Androgen accumulation andbinding to macromolecules in seminal vesicles: inhibition cyproterone.

Cyproterone reduces the accumulation of testosterone and dihydrotestosterone in seminal vesicles 30 minutes after intravenous administration of tritiated testosterone to castrated rats. Testosterone, added in vitro, binds to macromolecules from the supernatant fraction of the seminal vesicle homogenates; this interaction is antagonized competitively by cyproterone. Cyproterone may diminish androgenic effects by competition for binding molecules.

Intravesical nanocrystalline silver decreases experimental bladder inflammation.

PURPOSE: Interstitial cystitis is a sterile bladder inflammatory disease characterized by pelvic pain, urinary urgency and frequency. Nanocrystalline silver has anti-inflammatory properties, prompting us to investigate its effect in experimental bladder inflammation. MATERIALS AND METHODS: Nanocrystalline silver (0.01%, 0.05%, 0.1%, 0.5% or 1%) or phosphate buffered saline (Invitrogen) (0.5 ml) was introduced intravesically in Sprague-Dawley female rat (Charles River Laboratories, Wilmington, Massachusetts) bladders for 20 minutes, followed by vehicle or protamine sulfate (10 mg/ml for 30 minutes) and lipopolysaccharide (Sigma) (2 mg/ml for 45 minutes). Urine was collected throughout for histamine assay. The catheter was removed, the rat was returned to its cage and 4 hours later it was sacrificed. The bladder was harvested, minced and cultured overnight. The medium was collected for tumor necrosis factor-alpha assay. RESULTS: Mean +/- SD total urine histamine increased from 270 +/- 190 ng in 4 controls to 842 +/- 239 ng after protamine sulfate/lipopolysaccharide and it decreased to 505 +/- 187 ng in 6 animals after pretreatment with 1% nanocrystalline silver (p = 0.036). Tumor necrosis factor-alpha release in explant medium increased from 0.02 +/- 0.03 pg/mg in 6 controls to 0.28 +/- 0.15 pg/mg in 14 animals after treatment with protamine sulfate/lipopolysaccharide and it decreased to 0.12 +/- 0.11 pg/mg in 10 animals pretreated with nanocrystalline silver (p = 0.009). Nanocrystalline silver was not effective at less than 1% and at 1% alone it released 0.05 +/- 0.07 pg/mg tumor necrosis factor-alpha in 7 rats (vs phosphate buffered saline in 6, p = 0.387). Nanocrystalline silver (1%) significantly decreased bladder inflammation and mast cell activation. These effects were apparent even 4 days later. CONCLUSIONS: Intravesical administration of nanocrystalline silver (1%) decreased urine histamine, bladder tumor necrosis factor-alpha and mast cell activation without any toxic effect. This action may be useful for interstitial cystitis.

The full Bayesian significance test for mixture models: results in gene expression clustering.

Gene clustering is a useful exploratory technique to group together genes with similar expression levels under distinct cell cycle phases or distinct conditions. It helps the biologist to identify potentially meaningful relationships between genes. In this study, we propose a clustering method based on multivariate normal mixture models, where the number of clusters is predicted via sequential hypothesis tests: at each step, the method considers a mixture model of m components (m = 2 in the first step) and tests if in fact it should be m - 1. If the hypothesis is rejected, m is increased and a new test is carried out. The method continues (increasing m) until the hypothesis is accepted. The theoretical core of the method is the full Bayesian significance test, an intuitive Bayesian approach, which needs no model complexity penalization nor positive probabilities for sharp hypotheses. Numerical experiments were based on a cDNA microarray dataset consisting of expression levels of 205 genes belonging to four functional categories, for 10 distinct strains of Saccharomyces cerevisiae. To analyze the method's sensitivity to data dimension, we performed principal components analysis on the original dataset and predicted the number of classes using 2 to 10 principal components. Compared to Mclust (model-based clustering), our method shows more consistent results.

Prolonged anorexia and elevated plasma cytokine levels following myeloablative allogeneic hematopoietic cell transplant.

