Mechanisms and pathology of monocrotaline pulmonary toxicity.

Monocrotaline (MCT) is an 11-membered macrocyclic pyrrolizidine alkaloid (PA) that causes a pulmonary vascular syndrome in rats characterized by proliferative pulmonary vasculitis, pulmonary hypertension, and cor pulmonale. Current hypotheses of the pathogenesis of MCT-induced pneumotoxicity suggest that MCT is activated to a reactive metabolite(s) in the liver and is then transported by red blood cells (RBCs) to the lung, where it initiates endothelial injury. While several lines of evidence support the requirement of hepatic metabolism for pneumotoxicity, the mechanism and relative importance of RBC transport remain undetermined. The endothelial injury does not appear to be acute cell death but rather a delayed functional alteration that leads to disease of the pulmonary arterial walls by unknown mechanisms. The selectivity of MCT for the lung, as opposed to that of other primarily hepatotoxic PAs, appears likely to be a consequence of the differences in hepatic metabolism and blood kinetics of MCT. A likely candidate for a reactive metabolite of MCT is the dehydrogenation product monocrotaline pyrrole (MCTP). Secondary or phase II metabolism of MCT through glutathione (GSH) conjugation has been characterized recently and appears to represent a detoxification pathway. The role of inflammation in the progression of MCT-induced pulmonary vascular disease is uncertain. Both perivascular inflammation and platelet activation have been proposed as processes contributing to the response of the vascular media. This review presents the experimental evidence supporting these hypotheses and outlines additional questions that arise from them.


Aquatic insects and trace metals: bioavailability, bioaccumulation, and toxicity.

The uptake of metals from food and water sources by insects is thought to be additive. For a given metal, the proportions taken up from water and food will depend both on the bioavailable concentration of the metal associated with each source and the mechanism and rate by which the metal enters the insect. Attempts to correlate insect trace metal concentrations with the trophic level of insects should be made with a knowledge of the feeding relationships of the individual taxa concerned. Pathways for the uptake of essential metals, such as copper and zinc, exist at the cellular level, and other nonessential metals, such as cadmium, also appear to enter via these routes. Within cells, trace metals can be bound to proteins or stored in granules. The internal distribution of metals among body tissues is very heterogeneous, and distribution patterns tend to be both metal and taxon specific. Trace metals associated with insects can be both bound on the surface of their chitinous exoskeleton and incorporated into body tissues. The quantities of trace meals accumulated by an individual reflect the net balance between the rate of metal influx from both dissolved and particulate sources and the rate of metal efflux from the organism. The toxicity of metals has been demonstrated at all levels of biological organization: cell, tissue, individual, population, and community. Much of the literature pertaining to the toxic effects of metals on aquatic insects is based on laboratory observations and, as such, it is difficult to extrapolate the data to insects in nature. The few experimental studies in nature suggest that trace metal contaminants can affect both the distribution and the abundance of aquatic insects. Insects have a largely unexploited potential as biomonitors of metal contamination in nature. A better understanding of the physicochemical and biological mechanisms mediating trace metal bioavailability and exchange will facilitate the development of general predictive models relating trace metal concentrations in insects to those in their environment. Such models will facilitate the use of insects as contaminant biomonitors.


Determination of mercapturic acid excretions in exposure control to toxicants.

Toxicants can be converted in vivo by a variety of biotransformation reactions into substances that are more, equally, or less noxious than the parent compound. Although conjugation with glutathione is a process that usually results in less harmful products, these products might subsequently form new metabolites that exert more toxicity than the parent compound. These conjugation reactions are catalyzed by several classes of glutathione-S-transferase isoenzymes and thus result in the urinary or biliary excretion of N-acetyl-L-cysteine-S-conjugates (mercapturic acids). Inasmuch as GSH-S-transferase activity varies among different tissues, urinary excretion of mercapturic acids might reflect tissue-specific toxicity. Urinary mercapturic acids are biomarkers of internal and, in some cases, effective dose. The utility of these markers is, however, limited to times shortly after exposure. Studies on possible human deficiencies in some GSH-S-transferases might help us better understand interindividual variations in susceptibility to different toxicants and thus the differences in the pathway of mercapturic acid excretion pattern.


Validity and reliability of the Pressure Sore Status Tool.

There is not yet a universal system for describing the status of pressure sores. The purpose of this study was to assess the validity and reliability of an instrument developed by the researchers for evaluation of pressure sores, the Pressure Sore Status Tool (PSST). This study was part of a larger study, which included development of a theoretical model for creation of items for the PSST. A nine-member expert judge panel established content validity of items on the instrument. Data were analyzed using a content of validity index (average index for tool = .91) and judges' comments were used to modify two items on the PSST. Two Enterostomal Therapy (ET) nurses independently used the revised tool to rate 20 pressure sores on ten adult medical-surgical patients, at two observation times. Interrater reliability was established at r = .91 for first observation and r = .92 for the second observation (p < .001). Intrarater reliability was r = .99 for rater one and r = .96 for rater two (p < .001). Future research will focus on refinement and further reliability testing of the instrument.


The treatment of osteomyelitis underlying pressure ulcers.

Osteomyelitis is recognized as an often intractable hindrance to healing in the deep pressure ulcer. The mainstays of treatment of this disease have traditionally been surgical debridement followed by muscle flap revascularization, supplemented by antibiotic coverage. Hyperbaric oxygenation has also been shown to be effective in healing refractory osteomyelitis when used as an adjunct to surgical and medical therapy. This review defines the disease, and presents a current literature review and discussion of its treatment, including adequacy of debridement, options for wound closure, appropriate antimicrobial strategy, and the role of hyperbaric oxygenation. A short review of investigational modalities is also included.


Assessing and enhancing reliability.

When choosing a tool or instrument to gather data, the clinician must consider many factors including the validity, reliability, sensitivity, and specificity of the measuring device. While all of these factors are important measurement issues, this article focuses on assessment and enhancement of reliability.


A tool to document the competence of clinicians to prevent and manage pressure ulcers.

As one way to meet the standards of quality patient care, a new tool was developed to document the clinical competence of healthcare providers in preventing and managing care for patients with pressure ulcers. The "Clinical Competency Tool for Documentation of Pressure Ulcer Prevention and Management" is described as well as suggestions for incorporating its use in the education of healthcare providers.


Pain control after surgery: a patient's guide, Agency for Health Care Policy and Research.

What is pain? Pain is an uncomfortable feeling that tells you something may be wrong in your body. Pain is your body's way of sending a warning to your brain. Your spinal cord and nerves provide the pathway for messages to travel to and from your brain and the other parts of your body. Receptor nerve cells in and beneath your skin sense heat, cold, light, touch, pressure, and pain. You have thousands of these receptor cells, most sense pain and the fewest sense cold. When there is an injury to your body--in this case surgery--these tiny cells send messages along nerves into your spinal cord and then up to your brain. Pain medicine blocks these messages or reduces their effect on your brain. Sometimes pain may be just a nuisance, like a mild headache. At other times, such as after an operation, pain that doesn't go away--even after you take pain medicine--may be a signal that there is a problem. After your operation, your nurses and doctors will ask you about your pain because they want you to be comfortable, but also because they want to know if something is wrong. Be sure to tell your doctors and nurses when you have pain.


Clinical and biochemical aspects of carnitine deficiency and insufficiency: transport defects and inborn errors of beta-oxidation.

Carnitine is required for entry of long chain fatty acids into mitochondria where beta-oxidation occurs. Primary carnitine deficiency, due to a generic defect in cellular carnitine transport, exists in myopathic and systemic forms. Secondary carnitine deficiency may be due to multiplicity of inherited abnormalities, including deficiencies in carnitine palmitoyl-transferase acyl-CoA dehydrogenases, electron transfer flavoprotein, and 3-ketoacyl-CoA-thiolase. The clinical features, diagnosis, and treatment of these conditions are described.


Lipoprotein lipase: recent contributions from molecular biology.

Lipoprotein lipase (LPL) is a glycoprotein enzyme that is produced in several cells and tissues. LPL belongs to a large lipase gene family that includes, among others, hepatic lipase and pancreatic lipase. After secretion, LPL becomes anchored on the luminal surface of the capillary endothelial cells. There it hydrolyzes triglycerides in triglyceride-rich lipoproteins, generating free fatty acids that can serve either as a direct energy source or can be stored. Through this action LPL plays a pivotal role both in energy and in lipoprotein metabolism. LPL production is regulated in a tissue-specific fashion by developmental, hormonal, and nutritional factors. The recent availability of the regulatory sequences of the LPL gene will greatly facilitate these regulatory studies in the future. In man, several mutations resulting in familial LPL deficiency have been delineated at a molecular level. The study of these mutations is not only very beneficial from a clinical point of view but also contributes in a major way to our understanding of the structure-function relationship of LPL and other lipases. In this review major attention is given to molecular studies relating to the regulation of LPL production, to the defects underlying LPL deficiency, and to structure-function relationship of the lipases.


Oncogenes and tumor suppressor genes: new biochemical tests.

Oncogenes and tumor suppressor genes are genes involved in cell proliferation and differentiation. They play a crucial role in the initiation and progression of cancer. Some of these genes are found to be altered in human cancers, i.e., mutated, amplified, deleted, translocated, or abnormally regulated. Recently, the protein products of the genes have been purified, and antibodies against them have been developed. Studies of oncogenes and tumor suppressor genes at the DNA, mRNA, or protein level may reveal new ways for diagnosis, monitoring, prognosis, and treatment of cancer. In this article, the area of oncogenes and tumor suppressor genes is reviewed, with emphasis on clinical applications and biochemical testing. Although most of the currently known genetic markers are not sufficiently specific or sensitive, it is anticipated that the discovery of newer markers and the application of new analytical techniques may help in devising biochemical testing suitable for screening and early diagnosis of malignant diseases.


The role of neopterin as a monitor of cellular immune activation in transplantation, inflammatory, infectious, and malignant diseases.

