Testosterone increases the recruitment and/or survival of new high vocal center neurons in adult female canaries.

New neurons are added to the high vocal center (HVC) of adult male and female canaries. Exogenous testosterone induces a marked increase in HVC size in adult female canaries, though the mechanisms responsible for this increase remain unknown. To understand the mechanisms, we analyzed the effects of testosterone on neuronal recruitment in the female HVC. Intact adult female canaries received Silastic implants that were empty or filled with testosterone. Birds in the short-survival group received the Silastic implant, followed by a single injection of [3H]thymidine 2 days later, and were killed on the following day. Birds in the long-survival group were injected once a day for 5 days with [3H]thymidine and received the Silastic implant 20 and 40 days later. These birds were killed 60 days after the first injection of [3H]thymidine. The number of 3H-labeled ventricular zone cells above, rostral, or caudal to HVC was not affected by the hormone treatment in the short-survival birds, suggesting that testosterone did not affect neuronal production. However, the number of 3H-labeled HVC neurons that projected to robust nucleus of the archistriatum (RA) in the long-survival birds was three times greater in the hormone-treated than in the control group, though the total number of RA-projecting cells did not change significantly. Testosterone also induced an increase in the size of the HVC cells that project to RA. Thus, these experiments suggest that testosterone affects the recruitment and/or survival of newly generated RA-projecting HVC neurons but does not affect their production.     

Localized neuronal activation in the zebra finch brain is related to the strength of song learning

Songbirds (Oscines) learn their songs from a tutor. It is not known where in the brain the memories of these learned sounds are stored. Recent evidence suggests that song perception in songbirds involves neuronal activation in brain regions that have not traditionally been implicated in the control of song production or song learning, notably the caudal part of the neostriatum (NCM) and of the hyperstriatum ventrale. Zebra finch males (Taeniopygia guttata castanotis) were reared without their father and exposed to a tape-recorded song during the sensitive period for song learning. When, as adults, they were reexposed to the tutor song, the males showed increased expression of the protein products of the immediate early genes egr-1 (ZENK) and c-fos in the NCM and caudal hyperstriatum ventrale, but not in the conventional "song-control nuclei." The strength of the immediate early gene response (which is a reflection of neuronal activation) in the NCM correlated significantly and positively with the number of song elements that the birds had copied from the tutor song. These results show localized neural activation in response to tutor song exposure that correlates with the strength of song learning.     

Birth of projection neurons in the higher vocal center of the canary forebrain before, during, and after song learning.

The higher vocal center (HVc) of the canary brain projects to two forebrain nuclei: robustus archistriatalis (RA) and area X of lobus parolfactorius. The time of birth of HVc neurons projecting to these two regions was determined by combining [3H]thymidine autoradiography and retrograde fluorogold uptake. Birds were sacrificed at 13 months of age, 4 days after fluorogold injections into area X or RA. A single injection of [3H]thymidine in ovo (embryonic day 9) labeled 76% of area X-projecting cells and 0.8% of cells projecting to RA. The great majority of RA-projecting cells were produced during posthatching development (posthatching day 10-240; P10-P240), with a peak at P60 and a hiatus at P120. HVc reaches full adult size by P240, yet at that age the production of new RA-projecting cells continued at a rate comparable to that recorded during posthatching development. Late production of neurons interconnecting two distant regions of the brain may regulate source to target cell population size. Male canaries start to sing at P40. During subsequent months, they imitate external models and their song becomes more structured and stereotyped. At sexual maturity (P240), song is stable. Three interpretations are offered: (i) neurogenesis of RA-projecting cells is related to learning, and learning continues even after achievement of pattern stability; (ii) neurogenesis of RA-projecting cells is not related to learning; (iii) the production of RA-projecting cells serves different purposes during development and after sexual maturity.     