Myeloablative conditioning regimens commonly lead to prolonged anorexia and poor oral intake. In a prospective study of 147 patients receiving CY, total body irradiation and allogeneic hematopoietic cells, we determined the extent of decline in oral intake and assessed plasma cytokine levels and development of acute GVHD as explanations for protracted anorexia. For each patient, daily oral caloric intake was expressed as a percent of estimated basal requirements, calculated as basal energy expenditure, through day 20. Oral caloric intake was significantly reduced in 92% of patients and remained low. The nadir in oral intake occurred at days 10-12, when median oral caloric intake was 3% of basal energy requirements. Plasma cytokines known to affect appetite (IL2, IL6, tumor necrosis factor-alpha) were significantly elevated above normal following conditioning therapy (P<0.001 for each cytokine). Acute GVHD did not appear to affect oral intake to transplant day 20 in this cohort of patients; however, plasma levels of IL6 rose steeply before the clinical onset of GVHD. Persistent fever occurred with the greatest frequency in patients with most profound reduction in oral intake. We conclude that prolonged alterations in oral intake following this myeloablative regimen may be related to circulating cytokines known to alter eating behavior.

Genuine Bayesian multiallelic significance test for the Hardy-Weinberg equilibrium law.

Statistical tests that detect and measure deviation from the Hardy-Weinberg equilibrium (HWE) have been devised but are limited when testing for deviation at multiallelic DNA loci is attempted. Here we present the full Bayesian significance test (FBST) for the HWE. This test depends neither on asymptotic results nor on the number of possible alleles for the particular locus being evaluated. The FBST is based on the computation of an evidence index in favor of the HWE hypothesis. A great deal of forensic inference based on DNA evidence assumes that the HWE is valid for the genetic loci being used. We applied the FBST to genotypes obtained at several multiallelic short tandem repeat loci during routine parentage testing; the locus Penta E exemplifies those clearly in HWE while others such as D10S1214 and D19S253 do not appear to show this.

Multisensory regulation of maternal behavior and masculine sexual behavior: a revised view.

Frank Beach's view of the multisensory regulation in Norway rats of copulation in males (12) and of pup retrieval in females (23) is critically analyzed and revised in terms of Lashley's influence, Beach's other work, and current neurobiological knowledge. Beach's view was that no single sensory stimulus is essential to elicit these behaviors, but that all relevant stimuli available summate in the neocortex; consequently, (a) sexual "arousal" is increased in males, leading to copulation, and (b) the "efficiency," or likelihood, of retrieval is increased in postpartum mothers. The revised view is based on a component analysis in which each of these behaviors consists of a chain of motoric responses elicited by somatosensory stimulation. Distal stimuli emanating from the female or pups induce proximity by provoking orientation, attention and arousal; the meaning of these stimuli is largely learned by conditioned associations during the initial executions of the behavior, although odors may have a prepotent influence for some individuals. Stimuli are integrated in a multisensory manner by both subcortical and neocortical mechanisms. Generalizations concerning the reproductive behavior of other mammalian species are suggested.

The epilepsy of trisomy 9p.

Trisomy 9p is associated with structural abnormalities of the brain, neurologic dysfunction, and epilepsy. This report of a 27-year-old man with trisomy 9p and complex partial epilepsy is the first with a detailed description of the epilepsy associated with trisomy 9p. The patient's EEG shows multifocal independent spike discharges and an asymmetric generalized spike discharge. In the first MRI obtained on an adult with this disorder, we find poorly developed white matter, an atrophic corpus callosum and cerebellum, and a choroidal fissure cyst.

GABA(A) receptor regulation of kyphotic nursing and female sexual behavior in the caudal ventrolateral periaqueductal gray of postpartum rats.

