In defense of genuine ignorance: supporting vitality and relevance in graduate curricula.

Genuine ignorance, defined by John Dewey as curiosity and openmindedness in opposition to repetition of catch phrases and familiar propositions, is nurtured in graduate nursing curricula in which the educational process is congruent with course content. Preparation for advanced practice in the mental health environment of the foreseeable future required abandonment of the familiar medical model in favor of conceptual models consistent with current thinking in psychiatric nursing and exposure to current problems (homelessness, family violence, AIDS) and current problem solving strategies (brief treatment, family preservation). Involvement in practice-based research and operationalizing new perspectives on familiar clinical problems, are suggested as strategies for developing the advanced practitioner. Two of the authors, former graduate students, describe the impact of changed perspectives and research activity on their own practice.


Putting the unit to bed.

Bedtime on children's inpatient units taxes a staff's patience and energy. Many children are pressing their needs with great urgency. Unfortunately, by late evening staff members are frequently depleted and not emotionally available to the children. Inpatient nurses can address this situation by developing bedtime programs that focus on the particular nighttime needs of disturbed children. The Author details such a bedtime program and describes why it has been successful in helping patients get undisturbed sleep.


A symptom management program for adolescents with psychotic illnesses: theoretical basis.

The author describes the theoretical basis of a nursing intervention program for adolescents who have experienced nondrug-related psychotic episodes. The program is designed to empower mentally ill adolescents and to increase their level of functioning by assisting them to recognize and manage symptoms of their illnesses. The theoretical model predicts some factors that influence the adolescent's level of functioning.


Ecotoxicological testing: small is reliable.

The focus of environmental regulations has changed significantly since the introduction of the bioassay as a standard means of assessing environmental impact. Prominent in this change is an increasing emphasis on protecting the integrity of natural ecosystems, which incorporate community- and system-level properties as well as organismal and population processes. Consequently, support for the use of multispecies testing has widened to include not only ecologists in academia but environmental scientists in the regulatory and industrial sector as well. The reason for this trend is clear: the additional environmental realism gained from tests utilizing communities of organisms allows for greater insight into the potential hazard of chemicals and other forms of human activity to natural ecosystems that cannot be obtained from single species tests alone. Many of the problems cited for multispecies testing early in their evolution as a hazard assessment tool have been refuted or overcome. In particular, the use of natural microbial communities minimizes several shortcomings typically associated with multispecies toxicity testing. This article includes the utility of microcosm and mesocosm tests using aquatic microbial communities as hazard assessment tools in conjunction with accumulating information on their performance in toxicity testing protocols. An increasing body of experimental evidence supports an expansion in the use of these tests for a variety of regulatory and research purposes. A shift in research focus is needed, however, to answer remaining questions and further refine standard protocols for these valuable ecotoxicological tools.


Twenty years: a great beginning.

The only nursing organization whose major focus is the psychiatric mental health needs of severely emotionally disturbed children, adolescents and their families and the promotion of mental health of children, adolescents, and their families, has turned 20 this year. The author's purpose is to review the history and accomplishments of Advocates for Child Psychiatric Nursing, Inc. (ACPN), and to make some projections for future action by this nursing specialty organization.


Life-span studies in rats exposed to 239PuO2 aerosol. II. Nonpulmonary tumor formation in control and exposed groups.

Female young adult, SPF, Wistar rats, obtained from the same supplier over an 18-month period, were examined in a life-span study with inhaled 239PuO2. Nonpulmonary tumors were evaluated both in 1052 rats comprising 16 controls groups and in 2105 exposed rats. Tumors in the pituitary gland, mammary glands, uterus, and thyroid glands, in order of decreasing prevalence, accounted for 90% of all tumors. Uterine tumors comprised 55% of all nonpulmonary malignant tumors. A substantial variability in tumor incidence was seen in most organs and for most tumor types among the 16 cohort subgroups, which was not explained by husbandry conditions or mortality patterns. The incidence of thyroid tumors ranged from 0 to 21% and uterine tumors from 14 to 45% among control cohorts. Pulmonary metastases were seen in 12% of all rats irrespective of treatment, two thirds of which were uterine adenocarcinomas that appeared histologically similar to some primary lung adenocarcinomas. A tumor incidence of about 1.5% was associated with metal identification ear tags. Except in the lung, no significant difference was found in tumor location or type between control and exposed rats. A twofold or greater increase in tumors in exposed rats was found in Zymbal gland, bladder, brain, and liver; tumor incidence in each organ was < 1%.


Epidemiological factors of cancer in California.

California has 12% of the U.S. population. In 1991, the newly diagnosed cancer cases in California represented 10% of all new cancer cases in the country, and the yearly toll was 10% of all cancer deaths. Relative to all new cancer cases in the U.S., California had 10, 9.8, 9.8, and 9.3% of breast, lung, prostate, and colorectal cancers, respectively. Because of its large population and cancer incidence, the epidemiology of cancer in California is of particular interest. Epidemiological factors reviewed in this article include ethnicity, lifestyle, occupation, and environmental conditions. Ethnic factors: There is an increased incidence of cervical and gallbladder cancer among Hispanic women, and of stomach cancer in Hispanic men and women. In U.S.-born Chinese men, the most prevalent cancers are those of the lung and colon, which is also seen in American white men. In U.S.-born Chinese women, there is an upward displacement of breast cancer incidence. In U.S.-born Japanese men and women, the mortality rate is closer to that of American whites. Life-style: Members of the Mormon Church and Seventh-Day Adventists have only 50% of the U.S. standardized mortality rate for cancer associated with smoking. Increased coffee consumption has been found to be associated with increased occurrence of colon and bladder cancer; alcohol use has been reported to have a positive association with colorectal cancer. The large AIDS population in San Francisco has a 144-fold odds ratio of Kaposi's sarcoma and a fivefold odds ratio of lymphoma when compared with the general U.S. population. Occupational factors: An increased incidence of mesothelioma in asbestos workers, of gastric cancer, skin cancer, and lymphoma in men working in dusty environments, and of astrocytoma in individuals with prolonged exposure to low-frequency electric and magnetic fields has been recorded. Environmental factors: The drinking-water pool in northern California is contaminated with asbestos of the serpentine type, which is associated with mesothelioma of the peritoneum and carcinoma of the lung, gallbladder, and pancreas. Petrochemical fumes in the heavily industrialized San Francisco Bay area have not been associated with an increased occurrence of cancer. No significant incidence in cancer has been noted in the counties surrounding the nuclear power plant at San Onofre during 18 years of close observation.


Geographic survey of cancer in China.

Cancer incidence in China shows characteristics related to geographic distribution, ecological factors, dietary and nondietary habits, lifestyles and living conditions, and occupational factors. The random interaction of these factors resulted in a markedly uneven distribution of each of the major types of cancer throughout China. This article reviews the main types of cancer found in China in relation to their relevant epidemiological factors.


Environmental monitoring in Lithuania. Environmental distress signals: gastrointestinal epithelial barrier after exposure to chemical agents.

Lithuania's environment is heavily polluted as a result of domestic and transboundary contamination. The main ecological problems are related to atmospheric pollution; water contamination; soil, water, and forest acidification; nitrogen-compounds overload of soil, water, and food; and contamination with agricultural chemicals and heavy metals. The increased environmental distress is a menace to public health in Lithuania. Experimental studies need to be designed and used to ascertain the effects of environmental distress on the gastrointestinal tract epithelial barrier. Our electronmicroscopic and immunohistochemical study of human gastrointestinal endocrine cells revealed changes in the amount of secretory material and intracytoplasmic vacuolization after exposure to the environmental chemicals such as hexavalent chromium and the herbicide Saprol. The most affected were the EC (serotonin, motilin, substance P), D (somatostatin), A (glucagon), B (insulin), and mast (histamine, serotonin, heparin) cells. These results provide ultrastructural evidence of digestive tract epithelial barrier reaction as an expression of environmental distress signals of the organism.


Breast cancer: geographic variation and risk factors.

Cancer of the breast is the most frequent malignant neoplasm occurring in women in developed countries. The age-standardized incidence rates of breast cancer vary widely throughout the world, the highest being observed in white females in the U.S. In general, its incidence is much lower in developing countries, particularly in Asia. Incidence rates in Japan are also low, which contradicts the role of the high economic level of a country being associated with high risk of breast cancer. The range of variation in incidence worldwide reaches a tenfold difference. Though breast cancer incidence has been increasing, screening practices for early diagnosis have contributed to keeping mortality at lower levels. Geographical variations, time trends, and studies on populations migrating from low- to high-risk areas, which show that the incidence in such populations approaches that of the host country in one or two generations, clearly suggest an important role of environmental factors in the etiology of breast cancer. Since the 1960s, numerous analytical studies have been conducted that have investigated, in particular, reproductive habits, hormonal patterns, and more recently, dietary habits. This article reviews the known risk factors and current research directions.


Screening and pathological diagnosis of asbestosis and mesothelioma: a review.

X-ray screenings of workers employed in asbestos manufacturing in Hungary revealed 255 cases of asbestosis and 3 cases of malignant mesothelioma. The pathological diagnosis of asbestosis is not very difficult. The diagnosis of mesothelioma, however, is fraught with problems. To identify mesothelioma we use histochemical reactions with PAS diastase digestion and immunohistochemical reactions for cytokeratin, vimentin, and CEA. The PAS and CEA reactions are negative but the vimentin and cytokeratin are positive in mesothelioma. Cytogenetic and molecular genetic studies may contribute to the better understanding of the pathogenesis and, thus, open new perspectives in our understanding of mesotheliomas.


Association of oral carcinoma with nasswar (snuff dipping).

A total of 186 cases of oral carcinoma were treated at the Institute of Radiotherapy and Nuclear Medicine (IRNUM), Peshawar, and at the District Headquarter Teaching Hospital, Abbottabad, during a two-year period. These patients were investigated for their personal habits and environmental factors. Use of nasswar was the most significant habit. We found that 91% of patients had the habit of nasswar dipping for more than 10 years. A history of tobacco smoking was noted in 44% of cases. Of these, 96% were also nasswar addicts. A significant correlation of the oral lesions was found with the site of the nasswar (snuff) dipping. We concluded that nasswar and other types of smokeless tobacco are not safe alternatives to tobacco smoking.


Male genital tract tumors in Punjab, India.

