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SummaryCell type-specific transcriptional differences between brain tissues from donors with Alzheimer’s disease (AD) and unaffected controls have been well-documented, but few studies have rigorously interrogated the regulatory mechanisms responsible for these alterations. We performed single nucleus multiomics (snRNA-seq+snATAC-seq) on 105,332 nuclei isolated from cortical tissues from 7 AD and 8 unaffected donors to identify candidate cis-regulatory elements (CREs) involved in AD-associated transcriptional changes. We detected 319,861 significant correlations, or links, between gene expression and cell type-specific transposase accessible regions enriched for active CREs. Among these, 40,831 were unique to AD tissues. Validation experiments confirmed the activity of many regions, including several candidate regulators of APP expression. We identified ZEB1 and MAFB as candidate transcription factors playing important roles in AD-specific gene regulation in neurons and microglia, respectively. Microglial links were globally enriched for heritability of AD risk and previously identified active regulatory regions.

Polyamines have fundamental roles in brain homeostasis as key modulators of cellular excitability. Several studies have suggested alterations in polyamine metabolism in stress related disorders, suicide, depression, and neurodegeneration, making the pharmacological modulation of polyamines a highly appealing therapeutic strategy. Polyamines are small aliphatic molecules that can modulate cationic channels involved in neuronal excitability. Previous indirect evidence has suggested that polyamines can modulate anionic GABAA receptors (GABAARs), which mediate inhibitory signaling and provide a direct route to reduce hyperexcitability. Here, we attempted to characterize the effect that spermine, the polyamine with the strongest reported effect on GABAARs, has on human postmortem native GABAARs. We microtransplanted human synaptic membranes from the dorsolateral prefrontal cortex of four cases with no history of mental or neurological disorders, and directly recorded spermine effects on ionic GABAARs responses on microtransplanted oocytes. We show that in human synapses, inhibition of GABAARs by spermine was better explained by alkalization of the extracellular solution. Additionally, spermine had no effect on the potentiation of GABA-currents by diazepam, indicating that even if diazepam binding is enhanced by spermine, it does not translate to changes in functional activity. Our results clearly demonstrate that while extracellular spermine does not have direct effects on human native synaptic GABAARs, spermine-mediated shifts of pH inhibit GABAARs. Potential spermine-mediated increase of pH in synapses in vivo may therefore participate in increased neuronal activity observed during physiological and pathological states, and during metabolic alterations that increase the release of spermine to the extracellular milieu.

Zusammenfassung Dieses ubersichtsreferat bringt Ergebnisse einer Arbeitsgruppe aus Edinburgh, die in den letzten 15 Jahren den Silierungsprozes untersucht hat. Die Grundlagen der Silie-rung werden besprochen, und Angaben werden gemacht uber Ausrustung, chemische Methoden und bakteriologische Verfahren. Beschrieben werden Einflusse soldier Fak-toren, wie Feuchtigkeit und Temperatur einerseits, chemischer Zusammensetzung, physikalischer Beschaffenheit und Mikroflora des Ausgangsmaterials andererseits, auf den Silierungsprozes. Die Entwicklung von Clostridien zu verhindern durch schnelle Erzeugung und Aufrechterhaltung anaerober Bedingungen und durch Erhohung des Trockensubstanzgehaltes im Ausgangsmaterial auf bis zu 30 % wird als besonders wichtig angesehen.

Packages containing radioactive materials are transported by air to, from and within the UK, and this paper describes the results of the latest survey of these operations. The majority of the materials being shipped are destined for medical uses. Cargo handlers involved in the handling of radioactive materials at airports were found to receive annual exposures of up to some 2 mSv. Aircrew members on the flight deck and in cabin areas are estimated to receive annual doses below 0·2 mSv from such packages. On passenger aircraft, packages of radioactive materials are generally carried daily on the same routes and at the same times. There was no evidence of a passenger routinely flying on the same flight as radioactive cargo. However, using the most conservative assumptions of such routine travel, this would result in a potential annual dose of around 0·2 mSv.

An in depth study has been made of the optical properties of a series of non-thermochromic chiral nematic materials to determine the influence of refractive index dispersion on pitch measurements. The materials used were mixtures of a chiral nematic material, BL131a, and a nematic material BL130 (from Merck Ltd.) in which the pitch is changed by varying the concentration of the nematic component. Detailed measurements were made of the ordinary and extraordinary refractive indices as a function of wavelength across the visible spectrum. Dispersion effects changed the birefringence by approximately 10% across the visible spectrum. Reflection spectra were obtained and used to deduce the helicoidal pitch. Failure to include dispersion in the calculation led to a significant error in calculations of both the bandwidth and pitch of the material. Finally, as SSCT devices are electro-optic in nature, the influence of the conducting surface of the device on the optical properties is examined.

