Testosterone reactivity to competition and competitive endurance in men and women.

Transient shifts in testosterone occur during competition and are thought to positively influence dominance behavior aimed at enhancing social status. However, individual differences in testosterone reactivity to status contests have not been well-studied in relation to real-time expressions of competitive behavior among men and women. This research tests the association between changes in endogenous testosterone levels during competition and performance in terms of competitive endurance. Participant sex, social presence, and relative status outcomes (e.g., winning vs. losing) are tested as moderators of this relationship. In two studies, men and women (total N = 398) competed in the competitive will task (timed weight-holding) either individually or in the presence of an opponent (Study 1) or as a team with and without the presence of a competitor team (Study 2). Results showed a positive relationship between testosterone reactivity and performance for men, particularly those who won or ranked highest among their group - with increasing testosterone predicting better performance and decreasing testosterone predicting worse performance. For women, the effect only emerged among individuals who competed in dyads and lost. In Study 2, an exploratory mediation analysis revealed that individual differences in trait dominance predicted both testosterone reactivity to competition and task performance, with testosterone reactivity (moderated by sex and status outcome) partially explaining the direct relationship between dominance-related traits and behavior. Our goal was to examine testosterone reactivity in relation to real-time competitive effort and highlight the potential role of this relationship in explaining how individual differences in trait dominance produce competitive behavior.

Comparison of effectiveness of two commonly used two-handed mask ventilation techniques on unconscious apnoeic obese adults.

BACKGROUND.: Mask ventilation and tracheal intubation are basic techniques for airway management and mutually inclusive rescue measures to restore ventilation. The aim of this study was to compare the effectiveness of mask ventilation between two commonly used techniques of two-handed mask ventilation in obese unconscious apnoeic adults. METHODS.: Eighty-one obese adults received mask ventilation after induction using C-E clamp and modified V-E clamp techniques in a randomized crossover manner. Mechanical ventilation was provided using a pressure-control mode, at a rate of 10 bpm, with an inspiratory-to-expiratory time ratio of 1:2 and a pre-set plateau airway pressure of 20 cm H 2 O. The primary outcome was expired tidal volume. RESULTS.: The BMI for the subjects was 37 ( sd 4.9) kg m -2 . The failure rates for mask ventilation (tidal volume≤anatomical dead space) were 44% for the C-E technique and 0% for the V-E technique ( P <0.001). Tidal volume was significantly lower for the C-E than the V-E technique [371 ( sd 345) vs 720 (244) ml, P <0.001]. The peak airway pressures were 21 ( sd 1.5) cm H 2 O for the C-E technique and 21 (1.3) cm H 2 O for the V-E technique. CONCLUSIONS.: Mask ventilation using the modified V-E technique is more effective than with the C-E technique in unconscious obese apnoeic adults. Subjects who fail ventilation with the C-E technique can be ventilated effectively with the V-E technique. CLINICAL TRIAL REGISTRATION.: NCT02580526.

Oral chronic graft-versus-host disease: current pathogenesis, therapy, and research.

Optimal management of complex autoimmune diseases requires a multidisciplinary medical team including dentists to care for lesions of the oral cavity. In this review, we discuss the presentation, prevalence, diagnosis, and treatment of oral manifestations in chronic graft-versus-host disease (cGVHD), which is a major late complication in patients treated by allogeneic hematopoietic stem cell transplantation. We assess current general knowledge of systemic and oral cGVHD and present general treatment recommendations based on literature review and our clinical experience. Additionally, we review areas where the understanding of oral cGVHD could be improved by further research and address tools with which to accomplish the long-term goal of providing better health and quality of life to patients with cGVHD.

Mice: fighting by neonatally androgenized females.

Administration of testosterone propionate to female mice on the day of birth resulted in increased fighting after administration of testosterone during adulthood. This fighting, comparable to fighting among normal male mice, suggests that early androgenic stimulation organizes neural structures mediating aggression in the mouse.

