Role of 5-HT1A autoreceptors in the mechanism of action of serotoninergic antidepressant drugs: recent findings from in vivo microdialysis studies

Summary— Although a new generation of selective serotonin reuptake inhibitors (SSRIs) has been introduced in therapeutics as antidepressant drugs, a two to four week lag period still occurs between starting treatment with SSRIs and the onset of therapeutic effects in man. In vivo cerebral microdialysis can be used to measure extracellular concentrations of serotonin (5-hydroxytryptamine, 5-HT), which reflect intrasynaptic events. With the coupling of this new experimental method to very sensitive analytical assays such as liquid chromatography with electrochemical detection, it has recently been possible to obtain two major arguments supporting the hypothesis that somatodendritic 5-HT_1A autoreceptors situated in the raphe nuclei play an important role in the mechanism of action of SSRIs. First, in the rat, single administration of SSRIs at low doses comparable to those used therapeutically increases extracellular 5-HT concentrations in the vicinity of the cell body and the dendrites of serotoninergic neurones of the raphe nuclei. This effect is more marked than that observed in regions rich in nerve endings (frontal cortex). The magnitude of the activation of the serotoninergic neurotransmission depends on the brain area studied and the dose of the SSRIs administered to rats. This could be explained by simultaneous activation of somatodendritic 5-HT_1A autoreceptors by endogenous 5-HT in the raphe nuclei, thereby limiting the corticofrontal effects of the antidepressant. Second, SSRIs cause a larger increase in extracellular 5-HT concentrations in the nerve endings when administered chronically: 5-HT autoreceptors may have gradually desensitized during the 2–4 weeks of treatment with SSRIs. Preliminary studies of patients with depression appear to confirm these experimental results, as co-administration of a 5-HT_1A autoreceptor antagonist and a SSRI accelerated the onset of the antidepressant effect (< 1 week).     

猪脑钠素及其类似物的合成

以固相多肽合成方法合成了猪的二十六肽脑钠素(BNP)和它的一个类似物(Mpr⁴,D-Ala^6,13)-BNP(4-24)-NH₂,保护肽用HF裂解除去保护基、在碱性条件下空气氧化形成二硫桥后,粗产物经凝胶过滤和高效液相色谱分离纯化,均有与天然脑钠素相同的活性。合成肽相对于树脂初始取代量的产率分别为9.56%和11.03%。     

The (cost-)effectiveness of a lifestyle physical activity intervention in addition to a work style intervention on the recovery from neck and upper limb symptoms in computer workers

Background  

Neck and upper limb symptoms are frequently reported by computer workers. Work style interventions are most commonly used to reduce work-related neck and upper limb symptoms but lifestyle physical activity interventions are becoming more popular to enhance workers health and reduce work-related symptoms. A combined approach targeting work style and lifestyle physical activity seems promising, but little is known on the effectiveness of such combined interventions.     

Changes in protein turnover, IGF-I and IGF binding proteins in children with cancer