Cellulose nitrate membranes were embedded with two different commercially available liquid crystals and the transport of a model drug through the membranes was examined spectrophotometrically. It was found that upon changing the temperature of the system, membranes without liquid crystal showed no temperature dependent drug transport properties. Membranes embedded with liquid crystal however, showed a distinct temperature variation in the drug release. It was found that the rate of drug transport was dependent on the amount of liquid crystal deposited on the membrane and by cycling the temperature of the system, pulsatile drug release could be achieved.

DSC and optical microscopy were used to study the phase behaviour of blends of two members of a group of side-chain cholesteric liquid crystalline silicones. One of these siloxane-based polymers forms a single blue phase. The experimental phase diagram is constructed and then compared to the case in which one of the polymers is replaced by a chiral nematic liquid crystal, which also forms a blue phase.

The director reorientation in the liquid crystals (LCs) cells initiated by the trans‐cis isomerization of azo-dyes was studied with the aid of pump‐probe‐beam experiments. Two diAerent types of the samples were used, namely, a planar aligned LC layer, doped with an azo-dye, placed between substrates coated with rubbed poly(vinyl alcohol) (PVA) films, and an undoped LC layer placed between substrates, one of which (input) was coated with an untreated azopolymer film and other one was coated with rubbed PVA film. The cells were excited with nanosecond pulses of the second harmonic of an Nd:YAG laser. By comparing the reorientation dynamics with the help of dynamic holography method in both samples it was established that the values of development times of the orientational eAects were the same. The reorientation develops within 15‐17 ls and the eAciency of the orientational gratings is 13‐15%. In both kinds of samples the director orientation on the output surface with the rubbed PVA coating was not changed after irradiation. Contrary, the orientation of the director on the input substrate was changed in both cases. In case of a LC cell with azo-modified surface the reorientation is due to the photoisomerization of the azo-polymer film. In case of the cell with azo-dye-doped LC layer the photoisomerization of dye in the bulk of LC together with PVA film rearrangement on input substrate exert an influence on the director reorientation. ” 2000 Elsevier Science B.V. All rights reserved.

A waveguide absorber is a device mounted on a vibrating structure at the selected points to transfer energy from the structure to the device which dampens the energy. The waveguide absorbers reported here are made of viscoelastic material which absorbs vibration energy and dissipates it in the form of heat. The novelty of this approach to damping is the simplicity of application and the effectiveness in the broadband frequency range with relatively less material. In this study, the impedances of the circular viscoelastic waveguide absorbers were evaluated experimentally at different temperatures and the results were compared with those of prediction. The application of the waveguide absorbers in the most effective manner to maximize damping of the structure is also studied. The impedance matching techniques were studied to minimize the vibration amplitude of the structure.

The performance of three different types of spirals and a 200 mm diameter water washing cyclone have been assessed in open-circuit on-site testwork at the Norwich Park preparation plant on nominally 500 µ x 75 µm sized coal. The study is part of a program investigating alternative methods to heavy media cyclones and froth flotation for removing ash from fine coal from Central Queensland mines in the nominally 3 mm x 75 µm size range. The two spirals specifically developed for treating fine coal showed better cleaning efficiencies than the water washing cyclone on the +75 µm size fraction in the feed (essentially 1 mm top size). Their single start capacity was about half that of the water washing cyclone for the same clean coal ash content. The spirals readily produced a high ash reject (> 81%) in a single stage and, with the appropriate splitter configuration, a small middlings suitable for retreatment. Middlings splitter setting and vortex finder position (for the water washing cyclone) both provided rea...

Uranium oxides have been used as colourants in glassware since the 19th century and this type of glass is commonly referred to as vaseline glass. There are many collectors of vaseline glass in the UK who obtain pieces from the UK antiques market or from abroad. Dose rate measurements were made for a number of items of vaseline glass, and the uranium content of one item was measured. Potential doses to collectors were considered, along with implications for trade and transport due to the uranium content of the glassware. It was concluded that generally items of vaseline glass could give rise to low skin doses from beta radiation, though frequent wearing of necklaces made from vaseline glass may lead to doses in excess of the HPA (Health Protection Agency) dose criterion for consumer products that are not related to safety. Registration under the Radioactive Substances Act will not be required and almost all items of vaseline glass should be suitable for sending through the Royal Mail. For those items not accepted by Royal Mail, it is understood that the transport regulations for radioactive materials would not apply.

While there has been a great deal of interest in the role of brain-derived neurotrophic factor (BDNF) in mood disorders and/or the mode of action of antidepressants, less is known about the role of other growth factors. This paper is focused on a group of growth factors, the fibroblast growth factor (FGF) family and their potential role in mood disorders.

