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Basic Science (basic + science)
Terms modified by Basic Science Selected AbstractsORIGINAL RESEARCH,BASIC SCIENCE: Fluoxetine-Induced Decrements in Sexual Responses of Female Rats and Hamsters Are Reversed by 3,,5,-THPTHE JOURNAL OF SEXUAL MEDICINE, Issue 8 2010Cheryl A. Frye PhD ABSTRACT Introduction., Sexual dysfunction, as a result of selective-serotonin reuptake inhibitor (SSRI) treatment among women, is relatively common and is a factor in medication compliance. The mechanisms that underlie these side-effects of SSRIs are not well-understood. SSRIs can alter activity of catabolic enzymes that are involved in progesterone's conversion to 5,-pregnan-3,-ol-20-one (3,,5,-THP). 3,,5,-THP plays a key role in female reproductive physiology and behavior. Aims., This study aimed to determine whether 3,,5,-THP, in the midbrain ventral tegmental area (VTA) may be a potential mechanism for fluoxetine's reduction in sexual responding of female rodents. We hypothesized that if fluoxetine induces decrements in sexual responding in part through actions of 3,,5,-THP, then fluoxetine will inhibit sexual receptivity concomitant with reducing 3,,5,-THP levels, effects which can be reversed by 3,,5,-THP administration. Methods., Experiment 1 investigated effects of acute systemic fluoxetine [20 mg/kg intraperitoneal (IP)] and/or 3,,5,-THP [500 µg, subcutaneous (SC)] administration on sexual responding of ovariectomized, hormone-primed rats. Experiment 2 examined effects of 3,,5,-THP administration to the midbrain VTA (100 ng) on fluoxetine-induced decrements in lordosis of ovariectomized, hormone-primed rats and hamsters. Main Outcome Measures., Sexual responding was determined in rats and hamsters. For rats, the percentage of times that the lordosis response occurred following mounting by a sexually-vigorous male (lordosis quotients) was utilized. For hamsters, lateral displacement, the pelvic movement that females will make to facilitate intromissions by a male hamster, was utilized. Results., Fluoxetine significantly reduced lordosis, and this was reversed SC 3,,5,-THP. Intra-VTA 3,,5,-THP attenuated fluoxetine's detrimental effects on lordosis quotients and lateral displacement of rats and hamsters, respectively. Conclusions., Thus, fluoxetine's effects to disrupt female sexual responses may involve its effects on progestogens in the midbrain VTA. Frye CA, and Rhodes ME. Fluoxetine-induced decrements in sexual responses of female rats and hamsters are reversed by 3,,5,-THP. J Sex Med 2010;7:2670,2680. [source] ORIGINAL RESEARCH,BASIC SCIENCE: Neuroanatomical Evidence for a Role of Central Melanocortin-4 Receptors and Oxytocin in the Efferent Control of the Rodent Clitoris and VaginaTHE JOURNAL OF SEXUAL MEDICINE, Issue 6 2010Helene Gelez PhD ABSTRACT Introduction., The clitoris and the vagina are the main peripheral anatomical structures involved in physiological changes related to sexual arousal and orgasm. Their efferent control and, more particularly, the neurochemical phenotype of these descending neuronal pathways remain largely uncharacterized. Aim., To examine if brain neurons involved in the efferent control of the clitoris and the vagina possess melanocortin-4 receptor (MC4-R) and/or contain oxytocin (OT). Methods., Neurons involved in the efferent control of the vagina and clitoris were identified following visualization of pseudorabies virus (PRV) retrograde tracing. PRV was injected into the vagina and clitoris in adult rats in estrous. On the fifth day postinjection, animals were humanely sacrificed, and brains were removed and sectioned, and processed for PRV visualization. The neurochemical phenotype of PRV-positive neurons was identified using double or triple immunocytochemical labeling against PRV, MC4-R, and OT. Double and triple labeling were quantified using confocal laser scanning microscopy. Main Outcome Measure., Neuroanatomical brain distribution, number and percentage of double-labeled PRV/MC4-R and PRV-/OT-positive neurons, and triple PRV-/MC4-R-/OT-labeled neurons. Results., The majority of PRV immunopositive neurons which also expressed immunoreactivity for MC4-R were located in the paraventricular and arcuate nuclei of the hypothalamus. The majority of PRV positive neurons which were immunoreactive (IR) for OT were located in the paraventricular nucleus (PVN), medial preoptic area (MPOA), and lateral hypothalamus. PRV positive neurons were more likely to be IR for MC4-R than for OT. Scattered triple-labeled PRV/MC4-R/OT neurons were detected in the MPOA and the PVN. Conclusion., These data strongly suggest that MC4-R and, to a less extent, OT are involved in the efferent neuronal control of the clitoris and vagina, and consequently facilitate our understanding of how the melanocortinergic pathway regulates female sexual function. Gelez H, Poirier S, Facchinetti P, Allers KA, Wayman C, Alexandre L, and Giuliano F. Neuroanatomical evidence for a role of central melanocortin-4 receptors and oxytocin in the efferent control of the rodent clitoris and vagina. J Sex Med 2010;7:2056,2067. [source] ORIGINAL RESEARCH,BASIC SCIENCE: Acute and Repeated Flibanserin Administration in Female Rats Modulates Monoamines Differentially Across Brain Areas: A Microdialysis StudyTHE JOURNAL OF SEXUAL MEDICINE, Issue 5 2010Kelly A. Allers PhD ABSTRACT Introduction., Hypoactive sexual desire disorder (HSDD) is defined as persistent lack of sexual fantasies or desire marked by distress. With a prevalence of 10% it is the most common form of female sexual dysfunction. Recently, the serotonin-1A (5-HT1A) receptor agonist and the serotonin-2A (5-HT2A) receptor antagonist flibanserin were shown to be safe and efficacious in premenopausal women suffering from HSDD in phase III clinical trials. Aim., The current study aims to assess the effect of flibanserin on neurotransmitters serotonin (5-HT), norepinephrine (NE), dopamine (DA), glutamate, and ,-aminobutyric acid (GABA) in brain areas associated with sexual behavior. Methods., Flibanserin was administered to female Wistar rats (280,350 g). Microdialysis probes were stereotactically inserted into the mPFC, NAC, or MPOA, under isoflurane anesthesia. The extracellular levels of neurotransmitters were assessed in freely moving animals, 24 hours after the surgery. Main Outcome Measures., Dialysate levels of DA, NE, and serotonin from medial prefrontal cortex (mPFC), nucleus accumbens (NAC), and hypothalamic medial preoptic area (MPOA) from female rats. Results., Acute flibanserin administration decreased 5-HT and increased NE levels in all tested areas. DA was increased in mPFC and MPOA, but not in the NAC. Basal levels of NE in mPFC and NAC and of DA in mPFC were increased upon repeated flibanserin administration, when compared to vehicle-treated animals. The basal levels of 5-HT were not altered by repeated flibanserin administration, but basal DA and NE levels were increased in the mPFC. Glutamate and GABA levels remained unchanged following either repeated or acute flibanserin treatment. Conclusions., Systemic administration of flibanserin to female rats differentially affects the monoamine systems of the brain. This may be the mechanistic underpinning of flibanserin's therapeutic efficacy in HSDD, as sexual behavior is controlled by an intricate interplay between stimulatory (catecholaminergic) and inhibitory (serotonergic) systems. Allers KA, Dremencov E, Ceci A, Flik G, Ferger B, Cremers TIFH, Ittrich C, and Sommer B. Acute and repeated flibanserin administration in female rats modulates monoamines differentially across brain areas: A microdialysis study. J Sex Med 2010;7:1757,1767. [source] ORIGINAL RESEARCH,BASIC SCIENCE: Effect of Estrogen Deprivation on the Expression of Aquaporins and Nitric Oxide Synthases in Rat VaginaTHE JOURNAL OF SEXUAL MEDICINE, Issue 6 2009Sun-Ouck Kim MD ABSTRACT Introduction., The expression of aquaporin (AQP) water channels in rat vagina was recently reported. Aim., The purposes of this study were to investigate the effect of 17,-estradiol on the expression of the AQP-1 and AQP-2 water channels and nitric oxide synthase (NOS) isoforms in rat vagina. Methods., Female Sprague-Dawley rats (230,240 g, N = 90) were divided into three groups: control (N = 30), bilateral ovariectomy (N = 30), and bilateral ovariectomy, followed by subcutaneous injections of 17,-estradiol (50 µg/kg/day, N = 30). After 4 weeks, genital hemodynamics and vaginal secretions were measured after pelvic nerve stimulation, and the animals were then killed. The expression and cellular localization of AQP-1, AQP-2, endothelial NOS (e-NOS), and neuronal NOS (n-NOS) were determined in each group by immunohistochemistry and Western blot. Main Outcome Measures., The expression and cellular localization of AQPs and NOS isoforms after estrogen deprivation. Results., Estimated vaginal secretions (mg, mean ± standard error) were significantly lower in the ovariectomized group (2.9 ± 0.62) than in the control group (5.7 ± 1.25) and returned to the control value in the group after treatment with 17,-estradiol (6.5 ± 1.22) (P < 0.05). Both AQP-1 and e-NOS immunoreactivities were localized in the capillaries and venules of the lamina propria of the vagina, and n-NOS was expressed in the nerve fibers of the subepithelial lamina propria. The expression of AQP-2 was localized solely in the superficial layer of the vaginal epithelium. The protein expressions of AQP-2, e-NOS, and n-NOS were significantly lower after ovariectomy and were restored to the control level after 17,-estradiol treatment. However, there was no significant change in AQP-1 expression. Conclusions., Decreased vaginal secretion after estrogen deprivation may be partly due to functional changes in both AQPs and NOS isoforms in the vagina. The potential role of AQPs in water transport in the vagina might differ according to the type of AQP. Kim S-O, Lee H-S, Ahn K, and Park K. Effect of estrogen deprivation on the expression of aquaporins and nitric oxide synthases in rat vagina. J Sex Med 2009;6:1579,1586. [source] ORIGINAL RESEARCH,BASIC SCIENCE: Cavernous Neurotomy in the Rat is Associated with the Onset of an Overt Condition of HypogonadismTHE JOURNAL OF SEXUAL MEDICINE, Issue 5 2009Linda Vignozzi MD ABSTRACT Background., Most men following radical retropubic prostatectomy (RRP) are afflicted by erectile dysfunction (ED). RRP-related ED occurs as a result of surgically elicited neuropraxia, leading to histological changes in the penis, including collagenization of smooth muscle and endothelial damage. Aim., To verify whether hypogonadism could contribute to the pathogenesis of RRP-ED. Methods., Effects of testosterone (T), alone or in association with long-term tadalafil (Tad) treatment in a rat model of bilateral cavernous neurotomy (BCN). Main Outcome Measures., Penile tissues from rats were harvested for vasoreactivity studies 3 months post-BCN. Penile oxygenation was evaluated by hypoxyprobe immunostaining. Phosphodiesterase type 5 (PDE5), endothelial nitric oxide synthase (eNOS), and neuronal nitric oxide synthase (nNOS) mRNA expression were quantified by Real Time quantitative reverse transcription polymerase chain reaction (qRT-PCR). Results., In BCN rats, we observed the onset of an overt condition of hypogonadism, characterized by reduced T plasma level, reduced ventral prostate weight, reduced testis function (including testis weight and number of Leydig cells), with an inadequate compensatory increase of luteinizing hormone. BCN induced massive penile hypoxia, decreased muscle/fiber ratio, nNOS, eNOS, PDE5 expression, increased sensitivity to the nitric oxide donor, sodium nitroprusside (SNP), and reduced the relaxant response to acetylcholine (Ach), as well as unresponsiveness to acute Tad dosing. In BCN