A total of 95,797 tissue specimens were submitted to our laboratory for histopathological examination during the 21-year period from January 1964 to December 1984. Out of 21,281 cases diagnosed as tumors, 9,254 were found in the male population, comprising 6,846 malignant neoplasms and 2,408 benign neoplasms. There were 1,175 tumors of the male genital tract of which 1,118 were malignant and 57 were benign. The incidence of male genital tract cancer represented 16.33% of male malignancies. The relative frequency of malignant tumors of various organs in the male genital tract was penis, 42.49%; prostate, 40.34%; testis, 15.92%; scrotum, 0.71%; epididymis, 0.36%; spermatic cord, 0.09%; and urethra, 0.09%. All these tumors were classified into various histopathological types and their relative frequency was determined. Some of the rare tumors diagnosed included leiomyosarcoma of the penis, transitional cell carcinoma of the prostate gland, orchioblastoma of the testis, and carcinoma of the urethra. A separate study by this department on the pattern of cancer distribution revealed that cancer of the uterine cervix is the most common malignancy in females in this geographic region. We postulate that a common carcinogenic agent, either a virus or a biochemical (smegmatic) factor, may be responsible for the high incidence of carcinoma of the penis in males and carcinoma of the cervix in females. Educating people about the importance of penile hygiene, and, in particular, educating mothers to retract the foreskin of male babies and to wash it with soap and water when bathing them, will hopefully reduce the incidence of these cancers in regions of high prevalence.


Malignant lymphomas in Beijing.

We report on 1,082 cases of malignant lymphomas from the files of the Department of Pathology, Chinese PLA General Hospital, Beijing. We found non-Hodgkin's lymphomas (NHL) in 980 cases (91%) and Hodgkin's disease (HD) in the remaining 102 cases (9%). Among the NHL, the diffuse type was seen in 955 cases (97.4%) and the follicular type in 25 cases (2.6%). Among the diffuse NHL, the pleomorphic type was most frequently found (263 cases or 26.8%), followed in frequency by the mixed small and large cell (163 cases or 16.6%). The large-cell cleaved and noncleaved immunoblastic was found in 139 cases (14.2%), small cleaved cell in 132 cases (13.5%), lymphoblastic convoluted and nonconvoluted in 72 cases (7.3%), the small lymphocytic type in 128 cases (13.1%), plasmacytoid type in 40 cases (4.1%), and Burkitt type in 18 cases (1.8%). Using immunohistocytochemistry, we found T-cell lymphoma in 53% and B-cell lymphoma in 47% of cases. The distinctive differences of malignant lymphomas types between China and Western countries suggest the possibility of a relationship to environmental factors.


Gastric carcinoma in northwestern Turkey: epidemiologic characteristics.

We studied 252 newly diagnosed gastric cancer patients seen at our institution between 1977 and 1991 and compared the findings with 609 age- and gender-matched controls. There was no difference in the mean age and the M:F ratio. Most of our patients were rural dwellers from a low socio-economic group. The proximal portion of the stomach was most often involved. No statistically significant differences were found with regard to the use of coffee, alcohol, starchy food, and fresh fruits. The relative risk for gastric cancer was significantly higher statistically in individuals who consumed only small amounts of vegetables and bread. Although an increased relative risk was noted between gastric cancer and the amount of milk and meat consumed, this appears to have been fortuitous: an increased consumption of milk may have been due to patients attempts to alleviate symptoms, and a low meat intake most likely was due to the low income level of the majority of our patients.


Geographic pathology on the precursors of stomach cancer.

The classification of dysplasias of the gastric mucosa used in our institute includes adenomatous dysplasia, regenerative dysplasia, and cryptal dysplasia. We compared the incidence of gastric dysplasia in three regions of China which have quite different geographical environments: the loess plateau of Wuwei area in the Gansu Province, the island of the Yangtze River in the Jiangsu Province of southern China, and the coastal area of the Liaoning Province in northern China. The mortality rate of stomach cancer in these areas is more than 50 per 100,000. We found a total of 323 cases of gastric dysplasia in these three areas. Regenerative dysplasia is the most common precancerous lesion of the stomach and was found in 40% of the cases from the three high-risk areas of gastric cancer. The background lesions consist of gastric erosions, severe gastritis, gastric ulcers, and intestinal metaplasia, which indicate that some factors causing damage to gastric mucosa are very important in the histogenesis of stomach cancer. The gastric dysplasia sites involved are different in the three geographical regions studied. On the island of the Yangtze River, cardiac dysplasia and intestinal metaplasia are common (75%), and cancer of the cardia is also common. In the other two geographical areas, antral dysplasia predominates (85 to 91%). The finding of different sites of gastric dysplasia in different geographical environments may be very important in our search for etiological factors of gastric cancer and may allow for beneficial intervention in the prevention of this disease.


The role of endogenous angiotensin II in the regulation of renal haemodynamics and proximal fluid reabsorption in the rat.

1. The influence of endogenous angiotensin II (AII) on renal haemodynamics and tubular function was examined by clearance and micropuncture methods in anaesthetized rats during AII receptor blockade with the non-peptide antagonist DuP 753 (50 micrograms kg-1 min-1 i.v.). 2. Mean arterial pressure was reduced slightly (-5 +/- 2 mmHg) while filtration fraction and glomerular filtration rate rose by 30% without changes in renal plasma flow (RPF) or renal vascular resistance (RVR). 3. Fractional proximal fluid reabsorption (calculated from lithium clearance) fell from 73 to 64% (P < 0.01) and fractional distal sodium reabsorption decreased from 98 to 94% (P < 0.01). 4. Urine flow rate more than doubled, sodium output increased 4-fold and plasma renin concentration rose 8-fold while potassium excretion remained unchanged. 5. Proximal tubular fluid reabsorption (Jv) as measured by shrinking split-droplet micropuncture decreased by 21% (P < 0.01) during infusion of DuP 753 compared with 22.5% (P < 0.01) during converting enzyme inhibition by enalaprilat (MK422). 6. Responses to DuP 753 were similar to those previously documented with converting enzyme inhibitors except that DuP 753 failed to raise RPF. It is concluded that generation of intrarenal vasodilator paracrines has confounded conclusions about the renal action of converting enzyme inhibitors and we propose that in anaesthetized rats, endogenous angiotensin II (AII) has its major renal influences on glomerular filtration and proximal fluid reabsorption with little effect on renal vascular resistance.


Effects of muscarine on single rat adrenal chromaffin cells.

1. The action of muscarine on membrane currents and cytosolic calcium (Ca2+) of dissociated rat adrenal chromaffin cells was investigated using standard whole-cell voltage-clamp techniques and microfluorimetry of unclamped single cells. 2. In cells held at a constant holding potential negative to -40 mV, brief (5-10 s) applications of muscarine produced a transient activation of outward current. The activation of this current by muscarine also occurs in the presence of 5 mM-Co2+. 3. The outward current activated by muscarine at holding potentials negative to about -40 mV is blocked over 90% by either 200 microM-curare or 200 nM-apamin. One millimolar TEA produces variable blocking effects at such potentials. 4. The outward current activated by muscarine is transient even in the continuing presence of muscarine. Complete recovery between pairs of muscarine applications occurs over a 1-2 min period. If sufficient time was allowed for recovery between muscarine applications, the muscarine-activated outward current could be reliably elicited in dialysed cells for periods of 20-30 min. 5. Voltage ramps were used to examine effects of muscarine on currents over a range of membrane potentials. Over all potentials, muscarine activates a relatively voltage-independent component which is blocked almost completely by 200 nM-apamin and by 200 microM-curare. At potentials negative to about -40 mV, the apamin- and curare-sensitive current accounts for virtually all muscarine-activated current. This current appears to correspond to a Ca(2+)-activated, voltage-independent current found in these cells. Effects of muscarine on currents activated at potentials positive to 0 mV are complex. At potentials above 0 mV, muscarine can produce either an activation or an inhibition of outward current. The outward current activated at positive potentials was primarily voltage dependent and blocked by 1 mM-TEA. However, in some cells activation of voltage-dependent current was not observed and, in such cases, muscarine produced an inactivation of the voltage-dependent component of current. The inactivation of outward current could also be observed in the presence of 5 mM-Co2+ indicating that the inactivation does not occur secondarily to an effect of muscarine on Ca2+ current. The possibility is discussed that the inactivation of outward current occurs as a result of intrinsic inactivation properties of the voltage-dependent Ca(2+)-dependent K+ current. According to this hypothesis, the extent to which inactivation of voltage-dependent outward current is observed depends on the magnitude of the muscarine-induced cytosolic Ca2+ elevation and the level of depolarization of the cell.(ABSTRACT TRUNCATED AT 400 WORDS)


Membrane recapture and early triggered secretion from the newly formed endocytotic compartment in bovine chromaffin cells.

1. Recycling of secretory vesicles in cultured bovine adrenal medullary cells was investigated. 2. Extracellular horseradish peroxidase (HRP), a fluid phase marker, was taken up into cultured adrenal medullary cells following carbamylcholine-induced secretion of catecholamine. 3. The endocytosed HRP remained compartmentalized within the cell, migrating to a low density band on a Percoll density gradient. The endocytotic compartment was distinct from the major pool of catecholamine-containing chromaffin granules, which were found at much higher densities on the Percoll gradient. 4. The chromaffin granule membrane marker dopamine beta-hydroxylase was associated with the endocytosed HRP compartment as well as with the heavier chromaffin granules. 5. A subsequent challenge of the cells with carbamylcholine triggered the release of up to forty per cent of the endocytosed HRP. 6. The time course for secretion of the fluid phase marker was similar to that for catecholamine secretion. 7. Triggered release of HRP was dependent on extracellular calcium. The dependence on the extracellular calcium concentration was similar to that of catecholamine release. 8. Release of HRP could be triggered from electropermeabilized cells by raising the intracellular Ca2+ into the micromolar range. The intracellular Ca2+ dependence of triggered HRP release was similar to that for catecholamine release. 9. HRP could be secreted as early as 5 min, and as late as 2 h after endocytosis. 10. These data provide evidence that endocytotic vesicles can rapidly re-enter the secretory cycle. Endocytosed vesicles may therefore not have to recycle via the trans-Golgi reticulum to form high-density chromaffin granules in order to re-enter the regulated secretory pathway.


Neuronal selectivity of ATP-sensitive potassium channels in guinea-pig substantia nigra revealed by responses to anoxia.

1. Two sub-populations of pars compacta substantia nigra neurones were identified with very different electrophysiological properties and rostral-caudal distribution. Both cell types were identified by biocytin intracellular dye injection and found to be located within pars compacta containing tyrosine hydroxylase-positive cells. These sub-populations displayed distinctly different responses to transient anoxia. 2. The first group ('Phasic' neurones) exhibited a low threshold calcium conductance LTS gCa associated with bursts of action potentials, were located at the level of the mammillary bodies and were highly sensitive to anoxia. The second group ('rhythmic' neurones) fired in a rhythmic pattern, were located at the level of the accessory optic tract and were relatively insensitive to anoxia. 3. The anoxic response of phasic cells was characterized by membrane hyperpolarization (mean 12 mV), a decrease in input resistance (mean 36%) and cessation of action potential firing. The axonic response of these neurones was not blocked by TEA (5-10 mM), haloperidol (100 microM), the removal of extracellular calcium or depletion of endogenous dopamine. However, this effect was blocked by both the sulphonylurea tolbutamide (50-500 microM), and also by quinine (100 microM) and could be mimicked by application of diazoxide (1 mM). 4. Rhythmic cells displayed a variable response to anoxia consisting of either modest depolarization, hyperpolarization or no change in membrane potential, in all cases accompanied by little or no change in input resistance. The polarity of the membrane potential shift during anoxia was reversed by TEA (5-10 mM) or the removal of calcium. These cells were also relatively insensitive to diazoxide (1 mM). 5. It is concluded from the neuronal responses to anoxia and the pharmacological modification of these responses, that the ATP-sensitive potassium channel (KATP channel) is functionally operative in the substantia nigra and is primarily distributed on the phasically discharging cells of the rostral pars compacta. The relevance of this recently discovered ionic channel is discussed with regard to the normal and abnormal functioning of the substantia nigra.


