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.

Spray drying TB vaccines for pulmonary administration.

BACKGROUND: New developments in materials science provide innovative technologies that allow mucosal immunization against tuberculosis. Recent studies report that spray-drying Mycobacterium bovis Bacillus Calmette-Guérin (BCG) allows efficient aerosol delivery of TB vaccines to the lung. OBJECTIVES: To consider powder formulation of BCG for inhalation by spray-drying and its potential application to other vaccines given the unique challenges in the process, formulation and delivery. METHODS: Description of current advances in spray-drying and aerosol delivery, and its application to preparation of BCG TB vaccine for inhalation. Special consideration is given to physical properties, viability, stability and delivery aspects. RESULTS/CONCLUSION: Spray-drying generates powders with excellent dispersion qualities suitable for targeted delivery to the deep lung. TB vaccine for inhalation prepared by spray-drying is feasible, low-cost and pharmaceutically scaleable.

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.

Trojan particles: large porous carriers of nanoparticles for drug delivery.

We have combined the drug release and delivery potential of nanoparticle (NP) systems with the ease of flow, processing, and aerosolization potential of large porous particle (LPP) systems by spray drying solutions of polymeric and nonpolymeric NPs into extremely thin-walled macroscale structures. These hybrid LPPs exhibit much better flow and aerosolization properties than the NPs; yet, unlike the LPPs, which dissolve in physiological conditions to produce molecular constituents, the hybrid LPPs dissolve to produce NPs, with the drug release and delivery advantages associated with NP delivery systems. Formation of the large porous NP (LPNP) aggregates occurs via a spray-drying process that ensures the drying time of the sprayed droplet is sufficiently shorter than the characteristic time for redistribution of NPs by diffusion within the drying droplet, implying a local Peclet number much greater than unity. Additional control over LPNPs physical characteristics is achieved by adding other components to the spray-dried solutions, including sugars, lipids, polymers, and proteins. The ability to produce LPNPs appears to be largely independent of molecular component type as well as the size or chemical nature of the NPs.

Inhalation delivery of proteins from ethanol suspensions.

To circumvent inherent problems associated with pulmonary administration of aqueous-solution and dry-powder protein drugs, inhalation delivery of proteins from their suspensions in absolute ethanol was explored both in vitro and in vivo. Protein suspensions in ethanol of up to 9% (wt/vol) were readily aerosolized with a commercial compressor nebulizer. Experiments with enzymic proteins revealed that nebulization caused no detectable loss of catalytic activity; furthermore, enzyme suspensions in anhydrous ethanol retained their full catalytic activity for at least 3 weeks at room temperature. With the use of Zn(2+)-insulin, conditions were elaborated that produced submicron protein particles in ethanol suspensions. The latter (insulin/EtOH) afforded respirable-size aerosol particles after nebulization. A 40-min exposure of laboratory rats to 10 mg/ml insulin/EtOH aerosols resulted in a 2-fold drop in the blood glucose level and a marked rise in the serum insulin level. The bioavailability based on estimated deposited lung dose of insulin delivered by inhalation of ethanol suspension aerosols was 33% (relative to an equivalent s.c. injection), i.e., comparable to those observed in rats after inhalation administration of dry powder and aqueous solutions of insulin. Inhalation of ethanol in a relevant amount/time frame resulted in no detectable acute toxic effects on rat lungs or airways, as reflected by the absence of statistically significant inflammatory or allergic responses, damage to the alveolar/capillary barrier, and lysed and/or damaged cells.

The effect of a receptor layer on the measurement of rate constants.

Many cellular reactions involve a reactant in solution binding to or dissociating from a reactant attached to a surface. Most studies assume that the reactions occur on this surface, when in actuality the receptors usually lie in a thin layer on top of it. The effect of this layer is considered, particularly as it relates to the BIAcore measurement device, though the results are applicable to biological systems. A dimensionless parameter measuring the strength of the effect of the receptor layer is found. Asymptotic and singular perturbation techniques are used to analyse association and dissociation kinetics, though the effect of the receptor layer need not be small. Linear and nonlinear integral equations result from the analysis; explicit and asymptotic solutions are constructed for physically realizable cases. In addition, effective rate constants are derived that illustrate the combined effects of transport and the receptor layer on the measured rate constants. All these expressions provide a direct way to estimate rate constants from BIAcore binding data.

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.

A mechanistic analysis of carrier-mediated oral delivery of protein therapeutics.

This article summarizes the results of a theoretical analysis of protein absorption into the systemic circulation from the small intestine, with and without molecular 'carriers' designed to enhance absorption. The predictions are compared with experimental systemic protein concentrations following intraduodenal delivery of insulin, interferon alpha-2b, and human growth hormone. The results show that, from the standpoint of improving oral absorption, the primary consequence of carrier molecules is to increase epithelial membrane permeability, thereby leading to higher bioavailability. Several possible mechanisms of this permeability enhancement are discussed.

Formulation and physical characterization of large porous particles for inhalation.