The BIOMOSA (BIOsphere MOdels for Safety Assessment of radioactive waste disposal) project was part of the EC fifth framework research programme. The main goal of this project was to improve the scientific basis for the application of biosphere models in the framework of long-term safety studies of radioactive waste disposal facilities and to enhance the confidence in using biosphere models for performance assessments. The study focused on the development and application of a generic biosphere tool BIOGEM (BIOsphere GEneric Model) using the IAEA BIOMASS reference biosphere methodology, and the comparison between BIOGEM and five site-specific biosphere models. The site-specific models and the generic model were applied to five typical locations in Europe, resulting in estimates of the annual effective individual doses to the critical groups and the ranking of the importance of the exposure pathways for each of the sites. Uncertainty in the results was also estimated by means of stochastic calculations based on variation of the site-specific parameter values. This paper describes the generic model and the deterministic and stochastic results obtained when it was applied to the five sites. Details of the site-specific models and the corresponding results are described in two companion papers. This paper also presents a comparison of the results between the generic model and site-specific models. In general, there was an acceptable agreement of the BIOGEM for both the deterministic and stochastic results with the results from the site-specific models.

The results of surgical repair of straightforward rectovaginal fistula in 26 women (obstetric, 13; infection, nine; trauma, one; unknown but not radiation-induced or related to inflammatory bowel disease, three) were ultimately excellent; 23 patients were cured. However, this result obscures a high early failure rate in five of 12 patients having a transanal advancement flap and in one of eight having perineoproctotomy (lay open and repair). A temporary stoma was used in 11 patients (five of eight with a perineoproctotomy, three of 12 with an advancement flap and in three having another local procedure).

The electric-field-induced structural rearrangement of smectic layers in the antiferroelectric and ferroelectric phases of three different materials is reported. The materials all have high optical tilt angles (around 30 degrees ), compared with the steric tilt angles deduced from layer spacing measurements (around 18 degrees ). The chevron angles observed in devices agree well with values found for the steric tilt angle across the tilted mesophase range. Electric fields were applied to liquid crystal devices while the smectic layer structures, in both the depth and in the plane of the device, were probed using small angle x-ray scattering. Two separate aspects of the influence of the field on the layer structure were studied. First, the organization of the smectic layers in the antiferroelectric phase is described before, during, and after the application of an electric field of sufficient magnitude to induce a chevron to bookshelf transition. Second, the evolution of the field-induced layer structure change has been investigated as the field was incrementally increased in both the antiferroelectric and ferroelectric phases. It was found that the chevron to bookshelf transition has a distinct threshold in the antiferroelectric phase, but shows low or zero threshold behavior in the ferroelectric phase for all the materials studied.

The end of our century has been characterized by a quick scientific and technological growth. Among other, the brain, the human genome project and the computer science, they are some of the numerous fields that characterize this revolution.In the following work, we will show as these three fields of the knowledge have converged in a new area of the science denominated technology of the gene chip or microarrays. Although this methodology would allow the study of thousands of genes in one chip, in the following work we will center ourselves in its potential application for the study of the enzyme nitric oxide synthase (NOS), which is responsible for the production of the nitric oxide (NO). The technical base of this system is to be able to synthesize chains of DNA in a chip, which will be hybridized with the sample of interest that in turn are usually marked with fluorescent nucleotides. The results are analyzed using a sophisticated image analysis system. The relative estimate of the quantity of existent messenger in each sample will come determined by the intensity of the fluorescence, and for its comparison with internal controls. The discovery of at least three genes that are coded for NOS, as well as that of numerous allelic variations will allow a more exhaustive study of this molecule, which has been recognized by their vital importance.In this review we will put in perspective the utility of this technology in the genetic study of the enzyme NOS, and its utility for the understanding of the pathophysiology of some neurological illnesses.

The structures of the liquid crystalline chiral subphases exhibited by several materials containing either a selenium or sulphur atom have been investigated using a resonant x-ray scattering technique. This technique provides a unique structural probe for the ferroelectric, ferrielectric, antiferroelectric, and SmC(*)(alpha) phases. An analysis of the scattering features allows the structural models of the different subphases to be distinguished, in addition to providing a measurement of the helical pitch. This paper reports resonant scattering features in the antiferroelectric hexatic phase, the three- and four-layer intermediate phases, the antiferroelectric and ferroelectric phases and the SmC(*)(alpha) phase. The helicoidal pitch has been measured from the scattering peaks in the four-layer intermediate phase as well as in the antiferroelectric and ferroelectric phases. In the SmC(*)(alpha) phase, an investigation into the helical structure has revealed a pitch ranging from 5 to 54 layers in different materials. Further, a strong resonant scattering signal has been observed in mixtures of a selenium containing material with as much as 90% nonresonant material.