Photoperiodic induced changes in reproductive state of border canaries (Serinus canaria) are associated with marked variation in hypothalamic gonadotropin-releasing hormone immunoreactivity and the volume of song control regions

In temperate zone songbirds, such as canaries (Serinus canaria), seasonal variation in gonadal activity and behavior are associated with marked brain changes. These include gonadotropin-releasing hormone (GnRH) expression and the volume of brain areas controlling song production. Questions have been raised about the consistency of seasonal brain changes in canaries. Laboratory studies of the American singer strain raised doubts as to whether this strain exhibits a robust photoperiodic response along with changes in brain GnRH content, and studies of free-living canaries have failed to identify seasonal changes in volume of song control nuclei. We assessed differences in brain GnRH and the song control system associated with photoperiod-induced variation in reproductive state in Border canaries. We found that males and females maintained for 10 weeks on long days (14L:10D) regress their gonads, exhibit a decline in testosterone and initiate molt; a response consistent with the onset of absolute photorefractoriness (i.e., failed to respond to previously stimulating daylengths). All birds regained photosensitivity (i.e., exhibited gonadal response to stimulating daylengths) after experiencing short days (8L:16D) for 6 weeks. Furthermore, comparisons of birds in either a photosensitive, photostimulated, or photorefractory state revealed a marked increase in GnRH protein expression in the photosensitive and photostimulated birds over photorefractory birds. A similar variation was observed in the volume of key forebrain song nuclei. Thus, Border canaries demonstrate measurable neuroplasticity in response to photoperiodic manipulations. These data, along with previous work on other strains of canaries, indicate the presence of intra-specific variation in photoperiodically regulated neuroplasticity.     

Ciliary neurotrophic factor prevents retrograde neuronal death in the adult central nervous system.

The neurocytokine ciliary neurotrophic factor (CNTF) was described originally as an activity that supports the survival of neurons of the chicken ciliary ganglia in vitro. The widespread expression of CNTF and its principal binding protein, CNTF receptor alpha, in the central and peripheral nervous systems suggests a broader trophic role for this peptide. In the present study, we report that CNTF prevents axotomy-induced cell death of neurons in the anteroventral and anterodorsal thalamic nuclei of the adult rat. Using the polymerase chain reaction, we also demonstrate the presence of CNTF and CNTF receptor alpha mRNA in these same thalamic nuclei. The coincidence of CNTF and its receptor in a population of neurons responding to the factor suggests a paracrine function for CNTF. The present findings establish that CNTF has significant effects on neurons of the central nervous system in vivo and demonstrate that neurocytokines can prevent cell death in the adult central nervous system.     

Survival and differentiation of adult neuronal progenitor cells transplanted to the adult brain.

The dentate gyrus of the hippocampus is one of the few areas of the adult brain that undergoes neurogenesis. In the present study, cells capable of proliferation and neurogenesis were isolated and cultured from the adult rat hippocampus. In defined medium containing basic fibroblast growth factor (FGF-2), cells can survive, proliferate, and express neuronal and glial markers. Cells have been maintained in culture for 1 year through multiple passages. These cultured adult cells were labeled in vitro with bromodeoxyuridine and adenovirus expressing beta-galactosidase and were transplanted to the adult rat hippocampus. Surviving cells were evident through 3 months postimplantation with no evidence of tumor formation. Within 2 months postgrafting, labeled cells were found in the dentate gyrus, where they differentiated into neurons only in the intact region of the granule cell layer. Our results indicate that FGF-2 responsive progenitors can be isolated from the adult hippocampus and that these cells retain the capacity to generate mature neurons when grafted into the adult rat brain.     

