaction. Complicated CWP (PMF) is clearly associated with alterations in ventilatory, mechanical, and vascular function of the lungs. These abnormalities in PMF contribute to the observed premature morbidity and mortality of this disease.


Silicosis.

Silicosis is an ancient disease, but with modern understanding of safe levels of exposure, it should be a vanishing disease. Emphasis will be placed on newer concepts in the pathogenesis of the disease and the health effects of low levels of quartz dust in relation to current exposure standards. The ongoing controversy regarding the carcinogenicity of quartz is discussed.


The hard metal diseases.

Hard metal is a mixture of tungsten carbide and cobalt, to which small amounts of other metals may be added. It is widely used for industrial purposes whenever extreme hardness and high temperature resistance are needed, such as for cutting tools, oil well drilling bits, and jet engine exhaust ports. Cobalt is the component of hard metal that can be a health hazard. Respiratory diseases occur in workers exposed to cobalt--either in the production of hard metal, from machining hard metal parts, or from other sources. Adverse pulmonary reactions include asthma, hypersensitivity pneumonitis, and interstitial fibrosis. A peculiar, almost unique form of lung fibrosis, giant cell interstitial pneumonia, is closely linked with cobalt exposure.


Hypersensitivity pneumonitis.

Hypersensitivity pneumonitis is a syndrome caused by sensitization to any of a wide variety of environmental antigens and results in a pulmonary immunologic inflammatory process. The clinical syndrome occurs in a temporal relationship to exposure to the offending agent with resultant systemic or respiratory symptoms with defined chest radiographic and pulmonary function abnormalities. Definitive immune responses include those of the humoral and cellular system. Avoidance of exposure as treatment results in reversal of the clinical abnormalities.


Hazardous exposure and lung disease among farm workers.

Industrialization of farming, animal raising, and forestry has added new chemical and mechanical hazards that need to be recognized and prevented. Lung disease among farm workers can result from a wide variety of hazardous exposures that include organic dusts, chemicals, and toxic gases. In addition to nonspecific symptoms of mucous membrane irritation, farm workers can develop occupational asthma or bronchitis, organic dust toxic syndrome, hypersensitivity pneumonitis, silo filler's disease (toxic hemorrhagic pulmonary edema), and neuromuscular respiratory failure.


Health effects of synthetic vitreous fibers.

This article reviews the terminology and manufacturing process for synthetic vitreous fibers. The in vitro and in vivo animal experimental data that correlate fiber toxicity with dose, dimensions, and durability are summarized. Occupational exposure data are presented as well as the potential irritant effects of synthetic vitreous fibers. The ongoing human morbidity and mortality studies are summarized along with current occupational exposure standards. The discussion correlates physical properties related to fiber toxicity and the types of synthetic vitreous fibers.


Occupational lung cancer.

The Contribution of Occupational Exposures to Lung Cancer. The overall importance of occupational agents as a cause of lung cancer has been a controversial subject since the 1970s. A federal report, released in the late 1970s, projected a surprisingly high burden of occupational lung cancer; for asbestos and four other agents, from 61,000 to 98,000 cases annually were attributed to these agents alone. Many estimates followed, some much more conservative. For example, Doll and Peto estimated that 15% of lung cancer in men and 5% in women could be attributed to occupational exposures. A number of population-based case-control studies also provide relevant estimates. In a recent literature review, Vineis and Simonato cited attributable risk estimates for occupation and lung cancer that ranged from 4% to 40%; for asbestos alone, the estimates ranged from 1% to 5%. These estimates would be expected to vary across locations and over time. Nevertheless, these recent estimates indicate that occupation remains an important cause of lung cancer. Approaches to Prevention. Prevention of lung cancer mortality among workers exposed to agents or industrial processes that cause lung cancer may involve several strategies, including eliminating or reducing exposures, smoking cessation, screening, and chemo-prevention. For example, changes in industrial processes that have eliminated or reduced exposures to chloromethyl ethers and nickel compounds have provided evidence of reduced risk of lung cancer following these changes. Although occupational exposures are important causes of lung cancer, cigarette smoking is the most important preventable cause of lung cancer. For adults, the work site offers an important location to target smoking cessation efforts. In fact, the work site may be the only place to reach many smokers. As many as 70% of smokers participating in a work site program reported that they would not seek out other programs for smoking cessation. Furthermore, these programs may be as effective as other smoking cessation programs, with abstinence approaching 30%. By creating a supportive social environment, policies restricting smoking in the workplace may also assist smokers trying to quit. Screening of workers at high risk of lung cancer, with periodic chest radiography and sputum cytology, offers potential methods for early detection that may improve prognosis. However, the failure of those procedures to improve outcome from lung cancer among high-risk smokers makes screening of workers of doubtful value. Both epidemiologic and experimental evidence suggest that dietary factors may modify the risk of lung cancer. To date, attention has been focused on vitamin A and carotenoids.(ABSTRACT TRUNCATED AT 400 WORDS)