The accumulated knowledge about the organization and function of the human immune system contributes to a better understanding of the pathogenesis of most diverse disorders and is opening new avenues for therapeutic regimens. To gain further insight into the complex interactions within the components of the immune system, it has become increasingly necessary to develop rapid and simple methods to monitor the status of the immune system in patients. The determination of neopterin concentrations in human body fluids allows to investigate sensitively the cell-mediated immune status to be investigated with considerable sensitivity. In recent years it was shown that production and release of neopterin is inducible in human monocytes/macrophages by interferon gamma. Increased neopterin levels indicate endogenous formation of gamma interferon, and monitoring of neopterin levels therefore permits the activation status of the cell-mediated immune system to be examined. Neopterin concentrations in serum and in urine increase in parallel to the clinical course of infections with viruses, intracellular bacteria, and parasites. In patients with human immunodeficiency virus infection neopterin concentration in serum and urine is a significant predictor of disease progression, the statistical power being similar to CD4+ T-cell numbers. In patients with autoimmune disorders, neopterin levels correlate with the extent and the activity of the disease. Neopterin concentrations are also sensitive indicators of immunological complications in allograft recipients. In certain malignant diseases neopterin concentrations correlate with the stage of the disease and bear prognostic information. Results of neopterin measurements agree with the important role that the cellular immune system plays in these disorders.


Experimental podophyllotoxin (bajiaolian) poisoning: I. Effects on the nervous system.

Bajiaolian, one of the species in the Mayapple family (Podophyllum pelatum), has been widely used as a traditional Chinese herbal medicine for the remedies of snake bites, general weakness, poisons, condyloma accuminata, lymphadenopathy, and certain tumors in China. In Western medicine, Podophyllum was first used medically as a laxative in the early 19th century. Since 1940, the resin of podophyllum has also been used topically for various skin lesions, such as warts and condyloma. Human poisonings have been reported. An animal model was established to investigate the neurotoxic effects of Bajiaolian. Podophyllotoxin, the major active ingredient in Podophyllum, was injected (ip) to young adult male rats at doses of 0, 5, 10, or 15 mg.kg-1 b.w.. The animals were sacrificed 72 h after injection. Neuronal changes were readily observable in animals treated with 10 or 15 mg.kg-1 of the toxin. Edematous changes of the anterior horn motoneurons were observed in the spinal cord. No neuronal necrosis was found. The type of neuronal swelling is believed to be only a transient change and would probably subside with time if no further assaults occur. More serious and perhaps longer term of changes were found in the dorsal ganglion neurons and the nerve fibers (axons) in the central and peripheral nervous system. Severe depletion of the Nissl substance (RNA/polyribosomes) was observed in the dorsal root ganglion neurons. Alterations in these sensory neurons would give rise to and correlate with the sensory disturbances experienced by the patients. Bodian staining also revealed a dose-related increase in the coarseness (thickness) of the nerve fibers (axons) in the cerebellum, cerebral cortex, brainstem, and spinal cord. This is the first scientific study showing the neurotoxicity of Bajiaolian, a commonly used Chinese herbal medicine. Toxicities on other organ systems by this drug certainly exist. Caution should be exercised in the dispensing and usage of this medicine.


Experimental podophyllotoxin (bajiaolian) poisoning: II. Effects on the liver, intestine, kidney, pancreas and testis.

Young male rats were orally intubated with podophyllotoxin: Group I, control animals, orally fed with vehicle only; Group II, fed with an initial dose of 5 mg.kg-1 b.w., followed by a daily dose of 1.67 mg.kg-1 b.w. for 7d. Group III, fed with an initial dose of 15 mg.kg-1 b.w., followed by a daily dose of 5 mg.kg-1 b.w. for 7d. All animals were sacrificed 72 h after the last dosing. Histopathological examination revealed dose-related fatty change of the liver, atrophy and degenerative changes of the intestinal epithelial linings and testicular seminiferous tubules. Depletion of the pancreatic acinar cell granules was also apparent in the Group III animals. No pathology, however, was observed in the kidneys. The present study demonstrated for the first time degenerative changes in the liver, intestine, testis, and pancreas of animals ingested podophyllotoxin. These pathological changes correlate well with the clinical signs/symptoms of abnormal liver function, abdominal pain and diarrhea, and reduced serum amylase in humans poisoned by podophyllum. Inhibition of protein synthesis and mitosis (disruption of microtubules) are believed to be the underlying mechanisms of these changes observed in the animals intoxicated by podophyllotoxin.


Study of the relationship between the hepatotoxicity and free radical induced by 1,1,2-trichloroethane and 1,1,1-trichloroethane in rat.

The hepatotoxicity and the relationship between the hepatotoxicity and free radical induced by 1,1,2-trichloroethane (1,1,2-TCE) and 1,1,1-trichloroethane (1,1,1-TCE) were studied by whole animals test and the isolated perfused rat liver test. Enzymatic parameters measured during the test included the assay of levels of glutamic pyruvic transaminase (GPT), sorbital dehydrogenase (SDH) and glutamate dehydrogenase (GDH). The observation of the pathologic changes of the liver by the light microscope and the measurement of the relative total free radical concentration in the liver were also made. The results showed that 1,1,2-TCE caused definite pathologic changes of rat liver. It led to much higher values for GPT, SDH and GDH both in serum and perfusate than 1,1,1-TCE did (P < 0.01). The concentration of perfusate K+ caused by 1,1,2-TCE was higher than that by 1,1,1-TCE (P < 0.01). The value of the relative total free radical concentration induced by 1,1,2-TCE was also greater than that by 1,1,1-TCE (P < 0.05). The results suggested that the hepatotoxicity of 1,1,2-TCE was stronger than that of 1,1,1-TCE. The free radical concentration was increased proportionally to the increase of the hepatotoxicity of 1,1,2-TCE and 1,1,1-TCE. It appeared that free radical may play an important role in the mechanism of the hepatic injury induced by 1,1,2-TCE.


Effect of an environmental contaminant, diisopropyl methylphosphonate, on the blood pressure of the mallard.

During a toxicological test using diisopropyl methylphosphonate (DIMP) on mallards, an anaesthesia-like response was noted after oral dosing. In order to further elucidate these effects, arterial blood pressures were determined both pre- and post-dosing on adult male and female mallards by cannulation of the left carotid artery. A significant decrease in systolic, diastolic, and mean blood pressure was noted after the oral administration of DIMP. There was no significant difference in response between males and females. During the first 30 min after dosing, systolic pressure fell from an average of 158 mmHg, to 94 mmHg, diastolic decreased from 127 mmHg to 63 mmHg, and mean blood pressure dropped from 138 mmHg to 75 mmHg. However, there was no significant effect on pulse pressure, heart rate, or respiratory rate. These results are compared to physiological data cited in the literature for various CNS-acting drugs on mallards.


Dermal toxicity of paraphenylenediamine.

The guinea pigs were dermally exposed to paraphenylenediamine (PPD) and in presence of an oxidising agent hydrogen peroxide for 15 and 30 d to assess their effects on some enzymes, lipid peroxidation and histamine contents in the skin. The activities of acid and alkaline phosphatases, beta-glucuronidase, gamma glutamyl transpeptidase, histidase and tyrosinase were enhanced after application of either PPD or PPD plus hydrogen peroxide. The lipid peroxidation and histamine contents also showed marked elevation following exposure to the chemicals.


Acute toxic effects of mercuric chloride on the mucocytes of the epithelial lining of the accessory respiratory organ and skin of the air breathing catfish Heteropneustes fossilis (Bloch).

Acute toxicity of 0.3 ppm mercuric chloride on the mucocytes of the branchial diverticulum and skin of Heteropneustes fossilis results in cyclic increases followed by decreases in the density, area occupancy and volume at different intervals of exposure. The alterations in the two tissues do not follow the same path perhaps due to different modes of action of the mercury salt: The skin comes under direct contact effects, while the branchial diverticulum may be affected by hormonal imbalance caused by a stress effect.


Potential use of luminol-dependent chemiluminescence for estimation of free radicals produced in hepatic microsomes and reconstituted cytochrome P-450 systems.

The evaluation of luminol-dependent chemiluminescence (CL) for determination of free radicals generated during the oxidative reactions of microsomal enzymes in microsomes and reconstituted systems has been studied. The results indicated that the CL not only depended on NADPH induction but also on intact cytochrome P-450 enzymes. The light emission signal was strongly scavenged by SOD with inhibition rate of 93%. A concentration of 24 mumol.L-1 cadmium acetate and 2.5 mumol.L-1 mercuric chloride also inhibited the signal significantly as compared with the control. The study of CL in detecting free radicals formed by biotransformation of 44 xenobiotics suggested that some of the compounds known as free radicals producing agents by bioactivation increased the light emission in cytochrome P-450 enzyme system, such as carbon tetrachloride, chloroform, tetrachloroethylene etc., the others forming toxic metabolites by biotransformation induced the CL in some cases, such as carbon disulfide, benzene, methyldursban, methylparathion etc. or decreased the light emission, such as parathion, aniline and polychlorinated byphenyls etc., and still others whose toxic effects have no relationship with their biotransformation had no influence or an inhibitory effect on the CL, such as aminopyrine, TOCP, and acrylamide. CL in the cytochrome P-450 enzyme system remained unchanged during the biotransformation of carcinogens such as diethylnitrosamine, dipropylnitrosamine and benzo(a)pyrene as compared with the control. However, 3-methylcholanthrene and dimethylnitrosamine had an enhancing effect on the CL, while 2-acetylaminofluorene and 2-aminoanthracene showed an inhibition to the signals.


Effect of low benzene exposure on neurobehavioral function, AChE in blood and brain and bone marrow picture in mice.

The purpose of this study was to examine the effect of low level benzene exposure on neurobehavioral functions, AChE in blood and brain, bone marrow picture in Kunming mice. Forty adult Kunming male mice were divided into 4 groups. They were exposed to 12.52, 3.13, 0.78 and 0 ppm benzene for 2 h.d-1 for 30 d. Central nervous system (CNS) function was inhibited by 12.52 ppm and excited by 0.78 ppm benzene exposure, but irregularly affected by 3.13 ppm. AChE in blood and brain was decreased in 12.52, 3.13 ppm group. The weight of liver to body weight ratios in 12.52 ppm group was higher than those of control group significantly. Bone marrow picture revealed inhibited proliferation of white and red cell systems, especially in 12.52 ppm group, consisting of decrease of percentage of myeloblast, premyelocytes, myelocytes, erythroblasts and megakaryocytes, especially in 12.52 ppm group.


Time dependent tissue distribution of 203Hg in the white rat and Anabas testudineus, a freshwater teleost.

