CB2 receptors regulate natural killer cells that limit allergic airway inflammation in a murine model of asthma.

BACKGROUND: Allergic asthma is a chronic airway inflammatory disease involving the complementary actions of innate and adaptive immune responses. Endogenously generated cannabinoids acting via CB2 receptors play important roles in both homeostatic and inflammatory processes. However, the contribution of CB2-acting eicosanoids to the innate events preceding sensitization to the common house dust mite (HDM) allergen remains to be elucidated. We investigated the role of CB2 activation during allergen-induced pulmonary inflammation and natural killer (NK) cell effector function. METHODS: Lung mucosal responses in CB2-deficient (CB2-/- ) mice were examined and compared with wild-type (WT) littermates following intranasal exposure to HDM allergen. RESULTS: Mice lacking CB2 receptors exhibited elevated numbers of pulmonary NK cells yet were resistant to the induction of allergic inflammation exemplified by diminished airway eosinophilia, type 2 cytokine production and mucus secretion after allergen inhalation. This phenomenon was corroborated when WT mice were treated with a CB2-specific antagonist that caused a pronounced inhibition of HDM-induced airway inflammation and goblet cell hyperplasia. Unexpectedly, the preponderance of NK cells in the lungs of CB2-/- mice correlated with reduced numbers of group 2 innate lymphoid cells (ILC2s). Depletion of NK cells restored the allergen responsiveness in the lungs and was associated with elevated ILC2 numbers. CONCLUSIONS: Collectively, these results reveal that CB2 activation is crucial in regulating pulmonary NK cell function, and suggest that NK cells serve to limit ILC2 activation and subsequent allergic airway inflammation. CB2 inhibition may present an important target to modulate NK cell response during pulmonary inflammation.

Effect of NGF on the subcellular localization of group IIA secretory phospholipase A(2) (GIIA) in PC12 cells: role in neuritogenesis.

Phospholipases A(2) (PLA(2)s) are involved in neuritogenesis but the identity of the isoforms(s) contributing to this process is still not defined. Several reports have focused on secretory PLA(2)s (sPLA(2)) as the administration of exogenous sPLA(2)s to PC12 neuronal cells stimulates neurite outgrowth. The present study demonstrates that the endogenous group IIA sPLA(2) (GIIA), constitutively expressed in mammalian neural cells, changes its subcellular localization when PC12 cells are induced to differentiate by NGF treatment. Indeed, confocal analysis showed a time-dependent accumulation of GIIA in growth cones and neurite tips. Under identical conditions the subcellular distribution of another isoform (GV) was unaffected by NGF. Contrary to GX, another sPLA(2) isoform expressed by PC12 cells, the contribution of GIIA to neuritogenesis does not require its release in the extracellular medium.

Differential regulation of prohormone convertase 1/3, prohormone convertase 2 and phosphorylated cyclic-AMP-response element binding protein by short-term and long-term morphine treatment: implications for understanding the "switch" to opiate addiction.