High-resolution resonant polarized x-ray diffraction experiments near the sulfur K edge have been performed on free-standing liquid crystal films exhibiting the chiral smectic-C*FI2 phase. It is widely accepted that this phase has a four-layer repeat unit, but the internal structure of the repeat unit remains controversial. We report different resolved features of the resonant x-ray diffraction peaks associated with the smectic-C*FI2 phase that unambiguously demonstrate that the four-layer repeat unit is locally biaxial about the layer normal and that the measured angle, describing the biaxiality, is in good agreement with optical measurements.

High-resolution resonant polarized x-ray diffraction experiments near the sulfur K edge have been performed on free-standing liquid crystal films exhibiting the chiral smectic-C*FI2 phase. It is widely accepted that this phase has a four-layer repeat unit, but the internal structure of the repeat unit remains controversial. We report different resolved features of the resonant x-ray diffraction peaks associated with the smectic-C*FI2 phase that unambiguously demonstrate that the four-layer repeat unit is locally biaxial about the layer normal and that the measured angle, describing the biaxiality, is in good agreement with optical measurements.

Resonant x-ray scattering has been used to investigate the interlayer ordering of the antiferroelectric and ferrielectric smectic ${C}^{*}$ subphases in a device geometry. The liquid crystalline materials studied contain a selenium atom and the experiments were carried out at the selenium K edge allowing x-ray transmission through glass. The resonant scattering peaks associated with the antiferroelectric phase were observed in two devices containing different materials. It was observed that the electric-field-induced antiferroelectric to ferroelectric transition coincides with the chevron to bookshelf transition in one of the devices. Observation of the splitting of the antiferroelectric resonant peaks as a function of applied field also confirmed that no helical unwinding occurs at fields lower than the chevron to bookshelf threshold. Resonant features associated with the four-layer ferrielectric liquid crystal phase were observed in a device geometry. Monitoring the electric field dependence of these ferrielectric resonant peaks showed that the chevron to bookshelf transition occurs at a lower applied field than the ferrielectric to ferroelectric switching transition.

Benign and malignant tumors of the hand are rare in children. This article reviews some of the common tumors that affect the hand in children, with an emphasis on clinico-pathologic correlations. Illustrated case histories on some rare tumors are also included.

The layer structure in the antiferroelectric, ferrielectric, and ferroelectric phases of a liquid crystal device is reported, together with its electric field-induced deformation. The field-free chevron angle is comparable to the steric tilt angle, but differs significantly from the optical tilt angle. A sharp field threshold is observed for the chevron to bookshelf transition in the antiferroelectric phase at 1.3 V/μm, while layer deformations occur at much lower fields (0.3 V/μm) in the other subphases. Models are proposed for the layer deformations.

Prior studies in our laboratory demonstrated that part of the thalamus is necessary for activating the hypothalamo-pituitary-adrenocortical (HPA) axis in response to audiogenic stress in rats. The present studies were designed to determine how the auditory-responsive thalamic nuclei might activate the HPA axis. Both retrograde [Fluoro-Gold (FG)] and anterograde [Phasoleus vulgaris-leucoagglutinin (PHA-L) and biotinylated dextran amines (BDA)] tracers were employed to study the putative connectivity between the thalamus and the medial parvocellular region of the hypothalamic paraventricular nucleus (PAmp). In addition, rats receiving FG in the PAmp were subjected to audiogenic stress, and the distribution of both FG and the protein product of the immediate-early gene c-fos, Fos, were determined by double immunohistochemistry, to help assess putative functional links between the auditory-responsive thalamic nuclei and PAmp. The results of PAmp FG placement indicated retrogradely labeled cells in several areas, including the bed nucleus of the stria terminalis, hypothalamic regions, the supramammillary nucleus, some thalamic regions, and importantly, a few multisensory nuclei of the thalamus, including the parvicellular division of the subparafascicular and posterior intralaminar nuclei. Injections of the tracers PHA-L or BDA into these auditory-responsive posterior thalamic nuclei provided further evidence of projections to the PAmp. In addition, several forebrain areas were observed to receive moderate to heavy innervation. These areas included most of the regions described above, which, in turn, project to the PAmp. Because cells in the multisensory thalamic nuclei, hypothalamic, and forebrain areas were double labeled with FG and Fos, the results suggest that either direct projections from the thalamus to PAmp neurons, or indirect projections from the thalamus to stress-responsive forebrain areas projecting to the PAmp, might mediate activation of the HPA axis by audiogenic stress.