Transient expression and transport of brain-derived neurotrophic factor in the male zebra finch’s song system during vocal development

The distribution of brain-derived neurotrophic factor (BDNF) in the song system of male zebra finches changes with posthatching age. At day 20, the hyperstriatum ventrale, pars caudale is the only song nucleus in which neurons showed BDNF immunoreactivity. At day 45, the staining in hyperstriatum ventrale, pars caudale was denser than at day 20 and the robust nucleus of the archistriatum, another song nucleus, showed BDNF labeling. By day 65, two additional song nuclei, area X and the lateral magnocellular nucleus of the anterior neostriatum, have become immunoreactive. In the adult, however, the amount of BDNF labeling in all of these brain nuclei is sharply reduced. These sequential events, the anatomical connections between these song nuclei, and the labeling of relevant axons and terminals suggest anterograde transport of BDNF. Furthermore, the timing of BDNF expression coincident with the development of singing behavior suggests that this neurotrophin may be directly involved with the differentiation of the song system.     

Haemorrhoids are related to changes of cell function in mucosa and submucosa

Purpose

Epidemiology and risk factors of haemorrhoidal disease are not well defined. This study tried to evaluate if the appearance of haemorrhoids is related to a disturbed remodelling of the soft tissue of rectal mucosa and submucosa. Therefore, immunohistochemical expression profiles of five parameters as potential mediators in neoangiogenesis (EGFR), in inflammatory cell activity (COX-2), and in cell migration, differentiation, and wound healing (notch-3, c-myc, and ß-Catenin) were analysed (Saed et al., Fertil Steril 83(Suppl 1):1216–1219, 1; Saed et al., Fertil Steril 79:1404–1408, 2; Stojadinovic et al., Am J Pathol 167:59–69, 3).

Methods

Haemorrhoidal tissue specimens were collected from 44 patients. Healthy rectal mucosa was obtained from 16 non-fixed fresh cadavers and served as control. Histological and immunohistochemical markers like EGFR, COX-2, notch-3, c-myc, and ß-Catenin were analysed semi-quantitatively, separately for mucosal and submucosal layer.

Results

Significantly increased expressions were found for EGFR, COX-2, and notch-3 in the mucosal and submucosal layer of haemorrhoidal tissue in comparison to normal rectal tissue.

Conclusions

This finding confirms that haemorrhoidal disease may be regarded as a manifestation of a soft tissue disease.

     

Photosynthetic reaction center genes in green sulfur bacteria and in photosystem 1 are related.

Oxygenic photosynthesis of chloroplasts and cyanobacteria involves two photosystems, which originate from different prokaryotic ancestors. The reaction center of photo-system 2 (PS2) is related to the well-characterized reaction center of purple bacteria, while the reaction center of photosystem 1 (PS1) is related to the green sulfur bacteria, as is convincingly documented here. An operon encoding the P840 reaction center of Chlorobium limicola f.sp. thiosulfatophilum has been cloned and sequenced. It contains two structural genes, coding for proteins of 730 and 232 amino acids. The first protein resembles the large subunits of the PS1 reaction center. Putative binding elements for the primary donor, P840 in Chlorobium and P700 in PS1, and for the acceptors A0, A1, and FeS center X are conserved. The second protein is related to the PS1 subunit carrying the FeS centers A and B. An adjacent third gene, not belonging to the reaction center, encodes a protein related to dolichyl-phosphate-D-mannose synthase from yeast. The different origins of PS1 and PS2 are discussed.     

Gonadotropin-releasing hormone messenger ribonucleic acid levels are unaltered with changes in the gonadal hormone milieu of the adult male rat