Drug addiction is a state of altered brain reward and self-regulation mediated by both neurotransmitter and hormonal systems. Although an organism's internal system attempts to maintain homeostasis when challenged by exogenous opiates and other drugs of abuse, it eventually fails, resulting in the transition from drug use to drug abuse. We propose that the attempted maintenance of hormonal homeostasis is achieved, in part, through alterations in levels of processing enzymes that control the ratio of active hormone to pro-hormone. Two pro-hormone convertases, PC1/3 and PC2 are believed to be responsible for the activation of many neurohormones and expression of these enzymes is dependent on the presence of a cyclic-AMP response element (CRE) in their promoters. Therefore, we studied the effects of short-term (24-h) and long-term (7-day) morphine treatment on the expression of hypothalamic PC1/3 and PC2 and levels of phosphorylated cyclic-AMP-response element binding protein (P-CREB). While short-term morphine exposure down-regulated, long-term morphine exposure up-regulated P-CREB, PC1/3 and PC2 protein levels in the rat hypothalamus as determined by Western blot analysis. Quantitative immunofluorescence studies confirmed these regulatory actions of morphine in the paraventricular and dorsomedial nucleus of the hypothalamus. Specific radioimmunoassays demonstrated that the increase in PC1/3 and PC2 levels following long-term morphine led to increased TRH biosynthesis as evidence by increased TRH/5.4 kDa C-terminal proTRH-derived peptide ratios in the median eminence. Promoter activity experiments in rat somatomammotrope GH3 cells containing the mu-opioid receptor demonstrated that the CRE(s) in the promoter of PC1/3 and PC2 is required for morphine-induced regulation of PC1/3 and PC2. Our data suggest that the regulation of the prohormone processing system by morphine may lead to alterations in the levels of multiple bioactive hormones and may be a compensatory mechanism whereby the organism tries to restore its homeostatic hormonal milieu. The down-regulation of PC1/3, PC2 and P-CREB by short-term morphine and up-regulation by long-term morphine treatment may be a signal mediating the switch from drug use to drug abuse.

In vivo and in vitro bisphenol A exposure effects on adiposity.

In utero exposure to the ubiquitous plasticizer, bisphenol A (BPA) is associated with offspring obesity. As adipogenesis is a critical factor contributing to obesity, we determined the effects of in vivo maternal BPA and in vitro BPA exposure on newborn adipose tissue at the stem-cell level. For in vivo studies, female rats received BPA before and during pregnancy and lactation via drinking water, and offspring were studied for measures of adiposity signals. For in vitro BPA exposure, primary pre-adipocyte cell cultures from healthy newborns were utilized. We studied pre-adipocyte proliferative and differentiation effects of BPA and explored putative signal factors which partly explain adipose responses and underlying epigenetic mechanisms mediated by BPA. Maternal BPA-induced offspring adiposity, hypertrophic adipocytes and increased adipose tissue protein expression of pro-adipogenic and lipogenic factors. Consistent with in vivo data, in vitro BPA exposure induced a dose-dependent increase in pre-adipocyte proliferation and increased adipocyte lipid content. In vivo and in vitro BPA exposure promotes the proliferation and differentiation of adipocytes, contributing to an enhanced capacity for lipid storage. These findings reinforce the marked effects of BPA on adipogenesis and highlight the susceptibility of stem-cell populations during early life with long-term consequence on metabolic homeostasis.

[Heart failure provoked by a pacemaker lead-induced tricuspid stenosis]. / Insuffisance cardiaque par rétrécissement tricuspidien provoqué par une sonde d'électrostimulation. À propos d'un cas.

Tricuspid stenosis (TS) is an uncommon complication of ventricular pacemaker implantation. Mechanisms described by the literature are ventricular inflow obstruction by tricuspid vegetations (endocarditis) or multiple pacemaker leads and fibrosis secondary to mechanical trauma, accounting for perforation or laceration of the TV leaflets, or adherence between redundant loops and valve tissue. We present the case of iatrogenic tricuspid stenosis, observed in a 77-year-old man. Extrinsic tricuspid valve stenosis was detected by transthoracic echocardiography. Further investigations confirmed the intramyocardial lead position. Tricuspid valve stenosis due to transvenous leads are reported to be treated by surgical replacement, surgical valvuloplasty, or percutaneous balloon valvuloplasty.

Enhancement of fracture healing in the rat, modulated by compounds that stimulate inducible nitric oxide synthase: Acceleration of fracture healing via inducible nitric oxide synthase.

