Urodynamic function during sleep-like brain states in urethane anesthetized rats

AbstractThe aim was to investigate urodynamic parameters and functional excitability of the periaqueductal gray matter (PAG) during changes in sleep-like brain states in urethane anesthetized rats. Simultaneous recordings of detrusor pressure, external urethral sphincter (EUS) electromyogram (EMG), cortical electroencephalogram (EEG), and single-unit activity in the PAG were made during repeated voiding induced by continuous infusion of saline into the bladder.The EEG cycled between synchronized, high-amplitude slow wave activity (SWA) and desynchronized low-amplitude fast activity similar to slow wave and ‘activated’ sleep-like brain states. During (SWA, 0.5–1.5Hz synchronized oscillation of the EEG waveform) voiding became more irregular than in the ‘activated’ brain state (2–5Hz low-amplitude desynchronized EEG waveform) and detrusor void pressure threshold, void volume threshold and the duration of bursting activity in the external urethral sphincter EMG were raised. The spontaneous firing rate of 23/52 neurons recorded within the caudal PAG and adjacent tegmentum was linked to the EEG state, with the majority of responsive cells (92%) firing more slowly during SWA. Almost a quarter of the cells recorded (12/52) showed phasic changes in firing rate that were linked to the occurrence of voids. Inhibition (n=6), excitation (n=4) or excitation/inhibition (n=2) was seen. The spontaneous firing rate of 83% of the micturition-responsive cells was sensitive to changes in EEG state. In nine of the 12 responsive cells (75%) the responses were reduced during SWA.We propose that during different sleep-like brain states changes in urodynamic properties occur which may be linked to changing excitability of the micturition circuitry in the periaqueductal gray

Progesterone Withdrawal-Evoked Plasticity of Neural Function in the Female Periaqueductal Grey Matter

Cyclical changes in production of neuroactive steroids during the oestrous cycle induce significant changes in GABAA receptor expression in female rats. In the periaqueductal grey (PAG) matter, upregulation of α4β1δ GABAA receptors occurs as progesterone levels fall during late dioestrus (LD) or during withdrawal from an exogenous progesterone dosing regime. The new receptors are likely to be extrasynaptically located on the GABAergic interneurone population and to mediate tonic currents. Electrophysiological studies showed that when α4β1δ GABAA receptor expression was increased, the excitability of the output neurones in the PAG increased, due to a decrease in the level of ongoing inhibitory tone from the GABAergic interneurones. The functional consequences in terms of nociceptive processing were investigated in conscious rats. Baseline tail flick latencies were similar in all rats. However, acute exposure to mild vibration stress evoked hyperalgesia in rats in LD and after progesterone withdrawal, in line with the upregulation of α4β1δ GABAA receptor expression

Horizontal, oil-water flows in the dual continuous flow regime.

The research presented in this thesis is concerned with the flow behaviour of two-phase, liquid-liquid, oil-water flow through horizontal pipes. The test liquids used were oil (density 828kg/rn3, viscosity 6x iO 3 Pa s) and water, with experiments carried out in a purpose built test facility with a stainless steel pipe (internal dia. 38mm, length 8m). Visual observation of the flow was possible at low mixture velocities through a lm transparent pipe at the end of the test section. At higher mixture velocities local probes were used for flow pattern identification. These local probes were a conductivity probe for identifying the continuous phase, and a high frequency impedance probe for measuring local phase distribution. A dual sensor impedance probe was also developed for measuring local drop velocity and also the drop chord length distributions. Pressure gradient was also measured using a differential pressure transducer, and in-situ phase fractions were obtained using Quick Closing Valves. Experimental results show that the dual continuous flow regime, where both phases retain their continuity while there is mixing at the interface, dominates at all input oil fractions at low mixture velocities and intermediate oil fractions at high mixture velocities. In general the pressure drop of the two-phase mixture is lower than that of single phase oil. At higher mixture velocities a minimum in pressure gradient appeared at high oil fractions perhaps as a combination of the drag reduction phenomenon and the relative fraction of the oil and water layers in the pipe. At the highest mixture velocity this minimum was at the boundary of fully dispersed oil continuous flow with dual continuous flow. Velocity ratios are shown to increase with increasing oil fraction at low mixture velocities, with this trend reversing at high mixture velocities. These trends in the pressure gradient and velocity ratio can be explained using the phase distribution diagrams, with the interfacial curvature greatly affecting velocity ratio. Local chord length data shows that, in general, drop sizes decrease with increasing distance from the interface and that oil drops tend to be slightly larger than water drops. Mixture velocity did not significantly affect the drop size of either phase in dual continuous flow. A modified version of the two-fluid model was suggested for dual continuous flow that treats the upper and lower layers as dispersions and uses experimental entrainment to calculate their properties. Better predictions were obtained when friction factors that accounted for the drag reduction phenomenon were used to calculate wall shear stresses

