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Coupling between the lower and upper atmosphere, combined with loss of gas from the upper atmosphere to space, likely contributed to the thin, cold, dry atmosphere of modern Mars. To help understand ongoing ion loss to space, the Mars Atmosphere and Volatile Evolution (MAVEN) spacecraft made comprehensive measurements of the Mars upper atmosphere, ionosphere, and interactions with the Sun and solar wind during an interplanetary coronal mass ejection impact in March 2015. Responses include changes in the bow shock and magnetosheath, formation of widespread diffuse aurora, and enhancement of pick-up ions. Observations and models both show an enhancement in escape rate of ions to space during the event. Ion loss during solar events early in Mars history may have been a major contributor to the long-term evolution of the Mars atmosphere., (Copyright © 2015, American Association for the Advancement of Science.)

Background: The pattern recognition molecule pentraxin-3 (PTX3) is a novel potential marker of prognosis, as elevated levels are associated with both disease severity and mortality in patients with a wide range of conditions. However, the usefulness of PTX3 as a prognostic biomarker in a general hospital setting is unknown., Patients and Methods: The study cohort consisted of 1326 unselected, consecutive patients (age >40 years) admitted to a community hospital in Copenhagen, Denmark. Patients were followed until death or for a median of 11.5 years after admission. The main outcome measure was all-cause mortality. Serum samples collected from patients at admission and from 192 healthy control subjects were quantified for PTX3 level by enzyme-linked immunosorbent assay., Results: PTX3 was elevated in patients (median 3.7 ng mL(-1) , range 0.5-209.8) compared with healthy nonhospitalized subjects (median 3.5 ng mL(-1) , range 0.0-8.3; P = 0.0003). Elevated PTX3 levels, defined as above the 95th percentile of the concentration in healthy subjects, were associated with increased overall mortality during the study (P < 0.0001). This increase in mortality was greatest in the short term, with an unadjusted hazard ratio (HR) of 6.4 [95% confidence interval (CI) 3.8-11.0] at 28 days after admission, compared to 1.7 (95% CI 1.4-2.0) at the end of follow-up. These results were still significant after adjustment for age, gender and glomerular filtration rate: adjusted HR of 5.0 (95% CI 2.9-8.8) and 1.4 (95% CI 1.2-1.8), respectively., Conclusion: These results suggest that PTX3 could be a widely applicable marker of short-term mortality in hospitalized patients and may be useful in the initial risk stratification., (© 2014 The Association for the Publication of the Journal of Internal Medicine.)

A dual beam ion source for 200 keV ion implanter aimed to produce 200 keV H2 (+) and He(+) beams simultaneously has been developed. Not suitable to use the analyzing magnet, the purity of beam extracted from the source becomes important to the performance of implanter. The performance of ion source was measured. The results of experiments show that the materials of inlet tube of ion source, the time of arc ionization in ion source, and the amount of gas flow have significant influence on the purity of beam. The measures by using copper as inlet tube material, long time of arc ionization, and increasing the inlet of gas flow could effectively reduce the impurity of beam. And the method using the gas mass flow controller to adjust the proportion of H2 (+) and He(+) is feasible.

We aim to study the therapeutic effects of HBsAg-activated DCs and cytokine-induced killer (CIK) cells as adoptive immunotherapy in patients with Chronic Hepatitis B (CHB). Autologous HBsAg-activated DC-CIK cells were infused into patients with CHB to evaluate their effect on HBV-DNA, HBsAg, ALT, etc. The viral load in the treatment group decreased significantly (P < 0.001), while that in the control group did not decrease (P > 0.05). Twenty-one patients (63.6% efficiency) in the treatment group had a viral response (≥2 log decrease in viral load), while four patients (14.8% efficiency) from the control group had a viral response. There were significant differences in the viral responses of the two groups (the control group 63.6% versus the control group 14.8%, P < 0.001). We concluded that the immunity was enhanced after HBsAg activation in DCs and CIK cells. Reinfusion of autologous HBsAg-activated DC-CIK cells inhibited HBV proliferation in 21 of 33 (63.6%) patients., (© 2013 John Wiley & Sons Ltd.)

Summary: Slowly progressive degeneration of the hippocampal CA1 neurons was induced by 3-minute transient global ischemia in gerbils. Sustained degeneration of hippocampal CA1 neurons was evident 1 month after ischemia. To investigate the effects of an 18-mer peptide comprising the hydrophilic sequence of the rat saposin C domain (18MP) on this sustained neuronal degeneration, an intracerebroventricular 18MP infusion was initiated 3 days after ischemia. Histopathologic and behavior evaluations were conducted 1 week and 1 month after induction of ischemia. When compared with the vehicle infusion, 18MP treatment significantly increased the response latency time in a passive avoidance task. Increased neuronal density was also evident, as was the number of intact synapses in the hippocampal CA1 region at 1 week and 1 month after ischemia. 18MP treatment also significantly decreased the number of TUNEL-positive CA1 neurons 1 week after ischemia. Subsequent in vitro experiments using cultured neurons demonstrated that the 18MP at optimal extracellular concentrations of 1 to 100 fg/mL prevented nitric oxide-induced neuronal damage as expected and significantly up-regulated the expressions of bcl-x(L) mRNA and its translated protein. These results suggest that the gerbil model of 3-minute ischemia is useful in studying the pathogenesis of slowly progressive neuronal degeneration after stroke and in evaluating effects of novel therapeutic agents. It is likely that the 18MP at low extracellular concentrations prevents neuronal apoptosis possibly through up-regulation of the mitochondrial antiapoptotic factor Bcl-x(L).