OBJECTIVES: We investigated the effects on fracture healing of two up-regulators of inducible nitric oxide synthase (iNOS) in a rat model of an open femoral osteotomy: tadalafil, a phosphodiesterase inhibitor, and the recently reported nutraceutical, COMB-4 (consisting of L-citrulline, Paullinia cupana, ginger and muira puama), given orally for either 14 or 42 days. MATERIALS AND METHODS: Unilateral femoral osteotomies were created in 58 male rats and fixed with an intramedullary compression nail. Rats were treated daily either with vehicle, tadalafil or COMB-4. Biomechanical testing of the healed fracture was performed on day 42. The volume, mineral content and bone density of the callus were measured by quantitative CT on days 14 and 42. Expression of iNOS was measured by immunohistochemistry. RESULTS: When compared with the control group, the COMB-4 group exhibited 46% higher maximum strength (t-test, p = 0.029) and 92% higher stiffness (t-test, p = 0.023), but no significant changes were observed in the tadalafil group. At days 14 and 42, there was no significant difference between the three groups with respect to callus volume, mineral content and bone density. Expression of iNOS at day 14 was significantly higher in the COMB-4 group which, as expected, had returned to baseline levels at day 42. CONCLUSION: This study demonstrates an enhancement in fracture healing by an oral natural product known to augment iNOS expression.Cite this article: R. A. Rajfer, A. Kilic, A. S. Neviaser, L. M. Schulte, S. M. Hlaing, J. Landeros, M. G. Ferrini, E. Ebramzadeh, S-H. Park. Enhancement of fracture healing in the rat, modulated by compounds that stimulate inducible nitric oxide synthase: Acceleration of fracture healing via inducible nitric oxide synthase. Bone Joint Res 2017:6:-97. DOI: 10.1302/2046-3758.62.BJR-2016-0164.R2.

Prohormone convertase 2 (PC2) null mice have increased mu opioid receptor levels accompanied by altered morphine-induced antinociception, tolerance and dependence.

Chronic morphine treatment increases the levels of prohormone convertase 2 (PC2) in brain regions involved in nociception, tolerance and dependence. Thus, we tested if PC2 null mice exhibit altered morphine-induced antinociception, tolerance and dependence. PC2 null mice and their wild-type controls were tested for baseline hot plate latency, injected with morphine (1.25-10mg/kg) and tested for antinociception 30min later. For tolerance studies, mice were tested in the hot plate test before and 30min following morphine (5mg/kg) on day 1. Mice then received an additional dose so that the final dose of morphine was 10mg/kg on this day. On days 2-4, mice received additional doses of morphine (20, 40 and 80mg/kg on days 1, 2, 3, and 4, respectively). On day 5, mice were tested in the hot plate test before and 30min following morphine (5mg/kg). For withdrawal studies, mice were treated with the escalating doses of morphine (10, 20, 40 and 80mg/kg) for 4days, implanted with a morphine pellet on day 5 and 3 days later injected with naloxone (1mg/kg) and signs of withdrawal were recorded. Morphine dose-dependently induced antinociception and the magnitude of this response was greater in PC2 null mice. Tolerance to morphine was observed in wild-type mice and this phenomenon was blunted in PC2 null mice. Withdrawal signs were also reduced in PC2 null mice. Immunohistochemical studies showed up-regulation of the mu opioid receptor (MOP) protein expression in the periaqueductal gray area, ventral tegmental area, lateral hypothalamus, medial hypothalamus, nucleus accumbens, and somatosensory cortex in PC2 null mice. Likewise, naloxone specific binding was increased in the brains of these mice compared to their wild-type controls. The results suggest that the PC2-derived peptides may play a functional role in morphine-induced antinociception, tolerance and dependence. Alternatively, lack of opioid peptides led to up-regulation of the MOP and altered morphine-induced antinociception, tolerance and dependence.

Progestin regulation of galanin and prolactin gene expression in oestrogen-induced pituitary tumours.

