Dopamine antagonists reduce spontaneous electrical activity in cultured mammalian neurons from ventral mesencephalon

Mammalian neurons from ventral mesencephalon (VM) were grown in primary dissociated cell (PDC) culture. These neurons are predominantly non-dopaminergic. Many of these non-dopaminergic neurons have dopamine agonist and antagonist binding sites. Intracellular recordings were obtained from these neurons. When bathed in phosphate-buffered saline (PBS) solution they generated action potentials spontaneously. However, in the presence of haloperidol dissolved in PBS solution, the percentage of neurons which generated action potentials spontaneously was reduced in a dose-dependent manner (1–10 μM). This response was also obtained with (+) butaclamol (1 μM) but not with (−) butaclamol (1 μM). This neuroleptic inhibition of spontaneously generated action potentials was specific for neurons in PDC cultures of VM since neurons in PDC cultures of spinal cord did not demonstrate this phenomenon.     

Disorders of thermoregulation in adaptation to external cold and heat stimuli in patients with atopic eczema

Patients suffering from atopic eczema (AE) often exhibit disturbances of various neurovegetative (in particular, vasomotoric) skin functions. Thus, in 21 patients with AE we studied the response of the skin of one forearm to standardized 15-min exposure of the other arm to a cold and a warm bath (17 degrees-18 degrees C and 40 degrees-41 degrees C respectively). The results were compared with those in 23 age- and sex-matched healthy controls under similar environmental conditions. In most patients, during exposure of one forearm to warmth the skin temperature of the contralateral forearm remained unchanged or decreased slightly, whereas exposure to cold induced either a slight rise in skin temperature or an almost indiscernible decrease. In contrast to the normal temperature reaction of the non-exposed forearm to warmth exposure of the contralateral arm in most controls, our findings in atopic patients indicated a "rigid" or even "paradoxical" response to thermic stimuli. This abnormal pattern of thermoregulation may reflect an intrinsic disturbance of the peripheral and hypothalamic autonomous system involved in the pathogenetic conditions of AE.     

Anti-P30 IgA antibodies as prenatal markers of congenital toxoplasma infection

This study extends a previous study and confirms that the detection of anti-P30 IgA antibodies is very helpful in the diagnosis of acute acquired or congenital toxoplasmosis. Moreover, we demonstrate that an anti-P30 IgA response can be mounted in the fetuses infected by Toxoplasma gondii during their intra-uterine life as early as week 23 of gestation. A double-sandwich ELISA described in our previous work was used to detect anti-P30 IgA antibodies in 1378 human serum samples collected from 551 patients, including 162 fetuses whose mothers had been infected by T. gondii during pregnancy, 46 congenitally infected and 90 uninfected newborns and 253 women suspected of having been infected during pregnancy, including the mothers of fetuses and newborns previously described. Anti-P30 IgA antibodies were detected in all cases of acute toxoplasmosis but in no case of chronic toxoplasmosis: in the majority of cases, the IgA antibody titre fell below cut-off in 3-9 months. Among the 46 congenitally infected newborns, anti-P30 IgA antibodies were detected in sera of 41 infected newborns (38 at birth, two in the first months of life, one in the seventh month of life), while anti-P30 IgM antibodies were detected in only 30 cases at birth and in one case during the first month of life. Among 162 fetuses, anti-P30 IgA response was observed in five infected fetuses, but was not detected in either 152 uninfected fetuses or in five fetuses considered as infected. The absence or presence of anti-P30 IgA antibodies in the fetus is discussed in relation to the date of maternal infection and collection of the fetal blood. It clearly appears from our study that the combined testing of both IgM and IgA in the fetus and the newborn is essential for a more efficient diagnosis of infection.     

