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The aim of this study was to investigate layer and species variations in detrusor muscle strip responses to myogenic, neurogenic, and nicotinic, and muscarinic receptor stimulations. Strips from bladders of 9 dogs and 6 human organ transplant donors were dissected from inner and outer longitudinal muscle layers, at least 1 cm above urethral orifices. Strips were mounted in muscle baths and maximal responses to neurogenic stimulation using electrical field stimulation (EFS) and myogenic stimulation using potassium chloride (KCl, 120 mM) determined. After washing and re-equilibration was completed, responses to nicotinic receptor agonist epibatidine (10 μM) were determined followed by responses to EFS and muscarinic receptor agonist bethanechol (30 μM) in continued presence of epibatidine. Thereafter, strips and full-thickness bladder sections from four additional dogs and three human donors were examined for axonal density and intramural ganglia. In dog bladders, contractions to KCl, epibatidine, and bethanechol were 1.5- to 2-fold higher in the inner longitudinal muscle layer, whereas contractions to EFS were 1.5-fold higher in the outer (both pre- and post-epibatidine). Human bladders showed 1.2-fold greater contractions to epibatidine in the inner layer and to EFS in the outer, yet no layer differences to KCl or bethanechol were noted. In both species, axonal density was 2- to 2.5-fold greater in the outer layer. Dogs had more intramural ganglia in the adventitia/serosa layer, compared with more internal layers and to humans. These findings indicate several layer-dependent differences in receptor expression or distribution, and neurogenic responses in dog and human detrusor muscles, and myogenic/muscarinic differences between dog versus humans.

This study determined the effect of pelvic organ decentralization and reinnervation 1 yr later on the contribution of muscarinic and purinergic receptors to ex vivo, nerve-evoked, bladder smooth muscle contractions. Nineteen canines underwent decentralization by bilateral transection of all coccygeal and sacral (S) spinal roots, dorsal roots of lumbar (L)7, and hypogastric nerves. After exclusions, 8 were reinnervated 12 mo postdecentralization with obturator-to-pelvic and sciatic-to-pudendal nerve transfers then euthanized 8-12 mo later. Four served as long-term decentralized only animals. Controls included six sham-operated and three unoperated animals. Detrusor muscle was assessed for contractile responses to potassium chloride (KCl) and electric field stimulation (EFS) before and after purinergic receptor desensitization with α, β-methylene adenosine triphosphate (α,β-mATP), muscarinic receptor antagonism with atropine, or sodium channel blockade with tetrodotoxin. Atropine inhibition of EFS-induced contractions increased in decentralized and reinnervated animals compared with controls. Maximal contractile responses to α,β-mATP did not differ between groups. In strips from decentralized and reinnervated animals, the contractile response to EFS was enhanced at lower frequencies compared with normal controls. The observation of increased blockade of nerve-evoked contractions by muscarinic antagonist with no change in responsiveness to purinergic agonist suggests either decreased ATP release or increased ecto-ATPase activity in detrusor muscle as a consequence of the long-term decentralization. The reduction in the frequency required to produce maximum contraction following decentralization may be due to enhanced nerve sensitivity to EFS or a change in the effectiveness of the neurotransmission.

BACKGROUNDMost individuals with prior COVID-19 disease manifest long-term protective immune responses against reinfection. Accordingly, we tested the hypothesis that humoral immune and reactogenicity responses to a SARS-CoV-2 mRNA vaccine differ in individuals with and without prior COVID-19 disease.METHODSHealth care workers (n = 61) with (n = 30) and without (n = 31) prior COVID-19 disease received two 30 μg doses of Pfizer BNT162b2 vaccine 3 weeks apart. Serum IgG antibody against the spike receptor-binding domain; serum neutralizing activity; and vaccine reactogenicity were assessed longitudinally every 2 weeks for 56 days after the first injection.RESULTSThe COVID-19 group manifested more rapid increases in spike IgG antibody and serum neutralizing activity after the first vaccine dose but showed little or no increase after the second dose compared with the infection-naive group. In fact, spike IgG was at its maximum level after the first dose in 36% of the COVID-19 group versus 0% of the infection-naive group. Peak IgG antibody levels were lower but appeared to fall more slowly in the COVID-19 group versus the infection-naive group. Finally, adverse systemic reactions, e.g., fever, headache, and malaise, were more frequent and lasted longer after both the first and second injection in the COVID-19 group than in the infection-naive group.CONCLUSIONIndividuals with prior COVID-19 disease demonstrate a robust, accelerated humoral immune response to the first dose but an attenuated response to the second dose of BNT162b2 vaccine compared with controls. The COVID-19 group also experienced greater reactogenicity. Humoral responses and reactogenicity to BNT162b2 differ qualitatively and quantitatively in individuals with prior COVID-19 disease compared with infection-naive individuals.FUNDINGThis work was supported by Temple University institutional funds.