Objective. To study the effects of vitamin K on bone metabolize in simulated weightlessness rats. Method. Male SD rats were divided into three groups (n = 9): the free active control (FAC), the tail-suspended control (SC), and the tail-suspended group treated with vitamin K (SVK) (50 mg/kg weight/d). The experiment lasted for 3 weeks. Bone biomechanical properties, bone mineral contents (BMC) and bone biochemical markers of bone metabolism were determined. Result. Compared with SC, total and bound bone gla protein (BGP) of serum, BMC of the femur and tibia, femoral mechanical properties, ALP activity of tibia all increased significantly; while NO content of femoral trunk decreased significantly. Conclusion. Vitamin K improved the bone metabolism and bone structure, decreased bone loss, increased bone biomechanical properties, decreased catagmatic fatalness. It proved that vitamin K prevented bone loss of simulated weightlessness rats.

Two plasmids, designated pRTI and pTI, were constructed to allow the integration of a bacterial isoamylase gene (iso) into Saccharomyces cerevisiae G23-8 chromosome. The integrative plasmid pRTI comprises the iso gene from Pseudomonas amyloderamosa, a portion of S. cerevisiae ribosomal DNA (rDNA), S. cerevisiae trp1 gene deficient in promoter and the bacterial vector pSP72. The structure of plasmid pTI is similar to that of pRTI, except that it lacks an rDNA segment. The Aspergillus awamori glucoamylase and P. amyloderamosa isoamylase genes were expressed in the recombinant strain of S. cerevisiae under the control of the yeast alcohol dehydrogenase gene (adh1) promoter. Southern-blot analysis showed that these plasmids were integrated into the yeast chromosome in tandem repeat and dispersion copies. The recombinant strains could assimilate starch more efficiently than the recipient strain with a conversion rate of greater than 95%.

Objective: To determine the taxonomic status of Anopheles kunmingensis (AK) and An. liangshanensis(AL) from China., Methods: Sequence differences of rDNA-ITS2 and main morphological characters variability between different sources of AK and AL were compared., Results: The level of rDNA-ITS2 sequence differences among eight samples was under 2.9%. The total occurrence rates of main morphological characters examined in the female mosquitoes with pale fringe spot on V5.2, white basal band (or spot) on hind tarsomere IV, and larvae with bifurcated head hair 2-C were 43%(9/21), 89%(17/19), 40(4/10) in AK, and 79%(34/43), 44%(17/39), 20%(4/20) in AL, respectively. These rates calculated from separate colonies fluctuated within a wide range and overlapped, suggesting that there was no definite, stable morphological difference between AK and AL., Conclusion: The morphological and molecular variations between AK and AL were small and belong to intraspecific level. The AK and AL may be considered as the same species, and that the An. kunmingensis may be recognized as the synonym of An. liangshanensis.

It is becoming increasingly clear that astroglial cells are active participants in the process by which information is generated and disseminated within the central nervous system (CNS). In the hypothalamus, astrocytes regulate the secretory activity of neuroendocrine neurons. They contribute to facilitating sexual development by stimulating the release of luteinizing hormone-releasing hormone (LHRH), the neuropeptide that controls sexual development, from LHRH neurons. Astrocytes secrete several growth factors able to stimulate LHRH secretion. Two members of the epidermal growth factor (EGF) family--transforming growth factor alpha (TGFalpha) and the neuregulins (NRGs)-are produced in hypothalamic astrocytes and elicit LHRH secretion indirectly, via activation of receptor complexes formed by three members of the EGF receptor family, also located on astrocytes. Activation of these receptors results in the production of at least one neuroactive substance, prostaglandin E2 (PGE2), which stimulates LHRH secretion upon binding to specific receptors on LHRH neurons. Overexpression of TGFalpha in the hypothalamus accelerates puberty, whereas blockade of either TGFalpha or NRG actions delays the process, indicating that both peptides are physiological components of the neuroendocrine mechanism that controls sexual maturation. An increase in hypothalamic expression of at least two of the erbB receptors is initiated before the pubertal augmentation of gonadal steroid secretion and is completed on the day of the first preovulatory surge of gonadotropins. This secondary increase is brought about by gonadal steroids. Estrogen and progesterone facilitate erbB-mediated glia-to-LHRH neuron communication by enhancing astrocytic gene expression of at least one of the EGF-related ligands (TGFalpha) and two of the receptors (erbB-2 and erbB-4). They also facilitate the LHRH response to PGE2 via induction of PGE2 receptors in LHRH neurons. A search for genes that may act as upstream regulators of the pubertal process resulted in the identification of two potential candidates: Oct-2, a POU domain gene originally described in cells of the immune system, and TTF-1, a member of the Nkx family of homeodomain transcriptional regulators required for diencephalic morphogenesis. The hypothalamic expression of both genes increases during juvenile development before the first hormonal manifestations of puberty take place. Their mRNA transcripts are localized to specific hypothalamic cellular subsets, where they appear to regulate different, but interactive, components of the neuronal-glial complex controlling LHRH secretion. While Oct-2 transactivates the TGFalpha promoter, TTF-1 does so to the erbB-2 and LHRH genes but inhibits preproenkephalin promoter activity, suggesting that both transcriptional regulators may act coordinately in the normal hypothalamus to activate genes involved in facilitating the advent of puberty and repress those restraining sexual development. Altogether, these observations indicate that the central activation of the pubertal process involves the participation of both neuronal and astroglial networks and the contribution of upstream transcriptional regulators acting on both the neuronal and glial components of the system.