High Frequency Stimulation of the Pelvic Nerve Inhibits Urinary Voiding in Anesthetized Rats

Urge Urinary Incontinence: “a sudden and uncontrollable desire to void which is impossible to defer” is extremely common and considered the most bothersome of lower urinary tract conditions. Current treatments rely on pharmacological, neuromodulatory, and neurotoxicological approaches to manage the disorder, by reducing the excitability of the bladder muscle. However, some patients remain refractory to treatment. An alternative approach would be to temporarily suppress activity of the micturition control circuitry at the time of need i.e., urgency. In this study we investigated, in a rat model, the utility of high frequency pelvic nerve stimulation to produce a rapid onset, reversible suppression of voiding. In urethane-anesthetized rats periodic voiding was induced by continuous infusion of saline into the bladder whilst recording bladder pressure and electrical activity from the external urethral sphincter (EUS). High frequency (1–3 kHz), sinusoidal pelvic nerve stimulation initiated at the onset of the sharp rise in bladder pressure signaling an imminent void aborted the detrusor contraction. Urine output was suppressed and tone in the EUS increased. Stimulating the right or left nerve was equally effective. The effect was rapid in onset, reversible, and reproducible and evoked only minimal “off target” side effects on blood pressure, heart rate, respiration, uterine pressure, or rectal pressure. Transient contraction of abdominal wall was observed in some animals. Stimulation applied during the filling phase evoked a small, transient rise in bladder pressure and increased tonic activity in the EUS, but no urine output. Suppression of micturition persisted after section of the contralateral pelvic nerve or after ligation of the nerve distal to the electrode cuff on the ipsilateral side. We conclude that high frequency pelvic nerve stimulation initiated at the onset of an imminent void provides a potential means to control urinary continence

Nuclear and Metabolic Quantification for Enhanced Ductal Carcinoma In Situ Risk Stratification

Ductal carcinoma in situ (DCIS) is currently considered an early and localized form of ductal breast cancer stemming from the epithelial ductal cells. These lesions are largely heterogenous, categorized by their morphologies, amount of necrosis, and stromal changes. Even though 10-year mortality rate for DCIS is 1-2.6% while that of early invasive breast cancer is 7-10%. Yet, current recommended treatment for DCIS is breast-conserving surgery and radiation or mastectomy – the same treatment regimen recommended for early invasive breast cancer. This assumes that all DCIS will progress to invasive breast cancer if left untreated. However, mounting evidence indicates that a significant number of DCIS would remain indolence and never progress to invasive cancer. Current risk stratification is based on grade and hormone receptor (estrogen and progesterone) status. While the underlying mechanisms for DCIS to invasive cancer progression are not well understood, an improvement in the quantification of cellular morphology, the extracellular matrix and the metabolism modification of the tumor microenvironment could provide a more accurate and objective prognostication and treatment recommendations. DCIS is currently graded manually by a surgical pathologist using a representative number of areas on the slide. This risks grading bias between different pathologists. By using an automated software to measure quantifiable attributes such as nuclear density, size, and degree of variation of all areas of DCIS on the slide, we can have a more uniform and objective scoring system that would have minimal bias and variation. In addition, we will quantify heterogeneity of collagen arrangement, collagen fiber profile in the stroma as well as the metabolic modifications in the tumor microenvironment of “low risk” vs “high risk” DCIS to determine factors that could provide us with a better prognostication system.https://digitalcommons.unmc.edu/surp2022/1032/thumbnail.jp

Suppression of Urinary Voiding by Conditional High Frequency Stimulation of the Pelvic Nerve in Conscious Rats:Pelvic nerve stimulation suppresses urinary voiding

Female Wistar rats were instrumented to record bladder pressure and to stimulate the left pelvic nerve. Repeated voids were induced by continuous infusion of saline into the bladder (11.2 ml/h) via a T-piece in the line to the bladder catheter. In each animal tested (n = 6) high frequency pelvic nerve stimulation (1–3 kHz, 1–2 mA sinusoidal waveform for 60 s) applied within 2 s of the onset of a sharp rise in bladder pressure signaling an imminent void was able to inhibit micturition. Voiding was modulated in three ways: (1) Suppression of voiding (four rats, n = 13 trials). No fluid output or a very small volume of fluid expelled (<15% of the volume expected based on the mean of the previous 2 or 3 voids). Voiding suppressed for the entirety of the stimulation period (60 s) and resumed within 37 s of stopping stimulation. (2) Void deferred (four rats, n = 6 trials). The imminent void was suppressed (no fluid expelled) but a void occurred later in the stimulation period (12–44 s, mean 24.5 ± 5.2 s after the onset of the stimulation). (3) Reduction in voided volume (five rats, n = 20 trials). Voiding took place but the volume of fluid voided was 15–80% (range 21.8–77.8%, mean 45.3 ± 3.6%) of the volume expected from the mean of the preceding two or three voids. Spontaneous voiding resumed within 5 min of stopping stimulation. Stimulation during the filling phase in between voids had no effect. The experiments demonstrate that conditional high frequency stimulation of the pelvic nerve started at the onset of an imminent void can inhibit voiding. The effect was rapidly reversible and was not accompanied by any adverse behavioral side effects