INTRODUCTION AND OBJECTIVE:This study determined the effect of pelvic organ long-term decentralization and reinnervation one year later on the contribution of muscarinic and purinergic receptors to...

The newly recognized sensory role of bladder urothelium has generated intense interest in identifying its novel sensory molecules. Sensory receptor TRPV4 may serve such function. However, specific and physiologically relevant tissue actions of TRPV4, stretch‐independent responses, and underlying mechanisms are unknown and its role in human conditions has not been examined. Here we showed TRPV4 expression in guinea‐pig urothelium, suburothelium, and bladder smooth muscle, with urothelial predominance. Selective TRPV4 activation without stretch evoked significant ATP release—key urothelial sensory process, from live mucosa tissue, full‐thickness bladder but not smooth muscle, and sustained muscle contractions. ATP release was mediated by Ca2+‐dependent, pannexin/connexin‐conductive pathway involving protein tyrosine kinase, but independent from vesicular transport and chloride channels. TRPV4 activation generated greater Ca2+ rise than purinergic activation in urothelial cells. There was intrinsic TRPV4 activity without exogeneous stimulus, causing ATP release. TRPV4 contributed to 50% stretch‐induced ATP release. TRPV4 activation also triggered superoxide release. TRPV4 expression was increased with aging. Human bladder mucosa presented similarities to guinea pigs. Overactive bladders exhibited greater TRPV4‐induced ATP release with age dependence. These data provide the first evidence in humans for the key functional role of TRPV4 in urothelium with specific mechanisms and identify TRPV4 up‐regulation in aging and overactive bladders.

Aims We sought to determine whether somatic lumbar nerve transfer to the pelvic nerve's anterior vesical branch after sacral decentralization for detrusor muscle reinnervation also leads to aberrant innervation of the bladder outlet. Methods Twenty‐six female mongrel hound dogs underwent transection of sacral dorsal and ventral spinal roots (ie, sacral decentralization). Immediately afterward, 12 received genitofemoral nerve transfer and 9 received femoral nerve branch transfer. Five were left sacrally decentralized. Controls included 3 sham‐operated and 6 unoperated. Eight months postsurgery, the bladder and urethra were injected with retrograde tracing dyes cystoscopically. After 3 weeks, detrusor and urethral pressures were assayed electrophysiologically immediately before euthanasia and characterization of neural reinnervation. Results Electrical stimulation of spinal cords or roots did not lead to increased urethral sphincter pressure in nerve transfer animals, compared with decentralized animals, confirming a lack of functional reinnervation of the bladder outlet. In contrast, mean detrusor pressure increased after lumbar cord/root stimulation. In sham/unoperated animals, urethral and bladder dye injections resulted in labeled neurons in sacral level neural structures (dorsal root ganglia [DRG], sympathetic trunk ganglia [STG], and spinal cord ventral horns); labeling absent in decentralized animals. Urethral dye injections did not result in labeling in lumbar or sacral level neural structures in either nerve transfer group while bladder dye injections lead to increased labeled neurons in lumbar level DRG, STG, and ventral horns, compared to sacrally decentralized animals. Conclusion Pelvic nerve transfer for bladder reinnervation does not impact urethral sphincter innervation.