Galanin is a peptide widely distributed in the hypothalamic-pituitary axis. In the female rat pituitary, galanin is mainly present in lactotrophs, where it regulates their secretion and proliferation. Galanin expression is increased in oestrogen-induced prolactinomas, and it has been proposed that oestrogen effects on lactotroph function and proliferation could be mediated by galanin. Previous studies from our laboratory demonstrated that the synthetic progestin levonorgestrel antagonizes pituitary tumorigenesis of rats given oestrogen, reducing the number of proliferating cells and increasing cell death by nonapoptotic mechanism(s). To elucidate the role of galanin in levonorgestrel effects on the tumours, we examined galanin and prolactin mRNA and peptide expression in prolactinomas of rats receiving the progestin. Levonorgestrel reduced the pituitary weight and serum prolactin concentrations in oestrogen-treated rats. Galanin mRNA expression (determined by in situ hybridization), and the number of galanin expressing cells (determined by immunocytochemistry) were also reduced by the progestin in tumour-bearing rats. However, neither prolactin mRNA content, nor the number of prolactin-expressing cells, were modified by levonorgestrel treatment of oestrogen-receiving rats. The present study suggests that levonorgestrel controls pituitary growth by diminishing galanin expression. In contrast, changes in serum prolactin concentration seem to be more related to the reduction in tumour size, since the reduction in galanin expression was not large enough to regulate prolactin mRNA expression or the percentage of lactotrophs.

Glucocorticoid receptors and actions in the spinal cord of the Wobbler mouse, a model for neurodegenerative diseases.

We have studied glucocorticoid receptors (GR) and actions in the spinal cord of the Wobbler mouse, a model for amyotrophic lateral sclerosis and infantile spinal muscular atrophy. Basal and stress levels of circulating corticosterone (CORT) were increased in Wobbler mice. Single point binding assays showed that cytosolic type II GR in the spinal cord of Wobbler mice of both sexes were slightly reduced compared with normal littermates. Saturation analysis further demonstrated a non-significant reduction in Bmax with increased Kd. In the hippocampus, however, we found down-regulation of GR, a probable response to increased CORT levels. We also found that the basal activity of ornithine decarboxylase (ODC), a rate-limiting enzyme of polyamine biosynthesis, was higher in Wobbler mice than in control animals. Both groups showed a two-fold stimulation of ODC activity after treatment with dexamethasone (DEX). Additionally, Wobbler mice presented with an intense proliferation of astrocytes immunoreactive (ir) for glial fibrillary acidic protein (GFAP) in grey and white matter of the spinal cord. The enhanced GFAP-ir was attenuated after four days of treatment with a corticosterone (CORT) pellet implant, producing a pharmacological increase in peripheral circulating CORT. Taking into consideration the content of GR and the changes in ODC activity and GFAP-ir brought about by glucocorticoids, we suggest that Wobbler mice are hormone responsive. Further elucidation of glucocorticoid effects in this model may be relevant for understanding the possible use of hormones in human neurodegenerative diseases.

Changes of hypothalamic and plasma vasopressin in rats with deoxycorticosterone-acetate induced salt appetite.

Mineralocorticoids play a predominant role in development of salt appetite and hypertension. Since vasoactive peptides could mediate the central effects of mineralocorticoids, we evaluated changes of immunoreactive (IR) arginine vasopressin (AVP) in the paraventricular (PVN) and supraoptic (SON) hypothalamic nucleus during DOCA-induced salt appetite. In one model, rats having free access to water and 3% NaCl during 9 (prehypertensive stage) or 21 days (hypertensive stage) received DOCA (s.c., 10 mg/rat/in alternate days). A decrease in the IR cell area, number of IR cells and staining intensity was obtained in magnocellular PVN of rats treated during 9 days. After 21 days IR cell area and number of cells in the PVN also decreased, but staining intensity of remaining cells was normal. The same parameters were unchanged in the SON. In another model, animals treated with DOCA during 9 days had only access to 3% NaCl or water. The IR cell area in PVN and SON significantly increased in mineralocorticoid-treated and control animals, both drinking 3% NaCl. Staining intensity (PVN and SON) and number of IR cells (PVN) also augmented in DOCA-treated animals drinking salt respect of a group drinking water. Plasma AVP in rats treated with DOCA and offered salt and water, exhibited a 2-2.5 fold increase at the time of salt appetite induction. Plasma AVP was substantially higher in rats drinking salt only, while the highest levels were present in salt-drinking DOCA-treated rats. Thus, peptide depletion in the PVN may be due to increased release, because reduced levels of hypothalamic and posterior pituitary AVP were measured in this model. In rats drinking salt only the substantial increase of IR AVP in the PVN and SON, may be due to dehydration and hyperosmosis. Because DOCA-salt treated rats showed higher AVP levels in the PVN compared to untreated rats drinking salt only, it is possible that DOCA sensitized PVN cells to increase AVP production. The results suggest the vasopressinergic system could mediate some central functions of mineralocorticoids.