The distribution of mercury, an environmentally important toxicant, has been evaluated in a time dependent manner in different tissues of white rat and a freshwater teleost, Anabas testudineus. Sampling was performed at 15 min, 2, 6 and 48 h post injection (im) of 203Hg mercuric nitrate. Radioactivity of the 5% tissue homogenate, serum and bile was measured in a Gamma Counter. The rate of 203Hg accumulation is higher in fish immediately after administration which, however, is more or less of equal rate in the later period of observation in both the experimental animals. Partitioning of 203Hg occurs in a species specific manner with higher levels recorded in the brain and gonad of white rat. Spleen, liver and kidney, however, are the major tissues to accumulate mercury in both the species. The present study highlights that kidney is the target site of mercury retention with a higher kidney/liver ratio of mercury.


Effects of tetrandrine on lung-lipid contents of rats with experimental silicosis.

The wet weight, lipid contents and the percentages of PL components of lung tissues, SAM and AM of normal, Silicotic and TT treated rats were analysed. It was indicated that the wet weight, lipid contents of lung tissues, SAM and AM of Silicotic rats all were increased, and with the lapse of experimental period. In lung tissues the percentages of PC, PG and PI accounted for the total PL were increased and PS, S were decreased in comparison with those of normal rats. The PL percentages in SAM of Silicotic rats were not significantly different from those of normal rats. The wet weight, lipid contents of lung tissues, SAM and AM, percentages of PL components in lung tissues of TT treated rats were higher than that of normal rats and lower than that of silicotic rats. The percentages of PC, USPC accounted for the total PL in SAM of TT treated rats were lower while PI, PS,S were higher than that of normal and Silicotic rats. The other percentages of PL components were not significantly different from that of normal and silicotic rats.


Regeneration of respiratory epithelia in the rat after free grafting.

Following free grafting of septal mucosa from the rat to the rectus abdominis muscle, the mucosal membrane was found to degenerate into a flat squamous epithelium with loss of the majority of differentiated epithelial cells. Both the goblet cells and ciliated cells regenerated from stem cells, which appear in large numbers 2 days after transplantation. Microvilli were found initially on the surfaces of developing ciliated cells and were replaced 21 days post-grafting by cilia. The number of goblet cells during regeneration at first exceeded that of the ciliated cells, but decreased with the passage of time. After 4 months there were more ciliated cells, with the respiratory epithelium now appearing no different than the initially transplanted nasal mucosa.


Yearly chest radiography in the early detection of lung cancer following laryngeal cancer.

In a retrospective study of 556 patients (505 men, 51 women) with laryngeal cancer the incidence and prognosis of lung malignancies was studied in patients who were examined yearly by chest radiography. In 69 patients (12.4%) a lung malignancy was diagnosed, with 28 having a histologically confirmed second primary malignancy. All of these 69 patients were men. The incidence of radiologically detected lung malignancies, both second primary and metastatic cancer, is higher and more prolonged following supraglottic carcinoma than following glottic carcinoma. In 47 patients (68%) without symptoms, the lung malignancy was detected by routine annual chest radiography. The survival rate in patients with lung cancer detected by the yearly radiography was significantly higher than in patients diagnosed after symptoms (median survival 10 and 4 months, respectively). However, taking into account the lead time between early radiologic diagnosis and the time a tumor would have been diagnosed following symptoms, the observed survival benefit of yearly radiography was much lower, or even nil.


An epidemiological approach to the etiology of middle ear disease in The Netherlands.

The etiology of middle ear disease in Nijmegen, The Netherlands was studied on the basis of a data set collected in a prospective epidemiological study on otitis media with effusion (OME) in a cohort of 1439 preschool children. A factor analysis was used to evaluate two hypotheses: (1) that OME, acute otitis media (AOM), common cold and tonsillitis are manifestations of the same pathological entity, and (2) that a group of children can be distinguished who develop these conditions more frequently than average. The results only partly supported these hypotheses. The correlation between OME, AOM, common cold and tonsillitis was lower than expected from a review of the literature. Common cold appeared to be the ubiquitous ENT disease in childhood and, depending on the child's predisposition, could be accompanied by OME, AOM or tonsillitis. The course of middle ear and upper airway disease showed a gradual scale from "healthy" to "ill" with most of the children suffering from these conditions at an average frequency.


Pneumococcal antigens and serum antibody responses in experimentally induced sinusitis.

Maxillary sinusitis was induced in New Zealand White rabbits with Streptococcus pneumoniae serotype 3 and the serum antibody response was recorded by enzyme immunoassay. Activity of the three major immunoglobulin classes, viz. IgG, IgA and IgM, against the type-specific capsular polysaccharide, the cell wall C-polysaccharide as well as its subunit phosphorylcholine was analyzed. A pronounced increase in immunoglobulins reactive to the specific capsular antigen was observed throughout the study period, with the rise being particularly noticeable during the first 2 weeks. An increase in anti-C-polysaccharide antibodies was also evident, but no reaction to phosphorylcholine could be detected. Although the histological findings at 3 and 4 weeks varied in spite of similar serum antibody responses, a correlation appeared to exist between a more rapidly increasing anti-capsular IgG production and the prevalence of a purulent sinus secretion.


Langerhans cells in human middle ear cholesteatomas.

Langerhans cells have been found in cholesteatomas for many years. It is believed that they are immunocompetent cells and have the same role in cell-mediated immunologic mechanisms in cholesteatoma as well as in skin. This study used the transmission electron microscope to observe the cellular characteristics of Langerhans cells and the apposition phenomenon of Langerhans cells with lymphocyte-like cells in human middle ear cholesteatomatous tissue. These findings are evidence for cell-mediated immune responses in middle ear cholesteatomas. In vitro Langerhans cells conditioned medium prepared from Lewis rat skin was used to show its effects on protein synthesis and the differentiation of basal cells. Since the cellular behaviour of basal cells is important in the development and pathogenesis of cholesteatoma, the present study shows that Langerhans cells may have some role in the clinical formation of a cholesteatoma. Since cells extracted from rat skin may have a different response from that of cells from human middle ear cholesteatoma, further investigations are necessary to compare the biological effects of both tissues.


Cholesteatoma in children. An Egyptian overview.

There is a long-lasting debate concerning cholesteatoma in children. This retrospective epidemiological study includes 81 ears harboring cholesteatoma and treated surgically. All patients were Egyptian and were treated at Alazhar University Hospital, Cairo. Among this group 37 ears belonged to patients younger than 18 years old. To clarify comparison with adult patients, a system of classification based on certain anatomical criteria is proposed. Statistical analysis proved that cholesteatoma in children treated at Alazhar University Hospital differs significantly in two main aspects: it is associated with more pathological changes and is associated with higher morbidity. Additionally, patients younger than 12 years are at high risk for complications. A subgroup of adolescents with cholesteatoma is marginal and has disease representing the characteristics of both adults and younger children.


Differences between sheep excreting sodium predominantly in their urine or in their faeces: the effect of changes in sodium intake.

Sheep receiving a total of about 31 mmol day-1 (0.5 mmol kg-1) of sodium were classified according to the predominant route of sodium excretion; urinary (U) or faecal (F). U sheep had a greater water turnover than F sheep; their intake was 41% higher and they produced 133% more urine but there was little difference in faecal water loss. Most faecal sodium was readily exchangeable with water in both groups. When sodium intake was reduced by 80% (to 6 mmol day-1; 0.1 mmol kg-1), the reduction in total sodium excretion was equally effective in F sheep and U sheep after 48 h and after 2 weeks the overall losses of sodium were smaller in F sheep. On sodium intakes close to requirement (0.1 mmol kg-1 or less) the majority of the sheep excreted most of their sodium in faeces and did so on intakes up to 0.5 mmol kg-1 day-1. Excess dietary sodium is mainly excreted renally. When sodium intake is increased abruptly (by 20 mmol day-1, 0.3 mmol kg-1), total sodium excretion only increases gradually but after about 3 days it 'overshoots' as in humans.


Effect of intraduodenal HCl and soybean extract on pancreatic juice secretion during atropinization and cold vagal blockade in calves.

In order to elucidate the mechanisms by which intraduodenal hydrochloric acid (HCl) and soybean extract influence exocrine pancreatic secretion in the young ruminant, we conducted experiments repeatedly on six conscious calves with and without blockade of the extrinsic and intrinsic neural pathways. In the absence of blockade, each of the two stimuli increased the juice volume, the HCl effect being far stronger than that of soybean extract. Intrinsic cholinergic blockade by atropinization blocked the stimulatory work of soybean extract on pancreatic secretion and on HCl-stimulated protein but had a weak effect on the amount of juice evoked by HCl. Temporary vagal blockade by chilling virtually abolished the excitatory effects of both soybean extract and HCl. With or without blockade, duodenal HCl resulted in a noteworthy increase in plasmal secretin and a slight increase in cholecystokinin (CCK). With alimentary proteins, acidification of the duodenum was responsible for both the composition and secretion of pancreatic juice in young calves, generally via neural pathways. Atropine-sensitive nerves of the pancreas totally regulate the intestinal phase of pancreatic juice secretion allied with intraduodenal protein, whereas HCl-dependent excitation of the exocrine pancreas takes place partly via atropine-resistant nerves. However, as hardly any pancreatic juice was secreted independently of the vagi, the vagi are deemed to govern all the postprandial regulatory mechanisms of the exocrine pancreas in the young calf.


An analysis of the action of an analogue of almitrine bismesylate in the rat model of hypoxic lung disease.

Chronically hypoxic (CH) and normoxic control rats were used to assess the action of S9581, a water-soluble analogue of almitrine bismesylate. S9581 increased ventilation (Ve) by 34% in control and 20% in CH rats. During acute hypoxia Ve was raised and S9581 caused a further increase of 20% in both groups. Low doses of S9581 and almitrine enhanced the hypoxic ventilatory response in CH rats while high doses depressed it in both groups. Effects of S9581 on the pulmonary circulation were assessed in the isolated perfused lung of rats. As with almitrine a complex relationship of dose-dependent vasoconstriction and dilatation was revealed. In low doses, S9581 enhanced the hypoxic pulmonary vasoconstrictor response to 2% O2 whilst this was attenuated by high doses in both control and CH rats. S9581 seemed to act like almitrine bismesylate on both the ventilation (peripheral chemoreceptor) and the pulmonary circulation. For studying almitrine-like activity the water solubility of S9581 provides considerable advantages for the researcher.


Polyol pathway-mediated changes in cardiac muscle contractile properties: studies in streptozotocin-diabetic and galactose-fed rats.