We determined the effect of pelvic organ decentralization and reinnervation 1 yr later on urinary bladder histology and function. Nineteen canines underwent decentralization by bilateral transection of all coccygeal and sacral (S) spinal roots, dorsal roots of lumbar (L)7, and hypogastric nerves. After exclusions, eight were reinnervated 12 mo postdecentralization with obturator-to-pelvic and sciatic-to-pudendal nerve transfers, then euthanized 8-12 mo later. Four served as long-term decentralized only animals. Before euthanasia, pelvic or transferred nerves and L1–S3 spinal roots were stimulated and maximum detrusor pressure (MDP) recorded. Bladder specimens were collected for histological and ex vivo smooth muscle contractility studies. Both reinnervated and decentralized animals showed less or denuded urothelium, fewer intramural ganglia, and more inflammation and collagen, than controls, although percent muscle was maintained. In reinnervated animals, pgp9.5+ axon density was higher compared with decentralized animals. Ex vivo smooth muscle contractions in response to KCl correlated positively with submucosal inflammation, detrusor muscle thickness, and pgp9.5+ axon density. In vivo, reinnervated animals showed higher MDP after stimulation of L1–L6 roots compared with their transected L7–S3 roots, and reinnervated and decentralized animals showed lower MDP than controls after stimulation of nerves (due likely to fibrotic nerve encapsulation). MDP correlated negatively with detrusor collagen and inflammation, and positively with pgp9.5+ axon density and intramural ganglia numbers. These results demonstrate that bladder function can be improved by transfer of obturator nerves to pelvic nerves at 1 yr after decentralization, although the fibrosis and inflammation that developed were associated with decreased contractile function.

BackgroundCurrent recommendations in the United States are that subjects with a previous history of COVID-19 disease receive the full 2 dose mRNA vaccine regimen. We tested the hypothesis that humoral immune responses and reactogenicity to a SARS-CoV-2 mRNA vaccine (BNT-162b2) differ qualitatively and quantitatively in subjects with prior SARS-CoV-2 infection versus infection-naïve subjects.MethodsHealth care workers (n=61) from a single academic institution with and without prior COVID-19 received two 30 µg doses of BNT162b2 vaccine 3 weeks apart. The COVID group (n=30) received vaccine approximately 7 months post infection. IgG antibody against the Spike receptor-binding domain (RBD), serum neutralizing activity and vaccine adverse reactions were assessed every 2 weeks for 56 days after the 1st injection. A longitudinal design and long study duration allowed the onset, maximum response and initial decay rate of Spike IgG antibody to be assessed in each subject. In addition, Spike IgG antibody levels are expressed as µg / mL to provide normal values for clinical decision making.FindingsSpike IgG responses were highly variable in both groups. However, the COVID group manifested rapid increases in Spike IgG antibody and serum neutralizing activity post 1st vaccine dose but little or no increase in Spike IgG or serum neutralizing activity after the 2nd dose. In fact, Spike IgG was maximum prior to the 2nd dose in 36% of the COVID group and 0% of controls. Peak IgG antibody was lower but appeared to fall more slowly in the COVID than in the control group. Finally, adverse systemic reactions e.g., fever, headache and malaise, after both the 1st and 2nd injection were more frequent and lasted longer in the COVID group than in the control group.ConclusionsHealth care workers with prior COVID-19 demonstrate a robust, accelerated humoral immune response to the 1st dose of the COVID-19 mRNA vaccine but attenuated response to the 2nd dose. They also experience greater reactogenicity than controls. Accordingly, subjects with prior COVID-19 may require only a single dose of vaccine.

INTRODUCTION AND OBJECTIVE:The new sensory role of the urothelium and its pathological implications in bladder dysfunction has generated intense interest in identifying its pathological mediators. ...

Aims To assess bladder smooth muscle function and innervation after long-term lower spinal root transection in canines. Methods Thirteen female mixed-breed hound dogs underwent bladder decentralization, which included transection of all sacral dorsal and ventral roots caudal to L7 and hypogastric nerves, bilaterally (n = 3); all sacral roots and hypogastric nerves plus transection of L7 dorsal roots, bilaterally (n = 4); or a sham operation (n = 6). At a year after initial surgery, bladder function was assessed in vivo by stimulation of the pelvic plexus. The bladder tissue was harvested for ex vivo smooth muscle contractility studies. Remaining bladder was evaluated for nerve morphology immunohistochemically using neuronal marker PGP9.5, apoptotic activity using terminal deoxynucleotidyl transferase dUTP nick end labeling, and histopathology using a hematoxylin and eosin stain. Results Sacral root decentralization did not reduce maximum strength of pelvic plexus stimulation-induced bladder contraction, although long-term sacral dorsal and ventral root plus L7 dorsal root transection significantly decreased contraction strength. Electric field stimulation-induced contractions of the detrusor from all decentralized animals were preserved, compared to controls. Viable nerves and intramural ganglia were visualized in the bladder wall, regardless of group. There was no difference in amount of apoptosis in bladder smooth muscle between groups. Conclusion Bladder smooth muscle cells maintain their function after long-term bladder decentralization. While pelvic plexus-induced bladder contractions were less robust at 1 year after lower spinal root transection, the absence of atrophy and preservation of at least some nerve activity may allow for successful surgical reinnervation after long-term injury.