Testicular function is regulated by the negative feedback effect of sex hormones acting at the brain and pituitary to inhibit the secretion of LH and FSH. An important component of this feedback axis is presumed to involve regulation of secretion and possibly synthesis of GnRH by the brain. We tested the hypothesis that the castration-induced increase in gonadotropin secretion is subserved, at least in part, by increased synthesis of GnRH. Using in situ hybridization and an oligonucleotide probe to pro-GnRH messenger RNA (GnRH mRNA), we compared the level of cellular GnRH mRNA and the relative number of GnRH mRNA-containing neurons between intact and 21-day castrate adult male rats. To derive estimates of the number of GnRH cells and the cellular GnRH mRNA content, coronal sections from each animal were anatomically matched between intact and castrate groups. All identifiable cells within these sections were counted and analyzed with the aid of a computerized image analysis system, by an observer unaware of the animal's experimental group and were assigned an anatomical location for reference. In an initial experiment, we observed no difference in cellular GnRH mRNA signal level between intact (n = 4) and castrate (n = 5) animals (129 +/- 8 vs. 139 +/- 5 grains per cell); however, we did find a statistical difference between the intact and castrated groups in the relative number of GnRH mRNA-containing cells (intact: 212 +/- 15 vs. castrate: 320 +/- 18). To confirm this observation, we repeated the experiment by again comparing the number of GnRH mRNA-positive cells between intact (n = 4) and castrate (n = 4) rats. In this second experiment, we found no difference in the number of identifiable GnRH mRNA-containing cells between intact and castrate animals (272 +/- 14 vs. 274 +/- 36, respectively); this was the case for the total cell count as well as when the data were analyzed by anatomical region. To clarify the conflicting results on cell counts of Exps 1 and 2, we repeated the experiment a third time, again comparing both the number of GnRH mRNA-containing cells and the cellular content of GnRH mRNA. In this experiment, we observed that neither cell number nor content of GnRH mRNA differed between the intact and castrate groups. Again, this was the case for total cell count, as well as when the data were analyzed by anatomical region.(ABSTRACT TRUNCATED AT 400 WORDS)     

Precursors of sudden coronary death. Factors related to the incidence of sudden death.

Precursors of sudden death were sought in men--1838 civil servants in Albany, New York, and 2282 residents of Framingham, Massachusetts--under continuous surveillance for 16 years. In men 45-74 years old there were 234 deaths attributed to coronary heart disease (CHD) of which 109 occurred within one hour of onset of symptoms. More than half of all deaths due to CHD occurred outside the hospital and about 80 per cent of these were sudden. Most were unheralded by prior symptoms of CHD. Persons at high risk of death from CHD, including sudden death, can be identified long before the terminal unexpected catastrophe. The same precursive stigmata exist in persons subject ot coronary attacks whether or not immediately fatal. The risk of sudden death in these two populations was positively correlated with high blood pressure, the electrocardiographic pattern of left ventricular enlargement, obesity, and heavy cigarette usage. Sudden death is a common and possibly incidental expression of lethal coronary heart disease. The potential candidate for sudden death cannot be confidently distinguished from the individual who succumbs more slowly of myocardial infarction. The inescapable conclusion is that the prevention of sudden death requires the prevention of coronary attacks.     

Chronic exposure to methadone induces activated microglia and astrocyte and cell death in the cerebellum of adult male rats

Metabolic Brain Disease - Methadone is a centrally-acting synthetic opioid analgesic widely used in the methadone maintenance therapy (MMT) programs throughout the world. Considering its neurotoxic...     

Antifracture efficacy of antiresorptive agents are related to changes in bone density

There is a current debate about the extent to which antifracture efficacy of antiresorptive drugs are related to changes in bone mineral density (BMD). In vitro studies show that most of the variability in bone strength is related to BMD, and prospective studies have shown that low BMD is an important predictor of fracture risk. It seems that higher levels of bone turnover are also associated with increased fracture risk. Over the short term, a reduction in activation frequency or resorption depth would lead to fewer (and/or shallower) resorption sites and refilling of existing sites initially. There is also evidence that inhibiting resorption allows bone to respond to mechanical demands, preferentially thickening critical trabeculae, and this may help compensate for reduced connectivity. Each of these mechanisms would increase BMD and would disproportionately improve bone strength. Over the long term, maintaining bone mass and preventing loss of structural elements would result in progressively greater differences in BMD and fracture risk over time, relative to untreated women. The conceptual model predicts that both the short- and long-term antifracture efficacy of antiresorptive drugs will depend on the extent to which treatment can increase and maintain BMD. To examine this issue, we compiled data from clinical trials of antiresorptive agents and plotted the relative risk of vertebral fractures against the average change in BMD for each trial. The confidence intervals are large for individual trials, and there was substantial variability in antifracture efficacy at any given level of change in BMD. Overall, however, trials that reported larger increases in BMD tended to observe greater reductions in vertebral fracture risk. Poisson regression was used to quantify this relationship. The model predicts that treatments that increase spine BMD by 8% would reduce risk by 54%; most of the total effect of treatment was explained by the 8% increase in BMD (41% risk reduction). These findings are consistent with the short-term predictions of the conceptual model and with reports from randomized trials. The small but significant reductions in risk that were not explained by measurable changes in BMD might be related to publication bias, measurement errors, or limitations of current BMD technology.     