Regulation of gene expression by corticoid hormones in the brain and spinal cord.

Glucocorticoids (GC) and mineralocorticoids (MC) have profound regulatory effects upon the central nervous system (CNS). Hormonal regulation affects several molecules essential to CNS function. First, evidences are presented that mRNA expression of the alpha3 and beta1-subunits of the Na,K-ATPase are increased by GC and physiological doses of MC in a region-dependent manner. Instead, high MC doses reduce the beta1 isoform and enzyme activity in amygdaloid and hypothalamic nuclei, an effect which may be related to MC control of salt appetite. The alpha3-subunit mRNA of the Na,K-ATPase is also stimulated by GC in motoneurons of the injured spinal cord, suggesting a role for the enzyme in GC neuroprotection. Second, we provide evidences for hormonal effects on the expression of mRNA for the neuropeptide arginine vasopressin (AVP). Our data show that GC inhibition of AVP mRNA levels in the paraventricular nucleus is sex-hormone dependent. This sexual dimorphism may explain sex differences in the hypothalamic-pituitary-adrenal axis function between female and male rats. Third, steroid effects on the astrocyte marker glial fibrillary acidic protein (GFAP) points to a complex regulatory mechanism. In an animal model of neurodegeneration (the Wobbler mouse) showing pronounced astrogliosis of the spinal cord, in vivo GC treatment down-regulated GFAP immunoreactivity, whereas the membrane-active steroid antioxidant U-74389F up-regulated this protein. It is likely that variations in GFAP protein expression affect spinal cord neurodegeneration in Wobbler mice. Fourth, an interaction between neurotrophins and GC is shown in the injured rat spinal cord. In this model, intensive GC treatment increases immunoreactive low affinity nerve growth factor (NGF) receptor in motoneuron processes. Because GC also increases immunoreactive NGF, this mechanism would support trophism and regeneration in damaged tissues. In conclusion, evidences show that some molecules regulated by adrenal steroids in neurons and glial cells are not only involved in physiological control, but additionally, may play important roles in neuropathology.

Regulation of flunitrazepam binding in the dorsal horn of the spinal cord by adrenalectomy and corticosteroids.

Adrenal corticosteroids and adrenalectomy (ADX) have opposing effects on benzodiazepine binding sites in brain regions. These treatments were employed to study [3H]flunitrazepam (FLU) binding in regions punched out from the rat spinal cord. We found that binding was higher in dorsal horn than in ventral horn, and minimal in white matter. Clonazepam and RO 15-1788 largely displaced [3H]FLU binding, whereas RO 5-4864 was weakly active. Four days post-ADX, binding increased exclusively in the dorsal horn, and this effect was reversed by administration of corticosterone (CORT), but not dexamethasone (DEX) or aldosterone (ALDO) given over 4 days. When endogenous CORT was increased by administration of cold stress to adrenal-intact rats, reduced benzodiazepine (BDZ) binding was also observed in the dorsal horn. When added in vitro, only ALDO and not CORT or DEX, inhibited [3H]FLU binding. It is suggested that steroids with affinity for the type I corticosteroid receptor (CORT, ALDO) decrease [3H]FLU binding to a neural-type BDZ receptor in the dorsal horn. Reduction of the inhibitory BDZ system may be physiologically important, and can partly explain the enhancement of excitatory synaptic transmission produced by corticosteroids at the level of the spinal cord.