Changes in insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding proteins (IGFBPs) were correlated with protein synthesis and breakdown using [1- ¹³C]leucine before chemotherapy and during subsequent febrile neutropenia (FN) in eight children with cancer, aged 6.3–17.5 y. IGF-I levels were similar to age-matched controls before chemotherapy (mean ±SEM: 250 ±28 and 228 ±22 μg l^-1, respectively). During FN, IGF-I fell to 156 ±22 /ng l ^-1(p= 0:02), and rose to 276 ±27 μ g l ^-1 with recovery at 6 months (p = 0:004). Similarly, IGFBP-3 decreased from 4.0 ±0.2mgl^-1 before chemotherapy to 3.0 ±0.3 mgl^-1 during FN (p= 0:01), and returned to 4.1 ±0.2mgl ^-1 at 6 months (p= 0:01). IGF-I correlated with IGFBP-3 (r=+0:7, p <0:001). Scanning densitometry showed a decrease in IGFBP-3 from 94 to 54% during FN, when the presence of IGFBP-3 protease activity was observed. Compared with normal human serum, IGFBP-2 was elevated throughout the study. IGFBP-1 increased from 14.6 ±3.5 to 30.6 ±2.8/ngl^-1 (p = 0:004), whereas serum insulin decreased from 26.5 ±6.8 to 7.8 ±0.8 mUl^-1 (p= 0:03) before and during FN, respectively. Whilst IGF-I and IGFBP-3 fell, daytime growth hormone increased from 3.3 ±0.6 to 6.7±0.8mUl ^-1 (p= 0:01), and cortisol from 197 ±48 to 594±98nmoll ^-1 (p = 0:005). Albumin decreased from 47 ±2 to 38 ±2gl^-1 (p= 0:004) and improved to 47 ±2gl^-1 with recovery (p= 0:003). Protein synthesis increased from 4.5 ±0.4 to 5.0 ±0.6gkg^-1 d^-1 before chemotherapy and during FN, while protein breakdown rose from 5.4 ±0.4 to 6.3 ±0.4kg^-1d^-1. Increasing protein breakdown was related to falling IGF-I and IGFBP-3 levels. Modification of IGFBP-3 by circulating proteolytic activity may alter IGF bioavailability, allowing protein synthesis to increase during periods of severe catabolic stress.     

Clinical outcomes and maternal perceptions of an updated model of perinatal care

BACKGROUND: Postpartum hospital stays seem likely to remain limited even under new laws which mandate that insurers cover 48-hour hospitalization after uncomplicated delivery. Clinicians, who are increasingly practicing in capitated arrangements, need better information to maximize clinical benefit to mothers and newborns using finite resources. OBJECTIVE AND INTERVENTIONS: This study's aim was to evaluate the clinical outcomes, patient perceptions, and costs of a revised model of perinatal care services. In this model, a new postpartum care center was established for routine follow-up of newborns within 48 hours after hospital discharge, educational efforts were shifted from the postpartum hospitalization to the prenatal period, and lactation consultant hours were increased. DESIGN AND PARTICIPANTS: Controlled, nonrandomized (double cohort) study that compared mothers and newborns with hospital stays of 48 hours or less during the Baseline Care (preintervention) study period (N = 344) with those under the Revised Care (postintervention) study period (N = 456). SETTING: The Hayward, California, medical center of Kaiser Permanente, a nonprofit health maintenance organization. DATA COLLECTION: Telephone interviews were attempted with all mothers 3 weeks after delivery. Data on rehospitalizations, emergency department (ED) and clinic visits, and costs during the first 14 postpartum days were collected from computerized databases and chart review. OUTCOME MEASURES: The combined clinical outcome was defined as any undesirable health event, including rehospitalization, an ED visit, or an urgent clinic visit by either the mother or newborn within the first 14 days postpartum, or breastfeeding discontinuation within the first 21 days postpartum. Maternal satisfaction and costs were also studied. RESULTS: Of 876 attempted interviews, 800 were completed (91%). Analyses were adjusted for age, race, education, parity, breastfeeding experience, and other relevant variables. Among the interviewed mother-newborn pairs, 45% in the Revised Care group experienced the combined clinical outcome, compared with 52% in the Baseline Care group. Newborns in the Revised Care group (29%) were significantly less likely to make urgent clinic visits during the first 14 days of life than those in the Baseline Care group (36%). There were no differences between groups in newborn ED visits or rehospitalizations, maternal clinical outcomes, or breastfeeding continuation. Mothers in the Revised Care group expressed higher satisfaction with the newborn's care, the amount of information they received about newborn care and breastfeeding, and the amount of help they received with breastfeeding. Planned hospital care, planned follow-up visits, and unplanned care costs decreased by $149 per delivery, while the new prenatal class and increased lactation consultant services cost $58 per delivery, for an estimated overall reduction in cost. CONCLUSIONS: We conclude that the revised model of perinatal care in this health maintenance organization medical center improved clinical outcomes and maternal satisfaction for low-risk mothers and newborns without increasing costs.     

