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PubMed1996

Autoantibodies following parvovirus B19 infection.

This study was undertaken to assess the incidence and significance of autoantibody production following B19 infection, 53 patients with acute B19 infection (positive for serum anti-B19 IgM) were studied; symptoms were rash and arthralgia (n = 26), rash (n = 7), arthralgia (n = 16), aplastic crisis (n = 3), and intrauterine death (n = 1). These patients were followed for 26-85 months (mean 57 months) and re-assessed for persistent symptoms, serum anti-B19 antibodies, and serum autoantibodies. At follow-up, 14 test and two control patients had one or more serum autoantibodies (anti-nuclear antibody, anti-smooth muscle antibody, gastric parietal cell antibody, anti-reticulin antibody, anti-mitochondrial antibody, rheumatoid factor) at a titre of > or = 40 (P = 0.004). Seven test patients and no control patients had serum autoantibody at a titre > or = 160. Of these seven test patients, only one had persistent symptoms. At follow-up assessment, this woman was 48-year-old, had persistent arthralgia for 4 years following acute B19 infection, rheumatoid factor at a titre of 160 (1920 IU/ml), and had been independently diagnosed as having rheumatoid arthritis. In conclusion, results of the present study showed that low titre autoantibody production was common following symptomatic B19 infection, however, while interesting from a virological standpoint, this finding may be of little significance for future development of autoimmune disease.

Adolescent↗
PubMed1999

High-affinity [3H] kainic acid binding to brain membranes: a re-evaluation of ligand potency and selectivity.

[3H]Kainic acid ([3H]KA) is a widely used tool for studying the KA class of excitatory amino acid receptors. [3H]KA of significantly higher specific activity has become available permitting use of radioligand concentrations below the dissociation constant (K(D)) of the high-affinity binding site. We employed low radioligand (0.05-0.2 nM) and receptor concentrations (0.01 nM) to gain new insights into the binding characteristics of the high-affinity KA binding site in a standard preparation of lyzed synaptosomal membranes from the cerebral cortex of male Sprague-Dawley rats. Under these conditions, KA binds to a single class of high-affinity sites with a K(D) of 1.0+/- 0.3 nM. The potencies of competing agents are considerably higher than published reports. Specifically, domoic acid, glutamate, and glutamine exhibit IC(50) values for displacing [3H]KA of 0.37+/-0.02, 94+/-13, and 1500+/-500 nM, respectively. Domoate (1 microM) was tested against a panel of 32 central nervous system binding sites and found to be inactive at each, indicating this toxin displays considerable selectivity. This study illustrates the remarkable potency of domoic acid and underlines the importance of performing radioligand binding studies at concentrations of constituents that permit characterization of high-affinity interactions.

Animals↗
PubMed2003

Modulation of specific beta cell gene (re)expression during in vitro expansion of human pancreatic islet cells.

The need for transplantable beta cells with a stable phenotype has given rise to several strategies including the expansion of existing pancreatic islets and/or growth of new ones. In vitro studies of beta cell proliferation on extracellular matrices plus growth factors have highlighted a possible cell expansion technique; however, the technique was accompanied with loss of insulin secretion. Herein we showed that human islet cell proliferation was marked by a decreased expression of specific differentiation markers, particularly insulin, insulin promoting factor-1 (IPF-1), and glucokinase. After a 6-day expansion period, we tried to reexpress the beta cell differentiation markers with compounds known for their differentiation and/or insulin-secreting properties. Sodium butyrate was a potent factor of IPF-1, insulin, and glucokinase gene reexpression; it also clearly induced secretion of gastrin, a known neogenic factor. Other compounds, namely TGF-beta, calcitriol, GLP-1, and activin A, efficiently enhanced the glucose sensor machinery, particularly Glut-1 and glucokinase, thus triggering glucose responsiveness. Our results indicate that specific beta cell gene expression may be induced after expansion and dedifferentiation. This rekindles interest in human beta cell expansion. The possible stabilization of specialized genes needed by beta cells to fulfill their role as nutrient sensors and metabolic regulators may also be of interest to ensure graft maintenance and efficiency.