Effects of aortic pressure and vasoactive agents on the vascular resistance of the vasa vasorum in canine isolated thoracic aorta.

1. We have developed a new preparation for continuously measuring changes in vascular resistance of the vasa vasorum of the canine isolated thoracic aorta perfused at a constant flow rate with Krebs-bicarbonate solution. 2. An increase of more than 150 mmHg in aortic pressure caused a significant increase in the vascular resistance of the vasa vasorum. 3. 5-Hydroxytryptamine (5-HT), noradrenaline (NA), adrenaline and dopamine caused dose-dependent increases in the vascular resistance of the vasa vasorum. The decreasing order of potency in the vasoconstrictor responses was as follows: 5-HT >> NA = adrenaline >> dopamine. The 5-HT- and adrenaline-induced vasoconstrictor responses were inhibited by methysergide and by phentolamine plus propranolol, respectively. 4. Acetylcholine (ACh), isoprenaline (ISP), histamine (His), ATP, ADP and adenosine produced dose-related decreases in the vascular resistance of aortic vasa vasorum perfused with the Krebs solution containing 10(-5) M-NA. The decreasing order of potency in the response was as follows: ACh = ISP > His >> adenosine = ATP = ADP. The ACh-, ISP- and His-induced vasodilator responses were antagonized by atropine, propranolol and famotidine, respectively. 5. The results suggest that the preparation described is useful for studying the regulation of vascular resistance of aortic vasa vasorum and that aortic pressure and vasoactive compounds may directly regulate the vascular resistance of the vasa vasorum in canine isolated thoracic aorta.


Effects of carbon dioxide on tetanic contraction of frog skeletal muscles studied by phosphorus nuclear magnetic resonance.

1. Bullfrog skeletal muscles were stimulated tetanically for 2 s at a sarcomere length of 2.4 microns in Ringer solution saturated with a gas mixture of O2 and CO2 of various proportions, at 4 degrees C. Using 31P nuclear magnetic resonance (31P-NMR), concentrations of inorganic phosphate (P(i)) and phosphocreatine (PCr) and intracellular pH (pHi) in whole muscle were measured in order to correlate the changes in these metabolites with the mechanical responses. 2. Resting muscles were first equilibrated to 5% CO2, then the CO2 concentration was increased up to 30%. This resulted in a rapid increase in [H+] (pH 6.72 in 30%, and 7.21 in 5% CO2) with little change in P(i) or PCr concentrations. When these muscles were given a single tetanic stimulation force fell in proportion to the decrease in pHi. 3. When a series of tetanic stimulations, with a long recovery period between tetani, was applied to the muscles in high CO2, force declined until a steady level was attained. A considerable increase in [P(i)] accompanied this whereas the decrease in pHi was relatively small. The force decline was much greater than could be predicted by the decrease in pHi alone. The concentration of ATP did not change significantly. 4. By subtracting the direct effect of [H+] on force a relationship between force and total P(i) concentration in the steady state of repeated contraction-recovery cycles was obtained. Force was suppressed linearly by increasing P(i) up to 30 mmol (1 fibre water)-1, while this relationship suggested an interaction between the effects of [P(i)] and [H+]. 5. These results have also shown that the inhibitory effects of CO2 on muscle contraction are dual. While elevation of [H+] directly suppresses contraction, this also accelerates P(i) accumulation in actively contracting muscles, which further suppresses contraction.


Exponential activation of the cardiac Na+ current in single guinea-pig ventricular cells.

1. The cardiac Na+ current of guinea-pig was recorded using an improved oil-gap voltage clamp method. When a single ventricular cell was stretched between the internal and external solution compartments across an oil gap of about 40 microns in width, the sealing resistance in the oil gap was higher than 1 G omega and the time constant of the capacitive current was between 10 and 40 microseconds. Effective series resistance (Rs) was less than 50 k omega after Rs compensation. 2. The activation time course (I'Na) was separated from inactivation by dividing the digitized record of Na+ current with the inactivation variable h(t), which was obtained by fitting exponential functions to the decaying phase of current. I'Na started as a single exponential activation at time 0, which was defined by the decay of the capacitive current to 5% of its peak. 3. The Na+ tail current was recorded on repolarization after a short (1.2 ms) depolarizing pulse to -10 mV. Its single exponential decay at potentials negative to -50 mV, or its major exponential component of decay between -50 and -30 mV, was attributed to deactivation. The time constants of deactivation were similar to those of activation which were measured from I'Na on depolarization to comparable potentials. The m1 kinetics gave a better fit for Na+ activation than the m3 kinetics. 4. The time constant of deactivation was a linear function of the membrane potential on a semilogarithmic scale with an e-fold increase per 21.6 +/- 1.3 mV (n = 8) depolarization. The steady-state activation value (m(infinity)) was obtained from the amplitude of I'Na. Fitting a Boltzmann equation indicated a half-activation potential of -21.9 +/- 1.7 mV and a slope factor of 7.9 +/- 0.4 mV (n = 9). 5. m1 kinetics are more pertinent to a description of the cardiac Na+ current. Limitations in analysing the activation kinetics of Na+ current are discussed for the improved oil-gap voltage clamp method.


Classification of preganglionic neurones projecting into the cat cervical sympathetic trunk.

1. The spontaneous and reflex activity patterns of 167 single preganglionic axons dissected from the cervical sympathetic trunk were examined in chloralose-anaesthetized cats. Each neurone was classified into one of four major groups, on the basis of three principal criteria: the presence or absence of significant cardiac rhythmicity of the activity, the response to noxious stimulation of the skin, and the coupling of its activity to central inspiratory drive (phrenic nerve activity). Most neurones were also subjected to additional tests, which included carotid chemoreceptor stimulation, nasopharyngeal probing, systemic hypercapnia (ventilation with 8% CO2), hyperventilation, adrenaline-induced blood pressure rises and retinal illumination. 2. Group I neurones (n = 69; 41%) showed significant cardiac rhythmicity, indicating strong baroreceptor control. Most (54/69) were excited by noxious stimuli, the rest being unaffected. Their activity showed variable degrees of excitatory coupling to the central inspiratory drive, and was enhanced by hypercapnia (35/39). Their responses to stimulation of arterial chemoreceptors (12/15) and nasopharyngeal receptors (24/35) were excitatory. 3. Group II neurones (n = 39; 23%) were inhibited by noxious stimulation of skin. With nine exceptions, they showed no significant cardiac rhythmicity, although they were weakly inhibited by an adrenaline-induced blood pressure rise. Their coupling to central inspiratory drive was weak or absent, and their responses to hypercapnia and hyperventilation were variable. By contrast to other groups, they were inhibited by both chemoreceptor stimulation (9/10) and nasopharyngeal stimulation (17/18). 4. Group III neurones (n = 33; 20%) showed no significant cardiac rhythmicity, but their activity was closely coupled to central inspiratory drive. They were inhibited by hyperventilation (9/9) and excited by hypercapnia (20/21), but only fired during the central inspiratory phase and sometimes during late expiration. Their responses to noxious stimulation (28/33), chemoreceptor stimulation (8/11) and nasopharyngeal probing (24/24) were excitatory, but the induced activity was 'gated' by the respiratory cycle, occurring primarily during inspiration and avoiding the postinspiratory phase. 5. Group IV neurones (n = 26; 16%) showed no significant cardiac or respiratory related activity and were either excited (n = 22) or unaffected (n = 4) by noxious stimuli. One of the latter and three group II neurones were inhibited by retinal illumination; thirty-one other neurones of all classes were unaffected. 6. Approximately 45% of thoracic sympathetic neurones were silent under the experimental conditions. About 25% of these could be recruited by systemic hypercapnia leaving 34% without spontaneous and reflex activity.(ABSTRACT TRUNCATED AT 400 WORDS)


Effects of procaine and caffeine on calcium release from the sarcoplasmic reticulum in frog skeletal muscle.

1. Resting myoplasmic free [Ca2+] and [Ca2+] transients (delta [Ca2+]) were measured in single voltage-clamped frog skeletal muscle fibres in the presence and absence of procaine, caffeine or procaine plus caffeine using Fura-2 fluorescence and antipyrylazo III (Ap III) absorbance signals. The rate of release (Rrel) of calcium from the sarcoplasmic reticulum (SR) was calculated from the calcium transients and corrected for the relatively small decline due to depletion of calcium from the SR. 2. Procaine (1 mM) reversibly suppressed delta [Ca2+] and the corresponding Rrel by about 40% for 60-100 ms depolarizing steps to -40 to +20 mV. Procaine had little effect on either the waveform or voltage dependence of the Rrel records. 3. [Ca2+] transients calculated from Fura-2 fluorescence changes in the presence or absence of procaine had similar time courses and amplitudes as those calculated from the Ap III absorbance changes suggesting that 1 mM-procaine did not interfere with the ability of Ap III or Fura-2 to monitor delta [Ca2+]. 4. Although 1 mM-procaine depressed Rrel it had no effect on intramembrane charge movements (IQ) calculated from membrane currents recorded simultaneously with delta [Ca2+]. 5. Procaine (1 mM) reversibly inhibited the potentiating effect of 0.5 mM-caffeine on delta [Ca2+]. The amplitude and waveform of the Rrel records were similar in control fibres and in the presence of 1 mM-procaine plus 0.5 mM-caffeine. 6. In the presence of 0.5 mM-caffeine delta [Ca2+] after 10-20 ms voltage steps exhibited an increase in the time to peak and a slower decay time course compared with caffeine-free controls, suggestive of significant calcium-induced calcium release in the presence of caffeine. These effects of caffeine were completely and reversibly blocked by 1 mM-procaine. 7. In the absence of caffeine, 1 mM-procaine caused a small decrease in time to peak of delta [Ca2+] after 10-30 ms duration voltage steps compared to the bracketing control and wash runs without procaine. Rrel turned off faster after 10 ms pulses in procaine than in the absence of procaine, but the turn-off of release was about equally fast with or without procaine after pulses of 20 ms or longer. The effect of procaine after 10 ms pulses in the absence of caffeine may indicate suppression of a component of calcium-induced calcium release in control that inactivates during the pulse.(ABSTRACT TRUNCATED AT 400 WORDS)


The effect of a calmodulin inhibitor on intracellular [Ca2+] and contraction in isolated rat ventricular myocytes.