Contractile properties of left ventricular papillary muscles and atria from streptozotocin-diabetic and from non-diabetic rats fed a 40% galactose diet were measured in vitro. There was a characteristic slowing of twitch responses for both tissues and both treatments (P < 0.05). Time to peak contraction was prolonged by 18-33% and maximum rate of contraction was reduced by 10-17%. Relaxation was also affected, with a 13-37% increase in half-relaxation time and a 7-25% reduction in the maximum rate of relaxation. There were treatment differences between papillary muscles and left atrium, diabetes having a more marked effect on the former, whereas galactosaemia caused more pronounced changes in the latter. The resting beat rate of the right atrium was 22% reduced in diabetic and galactosaemic rats (P < 0.01). When maximally stimulated with isoprenaline, beat rate did not rise to the level of stimulated controls (P < 0.01). Papillary muscle speed-related contractile properties also showed a reduced response to isoprenaline in diabetic and galactosaemic groups compared to normal controls. The greatest deficit was found for maximum rate of relaxation where responsiveness was 41 and 34% less for diabetic and galactosaemic groups respectively (P < 0.01). Polyol pathway metabolites in diabetic ventricles were increased 8-fold. In galactosaemic rats galactitol accumulation led to a 530-fold increase in polyols. The data suggest that polyol pathway activity may be an important factor in the aetiology of contractile and chronotropic changes in diabetic and galactosaemic cardiomyopathy.


Avoidance of endotoxin-induced inflammation during studies of albumin clearance from caprine joints.

Intra-articular injection of radiolabelled, commercial goat serum albumin (GSA) produces acute arthritis in caprine joints. This inflammation distorts clearance values and vitiates studies of normal lymphatic function. Endotoxin, routinely found in commercial albumin preparations, appears to cause this local reaction. We describe a simple method for the preparation of low-endotoxin, radioiodinated serum albumin from aseptically collected serum. We have used this technique to prepare GSA for use as a tracer molecule in clearance studies of synovial joint lymphatic function. The isolated protein exhibits antigenic and chemical characteristics indistinguishable from those of commercial GSA but contains at least 1000-fold less endotoxin. In contrast to commercial GSA preparations, this albumin does not produce local inflammation when injected into synovial joints and is cleared from caprine joints in the normal monoexponential manner. Low levels of endotoxin seriously distort studies of articular albumin kinetics and may induce comparable artifacts when commercial protein preparations are used to study other physiological systems.


The effects of Na(+)-K(+)-Cl- co-transport and Cl(-)-HCO3-exchange blockade on the membrane potential and intracellular chloride levels of rat arterial smooth muscle, in vitro.

Membrane potential and intracellular chloride levels have been measured simultaneously in vascular smooth muscle from the femoral artery of the rat, in vitro, using double-barrelled chloride-sensitive microelectrodes. These values are compared in the presence and absence of bicarbonate, and inhibitors of Cl(-)-HCO3- exchange and Na(+)-K(+)-Cl- co-transport. Both DIDS and bumetanide caused a hyperpolarization of membrane potential (Em) and a fall in [Cl-]i, in the presence of extracellular HCO3-. The effects of bumetanide were reversible, but those of DIDS were not. The effect of both agents were additive. The results demonstrate that both Cl(-)-HCO3- exchange and Na(+)-K(+)-Cl- co-transport accumulate intracellular chloride in this preparation, and it is suggested that this may allow the modulation of membrane potential (and hence excitability) of smooth muscle.


Influence of extracellular bicarbonate on the short-circuit current and intracellular free calcium of human cultured sweat duct cells.

Transepithelial short-circuit current (Iscc) and intracellular free Ca2+ (Ca2+i) was studied in monolayers of cultured human sweat duct cells (CSDCs) in the presence or absence of HCO3- (and CO2) in the bathing solutions. Addition of HCO3- (and CO2) increased the control Iscc by more than 50%. The effect of HCO3- (and CO2) on Iscc was confined to the serosal bath. The HCO3- (and CO2) effect was also studied during stimulation with the cholinergic agonist methacholine (MCh), which in CSDC induces a complex response consisting of an initial Iscc and Ca2+i spike, which is independent of extracellular Ca2+, followed by regular Iscc and Ca2+i oscillations, which are absent during Ca(2+)-free bathing conditions. The sustained Iscc and Ca2+i oscillations, but not the initial Iscc and Ca2+i spike were abolished by the removal of extracellular HCO3- (and CO2). It is concluded that the Ca2+ influx and the Iscc in CSDCs are critically influenced by the presence of extracellular HCO3- (and CO2) in the bathing solutions.


Effect of stage of lactation and milk accumulation on mammary cell differentiation in lactating bats.

Mammary cell differentiation was measured in lactating pipistrelle bats (Pipistrellus pipistrellus) by assay of key enzyme activities, and by determination of protein and lactose synthesis rates in short-term tissue cultures. By these criteria, mammary cell differentiation did not change significantly with stage of lactation, but depended on the extent to which the gland was filled with milk. Key enzyme activities and in vitro synthesis rates were significantly higher in glands suckled immediately before tissue collection, compared with contralateral glands that were engorged with milk. This indicates that mammary cell differentiation in the lactating bat is regulated locally within each gland by a mechanism sensitive to milk accumulation, to the extent that, unlike other species, this obscures any underlying effect of stage of lactation.


Rapid stimulatory effect of bradykinin on glucose transport across the brush-border and basolateral membranes of rat jejunal enterocytes.

Bradykinin has been shown to stimulate sugar uptake by intact intestine, but the cellular locus of this action is unknown. In this study on rat we show that bradykinin (10(-7) M) stimulates both sodium-dependent glucose uptake at the brush-border membrane and carrier-mediated movement across the basolateral membrane of upper villus enterocytes. These results suggest a role for bradykinin in the local control of glucose transport though the mechanisms underlying these effects have still to be elucidated.


Transcellular openings through microvascular walls in acutely inflamed frog mesentery.

Openings in the endothelium of frog mesenteric microvessels associated with acute inflammation following mild thermal injury have been examined by reconstruction from serial ultrathin sections. While all the openings lay close to the intercellular junctions only a minority (seven out of thirty-eight) were continuous with the intercellular clefts. The majority of gaps or openings (thirty-one out of thirty-eight) were transcellular and passed through the peripheral cytoplasm of one endothelial cell, separated from the intercellular cleft by a cellular process which was usually less than 2 microns wide.


Evidence for a possible role of 5-hydroxytryptamine in the genesis of fatigue in man: administration of paroxetine, a 5-HT re-uptake inhibitor, reduces the capacity to perform prolonged exercise.

Seven healthy subjects exercised to exhaustion on a bicycle ergometer at a power output corresponding to 70% of maximum oxygen uptake after administration of either a placebo or 20 mg of paroxetine, a serotonin re-uptake inhibitor. Exercise time after paroxetine (median 94 min; range 84-127 min) was less (P < 0.05) than after placebo (median 116 min; range 86-133 min). The metabolic and cardiorespiratory responses to exercise were the same in both trials. This result supports the suggestion that there is a central component to fatigue which is mediated by the activity of serotoninergic neurones.


Voltage-sensitive elevation of cytosolic [Ca2+] in guinea-pig cardiac myocytes elicited by calcitonin gene-related peptide.

We have studied the effect of the 37-amino acid cardioactive peptide, calcitonin gene-related peptide (CGRP) on cytosolic [Ca2+] in guinea-pig ventricular myocytes following depolarization. Cytosolic [Ca2+] was measured in single myocytes using fura-2. The application of 20 mM K+ led to a transient rise of cytosolic [Ca2+] followed by an exponential decline. The subsequent application of 2 nM CGRP resulted in a marked increase in cytosolic [Ca2+]. In contrast, no such response was obtained without prior depolarization. The results suggest a basis for the cardiotropic effects of CGRP through an influence on cytosolic [Ca2+].


Confocal analysis of fluorescent bead uptake by mouse Peyer's patch follicle-associated M cells.

Latex beads coated with secretory immunoglobulin (IgA) instilled into mouse intestinal loops are taken up by M cells present in Peyer's patch follicle-associated epithelial tissue. Bead adsorption and uptake is greater at the edge compared with the apex of follicle domes. Coating beads with bovine serum albumin (BSA) causes a fourfold reduction in adsorption and a twentyfold reduction in uptake. Results demonstrate selectivity between adsorption and uptake and between the ability of different proteins to facilitate uptake.


Conserved, extended MHC haplotypes.

Extended major histocompatibility complex (MHC) haplotypes are fixed conserved regions of the short arm of the sixth human chromosome defined by their HLA-B, complotype (BF, C2, C4A, C4B), HLA-DR alleles. The regions of conservation may extend further. At least a third of normal MHC haplotypes in Caucasians are extended, and they are largely responsible for previously observed linkage disequilibrium in the region. They are relatively population-specific. Their presence has major implications for tissue transplantation, and particularly for the identification of unrelated donor-recipient pairs, since matching for extended haplotypes probably optimizes engraftment in individuals who have them. Even for those who do not, extended haplotypes provide the means for identifying likely MLR-I-negative donor-recipients, and for identifying the genes involved in this function. Extended haplotypes provide most of the markers for HLA-associated autoimmune diseases; like the MHCs of inbred and inbred recombinant strains of mice, they have aided in the analysis of the contribution of specific genes in this region to disease susceptibility and immune functions, particularly the antibody response. Finally, extended haplotypes must be taken into account when considering population genetic questions and when using HLA markers to identify individuals in forensic applications.


Blood antiphospholipid antibody levels are influenced by age, sex and HLA-B8,DR3 phenotype.

Antiphospholipid antibodies (APA) are known to be associated with a number of seemingly heterogeneous pathological conditions that are part of the antiphospholipid syndrome, formerly called anticardiolipin syndrome. Recent studies on the mechanism of action of these autoantibodies suggest that we are dealing with a new autoimmune syndrome which may occur either in a primary form or in the context of other autoimmune diseases, mainly systemic lupus erythematosus (SLE). Moreover, increased levels of APA have been found in elderly subjects, who are known to display increased frequency of autoimmune phenomena. It is well known that many autoimmune diseases, including SLE, are associated with HLA antigens, particularly with HLA-B8,DR3 phenotype. In our study, APA serum levels were analyzed in 26 old subjects and in 56 young ones. The results demonstrate that HLA-B8,DR3-positive young females display significantly higher levels of APA than HLA-B8,DR3-negative ones. Interestingly, the same is true for elderly subjects on the whole with respect to young individuals. These data are consistent with previous findings demonstrating that HLA-B8,DR3-positive subjects (mainly female) as well as old subjects display (also in the absence of any clinical manifestation), multiple immune dysfunctions that may underlie the predisposition to autoimmunity.