Pulmonary infections acquired in the workplace. A review of occupation-associated pneumonia.

The risk of humans acquiring pneumonia as a result of their occupation appears to have declined during the twentieth century in developed countries, such as the United States. Thus, some conditions that are traditionally associated with the workplace, such as woolsorters' disease, represent illnesses that are of historical interest only. Nevertheless, the problem of occupation-associated pneumonia remains substantial. First, large outbreaks of zoonotic infections continue to occur, especially psittacosis among poultry farmers and abattoir workers. Second, clusters of illnesses caused by recently recognized pathogens are now being reported, including legionnaires' disease in industrial workers and Chlamydia pneumoniae infections in military personnel. Finally, epidemics of old conditions are appearing in new settings, such as tuberculosis among nursing home workers. Thus, the transmission, control, and treatment of pneumonias acquired in the workplace represent intriguing and challenging areas of concern to the epidemiologist and clinician.


Respiratory disability. The uncoupling of oxygen consumption and disability.

In the past it was believed that respiratory disability could be objectively assessed by comparing the measured O2 consumption requirement of the job with the subjects' measured or estimated maximal oxygen consumption. More recently, it has become clear that this "classic" paradigm does not completely apply to all situations. This article reviews recent aspects of respiratory disability assessment.


Facilities in diabetic clinics in the UK: how much have they changed?

Two postal questionnaire surveys of facilities and staff available to hospital physicians responsible for the care of adults with diabetes in the United Kingdom have been carried out under the auspices of the British Diabetic Association. These surveys, in 1982-83 and 1990, achieved 92% and 94% responses, respectively, giving information on around 95% of UK health districts or their equivalent. Levels of provision and the use of existing facilities had, in general, improved over that time though several important deficiencies still remain. Respondents providing out-of-hours clinics and combined clinics with other specialties increased as did the availability of dietetic advice in outpatient clinics. Although the proportion of respondents reporting no specialist diabetes nursing assistance fell from 53% to 14%, this still left 29 reporting none at all. Access to blood glucose and HbA1 results, facilities for retinal examination, and access to photocoagulation had all improved but there was little change in the availability of adequate examination and educational facilities although this may have been due to a rise in expectations. Chiropodial care was less readily available in 1990 with 17% of respondents (compared with 11%) reporting a complete lack in the clinic. A recommendation that no locality should be without at least one physician with a special interest in diabetes was fulfilled in 81.9% of localities but some were still relatively poorly staffed.


The effect of chronic hyperglycaemia on the islet B-cell responsiveness in newly diagnosed type 2 diabetes.

The aim of the present study was to evaluate the effect of chronic hyperglycaemia on the pancreatic B-cell response to stimulation with a standard mixed meal or intravenous glucagon in 7 subjects with newly diagnosed Type 2 diabetes. Stimulation was performed at mean chronic fasting hyperglycaemia of 11.8 +/- 0.7 (SEM) mmol l-1 and at normoglycaemia obtained by an intravenous infusion of regular insulin followed by an insulin wash-out period. The incremental plasma C-peptide area under the curve after stimulation with the meal was similar at normo- and hyperglycaemia. In contrast, prestimulatory plasma C-peptide and the incremental plasma C-peptide area under the curve after stimulation with glucagon were significantly higher at chronic hyperglycaemia than at normoglycaemia (p less than 0.01 and p less than 0.05). In conclusion, chronic hyperglycaemia as seen in newly diagnosed Type 2 diabetes is associated with a complete lack of potentiation of postprandial islet B-cell secretion but a partly preserved potentiation of basal and post-glucagon islet B-cell secretion.


Peripheral glucose uptake and skeletal muscle GLUT4 content in man: effect of insulin and free fatty acids.