The recently discovered neuropeptide orphanin FQ (OFQ), and its opioid receptor-like (ORL1) receptor, exhibit structural features suggestive of the micro, kappa, and delta opioid systems. The anatomic distribution of OFQ immunoreactivity and mRNA expression has been reported recently. In the present analysis, we compare the distribution of orphanin receptor mRNA expression with that of orphanin FQ binding at the ORL1 receptor in the adult rat central nervous system (CNS). By using in vitro receptor autoradiography with (125)I-[(14)Tyr]-OFQ as the radioligand, orphanin receptor binding was analyzed throughout the rat CNS. Orphanin binding sites were densest in several cortical regions, the anterior olfactory nucleus, lateral septum, ventral forebrain, several hypothalamic nuclei, hippocampal formation, basolateral and medial amygdala, central gray, pontine nuclei, interpeduncular nucleus, substantia nigra, raphe complex, locus coeruleus, vestibular nuclear complex, and the spinal cord. By using in situ hybridization, cells expressing ORL1 mRNA were most numerous throughout multiple cortical regions, the anterior olfactory nucleus, lateral septum, endopiriform nucleus, ventral forebrain, multiple hypothalamic nuclei, nucleus of the lateral olfactory tract, medial amygdala, hippocampal formation, substantia nigra, ventral tegmental area, central gray, raphe complex, locus coeruleus, multiple brainstem motor nuclei, inferior olive, deep cerebellar nuclei, vestibular nuclear complex, nucleus of the solitary tract, reticular formation, dorsal root ganglia, and spinal cord. The diffuse distribution of ORL1 mRNA and binding supports an extensive role for orphanin FQ in a multitude of CNS functions, including motor and balance control, reinforcement and reward, nociception, the stress response, sexual behavior, aggression, and autonomic control of physiologic processes.

Neuronal mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) proteins are glucocorticoid-activated transcription factors that bind identical DNA response elements yet transduce distinct physiological/transcriptional actions. The present study assessed regulation of adrenocorticosteroid receptor RNA and protein following intermittent stress exposure, using Sprague Dawley (S-D) and stress-hyperresponsive Fischer 344 (F344) rat strains. The F344 (but not S-D) strain showed enhanced acute stress responsivity and enhanced corticosterone secretion following prolonged stress. F344 rats also showed reduced responsiveness to a novel stressor after prolonged stress exposure, suggestive of enhanced glucocorticoid negative feed-back. Upon prolonged stress, F344 rats down-regulated MR hnRNA in CA1, CA3, and dentate gyrus. Transcriptional changes were accompanied by decreased expression of the alpha 5' messenger RNA (mRNA) form, consistent with altered promoter utilization. In contrast, alpha 5' splice variant, full-length mRNA, and MR protein expression were not affected by stress in either strain, implying that transcriptional changes do not affect overall mRNA or protein expression. GR protein was increased in pyramidal and granule cell somata/nuclei of F344 rats despite lack of a change in mRNA expression. These data suggest that prolonged stress elicits restricted changes in MR and GR expression in the F344 strain only. Overall, stable expression of adrenocorticosteroid receptors is rigorously defended in hippocampal neurons, apparently through transcriptional and posttranscriptional mechanisms.

The lateral division of the central nucleus of the amygdala (CEAl) and the oval nucleus of the bed nucleus of the stria terminalis (BSTov) have been linked closely anatomically and functionally. To determine whether these regions may be subdivided further on a neurochemical basis, dual in situ hybridization was used to determine the colocalization of corticotropin-releasing hormone (CRH), enkephalin (ENK), or neurotensin (NT) with glutamic acid decarboxylase isoforms 65 and 67 [used concurrently as a marker for gamma-aminobutyric acid GABA] in these nuclei. It was found that, for both regions, each peptide invariably was localized in a GABAergic cell. Although there was a similar overlap in the distribution of NT with ENK in the BSTov and CEAl, it was observed that CRH and ENK rarely were colocalized in either nucleus. To determine whether these distinct neuronal populations could be activated differentially, male rats were given a systemic injection of interleukin-1beta (IL-1beta; 5 microg/kg, i.p.), a stimulus that results in a robust increase in c-fos mRNA expression in the BSTov and CEAl. The neurochemical identity of these activated neurons showed striking similarities between the BSTov and the CEAl; All IL-1beta-responsive cells were GABAergic, the majority of c-fos- positive cells expressed ENK mRNA (BSTov, 81%; CEAl, 94%), and some expressed NT mRNA (BSTov, 23%; CEAl, 22%), whereas very few expressed CRH mRNA (BSTov, 4%; CEAl, 1%). These data provide evidence for the existence of discrete neural circuits within the BSTov and CEAl, and the similarities in the patterns of neurochemical colocalization in these nuclei are consistent with the concept of an extended amygdala. Furthermore, these data indicate that intraperitoneal IL-1beta recruits neurochemically distinct pathways within the BSTov and CEAl, and it is suggested that this differential activation may mediate specific aspects of immune, limbic, and/or autonomic processes.