Bilateral lesions of the ventrolateral caudal periaqueductal gray inhibit lordosis and kyphosis, the postures of female sexual receptivity and maternal nursing that are characterized respectively by dorsoflexion and ventroflexion of the spinal column. These lesions also inhibit the solicitation behaviors that accompany lordosis, but they do not impair retrieval or licking of pups. We tested the hypothesis that reproductive behaviors affected by these lesions are tonically inhibited by activity of the GABA(A) receptor via site-specific manipulations of receptor activity. Rats were bilaterally implanted during pregnancy with guide cannulae aimed at the caudal periaqueductal gray and ovariectomized on day 1 postpartum. Microinfusions (0.25 microl/side) of saline or drug took place on days 5 and 7 postpartum into the dorsolateral column and on days 9 and 11 into the ventrolateral column. Five minutes post-infusion dams were reunited with their pups and their maternal behavior was observed for 30 min. Feminine sexual behaviors were evaluated post-weaning after another set of microinfusions in the ventrolateral caudal periaqueductal gray. Potential facilitation of kyphosis and lordosis was tested with the GABA(A) antagonist bicuculline (15 ng/side) during sub-threshold conditions, i.e., non-suckling pups or sub-threshold ovarian hormone dosages; potential inhibition of these postures was tested with the GABA(A) agonist muscimol (125 ng/side) during optimal conditions, i.e., suckling pups or supra-threshold ovarian hormone treatments. Dorsolateral drug manipulations were ineffective. In the ventrolateral periaqueductal gray bicuculline significantly increased and muscimol significantly decreased kyphosis, lordosis, and sexual solicitations compared with saline. Retrieval and licking of pups were not altered by GABA(A) manipulations. These findings suggest that the reproductive postures of female rats, lordosis and kyphosis, as well as sexual solicitations, are tonically inhibited by the neurotransmitter GABA within the ventrolateral caudal periaqueductal gray in the midbrain. In contrast, retrieval and licking of pups appear to be under separate neurochemical or neuroanatomical control, or both. Further, this tonic inhibition is likely relieved by excitatory somatosensory inputs to this site, from mounting and suckling respectively.

Forebrain expression of c-fos due to active maternal behaviour in lactating rats.

To reveal brain sites simultaneously active during the expression of maternal behaviour in lactating rats, we used immunocytochemical visualization of the nuclear protein product Fos of the immediate-early gene c-fos as a marker of neuronal activity. After a 48 h separation from their litter, day 7 postpartum dams received a 1 h period of physical interaction with pups either capable or incapable of suckling, inaccessible pups in a wire-mesh box, an empty box, or no stimulation. Physical interaction with pups elicited high levels of pronurturant maternal behaviour (retrieval, licking, mouthing), and suckling elicited nursing behaviour as well. Exposure to the box, with or without pups, elicited high levels of investigatory sniffing, self-grooming, and general activity. Distal stimulation from pups did not differentially activate Fos in any of 20 sites, including olfactory-processing structures such as the piriform cortex and medial amygdala. Physical interaction with pups, with or without suckling, elicited higher levels of Fos-immunoreactive nuclei than that of other conditions in numerous sites, including many previously implicated in maternal behaviour (medial preoptic nucleus, nucleus accumbens, lateral septum, lateral habenula, and the bed nucleus of the stria terminalis). Similar group patterns of Fos expression also occurred in sites not previously implicated in maternal behaviour (somatosensory cortex and paraventricular thalamic nucleus). Interaction with nonsuckling pups elicited the highest levels of Fos in the cortical amygdala, whereas suckling did not activate higher Fos than nonsuckling interaction in any site included in this report, including hypothalamic nuclei involved in lactation (paraventricular, supraoptic, and arcuate). There was little or no Fos in cingulate cortex, olfactory tubercle, medial septum, medial habenula, or ventromedial hypothalamus. These data suggest that trigeminal stimuli received by lactating rats during the performance of pronurturant maternal behaviour promote cellular activity resulting in neuronal expression of c-fos in many forebrain sites including the medial preoptic nucleus, several sites connected with it that are part of the mesotelencephalic dopamine system, and in the somatosensory cortex. In contrast, in these forebrain sites suckling does not elicit greater levels of Fos than that seen in nonsuckled rats and distal stimuli from pups are ineffective in increasing Fos levels compared with non-stimulated controls.

Psychiatry, psychotherapy and gastroenterology -- bringing it all together.

In this review, some aspects of functional gastrointestinal disorders are described, with particular reference to psychiatric and psychological features. Seven syndromes or conditions, which may present not uncommonly in a gastroenterology clinic, are identified and clarified. Thereafter, the roles of a psychiatrist and other mental health professionals (psychotherapists, psychologists) within gastroenterology are described, with particular reference to what an integrated service may offer.