Cell Differentiation↗
PubMed1999

Pharmacological re-evaluation of a GABA(B) receptor antagonist CGP 47332A in rat brain.

In rat neocortical slices maintained in Mg(2+)-free Krebs medium, the gamma-aminobutyric acid (GABA(B)) receptor agonist baclofen concentration-dependently depressed the frequency of spontaneous discharges (EC(50)=12 microM). This was reversibly antagonised by (R, S)-3-amino-2-hydroxy-propyl-P-n-butyl-phosphinic acid (CGP 47332A) (25, 100, 300 microM) which produced rightwards shifts of the baclofen concentration-response curves (pA(2) value=4.8+/-0.1). In electrically stimulated slices preloaded with [3H]GABA, CGP 47332A increased its release (EC(150)=100 microM) through antagonism of GABA(B) autoreceptors. Although CGP 47332A was some six times weaker on GABA(B) auto- than on heteroreceptors, yet its congener lacking the beta-hydroxy substituent displays equal potency in both binding (IC(50)=38 microM) and GABA(B) autoreceptor functional studies (EC(150)=38 microM) as previously reported [Froestl, W., Mickel, S.J. , Von Sprecher, G., Diel, P.J., Hall, R.G., Maier, L., Strub, D., Melillo, V., Baumann, P.A., Bernasconi, R., Gentsch, C., Hauser, K., Jaekel, J., Karlsson, G., Klebs, K., Maitre, L., Marescaux, C., Pozza, M.F., Schmutz, M., Steinmann, M.W., Van Riezen, H., Vassout, A., Mondadori, C., Olpe, H.R., Waldmeier, P.C., Bittiger, H., Phosphinic acid analogues of GABA: 2. Selective, orally active GABA(B) antagonists. J. Med. Chem. 38 (1995) 3313-3331.].

Animals↗
PubMed2000

Differences in the calcium-handling response of isolated rat and guinea-pig cardiomyocytes to metabolic inhibition: implications for cell damage.

Species differences in response to hypoxic damage have been observed in studies using whole hearts. The aims of this study were to determine whether (i) species differences in response to simulated hypoxia could be detected at the level of the single myocyte, and (ii) there were any interspecies differences in the Ca2+ handling properties of the cells. Ventricular myocytes were isolated from hearts of adult rats and guinea-pigs and electrically stimulated on the stage of a fluorescence microscope. Cell length was measured using an edge-tracking device, and total intracellular [Ca2+] ([Ca2+]i) determined using indo-1. Cells were exposed to metabolic inhibition (MI) (2.5 mM NaCN and no glucose) to simulate hypoxia followed by washout of CN and re-addition of glucose ('reperfusion'). Following exposure to MI, rat cells underwent rigor contracture in 18.8+/-0.8 min (n = 80 cells), whereas the time was longer for guinea-pig cells (32.9+/-1.2 min, n = 83) (P<0.001). If cells were reperfused after 1-5 min in rigor, then rat cells showed improved morphological recovery compared with guinea-pig cells (P< 0.05); thereafter recovery decreased with increasing time spent in rigor, and was similar in both groups. In indo-1 loaded cells, [Ca2+]i was significantly increased in cells from both species at the end of MI; however, the actual increase was much higher in guinea-pig cells. Upon reperfusion, [Ca2+]i recovered fully in rat cells, but in guinea-pig cells there was no significant decrease. The restoration of [Ca2+]i to normal levels in rat cells following MI was associated with improved contractile recovery compared with guinea-pig cells. We conclude that rat cells are more resistant to effects of MI than are guinea-pig cells; this may be related to species differences in Ca2+ handling during and following exposure to MI.

Animals↗
PubMed1995

Parvovirus B19 infection--persistence and genetic variation.