Role of the Salmonella pathogenicity island 1 effector proteins SipA, SopB, SopE, and SopE2 in Salmonella enterica subspecies 1 serovar Typhimurium colitis in streptomycin-pretreated mice

Salmonella enterica subspecies 1 serovar Typhimurium (serovar Typhimurium) induces enterocolitis in humans and cattle. The mechanisms of enteric salmonellosis have been studied most extensively in calf infection models. The previous studies established that effector protein translocation into host cells via the Salmonella pathogenicity island 1 (SPI-1) type III secretion system (TTSS) is of central importance in serovar Typhimurium enterocolitis. We recently found that orally streptomycin-pretreated mice provide an alternative model for serovar Typhimurium colitis. In this model the SPI-1 TTSS also plays a key role in the elicitation of intestinal inflammation. However, whether intestinal inflammation in calves and intestinal inflammation in streptomycin-pretreated mice are induced by the same SPI-1 effector proteins is still unclear. Therefore, we analyzed the role of the SPI-1 effector proteins SopB/SigD, SopE, SopE2, and SipA/SspA in elicitation of intestinal inflammation in the murine model. We found that sipA, sopE, and, to a lesser degree, sopE2 contribute to murine colitis, but we could not assign an inflammation phenotype to sopB. These findings are in line with previous studies performed with orally infected calves. Extending these observations, we demonstrated that in addition to SipA, SopE and SopE2 can induce intestinal inflammation independent of each other and in the absence of SopB. In conclusion, our data corroborate the finding that streptomycin-pretreated mice provide a useful model for studying the molecular mechanisms of serovar Typhimurium colitis and are an important starting point for analysis of the molecular events triggered by SopE, SopE2, and SipA in vivo.     

Properties of a facilitating calcium current in pace-maker neurones of the snail, Helix pomatia.

1. Simultaneous measurements of local voltage clamp currents from patches of soma membrane and K activity at the soma surface were used to analyse the time and voltage dependence of the slow inward current in bursting pace-maker neurones of the snail (Helix pomatia). 2. At low levels of depolarization (less than or equal to mV) a net inward current is recorded simultaneously with an efflux of K ions from the cell. 3. With larger depolarizations (20-170 mV from holding potential of -50 mV) the deficit in net outward charge transfer compared with K efflux and the appearance of inward-going tail currents following repolarization, reveal a persistent inward-going current also under these conditions. This inward current is carried primarily by Ca ions, as demonstrated by its voltage dependence (a minimum at about + 115 mV) and its disappearance in Co-Ringer. It is identified with the slow inward Ca current Iin slow (Eckert & Lux, 1976). 4. The inward current predicted from comparisons of current trajectories reaches a maximum at 15-20 msec (for depolarizations from -50 to 0 mV) and gradually declines with sustained depolarization. 5. Partial inactivation is removed by repolarization to -50 mV and the Ca dependent deficit is greater in the sum of repeated voltage clamp pulses than during sustained depolarization. It is largest for pulses of 25-100 msec duration, decreasing as pulse duration increases. 6. Responses to repeated activation with 100 msec pulses with different repolarization intervals reveal a minimum Iin slow at short intervals (e.g. 20 msec) due to failure to remove partial inactivation. At intermediate intervals (e.g. 200-400 msec) Iin slow shows facilitation. This is revealed in calculations of the net charge transfer and current deficits and is also shown in the tail currents following repolarization. The deficit increases progressively with repetitive stimulation. With longer intervals (e.g. 800-1000 msec) defacilitation during repeated stimulation after the first two pulses is revealed in calculations of deficits, current trajectories and in the tail currents. 7. Although facilitation depends on duration of repolarization between pulses, increasing intermediate hyperpolarizations from the holding potential of -50 mV are usually ineffective in increasing Iin slow. Strong preceding hyperpolarization can even decrease the magnitude of Iin slow and prevent its facilitation with repetitive stimulation,whereas preceding depolarizing pulses can increase Iin slow without preventing its facilitation with repetitive stimulation. 8. The properties of Iin slow are contrasted with previously described membrane conductances and compared with properties attributed to Ca fluxes in other systems.     

Respiratory mortality among firefighters.