Identification of the recombination site within the steroid 21-hydroxylase gene (CYP21) of the HLA-B47,DR7 haplotype.

The HLA haplotype A3-Cw6-B47-C4A91-BQ0-DR7 is associated with congenital adrenal hyperplasia (CAH), since it only carries the dysfunctional steroid 21-hydroxylase A pseudogene as well as the 5' adjacent complement C4A gene. The recombination site leading to the deletion of the complement C4B and steroid 21-hydroxylase B genes in this haplotype was studied by determining the 21-hydroxylase genomic DNA sequence in comparison to the standard CYP21A- and CYP21B-specific sequences. A 200-bp region between exons 7 and 8 was identified as a possible recombination site. Thus the deleted area comprises the 3' end of the CYP21A pseudogene, the entire C4B gene and the 5' end of the CYP21B gene. The findings were confirmed by PCR amplification of a 1.8-kb fragment of the CYP21 gene. This PCR system is specific for CYP21A/B recombinant genes and may be used for screening among CAH patients carrying this type of deletion.


Diverse biological parameters in clinically healthy sheep from a flock with scrapie: variations, and correlations with OLA antigens.

A comparison was made in the blood levels of various cell types and biochemical substances and in lymphocyte antigens between 107 healthy sheep from a flock contaminated with scrapie (HC sheep) and 93 sheep from a noncontaminated flock (NC sheep), which served as a control population. Significant differences between the two groups of sheep were found in some of the levels, as had previously been found with lymphocyte antigens. The HC sheep, which included genetically resistant animals, could be distinguished from the NC sheep by their lower levels of various white cells, a noticeable decrease in urea, a moderate decrease in Mg2+ and Mn2+ ions, beta- and gamma-globulins, serotonin and vitamin B12, a strong increase in uric acid and a moderate increase in K+, Cl-, HCO3-, Zn2+, and Al3+ ions, as well as in total lipids and in the albumin to globulin ratio. In this HC population, the only enzyme with an increased level was aldolase; the levels of the other 7 enzymes measured were lowered. The observed modifications were considered to be signs of latent disturbances in the leukocyte system and in hepatic and renal functions, in spite of apparent resistance. Eleven lymphocyte antigens were studied. These antigens are not independent of the blood levels of the various substances measured, but are often correlated in a statistically significant manner with some of them. In the HC sheep, the lymphocyte antigens correlated with the modified levels in the blood were different from those in the control population.(ABSTRACT TRUNCATED AT 250 WORDS)


Pediatric brain tumors.

The central nervous system is the second most common location for neoplasms in the pediatric age group. In this article, the characteristic imaging findings of the various supratentorial and infratentorial brain tumors are described.


T-cell receptors of man and mouse studied with antibodies against synthetic peptides.

We used polyclonal rabbit antibodies directed against synthetic peptides predicted from the gene sequence of the human T-cell receptor (TCR) beta-chain YT35 to study the antigen receptor on human helper T-cell leukemia lines and on normal mouse thymocytes. Antibodies were raised to peptides corresponding to joining segment (J beta) and to a conserved stretch of sequence around the first cysteine in the constant region (C beta). These peptides were selected on the basis of homology with corresponding segments of immunoglobulin light chains. The specificity of the antibodies was established using synthetic overlapping peptides that modelled the complete TCR beta-chain. Western blot analysis was performed against detergent lysates of T cells. Both of the antibodies reacted strongly with 2-3 polypeptides in the mass range 40-45 kDa in mouse and human cells. Clearance experiments using monoclonal antibodies against murine TCR alpha- and beta-chains and against human TCR beta-chain and immunoprecipitations with monoclonal antibody to the murine T3 complex established that these components represented the alpha/beta heterodimer. An additional component around 31 kDa was detected by anti-J beta antibodies in murine thymus extracts. The use of the affinity-purified antipeptide antibody in two-dimensional Western blot analyses allows the clear discrimination between the characteristic individual receptors of monoclonal neoplastic T cells and the polydisperse patterns representative of heterogeneous normal populations. Antigenic cross-reactions between T-cell receptor beta-chains of man and mouse observed with monoclonal antibodies and rabbit antisera to peptides are consistent with the homology in gene sequence between the two species.


Primary brain tumors in adults.

Adult primary brain tumors comprise a diverse group of neoplasms that vary in their behavior depending on such factors as cell of origin, site of occurrence, morphology, and pattern of spread. Although the incidence of primary brain tumors is increasing in frequency, the prognosis of patients with these neoplasms has improved considerably due to recent advances in microsurgery, radiation treatment, and chemotherapy. Central to the efficacy of these techniques, however, is the ability of the radiologist to diagnose and interpret the growth pattern of these tumors. This article describes various types of primary intracranial neoplasms found in the adult, with emphasis on imaging characteristics and their importance in neuro-oncologic evaluation and management.


MRI of cranial metastasis.

Recent advances in surgical techniques and new innovations in radiation treatment and chemotherapy have made the detection and characterization of intracranial metastasis increasingly important in the management of the cancer patient. This article reviews the more common sources of metastasis, their appearance, and more unusual types of involvement such as hemorrhage and spread to the leptomeninges and bony calvarium.


The relationship between evaluative research and audit.

Evaluative research and audit are distinct activities with different goals. However, they are interrelated in four ways: research provides a basis for defining good-quality care for audit purposes; audit can provide high-quality data for nonexperimental evaluative research; research into the effectiveness and cost-effectiveness of audit is needed to establish the value of different interventions; and, in common with other research areas, evaluative research needs to be audited to ensure high-quality work is performed. Recognition of the unique and interrelated roles of research and audit will be of benefit to both endeavours.


Cost-benefit analysis of the introduction of mass vaccination against hepatitis B in Italy.

The aim of the study was to evaluate the costs and benefits of introducing mass vaccination against hepatitis B in Italy, given the announcement of compulsory vaccination of all newborn babies from 1991. Benefits were calculated by summarizing the clinical course of hepatitis B in Italy and projecting its incidence rates to the next 30 years using Brown's exponential smoothing technique. Incidence rates were then applied to the survivors of a cohort of newborns in 1992, and the total number of cases avoidable through vaccination was derived. Direct and indirect marginal costs were estimated for these cases. The marginal costs of the vaccination campaign were estimated. Cost and benefits were compared for 99 years following the introduction of the vaccination, using an 8 per cent discount rate and a sensitivity analysis. Despite difficulties in data gathering, susceptibility to discounting and estimating costs, results show an unfavourable cost-benefit ratio which is influenced by a declining incidence of the disease. Vaccination of high-risk groups is probably more efficient.


An asbestos hazard in North Devon.

In March 1990, following the careless removal of asbestos-based ceiling tiles in a leisure centre in North Devon, delay in action by the local authority meant that the risk to staff and members of the public was ignored for four months. The Director of Public Health was then approached to tackle the problem of providing advice to both leisure centre staff and the public in order to deal with the concern that had arisen as a result of the delay. There was a public statement, a report to the local authority, and a 'hotline' for members of the public. Leisure centre staff members were individually interviewed by a doctor using a specially designed occupational health questionnaire and followed up as appropriate. Twenty-one chest X-rays were taken on the advice of the local chest physician. Although the level of exposure was small, and there was no significant threat to health, the incident caused major public concern, was an embarrassment to the local authority, and involved the Health and Safety Executive and considerable input from the Department of Public Health Medicine. Most importantly for a small district, it was a major public relations exercise for Public Health Medicine. This paper examines the appropriateness and effectiveness of intervention by Public Health Medicine in a situation where the risks were known to be very low but public anxiety, fuelled by compensation possibilities, was very high.


A methodology for collecting outcome measures for common hospital conditions.

An eight-month prospective analysis of routinely collected hospital data with 24-week follow-up of mortality and morbidity was carried out at two district general hospitals in Somerset Health District, to test the feasibility of collecting useful and valid outcome measures for two common hospital conditions, strokes and fractured hips. Data were collected on 163 consecutive admissions with a primary diagnosis of stroke (83 cases) or fractured hip (80 cases). At 24 weeks, 38 patients with stroke had died (mortality ratio 46 per cent, 95 per cent C.I. = 35.3-56.7 per cent) and 11 with fractured hip had died (mortality ratio 14 per cent, 95 per cent C.I. = 6.4-21.6 per cent). Seven patients (four with fractured hip and three with stroke) died after 24 weeks and before responding to the NHP questionnaire. One stroke patient could not be traced. Nottingham Health Profiles were received from 106 patients (41 with stroke and 65 with fractured hip). Both groups of patients had problems with physical mobility and lack of energy. Patients with fractured hips were more likely to complain of pain. It is concluded that the methods used to collect outcome measures in this study are widely applicable to other conditions, but the interpretation and comparability of the results require the collection of similar data elsewhere.


Policy and practice--an audit of neonatal BCG immunization in Avon.

Two surveys were carried out to audit the Avon Neonatal BCG Immunization Policy. The aim of the audit was to determine whether children with indications for neonatal BCG immunization had received the vaccine before attendance at routine six-week postnatal examination. In the first survey, 15 of 359 (4.2 per cent) infants were identified as eligible for BCG, of whom only two (13.3 per cent) had received it. These findings were discussed with the medical and nursing staff involved in the care of the infants in Avon, and action was taken to improve compliance with the policy. The survey was then repeated to complete the loop of the audit cycle and to observe whether the action taken had the desired effect. Forty of 644 (6.2 per cent) infants were identified as being eligible for BCG immunization in the repeat survey, of whom 32 (80 per cent) had received it. There was a statistically significant difference in results between the first and the second survey (p < 0.0001). It is concluded that completion of the audit cycle can markedly improve clinical practice.


Consultants' views of a district's services.