Objective: To clarify the taxonomic status of Anopheles lesteri and An. anthropophagus in China., Methods: Using molecular identification (PCR assay and rDNA-ITS2 sequencing) to examine the field anopheline mosquito specimens from Liaoning and Shandong. According to the ITS2 sequences, molecular phylogenetic tree was made., Results: According to the molecular identification, An. lesteri and An. anthropophagus were distributed both in Liaoning Province and Shandong Province. The length and GC content of rDNA-ITS2 sequence were 451 bp, 46.2% in An. lesteri (n = 6), and 448 bp, 46.0% in An. anthropophagus (n = 10), respectively. The ITS2 sequences from presentation sites were same in An. lesteri, while the intraspecies difference in An. anthropophagus was 0.88%. The specific difference between An. lesteri and An. anthropophagus was 25.7%. By analyzing molecular phylogenetic tree, the relationship between An. lesteri and An. sinensis, An. anthropophagus and An. liangshanensis was found to be closer., Conclusion: According to the molecular identification, it was defined that An. lesteri and An. anthropophagus were sympatric independent species in China.

Activation of LH-releasing hormone (LHRH) secretion, essential for the initiation of puberty, is brought about by the interaction of neurotransmitters and astroglia-derived substances. One of these substances, transforming growth factor alpha (TGFalpha), has been implicated as a facilitatory component of the glia-to-neuron signaling process controlling the onset of female puberty in rodents and nonhuman primates. Hypothalamic hamartomas (HH) are tumors frequently associated with precocious puberty in humans. The detection of LHRH-containing neurons in some hamartomas has led to the concept that hamartomas advance puberty because they contain an ectopic LHRH pulse generator. Examination of two HH associated with female sexual precocity revealed that neither tumor had LHRH neurons, but both contained astroglial cells expressing TGFalpha and its receptor. Thus, some HH may induce precocious puberty, not by secreting LHRH, but via the production of trophic factors--such as TGFalpha--able to activate the normal LHRH neuronal network in the patient's hypothalamus.

Activation of erbB-1 receptors by glial TGFalpha has been shown to be a component of the developmental program by which the neuroendocrine brain controls mammalian sexual development. The participation of other members of the erbB family may be required, however, for full signaling capacity. Here, we show that activation of astrocytic erbB-2/erbB-4 receptors plays a significant role in the process by which the hypothalamus controls the advent of mammalian sexual maturation. Hypothalamic astrocytes express both the erbB-2 and erbB-4 genes, but no erbB-3, and respond to neuregulins (NRGs) by releasing prostaglandin E(2) (PGE(2)), which acts on neurosecretory neurons to stimulate secretion of luteinizing hormone-releasing hormone (LHRH), the neuropeptide controlling sexual development. The actions of TGFalpha and NRGs in glia are synergistic and involve recruitment of erbB-2 as a coreceptor, via erbB-1 and erbB-4, respectively. Hypothalamic expression of both erbB-2 and erbB-4 increases first in a gonad-independent manner before the onset of puberty, and then, at the time of puberty, in a sex steroid-dependent manner. Disruption of erbB-2 synthesis in hypothalamic astrocytes by treatment with an antisense oligodeoxynucleotide inhibited the astrocytic response to NRGs and, to a lesser extent, that to TGFalpha and blocked the erbB-dependent, glia-mediated, stimulation of LHRH release. Intracerebral administration of the oligodeoxynucleotide to developing animals delayed the initiation of puberty. Thus, activation of the erbB-2-erbB-4 receptor complex appears to be a critical component of the signaling process by which astrocytes facilitate the acquisition of female reproductive capacity in mammals.

It is now clear that astroglial cells actively contribute to both the generation and flow of information within the central nervous system. In the hypothalamus, astrocytes regulate the secretory activity of neuroendocrine neurons. A small subset of these neurons secrete luteinizing hormone-releasing hormone (LHRH), a neuropeptide essential for sexual development and adult reproductive function. Astrocytes stimulate LHRH secretion via cell-cell signaling mechanisms involving growth factors recognized by receptors with either serine/threonine or tyrosine kinase activity. Two members of the epidermal growth factor (EGF) family and their respective tyrosine kinase receptors appear to play key roles in this regulatory process. Transforming growth factor-alpha (TGFalpha) and its distant congeners, the neuregulins (NRGs), are produced in hypothalamic astrocytes. They stimulate LHRH secretion indirectly, via activation of erbB-1/erbB-2 and erbB-4/erbB-2 receptor complexes also located on astrocytes. Activation of these receptors leads to release of prostaglandin E(2) (PGE(2)), which then binds to specific receptors on LHRH neurons to elicit LHRH secretion. Gonadal steroids facilitate this glia-to-neuron communication process by acting at three different steps along the signaling pathway. They (a) increase astrocytic gene expression of at least one of the EGF-related ligands (TGFalpha), (b) increase expression of at least two of the receptors (erbB-4 and erbB-2), and (c) enhance the LHRH response to PGE(2) by up-regulating in LHRH neurons the expression of specific PGE(2) receptor isoforms. Focal overexpression of TGFalpha in either the median eminence or preoptic area of the hypothalamus accelerates puberty. Conversely, blockade of either TGFalpha or NRG hypothalamic actions delays the process. Thus, both TGFalpha and NRGs appear to be physiological components of the central neuroendocrine mechanism controlling the initiation of female puberty. By facilitating growth factor signaling pathways in the hypothalamus, ovarian steroids accelerate the pace and progression of the pubertal process., (Copyright 1999 John Wiley & Sons, Inc.)