To investigate the relationship between glucose uptake and the content of the insulin regulatable glucose transporter, GLUT4, in skeletal muscle at near physiological insulin concentrations in vivo, we measured the effect of a 3h euglycemic insulin-infusion (40 mU m-2 min-1) on glucose uptake and skeletal muscle GLUT4 content in 10 healthy subjects. We found no correlation (r approximately 0.1) between individual muscle GLUT4 content and insulin-stimulated glucose uptake. Mean GLUT4 content in skeletal muscle was reduced by 19 +/- 6.3% (mean +/- SE, p less than 0.02) after insulin infusion. However, when the same subjects were made insulin resistant by infusion of lipid, as evidenced by a reduction of 16 +/- 7.2% (mean +/- SE, p less than 0.05), in insulin-stimulated glucose uptake, the effect of insulin on GLUT4 content was attenuated and no change in GLUT4 content was observed. Our results show that the total content of skeletal muscle GLUT4 is a poor predictor for in vivo response to near physiological insulin concentrations in healthy human subjects.


The effect of acipimox in patients with type 2 diabetes and persistent hyperlipidaemia.

A placebo-controlled, double-blind study was performed to assess the effect of 12 weeks treatment with acipimox (250 mg three times per day) on lipoproteins and glycaemic control in patients with Type 2 diabetes. All patients studied had persistent hyperlipidaemia despite acceptable glycaemic control on treatment with diet alone or diet and oral hypoglycaemic agents, achieving glycosylated haemoglobin (HbA1) of less than 10.5% but with fasting total triglycerides greater than 2.5 mmol l-1 or total cholesterol greater than 6.5 mmol l-1. Forty-eight patients were randomized to treatment, 21 to acipimox and 27 to placebo; 43 completed the trial. All patients had been diabetic for at least 1 year. Total cholesterol fell by 6% and total triglycerides by 19% following 12 weeks of acipimox, compared to rises in the placebo group of 1% and 16%, respectively (p less than 0.05). There were no significant differences between acipimox and placebo in the change in low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, apolipoproteins AI, AII, or B, or in glycaemic control during the treatment period. Acipimox is effective in reducing fasting total cholesterol and total triglycerides in patients with Type 2 diabetes with acceptable blood glucose control but persistent hyperlipidaemia. Acipimox does not adversely affect glucose tolerance.


Conventional and sprinkler needle injection of magnesium insulin.

Currently available short-acting insulin preparations fail to mimic the postprandial insulin profile of non-diabetic individuals. The activity of a novel insulin designed for faster absorption has been tested after subcutaneous injection. Magnesium insulin (50 U ml-1) given by sprinkler needle was compared with unmodified human insulin (100 U ml-1) given by conventional needle and unmodified human insulin (50 U ml-1) given by sprinkler needle in normal volunteers using a euglycaemic clamp. Magnesium insulin had a significantly faster onset of action resulting in a higher exogenous insulin level by 15 min, peak level was reached after 60 min compared with 75 min for the unmodified insulins, and duration of action was significantly shorter than both unmodified insulins. No significant differences were observed between the unmodified insulins for the first 5 h after injection, indicating that the observed differences to magnesium insulin could not be attributed to the insulin concentration or the type of needle used for insulin administration. Injection of magnesium insulin prior to a test breakfast in people with Type 2 diabetes resulted in significantly lower total and 0 to 120 min areas under the glucose curve, an earlier rise in exogenous insulin levels and a higher area under the insulin curve from 0 to 120 min compared with unmodified 100 U ml-1 human insulin.


Differential effects of near-normoglycaemia for 4 years on somatic nerve dysfunction and heart rate variation in type 1 diabetic patients.

To evaluate the long-term effects of near-normoglycaemia on somatosensory and autonomic nerve dysfunction, 55 poorly controlled Type 1 diabetic patients were allocated to intensified insulin treatment using continuous subcutaneous insulin infusion or multiple insulin injections and were studied prospectively for 48 months. They were divided into three groups according to their mean HbA1 levels during the study. Group 1 (n = 19) had mean HbA1 during months 3-48 in the normal range of less than 7.8% (near-normoglycaemic control), Group 2 (n = 18) showed moderately elevated mean HbA1 between 7.8 and 8.5% (satisfactory control), and Group 3 (n = 18) had clearly elevated mean HbA1 of greater than or equal to 8.6% (poor control). In the three groups studied, the changes in nerve conduction over baseline in the median and peroneal motor nerves as well as median and ulnar sensory nerves after 4 years were inversely related to the mean HbA1 levels of months 3-48 (all p less than 0.05). No significant associations with mean HbA1 were noted for the ulnar motor and sural sensory nerve conduction, vibration perception threshold, and heart rate variation. The percentages of patients with neuropathic symptoms decreased from 32 to 14% in Group 1, remained fairly constant in Group 2, and increased from 41 to 73% in Group 3 after 48 months when compared to baseline (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)


The effect of insulin infusion on capillary blood flow in the diabetic neuropathic foot.