PURPOSE: Relatively large (>5 microm) and porous (mass density <0.4 g/cm3) particles present advantages for the delivery of drugs to the lungs, e.g., excellent aerosolization properties. The aim of this study was, first, to formulate such particles with excipients that are either FDA-approved for inhalation or endogenous to the lungs; and second, to compare the aerodynamic size and performance of the particles with theoretical estimates based on bulk powder measurements. METHODS: Dry powders were made of water-soluble excipients (e.g., lactose, albumin) combined with water-insoluble material (e.g., lung surfactant), using a standard single-step spray-drying process. Aerosolization properties were assessed with a Spinhaler device in vitro in both an Andersen cascade impactor and an Aerosizer. RESULTS: By properly choosing excipient concentration and varying the spray drying parameters, a high degree of control was achieved over the physical properties of the dry powders. Mean geometric diameters ranged between 3 and 15 microm, and tap densities between 0.04 and 0.6 g/cm3. Theoretical estimates of mass mean aerodynamic diameter (MMAD) were rationalized and calculated in terms of geometric particle diameters and bulk tap densities. Experimental values of MMAD obtained from the Aerosizer most closely approximated the theoretical estimates, as compared to those obtained from the Andersen cascade impactor. Particles possessing high porosity and large size, with theoretical estimates of MMAD between 1-3 microm, exhibited emitted doses as high as 96% and respirable fractions ranging up to 49% or 92%, depending on measurement technique. CONCLUSIONS: Dry powders engineered as large and light particles, and prepared with combinations of GRAS (generally recognized as safe) excipients, may be broadly applicable to inhalation therapy.

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)

Inhalation of estradiol for sustained systemic delivery.

Large porous estradiol particles were formulated by spray drying estradiol in combination with various U.S. Food and Drug Administration (FDA)-approved or endogenous excipients. The powders were characterized in terms of their geometrical size, mass density, and aerosolization properties. Small nonporous particles were also prepared using the same excipients and were physically characterized to insure that they possessed a similar mean aerodynamic size as the large porous particles. The two powders were aerosolized into the lungs of rats via an endotracheal tube or subcutaneously injected as a control to assess relative bioavailability. Two different large porous particle formulations were found to produce elevated systemic estradiol concentrations upon inhalation for approximately 5 days, with relative bioavailabilities of 59.7% and 86.0%. Systemic estradiol concentrations following inhalation of two different small nonporous particle powders remained elevated for only approximately 1 day, with relative bioavailabilities of 18.3% and 38.7%. Bronchoalveolar lavage was performed up to 96 hours after inhalation of porous and nonporous estradiol powders. Small changes in neutrophil and macrophage populations were observed following inhalation of both the porous and nonporous powders.

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.

Large porous particles for sustained protection from carbachol-induced bronchoconstriction in guinea pigs.

PURPOSE: To determine whether a new formulated albuterol aerosol could sustain inhibition to bronchoconstriction for approximately one day in guinea pigs challenged with carbachol. METHODS: Large and porous particles, comprising a combination of endogenous or FDA-approved excipients and albuterol sulfate, were prepared by spray drying using a NIRO portable spray drier. The anesthetized animals inhaled 5 mg of large porous or small nonporous particles by forced ventilation via cannulae inserted in the lumen of their exposed tracheae. At regular intervals over a period of 36 hours after drug delivery, airway resistance was determined in response to carbachol challenge dose. RESULTS: Whereas inhalation of small nonporous albuterol particles protected from the carbachol-induced bronchoconstriction for up to 5 hours, inhalation of large porous albuterol particles produced a significant inhibition of carbachol-induced bronchoconstriction for at least 16 hours. CONCLUSIONS: The absence of substantial side effects, verified over a period of 24 hours by evaluating cardio-respiratory parameters as well as pulmonary inflammation, supports the utility of large porous albuterol particles for sustained therapies in asthma and other types of lung disease.

Areas of fat loss in overweight young females following an 8-week period of energy intake reduction.

In order to investigate the main areas of fat loss after an 8-week period of energy intake reduction, the distribution of body fat was assessed on 14 females (BMI 27.3+/-0.83 kgm(-2)) (mean +/- SEM), aged 18-22 years. Total body fat was determined by hydrostatic weighing and subcutaneous fat mass and distribution were assessed using ultrasound and waist-hip circumference ratios prior to, and following, an 8-week period during which subjects attempted to reduce their energy intake by about 4.2 MJ day(-1). Subjects lost an average of 2.99+/-0.34 kg (p < 0.001), with greater loss (p < 0.001) of internal fat (1.5+/-0.2 kg) than of subcutaneous fat (0.7+/-0.1). Subjects reduced their waist-hip ratio from 0.771+/-0.01 to 0.762+/-0.01 (p < 0.01), their waist circumference from 807+/-24 to 790+/-23 mm (p < 0.001) and their hip circumference from 1047+/-29 to 1037+/-29 mm (p < 0.001). Those with an android distribution of fat (n = 5) lost more weight than those with gynoid distribution (n = 9) (3.80+/-0.38 kg vs 2.54+/-0.14 kg, p < 0.05); they also showed a greater decrease in waist circumference (27+/-5 vs 14+/-4 mm, p < 0.05) and a greater loss from internal fat stores (2.1+/-0.3 kg vs 1.1+/-0.2 kg, p < 0.05). The findings suggest that individuals are prone to lose internal fat during a short period of reduced energy intake. As the visceral fat store is the largest internal fat depot in the body, this suggests that individuals are indeed losing fat that could predispose to upper body obesity.

Transport effects on surface-volume biological reactions.

Many cellular reactions involve a reactant in solution binding to or dissociating from a reactant confined to a surface. This is true as well for a BIAcore, an optical biosensor that is widely used to study the interaction of biomolecules. In the flow cell of this instrument, one of the reactants is immobilized on a flat sensor surface while the other reactant flows past the surface. Both diffusion and convection play important roles in bringing the reactants into contact. Usually BIAcore binding data are analyzed using well known expressions that are valid only in the reaction-limited case when the Damköhler number Da is small. Asymptotic and singular perturbation techniques are used to analyze dissociation of the bound state when Da is small and O(1). Linear and nonlinear integral equations result from the analysis; explicit and asymptotic solutions are constructed for physically realizable cases. In addition, effective rate constants are derived that illustrate the effects of transport on the measured rate constants. All these expressions provide a direct way to estimate the rate constants from BIAcore binding data.