A postal questionnaire survey of consultants in the Bath Health District was conducted to establish a means for individual consultants to express their views about the provision of health services in the district, so that by working together a new relationship between the District Health Authority (DHA) as purchaser and the clinicians as providers of services could commence. A response rate of 84 per cent was achieved. The survey sought views on clinical and management issues to be used in the development of service agreements (contracts) and views on topics identified by general practitioners (GPs) as areas in need of improvement. Detail is given of results relating to out-patient services, issues of communication and the continuing role of community hospitals. Most consultants sanctioned the appropriateness of referrals by GPs to out-patient services but they identified some out-patient referrals as inappropriate. This justifies a further review of the out-patient services to be purchased by the DHA. Consultants were in agreement that there was scope for review of out-patient follow-ups. They agreed with GPs that discharge summaries could be provided within 24 hours of patient discharge to improve communication with GPs and that consultants should be available by pager to be contacted by GPs, but disagreed with GPs about the feasibility of giving patients on waiting lists a firm admission date at the time of going on the waiting lists. The majority of consultants were in favour of continuing support for community hospitals. They identified overall social value of community hospitals and greater clinical value of out-patient services than in-patient services in community hospitals.(ABSTRACT TRUNCATED AT 250 WORDS)


Doctors' understanding of the specialty of Public Health Medicine: a survey of general practitioners and junior hospital doctors.

The Acheson report recommended that the new name for Community Medicine should be Public Health Medicine and that a new group of doctors with responsibility for communicable disease control be established. Three years after the report, general practitioners and junior hospital doctors in one health district were surveyed regarding their understanding of the specialty. This study identified some confusion about the titles and functions of doctors in Public Health Medicine. It is important to understand this problem and make efforts to rectify it.


The relative effects of sex and deprivation on the risk of early death.

Socio-economic factors and sex are both known to have a pronounced bearing on the risk of early death. To determine the relative effects of these factors in our Health Board, an analysis was carried out of all deaths under the age of 70 registered in Tayside during 1989 and 1990, by age, years of life lost, diagnosis and postcode sector/deprivation category. A yearly average of 14,520 years of life up to the age of 70 were lost by males compared with 8248 by females. When cancers of the breast and sex organs were excluded, just over a quarter (28 per cent) of the difference was due to the higher death rate in males resulting from injuries and poisoning and another quarter to ischaemic heart disease (23 per cent), with infant deaths in third place (17 per cent). Deprivation category analysis showed that deaths and years of lost life from ischaemic heart disease and injuries and poisoning in males in the most deprived areas were approximately one-third higher than in the most affluent. At the same time, the death rate in males from these causes in each area, from the most affluent to the most deprived, was approximately two and a half to three times as high as in females, as were lost years of life.(ABSTRACT TRUNCATED AT 250 WORDS)


In vitro infection of human macrophages by human T-cell leukemia/lymphotropic virus type I (HTLV-I).

HTLV-I is associated with a neurological syndrome designated Tropical Spastic Paraparesis/HTLV-I associated myelopathy (TSP/HAM). To determine whether HTLV-I can replicate in human primary macrophages and thus contribute to HTLV-I dissemination in the nervous system, elutriated human macrophages were infected cell-free with the HTLV-ICR and HTLV-IBOU isolates from patients with adult T-cell leukemia and TSP/HAM, respectively. Viral production was monitored by measuring the viral p24 gag antigen in the cell culture supernatant, by electron microscopy (EM) and by polymerase chain reaction (PCR) on viral DNA and RNA. The HTLV-I p24 gag antigen was detected 21 days after infection with either isolate, and the presence of mature viral particles was demonstrated by electron microscopy one month after infection. Viral sequences were amplified by PCR analysis of the infected macrophages' DNA. Spliced mRNAs for the p40tax and p27rex proteins, as well as the p12I, and p30II proteins encoded by the pX region were readily identified by reverse transcriptase PCR. Altogether, these data indicate that HTLV-I replication occurs in vitro in primary human macrophages. Whether macrophage infection occurs also in vivo and is a crucial step in the induction of the neurological manifestations observed in TSP/HAM remains an open question.


Coexistence of human T-lymphotropic virus types I and II among the Wayuu Indians from the Guajira Region of Colombia.

High prevalences of human T-lymphotropic virus type II (HTLV-II) infection have been found recently among certain Amerindian groups in North, Central, and South America. To determine if the Amerindians of Colombia are similarly affected, 523 sera, collected between 1987 and 1990 from nine culturally distinct Indian groups from widely separated regions, were tested for IgG antibodies against HTLV-I/II using enzyme-linked immunosorbent assay (ELISA) and Western blot. In addition, 243 sera from five non-Indian (black) and mixed-Indian (mestizo) populations were studied. Of the 766 individuals tested, 44 were ELISA positive, but of these, only four were Western blot positive. Three of the individuals confirmed positive by Western blot were infected with HTLV-II and one was infected with HTLV-I, as determined by differential ELISA. All four seropositive individuals belonged to a group of 62 Wayuu Indians, giving overall HTLV-I and HTLV-II seroprevalences of 1.6% and 4.8%, respectively. The coexistence of HTLV-I and HTLV-II in this Amerindian group provides an opportunity to study the factors governing transmission of these retroviruses.


Evaluation of enzyme immunoassay using a recombinant envelope protein expressed in insect cells for serological confirmation of HTLV-I infection.

A recombinant human T-lymphotropic virus type I (HTLV-I) envelope protein expressed in insect cells using a recombinant baculovirus was employed as the antigen in an enzyme immunoassay (renvEIA). Peripheral blood samples were obtained from asymptomatic carriers or healthy individuals. Plasma was tested for HTLV-I antibody by renvEIA, particle agglutination, and Western immunoblot (WB), and lymphocyte DNA was tested for HTLV-I proviral DNA amplification by polymerase chain reaction (PCR). Of 61 people aged 9 months or older, 23 were positive (gag+, env+) and 19 others were in the "indeterminate" category (gag+, env-) when their WB results were interpreted according to the WHO-proposed criteria. Thirty-seven cases, including all of the WB+ cases and 14 of 19 WB indeterminate cases, were positive by renvEIA. In 34 of 37 renvEIA-positive cases, the presence of long terminal repeat (LTR) and tax/rex region of HTLV-I proviral DNA was detected by polymerase chain reaction (PCR) and following Southern blot hybridization. Thus, renvEIA would be a useful supplemental assay to confirm the presence of HTLV-I antibody in HTLV-I asymptomatic carriers.


Association of mycoplasma with HIV-1 and HTLV-I in human T lymphocytes.

Recent findings from a number of investigators suggest associations between mycoplasma and HIV or AIDS. We used a quantitative morphometric technique to analyze electron micrographs of human T lymphocytes that were infected with both mycoplasma and/or HIV-1. We observed that lymphocytes which were associated with HIV-1 were much more likely to be associated with mycoplasma than cells that were not (p < .001). Similarly, cells with associated HTLV-I were more likely to be associated with mycoplasma than cells which were not associated with mycoplasma (p < .0001). In addition, mycoplasma and virus were observed in the same region in 90% of cases. These observations suggest that adherence of mycoplasma to lymphocytes that are chronically infected with human retrovirus may trigger viral release.


Genetic variants of HIV-1 in Thailand.

Serosurveys conducted prior to 1988 indicated a very low level of HIV-1 infection in Thailand, even among high-risk groups. The Ministry of Health has reported a dramatic increase in HIV-1 infection during the last three years. The geographic and demographic distribution of the epidemic is broad, involving multiple provinces and risk groups. Foci of higher incidence and prevalence have been noted in the urban center of Bangkok and in the northern provinces of Chiang Mai and Chiang Rai. Here we report the results of genetic characterization of 16 HIV-1 isolates from Thailand using a combination of polymerase chain reaction (PCR) typing and DNA sequencing. The complete sequence of gp160 (env) of five isolates, partial env sequence of six additional isolates, and the gag gene of two isolates were determined. Two highly distinct HIV-1 variants were found. One variant resembled those prevalent in North America and Europe; five of the isolates were of this type. The remaining eleven isolates were very similar to one another and represented a variant unlike any previously described. Phylogenetic tree analysis of complete env and gag genes placed the two variants on widely separated branches. Protein sequence comparisons indicate both general and specific features that distinguish the Northern Thailand variant both from the Bangkok variant and from virtually all previously sequenced HIV-1 isolates. A simple PCR test for distinguishing the two variants has been developed for use in epidemiologic surveys.


Characterization of the specificity of the human antibody response to the V3 neutralization domain of HIV-1.

The major neutralization domain of HIV-1, contained in the third variable region (V3) of the external envelope, is highly variable at positions flanking a conserved glycine-proline-glycine sequence. We investigated the relation between V3 sequences of HIV-1 variants circulating in a host and that host's antibody specificity. Multiple V3 sequences were obtained directly, via PCR and subsequent cloning, from serum RNA or cellular DNA from 26 individuals (from 12 around seroconversion). Then, specificity of sera from these individuals to a panel of V3 peptides was determined. The specificity (best recognized peptide) of the early antibody response accurately reflected the virus population circulating around seroconversion in 12/12 individuals and 4/4 HIV-1-infected chimpanzees. A change in serum specificity at later stages of infection was rare: five years after seroconversion, only 3 of 46 individuals had a specificity that differed completely from that in the first year. However, the V3 domain of the virus does change over time, as evidenced by the poor correlation between V3 sequences obtained late in infection and V3 antibody reactivity at the same time point. Thus, in contrast to the accurate antibody response to HIV-1 variants early after infection, generally a specific response to variants emerging at later stages seemed to be absent or of low level. Instead, the early response appeared to be preserved. Finally, we made use of the observed accurate reflection to analyze the variation for the V3 domain of HIV-1 in the Netherlands by probing specificities of early sera from 129 Dutch seroconverting individuals. Specific reactivity to RKSIHIGPGRAFYTTG was found in 36%, to RKSINIGPGRAFYTTG in 12% and to RKSIPIGPGRAFYTTG in 18% of these Dutch sera.


Reactivities of HIV-1 gag-derived peptides with antibodies of HIV-1-infected and uninfected humans.

A group of 41 peptides, each 24 amino acids long and overlapping with each other by 12 residues spanning the total gag open reading frame (orf) of HIV-1 (HTLV-IIIBH 10 isolate) were synthesized using Fmoc chemistry. The purified compounds were used in ELISA assays and tested for antibody reactivities in sera of human HIV-1-infected and noninfected individuals. Sera of HIV- humans showed reactivity against four defined regions, two in p17, one in p24, and one in p15. The values of these reactivities were elevated especially in serum samples of HIV- individuals showing cross-reaction with gag proteins on Western blot. Amino acid sequence comparison of HIV-1 gag proteins with those of human endogenous retroviruses (ERV K10, ERV 3) revealed significant similarities predominantly in the domains showing elevated antibody cross-reactions. The majority of sera from HIV-1+ individuals showed strong reactivities to the cross-reactive regions and to various other peptide sequences, a sequential epitope recognized by all HIV-1+ sera could, however, not be identified. The results suggest that human individuals may have immune reactions to endogenous retroviral protein sequences, which are enhanced by infections with HIV-1. Specific antibodies to HIV-1 gag proteins are probably mainly directed to tertiary structure defined epitopes formed by particle formation of the p24 monomers to the nucleocapsid.