The effect of a short-term improvement in glycaemic control induced by insulin infusion on foot skin capillary blood flow was previously unknown. In seven Type 2 (non-insulin-dependent) diabetic subjects with neuropathy capillary blood flow was measured in the great toe nailfold by television microscopy. An estimate of arteriovenous shunt flow was obtained simultaneously in the pulp of the great toe by laser Doppler flowmetry. After omission of oral hypoglycaemic therapy for 24 h mean blood glucose was 15.7 +/- 0.7 (SEM) mmol l-1. A priming infusion of 0.1 U kg-1 of insulin was given intravenously over 15 min, followed by a variable rate insulin infusion adjusted to steadily reduce blood glucose avoiding hypoglycaemia. At the end of the study blood glucose was reduced to 6.9 +/- 0.7 mmol l-1 (p less than 0.001). During the insulin infusion, capillary blood velocity increased by 28.8% (p less than 0.05), and the diameter of the capillary erythrocyte column increased from 7.6 +/- 0.2 to 9.2 +/- 0.3 micron (p less than 0.01). Thus during the insulin infusion, the calculated capillary flow increased to 226 +/- 36% above basal values (p less than 0.01). Laser Doppler flow did not change significantly, suggesting that during insulin infusion skin blood flow is redistributed with an increase in capillary flow relative to arteriovenous shunt flow.


Does increased glomerular filtration rate or disturbed tubular function early in the course of childhood type 1 diabetes predict the development of nephropathy?

To clarify whether glomerular hyperfiltration or disturbances in renal tubular function may be early markers of the later development of nephropathy a follow-up study was performed in 34 young Type 1 diabetic patients, who had originally been investigated 12 years previously. The initial median age was 14 (range 7-18) years and median diabetes duration 7 (2-14) years. At initial examination only one of the 34 diabetic patients exhibited increased urinary albumin excretion rate. The median glomerular filtration rate was increased (136 vs 107 ml min-1 1.73 m-2; p less than 0.0001) and median threshold concentration of phosphate per litre of glomerular filtrate was decreased (1.27 vs 1.76 mmol l-1; p less than 0.0001) in the diabetic group as compared to that of 28 healthy children. At follow-up 17 patients showed increased urinary albumin excretion rate and the median glomerular filtration rate in this group was significantly lower than that of 17 patients with normal urinary albumin excretion rate (108 vs 125 ml min-1 1.73 m-2; p less than 0.05). However, no relationships were found between the increased urinary albumin excretion (incipient and/or overt diabetic nephropathy) at follow-up to either the initial glomerular filtration rate (134 vs 137 ml min-1 1.73 m-2; p greater than 0.05) or to renal tubular function assessed from urinary excretion rate of beta 2-microglobulin (0.059 vs 0.069 microgram min-1; p greater than 0.05) and the renal threshold concentration of phosphate per litre of glomerular filtrate (1.29 vs 1.22 mmol l-1; p greater than 0.05).


Increased incidence of end-stage renal failure secondary to diabetes mellitus in Asian ethnic groups in the United Kingdom.

Diabetic renal disease is more common in patients of Asian ethnic origin than White Caucasians in the United Kingdom. This study determines whether a disparity in the incidence of end-stage renal failure secondary to diabetes mellitus exists between these ethnic groups. The incidence of treated end-stage renal failure was estimated using the person-time at risk incidence rate for patients receiving renal replacement therapy secondary to diabetes mellitus in the county of Leicestershire from 1979 to 1988. The incidence rate of end-stage renal failure expressed for the estimated population of patients with diabetes mellitus in patients of Asian ethnic origin was 486.6 (95% CI, 185.1 to 788.1) cases per million person-years per year, compared to 35.6 (17 to 54.2) in White Caucasians. All patients of Asian ethnic origin developing end-stage renal failure had non-insulin-dependent diabetes. The high incidence of end-stage renal failure secondary to diabetes mellitus in patients of Asian ethnic origin in the UK imparts significant public health implications for resource planning and allocation, and the need to initiate strategies to ameliorate renal disease in this ethnic group.