Neural mediation of nursing and related maternal behaviors.

Nursing is the behavioral concomitant of lactation and the most generalizable maternal behavior across mammals. In lactating rats nursing often occurs in the kyphotic (upright crouched) posture; like the neuroendocrine determinants of milk synthesis and release, kyphosis requires suckling by the young. The dam's active pronurturant behaviors, such as retrieval and licking of pups, requires perioral somatosensory stimulation, which is often a precursor of kyphosis as well, and is inhibited by suckling. The sequential nature of maternal behaviors and the dissociations in their somatosensory regulation are critical to understanding their neural mediation, as exemplified by our recent work in lactating rats. We found that the caudal lateral and ventrolateral midbrain periaqueductal gray (cPAGl,vl) is a sensorimotor integration site for the kyphotic nursing posture. Destruction of the cPAGl,vl, or increased activity of the inhibitory neurotransmitter GABA within it, severely reduced kyphosis, increased nursing in more atypical postures, and had little or no effect on pronurturance. Various forebrain sites are known to mediate retrieval and licking of pups. Inhibition of dopaminergic activity in the nucleus accumbens of dams via microinfusions of a mixed D1/D2 dopamine receptor antagonist, cis-flupenthixol (FLU), dose-dependently reduced these active behaviors, while increasing nursing duration. Retrieval was inhibited, however, only by infusions of FLU that included the nucleus accumbens shell, which is reciprocally connected with other sites implicated in retrieval of pups. Thus, maternal behavior is not a unitary process but rather a complex category consisting of sequential behavioral components that have their own sensory and neural determinants.

Haloperidol inhibits maternal retrieval and licking, but enhances nursing behavior and litter weight gains in lactating rats.

Abstract To determine whether the motorically-active and -inactive components of maternal behavior in rats are differentially affected by dopamine, we administered haloperidol, a dopamine receptor antagonist, to lactating rats on day 7 (+/-1) post-partum, 3 h after dam-litter separation and 1 h before their reunion. Compared to treatment with saline or domperidone, a peripherally-active dopamine antagonist, haloperidol treatment inhibited retrieval and licking of pups in a dose-dependent manner and hastened the onset of nursing behavior, but impaired the high crouch posture at the highest doses (8 and 10 mg/kg). Also, litters of dams treated with 0.2, 0.4, or 1.0 mg/kg haloperidol gained almost twice as much weight as litters of controls or of dams treated with 5 to 10 mg/ kg haloperidol. To determine whether the milk ejection pattern accounts for differential litter weight gain after moderate and high doses of haloperidol, milk ejections were assessed by pup stretch and nipple-switching responses for 30 min after the onset of crouching following a 4 h dam-litter separation on day 12 or 13 post-partum. The litters of dams treated with 1 or 3 mg/kg haloperidol had substantially greater litter weight gains than litters of control dams or of dams treated with 5 mg/kg haloperidol. The smaller litter weight gain of 5 mg/kg haloperidol litters was due to a retardation of milk ejections in their dams, while the smaller gain of control litters was due, at least in part, to greater behavioral activation by their dams. Non-dopaminergic effects of large doses of haloperidol (>/=5 mg/kg) may have reduced the display of the high crouching posture during nursing and contributed to the retardation of milk ejections. Thus, dopamine is necessary for the motorically-active components of maternal behavior, but its inhibition may be necessary for the assumption of the immobile nursing postures and for maximal litter weight gains. We hypothesize that extra-hypothalamic as well as tuberoinfundibular dopaminergic systems are inactivated by the suckling stimulus.

Bone density loss during treatment of chronic GVHD.