rats, chronic Tad-administration normalizes penile oxygenation, smooth muscle loss, PDE5 expression, SNP sensitivity, and the responsiveness to the acute Tad administration. Chronic Tad treatment was ineffective in counteracting the reduction of nNOS and eNOS expression, along with Ach responsiveness. T supplementation, in combination with Tad, reverted some of the aforementioned alterations, restoring smooth muscle content, eNOS expression, as well as the relaxant response of penile strips to Ach, but not nNOS expression. Conclusion., BCN was associated with hypogonadism, probably of central origin. T supplementation in hypogonadal BCN rats ameliorates some aspects of BCN-induced ED, including collagenization of penile smooth muscle and endothelial dysfunction, except surgically induced altered nNOS expression.Vignozzi L, Filippi S, Morelli A, Marini M, Chavalmane A, Fibbi B, Silvestrini E, Mancina R, Carini M, Vannelli GB, Forti G, and Maggi M. Cavernous neurotomy in the rat is associated with the onset of an overt condition of hypogonadism. J Sex Med 2009;6:1270,1283. [source] ORIGINAL RESEARCH,BASIC SCIENCE: Effects of ACE Inhibition and Beta-Blockade on Female Genital Structures in Spontaneously Hypertensive RatsTHE JOURNAL OF SEXUAL MEDICINE, Issue 6 2007Jorge E. Toblli MD ABSTRACT Introduction and Aim., This study evaluated the possible differences between an angiotensin converting enzyme (ACE) inhibitor and a beta-blocker concerning their potential protective role on female external genitalia in spontaneously hypertensive rats (SHR). Main Outcome Measures., Morphological changes in the clitoris after antihypertensive treatments. Methods., For 6 months, SHR received no treatment; SHR + ramipril (RAM), SHR + atenolol (AT), and control Wistar Kyoto (WKY) rats received no treatment. Clitorises were processed for immunohistochemistry using anti-,-smooth muscle actin (,-SMA), anti-collagen I and III, anti-transforming growth factor ,1 (TGF,1), and anti-endothelial nitric oxide synthase (eNOS) antibodies. Results., SHR + RAM and SHR + AT presented significantly lower blood pressure in both groups vs. untreated SHR. Compared with WKY, ,-SMA was increased in the arteries and in the cavernous spaces of the clitoris together with a marked increase in wall/lumen ratio in clitoral vessels in untreated SHR. All these alterations were diminished in SHR + AT (P < 0.01). SHR + RAM presented differences with respect to SHR + AT in the reduction of these variables. TGF,1 expression in the vessel wall from the clitoris and collagen I and III deposition in the interstitium from the clitoris in untreated SHR were significantly more (P < 0.01) than in WKY. While SHR + AT showed a mild decrease in these variables, SHR + RAM presented a significant reduction (P < 0.01) in TGF,1 expression interstitial fibrosis and in both types of collagens. Positive immunostaining of eNOS in the sinusoidal endothelium from the clitoris was less (P < 0.01) in untreated SHR (3.4 ± 1.3%) and SHR + AT (5.1 ± 1.2%) than in SHR + RAM (17.2 ± 1.6%) and WKY (15.9 ± 1.7%). Untreated SHR and SHR + AT presented more surrounding connective tissue at the perineurium in the clitoris (P < 0.01) than SHR + RAM. Conclusion., ACE inhibition provided a considerable protective role on the female external genitalia structures in SHR by a mechanism that may be, at least in part, independent of the degree of blood pressure lowering. Toblli JE, Cao G, Casabé AR, and Bechara AJ. Effects of ACE inhibition and beta-blockade on female genital structures in spontaneously hypertensive rats. J Sex Med 2007;4:1593,1603. [source] ORIGINAL RESEARCH,BASIC SCIENCE: Immunohistochemical Description of Cyclic Nucleotide Phosphodiesterase (PDE) Isoenzymes in the Human Labia MinoraTHE JOURNAL OF SEXUAL MEDICINE, Issue 3 2007Stefan Ückert PhD ABSTRACT Introduction., Up until now, only minimal research has been carried out on those female genital organs known to contribute to the normal cycle of sexual arousal and orgasm. Some findings indicated that there might be a significance of cyclic nucleotide-mediated pathways in the control of the normal function of female genital tissues. Aim., To elucidate, by means of immunohistochemistry, the distribution of the phosphodiesterase (PDE) isoenzymes 1, 3, 4, 5, 10, and 11 in the human labia minora. Main Outcome Measures., The amount of immunohistochemical staining specific for cyclic adenosine monophosphate (cAMP)- and/or cyclic guanosine monophosphate (cGMP)-degrading PDE isoenzymes was detected. Methods., Human labial tissue was obtained from four female cadavers (age at death: 18,42 years). Vibratome sections prepared from formaldehyde-fixated tissue specimens were incubated with primary antibodies directed against the respective PDE isoenzymes. Sections were then incubated with fluorochrome (fluorescein isothiocyanate, Texas Red)-labeled secondary antibodies. Visualization was commenced by means of a laser fluorescence microscope. Results., Immunostaining indicating the expression of PDE4 and PDE5 was abundantly observed in the smooth musculature of vessels interspersing the tissue. Immunoreactions specific for PDE3 were recognized in epithelial and subepithelial layers, sebaceous glands, and interstitial or neuroendocrine-like single cells located in the epithelium. Signals related to PDE10 and PDE11 were limited to the epithelium or glandular-like structures, respectively. Conclusions., Our results, for the first time, demonstrate the presence of cAMP- and cGMP-PDE isoenzymes in the human labia minora and give a hint to a significance of PDE4 and PDE5 in the control of labial vascular tissue function. Ückert S, Oelke M, Albrecht K, Stief C, Jonas U, and Hedlund P. Immunohistochemical description of cyclic nucleotide phosphodiesterase (PDE) isoenzymes in the human labia minora. J Sex Med 2007;4:602,608. [source] ORIGINAL RESEARCH,BASIC SCIENCE: Effect of the Destruction