Morbidity, mortality, and albuminuria in type 2 diabetic patients: a three-year prospective study of a random cohort in general practice.

In a 3-year prospective study, the prevalence of albuminuria and its relationship to macrovascular disease, pre-existing vascular risk factors and mortality rate were studied in a random cohort of 290 patients with Type 2 diabetes mellitus in general practice. Newly occurring micro- or macroalbuminuria was associated with significantly (p less than 0.05) higher systolic blood pressure: median (IQ range) 157 (140-170) vs 150 (130-160) mmHg, in addition to higher serum triglycerides: median (IQ range) 2.71 (1.84-4.25) vs 1.84 (1.35-3.14) mmol l-1, and C-peptide levels: median (IQ range) 1.30 (0.98-2.16) vs 1.10 (0.82-1.58) nmol l-1, at 3-year follow-up. Patients with macroalbuminuria at final examination had significantly higher systolic and diastolic blood pressure, serum triglyceride and beta 2-microglobulin levels, decreased HDL-cholesterol, and a significantly higher prevalence of carotid artery stenoses and peripheral vascular disease. Patients dying from vascular causes showed significantly higher urinary albumin levels at entrance as compared to the surviving patients: median (IQ range): 42.2 (11-249.7) vs 10.4 (4.6-28.0) mg l-1, p less than 0.008, and overall mortality rate was significantly linked with the presence of macroalbuminuria (26% vs 5% in normoalbuminuric patients). A comparison between the results of the initial and the final examination indicated an overall worsening of renal variables (albuminuria: median (IQ range): female 9.5 (4.5-21) vs 13.4 (5.1-39.7) mg l-1, (p less than 0.05); male 13.8 (4.7-34.1) vs 32.6 (8.1-78.7) (p less than 0.001), despite a significant improvement in metabolic variables.(ABSTRACT TRUNCATED AT 250 WORDS)


Clinical and metabolic characteristics of type 1 and type 2 diabetes: an epidemiological study from the Närpes community in western Finland.

Clinical and metabolic characteristics of all known Type 1 and Type 2 diabetic patients in a well-defined area in Western Finland are described. Retrospective data from the time of diagnosis and follow-up data were examined. Overall prevalence of diabetes was 25.4 cases per 1000 population. Patients were defined as having Type 1 or Type 2 diabetes based upon early insulin requirement and C-peptide levels. Applying these criteria 84% of the patients had Type 2 diabetes. Onset before the age of 40 years was observed in only 3% of Type 2 diabetic patients. This age limit therefore had a sensitivity of 97% and a specificity of 90% in correctly predicting Type 2 diabetes. At diagnosis, hypertension was observed in 2% of Type 1 and in 75% of Type 2 diabetic patients; the corresponding numbers at follow-up were 6 and 63%. At investigation, 27% of Type 1 and 22% of Type 2 diabetic patients had microalbuminuria. Retinopathy was observed in only 12% of Type 2 compared with 54% of Type 1 diabetic patients. The presence of retinopathy was associated with longer diabetes duration both among Type 1 and Type 2 diabetic patients. A significant decrease in C-peptide concentration was observed in Type 2 diabetic patients with increasing diabetes duration. The data therefore suggest that Type 2 diabetes is associated with a deterioration of beta-cell function with time.


Education and employment experiences in young adults with type 1 diabetes mellitus.

Educational attainment, employment experiences, and self-esteem were measured using semi-structured questionnaires in young adults with Type 1 diabetes mellitus and in a group of age/sex matched healthy controls. Results showed that subjects with diabetes and their matched controls obtained comparable qualifications at all levels. However, subjects with diabetes were less likely to feel competent with regard to their educational performance, and many of this group reported experiencing difficulties at school. There were no differences in the proportion of each group who had experienced unemployment, although this was explained more by social class and educational attainment. Whereas only a minority had decided to withhold information about their condition from their employers, one-third of those with diabetes had experienced health-related problems in obtaining employment. This study suggests that the educational achievements and employment experiences of young adults with diabetes may not differ from those of healthy controls. However subjective reports of difficulties in these areas may be associated with reduced self-esteem. Confirmation of these findings should be carried out in a larger sample, using a prospective design.