53 patients with acute B19 infection were studied; symptoms at acute infection were rash and arthralgia (n = 26), rash (n = 7), arthralgia (n = 16), aplastic crisis (n = 3), and intrauterine fetal death (n = 1). These patients were followed for 26-85 months (mean 57 months) and re-assessed for persistent symptoms, anti-B19 antibodies, and B19 DNA. At follow-up, 7 individuals were positive for serum B19 DNA, compared with none of the controls (2-tailed p value = 0.016). All 7 of those persistently infected were women, 3 of whom had symptoms; 1 had a chronic haemolytic anaemia (initial presentation was aplastic crisis); 1 had persistent arthralgia in both knees (initial presentation was bilateral knee arthralgia); and 1 had arthralgia in one knee and chronic fatigue syndrome (initial presentation was bilateral arthralgia in knees and shoulders). For the 7 persistently infected patients, serum from the time of diagnosis of acute B19 infection was available for 4, all of which contained B19 DNA. With single-stranded conformational polymorphism (SSCP) assay of these 11 PCR products, identical SSCP types were demonstrated in 5 of 7 follow-up isolates. In 2 of the 4 cases for which both acute and follow-up PCR product was available, the SSCP type of the follow-up product was different from that of the acute product. Two B19 virus types were demonstrated in one patient (with persistent arthralgia and chronic fatigue syndrome) at follow-up assessment.

Adolescent↗
PubMedDate not supplied

Chronobiologic quantification of nocturnal low-dose dopamine effect on circadian rhythms of thyroid-related hormones and prolactin (PRL).

Six clinically-healthy young men provided plasma samples every 30 min for 24 h (from 09:00-09:00 on 2 occasions. TSH, free T3 and free T4 were determined in the 30-min samples, while prolactin was determined in samples 1-3h apart. During the first test span, each man received an infusion of physiologic saline between 21(00)-01(00). Upon re-sampling several weeks later, 3 men received a low dose of dopamine (0.1 microgram/kg/min) and 3 men received a high dose (1.0 microgram) over the same hours (21:00-01:00). The least-squares fit of a 24-h cosine to each data series described a statistically-significant circadian rhythm (p less than 0.01) for each subject on each day of study. While overall group comparisons revealed no significant difference in mesor for any hormone studied, some intra-individual differences in rhythm parameters between saline and dopamine infusion were found. Dopamine Rx produced a statistically-significant increase in amplitude for PRL and T4 and an advance in acrophase for TSH, T3 and T4, but a delay for PRL. Studies measuring hormones of interest for the 24th immediately preceding and the 24th immediately following dopamine infusion at varying circadian stages (rather than only between 21:00-01:00) are warranted and have to be individualized--one of the points of this paper. The other main point is that data reduction to a mean and a standard deviation entails loss of information that can be recovered by chronobiologic methods, here used only as a model, in view of the limitations of the sampling design on hand.

Circadian Rhythm↗
PubMed2006

The effect of hypovolemia due to hemorrhage on the minimum alveolar concentration of isoflurane in the dog.

OBJECTIVE: To determine the effect of hypovolemia on the minimum alveolar concentration (MAC) of isoflurane in the dog. STUDY DESIGN: Randomized, cross-over trial. ANIMAL POPULATION: Six healthy intact mixed breed female dogs weighing 18.2-29.0 kg. METHODS: Dogs were randomly assigned to determine the MAC of isoflurane in a normovolemic or hypovolemic state with a minimum of 18 days between trials. On both occasions, anesthesia was initially induced and maintained for 40 minutes with isoflurane delivered in oxygen while vascular catheters were placed in the cephalic vein and dorsal metatarsal artery. In dogs assigned to the hypovolemic group, 30 mL kg(-1) of blood was removed at 1 mL kg(-1) minute(-1) from the arterial catheter. All dogs were allowed to recover from anesthesia. Thirty minutes after the discontinuation of isoflurane, anesthesia was re-induced with isoflurane in oxygen delivered by face mask. The tracheas were intubated, and connected to an anesthetic machine with a Bain anesthetic circuit. Mechanical ventilation was instituted at a rate of 10 breaths minute(-1) with the tidal volume set to deliver 10-15 mL kg(-1). Airway gases were monitored continuously and tidal volume was adjusted to maintain an end-tidal carbon dioxide level of 35-40 mmHg (4.67-5.33 kPa). Body temperature was maintained at 37-38 degrees C (98.6-100.4 degrees F). The MAC determination was performed using an electrical stimulus applied to the toe web and MAC was defined as the mean value of end-tidal isoflurane between the concentrations at which a purposeful movement did and did not occur in response to the electrical stimulus. The MAC values were compared between groups using a Student's t-test. RESULTS: The MAC of isoflurane was significantly less in hypovolemic dogs (0.97 +/- 0.03%) compared with normovolemic dogs (1.15 +/- 0.02%) (p < 0.0079). CONCLUSIONS AND CLINICAL RELEVANCE: The MAC of isoflurane is reduced in dogs with hypovolemia resulting from hemorrhage. Veterinarians should be prepared to deliver a lower percentage of isoflurane to maintain anesthesia in hypovolemic dogs during diagnostic and therapeutic procedures.