of Cells Containing the Serotonin Reuptake Transporter on Urethrogenital ReflexesTHE JOURNAL OF SEXUAL MEDICINE, Issue 2 2007Karla Gravitt BSc ABSTRACT Introduction., The urethrogenital (UG) reflex is an autonomic and somatic response that mimics some of the physiological changes seen during ejaculation. The UG reflex is tonically inhibited by neurons in the ventral medulla, an area containing serotonin neurons. Aim., To examine the effect of lesions of brain neurons containing the serotonin reuptake transporter (SERT) on ejaculatory-like reflexes. Methods., Anti-SERT saporin (80 nL, 1 mM) or saline was injected bilaterally into the ventrolateral medulla of male Sprague,Dawley rats. Ten to 18 days later, animals were deeply anesthetized and the presence of the UG reflex was examined before and after acute spinal cord transection (T9,10). Following the experiment the presence and number of serotonin and norepinephrine containing neurons (using tryptophan hydroxylase and dopamine beta-hydroxylase, respectively) was performed. Main Outcome Measures., The UG reflex and cell counts. Results., In saline-injected controls the UG reflex was not evoked in the anesthetized, intact preparation, indicating the presence of the supraspinal inhibition, as previously reported. Injection of anti-SERT saporin into the ventrolateral medulla allowed the UG reflex to be activated in the intact preparation, thus removed the inhibition. This was associated with a decrease in the number of serotonin neurons in the ventrolateral medulla and raphe. No change in the number of noradrenergic neurons was observed. Conclusion., These studies suggest that ventral medullary neurons containing SERT are involved in the tonic inhibition of the UG reflex. Gravitt K, and Marson L. Effect of the destruction of cells containing the serotonin reuptake transporter on urethrogenital Reflexes. J Sex Med 2007;4:322,331. [source] ORIGINAL RESEARCH,BASIC SCIENCE: A Prospective Study Examining the Anatomic Distribution of Nerve Density in the Human VaginaTHE JOURNAL OF SEXUAL MEDICINE, Issue 6 2006Rachel Pauls MD ABSTRACT Introduction., Women possess sufficient vaginal innervation such that tactile stimulation of the vagina can lead to orgasm. However, there are few anatomic studies that have characterized the distribution of nerves throughout the human vagina. Aim., The aim of this prospective study was to better characterize the anatomic distribution of nerves in the adult human vagina. A secondary aim was to assess whether vaginal innervation correlates with the subject's demographic information and sexual function. Methods., Full-thickness biopsies of anterior and posterior vagina (proximal and distal), cuff, and cervix were taken during surgery in a standardized manner. Specimens were prepared with hematoxylin and eosin, and S100 protein immunoperoxidase. The total number of nerves in each specimen was quantified. Enrolled patients completed a validated sexual function questionnaire (Female Sexual Function Index, FSFI) preoperatively. Main Outcome Measures., A description of vaginal innervation by location and an assessment of vaginal innervation in association with the subject's demographic information and sexual function. Results., Twenty-one patients completed this study, yielding 110 biopsy specimens. Vaginal innervation was somewhat regular, with no site consistently demonstrating the highest nerve density. Nerves were located throughout the vagina, including apex and cervix. No significant differences were noted in vaginal innervation based on various demographic factors, including age, vaginal maturation index, stage of prolapse, number of vaginal deliveries, or previous hysterectomy. There were no correlations between vaginal nerve quantity and FSFI domain and overall scores. Fifty-seven percent of the subjects had female sexual dysfunction; when compared to those without dysfunction, there were no significant differences in total or site-specific nerves. Conclusions., In a prospective study, vaginal nerves were located regularly throughout the anterior and posterior vagina, proximally and distally, including apex and cervix. There was no vaginal location with increased nerve density. Vaginal innervation was not associated with demographic information or sexual function. Pauls R, Mutema G, Segal J, Silva WA, Kleeman S, Dryfhout V, and Karram M. A prospective study examining the anatomic distribution of nerve density in the human vagina. J Sex Med 2006;3:979,987. [source] ORIGINAL RESEARCH,BASIC SCIENCE: Erectile Dysfunction in Hypercholesterolemic Atherosclerotic Apolipoprotein E Knockout MiceTHE JOURNAL OF SEXUAL MEDICINE, Issue 4 2006Delphine Behr-Roussel PharmD ABSTRACT Introduction., Erectile dysfunction (ED) and cardiovascular diseases share the same risk factors. Although the use of hypercholesterolemic rabbit models has proven to be useful to illustrate the link between ED and hypercholesterolemia, the cost of daily maintenance of the animals and necessity for important amounts of drug have limited their use. Aim., We aimed to develop a new model of atherosclerosis-associated ED in a well-known experimental model of atherosclerosis, the apolipoprotein E knockout (ApoE KO) mouse. Methods., Erectile function was evaluated by recording frequency-dependent increases in intracavernous pressure following electrical stimulation of the cavernous nerve in 26-, 32-, and 38-week-old ApoE KO mice fed a Western-type diet and age-matched C57BL6/J anesthetized mice. Atherosclerotic lesions were evaluated by planimetry in oil red O-stained aortas. Results., We found that in contrast to C57BL6/J mice, ApoE mice displayed atherosclerotic lesions covering 22% of the aortic luminal surface at 26 weeks of age and increasing to 27% and 35% at 32 weeks and 38 weeks of age, respectively. The amplitude of erectile responses to electrical stimulation of the cavernous nerve was markedly