Use of a family record in diabetes clinics.

As a result of a two-year study funded by a BDA Diabetes Development Project, data are presented on the usefulness of a family record in paediatric diabetes clinics. There was a poor response to the invitation to try the family record. Examples are given of its potential usefulness but it is acknowledged that it is likely to be more useful if a psychiatrist or psychotherapist is part of the team.


Varieties of numerical abilities.

This paper provides a tutorial introduction to numerical cognition, with a review of essential findings and current points of debate. A tacit hypothesis in cognitive arithmetic is that numerical abilities derive from human linguistic competence. One aim of this special issue is to confront this hypothesis with current knowledge of number representations in animals, infants, normal and gifted adults, and brain-lesioned patients. First, the historical evolution of number notations is presented, together with the mental processes for calculating and transcoding from one notation to another. While these domains are well described by formal symbol-processing models, this paper argues that such is not the case for two other domains of numerical competence: quantification and approximation. The evidence for counting, subitizing and numerosity estimation in infants, children, adults and animals is critically examined. Data are also presented which suggest a specialization for processing approximate numerical quantities in animals and humans. A synthesis of these findings is proposed in the form of a triple-code model, which assumes that numbers are mentally manipulated in an arabic, verbal or analogical magnitude code depending on the requested mental operation. Only the analogical magnitude representation seems available to animals and preverbal infants.


Cognitive mechanisms in numerical processing: evidence from acquired dyscalculia.

This article discusses cognitive neuropsychological research on acquired dyscalculia (i.e., impaired numerical processing resulting from brain damage), surveying issues of current interest, and illustrating the ways in which analyses of acquired deficits can contribute to an understanding of normal processing. I first review the logic whereby inferences concerning normal cognition are drawn from patterns of impaired performance. I then consider research exploring the general functional architecture of the cognitive numerical processing mechanisms, and finally turn to studies aimed at probing the internal structure and functioning of individual processing components.


Images of numbers, or "When 98 is upper left and 6 sky blue".

Some people declare that they possess a personal visual representation of numbers: some automatically "see" the numbers they are confronted with in a precise location in a structured mental space, others "associate" specific colours with given numbers. Such visuo-spatial representations of numbers were first described by Galton in 1880 but have since received little attention from psychologists. It is the aim of this article to describe these mental representations and discuss their role in number processing. The authors first review Galton's observations, and then present their own. Finally, they discuss the relevance of these visuo-spatial representations in relation to contemporary debates on number representation and calculation.


Preverbal and verbal counting and computation.

We describe the preverbal system of counting and arithmetic reasoning revealed by experiments on numerical representations in animals. In this system, numerosities are represented by magnitudes, which are rapidly but inaccurately generated by the Meck and Church (1983) preverbal counting mechanism. We suggest the following. (1) The preverbal counting mechanism is the source of the implicit principles that guide the acquisition of verbal counting. (2) The preverbal system of arithmetic computation provides the framework for the assimilation of the verbal system. (3) Learning to count involves, in part, learning a mapping from the preverbal numerical magnitudes to the verbal and written number symbols and the inverse mappings from these symbols to the preverbal magnitudes. (4) Subitizing is the use of the preverbal counting process and the mapping from the resulting magnitudes to number words in order to generate rapidly the number words for small numerosities. (5) The retrieval of the number facts, which plays a central role in verbal computation, is mediated via the inverse mappings from verbal and written numbers to the preverbal magnitudes and the use of these magnitudes to find the appropriate cells in tabular arrangements of the answers. (6) This model of the fact retrieval process accounts for the salient features of the reaction time differences and error patterns revealed by experiments on mental arithmetic. (7) The application of verbal and written computational algorithms goes on in parallel with, and is to some extent guided by, preverbal computations, both in the child and in the adult.


Cognitive arithmetic: a review of data and theory.

The area of cognitive arithmetic is concerned with the mental representation of number and arithmetic, and the processes and procedures that access and use this knowledge. In this article, I provide a tutorial review of the area, first discussing the four basic empirical effects that characterize the evidence on cognitive arithmetic: the effects of problem size or difficulty, errors, relatedness, and strategies of processing. I then review three current models of simple arithmetic processing and the empirical reports that support or challenge their explanations. The third section of the review discusses the relationship between basic fact retrieval and a rule-based component or system, and considers current evidence and proposals on the overall architecture of the cognitive arithmetic system. The review concludes with a final set of speculations about the all-pervasive problem difficulty effect, still a central puzzle in the field.