Cell proliferation and inhibition of apoptosis are related to c-Kit activation in leukaemic lymphoblasts

Receptor tyrosine kinase (RTK) activity may contribute to carcinogenesis. The c-Kit receptor, a member of the RTK family, is expressed in immature haematopoietic system cells. Acute lymphoblastic leukaemia (ALL) presents incompletely differentiated lymphoblasts, and consequently, c-Kit expression can be detected in these cells. The BCR-ABL kinase, which is usually present in both ALL and chronic myeloid leukaemia, can trigger signalling pathways with neoplastic effects. However, a certain number of ALL patients and chronic myeloid leukaemia patients do not express this kinase, raising the question of which other proteins that intervene in signalling pathways may be involved in the development of these diseases.

Objectives: To test whether c-Kit has proliferative effects and affects the inhibition of apoptosis of leukaemic lymphoblasts that do not express BCR-ABL.

Methods: We cultured RS4:11 lymphoblasts and analysed the expression and activation of c-Kit by immunofluorescence, and flow cytometry, evaluation of cell proliferation, apoptosis, cyclin D1 and Bak expression were carried out by flow cytometry; activation of AKT and survivin expression were tested by immunoblot.

Results: The c-Kit receptor was found to induce proliferation and to increase the expression of cyclin D1 via the PI3K/AKT/NF-kB signalling pathway. Additionally, the c-Kit/PI3K/AKT pathway increased the inhibition of apoptosis and survivin expression. Similarly, c-Kit was observed to reduce the expression of the pro-apoptotic Bak protein.

Conclusion: These results suggest that, in leukaemic lymphoblasts, c-Kit triggers a signalling pathway with proliferative and anti-apoptotic effects; information to this effect has not yet been reported in the literature.     

Variable rate of singing and variable song duration are associated with high immediate early gene expression in two anterior forebrain song nuclei

The duration of songs and the intervals between these songs are more variable when wild, adult, free-ranging chipping sparrows sing at dawn than when they sing during the day. The more variable delivery is used to interact with males, and the stereotyped delivery is used to attract females. In captive birds, however, the variability observed at dawn persists during the day. We quantified the expression of an immediate early gene, ZENK, in wild and captive birds and found that the level of song-associated ZENK expression in two song nuclei, Area X and lMAN, was positively related to variability in song duration and intersong interval and could be dissociated from the social context in which the song occurred. Thus, a combination of field and laboratory approaches helped us identify nuclei, context, and behavioral features associated with a change in gene expression thought to be a marker of behavioral variability.     

Changes in transferrin are related to changes in insulin resistance: the SLIM study

Aims To determine the effect of a lifestyle intervention on serum transferrin and ferritin levels and the relationship between changes in transferrin and ferritin and changes in glucose tolerance and insulin resistance. Methods Randomized controlled lifestyle intervention directed at a healthy diet and increased physical activity in subjects with impaired glucose tolerance. Results After 1 year, the change in ferritin levels in the intervention group as compared with the control group did not reach statistical significance (P = 0.06). Transferrin change was independently related to the change in homeostasis model assessment of insulin resistance and ferritin change was related to the change in 2‐h free fatty acids. Conclusions Changes in insulin sensitivity and postprandial lipid metabolism are related to changes in iron metabolism.     