Although firefighters have been shown in some studies to suffer chronic respiratory morbidity from their occupational exposures, an increased risk for dying from non-malignant respiratory diseases has not been documented in any previous retrospective cohort mortality study. In order to assess the possibility that an unusually strong "healthy worker effect" among firefighters might mask this increased risk, a mortality analysis of firefighters was carried out in three cities in relation to the United States population and also to a comparison cohort of police officers. The firefighters were employed between 1945 and 1980 and experienced 886 deaths by 1 January 1984; compared with the United States population they had a significantly reduced risk of dying from all causes (SMR = 82, 95% confidence interval, 77-87), and from non-malignant circulatory diseases (SMR = 81, 95% confidence interval 73-89), but no significant difference in risk of non-malignant respiratory diseases (SMR = 88, 95% confidence interval 66-117). Compared with police, the firefighters experienced a trend toward improved mortality outcomes for all causes investigated (SMR = 82), but they had an excess of deaths from non-malignant respiratory diseases (SMR = 141). The results indicate that firefighters are probably at increased risk for dying from non-malignant respiratory diseases; this increased risk may have been missed in previous studies because of the limitations of using a general reference population.     

A genealogical study of Alzheimer disease in the Saguenay region of Quebec

We performed an analysis of inbreeding and kinship among the ascending genealogies of 205 autopsy-confirmed Alzheimer disease (AD) subjects recruited in the Saguenay area of Québec. We hypothesized that if some traits pertaining to the disease were determined by inherited factors, and if the corresponding genes were not too frequent in the population, it might be possible to detect some clusters of patients related to common ancestors and presenting a level of kinship and/or inbreeding higher than is observed in the unaffected population of the same age. In view of the heterogeneity of the disease, we also verified if some of the factors investigated could be associated more specifically with subsets of cases based on age of onset and on apolipoprotein E (APOE) genotype. Results were compared with those obtained on 205 controls matched for gender, place and year of birth. We found that late-onset AD cases with an APOE-epsilon 4 were significantly more inbred than controls and that this increase was explained by the high level of inbreeding of a few cases whose parents were related at the first-cousin level. This could possibly indicate the implication of a recessive element in a small subset of AD cases in the Saguenay population. We also found that late-onset epsilon 4+ cases were significantly more closely related among themselves than with controls. This increase in kinship may be attributable to the presence of the epsilon 4 allele or to some other unidentified genetic factor possibly acting in conjunction with APOE-epsilon 4.     

Effects of systemic treatment with irbesartan and losartan on central responses to angiotensin II in conscious, normotensive rats

Angiotensin AT1 receptor antagonists represent a novel class of cardiovascular drugs. In conscious, normotensive rats, irbesartan ((2-n-butyl-3-[(2'-(1H-tetrazol-5-yl)-biphenyl-4-yl) methyl]-1,3-diaza-spiro[4,4]non) and losartan ((2 n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl -4-yl) methyl] imidazol), two specific, high- affinity angiotensin AT1 receptor antagonists administered intravenously (i.v.) at doses of 0.3, 1, 3 and 10 mg/kg body weight, or orally (p.o.) at doses of 1, 3, 10 and 30 mg/kg body weight, antagonized the pressor responses to i.v. angiotensin II (50 ng/kg body weight) in a dose-related manner and with similar potency. In the following sets of experiments, we tested the hypothesis that these angiotensin AT1 receptor antagonists, when applied systemically, can inhibit the effects of angiotensin AT1 receptor stimulation in the brain. Irbesartan and losartan were administered i.v. or p.o. at doses of 3, 10, 30 and 100 mg/kg body weight. The responses to 100 ng angiotensin II injected into the lateral brain ventricle (i.c.v.), namely blood pressure increase, vasopressin release into the circulation and drinking, were recorded for up to 3 h. While both angiotensin AT1 receptor antagonists dose-dependently attenuated the pressor responses to central angiotensin AT1 receptor stimulation to a similar degree (maximal inhibition, irbesartan: 62% i.v., 39% p.o.; losartan: 62% i.v., 46% p.o.; respectively), irbesartan was more effective with respect to the inhibition of vasopressin release (76% i.v., 65% p.o.) and drinking (63% i.v., 79% p.o.) than losartan (58% i.v., 33% p.o and 22% i.v., 56% p.o., respectively). We conclude that systemically administered angiotensin AT1 receptor antagonists have access to central angiotensin receptors. The degree of central angiotensin AT1 receptor blockade following peripheral application may vary between different representatives of this class of drugs.