Large porous particles for pulmonary drug delivery.

A new type of inhalation aerosol, characterized by particles of small mass density and large size, permitted the highly efficient delivery of inhaled therapeutics into the systemic circulation. Particles with mass densities less than 0.4 gram per cubic centimeter and mean diameters exceeding 5 micrometers were inspired deep into the lungs and escaped the lungs' natural clearance mechanisms until the inhaled particles delivered their therapeutic payload. Inhalation of large porous insulin particles resulted in elevated systemic levels of insulin and suppressed systemic glucose levels for 96 hours, whereas small nonporous insulin particles had this effect for only 4 hours. High systemic bioavailability of testosterone was also achieved by inhalation delivery of porous particles with a mean diameter (20 micrometers) approximately 10 times that of conventional inhaled therapeutic particles.

Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors.

We provide evidence that cyclooxygenase (COX)-2-derived prostaglandins contribute to tumor growth by inducing newly formed blood vessels (neoangiogenesis) that sustain tumor cell viability and growth. COX-2 is expressed within human tumor neovasculature as well as in neoplastic cells present in human colon, breast, prostate, and lung cancer biopsy tissue. COX-1 is broadly distributed in normal, as well as in neoplastic, tissues. The contribution of COX-2 to human tumor growth was indicated by the ability of celecoxib, an agent that inhibits the COX-2 enzyme, to suppress growth of lung and colon tumors implanted into recipient mice. Mechanistically, celecoxib demonstrated a potent antiangiogenic activity. In a rat model of angiogenesis, we observe that corneal blood vessel formation is suppressed by celecoxib, but not by a COX-1 inhibitor. These and other data indicate that COX-2 and COX-2-derived prostaglandins may play a major role in development of cancer through numerous biochemical mechanisms, including stimulation of tumor cell growth and neovascularization. The ability of celecoxib to block angiogenesis and suppress tumor growth suggests a novel application of this anti-inflammatory drug in the treatment of human cancer.

Sex differences in serum luteinizing hormone and testosterone in the human neonate during the first few hours after birth.

Blood was obtained from human male and female neonates within a few minutes after birth, and at intervals thereafter for up to 21 h. Serum LH was substantially higher at birth for boys than girls. For most boys, serum LH fell precipitously during the next hour; serum LH remained low for the remainder of the period sampled in both boys and girls. In girls, serum testosterone was low at birth and remained low for at least 21 h. At birth, serum testosterone in boys was higher than for girls, increased dramatically during the first 3 h after birth, and remained elevated (2 to 3 times higher than for girls) between 3 and 12 h after birth. In newborn human males, a sudden discharge of hypophyseal LH appears to stimulate neonatal secretion of testosterone by the testes. The functional significance of this phenomenon remains to be determined.

Colocalization of androgen receptors and mating-induced FOS immunoreactivity in neurons that project to the central tegmental field in male rats.

Bilateral lesions of the central tegmental field (CTF) in male rats virtually eliminate mating behavior. This study examined if mating-induced Fos expression (a measure of neuronal activation) and androgen receptors (AR) are colocalized in brain and spinal cord neurons which project to the CTF. Animals received unilateral injections of the retrograde tracer Fluorogold (FG) in the lateral part of the CTF (CTFl), and 10 days later were killed after ejaculating with females. Brains and spinal cords were examined for FG transport, AR-immunoreactivity (AR-ir), and Fos-immunoreactivity (Fos-ir). AR-ir and Fos-ir were visualized with fluorescence microscopy using cyanine-conjugated and fluorescein-conjugated secondary antibodies. The CTFl received projections from AR-containing neurons in forebrain structures (bed nucleus of stria terminalis, medial preoptic area, lateral and ventromedial hypothalamus), in the central amygdala and various mid- and hindbrain structures (dorsolateral tegmentum, superior and inferior colliculi, pedunculopontine nucleus), and in the lumbosacral spinal cord (lamina X). Some of the AR-containing neurons in bed nucleus of stria terminalis and in the dorsal part of the medial preoptic area with projections to the CTFl were activated by mating. Most AR-containing neurons in spinal lamina X with projections to the CTFl were also activated by mating. Information from spinal cord and pontine nuclei and from outputs descending from the forebrain may be relayed in the CTFl. Thus, as part of a network of hormone-sensitive neurons linking brain and spinal cord mechanisms for mating, the CTFl could participate in the integration of visceral and somatic information relevant for sexual behavior.