impaired in 26-week-old ApoE KO mice as compared with age-matched C57BL6/J mice. Impairment in erectile function persisted in ApoE KO mice 32 and 38 weeks of age. Conclusions., The ApoE KO mouse, a well-characterized model to study disorders associated with hypercholesterolemia and atherosclerosis in cardiovascular research, could therefore be suitable for investigation of disease-modifying effects of new therapeutic strategies aiming to target both atherosclerosis and ED. Behr-Roussel D, Darblade B, Oudot A, Compagnie S, Bernabé J, Alexandre L, and Giuliano F. Erectile dysfunction in hypercholesterolemic atherosclerotic apolipoprotein E knockout mice. J Sex Med 2006;3:596,603. [source] ORIGINAL RESEARCH,BASIC SCIENCE: Enhancement of Both EDHF and NO/cGMP Pathways Is Necessary to Reverse Erectile Dysfunction in Diabetic RatsTHE JOURNAL OF SEXUAL MEDICINE, Issue 3 2005Javier Angulo PhD ABSTRACT Aims and Methods., Phosphodiesterase 5 (PDE5) inhibitors are less effective in the treatment of erectile dysfunction (ED) in diabetic men than in nondiabetic patients. We have evaluated the effects of sildenafil, a PDE5 inhibitor that enhances the nitric oxide (NO)/cGMP pathway, calcium dobesilate (DOBE), which potentiates endothelium-derived hyperpolarizing factor (EDHF)-mediated responses and the combination of both on erectile responses elicited by cavernosal nerve electrical stimulation (CNES) in a rat model of ED after 8 weeks of streptozotocin-induced diabetes. Results., After 8 weeks of diabetes, erectile responses to CNES were significantly decreased in diabetic animals compared with nondiabetic time controls. While intravenous administration of sildenafil (0.3 mg/kg) or DOBE (10 mg/kg), individually, enhanced erectile responses in nondiabetic rats (214.7 ± 34.1% and 268.5 ± 30.1% of control response at 1 Hz, respectively), each failed to significantly enhance erectile responses in diabetic rats. Only when administered in combination did DOBE and sildenafil markedly potentiate erectile responses in these animals (380.1 ± 88.6% of control response at 1 Hz), completely restoring erectile function. Conclusions., These findings emphasize the importance of NO/cGMP and EDHF pathways for normal erectile function. They also give support to the in vitro observation that diabetes impairs NO and EDHF-dependent responses, precluding the complete recovery of erectile function with PDE5 inhibitors and explaining the relatively poor clinical response of diabetic men with ED to PDE5 inhibition. Finally, our study suggests that a pharmacological approach that combines enhancement of NO/cGMP and EDHF pathways could be necessary to treat ED in many diabetic men. [source] ORIGINAL RESEARCH,BASIC SCIENCE: A Nitric Oxide-Releasing PDE5 Inhibitor Relaxes Human Corpus Cavernosum in the Absence of Endogenous Nitric OxideTHE JOURNAL OF SEXUAL MEDICINE, Issue 1 2005Jasjit S. Kalsi BSc, MRCS ABSTRACT Introduction., In conditions with severe deficiency of endogenous nitric oxide (NO), such as long-term diabetes and cavernosal nerve injury, phosphodiesterase type 5 (PDE5) inhibitors have reduced efficacy in the treatment of erectile dysfunction. NO-releasing PDE5 inhibitors could be an alternative therapeutic approach in such cases. Aim., We therefore aimed to compare sildenafil and NO-releasing sildenafil (NCX-911) in relaxing human corpus cavernosum in the absence or presence of endogenous NO. Methods., The two compounds were compared in reducing the phenylephrine-induced tone of human corpus cavernosum in the presence or absence of an inhibitor of NO synthase (L-NAME; 500 µM) or an inhibitor of soluble guanylate cyclase (ODQ, 10 µM). Results., NCX-911 was as potent as sildenafil in control conditions (EC50 = 733.1 ± 94.4 nM and 800.7 ± 155.8 nM, respectively). The potency of NCX-911 was not altered but that of sildenafil decreased significantly in the presence of L-NAME (EC50 = 980.4 ± 106.7 nM and 2446.7 ± 256.8 nM, respectively; P < 0.001 for sildenafil vs. control). Both compounds below 1 µM failed to induce relaxation in the presence of ODQ (EC50 = 6578 ± 1150 nM and 6488 ± 938 nM for NCX-911 and sildenafil, respectively). Conclusion., These results show that the potency of NCX-911 was maintained unlike sildenafil in the absence of endogenous NO confirming the potential use of NO-releasing PDE5 inhibitors in NO-deficient conditions. [source] Free Paper Session 1A: Basic ScienceINTERNATIONAL JOURNAL OF STROKE, Issue 2009Article first published online: 17 AUG 200 No abstract is available for this article. [source] Epidural Steroid Injection,How Should the Indications for Use be Derived: Systematic Review or Basic Science?PAIN PRACTICE, Issue 3 2009Craig T. Hartrick MD, FIPP Editor in Chief, Pain Practice Editorial Board No abstract is available for this article. [source] Clinical Implications of Advances in the Basic Science of Liver Repair and RegenerationAMERICAN JOURNAL OF TRANSPLANTATION, Issue 9 2009S. J. Karp Recent advances in our understanding of the basic mechanisms that control liver regeneration and repair will produce the next generation of therapies for human liver disease. Insights gained from large-scale genetic analysis are producing a new framework within which to plan interventions. Identification of specific molecules that drive regeneration will increase the options for live-donor liver transplantation, and help treat patients with small-for-size syndrome or large tumors who would otherwise have inadequate residual mass after resection. In a complementary fashion, breakthroughs in the ability to manipulate various cell types to adopt the hepatocyte or cholangiocyte phenotype promise to revolutionize therapy for acute liver failure and metabolic liver disease. Finally, elucidating the complex interactions of liver cells with each other and various matrix components during the response to injury is essential for fabricating a liver replacement