Gene expression in Peyronie's disease.

Currently, surgical intervention is the only efficacious treatment for Peyronie's disease (PD), a fibromatosis of the tunica albuginea of the penis. Therapies based on the molecular pathways for this disease could provide alternatives to surgical treatment but only recently has the pathophysiology of the Peyronie's disease plaque been investigated at the molecular level. In this review, we examine the current knowledge of gene expression in the PD plaque and the relationship of PD with other fibrotic conditions such as Dupytren's disease. TGFbeta1, along with other growth factors, pro-fibrotic genes, and collagen, are expressed in fibroblasts and myofibroblasts. Myofibroblasts are normally involved in wound contracture and largely eliminated via apoptosis during the late stages of wound remodeling. In the PD plaque, however, these cells persist and may play an important role in the PD plaque fibrosis. The expression levels of TGFbeta1 and pro- and anti-fibrotic gene products, along with the nitric oxide/reactive oxygen species (NO/ROS) ratio in the tunica albuginea, appear to be essential for the formation and progression of the PD plaque and effect the expression of multiple genes. This can be assessed with the recently developed DNA-based chip arrays and results with the PD plaque have been encouraging. OSF-1 (osteoblast recruitment), MCP-1 (macrophage recruitment), procollagenase IV (collagenase degradation), and other fibrotic genes have been identified as being possible candidate regulatory genes. Finally, possible therapeutic avenues for gene-based therapy in the treatment of PD are discussed that may eventually reduce the need for surgical intervention.

Estrogens up-regulate type I and type II glucocorticoid receptors in brain regions from ovariectomized rats.

The effects of 1-4 days of estradiol (E2) treatment on type I and type II glucocorticoid receptors (GCR) were determined in cytosolic fractions from brain regions of ovariectomized rats. Four days after E2 administration, type I GCR increased in septum, amygdala, hypothalamus and hippocampus, but decreased in the anterior pituitary. Type II GCR increased in septum and hypothalamus only. For both receptor types, changes occurred earlier in septum (1 day) than in the other regions. The E2 increment was due to an increase in Bmax, without changes in Kd. The up-regulation of type II GCR by E2 was also confirmed immunocytochemically in four nuclei of the septal area. In a parallel study, E2 receptors were determined in nuclear and cytosol fractions from the same regions analyzed for GCR. In rats receiving E2, estrogen receptors decreased in cytosol and increased in nuclei from septum, amygdala, hypothalamus and anterior pituitary, but did not change in hippocampus. The results suggest that GCR in certain neuroendocrine regions are regulated by E2, without taking into account whether the areas involved contain high (anterior pituitary), moderate (septum, hypothalamus, amygdala) or low (hippocampus) levels of E2 receptors. Our model may shed light on sex differences in GCR and on E2 regulation of glucocorticoid action in brain and the pituitary.

Estradiol abolishes autologous down regulation of glucocorticoid receptors in brain.

We have previously reported that estrogen treatment of steroid-free, ovariectomized-adrenalectomized (OVX-ADX) rats, increased binding to glucocorticoid type II receptors (GR) in some brain regions. The present report studied the effects of estradiol in OVX-ADX rats receiving chronic corticosterone (CORT) treatment. Using binding assays, GR was reduced by CORT replacement in cytosol of hippocampus and septum, but not in whole hypothalamus. GR were recovered after 4 days of estradiol therapy. Using Mab7, a monoclonal antibody against the activated nuclear form of GR, we observed that estrogen treatment increased immunoreactivity measured by computerized densitometry in areas targeted by glucocorticoids. Significantly higher staining for GR developed in CA1 and CA2 hippocampal subfields, paraventricular nucleus of the hypothalamus and lateral ventral septal nuclei of estradiol-receiving, CORT-treated OVX-ADX rats. The amplification of the glucocorticoid biological signal by female sex hormones, may thus affect several neuroendocrine parameters and the outcome of stress-related diseases.