Direct lung delivery of para-aminosalicylic acid by aerosol particles.

Para-aminosalicylic acid (PAS), a tuberculostatic agent, was formulated into large porous particles for direct delivery into the lungs via inhalation. These particles possess optimized physical properties for deposition throughout the respiratory tract, a drug loading of 95% by weight and physical stability over 4 weeks at elevated temperatures. Upon insufflation in rats, PAS concentrations were measured in plasma, lung lining fluid and homogenized whole lung tissue. Systemic drug concentrations peaked at 15 min, with a maximum plasma concentration of 11+/-1 microg/ml. The concentration in the lung lining fluid was 148+/-62 microg/ml at 15 min. Tissue concentrations were 65+/-20 microg/ml at 15 min and 3.2+/-0.2 microg/ml at 3h. PAS was cleared within 3 h from the lung lining fluid and plasma but was still present at therapeutic concentrations in the lung tissue. These results suggest that inhalation delivery of PAS can potentially allow for a reduction in total dose delivered while providing for higher local and similar peak systemic drug concentrations as compared to those obtained upon oral PAS dosing. Similar particles could potentially be used for the delivery of additional anti-tuberculosis agents such as rifampicin, aminoglucosides or fluoroquinolones.

Androgen receptor immunoreactivity and mating-induced Fos expression in forebrain and midbrain structures in the male rat.

The distribution of androgen receptor immunoreactive-neurons, mapped with the PG21 anti-androgen receptor antibody, was compared in male rat brains with the distribution of Fos-immunoreactive neurons induced by mating. In gonadally intact, but not in castrated male rats, substantial numbers of androgen receptor-containing neurons were present in a variety of forebrain and midbrain regions. The PG21 antibody apparently had a higher affinity for occupied than for non-occupied androgen receptors. Androgen receptor-immunoreactive regions included the medial preoptic area and other forebrain areas previously identified as containing androgen receptors, the dorsal and ventral periaqueductal gray, and a midbrain region that included the lateral part of the central tegmental field, part of the caudal zona incerta, the subparafascicular nucleus of the thalamus and the peripeduncular nucleus. Fos-expressive neurons were essentially absent in non-mated males but were present in the brains of rats which mated to ejaculation. All brain regions in which androgen receptor-immunoreactive neurons were counted also expressed Fos immunoreactivity after mating, and there was considerable overlap between the distributions of androgen receptor- and Fos-immunoreactive neurons. In a second experiment, we used immunofluorescent techniques to document the intraneuronal co-localization of Fos with androgen receptor immunoreactivity in the medial preoptic area, medial amygdala, and central tegmental field. In these regions mating-induced Fos immunofluorescence was exclusively localized in androgen receptor-immunofluorescent neurons. However, not all androgen receptor neurons were Fos expressive, suggesting that only some androgen-sensitive neurons were activated during mating. These results are consonant with the view that hormone actions on forebrain and midbrain structures influence the neuronal activity correlated with mating.

Analysis of stained objects in histological sections by spectral imaging and differential absorption.