device. This focused review will discuss how a variety of important scientific advances are likely to impact the treatment of specific types of liver disease. [source] The Pancreas: An Integrated Textbook of Basic Science, Medicine and Surgery.BRITISH JOURNAL OF SURGERY (NOW INCLUDES EUROPEAN JOURNAL OF SURGERY), Issue 11 20082nd Edn H. Beger, A. Warshaw, D. Whitcomb (eds)., J. Neoptolemos, K. Shiratori, M. Büchler, M. Lerch, R. Kozarek No abstract is available for this article. [source] Basic science of epidermolysis bullosa and diagnostic and molecular characterization: Proceedings of the IInd International Symposium on Epidermolysis Bullosa, Santiago, Chile, 2005INTERNATIONAL JOURNAL OF DERMATOLOGY, Issue 8 2007Ellen G. Pfendner PhD First page of article [source] Basic science: The cutting edge in optical diagnostics and therapeutics of tissues and cellsLASERS IN SURGERY AND MEDICINE, Issue S18 2006Article first published online: 3 MAR 200 First page of article [source] Poster session 1: A. Basic science, genetics, neuropharmacology, Parkinson's DiseaseMOVEMENT DISORDERS, Issue S5 2002Article first published online: 21 OCT 200 [source] Basic science and translational research in female pelvic floor disorders: Proceedings of an NIH-sponsored meetingNEUROUROLOGY AND URODYNAMICS, Issue 4 2004Anne M. Weber Abstract Aims To report the findings of a multidisciplinary group of scientists focusing on issues in basic science and translational research related to female pelvic floor disorders, and to produce recommendations for a research agenda for investigators studying female pelvic floor disorders. Methods A National Institutes of Health (NIH)-sponsored meeting was held on November 14,15, 2002, bringing together scientists in diverse fields including obstetrics, gynecology, urogynecology, urology, gastroenterology, biomechanical engineering, neuroscience, endocrinology, and molecular biology. Recent and ongoing studies were presented and discussed, key gaps in knowledge were identified, and recommendations were made for research that would have the highest impact in making advances in the field of female pelvic floor disorders. Results The meeting included presentations and discussion on the use of animal models to better understand physiology and pathophysiology; neuromuscular injury (such as at childbirth) as a possible pathogenetic factor and mechanisms for recovery of function after injury; the use of biomechanical concepts and imaging to better understand the relationship between structure and function; and molecular and biochemical mechanisms that may underlie the development of female pelvic floor disorders. Conclusions While the findings of current research will help elucidate the pathophysiologic pathways leading to the development of female pelvic floor disorders, much more research is needed for full understanding that will result in better care for patients through specific rather than empiric therapy, and lead to the potential for prevention on primary and secondary levels. © 2004 Wiley-Liss, Inc. [source] Respirology year-in-review 2008: Basic scienceRESPIROLOGY, Issue 3 2009Martin R.J. KOLB First page of article [source] Priapism: Pathogenesis, Epidemiology, and ManagementTHE JOURNAL OF SEXUAL MEDICINE, Issue 1pt2 2010Gregory A. Broderick MD ABSTRACT Introduction., Priapism describes a persistent erection arising from dysfunction of mechanisms regulating penile tumescence, rigidity, and flaccidity. A correct diagnosis of priapism is a matter of urgency requiring identification of underlying hemodynamics. Aims., To define the types of priapism, address its pathogenesis and epidemiology, and develop an evidence-based guideline for effective management. Methods., Six experts from four countries developed a consensus document on priapism; this document was presented for peer review and debate in a public forum and revisions were made based on recommendations of chairpersons to the International Consultation on Sexual Medicine. This report focuses on guidelines written over the past decade and reviews the priapism literature from 2003 to 2009. Although the literature is predominantly case series, recent reports have more detailed methodology including duration of priapism, etiology of priapism, and erectile function outcomes. Main Outcome Measures., Consensus recommendations were based on evidence-based literature, best medical practices, and bench research. Results., Basic science supporting current concepts in the pathophysiology of priapism, and clinical research supporting the most effective treatment strategies are summarized in this review. Conclusions., Prompt diagnosis and appropriate management of priapism are necessary to spare patients ineffective interventions and maximize erectile function outcomes. Future research is needed to understand corporal smooth muscle pathology associated with genetic and acquired conditions resulting in ischemic priapism. Better understanding of molecular mechanisms involved in the pathogenesis of stuttering ischemic priapism will offer new avenues for medical intervention. Documenting erectile function outcomes based on duration of ischemic priapism, time to interventions, and types of interventions is needed to establish evidence-based guidance. In contrast, pathogenesis of nonischemic priapism is understood, and largely attributable to trauma. Better documentation of onset of high-flow priapism in relation to time of injury, and response to conservative management vs. angiogroaphic or surgical interventions is needed to establish evidence-based guidance. Broderick GA, Kadioglu A, Bivalacqua TJ, Ghanem H, Nehra A, and Shamloul R. Priapism: Pathogenesis, epidemiology and management. J Sex Med 2010;7:476,500. [source] Aerodigestive Tract Invasion by Well-Differentiated Thyroid Carcinoma: Diagnosis, Management, Prognosis, and BiologyTHE LARYNGOSCOPE, Issue 1 2006Judith Czaja McCaffrey MD