Anesthesia, Inhalation↗
PubMed2001

Enduring resistance to extinction of cocaine-seeking behavior induced by drug-related cues.

The conditioning of cocaine's pharmacological actions with environmental stimuli is thought to be a critical factor in long-lasting relapse risk associated with cocaine addiction. To study the significance of environmental stimuli in enduring vulnerability to relapse, the resistance to extinction of drug-seeking behavior elicited by a cocaine-related stimulus was examined. Male Wistar rats were trained to associate discriminative stimuli (S(D)) with the availability of intravenous cocaine (S(+)) vs. the availability of non-rewarding (S(-)) saline solution, and then placed on extinction conditions during which intravenous solutions and S(D) were withheld. The rats were then presented with the S(+) or S(-) alone in 60-min reinstatement sessions conducted at 3-day intervals. To examine the long-term persistence of the motivating effects of the cocaine S(+), a subgroup of rats was re-tested following an additional three months of abstinence during which time the rats remained confined to their home cages. Re-exposure to the cocaine S(+) selectively elicited robust responding at the previously active lever. The efficacy and selectivity of this stimulus to elicit responding remained unaltered throughout a 34-day phase of repeated testing as well as following the additional extended abstinence period. In pharmacological tests, conducted in a separate group of rats, the dopamine (DA) D(1) antagonist SCH 39166 (10 microg/kg), the D(2/3) antagonist nafadotride (1 mg/kg), and the D(2/3) agonist PD 128907 (0.3 mg/kg) suppressed the cue-induced response reinstatement while the D(1) agonist SKF 81297 (1.0 mg/kg) produced a variable behavioral profile attenuating cue-induced responding in some rats while exacerbating this behavior in others. The results suggest that the motivating effects of cocaine-related stimuli are highly resistant to extinction. The undiminished efficacy of the cocaine S(+) to induce drug-seeking behavior both with repeated testing and following long-term abstinence parallels the long-lasting nature of conditioned cue reactivity and cue-induced cocaine craving in humans, and confirms a significant role of learning factors in long-lasting vulnerability to relapse associated with cocaine addiction. Finally, the results support a role of DA neurotransmission in cue-induced cocaine-seeking behavior.

Amygdala↗
PubMed2006

The missing Madagascan mid-domain effect.

Species richness varies enormously across geographical gradients, a well-known phenomenon for which there are many hypothesized explanations. One recent hypothesis uses null models to demonstrate that random re-distribution of species' ranges within a given domain leads to a 'mid-domain effect' (MDE): increasing species richness towards the centre of the area. Madagascar is especially well-suited for empirical evaluation of mid-domain models by virtue of its large endemic fauna and its clearly defined boundaries. Lees et al. [Biol. J. Linn. Soc.67 (1999) 529] observed patterns of species richness consistent with MDEs in the Madagascan rainforest (a slim, north-south belt). In this study, we test one-dimensional and two-dimensional mid-domain model predictions for the birds and mammals of the entire island of Madagascar. When only latitudinal extents of species' distribution are considered, patterns of richness in Madagascar show an MDE. However, this pattern disappears for both taxa after accounting for the tendency of latitudinal bands nearer the middle of the country to be larger. Two-dimensional mid-domain model predictions of species richness are qualitatively opposite to observed patterns. Instead, island-wide spatial gradients of species richness in Madagascar relate strongly to patterns of primary productivity and amount of remaining natural habitat. Earlier work that showed a mid-domain peak within the rainforest biome (effectively after controlling for climate and natural habitat) seems likely to have reflected methodological artefacts. The classic case in which MDEs should occur is, in fact, inconsistent with the mid-domain hypothesis.