Performance of a diagnostic system (Iliad) as a tool for quality assurance.

Quality assurance improves health care through detection of quality problems and feedback to the care giver. Current review procedures employed by the Peer Review Organizations (PROs), however, appear to underdetect quality problems, particularly those arising from diagnostic errors. We studied the use of an expert diagnostic system, Iliad, to detect quality problems arising from diagnostic errors. One hundred cases were selected from among those Medicare cases reviewed by the Utah PRO (UPRO) and which contained diagnoses recognized by Iliad. Iliad flagged 28 cases out of the 100 as containing diagnostic errors, and a gold standard physician review confirmed quality problems in 17 cases (60.7%). The UPRO review found 28 cases with quality problems, mostly treatment and documentation errors. The quality problems detected by Iliad appeared to be more serious than those detected by the UPRO review. Among the six cases with quality problems detected by both the UPRO and the Iliad review, there was none for which the same quality problem was detected by the two procedures. The two review procedures were therefore complementary.


Representation of preferences in decision-support systems.

The recommendations of computer-based decision-support systems depend on the preferences of the expert who is responsible for the decisions. Often, these preferences are only represented implicitly, rather than explicitly, in the system. Decision-theoretic preference models that explicitly represent the preferences of the decision maker provide numerous advantages for decision-support systems. In this paper, we describe these advantages. The creation and refinement of decision-theoretic preference models, however, is a difficult task. We describe an accurate and efficient method for determining the preferences of domain experts and refining the model that captures those preferences. In this preference assessment method, we simulate familiar decisions in the expert's area of expertise. We then infer the preferences of the expert from the choices that the expert makes on the simulated decisions, and use the preference information to refine the model automatically.


Evaluation of a Meta-1-based automatic indexing method for medical documents.

This paper describes MetaIndex, an automatic indexing program that creates symbolic representations of documents for the purpose of document retrieval. MetaIndex uses a simple transition network parser to recognize a language that is derived from the set of main concepts in the Unified Medical Language System Metathesaurus (Meta-1). MetaIndex uses a hierarchy of medical concepts, also derived from Meta-1, to represent the content of documents. The goal of this approach is to improve document retrieval performance by better representation of documents. An evaluation method is described, and the performance of MetaIndex on the task of indexing the Slice of Life medical image collection is reported.


A specialized framework for medical diagnostic knowledge-based systems.

For a knowledge-based system (KBS) to exhibit an intelligent behavior, it must be endowed with knowledge enabling it to represent the expert's strategies. The elicitation task is inherently difficult for strategic knowledge, because strategy is often tacit, and, even when it has been made explicit, it is not an easy task to describe it in a form which may be directly translated and implemented into a program. This paper describes a Specialized Framework for Medical Diagnostic Knowledge-Based Systems that can help an expert in the process of building KBSs in a medical domain. The framework is based on an epistemological model of diagnostic reasoning which has proven to be helpful in describing the diagnostic process in terms of the tasks that it is composed of. It allows a straightforward modeling of diagnostic reasoning at the knowledge level by the domain expert, thus helping to convey domain-dependent strategies into the target KBS.


Analysis of physician questions in an ambulatory care setting.

We collected 69 questions generated by physicians based on their active patient medical records. Each question was associated with a single term in a specific record (Key Term). These questions were analyzed with respect to word content and concept content. Concepts were matched to the National Library of Medicine's Metathesaurus (Meta-1). Sixty-eight Key Terms were completely matched by Meta-1 terms. Each question matched to an average of 3.7 Meta-1 terms for a total of 255 concepts. Based on word count, these 255 concepts accounted for 43%, stop words accounted for 36%, and numbers and drug trade names accounted for 3% of the words. The remaining 18% of the words could be matched to 143 concepts not in Meta-1. Review of all concepts showed that they could be divided into medical terms (Noun Concepts), modifiers (Modifier Concepts), and concepts that provided context for the questions (Relation Concepts). The majority of Relation Concepts did not match concepts in Meta-1. A vocabulary of Relation Concepts would provide a useful starting point for a computer system designed to aid physicians in answering these questions.