Many studies examining the innervation of genitourinary structures focus on either afferent or efferent inputs, or on only one structure of the system. We aimed to clarify innervation of the bladder, external urethral sphincter (EUS) and clitoris. Retrograde dyes were injected into each end organ in female dogs. Spinal cord, mid-bladder, and spinal, caudal mesenteric, sympathetic trunk and pelvic plexus ganglia were examined for retrograde dye-labeled neurons. Neurons retrogradely labeled from the bladder were found primarily in L7-S2 spinal ganglia, spinal cord lateral zona intermedia at S1-S3 levels, caudal mesenteric ganglia, T11-L2 and L6-S2 sympathetic trunk ganglia, and pelvic plexus ganglia. The mid-bladder wall contained many intramural ganglia neurons labeled anterogradely from the pelvic nerve, and intramural ganglia retrogradely labeled from dye labeling sites surrounding ureteral orifices. Neurons retrogradely labeled from the clitoris were found only in L7 and S1 spinal ganglia, L7-S3 spinal cord lateral zona intermedia, and S1 sympathetic trunk ganglia, and caudal mesenteric ganglia. Neurons retrogradely labeled from the EUS were found in primarily at S1 and S2 spinal ganglia, spinal cord lamina IX at S1-S3, caudal mesenteric ganglia, and S1-S2 sympathetic trunk ganglia. Thus, direct inputs from the spinal cord to each end organ were identified, as well as multisynaptic circuits involving several ganglia, including intramural ganglia in the bladder wall. Knowledge of this complex circuitry of afferent and efferent inputs to genitourinary structures is necessary to understand and treat genitourinary dysfunction. Anat Rec, 2018. © 2018 Wiley Periodicals, Inc.

Aims Lumbar to sacral rerouting surgery can potentially allow voiding via a skin-central nervous system-bladder reflex pathway. Here, we assessed if this surgery was effective in treating neurogenic bladder dysfunction/sphincter in felines. Methods Eight cats underwent spinal cord transection (SCT) at thoracic level 10/11. Unilateral L7 to S1 ventral root anastomosis was performed 1 month later in six cats. Two cats served as transection-only controls. Electrical and manual stimulation of L6-S1 dermatomes, and urodynamics were performed at 3, 5, 7, and 9/10 months post transection. At 9/10 months, cats were also evaluated by direct electrophysiological testing of anastomosed roots with urodynamics, then tissue collection and examination of the root anastomosis site and lumbosacral cord ventral horns for cells retrogradely labeled from tracer dye injected 2 weeks earlier into the bladder wall. Results At 9/10 months, four of six rerouted cats exhibited increased detrusor pressure provoked by cutaneous stimulation, one cat bilaterally. Two cats presented with a voiding stream after ipsilateral cutaneous stimulation at 7 and 9 months. All six rerouted animals showed regrowth of axons from the L7 ventral horn to the bladder, although some aberrant axonal regrowth was also observed. Conclusion L7 to S1 ventral root rerouting below the level of SCT showed successful axonal regrowth to the bladder from the L7 spinal cord segment in all rerouted animals, and induced increased detrusor pressure response to cutaneous stimulation in a subset. This feasibility study paves the way for future animal studies for bladder reinnervation.

Bladder dysfunction is associated with the overexpression of the intermediate filament (IF) proteins desmin and vimentin in obstructed bladder smooth muscle (BSM). However, the mechanisms by which these proteins contribute to BSM dysfunction are not known. Previous studies have shown that desmin and vimentin directly participate in signal transduction. In this study, we hypothesized that BSM dysfunction associated with overexpression of desmin or vimentin is mediated via c-Jun N-terminal kinase (JNK). We employed a model of murine BSM tissue in which increased expression of desmin or vimentin was induced by adenoviral transduction to examine the sufficiency of increased IF protein expression to reduce BSM contraction. Murine BSM strips overexpressing desmin or vimentin generated less force in response to KCl and carbachol relative to the levels in control murine BSM strips, an effect associated with increased JNK2 phosphorylation and reduced myosin light chain (MLC20 ) phosphorylation. Furthermore, desmin and vimentin overexpressions did not alter BSM contractility and MLC20 phosphorylation in strips isolated from JNK2 knockout mice. Pharmacological JNK2 inhibition produced results qualitatively similar to those caused by JNK2 knockout. These findings suggest that inhibition of JNK2 may improve diminished BSM contractility associated with obstructive bladder disease.