Seasonal-like growth and regression of the avian song control system: neural and behavioral plasticity in adult male Gambel's white-crowned sparrows

Birdsong is regulated by a series of discrete brain nuclei known as the song control system. In seasonally-breeding male songbirds, seasonal changes in steroid sex hormones regulate the structure and electrophysiology of song control system neurons, resulting in dramatic changes in singing behavior. Male songbirds can be brought into the laboratory, where circulating levels of steroid hormone and photoperiod can be abruptly manipulated, providing controlled conditions under which rapid “seasonal-like” changes in behavior and morphology can be carefully studied. In this mini-review, we discuss the steroidal and cellular mechanisms underlying seasonal-like growth and regression of the song control system in adult male Gambel’s white-crowned sparrows (Zonotrichia leucophrys gambelii), and its impact on song behavior. Specifically, we discuss recent advances concerning: (1) the role of androgen and estrogen receptors in inducing seasonal-like growth of the song control system; (2) how photoperiod modulates the time course of testosterone-induced growth of the song control system; (3) how bilateral intracerebral infusion of androgen and estrogen receptor antagonists near the song control nucleus HVC prevents seasonal-like increases in song stereotypy but not song rate; and (4) the steroidal and cellular mechanisms that mediate rapid regression of the song control system. Throughout this mini-review we compare data collected from white-crowned sparrows to that from other songbird species. We conclude by outlining avenues of future research.     

Blood platelet count and function are related to total and cardiovascular death in apparently healthy men

BACKGROUND. Experimental animal and clinical studies indicate that blood platelets have an important role in atherosclerosis and formation of thrombi. Prospective studies presenting evidence of an association between blood platelet count and cardiovascular mortality have not been performed. METHODS AND RESULTS. From 1973 to 1975, blood platelets were counted, and their responsiveness to aggregating agents was studied in healthy middle-aged men. The aim was to assess the possible association between these variables and coronary heart disease. At 13.5 years of follow up, a significantly higher coronary heart disease mortality was observed among the 25% of subjects with the highest platelet counts. Platelet aggregation performed in a random subsample (150 of the 487 men), moreover, revealed that the 50% with the most rapid aggregation response after ADP stimulation had significantly increased coronary heart disease mortality compared with the others. These associations could not be explained by differences in age, lipids, blood pressure, or smoking habits. CONCLUSIONS. The present study is the first to present conclusive, prospective evidence of an association between platelet concentration and aggregability and long-term incidence of fatal coronary heart disease in a population of apparently healthy middle-aged men.     

Androgen deprivation induces phenotypic and functional changes in the thymus of adult male mice

The functional immunological consequences of thymic regeneration after castration were studied in adult male C57Bl/6 mice. Phenotypic profiles of thymocytes present in the enlarged thymuses of castrate animals demonstrated a significant decrease in the proportion of thymocytes positive for the suppressor/cytotoxic phenotype (CD4-CD8+; P = 0.005). Thymic enlargement in castrate animals was accompanied by increased capacity of thymocytes to incorporate thymidine in response to Concanavalin A in vitro. Spleens from castrate mice also were enlarged, and in vitro generation of functional suppressor cells by splenocytes from castrate animals was decreased. Testosterone replacement resulted in thymic regression, with a shift toward expression of mature thymocyte phenotypes, a decrease in the double-positive phenotype (CD4+CD8+), and a relative predominance of the CD4-CD8+ suppressor/cytotoxic phenotype over the CD4+CD8- helper phenotype. Unstimulated thymidine incorporation by thymocytes from androgen-treated animals was decreased compared to controls (P = 0.050). Spleen size was not altered by androgen administration. These findings suggest that in the adult animal, changes in androgen status effect alterations in thymocyte phenotypic profiles and thymocyte function, with removal of androgens shifting the T cell balance toward the CD4 helper subset and administration of androgens changing the balance toward CD8 suppressor/cytotoxic T cell predominance.