Ranking radiotherapy treatment plans using decision-analytic and heuristic techniques.

Radiotherapy treatment optimization is done by generating a set of tentative treatment plans, evaluating them, and selecting the plan closest to achieving a set of conflicting treatment objectives. The evaluation of potential plans involves making trade-offs among competing possible outcomes. Multiattribute decision theory provides a framework for specifying such trade-offs and using them to select optimal actions. Using these concepts, we have developed a plan-ranking model which ranks a set of tentative treatment plans from best to worst. Heuristics are used to refine this model so that it reflects the clinical condition of the patient being treated and the practice preference of the physician prescribing the treatment. A figure of merit is computed for each tentative plan and is used to rank the plans. The approach described is very general and can be used for other medical domains having similar characteristics. The figure of merit can also be used as an objective function by computer programs that attempt to automatically generate an optimal treatment plan.


LMSMVE: a program for least median of squares regression and robust distances.

The program LMSMVE performs robust regression analysis by using the method of the least median of squares. It also computes robust distances to locate leverage points, that is, outliers with respect to the set of independent variables. LMSMVE constructs plots of least median of squares residuals against robust distances. Both methods can tolerate up to half the data being outliers before they fail to give results that describe the bulk of the data. A complete system that operates directly on SYSTAT files is available for the IBM PC and compatibles; it includes a utility that converts ASCII files to SYSTAT format.


Automated lanes detection and comparison of bacterial electrophoretic protein fingerprints using fast Fourier transformation.

A method of computer-automated analysis of bacterial fingerprints produced by electrophoresis of proteins in a one-dimensional slab gel system is described. Proteins were visualized by silver staining. Western blotting, or autoradiography. Gels were recorded with a CCD camera, and after initial manual removal of the unwanted image margins, track margins were identified and extracted and a normalized trace was produced automatically using Fourier routines to smooth plots required for this process. Normalized traces were then compared by Fourier correlation after application of a high-pass step filter.


Analysis of beat-to-beat cardiovascular hemodynamic variables obtained from long-term biotelemetry.

Manual methods of large volume data storage, retrieval, and analysis are difficult, time consuming, and present numerous opportunities for calculation errors. We have designed and implemented a comprehensive computer-based system for performing these functions. Development of this system was necessary since left ventricular (LV) blood pressure and two regional LV wall thickness measurements were obtained during long-term extracorporeal biotelemetry of miniswine for 24-h periods. During a single recording period over 100,000 individual cardiac cycles were recorded on analog tape and later analysed for determination of global myocardial oxygen demand and regional myocardial function. In addition, custom designed software was developed to determine the extent and duration of myocardial dysfunction. Batch file commands enabled the customized software to operate without prompting by the user thus optimizing the time usage of the computer, and the computer based data acquisition and analysis system. Although this system was designed specifically for analysing cardiovascular hemodynamic variables, it is flexible and can be applied to other experimental applications.


A combined one- and two-way analysis of variance microcomputer program.

A simple microcomputer program in BASIC is designed to compute both the one-way and two-way analysis of variance. The program is an interactive one and can be easily and promptly used for statistical analysis of biomedical data. The applicability of the program is illustrated by data obtained from the percutaneous absorption of dihydroergotamine into the excised skin of rabbits.


Microcontroller-based system for collecting anaerobic blood samples from a running greyhound.

Many physiological variables change rapidly in the blood during sprint exercise. To characterize the dynamics and extent of these changes, blood samples must be obtained during exercise. We describe herein a portable, microcontroller-based system used to automatically obtain repeated, anaerobic, arterial blood samples from greyhounds before, during, and following a race on a track. In addition, the system also records the blood temperature in the pulmonary artery each time a blood sample is taken. The system has been tested for more than 2 years and has proven to be reliable and effective.


A computer model of the kidney.

We developed a computer model of renal function that factors perfusion pressure, serum sodium, potassium, antidiuretic hormone and aldosterone concentrations to derive urine output, urinary sodium and urinary potassium excretion. The model implements Uttamsingh's (Uttamsingh, R.J., et al. Mathematical model of the human renal system. Med. Biol. Eng. Comput. 23 (1985) 525-536) analytical equations as an electrical circuit suitable for network analysis. This model is useful for studying the effects of renal blood flow and the humoral milieu on renal function in normal kidneys either as a stand-alone unit or in combination with other physiological electrical models.