Animals↗
PubMed2003

CB 1954: from the Walker tumor to NQO2 and VDEPT.

CB 1954 [5-(aziridin-1-yl)-2,4-dinitrobenzamide] has been the subject of continued interest for over 30 years. As an anti-cancer agent, it represents one of the very few examples of a compound that shows real anti-tumor selectivity. Unfortunately, for the treatment of human disease, this anti-tumor selectivity was seen only in certain rat tumors. The basis for the anti-tumor selectivity of CB 1954 is that it is a prodrug that is enzymatically activated to generate a difunctional agent, which can form DNA-DNA interstrand crosslinks. The bioactivation of CB 1954 in rat cells involves the aerobic reduction of its 4-nitro group to a 4-hydroxylamine by the enzyme NQO1 (DT-diaphorase). The human form of NQO1 metabolizes CB 1954 much less efficiently than rat NQO1. Thus human tumors are insensitive to CB 1954. In view of the proven success of CB 1954 in the rat system, it would be highly desirable to re-create its anti-tumor activity in man. This has led to the development of CB 1954 analogs and other prodrugs activated by nitroreduction such, as those based on a self-immolative activation mechanism. A gene therapy-based approach for targeting cancer cells and making them sensitive to CB 1954 and related compounds has been developed. VDEPT (gene-directed enzyme prodrug therapy) has been used to express an E. coli nitroreductase in tumor cells and human tumor cells transduced to express this enzyme are very sensitive to prodrugs activated by nitroreduction. CB 1954 is in clinical trial for this application. Recently it has been shown that a latent nitroreductase is present in some human tumors. This is NQO2--an enzyme that requires for activity, the non-biogenic compound dihydronicotinamide riboside (NRH) as a cosubstrate. When active, NQO2 is 3000 times more effective than human DT-diaphorase in the reduction of CB 1954. NRH and reduced pyridinium derivatives that, like NRH, act as co-substrates for NQO2, produce a dramatic increase in the cytotoxicity of CB 1954 against human cell lines in vitro and its anti-tumor activity against certain human xenografts in vivo. NQO2 activity is substantially raised in tumor samples from colorectal and hepatoma patients (up to 14-fold). A phase I clinical trial of an NQO2 co-substrate with CB 1954 is scheduled.

Animals↗
PubMed2006

Primary care staff's views and experiences related to routinely advising patients about physical activity. A questionnaire survey.

BACKGROUND: United Kingdom public health policy has recently re-emphasised the role of primary health care professionals in tackling increasing levels of physical inactivity within the general population. However, little is known about the impact that this has had in practice. This study explores Scottish primary care staff's knowledge, attitudes and experiences associated with advising patients about physical activity during routine consultations. METHODS: A cross-sectional questionnaire survey of general practitioners (or family physicians), practice nurses and health visitors based in four health regions was conducted during 2004. The main outcome measures included: (i) health professionals' knowledge of the current physical activity recommendations; (ii) practice related to routine physical activity advising; and (iii) associated attitudes. RESULTS: Questionnaires were returned by 757 primary care staff (response rate 54%). Confidence and enthusiasm for giving advice was generally high, but knowledge of current physical activity recommendations was low. In general, respondents indicated that they routinely discuss and advise patients about physical activity regardless of the presenting condition. Health visitors and practice nurses were more likely than general practitioners to offer routine advice. Lack of time and resources were more likely to be reported as barriers to routine advising by general practitioners than other professional groups. However, health visitors and practice nurses were also more likely than general practitioners to believe that patients would follow their physical activity advice giving. CONCLUSION: If primary health care staff are to be fully motivated and effective in encouraging and supporting the general population to become more physically active, policymakers and health professionals need to engage in efforts to: (1) improve knowledge of current physical activity recommendations and population trends amongst frontline primary care staff; and (2) consider the development of tools to support individual assessment and advice giving to suit individual circumstances. Despite the fact that this study found that system barriers to routine advising were less of a problem than other previous research has indicated, this issue still remains a challenge.

Adult↗