We describe a new light microscopic imaging system and method to perform high through put color image analysis on histological tissue sections. The system features a computer-controlled, random-access liquid crystal tunable filter and high-resolution digital camera on a conventional brightfield microscope. For any combination of stains, the method determines the spectral transmittance of each stain on the slide and selects two or more wavelengths at which the differential absorption between stain and counterstain is greatest and the exposure time is reasonably short. Flatfield corrected digital images at these wavelengths are acquired and divided to produce a gray scale ratio image. The ratio image is calculated such that the stained features of interest are highlighted above a uniform background and the counterstained features are highlighted below background. Image threshold procedures using either visual inspection or a threshold value determined by the image mean intensity and standard deviation are used to segment the stained features of interest for subsequent morphometry. Results are presented for peroxidase-AEC-labeled tumor tissue and trichrome-stained biomaterial implant tissues. In principle, the method should work for any combination of colored stains. (J Histochem Cytochem 47:1307-1313, 1999)

Effect of nitrogen dioxide on surface membrane fluidity and insulin receptor binding of pulmonary endothelial cells.

Nitrogen dioxide (NO2), an environmental oxidant pollutant, is known to peroxidize membrane lipids of lung cells. We evaluated the ability of NO2 to alter the surface membrane fluidity, lipid composition, and insulin receptor binding of porcine pulmonary artery endothelial cells in culture. After 3- to 24-hr exposure to 5 ppm NO2, cells were labeled with either 1-(4-trimethylaminophenyl)-6-phenyl-1,3,5-hexatriene (TMA-DPH), a cationic fluorescent aromatic hydrocarbon that anchors at the lipid-water interface, or fluorescamine, a fluorescent molecular probe that covalently binds with amino groups of surface phospholipids and proteins. Membrane fluidity was measured by monitoring changes in the steady-state fluorescence anisotropies (rs) for TMA-DPH and fluorescamine. Insulin specific receptor binding was monitored by measuring time-dependent binding of 125I-insulin. Following NO2 exposure, rs values for TMA-DPH and fluorescamine were increased significantly in a time-dependent fashion, with maximum increases at 24 hr (P less than 0.001). Similar increases in rs values were observed in isolated plasma membranes as well as in lipid vesicles prepared from total lipid extracts of endothelial cells or their plasma membranes. Phosphatidylethanolamine plus phosphatidylserine content in lipid extracts from 24-hr but not 3- to 12-hr NO2-exposed cells was increased significantly (P less than 0.01) compared to control cells. Specific binding of 125I-insulin to cells exposed to NO2 for 12 and 24 hr (but not 3 and 6 hr) was reduced significantly (P less than 0.05) compared to binding in control cells. Scatchard analysis of the binding data indicated that NO2 exposure caused a 5-fold reduction in insulin receptor binding sites in endothelial cells. Recovery was achieved 24 hr after NO2 exposure with, but not without, changing culture medium. These results indicate that NO2 exposure causes reversible changes in the physical state of lipids in the superficial lipid domains of the pulmonary endothelial cell plasma membrane, and these alterations may interfere with plasma membrane-dependent functions such as receptor-ligand interaction.

Preoptic and subthalamic connections with the caudal brainstem are important for copulation in the male rat.

Bilateral lesions of either the medial preoptic area/anterior hypothalamus (MPAH) or a subthalamic region that includes the caudal zona incerta eliminate copulation in male rats. Pathways connecting the MPAH and subthalamus with the caudal brainstem may help regulate sexual behavior. Experiment 1 showed that bilateral coronal transections of the pontine tegmentum reduce mating and that the combination of a unilateral tegmental cut with a contralateral excitotoxin lesion of either the MPAH (Experiment 2) or subthalamus (Experiment 3) virtually eliminates copulation. Asymmetric bilateral damage appears to eliminate mating through a bilateral effect common to the transection and the lesion--the destruction of connections linking the MPAH and subthalamus with the caudal brainstem. These results indicate that preoptic and subthalamic connections with the caudal brainstem are important for copulation in the male rat.

Connections between the pontine central gray and the ventromedial hypothalamus are essential for lordosis in female rats.