Anti-CD4 antibodies are associated with HIV-1 seroconversion and may be detectable before anti-HIV-1 antibodies. The Multicenter AIDS Cohort Study.

We examined the sera from 14 HIV-1 seroconverters for the presence of autoantibodies against CD4. Anti-CD4 antibodies were detected in the serum of 11 of 13 HIV-1-infected persons at the time of HIV-1 seroconversion. In 6 of 14 persons from whom a serum was obtained prior to HIV-1 seroconversion, anti-CD4 antibodies were found 90 to 540 days before antibodies to HIV-1 were detectable. In comparison, anti-CD4 antibodies were present in only 7 serum samples from 62 HIV-1 seronegative individuals, including 50 from a seronegative homosexual male cohort. These results suggest that anti-CD4 antibodies are generated in response to early HIV-1 infection and possibly could be used as a marker for HIV-1 infection in some infected persons who are seronegative for HIV-1.


A CD4-derived peptide carrier blocks acute HIV-1 infection in vitro and binds to gp120 in the presence of Walter-Reed stage 1-6 HIV+ sera.

A peptide containing amino acid residues 41-84 of the CD4 molecule was synthesized and coupled through a thioether bond to human serum albumin. This conjugate bound to gp120 with an affinity that was half that of CD4 and blocked the HIV infection in vitro with an efficacy tenfold lower than that of CD4. More importantly, the CD4 peptide-human serum albumin conjugate could bind to gp120 in the presence of HIV+ sera from 18 Walter Reed stage 1-6 patients.


Identification and validation of a new nursing diagnosis: sick role conflict.

The purpose of this research is to assess the presence, etiology, and effects of sick role conflict experienced by hospitalized patients. Data from 99 hospitalized adult subjects were analyzed using a path analysis design. Patients were interviewed at the bedside using a structured interview tool developed by the researchers. It was found that subjects who occupied multiple roles, who were not adequately prepared for hospitalization, and who had an acute rather than chronic illness were prone to experience sick role conflict when hospitalized. Those subjects experiencing sick role conflict did not fully assume the sick role as defined by Parsons (1966). As a consequence of incomplete sick role assumption, an increased incidence of human responses such as guilt, powerlessness, anxiety, decreased self-esteem, depression, appetite change, and insomnia were reported. The researchers urge nurses to assume responsibility for diagnosing and treating sick role conflict, a human response to hospitalization commonly seen among patients.


Concept analysis of fear.

The nursing diagnosis fear is clarified through the technique of concept analysis. Uses of the concept of fear in prominent theories of human behavior and in nursing are reviewed. Five critical attributes occurring in all cases of fear are identified--a model case, a related case, a contrary case, and an illegitimate case are presented. Antecedents to fear are derived. Consequences of fear are discussed and are related to nursing interventions. Empirical referents that demonstrate occurrence of the concept of fear are determined, classified, and related to critical attributes. This concept analysis provides an essential conceptual base for instrument development and clinical research on fear.


Metacognitive skills in diagnostic reasoning: making the implicit explicit.

The metacognitive skills of monitoring, analyzing, predicting, planning, evaluating, regulating, and revising frame the nursing process and support clinical reasoning. Nurse educators who encourage metacognitive skill acquisition are likely to accelerate student comprehension, understanding, and mastery of nursing diagnosis, nursing process, and clinical reasoning. The models presented in this article have implications for teaching and learning clinical/diagnostic reasoning.


The use of quantitative scintigraphy in the measurement of portal-systemic shunting in rats.

Portal-systemic shunting was studied in 54 portal hypertensive rats both in vivo and in vitro using radioactive microspheres. The animals underwent partial portal vein ligation around needles of varying diameter to produce a wide range of shunting. Two to four weeks later, quantitative lung-liver scintigraphic and whole body images were obtained in vivo following ileocolic vein injection with 99mTc-MAA. After sacrifice, the lung and liver activities were determined by the gamma camera, a dose calibrator, and a well counter. Portal-systemic shunting ranged from 0.1-97.6%. When shunting was compared in vivo and in vitro, an excellent correlation was found (r = 0.99, p < 0.001). A subgroup of 24 animals had consecutive injections of 99mTc-MAA and 51Cr-labeled 15 microns microspheres, which, although different in size, yielded similar results (r = 0.89, p < 0.001). We conclude that in small laboratory animals a wide range of shunting can be measured accurately in vivo by quantitative scintigraphy.


Myocardial oxidative metabolism in normal subjects in fasting, glucose loading and dobutamine infusion states.

Experimental studies indicated the clearance rate constant of 11C-acetate as an index of regional myocardial oxygen consumption. To assess the response of the clearance rate from the left ventricular (LV) myocardium to the change in plasma substrate levels and to the increase in the cardiac work load in normal subjects, a total of 18 dynamic positron emission tomographic studies were performed at rest in the fasting state (control) (n = 7), after oral glucose administration (n = 4), and during dobutamine infusion (n = 7) in 7 normal volunteers. The clearance rate constant (Kmono) was similar in the control (0.065 +/- 0.017 min-1) and glucose loading states (0.059 +/- 0.008 min-1), whereas a significant increase in Kmono was observed during dobutamine infusion (0.106 +/- 0.018 min-1) (p < 0.01) in relation to the increase in the pressure-rate product with a correlation coefficient of 0.873 (p < 0.01). When the LV myocardium was divided into 6 segments, there were no significant differences among the segments in Kmono values in any condition. These normal responses should be valuable for assessing oxidative metabolic reserve and regional changes in oxidative metabolism in patients with coronary artery disease.


Favorable biodistribution of 99mTc-ECD for brain SPECT comparing with 123I-IMP using alternative body scan.

In order to evaluate the lung and brain uptake of 99mTc ethyl cysteinate dimer (99mTc-ECD) and N-isopropyl-p-[123I]-iodoamphetamine (123I-IMP), alternative body scans were carried out in 15 cases of cerebrovascular disease. The biodistribution of 99mTc-ECD was 5.5 +/- 0.7%, 3.8 +/- 0.7% in the brain; 13.1 +/- 3.7%, 2.2 +/- 1.2%, in the lung at 15 min and at 4 hours, respectively, whereas that of 123I-IMP was 3.9 +/- 1.4%, 5.0 +/- 1.0% in the brain; 32.2 +/- 7.6%, 12.7 +/- 3.3%, in the lung at 15 min and at 4 hours, respectively. 99mTc-ECD accumulated in comparatively high amounts in the brain but remained low in the lung in the early image compared to 123I-IMP. However there was a high inverse correlation between brain and lung uptake of 123I-IMP (r = -0.82), but not of 99mTc-ECD (r = -0.18). We concluded that 99mTc-ECD had a better biodistribution in terms of low lung accumulation than 123I-IMP in brain SPECT.


Regional cerebral glucose metabolism in patients with Parkinson's disease with or without dementia.

By means of positron emission tomography, the cerebral glucose metabolism in 5 patients with Parkinson's disease with dementia was compared with that in 9 patients without dementia, and that in 5 normal volunteers. The metabolic rates for glucose were measured by placing one hundred regions of interest. In the demented patients, cerebral glucose metabolism was diffusely decreased compared with that of the non-demented patients and the normal controls. The most significant decrease in glucose metabolism was observed in the angular gyrus (49.7% of the normal controls). The glucose metabolism in the cingulate, pre- and postcentral, occipital and subcortical regions was relatively spared (62.1 to 85.5% of the normal controls). In the patients without dementia, the glucose metabolism in each region was not significantly different from that in the normal controls. These results suggest that diffuse glucose hypometabolism in the cerebral cortex may correlate with that of patients with Parkinson's disease with dementia.


Ga-67 citrate scan in vascular graft infection.

The clinical utility of the Ga-67 scan has been studied in 9 patients with clinical suspicion of vascular graft infection. Eleven grafts were analyzed: 4 aortobifemoral, 2 iliofemoral, 3 femoropopliteal, 1 axillofemoral, and 1 axillobifemoral. The Ga-67 scan was positive in 8 grafts with bacteriological proof of infection and negative in 3 grafts in which infection was ruled out by clinical follow-up. A Ga-67 scan also demonstrated the spread of infection to the thigh in two patients and to the pelvis in another two patients. In 4 patients CT was performed. The CT findings included graft thrombosis, perigraft fluid collection and thickened graft wall. No discrepancies were found between the CT scan and Ga-67 scan. In three patients a control Ga-67 scan was carried out after specific antibiotic and surgical treatment. Two of these showed increased Ga-67 uptake and spreading of infection along the graft; in the other patient, a Ga-67 scan revealed normalization after resolution of an abdominal abscess. In conclusion, the Ga-67 scan proved useful in the diagnosis of vascular graft infection, the definition of location of the extent of the disease and in the evaluation of the efficiency of treatment.


Single photon emission computed tomography using 201Tl chloride in pulmonary nodules: comparison with 67Ga citrate and 99mTc-labeled hexamethylpropyleneamine-oxime.

A single photon emission computed tomography (SPECT) with 201Tl chloride (Tl-201) was carried out prospectively in 50 patients with pulmonary nodules and its diagnostic value was compared with those of 67Ga citrate (Ga-67) and 99mTc-labeled hexamethylpropyleneamine-oxime (Tc-99m-HMPAO). Tl-201 SPECT provided 88% (early)-91% (delayed) sensitivity, 85% (early and delayed) specificity and 87% (early)-89% (delayed) accuracy. The sensitivity of the Tl-201 planar image was 56 (early)-62% (delayed), which was significantly lower than that of SPECT. Delayed SPECT images at 2 hour postinjection were more preferable to disclose the malignant pulmonary nodule than early SPECT images at 15 minutes postinjection. The application of SPECT with Ga-67 failed to improve the sensitivity of planar imaging for malignant pulmonary nodules. Tc-99m-HMPAO was concentrated in 62% of 13 patients with malignant pulmonary nodules, which was slightly higher than Ga-67 in 54% of 28 patients. In an analysis of the histologic types of lung cancer, the sensitivity of Tl-201 was not significantly different in all types. On the other hand, Ga-67 was positive only in 25% of 12 patients with adenocarcinoma. A combination of SPECT and Tl-201 is the best choice among routine scintigraphic techniques for depicting malignant pulmonary nodules. The Tl-201 SPECT image may play a complementary role in the characterization of pulmonary nodules which are revealed on a plain radiograph and computed tomography.