Dendritic domains of medium spiny neurons in the primate striatum: Relationships to striosomal borders

Medium spiny neurons are the projection neurons of the striatum. They receive the majority of striatal afferents, and they make up the vast majority of all neurons in the striatum. These densely spiny cells thus constitute a major substrate for input-output processing in the striatum. In the experiments described here we analyzed the dendritic fields of spiny neurons in the squirrel monkey striatum and plotted their orientations with respect to the borders between striosomes and matrix. Medium-sized spiny neurons in the caudate nucleus were filled intracellularly in a fixed-slice preparation with the fluorescent dye Lucifer Yellow. Dendritic arbors were reconstructed following immunostaining of the injected neurons with antiserum to Lucifer Yellow and counterstaining for striosome/matrix compartments. A majority of the medium spiny neurons studied had dendritic arborizations that remained within their compartment of origin. Thus the striosome/matrix subdivision not only partitions neurotransmitter molecules and extrinsic striatal connections into two domains in the primate caudate nucleus, but also constrains the dendritic arbors of many projection neurons there. Other medium spiny neurons, however, in both striosomes and matrix, had dendrites that crossed from one compartment into the other. About a quarter of the spiny neurons reconstructed had at least one such crossing dendrite. These results suggest that compartmentalization of afferent and efferent processing by projection neurons in the primate striatum is not absolute. For a subpopulation of spiny neurons in striosomes and matrix, inputs to one compartment could have a direct influence on output cells of the other. © 1993 Wiley-Liss,Inc.     

INTRAVENOUS INFUSION OF GLUCOSE AND SODIUM BICARBONATE IN HYALINE MEMBRANE DISEASE

A controlled trial of the effect of intravenous infusion of glucose and sodium bicarbonate was performed in 48 low weight newborn infants with hyaline membrane disease. The experimental design included diagnosis by clinical and radiological criteria and random assignment to the treatment and control series. In treated infants the mortality rate was lower, early death occurred less frequently and the neonatal survival curve was improved when compared with controls. Only the difference in survival curves of treated and control patients was statistically significant. Systolic blood pressure was found to be a factor of considerable prognostic significance. We conclude that intravenous infusions of glucose and sodium bicarbonate should be part of the routine therapy of infants with hyaline membrane disease.     

Autoradiographic localization and biochemical characteristics of M1 and M2 muscarinic binding sites in the striatum of the cat, monkey, and human

The autoradiographic distribution of M1 and M2 muscarinic cholinergic binding sites was studied in the striatum of the cat, monkey, and human, and concurrent binding assays were carried out on striatal tissue sections from the cat. M1 sites were directly labeled with 3H-pirenzepine; M2 sites were labeled as a consequence of binding competition between pirenzepine and 3H-N-methylscopolamine. Serial section analysis with autoradiograms and stained tissue sections allowed for comparisons among M1 and M2 binding distributions and AChE staining patterns. The 2 subtypes of binding sites demonstrated distinct striatal distributions. M2 sites were virtually homogeneous except in the ventral striatum, where zones of sparse and especially dense binding were observed. Striatal M1 sites were generally more abundant than M2 sites and showed similar heterogeneity in the ventral striatum. Dorsally, however, patches of dense M1 binding were found, and proved to correspond with AChE-poor striosomes, hallmarks of striatal compartmentalization. The finding of differing distributions for the 2 subtypes of muscarinic cholinergic binding sites suggests a mechanism for the intrinsic spatial segregation of striatal cholinergic function. Further, the striosomal patterning of M1 binding indicates that certain aspects of cholinergic function in the striatum may be constrained and thus regulated by the compartmental ordering characteristic of this region of the basal ganglia.