1. The effect of the calmodulin inhibitor N-(6-aminohexyl)-5-chloro-1-naphthalenesulphonamide (W7; 10 microM) on intracellular [Ca2+] ([Ca2+]i) and [H+], and on contraction, has been studied in myocytes isolated from the ventricles of rat hearts. [Ca2+]i and [H+] were monitored using the fluorescent dyes Fura-2 and 2',7'-bis(carboxyethyl)-5,6-carboxyfluorescein (BCECF) respectively. 2. W7 decreased the size of both the Fura-2 fluorescence (a function of [Ca2+]i) transient and twitch, but had no effect on their time course. 3. The decrease in the size of the Fura-2 fluorescence transient in the presence of W7 was accompanied by a decrease in the increase of Fura-2 fluorescence that could be elicited by releasing Ca2+ from the sarcoplasmic reticulum using 10 mM-caffeine. 4. There was a decrease in the apparent sensitivity of the contractile proteins to Ca2+ in the presence of W7 which may account, in part, for the decrease in the twitch observed in the presence of W7. 5. Test beats were interpolated at different test intervals after a train of steady-state contractions. Mechanical restitution curves were constructed by plotting the size of the test beat against the test interval. Both the size and the duration of the twitch increased as the test interval was prolonged. W7 slowed this mechanical restitution but had no effect on the changes in the duration of the twitch. 6. Intracellular pH was not altered by W7. 7. These results are discussed in terms of the known actions of calmodulin and W7.


Impact of antral mechanoreceptor activation on the vago-vagal reflex in the rat: functional zonation of responses.

1. Activation of gastric sensory afferents alters gastric motor and secretory function via the gastric vago-vagal reflex. In this report, we investigated in the rat the impact of gastric mechanoreceptor activation on the brain stem components of the reflex, which are located in the dorsal vagal complex (DVC), i.e. the nucleus of the solitary tract (NTS) and the subjacent dorsal motor nucleus (DMN). 2. In our extracellular recordings of single-cell activity in the DVC, we observed a relation between the response to antral distention and the location of the cell in the DVC. Specifically, cells that were excited by antral distention (ON cells) were located dorsal to those that were inhibited (OFF cells) by the same stimulus (mean depth = 536 +/- 15 and 627 +/- 14 microns for ON and OFF cells, respectively). 3. For a subset of DVC cells, the location was marked by ionophoretic ejection of Pontamine Blue from the recording barrel. Histological analysis indicated that ON cells were located in the NTS, and OFF cells were located in the ventral NTS or within the boundaries of the DMN. Together, these data led to the hypothesis that ON and OFF cells are functionally different groups of neurones, i.e. ON cells may be NTS neurones, and OFF cells may be DMN neurones. We tested this directly by employing both an intragastric balloon and a non-traumatic vagal stimulating electrode to determine whether inflation-related cells were NTS or DMN cells via orthodromic and antidromic activation, respectively. 4. Almost all ON cells (12/13) were orthodromically activated by vagal stimulation, i.e. they were NTS neurones. One ON cell was antidromically activated, and therefore was a DMN neurone. Of the twenty-eight OFF cells that were encountered, ten were classified as NTS neurones because they were orthodromically inhibited by vagal stimulation. The remaining eighteen OFF cells were orthodromically inhibited and antidromically activated (i.e. DMN neurones). Thus, our results support the hypothesis that ON and OFF cells can be functionally distinct populations of neurones, in that almost all ON cells are NTS cells and approximately 2/3 of the OFF cells are DMN neurones. 5. The response to mechanoreceptor activation was different for NTS and DMN neurones. NTS cells were activated (55%) or inhibited (45%) by balloon distention of the stomach, whereas DMN cells were almost exclusively inhibited (95%) by this stimulus. This information provides insight into the organization of excitatory and inhibitory connections of the brain stem components that mediate gastric vago-vagal reflexes.


Myoplasmic free Mg2+ concentration during repetitive stimulation of single fibres from mouse skeletal muscle.

1. The role of the myoplasmic free Mg2+ concentration ([Mg2+]i) in fatigue was studied in intact single fibres isolated from mouse skeletal muscle. Fatigue was produced by repeated tetanic stimulation. The fluorescent Mg2+ indicator furaptra was pressure injected into fibres. In vivo calibrations were performed to convert fluorescence signals into [Mg2+]i. 2. [Mg2+]i at rest was 0.78 +/- 0.05 mM (mean +/- S.E.M., n = 14). An increase of the extracellular [Mg2+] from 0.5 to 20 mM resulted in a small elevation of [Mg2+]i (86 microM in 5 min). Removal of extracellular Na+ did not affect [Mg2+]i. An intracellular alkanization of about 0.6 pH units gave a [Mg2+]i reduction of 65 microM. 3. During fatiguing stimulation [Mg2+]i initially remained almost constant and it then suddenly started to rise towards the end of the stimulation period. The onset of the [Mg2+]i rise was always followed by a rapid tension decline. In fatigue [Mg2+]i was approximately twice as high as at rest. 4. Fibres were injected with MgCl2 to study if the rise in [Mg2+]i could explain the tension decline in fatigue. An elevation of [Mg2+]i was accompanied by a tension reduction but the [Mg2+]i for a given tension was generally much higher in rested fibres injected with MgCl2 than in fatigued fibres. Thus the rise in [Mg2+]i as such cannot explain the tension reduction in fatigue. 5. Injection of MgCl2 was also used to assess the intracellular Mg2+ buffering. The mean Mg2+ buffer power (i.e. the ratio of the change in [Mg2+]i to the amount of Mg2+ added) was 0.62. 6. ATP is the quantitatively most important binding site for Mg2+ at rest and ATP breakdown is then a likely source of the [Mg2+]i increase in fatigue. The role of ATP breakdown in the increase of [Mg2+]i was studied with metabolic inhibition: fibres were exposed to iodoacetic acid to inhibit glycolysis and cyanide to inhibit oxidative phosphorylation. The pattern during metabolic inhibition was similar to that observed during fatigue. After remaining almost constant during a lengthy period, [Mg2+]i rose rapidly and this rise preceded a period of rapid tension decline. The fibres thereafter went into rigor and [Mg2+]i stabilized at an elevated level; the mean [Mg2+]i increase in rigor was 1.30 mM. 7. We have used modelling to determine the likely change in the intracellular ATP concentration ([ATP]i) for the observed changes in [Mg2+]i.(ABSTRACT TRUNCATED AT 400 WORDS)


Vagal control of mucus glycoconjugate secretion into the feline trachea.

1. We examined the effects of frequencies and patterns of electrical stimulation of the peripheral cut ends of the vagus nerves on the release of mucus glycoconjugates into feline trachea in vivo. Mucus glycoconjugates, radiolabelled biosynthetically with [35S]sulphate and [3H]glucose, were washed from a tracheal segment in situ, and dialysed before being counted and assayed chemically by the periodic acid-Schiff (PAS) method. 2. Vagal stimulation with regular pulses (10 V, 2 ms duration) at 1, 2.25, 4.5, 9 and 18 Hz produced frequency-dependent increases in the output of mucus glycoconjugates. 3. The muscarinic agonist pilocarpine (0.1-10 microM), given intrasegmentally, produced dose-dependent increases in the output of mucus glycoconjugates. 4. Pretreatment with atropine, phentolamine and propranolol reduced but did not abolish the effects of vagal stimulation. Vagus nerve stimulation still caused frequency-dependent increases in the output of mucus glycoconjugates. 5. High frequency stimulations at 22.5 and 47.5 Hz given intermittently (1 s burst then 4 s rest), whether in the absence or presence of cholinergic and adrenergic blockade, produced similar secretory responses as the same number of pulses delivered in regular trains at 4.5 and 9.5 Hz. This suggests that neither cholinergic nor non-adrenergic, non-cholinergic (NANC) nerve mechanisms in this system are potentiated by high frequency, intermittent burst stimulation. 6. In the absence of atropine, regular vagal stimulation had a greater effect on heart rate than did the same number of pulses delivered in bursts. 7. High molecular weight glycoconjugates from secretions were taken from the void volume of a Sepharose CL-2B gel filtration column and separated further by density-gradient centrifugation. Macromolecular components were observed at two densities, a typical mucin at 1.52 g ml-1, and a high density atypical component at 1.63 g ml-1. In secretions collected during vagal stimulation, either in the absence or presence of cholinergic and adrenergic blockade, the ratio of low density to high density macromolecules was higher than in unstimulated secretions. This can be explained if both cholinergic and NANC nervous vagal mechanisms stimulate the output of typical (density = 1.52 g ml-1) mucins into the feline trachea.


A submucosal mechanism of action for prostaglandin E2 on hexose absorption and metabolism in mouse intestine.

1. The involvement of prostaglandin E2 (PGE2) in hexose absorption and metabolism was studied in mouse small intestinal villus cells. 2. Phlorizin-sensitive, Na(+)-dependent alpha-methyl-D-glucoside (alpha-MG) uptake (0.8 mM) during 2 min cell incubations (37 degrees C) was 74 +/- 4 nmol (mg protein)-1. Maximal uptake was 110 +/- 8 nmol (mg protein)-1, representing an accumulation of 50-fold. Metabolism of D-glucose (5 mM) to L-lactate was 38 nmol min-1 (mg protein)-1. 3. Incubation of isolated cells with indomethacin or PGE2 did not affect alpha-MG uptake or D-glucose metabolism. By including indomethacin during cell isolation from whole intestine, alpha-MG uptake was inhibited dose dependently (50-250 microM) by up to 70% (P < 0.001). PGE2 present during both isolation and incubation inhibited by 85% (P < 0.001) at 1 microM and by 27% (P < 0.05) at 0.1 microM, with no effect at lower concentrations. alpha-MG uptake was reduced to 38% (P < 0.01) when 1 microM-PGE2 and 250 microM-indomethacin were presented in combination. When present during cell isolation and incubation, 1 microM-PGE2 inhibited lactate production by 24% (P < 0.05), except when present in combination with 250 microM-indomethacin. Indomethacin, itself, had no effect on lactate production. 4. A submucosal mechanism is proposed to account for the observed inhibitory effects of PGE2 on brush-border uptake of alpha-MG and cellular lactate production. Indomethacin appears to exert not only an effect of its own, possibly via PG-independent actions within the submucosa, but at high concentrations also disrupts the effects of exogenously applied PGE2.


Simultaneous measurements of cardiac noradrenaline spillover and sympathetic outflow to skeletal muscle in humans.

1. Muscle sympathetic nerve activity (MSA) was recorded in the peroneal nerve at the knee by microneurography in ten healthy subjects and determinations were made simultaneously of intra-arterial blood pressure, and whole-body and cardiac noradrenaline spillover to plasma. Measurements were made at rest, during isometric handgrip at 30% of maximum power and during stress induced by forced mental arithmetic. 2. At rest there were significant positive correlations between spontaneous MSA (expressed as number of sympathetic bursts min-1) and both spillover of noradrenaline from the heart and concentration of noradrenaline in coronary sinus venous plasma. 3. Both isometric handgrip and mental arithmetic led to sustained increases of blood pressure, heart rate and MSA. Plasma concentrations of noradrenaline and spillover of noradrenaline (total body and cardiac) increased. In general the effects were more pronounced during handgrip than during stress. 4. When comparing effects during handgrip and stress the ratio between the fractional increases of MSA and cardiac noradrenaline spillover were significantly greater during handgrip. 5. The data suggest (a) that there are proportional interindividual differences in the strength of resting sympathetic activity to heart and skeletal muscle which are determined by a common mechanism and (b) that handgrip and mental stress are associated with differences in balance between sympathetic outflows to heart and skeletal muscle.