Nine adult patients 31-47 (median 39) years of age treated with prednisone and cyclosporin A (CsA) for chronic graft-versus-host disease (GVHD) were evaluated for biochemical factors associated with skeletal turnover at initiation of immunosuppressive therapy (3 months after marrow transplant) and 9 months later (follow-up). Absorptiometry studies of the wrist and lumbar spine were also performed. Serum levels of 1,25-dihydroxycholecalciferol (1,25(OH)2D) were decreased at enrollment, particularly in the six males. Values for all nine patients remained low at follow-up. Levels of serum 25-hydroxycholecalciferol (25(OH)D), parathyroid hormone, and ionized calcium were normal at enrollment and follow-up. Mean urine hydroxyproline and calcium levels were elevated at enrollment, suggesting increased bone resorption; the mean values decreased to the high normal range at follow-up. Urine magnesium excretion was elevated in eight of nine patients at baseline and remained elevated at follow-up in three of eight evaluable patients. Single and dual photon absorptiometry of the wrist and spine, respectively, and dual energy X-ray absorptiometry of the spine, were utilized to evaluate bone mineral density over time. The precision of these tests was, respectively, +/- 3.5%, +/- 3.1% and +/- 1.0%. Results showed a significant ( > 2.5 times the precision) decrease over 9 months in bone mineral density in three of five evaluable males and all three females. The findings indicate increased collagen and bone turnover, increased urinary magnesium and calcium excretion and a significant risk of osteoporosis in patients receiving treatment for chronic GVHD. Preventive measures, including gonadal hormone replacement in females, should be initiated early after transplantation. Further studies are needed to identify patients at highest risk of bone loss and to monitor the effects of preventive therapy.

Trigeminal lesions and maternal behavior in Norway rats: I. Effects of cutaneous rostral snout denervation on maintenance of nurturance and maternal aggression.

Cutaneous desensitization of the upper, rostral snout by bilateral section of the infraorbital nerves in lactating Norway rat dams markedly, but transiently, disrupted retrieval and licking of pups, nursing behavior, and fighting with a strange male intruder. Removal of the mystacial vibrissae, which provide major inputs to the infraorbital nerves, or cutaneous desensitization of the chin by bilateral sectioning of the mental nerves did not disrupt these behaviors. However, cutaneous desensitization of both the upper and lower rostral snout exacerbated and prolonged the effects produced by infraorbital denervation alone. The control of maternal behavior and aggression by somatosensory reflexes and the possible bases for rapid behavioral recovery after partial trigeminal sensory denervations are discussed.

Functions of the caudal periaqueductal gray in lactating rats: kyphosis, lordosis, maternal aggression, and fearfulness.

Severe impairment of the kyphotic nursing posture in lactating rats found previously after prepartum lesions of the caudal intercollicular periaqueductal gray (cPAG-x) was confirmed and was extended to a continuous 24-hr period. Litters of cPAG-x dams gained approximately 10% less weight postnatally than controls, which was in part related to their dams' compensatory prone nursing posture that was ineffective for milk letdown. Sexual proceptivity and receptivity (lordosis) during the postpartum estrus were virtually eliminated in subjects with relatively large bilateral cPAG lesions. The doubling of maternal attacks toward a male intruder after lesioning was also confirmed and was related to reduced fearfulness in an elevated plus-maze. Thus, the cPAG plays a multifaceted role in parturient rats; it is involved in the mediation of nursing, sexual, aggressive, and fear behaviors.

Maternal motivation of lactating rats is disrupted by low dosages of haloperidol.

Motorically-active maternal behaviors of rats, such as retrieval and licking of pups, are known to be reduced or suspended following systemic injection of > or = 0.2 mg/kg haloperidol (HAL), a dopamine (DA) receptor blocker. Further, when these behaviors are thwarted by muzzling, dams persistently attempt to make snout contact with pups by pushing them with the muzzle, indicative of intense maternal motivation. To evaluate whether time spent contact-seeking by muzzle-pushing is impaired by dosages of HAL too low to reduce retrieval and licking of pups, dams were fitted with a full muzzle (FM), given 0, 0.05 or 0.10 mg/kg HAL, and reunited with their pups for 30 min after a 4-h separation. Similarly-treated dams fitted with a control muzzle, which allows perioral contact with pups, displayed essentially normal maternal behavior. In FM dams, low dosages of HAL severely and dose-dependently reduced muzzle-pushing, as well as actual contact by handling-touching and moving pups with their paws, although the latency to initiate these behaviors by responders was not impaired. A threshold level of DA is apparently necessary for efficient motor control (handling) and for maternal incentive, persistent effort to achieve contact with pups (muzzle-pushing), consistent with an arousal explanation of the action of DA.