Orphanin FQ (OFQ) is the endogenous agonist of the opioid receptor-like receptor (ORL-1). It and its precursor, prepro-OFQ, exhibit structural features suggestive of the opioid peptides. A cDNA encoding the OFQ precursor sequence in the rat recently has been cloned, and the authors recently generated a polyclonal antibody directed against the OFQ peptide. In the present study, the authors used in situ hybridization and immunohistochemistry to examine the distribution of OFQ peptide and mRNA in the central nervous system of the adult rat. OFQ immunoreactivity and prepro-OFQ mRNA expression correlated virtually in all brain areas studied. In the forebrain, OFQ peptide and mRNA were prominent in the neocortex endopiriform nucleus, claustrum, lateral septum, ventral forebrain, hypothalamus, mammillary bodies, central and medial nuclei of the amygdala, hippocampal formation, paratenial and reticular nuclei of the thalamus, medial habenula, and zona incerta. No OFQ was observed in the pineal or pituitary glands. In the brainstem, OFQ was prominent in the ventral tegmental area, substantia nigra, nucleus of the posterior commissure, central gray, nucleus of Darkschewitsch, peripeduncular nucleus, interpeduncular nucleus, tegmental nuclei, locus coeruleus, raphe complex, lateral parabrachial nucleus, inferior olivary complex, vestibular nuclear complex, prepositus hypoglossus, solitary nucleus, nucleus ambiguous, caudal spinal trigeminal nucleus, and reticular formation. In the spinal cord, OFQ was observed throughout the dorsal and ventral horns. The wide distribution of this peptide provides support for its role in a multitude of functions, including not only nociception but also motor and balance control, special sensory processing, and various autonomic and physiologic processes.

Many stressors elicit changes in corticotrophin (CRH), enkephalin (ENK), and neurotensin (NT) mRNA levels within the medial parvocellular region of the paraventricular nucleus of the hypothalamus (mpPVN), and the pattern of changes in mRNA levels appears to depend on the physical characteristics of the stressor. We questioned whether psychologically distinct stressors would cause different patterns of neuropeptide mRNA expression within the PVN. Psychologically distinct stressors were created by employing a paradigm of escapable (controllable) vs. non-escapable (yoked) tail shock. An adult male rats could terminate the stress stimulus by performing wheel-turning behaviour; his behaviour also terminated the stress for his yoked partner, who had no control over the termination of the shock. Four h post-stress, brains were collected and processed for in-situ hybridization histochemistry. Tail-shock stress stimulated a significant increase in CRH, ENK, and NT mRNA levels within the mpPVN. The number of CRH identified neurones coexpressing AVP mRNA was also significantly elevated in both stress groups. Moreover, the pattern and magnitude of the stress-induced increases in mRNA was similar in both stress groups. Additionally, no stress-induced changes in CRH mRNA levels were observed in the central nucleus of the amygdala. In sum, two psychologically distinct stressors, escapable vs. yoked tail shock stress, stimulated similar increases in CRH, NT, ENK, and AVP mRNA levels within the mpPVN. These results suggest that physical attributes of a stress, rather than psychological, may be the more important factors in determining the PVN mRNA response.

In recent years nitric oxide (NO) has emerged as a unique biological messenger. NO is a highly diffusible gas, synthesized from L-arginine by the enzyme nitric oxide synthase (NOS). Three unique subtypes of NOS have been described, each with a specific distribution profile in the brain and periphery. NOS subtype I is present, among other areas, in the hippocampus, hypothalamus, pituitary and adrenal gland. Together these structures form the limbic-hypothalamic-pituitary-adrenal (LHPA) or stress axis, activation of which is one of the defining features of a stress response. Evidence suggests that NO may modulate the release of the stress hormones ACTH and corticosterone, and NOS activity and transcription is increased in the LHPA axis following various stressful stimuli. Furthermore, following activation of the stress axis, glucocorticoids are thought to down-regulate the transcription and activity of NOS via a feedback mechanism. Taken together, current data indicate a role for NO in the regulation of the LHPA axis, although at present this role is not well defined. It has been suggested that NO may act as a cellular communicator in plasticity and development, to facilitate the activation or the release of other neurotransmitters, to mediate immune responses, and/or as a vasodilator in the regulation of blood flow. In the following review we summarize some of the latest insights into the function of NO, with special attention to its relationship with the LHPA axis.