POU homeodomain genes are transcriptional regulators that control development of the mammalian forebrain. Although they are mostly active during embryonic life, some of them remain expressed in the postnatal hypothalamus, suggesting their involvement in regulating differentiated functions of the neuroendocrine brain. We show here that Oct-2, a POU domain gene originally described in cells of the immune system, is one of the controlling components of the cell-cell signaling process underlying the hypothalamic regulation of female puberty. Lesions of the anterior hypothalamus cause sexual precocity and recapitulate some of the events leading to the normal initiation of puberty. Prominent among these events is an increased astrocytic expression of the gene encoding transforming growth factor-alpha (TGF alpha), a tropic polypeptide involved in the stimulatory control of LHRH secretion. The present study shows that such lesions result in the rapid and selective increase in Oct-2 transcripts in TGF alpha-containing astrocytes surrounding the lesion site. In both lesion-induced and normal puberty, there is a preferential increase in hypothalamic expression of the Oct-2a and Oct-2c alternatively spliced messenger RNA forms of the Oct-2 gene, with an increase in 2a messenger RNA levels preceding that in 2c and antedating the peripubertal activation of gonadal steroid secretion. Both Oct-2a and 2c trans-activate the TGF alpha gene via recognition motifs contained in the TGF alpha gene promoter. Inhibition of Oct-2 synthesis reduces TGF alpha expression in astroglial cells and delays the initiation of puberty. These results suggest that the Oct-2 gene is one of the upstream components of the glia to neuron signaling process that controls the onset of female puberty in mammals.

Prostaglandin E2 (PGE2) mediates the stimulatory effect of norepinephrine (NE) on the secretion of luteinizing hormone-releasing hormone (LHRH), the neuropeptide controlling reproductive function. In rodents, this facilitatory effect requires previous exposure to estradiol, suggesting that the steroid affects downstream components in the cascade that leads to PGE2-induced LHRH release. Because astroglia are the predominant cell type contacting LHRH-secreting nerve terminals, we investigated the involvement of hypothalamic astrocytes in the estradiol facilitation of PGE2-induced LHRH release. A subpopulation of LHRH neurons was found to express the mRNA encoding the PGE2 receptor subtype EP1-R, which is coupled to calcium mobilization. The LHRH-producing cell line GT1-1 also contains EP1-R mRNA and, to a lesser extent, the three alternatively spliced forms of EP3-R mRNA (alpha, beta, and gamma) that encode receptors linked to inhibition and stimulation of cAMP formation. Hypothalamic astrocytes treated with estradiol produced a conditioned medium that when applied to GT1-1 cells resulted in a selective upregulation of EP1-R and EP3gamma-R mRNAs. The conditioned medium also enhanced the LHRH response to EP1-R and EP3-R agonists and the cAMP response to EP3-R activation. Thus, one mechanism by which estradiol facilitates the effect of neurotransmitters acting via PGE2 to stimulate LHRH release is by enhancing the glial production of substances that upregulate PGE2 receptors on LHRH neurons. The existence of such a mechanism underscores the emerging importance of glial-neuronal communication in the control of brain neurosecretory activity.

In mammalian species, ovulation occurs following a massive release of hypothalamic gonadotropin-releasing hormone (GnRH). Several chemicals, including norepinephrine (NE) and neuropeptide Y (NPY), are responsible for the initiation and/or magnitude and duration of this pre-ovulatory GnRH surge. In the central nervous system, NE neural cell bodies are located in the brainstem; some are co-localized with NPY neurons and/or co-express the NE transporter (NET) gene which dictates NET protein production. The activity of NET at NE terminals is critical for synaptic NE function. In the rabbit, coitus induces a hypothalamic NE release which precedes the GnRH surge. We hypothesize that the coital stimulus is transmitted to the brainstem and transformed and integrated into GnRH-stimulating signals via NE, NET and/or NPY. However, very little is known about the distribution of cells expressing NET, NPY and tyrosine hydroxylase (TH, the rate-limiting enzyme of NE synthesis) in this species. Therefore, we utilized the sensitive in situ hybridization technique to identify the presence of these messages in conjunction with the location of NE cells, the latter being marked by dopamine beta-hydroxylase (DBH), the specific enzyme for NE synthesis. Three non-mated New Zealand White does were perfused with 4% paraformaldehyde and their brainstems were sectioned at 20-micron thick between 2 mm caudal to the obex and the rostral pons. Serial sections were immunohistochemically stained for DBH and hybridized with rabbit-specific TH and NET cRNAs and a human NPY probe. The data suggest that several DBH-positive areas in the medulla expressed one or more messages, i.e. the lateral tegmentum (A1) and the nucleus of the solitary tract (A2) expressed all three mRNAs, the area postrema (AP) contained NET and TH mRNAs but not NPY cells. In the pons, the locus coeruleus (LC), subnucleus of coeruleus (LCs) and lateral tegmental nuclei (A5) expressed NET and TH mRNAs but contained little or no NPY message. The distribution patterns of TH and NET appeared to be similar in the LC, LCs, A2 and AP.