Maturation of carotid chemoreceptor sensitivity to hypoxia: in vitro studies in the newborn rat.

1. A preparation was developed to record single-fibre chemoreceptor afferent activity from carotid bodies of newborn and adult rats in vitro. The response to severe hypoxia was studied as a function of developmental age in four age groups: 1-2, 4-7, 10-15 days and adult (25-30 days). 2. During superfusion with HEPES-saline at room PO2 and at 26 or 35 degrees C, afferent chemoreceptor activity could be recorded in all age groups. No significant difference was found among groups in baseline discharge frequency at 26 or 35 degrees C. 3. All chemoreceptors responded to anoxia (PO2 congruent to 0 Torr) with a rapid increase in discharge frequency. At 35 degrees C, peak discharge frequency of single chemoreceptor afferents was significantly greater in the adult (15.7 +/- 1.6 Hz, mean +/- S.E.M., n = 18) and 10-15 days (11.2 +/- 4.2, n = 8) compared to rats of 1-2 days (4.3 +/- 0.7, n = 14) and 4-7 days of age (3.9 +/- 1.0, n = 7). 4. At 2 min into the anoxia period, all chemoreceptor activities were reduced from their peak discharge levels. At 35 degrees C, this decrease was significantly greater in the adult compared to the newborn. 5. During the period of decreased activity during anoxia, the chemoreceptor discharge could not be increased by inter-stream injection of acetylcholine (100 micrograms) or dopamine (100 micrograms), although these drugs were effective in increasing discharge rate prior to hypoxia. 6. We conclude that: (1) postnatal maturation of chemoreceptor sensitivity to hypoxia is present in vitro, (2) maturation occurs between the first and second week after birth in the rat, and (3) the decrease in activity during prolonged anoxia is not greater in the newborn compared to the adult. Thus, maturational changes occur in the sensitivity of the glomus cell-nerve ending complex to hypoxia.


Second-messenger regulation of sodium transport in mammalian airway epithelia.

1. Sodium absorption is the dominant ion transport process in conducting airways and is a major factor regulating the composition of airway surface liquid. However, little is known about the control of airway sodium transport by intracellular regulatory pathways. 2. In sheep tracheae and human bronchi mounted in Ussing chambers under short circuit conditions, the sodium current can be isolated by pretreating tissues with acetazolamide (100 microM) to inhibit bicarbonate secretion, bumetanide (100 microM) to inhibit chloride secretion and phloridzin (200 microM) to inhibit sodium-glucose cotransport. This sodium current consists of amiloride-sensitive (57%) and amiloride-insensitive (43%) components. 3. The regulation of the isolated sodium current by three second messenger pathways was studied using the calcium ionophore A23187 to elevate intracellular calcium, a combination of forskolin and the phosphodiesterase inhibitor zardaverine to elevate intracellular cyclic AMP, and the phorbol ester 12,13-phorbol dibutyrate (PDB) to stimulate protein kinase C. 4. In sheep trachea, A23187 produces a dose-related inhibition of the sodium current with maximal effect (38% of ISC) at 10 microM and IC50 1 microM. This response affects both the amiloride-sensitive and insensitive components of the sodium current and is not altered by prior stimulation of protein kinase C or elevation of intracellular cyclic AMP. In human bronchi, A23187 (10 microM) produced a significantly greater inhibition of ISC (68%), a response which was unaffected by prior treatment with PDB or forskolin-zardaverine. 5. In sheep trachea, stimulation of protein kinase C with PDB produced a dose-related inhibition of ISC maximal (56% of ISC) at 50 nM (IC50 7 nM). This response was abolished by amiloride (100 microM) pretreatment suggesting a selective effect on the amiloride-sensitive component of the sodium current. The response was not altered by prior elevation of intracellular calcium or cyclic AMP. PDB (10 nM) caused a similar inhibition of ISC in human bronchi (43%). The effect of PKC stimulation following pretreatment with A23187 was diminished in human bronchi. Elevating intracellular cyclic AMP did not alter this response. 6. Addition of forskolin (1 microM) together with the phosphodiesterase inhibitor zardaverine (100 microM) produced a mean 35-fold increase in intracellular cyclic AMP in sheep trachea. This was associated with a small, but significant, 6% transient increase in ISC followed by a significant 4% fall. Neither effect could be abolished by amiloride pretreatment. In human bronchi, a small decrease in ISC which could not be distinguished from that occurring in controls was observed.(ABSTRACT TRUNCATED AT 400 WORDS)


Acetylcholine released from guinea-pig submucosal neurones dilates arterioles by releasing nitric oxide from endothelium.

1. The role of the endothelium as an effector of the neurogenic cholinergic vasodilatation in submucosal arterioles of the guinea-pig ileum was investigated by measuring changes in arteriolar diameter in response to exogenous application of muscarine or electrical stimulation of the submucosal ganglia. 2. NG-Monomethyl-L-arginine (L-NMMA), an inhibitor of nitric oxide (NO) synthesis, competitively inhibited the vasodilatation produced by muscarine in arterioles which had been preconstricted with the prostaglandin analogue U46619. L-Arginine (10 mM), but not D-arginine (10 mM), prevented the inhibition by L-NMMA. 3. Neither tetrodotoxin (TTX, 1 microM), nor the cyclo-oxygenase inhibitor, indomethacin (10 microM), altered the muscarinic vasodilatation or the inhibitory effect of L-NMMA. 4. Sodium nitroprusside (SNP), an activator of the soluble guanylate cyclase, dilated the arterioles in a concentration-dependent manner. This vasodilatation was unaffected by L-NMMA but was abolished by the guanylate cyclase inhibitor, methylene blue (10 microM). In addition, methylene blue antagonized the muscarinic vasodilatation to a similar degree as did L-NMMA. 5. The vasodilatation produced by ganglionic stimulation (10 Hz, 10 s) was blocked by TTX and the muscarinic receptor antagonist, 4-diphenylacetoxy-N-methyl-piperidine methiodide (4-DAMP, 1 microM). The neurally evoked vasodilatation was inhibited by 70% in the presence of L-NMMA; this inhibition was prevented by L-arginine. Methylene blue inhibited the neurogenic vasodilatation to the same extent as did L-NMMA. 6. These results show that arteriolar vasodilatation by muscarine is mediated mainly through the release of NO formed from L-arginine; the origin of the L-arginine appears to be the endothelium. These results also demonstrate that acetylcholine released from submucosal nerves onto submucosal blood vessels reaches the endothelium to cause the release of NO formed from L-arginine; the endothelial-derived NO dilates the arteriole.


Interhemispheric inhibition of the human motor cortex.

1. Using two magnetic stimulators, we investigated the effect of a conditioning magnetic stimulus over the motor cortex of one hemisphere on the size of EMG responses evoked in the first dorsal interosseous (FDI) muscle by a magnetic test stimulus given over the opposite hemisphere. 2. A single conditioning shock to one hemisphere produced inhibition of the test response evoked from the opposite hemisphere when the conditioning-test interval was 5-6 ms or longer. We shall refer to this as interhemispheric inhibition. However, the minimum latency of inhibition observed using surface EMG responses may have underestimated the true interhemispheric conduction time. Single motor unit studies suggested values 4-7 ms longer than the minimum interval observed with surface EMG. 3. Interhemispheric inhibition was seen when the test muscle was active or relaxed. Increasing the intensity of the conditioning stimulus increased the duration of inhibition: increasing the intensity of the test stimulus reduced the depth of inhibition. 4. The conditioning coil had to be placed on the appropriate area of scalp for inhibition to occur. The effect of the conditioning stimulus was maximal when it was applied over the hand area of motor cortex, and decreased when the stimulus was moved medial or lateral to that point. 5. The inhibitory effect on the test stimulus probably occurred at the level of the cerebral cortex. In contrast to the inhibition of test responses evoked by magnetic test stimuli, test responses evoked in active FDI by a small anodal electric shock were not significantly inhibited by a contralateral magnetic conditioning stimulus. Similarly, H reflexes in relaxed forearm flexor muscles were unaffected by conditioning stimuli to the ipsilateral hemisphere. However, inhibition was observed if the experiment was repeated with the muscles active.


Estimating the strength of common input to human motoneurons from the cross-correlogram.

1. The relationship between the motor unit discharge pattern (rate and variability) and synchronization of motor unit pairs was studied in the first dorsal interosseus muscle of human subjects. In separate trials of up to 4 min duration, subjects voluntarily controlled the mean discharge rate of an identified motor unit at one of several prescribed rates (range 7.5-17.5 Hz). 2. The effect of discharge rate on the synchronous peak in the cross-correlogram was examined in eighty motor unit pairs from six subjects. Five commonly used synchronization indices were used to quantify synchrony in the cross-correlograms constructed from different discharge-rate trials. For each synchronization index, the apparent magnitude of synchrony increased at lower motor unit discharge rates. The synchronization indices were not equally sensitive to discharge rate; increases in the different indices ranged from 72 to 494% between the highest and lowest discharge rates. 3. A model of the membrane potential trajectory underlying rhythmic motoneuron discharge was used to explain the observed increase in the magnitude of the synchronization indices at lower discharge rates. The essential feature of this model is that the probability of a common-input EPSP causing a synchronous discharge in two motoneurons is independent of discharge rate. This means that the number of synchronous action potentials in excess of chance in any trial depends on the properties of the common-input EPSPs and the duration of the trial, but is not related to motor unit discharge rates. The model also demonstrated that when the excess synchronous counts are normalized to motor unit discharge rate, or baseline counts in the histogram (as in the conventional synchronization indices), the magnitude of the index increases when the motor unit discharge rates are low. 4. The strength of common input to motoneurons could be misinterpreted if conventional synchronization indices are used because of discharge-rate effects. The model was used to derive an index of the strength of common input to motoneurons (CIS) that was independent of motor unit discharge rate. CIS is the frequency of synchronous action potentials in the motor unit pair in excess of those expected due to chance (calculated during periods of tonic discharge in both units). The mean CIS in first dorsal interosseus motor unit pairs ranged from 0.052 to 1.005 extra synchronous action potentials per second across subjects. 5. Discharge variability was correlated with each of the synchronization indices and the CIS.(ABSTRACT TRUNCATED AT 400 WORDS)


Physiological evidence for a slow K+ conductance in human cutaneous afferents.