Lesions and knife cuts were used to study central gray (CG) and ventromedial hypothalamic (VMH) mediation of sexual receptivity in female rats. Lesions of the midbrain-pontine CG eliminated lordosis in female rats. Bilateral sagittal knife cuts that bracketed the rostral pontine CG also eliminated lordosis, and an experiment with the retrograde tracer Fluoro-Gold confirmed the effectiveness of these cuts in severing the lateral connections linking the VMH and the CG. Finally, females with a unilateral hypothalamic cut combined with a contralateral CG transection almost never showed lordosis. Each cut, at a different level for each side of the brain, transected axons linking the VMH and the CG. The demonstration that this combination eliminated lordosis provides new evidence that the lateral connections between the VMH and the CG are essential for the display of sexual receptivity in female rats.

Recent advances in pulmonary drug delivery using large, porous inhaled particles.

The ability to deliver proteins and peptides to the systemic circulation by inhalation has contributed to a rise in the number of inhalation therapies under investigation. For most of these therapies, aerosols are designed to comprise small spherical droplets or particles of mass density near 1 g/cm3 and mean geometric diameter between approximately 1 and 3 micron, suitable for particle penetration into the airways or lung periphery. Studies performed primarily with liquid aerosols have shown that these characteristics of inhaled aerosols lead to optimal therapeutic effect, both for local and systemic therapeutic delivery. Inefficient drug delivery can still arise, owing to excessive particle aggregation in an inhaler, deposition in the mouth and throat, and overly rapid particle removal from the lungs by mucocilliary or phagocytic clearance mechanisms. To address these problems, particle surface chemistry and surface roughness are traditionally manipulated. Recent data indicate that major improvements in aerosol particle performance may also be achieved by lowering particle mass density and increasing particle size, since large, porous particles display less tendency to agglomerate than (conventional) small and nonporous particles. Also, large, porous particles inhaled into the lungs can potentially release therapeutic substances for long periods of time by escaping phagocytic clearance from the lung periphery, thus enabling therapeutic action for periods ranging from hours to many days.

Excitotoxin lesions of the zona incerta/lateral tegmentum continuum: effects on male sexual behavior in rats.

In male rats, ibotenic acid and N-methyl-D-aspartic acid were used to destroy neuronal perikarya intrinsic to an anterior-posterior continuum including the caudal zona incerta and lateral tegmentum. Some lesions virtually eliminated male sexual behavior - an effect most closely associated with damage to the lateral hypothalamus and zona incerta. Many lesioned males who copulated to ejaculation with normally active females showed little or no mating with receptive, but relatively inactive, females. Although it is possible to identify a critical region within the subthalamus whose destruction eliminates male sexual behaviour, sexually-relevant neuronal cell bodies appear to be distributed throughout the lateral hypothalamic/incertal/tegmental continuum.

Zona incerta lesions: effects on copulation, partner-preference and other socio-sexual behaviors.

Sexually active males prefer a sexually receptive female to a non-receptive female, and partner-preference tests provide one way of studying the effect of brain damage on sexual motivation. Male rats with bilateral electrolytic lesions of the caudal zona incerta do not mate, and we studied the effects of zona incerta destruction on copulation and partner-preference. Lesioned males did not mate but were not indifferent to sexually receptive females. They continued to show a strong preference for a sexually receptive female over a non-receptive female. In addition, lesioned males showed many incomplete mounts i.e. mounts not accompanied by the pelvic thrusting necessary for intromission and ejaculation. Anogenital investigation of the receptive female was common. Taken together, these facts suggest that zona incerta destruction eliminates copulation without affecting sexual motivation, and that the failure to mate after lesioning probably reflects an inability to properly engage the locomotor responses of copulation.

Midbrain lesions, dopamine and male sexual behavior.