The concept is proposed that the central control of mammalian female puberty requires the interactive participation of neuronal networks and glial cells of the astrocytic lineage. According to this concept neurons and astrocytes control the pubertal process by regulating the secretory activity of those neurons that secrete luteinizing hormone-releasing hormone (LHRH). LHRH, in turn, governs sexual development by stimulating the secretion of pituitary gonadotropins. Astrocytes affect LHRH neuronal function via a cell-cell signaling mechanism involving several growth factors and their corresponding receptors. Our laboratory has identified two members of the epidermal growth factor/transforming growth factor (EGF/TGF alpha) family as components of the glial-neuronal interactive process that regulates LHRH secretion. Transforming growth factor alpha (TGF alpha) and its distant congener neu-differentiation factor, NDF, are produced in hypothalamic astrocytes and stimulate LHRH release via a glial intermediacy. The actions of TGF alpha and NDF on hypothalamic astrocytes involve the interactive activation of their cognate receptors and the synergistic effect of both ligands in stimulating the glial release of prostaglandin E2 (PGE2). In turn, PGE2 acts directly on LHRH neurons to stimulate LHRH release. A variety of experimental approaches has led to the conclusion that both TGF alpha and NDF are physiological components of the central mechanism controlling the initiation of female puberty.

Emerging evidence suggests that, in addition to neuronal inputs, growth factors of glial origin are also important in the control of mammalian puberty via a cell-cell interaction that ultimately affects the neurons that release gonadotropin-releasing hormone (GnRH), a neurohormone controlling sexual development. Among these growth factors, transforming growth factor-alpha (TGF alpha) appears to be one of the physiologic components that controls the onset of female puberty by affecting GnRH neuronal activity in a glia-mediated autocrine/paracrine manner. Specifically, TGF alpha induces glia to produce bioactive substances, such as prostaglandin E2 (PGE2). In turn, PGE2 directly acts on GnRH neurons to stimulate the release of GnRH. Furthermore, the neuroregulin of glial origin neu differentiation factor (NDF) was found to facilitate the action of TGF alpha, suggesting that other growth factors may exert their biologic effects on GnRH neuronal function via a glia/neuron interaction. Another indication that glial cells may be involved in the regulation of neuroendocrine function is the presence of estrogen receptors on hypothalamic astrocytes. Thus, region-specific glial cells appear to play an integral role in the regulation of neuroendocrine function.

Previous studies demonstrated the involvement of transforming growth factor-alpha (TGF alpha), a member of the epidermal growth factor (EGF) family, in the developmental regulation of hypothalamic LHRH release. Although both TGF alpha and EGF stimulate LHRH release, they do not appear to act directly on LHRH neurons, as no EGF/TGF alpha receptors are detected on these cells in vivo. Instead, the stimulatory effect of TGF alpha on LHRH release seems to require a glial intermediacy. The present study identifies one of the glial molecules involved in this process. In vitro exposure of purified hypothalamic astrocytes to TGF alpha or EGF in a defined medium led to activation of the cyclooxygenase-mediated pathway of arachidonic acid metabolism, as indicated by an increase in PGE2 release, but failed to affect lipooxygenase-mediated metabolism, as assessed by the lack of increase in leukotriene C4 production; addition of TGF alpha- (T-CM) or EGF-conditioned medium to cultures of LHRH-producing GT1-1 cells stimulated LHRH release. In contrast, direct exposure of GT1-1 cells to the growth factors was ineffective. Incubation of the cells in medium conditioned by untreated astrocytes (CM) was also ineffective. Blockade of either EGF receptor signal transduction or cyclooxygenase activity in the astrocytic cultures prevented both TGF alpha-induced PGE2 formation in astrocytes and the stimulatory effect of T-CM on LHRH release. Immunoneutralization of PGE2 actions or selective removal of the PG from T-CM also prevented T-CM-induced LHRH release. Addition of exogenous PGE2 restored the effect. Thus, PGE2 is one of the glial molecules involved in mediating the stimulatory effect of TGF alpha on LHRH release. The effectiveness of PGE2 in eliciting LHRH release was, however, greatly reduced when PG was delivered to GT1-1 cells in astrocyte-defined medium instead of CM. Thus, astrocytes appear to produce a yet to be identified substance(s) that facilitates the stimulatory effect of PGE2 on LHRH output. We postulate that the ability of TGF alpha to enhance LHRH release depends on the potentiating interaction of PGE2 with these additional glial-derived molecules.

