Chang H-Y, Cheng C-L, Chen J-JJ, de Groat WC. Serotonergic drugs and spinal cord transections indicate that different spinal circuits are involved in external urethral sphincter activity in rats. Am J Physiol Renal Physiol 292: F1044 -F1053, 2007. First published October 17, 2006; doi:10.1152/ajprenal.00175.2006.-Lower urinary tract function is regulated by spinal and supraspinal reflexes that coordinate the activity of the urinary bladder and external urethral sphincter (EUS). Two types of EUS activity (tonic and bursting) have been identified in rats. This study in urethane-anesthetized female rats used cystometry, EUS electromyography, spinal cord transection (SCT) at different segmental levels, and analysis of the effects of 5-HT1A receptor agonist (8-OH-DPAT) and antagonist (WAY100635) drugs to examine the origin of tonic and bursting EUS activity. EUS activity was elicited by bladder distension or electrical stimulation of afferent axons in the pelvic nerve (pelvic-EUS reflex). Tonic activity evoked by bladder distension was detected in spinal cord-intact rats and after acute and chronic T8 -9 or L3-4 SCT but was abolished after L6 -S1 SCT. Bursting activity was abolished by all types of SCT except chronic T8 -9 transection. 8-OH-DPAT enhanced tonic activity, and WAY100635 reversed the effect of 8-OH-DPAT. The pelvic-EUS reflex consisted of an early response (ER) and late response (LR) when the bladder was distended in spinal cord-intact rats. ER remained after acute or chronic T8 -9 and L3-4 SCT, but was absent after L6 -S1 SCT. LR occurred only in chronic T8 -9 SCT rats where it was enhanced or unmasked by 8-OH-DPAT. The results indicate that spinal serotonergic mechanisms facilitate tonic and bursting EUS activity. The circuitry for generating different patterns of EUS activity appears to be located in different segments of the spinal cord: tonic activity at L6 -S1 and bursting activity between T8 -9 and L3-4. bladder; electromyography; 5-HT1A receptor; pelvic nerve; bursting THE STORAGE AND RELEASE OF urine are dependent on the coordinated activity of the urinary bladder smooth muscle and the external urethral sphincter (EUS) striated muscle in the lower urinary tract (LUT). This coordination is mediated by neural mechanisms in the brain and spinal cord that are stimulated by afferent input from the bladder. In normal rats, the EUS exhibits tonic activity before the onset of voiding and bursting activity during voiding. It is believed that bursting activity represents rhythmic contractions and relaxations of the EUS that are necessary for efficient bladder emptying (20). A detailed analysis (4) of the EUS bursting pattern has shown that it consists of silent (urethral opening) and active (urethral closing) periods, averaging 104 and 67 ms in duration, respectively. Efficient voiding depends on the duration and number of urethral openings during voiding. Suppression of EUS bursting activity with neuromuscular blocking agents decreases voiding efficiency (31).Initial studies in deeply anesthetized rats ...

This chapter argues that in attempting to justify measurement methods, a circularity inherent in empiricist foundationalism is found. Dealing with this circularity means accepting it and admitting that justification in empirical science must be coherentist. Within such coherentism, epistemic iteration provides an effective method of scientific progress, resulting in the enrichment and self-correction of the initially affirmed system.

Despite the tight historical links between science and philosophy, hearkening back to Plato, Aristotle, and others (here evoked with Raphael's famous School of Athens), present-day scientists often perceive philosophy as completely different from, and even antagonistic to, science. To the contrary, we believe philosophy can have an important and productive impact on science. Image credit: Shutterstock.com/Isogood_patrick. a Institut d'histoire et de philosophie des sciences et des techniques (UMR8590),

Triple-negative breast cancer (TNBC) relapses more frequently than hormone receptor-positive subtypes and is often associated with poor outcomes. This retrospective study reviewed the pattern of distant metastasis with regard to survival in patients with TNBC. A total of 205 TNBC patients were analyzed. TNBC patients with lung metastases had the longest median post-metastatic OS (with 95% confidence interval) of 16.6 (10.3-22.9) months, followed by the bone, 16.3 (11.7-20.8) months, the liver, 8.9 (3.5-14.4) months, the pleura, 7.5 (2.8-12.3) months, and the brain, 4.3 (0.6-8.0) months. Kaplan-Meier plots indicated that TNBC patients with metastatic spread to brain, liver, and pleural had poorer post-metastatic OS rate than patients with lung metastases (p = 0.001, 0.004, and 0.029, respectively). Moreover, brain and liver metastases correlated significantly with poorer post-metastatic OS as compared to bone metastasis (p = 0.004 and 0.011, respectively). Route of first metastasis correlated significantly with survival of TNBC patients with brain metastases being the poorest survival indicator, followed by metastases to liver, pleura, bone, and lung.

This study was conducted to examine reflex mechanisms that mediate urinary bladder and external urethral sphincter (EUS) coordination in urethane-anesthetized female Sprague-Dawley rats. We investigated the properties of EUS reflexes elicited by electrical stimulation of pelvic nerve afferent axons (pelvic-EUS reflex). The changes in the reflexes induced by bladder distension and administration of agonists or antagonists for glutamatergic or serotonergic receptors were examined. The reflexes consisted of an early response (ER, 18- to 22-ms latency) and a late, long-duration (>100-ms latency) response (LR), which consisted of bursts of activity at 20- to 160-ms interburst intervals. In a few experiments, a reflex with an intermediate (40- to 70-ms) latency was also identified. With the bladder empty, the ER, but not the LR, was detected in the majority of experiments. The LR was markedly enhanced when the bladder was distended. The ER remained, but the LR was abolished, after spinal cord transection at T8-T9. The ER and LR were significantly decreased 75 and 35%, respectively, by the N-methyl-D-aspartate receptor antagonist MK-801 (0.3 mg/kg iv), but only decreased 18 and 14%, respectively, by the alpha-amino-5-methylisoxazole-4-propionate receptor antagonist LY-215490 (3 mg/kg iv). The serotonin (5-HT1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (1 mg/kg iv) enhanced spontaneous EUS activity and the pelvic-EUS reflex. WAY-100635 (0.1-1 mg/kg iv), a 5-HT1A antagonist, reversed the effect of 8-hydroxy-2-(di-n-propylamino)-tetralin and suppressed EUS activity and the pelvic-EUS reflex. These results indicate that glutamatergic and serotonergic mechanisms are important in the reflex pathways underlying bladder- sphincter coordination in rats.