1. The depression in axonal excitability that follows short trains of impulses (H1) may lead to spike frequency adaptation to a sustained stimulus, and has been attributed to a slow K+ conductance. The present experiments sought indirect evidence for slow K+ channels at the node of Ranvier of human cutaneous afferents based on the demonstration of post-tetanic changes in excitability typical of H1. 2. The excitability changes in low-threshold cutaneous afferents in the digital nerves of the index finger were explored using a submaximal test pulse conditioned by trains of supramaximal stimuli, containing up to 100 impulses. Changes in the amplitude of the compound sensory action potential set up by a constant test stimulus were used as a measure of the changes in excitability. These changes in amplitude were paralleled by inverse changes in latency. 3. When the conditioning stimulus was a single supramaximal pulse, excitability was enhanced at conditioning-test intervals of 4-40 ms, with a peak at 6-8 ms. When the conditioning stimulus consisted of a train of ten pulses delivered at 200 Hz, the recovery cycle was dominated by subnormality that was maximal at 20 ms and subsided gradually over 50 ms. 4. The post-train depression in excitability increased as the number of pulses in the conditioning train increased to ten but changed little with further increases in train duration. The degree of depression increased with the pulse frequency within the train. Cooling the hand from a skin temperature of 35 to 25 degrees C slowed the recovery processes but did not alter the magnitude of the post-train depression. 5. These characteristics are typical of the H1 phase of post-tetanic depression in axonal excitability. The extent of the depression in excitability suggests, first, that there may be a significant K+ conductance at the nodes of human cutaneous afferents and, secondly, that H1 may play a significant role in limiting repetitive discharge in normal and pathological afferents.


Effect of an inhaled thromboxane mimetic (U46619) on in vivo pulmonary resistance and airway hyperresponsiveness in dogs.

1. We investigated the role of thromboxane A2 in the airway hyperresponsiveness that follows the inhalation of ozone in dogs by examining the responses to an inhaled thromboxane analogue (U46619). 2. Measurements of pulmonary resistance were made in anaesthetized dogs; the concentration of inhaled agonist causing an increase of 5 cmH2O l-1 s was calculated (provocative concentration). The effect of inhaled U46619 was studied on in vivo canine airway resistance, on airway responsiveness and on airways made hyperresponsive following the inhalation of ozone. 3. Inhaled thromboxane is a potent constrictor of the canine airway. The mean provocative concentration was 2.13 x 10(-4) M, compared to acetylcholine which was 3.23 x 10(-2) M. 4. Inhaled thromboxane did not result in the development of airway hyperresponsiveness to acetylcholine. Following U46619 inhalation the mean provocative concentration to acetylcholine was 3.92 x 10(-2) M. 5. Canine airway was not hyperresponsive to inhaled thromboxane following the inhalation of ozone. This was not due to an inhibition of acetylcholinesterase as the dogs were hyperresponsive to carbachol (a muscarinic agonist not degraded by endplate cholinesterase). 6. These experiments do not support a role for thromboxane in the development of airway hyperresponsiveness following the inhalation of ozone in dogs.


Mitochondrial and sarcolemmal Ca2+ transport reduce [Ca2+]i during caffeine contractures in rabbit cardiac myocytes.

1. Contraction and intracellular Ca2+ (Ca2+i) transients were measured in isolated rabbit ventricular myocytes during twitches and contractures induced by rapid application of 10 mM-caffeine. 2. The amplitude of caffeine-induced contractures and the accompanying Ca2+i transients were larger than during normal twitches and also declined more slowly. This may be because only a fraction of sarcoplasmic reticulum (SR) Ca2+ is released during a normal twitch, or because of a temporal overlap of SR Ca2+ release and uptake during the twitch. 3. When a caffeine contracture was initiated in Na(+)-free, Ca(2+)-free medium (to prevent sarcolemmal Na(+)-Ca2+ exchange) the contracture and Ca2+i transient were larger and decreased much more slowly. Thus, Ca2+ extrusion via Na(+)-Ca2+ exchange may limit the amplitude of caffeine-induced contractures. 4. Relaxation half-time (t1/2) for the twitch (0.17 +/- 0.03 s) was increased to 0.54 +/- 0.07 s for caffeine contractures in control solution and 8.8 +/- 1 s for caffeine-induced contractures in Na(+)-free, Ca(2+)-free solution. These results confirm that the SR Ca2+ pump and Na(+)-Ca2+ exchange are the predominant mechanisms for cytoplasmic Ca2+ removal during relaxation. However slower mechanisms can still reduce intracellular [Ca2+]. 5. Relaxation of caffeine contractures in Na(+)-free solution was further slowed when (a) mitochondrial Ca2+ uptake was inhibited with the oxidative phosphorylation uncoupler, FCCP (t1/2 = 19.7 +/- 3.2 s), or (b) the sarcolemmal Ca(2+)-ATPase pumping ability was depressed by a large transmembrane [Ca2+] gradient (t1/2 = 27.5 +/- 6.9 s). 6. When the four Ca2+ transport systems were simultaneously inhibited (i.e. SR Ca2+ pump, Na(+)-Ca2+ exchange, mitochondrial Ca2+ uptake and sarcolemmal Ca2+ pump), relaxation was practically abolished, but the cell could recover quickly when Na+ was reintroduced and caffeine removed. 7. We conclude that, under our experimental conditions, the sarcolemmal Ca2+ pump and mitochondria are approximately 37- and 50-fold slower than the Na(+)-Ca2+ exchange at removing Ca2+ from the cytoplasm. Additionally, the SR Ca2+ pump is about 3-4 times faster than Na(+)-Ca2+ exchange.


Vibrotactile sensitivity of slowly adapting type I sensory fibres associated with touch domes in cat hairy skin.

1. Recordings were made from single slowly adapting type I (SAI) afferent fibres associated with touch domes in the cat hairy skin. Controlled vibratory stimuli were used first, to characterize the precision with which these SAI afferents reflect the temporal aspects of vibrotactile stimuli, and second, to determine whether earlier disparate reports of SAI responsiveness to vibration may be attributable to highly specific stimulus requirements. 2. Eighteen SAI fibres from femoral cutaneous nerve branches were examined; each was associated with one to three touch domes. SAI responses to both steps and sinusoidal vibration (1-1.5 s in duration) were affected profoundly by both probe size and position. Punctate stimulus probes (250 microns) produced much higher response levels and steeper stimulus-response relations than those elicited with large (2 mm) probes, probably on account of focal distortion created within the dome by the smaller probes. SAI sensitivity to vibration was also affected markedly by the amplitude of any pre-indentation on which the vibration was superimposed; sensitivity was much lower when the pre-indentation exceeded 100 microns, in particular with larger stimulus probes. 3. Measures of both vibration sensitivity and the precision of impulse patterning demonstrated that, if appropriate stimulus parameters are chosen, the SAI fibres can respond to 1 s trains of vibration (amplitude < or = 100 microns) in a tightly phase-locked, 1:1 manner for frequencies up to 500 Hz. At frequencies from approximately 100-500 Hz the SAI fibres displayed broad 1:1 plateaus, where their response rate remained constant over a range of amplitudes, and phased-locking was tightest. Responses remained phase-locked up to 1000 Hz, but could not follow the vibration with a 1:1 pattern above 500 Hz. 4. The results demonstrate that with appropriate stimulus parameters, touch dome-associated SAI fibres are capable of signalling vibrotactile information over a similar bandwidth of frequencies as do Pacinian sensory fibres. The variability in past reports of SAI vibration sensitivity may relate principally to differences in stimulus conditions. However, in view of the SAI capacity for responding to vibration with temporally precise, patterned activity, it appears that their reported failure to contribute to vibrotactile sensibility must be attributed to limitations imposed in the central processing of SAI signals.


Inward current caused by sodium-dependent uptake of GABA in the crayfish stretch receptor neurone.

A two-microelectrode current-voltage clamp and Cl(-)-selective microelectrodes were used to examine the effects of gamma-aminobutyric acid (GABA) on membrane potential, current and intracellular Cl- activity (aiCl) in the crayfish stretch receptor neurone. All experimental solutions were CO2-HCO3- free. 2. GABA (500 microM) produced a mono- or biphasic depolarization (amplitude < or = 10 mV), often with a prominent initial depolarizing component followed by a transient shift to a more negative level. In some neurones, an additional depolarizing phase was seen upon washout of GABA. Receptor desensitization, being absent, played no role in the multiphasic actions of GABA. 3. The pronounced increase in membrane conductance evoked by GABA (500 microM) was associated with an increase in aiCl which indicates that the depolarizing action was not due to a current carried by Cl- ions. 4. The currents activated by GABA under voltage clamp conditions were inwardly directed when recorded at the level of the resting membrane potential, and they often revealed a biphasic character. The reversal potential of peak currents activated by pulses of 500 microM-GABA (EGABA) was 9-12 mV more positive than the reversal potential of the simultaneously measured net Cl- flux (ECl). ECl was 2-7 mV more negative than the resting membrane potential. 5. EGABA (measured using pulses of 500 microM-GABA) was about 10 mV more positive than the reversal potential of the current activated by 500 microM-muscimol, a GABA agonist that is a poor substrate of the Na(+)-dependent GABA uptake system. 6. In the absence of Na+, the depolarization and inward current caused by 500 microM-GABA were converted to a hyperpolarization and to an outward current. Muscimol produced an immediate outward current both in the presence and absence of Na+. 7. Following block of the inhibitory channels by picrotoxin (100-200 microM), the depolarizing effect of 500 microM-GABA was enhanced and the transient hyperpolarizing shifts were abolished. 8. In the presence of picrotoxin, GABA (> or = 2 microM) produced a concentration-dependent monophasic inward current which had a reversal potential of +30 to +60 mV. This current was inhibited in the absence of Na+ and by the GABA uptake blocker, nipecotic acid. Unlike the channel-mediated current, the picrotoxin-insensitive current was activated without delay also at low (2-10 microM) concentrations of GABA.(ABSTRACT TRUNCATED AT 400 WORDS)


Synaptically triggered action potentials begin as a depolarizing ramp in rat hippocampal neurones in vitro.