In rodents, two types of glucocorticoid receptors, the mineralocorticoid (MR; type I) and the glucocorticoid (type II) receptors, have been demonstrated to play a role in hypothalamic-pituitary-adrenal (HPA) axis regulation. Because MR shows a very high affinity for cortisol, it has been suggested that MR plays an important role in restraint of CRH and ACTH secretion during the nadir of the circadian rhythm. Although a number of studies have established the importance of MR in rodents, the functional role of MR in humans has not been determined. These studies evaluated whether spironolactone, an MR antagonist, had a detectable effect on HPA axis regulation in humans, and whether the effect was greatest during the evening, when plasma cortisol concentrations are in the MR range. Compared to the placebo day, after a single dose of spironolactone at either 0800 or 1600 h, there is a significant increase in plasma cortisol, which is preceded by a rise in ACTH and beta-endorphin. A significant effect of spironolactone on cortisol secretion was demonstrated with no differences between the morning and evening. Because the effect of spironolactone on cortisol was short lived, a second experiment was conducted using two doses of spironolactone, again sampling in the morning and evening. After two doses of spironolactone, plasma cortisol levels showed a significant and sustained spironolactone-induced elevation for the entire sampling period. However, neither plasma beta-endorphin nor ACTH was increased compared to levels on the placebo day. These data suggest that MR appear to play a clear role in HPA axis regulation during the time of the circadian peak as well as the trough. Furthermore, MR blockade may affect the sensitivity of the adrenal to ACTH.

Initially, opioid signaling had been thought to be mainly inhibitory in nature. However, it has been shown that opioids can activate specific signaling pathways and induce immediate early gene (IEG) transcription in brain. IEGs can then regulate the transcription of other genes, leading to changes in neuronal function in response to extracellular stimuli. This study was designed to identify brain regions that demonstrate specific induction of the IEG c-fos, a component of the AP-1 transcription factor, in response to acute morphine, and to contrast this induction with the stressful effects of the injection itself. Rats received either 10 mg/kg morphine or an equivalent volume of saline injected subcutaneously. Animals were then sacrificed 15, 30, or 60 min after injection. Specific induction of c-fos mRNA by morphine was seen in dorsomedial caudate-putamen, paraventricular nucleus of the thalamus, central and intralaminar thalamic nuclei, dorsal central grey, superior colliculus, lateral parabrachial nucleus, inferior olivary complex, and caudal nucleus tractus solitarius. These findings represent the first complete anatomical mapping of c-fos induction in rat brain, and show that acute morphine administration alters gene expression in several areas related to known functional properties of opioids. However, regions showing c-fos induction are not all classically associated with opioid receptors and opioid-mediated effects. These findings are considered in the context of the effects of opioids on neural circuitry as well as direct, receptor-mediated effects of morphine on neural cells.

Disturbances of the limbic-hypothalamic-pituitary-adrenal axis and the serotonin system are commonly found in depressive illness. Studying the effect of stress on these two neurobiological systems may give us important clues into the pathophysiology of affective illness and help us understand how stress and mood disorders are related.We studied the effect of chronic unpredictable stress and antidepressant treatment on serotonin 1A (5-HT1A), glucocorticoid (GR), anti mineralocorticoid (MR) receptor levels in rat hippocampus, using in situ hybridization and receptor autoradiography. We also used in situ hybridization to quantify hippocampal 5-HT1A, GR, and MR messenger (mRNA) levels in a small group of suicide victims with a history of depression, compared to matched controls (n = 6).We found that rats subjected to chronic unpredictable stress showed a significant elevation of basal plasma corticosterone compared to nonstressed rats. Chronic stress also caused a decrease in 5-HT1A mRNA and binding in the hippocampus. In addition, chronic stress produced alterations on the MR/GR mRNA ratio in this same region. The decreases in 5-HT1A mRNA and binding, as well as the MR/GR alterations, were prevented in animals that received imipramine or desipramine antidepressant treatment. Zimelidine was unable to reverse stress-induced increases in corticosterone, and was only partially successful in preventing the stress-induced receptor changes in the hippocampus. Suicide victims with a history of depression showed changes that were very similar to the changes found in chronic stress.Alterations in hippocampal 5-HT1A levels and in the MR/GR balance may be one of the mechanisms by which stress may trigger and/or maintain depressive episodes.

This study examines the optical response and physical properties of the homologous series 4-n-butyl-4'-n-alkoxyazobenzene. The members of this series all exhibit liquid crystalline phase behavior, and have also been used as dopants in 4-cyano-4'- n'pentylbiphenyl (5CB), a room temperature nematic liquid crystal. The guest-host system and the azobenzene series have been characterized using optical microscopy and UV-vis spectrophotometry. Illumination of these systems with light of a suitable wavelength induces a trans-cis isomerization of the azo- dye molecules which results in a reorientation of the liquid crystal director, often to such an extent that the liquid crystal phase is disrupted, causing an in situ isothermal phase transition. The response of the liquid crystal system to a linearly polarized beam of exciting radiation is examined with the use of a probe He:Ne laser. Changes in light transmission are then detected with a photodiode. Responses are discussed in terms of homologue, cell thickness and temperature.© (1998) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

In England and Wales, approximately 24 000 patients present each year with colorectal adenocarcinoma [1]. In the USA there are 157 000 new cases annually [2]. The main treatment modality is surgical, but due to the insidious nature of the disease and the lack of a suitable screening tool, only about 50–82% [1, 3–8] have surgery undertaken with curative intent. This leaves a very large number of patients with colorectal cancer who require palliation of symptoms.