Reversible upper tract dilatation with ileal conduit stomal ulceration or encrustation.

Six pediatric patients with progressive upper tract dilatation were noted to have stomal encrustation and ulceration. In all cases, the upper tract dilatation subsided with effective conservative treatment of the stomal lesion thus obviating surgical revision of the stoma.

Site and behavioral specificity of periaqueductal gray lesions on postpartum sexual, maternal, and aggressive behaviors in rats.

Bilateral electrolytic lesions of the lateral and ventrolateral caudal periaqueductal gray (cPAGl,vl) of lactating rats are known to severely reduce suckling-induced kyphosis (upright crouched nursing), which is necessary for maximal litter weight gains, and impair sexual behavior during the postpartum estrous, while heightening nursing in other postures and attacks on unfamiliar adult male intruders. In the present report, the site specificity of the cPAG with respect to the control of these behaviors was determined by comparing lesions of the cPAGl,vl with similarly sized lesions within the rostral PAG (rPAG) and surrounding mesencephalon. The previously seen effects of prepartum cPAGl,vl lesions on kyphotic nursing, sexual proceptivity and receptivity, maternal aggression, and daily litter weight gains were replicated. Additionally, the post-lesion facilitation of aggression was found to be behaviorally specific, first by being directed toward an adult, but not to a nonthreatening juvenile male rat, and second, by requiring the recent presence of the pups, being eliminated or decreased 24 h after removal of the litter. Damage to the rPAG did not affect nursing or sexual behaviors, and had only a minimal effect on maternal aggression. Lesions of the rPAG, however, greatly impaired the dams' ability to rapidly release pups held in the mouth, but not to pick them up or carry them directly to the nest during retrieval. Separate regions of the PAG, therefore, are differentially involved in the control of specific components of behaviors in lactating rats.

Metabolic responses to suckling in postpartum lactating rats.

The effects of suckling on the metabolic activity both of pituitary tissue and of subnuclei in the supraoptic and paraventricular nuclei of the hypothalamus were assessed by means of the [14C]deoxyglucose (2-DG) method of autoradiography. Three groups of female rats were deprived of their pups and of food for 6 h on the fifth or sixth day after parturition. Metabolic activity was assessed either before, during, or after a bout of suckling. The anterior pituitary is more active in suckled than in either non-suckled or postsuckled females. These differences may be a consequence of depletion/transformation/repletion of prolactin during a bout of suckling. The posterior pituitary is metabolically more active in suckled females and in postsuckled females than in non-suckled rats. These differences may reflect metabolic activity needed for the dynamics of oxytocin release and the restoration of ionic gradients. The dorsal and ventral subdivisions of the supraoptic nucleus and the lateral, dorsal, and posterior subnuclei of the paraventricular nucleus were more active in postsuckled females than in non-suckled females. These metabolic changes in the subnuclei of the magnocellular neurohypophysial system may reflect increased resynthesis of oxytocin (and vasopressin) in the cell bodies following a bout of suckling.

Acquiring simultaneous EEG and functional MRI.

OBJECTIVE: Electroencephalography (EEG) is a challenge to record simultaneously with functional MRI (fMRI), for it is prone to large artifacts induced by both the static and the time-variant fields of the MR scanner. However, truly concurrent EEG/fMRI recording has great potential for clinical and scientific neurological applications. We have devised a method for acquiring EEG simultaneously with fMRI that minimizes contamination of the EEG signals. METHODS: We recorded EEG differentially during fMRI using special twisted dual-lead electrodes in a bipolar montage, and a combination of analog pre-processing and digital post-processing of the EEG data. We implemented a functional scan protocol that typically yields artifact-free EEG over 87% of the MR scanning period. RESULTS: Our approach greatly reduced gradient, radio frequency, motion and ballistocardiographic artifact in the EEG, and allowed continuous monitoring of the EEG during functional scanning. To illustrate the quality of the EEG following post-processing, we demonstrated that EEG recorded during fMRI retains useful spectral information. CONCLUSIONS: Quality EEG may be recorded simultaneously with fMRI. With this union, activation maps could be made of any relevant changes in the EEG, such as inter-ictal spikes or spectral variations, or of evoked response potentials (ERPs).