Estradiol increases glucocorticoid binding and glucocorticoid induction of ornithine decarboxylase in the rat spinal cord.

Previous results demonstrated that estradiol (E2) treatment of ovariectomized-adrenalectomized (OVX-ADX) rats increased glucocorticoid (GC) binding in brain regions. The experimental protocol was extended to the spinal cord, a GC target tissue in which ornithine decarboxylase (ODC) is markedly induced by GC treatment. First, we measured GC binding to type I and type II receptors in ventral horn, dorsal horn and lateral funiculus of OVX-ADX rats treated during 4 days with E2 or vehicle. In E2-treated rats, type II receptors increased solely in dorsal horn, whereas type I sites remained unchanged. Second, in a group of OVX-ADX rats receiving dexamethasone (DEX), pretreatment with E2 superinduced ODC in ventral horn and lateral funiculus, but not in dorsal horn. Third, we found that the dorsal horn was relatively enriched in E2 receptors compared to other areas. Therefore, E2 stimulation of GC binding to type II sites may be mediated through E2 receptors localized in the dorsal horn. We suggest that combined treatment with E2 and DEX employs a transsynaptic mechanism for ODC induction at the ventral horn and lateral funiculus, with hormonal interaction taking place at the dorsal horn level.

Chronic corticosterone impairs inhibitory avoidance in rats: possible link with atrophy of hippocampal CA3 neurons.

The aim of our work was to evaluate the effect of a chronic (22 days) administration of corticosterone, which induces supraphysiological serum levels of the hormone, on an inhibitory avoidance learning in rats (one-trial step-through learning task, footshock: 0.5 mA, 2 s). We also studied hippocampal markers of neuroanatomical CA3 pyramidal neuron atrophy by using the Golgi staining method. Chronic exposure to high CORT serum levels induced a significant impairment of inhibitory avoidance learning. The CORT group also showed hippocampal glucocorticoid receptor (GR) downregulation and the decrease of hippocampal CA3 branch points and total dendritic length in the apical tree that would be causally related with the learning impairment.

Prospective randomized study of St Jude Medical versus Björk-Shiley or Starr-Edwards 6120 valve prostheses in the mitral position. Three hundred and fifty-seven patients operated on from 1979 to December 1983.

During a 5 year period (January 1979-December 1983) 357 patients were submitted to mitral valve replacement. These were performed by the same surgeon and were randomized in 2 groups: Group A consisted of 179 patients who received a St Jude Medical (SJM) prosthesis in the mitral position. Group B comprised 178 patients with a Björk-Shiley valve (BSM) initially (113 patients from 1979 to December 1981 matched with 111 SJM) and later a Starr-Edwards 6120 valve prosthesis (65 patients matched with 63 SJM). Analysis of 21 preoperative clinical, hemodynamic data and operative variables showed the groups to be well randomized. All patients were anticoagulated postoperatively. A follow-up study was performed each year postop: at the end of 1986 there was a 35 to 95 months follow-up with a mean of 64.7 months (1596 patient years follow-up). Fifteen patients were lost to follow-up. There were 8.4% deaths related to the prosthesis in group A and 20.2% in group B (p less than 0.001). The difference was due mainly to deaths from thromboembolic complications and sudden deaths. The rate of peripheral arterial embolic complications was 2.3% in group A and 4.3% in group B per patient year (NS). The difference between the 2 groups is significant for all thromboembolic events including sudden deaths: 3.1% in group A and 7.9% per patient year in group B (p less than 0.001). There were no statistical differences in the rates of endocarditis per patient year (0.3% in group A, 0.9% in group B), reoperation (0.75% in group A, 0.89% in group B), or anticoagulant related hemorrhage (1.6% in group A, 2.4% in group B). Actuarial survival rate, including all postoperative deaths, is significantly different (p less than 0.05) at 5 years, 87.6% +/- 4.5 (group A) versus 77.4% +/- 6 (group B) and at 7 years follow-up, 83.4% +/- 6.5 (group A) versus 73.2% +/- 7.2 (group B). The probability of freedom from death and complications related to the prosthesis is significantly different (p less than 0.001) at 5 years postoperatively: 79% +/- 6.5 for group A versus 54% +/- 7.5 for group B and at 7 years: 72% +/- 7.5 (group A) versus 46% +/- 8.5 (group B). Comparison of subgroups, 113 BSM versus 111 SJM (1979-81) and 65 SE 6120 versus 63 SJM (1982-83) showed similar significant differences in the results: however there were more early deaths, valve thrombosis, valve dysfunctions and sudden late deaths in the BSM group and more peripheral arterial emboli in the SE 6120 group.(ABSTRACT TRUNCATED AT 400 WORDS)