Lineage-associated tracts defining the anatomy of the Drosophila first instar larval brain

AbstractFixed lineages derived from unique, genetically specified neuroblasts form the anatomical building blocks of the Drosophila brain. Neurons belonging to the same lineage project their axons in a common tract, which is labeled by neuronal markers. In this paper, we present a detailed atlas of the lineage-associated tracts forming the brain of the early Drosophila larva, based on the use of global markers (anti-Neuroglian, anti-Neurotactin, inscuteable-Gal4>UAS-chRFP-Tub) and lineage-specific reporters. We describe 68 discrete fiber bundles that contain axons of one lineage or pairs/small sets of adjacent lineages. Bundles enter the neuropil at invariant locations, the lineage tract entry portals. Within the neuropil, these fiber bundles form larger fascicles that can be classified, by their main orientation, into longitudinal, transverse, and vertical (ascending/descending) fascicles. We present 3D digital models of lineage tract entry portals and neuropil fascicles, set into relationship to commonly used, easily recognizable reference structures such as the mushroom body, the antennal lobe, the optic lobe, and the Fasciclin II-positive fiber bundles that connect the brain and ventral nerve cord. Correspondences and differences between early larval tract anatomy and the previously described late larval and adult lineage patterns are highlighted. Our L1 neuro-anatomical atlas of lineages constitutes an essential step towards following morphologically defined lineages to the neuroblasts of the early embryo, which will ultimately make it possible to link the structure and connectivity of a lineage to the expression of genes in the particular neuroblast that gives rise to that lineage. Furthermore, the L1 atlas will be important for a host of ongoing work that attempts to reconstruct neuronal connectivity at the level of resolution of single neurons and their synapses

Female psychopharmacology matters! Towards a sex-specific psychopharmacology

There is increasing recognition that women have a higher prevalence of certain psychiatric illnesses, and a differential treatment response and course of illness compared to men. Additionally, clinicians deal with a number of disorders like premenstrual syndrome, premenstrual dysphoric disorder, and postpartum depression, which affect women specifically and for which treatment and biological pathways are still unclear. In this article we highlight recent research which suggests that different biological mechanisms may underlie sex differences in responsiveness to stress. Sex differences are evident at the receptor level; where the corticotropin-releasing factor receptor shows differential coupling to adaptor proteins in males and females. The neuropeptide oxytocin also shows sex-specific effects in a range of social behaviors. It may act as a biomarker in post-traumatic stress disorder where sex differences are evident. Studies in women using hormonal contraception show that some of these oxytocin-mediated effects are likely influenced by sex hormones. In female rats rapid changes in circulating progesterone levels are associated with exaggerated behavioral responses to mild stress and blunted responses to benzodiazepines that could be prevented by acute treatment with low-dose fluoxetine. Perceived barriers in research on women have hindered progress. The development of a sex-specific psychopharmacology as a basis for translating this type of research into clinical practice is vital to improve treatment outcomes for women

Acid reflux induced laryngospasm as a potential mechanism of sudden death in epilepsy

Objective Recent research suggests that obstructive laryngospasm and consequent respiratory arrest may be a mechanism in sudden unexpected death in epilepsy. We sought to test a new hypothesis that this laryngospasm is caused by seizures driving reflux of stomach acid into the larynx, rather than spontaneous pathological activity in the recurrent laryngeal nerve. Approach We used an acute kainic acid model under urethane anesthesia to observe seizure activity in Long−Evans rats. We measured the pH in the esophagus and respiratory activity. In a subset of experiments, we blocked acid movement up the esophagus with a balloon catheter. Main results In all cases of sudden death, terminal apnea was preceded by a large pH drop from 7 to 2 in the esophagus. In several animals we observed acidic fluid exiting the mouth, sometimes in large quantities. In animals where acid movement was blocked, sudden deaths did not occur. No acid was detected in controls. Significance The results suggest that acid movement up the esophagus is a trigger for sudden death in KA induced seizures. The fact that blocking acid also eliminates sudden death implies causation. These results may provide insight to the mechanism of SUDEP in humans