Increase in serum cardiac myosin light chain I associated with elective percutaneous transluminal coronary angioplasty in patients with ischemic heart disease.

Changes in serum myosin light chain I (MLCI) due to elective percutaneous transluminal coronary angioplasty (PTCA) were studied after PTCA (0, 8 and 48 hours) in 57 patients with old myocardial infarction (MI group) and 20 patients with angina pectoris (AP group). The AP group showed no increase after PTCA. In contrast, in the MI group there were 16 patients in whom MLCI at 48 hours was increased by 1.0 ng/ml or more (MI1 group) and another group of 41 patients who showed no increase in MLCI (MI2 group). The MI1 group had a significantly higher incidence of (1) non-Q wave myocardial infarction (62.5% vs. 17.1%, p < 0.01), (2) 99% stenosis of a coronary artery (50.0% vs. 12.2%, p < 0.01), and (3) redistribution in a hypoperfusion area found in the delayed image of resting thallium-201 (201Tl) myocardial scintigraphy (85.7% vs. 15.8%, p < 0.01). The left ventricular ejection fraction (LVEF) was significantly improved in the MI1 group, 3 to 4 months later (from 0.49 +/- 0.12 to 0.58 +/- 0.11, p < 0.01), in contrast to the patient of MI2 group who did not show any improvement. The AP group was not considered to have a bulk of myocardium impaired enough to show a release of MLCI due to PTCA-associated transient coronary occlusion. In the MI1 group, however, MLCI was probably released from the chronically under-perfused, but still salvageable, portion of the myocardium. This is consistent with the improvement in LVEF observed 3 to 4 months after the relief of severe coronary stenosis.(ABSTRACT TRUNCATED AT 250 WORDS)


Brain perfusion abnormalities in a thinner and amphetamine abuser detected by I-123 IMP scintigraphy.

MR images and three dimensional surface images (3-D images) using N-isopropyl-p-[I-123] iodoamphetamine (I-123 IMP) were obtained in a patient who acknowledged using thinner and amphetamine. While MR images could not find any definite abnormality, 3-D images with I-123 IMP demonstrated multifocal defects. 3-D images with I-123 IMP might be able to detect an early abnormality in brain perfusion in a drug abuser.


Functional imaging and localization of electromagnetic brain activity.

Functional imaging of electric brain activity requires specific models to transform the signals recorded at the surface of the human head into an image. Two categories of model are available: single-time-point and spatio-temporal methods. The instantaneous methods rely only on the few voltage differences measured at one sampling point. To create a spatial image from this limited information, they require strict assumptions that rarely conform with the underlying physiology. Spatio-temporal models create two kinds of images: first, a spatial image of discrete equivalent multiple dipoles or regional sources, and second, an image of source current waveforms that reflect the temporal dynamics of the brain activity in circumscribed areas. The accuracy of the spatial image is model dependent and limited, but it can be validated from the spatio-temporal data by the "regional source imaging" technique, introduced here. The source waveforms are linear combinations of the scalp waveforms, and thus, specific derivations which image local brain activities at a macroscopic level. Brain source imaging of somatosensory evoked potentials revealed temporally overlapping activities from the brainstem, thalamus and from multiple sources in the region of the contralateral somatosensory projection areas.


Positron emission tomography.

Positron emission tomography (PET) allows for the absolute measurement of regional tissue physiological, biochemical and pharmacological processes. This ability is a consequence of the nature of positron emission and the type of tracers which can be labelled with positron emitting radionuclides. The spatial resolution of state of the art scanners is in the order of 4 mm full width at half maximum (FWHM). However, due to statistical limitations, in practice normally a resolution of 7 to 8 mm FWHM is used. For the same reason, although there is no limit to the temporal resolution, studies usually require many seconds to several minutes to obtain a good signal to noise ratio. If a slow kinetic process is followed, studies can be extended to several hours in order to characterise the entire physiological process. A major advantage of PET is its flexibility. Several parameters (e.g., blood flow, oxygen consumption, glucose consumption, receptor density, etc.) can be measured in the same setting. Different aspects of a certain pathology can, therefore, be studied in the same patient.


Functional imaging of the brain using single photon emission computerized tomography (SPECT).

The use of tracers is an important technique available for studying cerebral function. Changes in 'signal' are large, but as a result of its photon limited nature, the measurement of this signal is limited: spatially, temporally and in terms of accuracy. The most commonly used single photon (SPECT) system (as apposed to positron) is that with a rotating gamma camera, although multi-headed devices and special purpose rings are now also commonly available. The problems of obtaining good functional information are however identical. Firstly the devices need to be optimised in terms of resolution and sensitivity. Secondly several sources of error, notably those associated with scatter, attenuation and limited spatial resolution, need to be corrected, with the aim of obtaining quantitative estimates of radioactivity concentration. Finally such quantitative estimates need to be converted into meaningful estimates of physiological variables by use of an appropriate model. The general aim of many SPECT measurements is to estimate blood flow for example using Tc-99m labelled HMPAO as a tracer. Good results have been obtained in many clinical conditions: stroke, dementia, tumour and epilepsy, for example. Many other tracers are also available, for example to measure density of receptor sites. The use of SPECT in conjunction with other techniques after image registration is suggested as being an essential tool in extracting maximal clinical information.


Nuclear magnetic resonance and the brain.

The first successful demonstrations of nuclear magnetic resonance (NMR) in bulk matter were reported in 1946 (Bloch, Hansen and Packard 1946; Purcell, Torrey and Pound 1946). Since then NMR has become a widespread technique for investigating matter of all kinds. In the 1970's NMR was applied to living systems, including man, in 2 distinct approaches. One application was in the production of images (Lauterbur 1973), called Magnetic Resonance Imaging or MRI, and the other in the production of NMR spectra (Moon and Richards 1973; Hoult et al. 1974), called Magnetic Resonance Spectroscopy or MRS. By appropriate manipulation of the NMR signal an NMR image may be generated. This can be a 2D image of a single slice, or a set of 2D images of parallel slices, or a 3D image. 2D images may be obtained directly in any orientation, axial, coronal, sagittal. The method uses no ionizing radiation and is inherently safe. It is non-invasive, although paramagnetic solutions may be injected intravenously to improve contrast. MRI images observed in normal clinical practice are maps of the NMR signals from water and fat in the tissues; they depend on proton density, but also significantly on the relaxation times T1 and T2. Images can be provided of flow (MR angiography) and diffusion (free, restricted or anisotropic). Images are typically 512 x 512 pixels with spatial resolution of about 0.5 mm. The images can be correlated with anatomical structures and indeed MRI is a primary source of such structures with localization precision of 0.5 mm as in CT.(ABSTRACT TRUNCATED AT 250 WORDS)


Integrated presentation of multimodal brain images.

This article discusses the fusion of brain images from multiple modalities as well as the presentation of the integrated image information. The paper has three parts. First, individual brain imaging modalities are compared as regards clinical appreciation, invasiveness, dimensionality, spatial resolution, temporal resolution, and cost. Next, methods to combine multiple images are briefly surveyed and collated by characteristics as accuracy, patient-friendliness, reproducibility, labour-extensiveness, feasibility of retrospective matching, and general applicability. Finally, techniques to display multimodal image information are outlined and examples of the various options for integrated presentation are shown.


Geometry driven multimodality matching of brain images.

Clinical diagnosis, as well as therapy planning and evaluation, are increasingly supported by multimodal images. There are many instances desiring integration of the information obtained by various imaging devices. This paper describes a new approach to match images of different modalities. Differential operators are used in combination with Gaussian blurring to extract geometric features from the images that correspond to similar structures. The resulting 'feature' images may be used with existing matching techniques that minimize the distance between the features in the images to be matched. Our first application of this new approach concerns matching of MRI and CT brain images. The so-called L upsilon upsilon operator produces a ridge-like feature image from which in CT and MRI the center curve of the cranium is easily extracted. First results of this operator's performance in matching tasks are shown. Another promising operator is the 'umbilicity' operator, which is presented in combination with SPECT images.


Attenuation of dipoles modelled from SEP due to a lacunar infarct or altered stimulus rate.

In normal subjects and patients with sensory, sensorimotor or motor deficit, due to a unilateral infarct affecting the thalamocortical radiation, SEPs to median nerve stimulation were analyzed by a spatiotemporal dipole model which describes an evoked potential by a limited number of stationary dipoles with time varying amplitudes. In the normal subjects the SEPs were explained by one dipole in the brainstem and two dipoles in the cortical hand area contralateral to stimulation, all with different time courses. Increasing the stimulus rate to 6.2 Hz yielded a reduction of the moment of both cortical dipoles but hardly affected brainstem dipole moment. In the five patients with sensory or sensorimotor deficit the strength of one or both cortical dipoles was reduced on the side of the lesion. In the patients with pure motor deficit cortical dipole activity was normal. The brainstem dipole was preserved in all patients.


Spatial integration of multimodal brain images in cerebral infarction.

Different structural as well as functional imaging techniques are becoming increasingly important in the investigation of patients suffering from an ischemic stroke. Available imaging procedures usually provide complementary data, but the images can not easily be compared due to differences in patient positioning, angulation, and slice thickness. We studied the value of spatial integration of images from different modalities in a patient with an ischemic stroke and used skin markers to integrate the obtained information. Computed tomography (CT), magnetic resonance imaging (MRI), 99mTcHMPAO-single photon emission computed tomography (SPECT) and magnetic resonance spectroscopic imaging (MRSI) were performed in a patient, presenting with a right sided hemiparesis caused by an ischemic stroke. Combination of MRI with CT demonstrated that the infarction visible on CT and MRI corresponded in size and volume. Furthermore, structural and functional images could readily be integrated, thus allowing us to obtain accurate information in this stroke patient. Different imaging modalities provide complementary information in the acute phase of cerebral infarction and multimodality matching can be of great value for improvement of our understanding of the pathophysiology and course of ischemic stroke.