Glucocorticoid regulation of in vitro astrocyte phagocytosis.

Astrocytes participate in central nervous system injury, degenerative diseases and also perform macrophagic functions. The present work investigates: 1) the effect of the physiological glucocorticoid corticosterone (CORT) and the synthetic agonist dexamethasone (DEX) on latex beads phagocytosis by neonatal rat cortical astrocytes in culture, and 2) the expression of immunoreactive glucocorticoid receptors (GR) in astrocytes cultured in different media with or without a pulse application of CORT. The results indicated that glucocorticoids reduced astrocyte phagocytic activity, as occurred with macrophages, independently of the culturing conditions employed. The extent of phagocytosis was inversely related to nuclear immunostaining for GR in cultures in fetal calf serum, which contained endogenous glucocorticoid. However, no correlation was found between nuclear GR and phagocytosis for cultures in glucocorticoid-free medium or in medium containing CORT. It is suggested that additional factors, besides the GR, may be involved in glucocorticoid modulation of astrocyte phagocytosis.

[Hemodynamic data during muscular exercise after myocardial infarction. Correlations with coronaro-ventriculographic data]. / Données hémodynamiques recueilles au cours de l'exercice musculaire après infarctus du myocarde. Confrontation aux données coronaro-ventriculographiques.

Forty six patients aged 25 to 67 years (average : 52 years) underwent measurement of pulmonary arterial pressure (PAP), systemic pressure and cardiac output (Fick) at rest and during exercise in the recumbent position 12 +/- 3 weeks after uncomplicated myocardial infarction; the results were then compared with those of coronary angiography and right anterior oblique monoplane left ventriculography. The site of infarction was anterior in 18 cases and postero-diaphragmatic in 28 cases; it was non-transmural in 4 cases. Twenty patients (43%) had multivessel disease; this was equally common in anterior and inferior wall infarction. Regional wall abnormalities of 3 or more segments were observed in 14 cases. Mean PAP increased from 12,3 +/- 4,6 Torr at rest to 27,8 +/- 10,5 Torr on exercise. In 17 patients (Group A) PAP was normal at rest and during exercise (10 +/- 2 Torr and 18 +/- 3 Torr respectively); 25 patients (Group B) had normal resting PAP (12 +/- 3 Torr) but an abnormal rise on exercise (32 +/- 8 Torr); in 4 patients (Group C) PAP was abnormal at rest (24 +/- 4 Torr) and on exercise (44 +/- 7 Torr). The increase in PAP on exercise was inversely correlated to the ejection fraction (p less than 0.001) and related to the extent of left ventricular hypokinesia (p less than 0.001). Patients in Group A had higher ejection fractions (p less than 0.05), dp/dt/p index (p less than 0.01) and left ventricular compliance (p less than 0.01), lower resting (p less than 0.01) and exercise (p less than 0.05) systemic pressures and small regional wall abnormalities (p less than 0.01) than patients in Group B.(ABSTRACT TRUNCATED AT 250 WORDS)