Objectives/Hypothesis: 1) To describe the clinical entity invasive well-differentiated thyroid carcinoma (IWDTC), 2) to determine prognostic factors for survival in patients with IWDTC, 3) to describe and compare types of surgical resection to determine treatment efficacy, 4) to offer a staging system and surgical algorithm for management of patients with IWDTC, 5) to examine alterations in expression of E-cadherin and ,-catenin adhesion molecules in three groups of thyroid tissue and propose a cellular mechanism for invasion of the aerodigestive tract. Study Design: Basic science: quantification of expression of E-cadherin and ,-catenin in three groups of thyroid tissue. Clinical: retrospective review of patients with IWDTC surgically treated and followed over a 45-year time period. Methods: Basic science: immunohistochemical staining was used with antibodies against E-cadherin and ,-catenin in three groups of tissue: group 1, normal control thyroid tissue (n = 10); group 2, conventional papillary thyroid carcinoma (n = 20); group 3, IWDTC (n = 12). Intensity scores were given on the basis of protocol. One-way analysis of variance (ANOVA) was used to evaluate differences between groups. Post hoc ANOVA testing was completed. P < .05 was significant. Clinical: patients were divided into three surgical groups within the laryngotracheal subset: group 1, complete resection of gross disease (n = 34); group 2, shave excision (n = 75); group 3, incomplete excision (n = 15). Cox regression analysis was used to determine significance of prognostic factors. Kaplan-Meier plots were used to evaluate survival. P < .05 was significant. Results: Basic science: a significant difference between the three thyroid tissue groups for E-cadherin expression was demonstrated on one-way ANOVA testing. When controls were compared with either experimental group in post hoc ANOVA testing, differences between all groups were demonstrated (P < .001). For ,-catenin, the intensities of the three groups were not different by one-way ANOVA testing. Similar nonsignificant results were found on post hoc ANOVA testing. Clinical: there was a statistically significant difference in survival for patients with and without involvement of any portion of the endolarynx or trachea (P < .01). There was a significant difference among all three surgical groups when compared (P < .001). When complete and shave groups were compared with gross residual group there was a significant decrease in survival in incomplete resection group (P < .01). Cox regression analysis demonstrated invasion of larynx and trachea were significant prognostic factors for poor outcome. The type of initial resection was significant on multivariate analysis. Removal of all gross disease is a major factor for survival. Conclusions: Basic science: there is a decrease in membrane expression of E-cadherin in IWDTC, and loss of this tumor suppressor adhesion molecule may contribute to the invasive nature of well-differentiated thyroid carcinomas. Clinical: laryngotracheal invasion is a significant independent prognostic factor for survival. Patients undergoing shave excision had similar survival when compared with those undergoing radical tumor resection if gross tumor did not remain. Gross intraluminal tumor should be resected completely. Shave excision is adequate for minimal invasion not involving the intraluminal surfaces of the aerodigestive tract. [source] Role of Sun Exposure in MelanomaDERMATOLOGIC SURGERY, Issue 4 2006GIL B. IVRY BS BACKGROUND Malignant melanoma is the third most common skin cancer in the United States. It is commonly thought that sun exposure is causative in these tumors. Recently, however, the significance of the role of sun exposure in melanoma has come into question. Some have suggested that other factors, such as genetics, play a larger role, and that sun protection may even be harmful. OBJECTIVE AND METHODS To investigate the role of sun exposure in melanoma etiology. An extensive review of basic science and clinical literature on this subject was conducted. RESULTS Although exceptions exist, sun exposure likely plays a large role in most melanomas. The pattern of this exposure, however, is not fully known, and controversy exists, especially in the use of sunscreens. Sun exposure may interact with genetic factors to cause melanomas, and sun protective measures appear to be prudent. CONCLUSIONS The cause of melanoma is probably variable and multifactorial. Sun exposure may play a primary or supporting role in most melanoma tumors. [source] Ions, genes and insulin release: from basic science to clinical disease Based on the 1998 R. D. Lawrence LectureDIABETIC MEDICINE, Issue 2 2000M. J. Dunne Summary In 1968, reports of the first microelectrode recordings of insulin-secreting cells were published. Thirty years later it is now established that electrical responses of ,-cells play a critical role in stimulus-secretion coupling. It is now also clear that defects in ion channel genes compromise the mechanisms which govern secretion and lead to the onset of disease. Here, the physiology of insulin release is reviewed in the context of ion channels, the ionic control of insulin release and the pathophysiology of hyperinsulinism of infancy. [source] Workshop on Idiopathic Generalized Epilepsies: Bridging basic science and clinical research (October 3,6, 2007; Antalya, Turkey)EPILEPSIA, Issue 11 2008Edward H. Bertram First page of article [source] Ultra-rapid opiate detoxification: from clinical applications to basic scienceADDICTION BIOLOGY, Issue 2 2003EMMANUEL STREEL Rapid or ultra-rapid opiate detoxification has become increasingly popular in both private and public addiction centres. These techniques seem to facilitate the transfer of opiate-dependent patients from opiate agonist to opiate antagonist. Despite the probable complex neuropharmacological aspects involved in these procedures, their