Studies in female rats have shown that transforming growth factor alpha (TGF alpha) stimulates release of luteinizing hormone-releasing hormone (LHRH), the neuropeptide controlling sexual maturation, and that expression of the TGF alpha gene in the hypothalamus increases during both the initiation of normal puberty and after hypothalamic lesions that induce sexual precocity. Since blockade of epidermal growth factor receptors (EGFR), which mediate TGF alpha actions, delayed the normal timing of puberty, it was postulated that TGF alpha/EGFR contributes to the neuroendocrine process that underlies the initiation of normal female puberty. The present study was undertaken to examine the hypothesis that hypothalamic expression of the TGF alpha gene and its receptor changes in relation to the stage of sexual development in nonhuman primates, and to determine whether these changes are accompanied by corresponding alterations in LHRH gene expression. DNA fragments complementary to the coding regions of the rhesus monkey TGF alpha, EGFR and LHRH genes were cloned by reverse transcription-polymerase chain reaction (RT-PCR), sequenced and used to prepare monkey-specific antisense RNA probes. A quantitative RT-PCR was developed in which the cloned sequences were utilized to prepare RNA standards for the quantitation of tissue mRNA levels. Both TGF alpha and EGFR mRNA levels in the medial basal hypothalamus and preoptic area of female monkeys were elevated during neonatal life (1 week to 6 months of age), when FSH secretion is also high, decreased during juvenile development (8-18 months of age), when secretion of both FSH and LH is low, and markedly increased during the expected time of puberty (30-36 months of age). No such changes were observed in either the cerebellum or the cerebral cortex, two brain regions irrelevant to neuroendocrine reproductive control. In contrast to the pronounced alterations in hypothalamic TGF alpha/EGFR gene expression observed during sexual development, LHRH mRNA levels did not vary significantly during this time. Hybridization histochemistry revealed the presence of both TGF alpha and EGFR mRNAs in cells scattered throughout the hypothalamus, but more predominantly in the median eminence, suprachiasmatic nuclei, optic chiasm and cells along the wall of the third ventricle. These results demonstrate that increases in TGF alpha and EGFR gene expression, specific to the neuroendocrine brain, occur during developmental phases in which gonadotropin output is also elevated--most noticeably at the time of puberty.(ABSTRACT TRUNCATED AT 400 WORDS)

Certain glial cells of the hypothalamus have been implicated in the neuroendocrine control of reproductive development. Hypothalamic astrocytes appear to exert this function via a cell-cell interactive mechanism that involves the production of transforming growth factor alpha (TGF alpha), a polypeptide able to affect both glial and neuronal functions in the CNS. In the hypothalamus, TGF alpha stimulates neuronal secretion of luteinizing hormone-releasing hormone (LHRH), the neuropeptide controlling sexual development, via activation of epidermal growth factor receptors (EGFR). Since astrocytes but not LHRH neurons express EGFR, it has been postulated that the stimulatory effect of TGF alpha on LHRH release is not exerted directly on LHRH neurons, but rather via glial intermediacy. The present experiments were undertaken to define whether TGF alpha is able to exert paracrine/autocrine effects on isolated hypothalamic astrocytes, and to determine if estradiol-previously shown to increase TGF alpha mRNA levels in the hypothalamus of immature animals--can act directly on hypothalamic astrocytes to upregulate TGF alpha gene expression. Treatment with either TGF alpha or its structural homolog, epidermal growth factor (EGF), increased TGF alpha mRNA levels within 8 hr of exposure; the phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate (TPA) was similarly effective. Blockade of EGFR with either tyrphostin RG-50864, an inhibitor of tyrosine kinase activity, or a monoclonal antibody that prevents ligand binding abolished the upregulatory effect of TGF alpha on TGF alpha mRNA levels. In contrast to hypothalamic astrocytes, cerebellar astrocytes did not respond to either TGF alpha or EGF with changes in TGF alpha mRNA abundance.(ABSTRACT TRUNCATED AT 250 WORDS)

Recent findings have led to the concept that transforming growth factor alpha (TGF alpha) contributes to the neuroendocrine regulation of female puberty by stimulating the release of luteinizing hormone-releasing hormone (LHRH), the neurohormone controlling sexual development. It was postulated that this effect is mediated by epidermal growth factor receptors (EGFR) and that EGFR may not be located on LHRH neurons, so that TGF alpha-induced LHRH release would require an intermediate cell-to-cell interaction, presumably of glial-neuronal nature. The present study was undertaken to characterize the presence of EGFR in rat hypothalamus and to determine if changes in EGFR gene expression and EGFR protein occur at the time of puberty. RNA blot hybridization demonstrated that the hypothalamus expresses all mRNA species known to encode EGFR. RNase protection assays revealed that alternative splicing of the EGFR primary mRNA transcript occurs in the hypothalamus and produces a predominant transcript encoding the full-length EGFR and a much less abundant, shorter mRNA encoding a truncated, and presumably secreted form of EGFR. EGFR-like immunoreactive material was found in several hypothalamic regions including the organum vasculosum of the lamina terminalis, supraoptic, suprachiasmatic, and paraventricular nuclei, ependymal cells lining the third ventricle, some astrocytes associated with blood vessels, astrocytes of the pial surface, and tanycytes and glial cells of the median eminence (ME). Low levels of EGFR mRNA were detected by hybridization histochemistry in cells of the same areas containing EGFR-like immunoreactivity. Double-immunohistochemistry revealed that even though LHRH neurons are in close proximity to EGFR-positive cells, they do not contain EGFR. In the ME, EGFR-immunonegative LHRH nerve terminals tightly coexist with EGFR-positive cells, presumably tanycytes and glial astrocytes. EGFR mRNA levels measured by quantitative reverse transcription-polymerase chain reaction assay (RT-PCR) in the ME-arcuate nucleus region at the time of puberty decreased in the morning of the first proestrus, i.e., preceding the first preovulatory surge of gonadotropins, and rebounded at the time of the surge. Functional EGFR protein levels, detected by the ability of the receptor to autophosphorylate in response to ligand or divalent antibody-induced activation, changed in a similar manner at the time of puberty. No such changes were observed in the cerebellum, a brain region irrelevant to neuroendocrine reproductive control. These results demonstrate the existence of EGF receptors in the prepubertal female rat hypothalamus and suggest that changes in EGFR gene expression and biologically active EGFR protein contributes to the neuroendocrine process underlying the first preovulatory surge of gonadotropins.(ABSTRACT TRUNCATED AT 250 WORDS)