Destruction of the medial preoptic area (MPOA) eliminates mating in male rats and this region is believed to play a major role in the control of male sexual behavior. Efferents from the MPOA pass through and/or terminate in 4 midbrain regions: the dorsolateral tegmentum (DLT), the central gray, and the A9 and A10 areas. The present study reports the effects of bilateral destruction of each of these midbrain regions on brain catecholamines and sexual behavior in male rats. DLT lesions eliminated mating, reproducing the effect of bilateral preoptic lesions. The sexual activity of males with central gray lesions was accelerated in the sense that the mounting rate for these males was significantly faster than for controls and lesioned males ejaculated more frequently and with shorter latencies than did controls. A9 lesions impaired mating--lesioned males mounted at a slower rate and ejaculated less frequently than controls. Males with A10 lesions took longer to re-initiate mating after an ejaculation than controls, but copulation per se (as reflected in mount rate, ejaculation frequency and latency to ejaculate) was not affected by A10 damage. Brain catecholamine levels were not affected by either DLT or central gray lesions. A9 lesions produced a significant depletion in neostriatal dopamine which was highly correlated with mount latency, mount rate, ejaculation latency and ejaculation frequency. A10 lesions produced a significant depletion of dopamine in the nucleus accumbens and cingulate cortex, but these effects were not significantly correlated with any measure of sexual behavior.

Preoptic lesions increase the display of lordosis by male rats.

Male rats do not normally show feminine patterns of sexual behavior even when injected with the ovarian hormones estrogen and progesterone. We find that brain lesions which damage the preoptic-anterior hypothalamic continuum augment the display of lordosis in hormone-treated male rats. The most effectively feminizing brain lesions are ones which bilaterally destroy a substantial portion of the medial preoptic area encompassing the sexually dimorphic nucleus of the preoptic area (SDN-POA). Males with particularly large preoptic lesions are receptive following estrogen treatment and show a progesterone facilitation of receptivity. In this respect, they cannot be behaviorally distinguished from females. Thus, axons originating in and/or passing through the preoptic area apparently inhibit the display of feminine sexual behaviors in males. Preoptic development and lordosis are each predictably affected by perinatal stimulation by testicular hormones, and hormone-stimulated preoptic development may form the neurological basis for some of the defeminizing effects of perinatal hormonal exposure. Our results raise the possibility that the site of this behavioral defeminization is the SDN-POA.

Androgen receptor and mating-induced fos immunoreactivity are co-localized in limbic and midbrain neurons that project to the male rat medial preoptic area.

Two studies were designed to document neuronal colocalization of androgen receptor immunoreactivity and mating-induced Fos immunoreactivity (AR-ir, Fos-ir) in brain of male rats and to examine the extent to which limbic and midbrain neurons that project to the preoptic area are androgen sensitive and activated by mating. Brains from male rats, killed 1 h after ejaculating with receptive females, were examined for Fos-ir and AR-ir and compared with those from control rats not given access to females. PG21 anti-AR and anti-c-fos primary antibodies were visualized by fluorescence microscopy using cyanine-conjugated and fluorescein-conjugated secondary antibodies. In mated males (Expt. 1), Fos-ir and AR-ir were colocalized in neurons of the medial preoptic nucleus (MPN), the dorsal medial amygdala (dMEA), the central tegmental field (CTF), the bed nucleus of the stria terminalis, the anterior hypothalamus, the lateral hypothalamus, and the ventral premamillary nucleus. In Expt. 2, male rats received a unilateral injection of the retrograde tracer FluoroGold (FG) in the preoptic area and four days later were killed after ejaculating with receptive females. Brains were subsequently examined for FG transport, Fos-ir and AR-ir. Fluorogold-containing neurons were present in dMEA and CTF as well as in other hypothalamic and limbic regions known to project to the MPN. In dMEA and CTF, nuclear colocalization of AR-ir and mating-induced Fos-ir was present in a proportion of FG-containing neurons. Sexually relevant information may be carried through the brain by an interconnected network of hormone-sensitive neurons.