development over nearly three decades is notable for the almost complete absence of clinically relevant animal studies. This paper discusses the historical background of this occurrence, and reviews the small number of animal studies that have been conducted. Many discussions and arguments about the techniques seem to underscore their true purpose, which is not "simply to detoxify" opiate-addicted patients but to initiate long-term management with naltrexone. For this reason, it may be better to conceptualize these techniques not as "rapid detoxification" but as "rapid antagonist induction". [source] IS EVOLUTIONARY BIOLOGY STRATEGIC SCIENCE?EVOLUTION, Issue 1 2007Thomas R. Meagher There is a profound need for the scientific community to be better aware of the policy context in which it operates. To address this need, Evolution has established a new Outlook feature section to include papers that explore the interface between society and evolutionary biology. This first paper in the series considers the strategic relevance of evolutionary biology. Support for scientific research in general is based on governmental or institutional expenditure that is an investment, and such investment is based on strategies designed to achieve particular outcomes, such as advance in particular areas of basic science or application. The scientific community can engage in the development of scientific strategies on a variety of levels, including workshops to explicitly develop research priorities and targeted funding initiatives to help define emerging scientific areas. Better understanding and communication of the scientific achievements of evolutionary biology, emphasizing immediate and potential societal relevance, are effective counters to challenges presented by the creationist agenda. Future papers in the Outlook feature section should assist the evolutionary biology community in achieving a better collective understanding of the societal relevance of their field. [source] Phospho-proteomic immune analysis by flow cytometry: from mechanism to translational medicine at the single-cell levelIMMUNOLOGICAL REVIEWS, Issue 1 2006Omar D. Perez Summary:, Understanding a molecular basis for cellular function is a common goal of biomedicine. The complex and dynamic cellular processes underlying physiological processes become subtly or grossly perturbed in human disease. A primary objective is to demystify this complexity by creating and establishing relevant model systems to study important aspects of human disease. Although significant technological advancements over the last decade in both genomic and proteomic arenas have enabled progress, accessing the complexity of cellular interactions that occur in vivo has been a difficult arena in which to make progress. Moreover, there are extensive challenges in translating research tools to clinical applications. Flow cytometry, over the course of the last 40 years, has revolutionized the field of immunology, in both the basic science and clinical settings, as well as having been instrumental to new and exciting areas of discovery such as stem cell biology. Multiparameter machinery and systems exist now to access the heterogeneity of cellular subsets and enable phenotypic characterization and functional assays to be performed on material from both animal models and humans. This review focuses primarily on the development and application of using activation-state readouts of intracellular activity for phospho-epitopes. We present recent work on how a flow cytometric platform is used to obtain mechanistic insight into cellular processes as well as highlight the clinical applications that our laboratory has explored. Furthermore, this review discusses the challenges faced with processing high-content multidimensional and multivariate data sets. Flow cytometry, as a platform that is well situated in both the research and clinical settings, can contribute to drug discovery as well as having utility for both biomarker and patient-stratification. [source] Botulinum toxin injection therapy in the management of lower urinary tract dysfunctionINTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 2006A. K. PATEL Summary We have great pleasure in introducing this supplement containing a collection of articles reviewing the contemporary clinical management of functional disorders of the lower urinary tract (LUT) with particular emphasis on the potential role of botulinum toxin injection therapy. Detrusor sphincter dyssynergia (DSD), detrusor overactivity (DO), painful bladder syndrome (PBS) and LUT symptoms consequent on bladder outflow obstruction (LUTS/BPH) have all been treated by the injection of botulinum toxin. This treatment can be administered as a minimally invasive, outpatient procedure which on the initial trials for DO (particularly of neurogenic aetiology) shows a remarkable efficacy with effects lasting up to a year after a single treatment with few significant side effects. Success has been reported with the management of detrusor sphincter dyssynergia and preliminary series report positive outcomes in the management of PBS and LUTS/BPH. However, most of the studies to date include small numbers and have a recruitment bias with few randomised controlled trials having been reported. The answers to some of the key questions are addressed with reference to our contemporary knowledge. It is clear that considerable work both clinical and basic science still needs to be performed to answer the many remaining questions with regard to this treatment modality but undoubtedly it will be a major future treatment option in those with intractable symptoms or those unable to tolerate medications. Currently, all botulinum toxin use for urological conditions is off-label and unlicensed, therefore caution should be exercised until future large randomised studies are reported. [source] | |||||||||||||||||||||||||||||||||||||