117 cases of acute arsenic poisoning, caused by ingestion of food contaminated by As2O2, presented with abdominal pain, vomiting, nausea and diarrhea. The average level of urinary arsenic was 3.926 mg/L. The incidence of neuritis, poisoning hepatopathy and abdominal ECG was respectively 7.7%, 32.54%, 35.9%. All the cases recovered after oral or parenteral administration of dimecapto succinate (DMS) in six weeks. DMS is the drug of choice in the treatment of arsenic poisoning.

The effect in preventing and treating glycerol-induced acute renal failure (ARF) in rabbit with Ligusticum wallichii (LW) has been studied. 33 male and female rabbits weighing 2.0-3.0 Kg were divided into three groups randomly: (1) LW treated group. (2) pathological control group and (3) normal control group. The measurement of plasma 6-keto-PGF1 alpha, TXB2 concentration and 6-keto-PGF1 alpha/TXB2 ratio were carried out with radioimmunoassay after 24 hr, 48 hr and 72 hr of ARF. The results showed that plasma TXB2 concentration obviously increased (P < 0.01), 6-keto-PGF1 alpha concentration had no obvious changes (P > 0.05), 6-keto-PGF1 alpha/TXB2 ratio markedly decreased and LW could reduce plasma TXB2 concentration, slightly increase the plasma 6-keto-PGF1 alpha concentration, keep 6-keto-PGF1 alpha/TXB2 ratio in normal level after ARF. It showed that LW could inhibit effectively platelet activation, correct 6-keto-PGF1 alpha/TXB2 imbalance and have a preventing and treating effect for ARF.

Expression of p53 protein was examined in 67 cases of primary transitional cell carcinoma of the bladder and 6 normal controls using an immunohistochemical method on paraffin sections. Positive nuclear staining for p53 in malignant cells was found in 34 (51%) of the 67 cancer patients; no positive staining for p53 was detected in any of the normal controls or in the benign cells, including stromal and inflammatory cells, within the tumor tissue. There were 8 positive cases (33%) in 24 grade G1 tumors, 12 (48%) in 25 G2 tumors and 14 (78%) in 18 G3 tumors. p53 protein was detected positively in 14 (36%) of 39 superficial tumors (Tis-T1) and in 20 (71%) of 28 invasive tumors (T2-T4). Thus, positive staining for p53 was found more frequently in poorly differentiated tumors (chi-squared test: G3/G1 + G2 P < 0.01) and in invasive tumors (chi-squared test: T2-T4/Tis-T1 P < 0.01). Expression of p53 was also closely associated with recurrence of tumors. Alterations in p53 expression may be of prognostic value in cases of bladder transitional cell carcinoma.

Expression of the ras and the c-erbB-2 oncogene products was investigated in 56 cases of human bladder transitional cell carcinoma and 6 samples of human normal bladder tissue using an immunohistochemical method. Thirty of the 56 cases of bladder tumor were found to be immunohistologically positive with the monoclonal anti-ras p21 antibody, while 19 of 56 cases were positive with the polyclonal anti-c-erbB-2 oncoprotein antibody. All 6 controls were negative with both antibodies. The ras p21 positive staining was found more frequently in the well or moderately differentiated, superficial and non-recurrent tumors than in the poorly differentiated (p < 0.01), muscle invasive (p < 0.05) and recurrent tumors (p < 0.01), while the c-erbB-2 gene product was more commonly detected in high-grade (p < 0.01), invasive (p < 0.01) and recurrent tumors (p < 0.05). Thus, the expression of either ras or c-erbB-2 was closely associated with the histological grade, clinical stage and recurrence of bladder transitional cell carcinomas.

The DNA-Malignancy-Grade(DNA-MG) of paraffin-embedded tumor specimens from 38 patients with bladder tumor was determined by image cytometry. A good correlation was found of DNA-MG with clinical staging and histopathological grading. The DNA-MG of T1 and G1 bladder tumor was less than 3.00, while that of T3-4 and G3 bladder tumor was greater than 3.00. The 5-year survival of patients with DNA-MG < 3.00 and > 3.00 was 100% and 36.9%, respectively. The data indicate that DNA-MG plays an important role in the assessment of the prognosis and the planning of treatment.