1. During just-suprathreshold synaptic activation of CA1 pyramidal cells in rat hippocampal slices in vitro the action potential begins as a slow depolarizing ramp, superimposed on the underlying EPSP and forming an integral part of the action potential. We call this ramp a synaptic prepotential (SyPP). 2. In order to examine the SyPP, a procedure for subtraction of the underlying EPSP was necessary. Because action potentials were only elicited by a subset of EPSPs with larger than average amplitude, a subtraction of the mean subthreshold EPSP would not give valid results. Instead, an EPSP to be subtracted was selected from an assemblage of subthreshold EPSPs, so that its amplitude matched the initial part of the spike-generating EPSP. 3. Virtually all action potentials started with a SyPP. Using an amplitude criterion of 1 S.D. of the mean of the matching subthreshold EPSPs, just-suprathreshold EPSPs gave prepotentials in 72-100% of all action potentials from fifteen randomly selected cells. With a criterion of 2 S.D.S, the frequency of occurrence ranged from 36 to 100%. 4. With a constant stimulus strength, there was a certain variability of the spike latencies. Shorter latency spikes had steeper, but smaller SyPPs than later spikes, suggesting that the slope of SyPP influenced the timing of the cell discharge. 5. The SyPP was best fitted by a single, exponentially rising curve, and was both smaller and slower than the large amplitude action potential. Its amplitude was 1-6 mV and the time constant 1-5 ms, which was 10-50 times slower than that of the upstroke of the action potential. 6. A properly timed hyperpolarizing current pulse could block the large amplitude action potential, thereby unmasking the SyPP as an initial depolarizing ramp. 7. The SyPP was more sensitive than the large amplitude action potential to intracellular injection of QX-314, a lidocaine derivative. At the concentrations used (10 or 30 mM) no detectable changes were seen in the large amplitude action potential. 8. Droplet application of a specific N-methyl-D-aspartate receptor antagonist, DL-2-amino-5-phosphonovaleric acid (1 mM), reduced both the EPSP and the firing probability, but did not change the SyPP. 9. The SyPP amplitude and time course depended upon the membrane potential at which the cell was activated. Depolarization enhanced and prolonged the SyPP, while hyperpolarization gave opposite effects. In part, the depolarization-induced amplitude increase could be attributed to membrane accommodation. 10. Antidromically evoked action potentials never started with a prepotential.(ABSTRACT TRUNCATED AT 400 WORDS)


Effects of continuous heating at mild temperatures on the translocation of hsp70 and protein synthesis in NRK cells.

We investigated intracellular translocation of hsp70 and total protein synthesis during heating at mild temperatures in NRK (normal rat kidney) cells. When cells were heated at 41 degrees C, the hsp70 was translocated into the nuclei/nucleoli, then returned gradually to the cytoplasm during heating. Concomitantly, total protein synthesis first decreased to 80% of the control level, then recovered by 2 hr. This indicates the acquisition of translational thermotolerance during heating at 41 degrees C. The return of hsp70 to the cytoplasm seems to be related to the recovery of total protein synthesis. Similar relationships were obtained at 42 degrees C heating in the presence of glycerol. These results suggest that translocation of hsp70 into the nuclei/nucleoli is important for the recovery of protein synthesis (acquisition of translational thermotolerance) during heating at mild temperatures.


Two components of calcium-activated potassium current in rat adrenal chromaffin cells.

1. The activation of calcium (Ca2+)-dependent potassium (K+) currents in dissociated rat adrenal chromaffin cells was investigated using the dialysed cell recording technique. 2. Ca(2+)-dependent K+ current was the major component of outward current at command potentials from -30 mV to about +50 mV. 3. Two components of Ca(2+)-dependent outward current could be distinguished based on the voltage dependence of activation, the properties of tail currents following repolarization, and pharmacological properties. 4. One Ca(2+)-dependent current was similar to an after-hyperpolarization current (often termed IAHP) observed in other cell types. This current was largely blocked by 200 nM-apamin or 200 microM-curare, was associated with slow Ca(2+)-dependent tail current, and exhibited little dependence on voltage. In cells with cytosolic Ca2+ buffered to 500 nM-1 microM, curare-sensitive current accounted for most of the membrane current at potentials negative to about -40 mV. 5. A second component of Ca(2+)-activated K+ current exhibited voltage-dependent activation, was completely blocked by 1 mM-TEA, and turned off rapidly following repolarization. An unusual aspect of the TEA-sensitive currents was that they appeared to inactivate under conditions of constant cytosolic Ca2+. 6. A novel observation during these experiments was a slow hump of outward current which appears to result from a non-monotonic elevation in cytosolic Ca2+ during prolonged voltage jumps.


Comparison of the measured gamma ray dose and the DS86 estimate at 2.05 km ground distance in Hiroshima.

The gamma ray dose at 2.05 km ground distance from the Hiroshima atomic bomb hypocenter was measured from roof tile samples by a thermoluminescence technique. Two tile samples collected at 2.45 km also were analyzed to check the reliability of the background estimates. The result for the 2.05 km distance was 129 +/- 23 mGy for five-tile sample average. This value is 2.2 times larger than the corresponding DS86 estimate. These results and those in the literature show the DS86 estimate is 50% or less of the measured value 2.05 km from the Hiroshima hypocenter.


Effects of 5-fluorouracil on hematopoietic stem cells in normal and irradiated mice.

The effects of 5-fluorouracil (5-FU) on hematopoietic stem cells (CFU-S) and nucleated cells in mouse femur and spleen were studied in normal and X-irradiated mice (ddY-SLC male, 8-10 weeks old). Changes in the number of circulating blood cells also were investigated in mice treated with 5-FU. A single dose of 5-FU (150 mg/kg) was injected i.p. The femoral CFU-S decreased after 5-FU treatment up to day 3 when it reached 2% of the control value. The cells then increased, reaching a maximum about twice that of control by day 12. A very similar profile was found for splenic CFU-S. Post-irradiation recovery for femoral and splenic CFU-S in mice treated with 5-FU 3 days before X-irradiation (1.9 Gy) was faster than in mice given irradiation alone. Regrowth rates of CFU-S were almost the same as in mice treated with 5-FU alone. The radiosensitivity of the CFU-S population in mice treated first with 5-FU at different times before X-irradiation (1.9 Gy) changed day-by-day after treatment. The maximal survival for femoral CFU-S was found in mice treated with 5-FU 5 days before irradiation, and for splenic CFU-S in mice treated 12 days before irradiation.


Novel TCR gene rearrangements and expression in radiation-induced thymic lymphomas.

Using the intrathymic (i.t.) injection assay with a B10.Thy 1 congenic donor-host combination, we previously demonstrated that the pre-neoplastic cells (thymic prelymphoma cells) exist in immature T cell subpopulations; mainly in CD4-CD8- double negative (DN) and CD4-CD8+ single positive (SP) thymocytes and to some extent in CD4+CD8+ double positive (DP) thymocytes. Most thymic lymphomas that developed from these prelymphoma cells showed concomitant TCR alpha, beta and gamma gene rearrangements and expression. In this lymphomas, two lymphomas also showed TCR delta gene rearrangements. This represents the intermediate stages of TCR gene rearrangement. Every lymphoma, however, expressed CD3-associated alpha beta TCR on the cell surface, but not gamma delta TCR. Novel rearrangements of V gamma 4 and J gamma 4-C gamma 4 segments with non-gamma elements were found respectively in a concerted and symmetrical fashion. Recombinase-mediated inter-chromosomal exchanges characteristic of thymic lymphomas may function in radiation-induced lymphomagenesis.


Effects of fetal exposure to gamma rays on aggressive behavior in adult male mice.

Aggressive behavior (AB) in first generation (F1) hybrid male C57BL/6xC3H mice irradiated on the 14th day of gestation was studied at 100-135 days of age. Gravid female mice were irradiated with 1.0 or 2.0 Gy of gamma rays to the whole body. The AB of pairs of mice were recorded with a capacitance-induction motility monitor and on videotape. Recordings were continued for 90 min, starting at 2:00 PM. Vigorous wrestling, boxing and biting were regarded as AB. Data recorded at 15-min intervals were stored on micro-computer discs. The body weight for the irradiated group was significantly lower than that for the control group. The number of instances of AB was significantly higher in the irradiated group. The AB of the 2.0 Gy group was significantly more intensive than that of the control group. No difference in the duration of AB was found for the 2 irradiated and the control groups. Results demonstrate that male mice irradiated prenatally show increased aggressiveness.


Rheumatoid cachexia: depletion of lean body mass in rheumatoid arthritis. Possible association with tumor necrosis factor.

To investigate body composition and serum tumor necrosis factor (TNF) levels in a series of 24 patients with rheumatoid arthritis (RA). Body composition assessment by anthropometric measures and bioelectrical impedance. Cytokine determination in serum by ELISA: When compared to United States population norms, 16 of the subjects (67%) were cachectic. In regression models, lean body mass (LBM) was inversely associated with the number of swollen joints (p < 0.025). Elevated TNF-alpha was found in 3 of 5 flaring patients vs 0 of 18 patients with less active disease (p = 0.001). These 3 were all cachectic, while the 2 flaring patients without detectable TNF had normal LBM (p < 0.03). Among the whole group, there was a trend toward increasing disability with decreased LBM after adjusting for joint pain and disease duration (p < 0.07). Cachexia is common in RA, and may be cytokine driven. Given the prognostic impact of LBM wasting in other diseases, the effect of rheumatoid cachexia on outcome in RA deserves further study.


Detection of myeloid precursors (granulocyte/macrophage colony forming units) in the bone marrow adjacent to rheumatoid arthritis joints.

Various cytokines were recently found to be involved in the pathogenesis of rheumatoid arthritis (RA) and particularly, cytokines with hematopoietic activity have been detected in synovial tissues. We counted the number of myeloid precursors in terms of granulocyte/macrophage colony forming units (CFU-GM) and the number of stromal cell progenitors in terms of fibroblast colony forming units (CFU-F) in the tibial bone marrow adjacent to the joints affected by RA (n = 21), osteoarthritis (OA) (n = 10), and trauma (n = 2) using the colony formation unit assay. We also quantitated the amounts of interleukin 1 beta (IL-1 beta), IL-6, and granulocyte/macrophage colony stimulating factor (GM-CSF) in the culture supernatant of synovial tissue explants of these patients by enzyme linked immunosorbent assay (ELISA). The mean number (+/- SEM) of CFU-GM in patients with RA (7.4 +/- 4.9) was greater than that in patients with OA (0.5 +/- 0.2), while CFU-GM was not detected in trauma patients. The number of CFU-GM in the tibial bone marrow of patients with RA correlated well with the amount of IL-1 beta (r = 0.64, p < 0.01), but not with GM-CSF or with IL-6 from synovial tissues. These findings suggest that active bone marrow is present adjacent to the affected joints in patients with RA and that hematopoietic activity is influenced by IL-1 beta produced in nearby synovial tissues.


HLA in Singapore Chinese with rheumatoid arthritis.

The HLA-A, B, C, DR and DQ antigens were determined in 50 Singapore Chinese patients with rheumatoid arthritis (RA). There was a significant increase in the prevalence of HLA-Bw46, DRw53 and DQ3 in patients with RA. The linkage disequilibrium between Bw46 and DRw53 explains this association. This major histocompatibility complex association differs from the HLA-DR4 link in Caucasian populations and suggests that RA is an immunogenetically heterogeneous disease.


Effect of low doses of deflazacort vs prednisone on bone mineral content in premenopausal rheumatoid arthritis.