The technique of in situ hybridization with specific ribonucleotide probes was used to determine the distribution patterns of mRNA encoding the alpha 1a-, alpha 1b- and alpha 1d-adrenoceptor (AR) subtypes in rat brain and spinal cord. The expression pattern of alpha 1a-AR mRNA has not been reported previously, and was found to be widespread throughout the rat central nervous system. High levels were found in regions of the olfactory system, several hypothalamic nuclei, and regions of the brainstem and spinal cord, particularly in areas related to motor function. Regions expressing moderate levels of mRNA for this receptor were the septum, bed nucleus of the stria terminalis, cerebral cortex, amygdala, cerebellum and pineal gland. Low expression levels were detected in the hippocampal formation. Most nuclei in the basal ganglia and thalamus expressed extremely low or undetectable levels of alpha 1a-AR mRNA. The expression patterns of the alpha 1b- and alpha 1d-AR mRNAs were similar to those described using oligonucleotide probes in earlier studies. High expression of alpha 1b-AR mRNA was noted in the pineal gland, most thalamic nuclei, lateral nucleus of the amygdala and dorsal and median raphe nuclei. Moderate expression levels were noted throughout the cerebral cortex, and in some olfactory, septal, and brainstem regions. The distribution of alpha 1d-AR mRNA was the most discrete of the three receptors examined. Expression was strong in the olfactory bulb, cerebral cortex, hippocampus, reticular thalamic nucleus, regions of the amygdala, motor nuclei of the brainstem, inferior olivary complex and spinal cord. Comparison of the distributions of the alpha 1a-, alpha 1b- and alpha 1d-AR mRNA suggests unique functional roles for each of these receptors.

The aim of this study was to evaluate the operative repair of rectoceles in a defined group of women by a technique designed to deal with the cause (failure of the rectovaginal septum) rather than the effect (rectal and vaginal wall bulging).Only women whose defecation was aided by vaginal digitation and who had large rectoceles on proctography were included. Any other clinical symptoms in the absence of vaginal digitation, even when proctography demonstrated a rectocele, were not taken as indicators for surgery in this study. There were nine women, median age 50 years (range, 32 to 61). The rectovaginal septum was repaired with Marlex mesh through a perineal approach by one surgeon. The median follow-up period was 29 months.Eight of the nine women achieved successful evacuation after surgery without the need for vaginal digitation. Rectocele size, depth, and the percent of barium trapped in the rectocele on proctography were all improved. Anorectal physiology measurements were unchanged by surgery.Operative repair of the rectovaginal septum removes the need for vaginal digitation in most women with large rectoceles on proctography. Further studies in well-defined groups of women are needed to establish how well rectocele repair aids women with a variety of other pelvic and perineal symtoms.

The paraventricular nucleus of the hypothalamus (PVN) serves as the origin of the final common pathway in the secretion of glucocorticoid hormones in response to stress. Various stress-related inputs converge upon the cells of the medial parvocellular division of the PVN. These neurons, which synthesize and release corticotropin-releasing hormone, arginine vasopressin, and other secretagogues, are responsible for a cascade of events which culminates in the adrenocorticotropin-induced release of corticosteroids from the adrenal cortex. Previous data have suggested complex afferent regulation of PVN neurons, although the neuronal pathways by which the effects of stress are mediated remain to be fully disclosed. The present experiment sought to identify forebrain areas potentially involved in afferent regulation of the PVN in response to an acute stressor. Discrete injections of the retrograde tracer Fluoro-gold were delivered to the PVN, and rats were subsequently subjected to an acute swim stress. Brains were processed immunocytochemically for the simultaneous detection of the tracer and Fos, the protein product of the immediate early gene c-fos, utilized as a marker for neuronal activation. The majority of Fluoro-gold/Fos labeled neurons were detected in the parastrial nucleus, the medial preoptic area, the anterior hypothalamic area, the dorsomedial hypothalamic nucleus and adjacent posterior hypothalamic area, and, to a lesser extent, the supramammillary nucleus. These findings are discussed in relation to neural pathways mediating activation and inhibition of the hypothalamic-pituitary-adrenocortical axis.

The many treatments for haemorrhoids highlight a lack of consensus. Differences in patients' and surgeons' priority make objective evaluation of haemorrhoid treatment difficult; different types of haemorrhoids are being treated in patients from different socio-economic backgrounds by surgeons of varying expertise from within different cultural settings. In this article we have reviewed the results of common treatments for haemorrhoids and give an outline of our operative technique when performing haemorrhoidectomy.