Hypothalamic injury causes female sexual precocity by activating luteinizing hormone-releasing hormone (LHRH) neurons, which control sexual development. Transforming growth factor-alpha (TGF-alpha) has been implicated in this process, but its involvement in normal sexual maturation is unknown. The present study addresses this issue. TGF-alpha mRNA and protein were found mostly in astroglia, in regions of the hypothalamus concerned with LHRH control. Hypothalamic TGF-alpha mRNA levels increased at times when secretion of pituitary gonadotropins--an LHRH-dependent event--was elevated, particularly at the time of puberty. Gonadal steroids involved in the control of LHRH secretion increased TGF-alpha mRNA levels. Blockade of TGF-alpha action in the median eminence, a site of glial-LHRH nerve terminal association, delayed puberty. These results suggest that TGF-alpha of glial origin is a component of the developmental program by which the brain controls mammalian sexual maturation.

We previously demonstrated that the immature rat ovary synthesizes nerve growth factor (NGF), and that interference of NGF actions by immunoneutralization during neonatal life prevents development of the ovarian sympathetic innervation and delays follicular maturation. Since the actions of NGF are exerted via binding to specific cell surface receptors, the present study was undertaken to define and characterize the presence of NGF receptors (NGFrec) in the developing rat ovary. NGF interacts with two classes of NGFrec. The most abundant is a low affinity form expressed in the central nervous system and peripheral tissues. This receptor is encoded by a single 3.8-kilobase mRNA species. Cross-linking of [125I]NGF to ovarian membranes followed by immunoprecipitation, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and autoradiography showed the presence of a approximately 90-kilodalton molecular species which corresponds in size to the predominant NGF receptor species cross-linked to its ligand. While ovarian NGFrec may be of neuronal origin and reach the gland exclusively by anterograde axonal transport, RNA blot hybridization demonstrated that the ovary expresses the NGFrec mRNA species that encodes the low affinity NGF receptor and, thus, implicated the ovary itself as a site of NGFrec synthesis. NGFrec mRNA levels decreased abruptly after the first ovulation, suggesting that NGFrec may be synthesized in growing follicles and that this capacity is lost after follicular rupture and luteinization.(ABSTRACT TRUNCATED AT 250 WORDS)

The content of GnRH and its precursor peptide were quantified in female rats bearing lesions in the anterior medial preoptic nucleus (AMPO) and the suprachiasmatic nucleus (SCN), and the effects of the lesions on the synthetic activity of the GnRH neurons were evaluated. Electrolytic lesions which induced persistent estrous (PE), or irregular estrous cycles, were produced by passing 5-10 microA of direct current into the AMPO or the SCN of female rats which exhibited regular 4 days estrous cycles before the lesions. Approximately 5 weeks after lesion placement, blood samples were withdrawn from catheterized, freely moving animals and plasma LH, PRL, estrogen, and progesterone were determined by RIA. The preovulatory surges of LH and PRL were eliminated in AMPO- or SCN-lesioned PE rats. Moreover, the LH surge was eliminated and the PRL surge significantly attenuated after estrogen and progesterone treatment of rats bearing complete lesions, irrespective of the presence of ovaries. Irregular cycling animals with incomplete AMPO or SCN lesions, exhibited attenuated LH surge and PRL surge similar to proestrous controls. In one incidence this occurred spontaneously, and could also be induced by sequential estrogen and progesterone injections. After ovariectomy, plasma LH levels were significantly lower in the lesioned animals as compared to sham operated rats (P less than 0.05). Similar secretory patterns of LH and PRL were obtained from a second series of sham-operated rats during the different stages of the estrous cycle or from AMPO- or SCN-lesioned rats during persistent estrus. After 2 months the animals were killed between 0830 and 0930 h, and the preoptic area and the basal hypothalamus were microdissected from the brain sections. After extraction and purification, proGnRH and GnRH levels were measured by RIA. ProGnRH levels in the preoptic area were significantly reduced in AMPO- or in SCN-lesioned rats, compared to proestrous controls (P less than 0.01). In contrast, GnRH levels in either area did not differ in AMPO- or in SCN-lesioned animals compared to sham-operated, proestrous controls. Therefore, lesions of the AMPO or the SCN produce PE and reduce proGnRH without reducing GnRH levels. These data would suggest that the AMPO and the SCN participate in the control of the estrous cycle and are necessary for preovulatory surges of PRL and LH to occur and that the AMPO and the SCN form part of the neural circuit that regulates GnRH synthesis and/or release.

We analyzed the cause of blindness in 60 people with intracranial tumors. Twenty-three (38.3%) had binocular blindness, thirty-seven (61.2%) had monocular blindness. The most common tumors producing blindness were pituitary chromophobe adenomas and craniopharyngiomas. Blindness in this series resulted usually from intracranial tumors, which directly or indirectly involved the optic nerve or optic chiasma. These tumors were sometimes misdiagnosed when these patients were first examined by physicians. Specific ophthalmic examinations should permit the diagnosis to be made earlier.