Longterm administration of steroid drugs, particularly prednisone, is known to induce osteoporosis, as well as bone growth inhibition and delayed fracture union. Recently deflazacort, an oxazoline prednisone derivative, has been developed to reduce such deleterious effects. We carried out a comparative study in premenopausal patients with rheumatoid arthritis (RA). Sixteen cases whose mean age was 36.5 years and mean disease duration 29 months, all fulfilling ARA criteria, were evaluated in a randomized, double blind trial. Visually identical deflazacort or prednisone capsules were given and patients were instructed to maintain an adequate calcium intake. Laboratory tests focussed on bone mineral density in lumbar spine, femoral neck and Ward's triangle and whole body mineral content. Differences between baseline and 12-month values were processed statistically. Persistent synovitis control proved similar for both drugs and features suggestive of Cushing's syndrome were only found in the prednisone group. The difference in whole body bone mineral content between the deflazacort and prednisone groups just failed to reach statistical significance. In the deflazacort group, the difference between the nonsignificant bone mineral density increase at the femoral neck and the significant decrease in the prednisone group proved statistically significant. Ward's triangle was the most sensitive area to bone mineral density changes in patients receiving prednisone, with a highly significant intergroup difference (p < 0.01). We believe this is the first study on corticosteroid induced osteoporosis, as evaluated by whole body mineral content measurements in premenopausal patients with short term RA, showing that deflazacort is a promising alternative in cases severe enough to require steroid therapy.


Frequent induction of insulin autoantibodies by D-penicillamine in patients with rheumatoid arthritis.

D-Penicillamine is a drug known to induce various immunological abnormalities. We used a competitive radiobinding assay, to evaluate the presence of insulin autoantibodies in 42 patients with rheumatoid arthritis (RA), under various treatment modalities. In 11/42 (26.2%) patients, the levels of insulin autoantibodies (range 59-1970 nU/ml) exceeded our upper limit of normal range (50 nU/ml). Nine of these 11 (81.8%) insulin autoantibodies positive patients had been treated with D-penicillamine. Out of 21 D-penicillamine treated patients, 9 (42.9%) were insulin autoantibodies positive (range 80 to 1970 nU/ml). An inverse correlation was found between the concentration of insulin autoantibodies and the time interval since the last drug administration, R = -0.58 (p < 0.05). No correlation was found between the autoantibodies levels and age, or duration of D-penicillamine treatment. In summary, elevated concentration of serum insulin autoantibodies are most probably induced by D-penicillamine therapy in patients with RA and tend to decrease after the drug withdrawal.


Dietary omega-3 fatty acid supplementation and naproxen treatment in patients with rheumatoid arthritis.

In a controlled, double blind, clinical trial we tested the effect of dietary omega-3 fatty acid supplementation with and without naproxen and placebo, respectively, in 67 patients with active rheumatoid arthritis. The patients were randomized into 3 groups that received the following treatment: Group 1, corn oil ("placebo omega-3 fatty acids"), 7 g/day for 16 weeks, and naproxen, 750 mg/day for 10 weeks followed by a stepwise reduction to 0 mg/day during the following 3 weeks; Group 2, omega-3 fatty acids, 3.8 g of eicosapentaenoic acid plus 2.0 g of docosahexaenoic acid, and naproxen, 750 mg/day for 16 weeks; and Group 3, omega-3 fatty acids as Group 2 and naproxen as Group 1. At the end of the trial, patients in Group 2 had improved with respect to duration of morning stiffness and global assessment by physician and patient. In Groups 1 and 3 there was a significant deterioration for most of the variables measured. However, for duration of morning stiffness the deterioration was significantly less pronounced in Group 3 compared with Group 1. These effects might be ascribed to the dietary omega-3 fatty acid supplementation.


Questionnaire study of the use of surgical shoes prescribed in a rheumatology outpatient clinic.

Our questionnaire study was undertaken to ascertain the proportion of patients who use an appliance and to what extent, up to a year after being prescribed. Twenty-four percent no longer used the appliance. Two-thirds wore their orthosis for more than 6 hours/day. Half the patients had surgical shoes--moulded and bespoke, most found their shoes of benefit. Moulded shoes were found to be worn more frequently and to be more comfortable, easier to put on and more attractive. Patients reported a significantly greater improvement in their condition with moulded shoes than with bespoke shoes.


Kates forefoot arthroplasty in rheumatoid arthritis. A 5-year followup study.

The longterm results of Kates forefoot arthroplasty in 74 feet of 41 patients with rheumatoid arthritis (RA) after a mean followup of 5.2 years was considered to be good by 38 patients and poor by 3 patients. The average walking distance had doubled. The mean hallux valgus angle was reduced from 46 to 27 degrees. Surgical results proved to depend on the quality of the arc of the remaining stumps, and not on the severity or activity of RA. Reoperations were necessary in 16 feet of 10 patients because of too prominent distal metatarsal stumps. Despite the absence of pain, 28 patients were not satisfied with the function of the hallux. This might be improved by performing arthrodesis of the first metatarsophalangeal joint.


Measurement of disease activity in systemic lupus erythematosus. Prospective validation of 3 clinical indices.

Several clinical indices have been proposed to measure disease activity in patients with systemic lupus erythematosus. Only a few have been subjected to extensive analysis. We report a methodological comparison of reliability, validity, responsiveness, and feasibility of the Lupus Activity Criteria Count, the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), and our own simplified modification of the latter (MEX-SLEDAI). They were applied prospectively to 39 patients with diverse degrees of disease activity in 3 consecutive visits. Inter-observer reliability outweighed experts' evaluation (rs = 0.86 to 0.89, p < 0.0001 versus 0.74). Significant association was demonstrated between indices and experts' judgment, managing physician's opinion, changes in treatment and clinical course. Moreover, indices showed good convergent validity (rs = 0.76 to 0.79, p < 0.0001), and responsiveness. MEX-SLEDAI was the least expensive instrument.


Incidence of and risk factors for hospitalizations in systemic lupus erythematosus: a prospective study of the Hopkins Lupus Cohort.

To determine the incidence of and risk factors for hospitalization in systemic lupus erythematosus (SLE). A prospective study of hospitalizations in 1989 and 1990 in the Hopkins Lupus Cohort was conducted. Of 261 patients with SLE in the Hopkins Cohort, 147 (56.3%) were hospitalized in 1989 or 1990. The incidence of hospitalization was 0.69 admissions/person-year. The mean length of stay was 9.6 days +/- 12.7 (SD). Activity of SLE accounted for 35% of admissions. Risk factors for hospitalization for active lupus in 1990 included activity of SLE in 1989 (measured by either the highest physician's global assessment in 1989, p = 0.004, highest lupus activity index (LAI) score in 1989, p = 0.002, or highest systemic lupus erythematosus disease activity index score in 1989, p = 0.008), an average prednisone dose greater than 10 mg in 1989 (p = 0.002), and the presence of neurologic lupus in 1989 (p = 0.02). Medical admissions other than for active SLE accounted for an additional 27% of admissions; one-half of these admissions (47%) were for complications of SLE and/or its treatment, with coronary artery disease the most common (21% of medical admissions). Infections were responsible for 14% of admissions. The majority of infections were bacterial (90%). Risk factors for hospitalization for infection in 1990 included active SLE in 1989 (p = 0.03), average prednisone dose of greater than 10 mg in 1989 (p = 0.04), immunosuppressive drug use in 1989 (p = 0.003), neurologic SLE in 1989 (p = 0.02) and previous hospitalization in 1989 (p = 0.03). Hospitalization is common in the Hopkins Lupus Cohort, with active SLE (35%), infection (14%, infection and/or active SLE; 11%, infection alone) and medical complications of SLE (13%) as the 3 most common causes.


Significance of plasma endothelin-1 levels in patients with systemic sclerosis.

Endothelin-1 (ET-1) is a novel potent vasoconstrictor peptide discovered in the supernatant fraction of cultured endothelial cells. We measured plasma levels of ET-1 using a sensitive sandwich enzyme immunoassay. Plasma concentrations of ET-1 in 31 patients with systemic sclerosis (SSc) (1.90 +/- 0.47 pg/ml) were higher than those (1.31 +/- 0.10 pg/ml) in 25 age and sex matched healthy subjects. Patients with SSc with diffuse scleroderma had higher levels of ET-1 compared with those with limited scleroderma. Plasma ET-1 levels correlated inversely with carbon monoxide diffusing capacity (DLco). Measurement of plasma ET-1 levels may be useful as a predictor of prognosis of SSc.


Raynaud's phenomenon in primary Sjögren's syndrome. Association with other extraglandular manifestations.

One hundred and four patients with primary Sjögren's syndrome (SS) were evaluated for the presence (29%) or absence of Raynaud's phenomenon (RP). The clinical course of RP was, in general, benign and caused no vascular sequelae. In patients with primary SS having RP, nonerosive arthritis, vasculitis and pulmonary fibrosis were significantly more frequent than in those without RP. Myositis also appeared more frequently associated with RP, but the difference reached statistical significance only when combined in meta-analysis with 2 other comparable series. There were no differences in the autoantibody profiles of the 2 groups.


Reproductive function prior to disease onset in women with scleroderma.

We tested in a retrospective study the hypothesis that women with scleroderma have an increased risk, before disease presentation, of problems in pregnancy. Reproductive history, as reported from a validated postal questionnaire, was obtained from 204 women with scleroderma [mean year of birth (yob) 1942] and compared to that reported by 233 women with primary Raynaud's phenomenon (mean yob 1948) and 189 healthy women from a population register (mean yob 1950). Only pregnancies occurring before symptom onset in the scleroderma group were considered for analysis. All analyses were adjusted for job, social class, age at first pregnancy, smoking habit, and where relevant, parity. The results are expressed as odds ratios (OR) [with 95% confidence limits (CL)] giving the risk of developing scleroderma, with previous exposure to each of the specific reproductive variables analyzed, relative to the 2 comparison groups. The women with scleroderma were more likely than the population women to have had a delay in conception (> or = 12 months): OR 2.6 (1.1, 5.7) or be infertile: OR 2.3 (0.7, 7.2). These differences were not apparent when the scleroderma group was compared to the women with Raynaud's: OR's 0.7 and 1.1, respectively. Similarly there was a greater self report of maternal ill health in pregnancy in the group with scleroderma compared to the population women: OR 2.1 (1.2, 3.5) but not compared to the women with Raynaud's: OR 1.0 (0.7, 1.6).(ABSTRACT TRUNCATED AT 250 WORDS)


Subcutaneous bursitis in scleroderma.

We encountered 3 types of subcutaneous bursitis in our patients with scleroderma: dry bursitis characterized by a rub, sterile bursitis characterized by inflammatory effusions without crystals by polarizing microscopy, and septic (staphylococcal) subcutaneous bursitis. The latter, which occurred in 6 of 40 consecutive patients, had a protracted course, was often complicated by fistulas, and tended to involve several bursae particularly in patients with extensive calcinosis.


The prevalence of ankylosing spondylitis among Norwegian Samis (Lapps).

A population survey of the Sami (Lapp) population of the municipalities Karasjok and Kautokeino in north Norway revealed a prevalence of ankylosing spondylitis (AS) according to the New York criteria of 1.8%. Eleven cases of AS were found, 7 men and 4 women. Only 4 of the 11 observed cases of AS were aware of the diagnosis of AS prior to the survey. Ten of 11 patients with AS possessed HLA-B27 (91%) which is found in 24% of the general Sami population in this area. It was calculated that 6.8% of B27 positive persons had AS.