Background Peripheral nerve interfacing has many applications ranging from investigation of neural signals to therapeutic intervention for varied diseases. This need has driven technological advancements in the field of electrode arrays and wireless systems for in-vivo electrophysiological experiments. Hence we present our fully implantable, programmable miniaturized wireless stimulation and recording devices. New method The method consists of technological advancements enabling implantable wireless recording up to 128 channels with a sampling rate of 50Khz and stimulation up to ±4 mA from 15 independent channels. The novelty of the technique consists of induction charging cages which enables freely moving small animals to undergo continuous electrophysiological and behavioral studies without any impediments. The biocompatible hermetic packaging technology for implantable capsules ensures stability for long-term chronic studies. Results Electromyographs wirelessly recorded from leg muscles of a macaque and a rat using implantable technology are presented during different behavioral task studies. The device's simultaneous stimulation and recording capabilities are reported when interfaced with the vagus and pelvic nerves. Comparison with existing method(s) The wireless interfacing technology has a large number of recording and stimulating channels without compromising on the signal quality due to sampling rates or stimulating current output capabilities. The induction charging technology along with transceiver and software interface allows experiments on multiple animals to be carried out simultaneously. Conclusions This customizable technology using wireless power transmission, reduced battery size, and miniaturized electronics has paved way for a robust, fully implantable, hermetic neural interface system enabling the study of bioelectronic medical therapies.

INTRODUCTION AND OBJECTIVES:Carbachol, a mixed muscarinic and nicotinic agonist similar to acetylcholine, is often used for in-vitro bladder contraction with the implicit assumption that it causes ...

INTRODUCTION AND OBJECTIVES:We aim to surgically reinnervate a lower motor neuron neurogenic bladder via obturator-to-pelvic and sciatic-to-pudendal nerve transfer. Behavioral observations provide the most global assessment of functional recovery. We sought to determine whether observed micturition postures disappear in decentralized animals and reappear after reinnervation.METHODS:Three groups of female canines were used: 1) Long-term survival (12 months) after transection of all ventral and dorsal sacral roots, the dorsal roots of L7 and hypogastric nerves, bilaterally (n=4); 2) Procedures described in Group 1, followed by obturator-to-pelvic nerve and sciatic-to-pudendal nerve transfer (n=3); 3) Unoperated control animals (n=3). Micturition postures were monitored for 24 hours at monthly intervals via video recording. Bacteriuria was tracked midway through the study with urine Multistix test strip assays, body temperature, and cultured urine specimens by a commercial clinical laboratory. Awake cystomet...

INTRODUCTION AND OBJECTIVES:Recognition of the urothelium as a new sensory structure and its potential role in mediating bladder dysfunction has led to great interest in identifying its pathologica...

OBJECTIVEPrevious patient surveys have shown that patients with spinal cord or cauda equina injuries prioritize recovery of bladder function. The authors sought to determine if nerve transfer after long-term decentralization restores bladder and sphincter function in canines.METHODSTwenty-four female canines were included in this study. Transection of sacral roots and hypogastric nerves (S Dec) was performed in 6 animals, and 7 animals underwent this procedure with additional transection of the L7 dorsal roots (L7d+S Dec). Twelve months later, 3 L7d+S Dec animals underwent obturator-to-pelvic nerve and sciatic-to-pudendal nerve transfers (L7d+S Dec+Reinn). Eleven animals served as controls. Squat-and-void behaviors were tracked before and after decentralization, after reinnervation, and following awake bladder-filling procedures. Bladders were cystoscopically injected with Fluoro-Gold 3 weeks before euthanasia. Immediately before euthanasia, transferred nerves were stimulated to evaluate motor function. Dorsal root ganglia were assessed for retrogradely labeled neurons.RESULTSTransection of only sacral roots failed to reduce squat-and-void postures; L7 dorsal root transection was necessary for significant reduction. Three L7d+S Dec animals showing loss of squat-and-void postures post-decentralization were chosen for reinnervation and recovered these postures 4–6 months after reinnervation. Each showed obturator nerve stimulation–induced bladder contractions and sciatic nerve stimulation–induced anal sphincter contractions immediately prior to euthanasia. One showed sciatic nerve stimulation–induced external urethral sphincter contractions and voluntarily voided twice following nonanesthetized bladder filling. Reinnervation was confirmed by increased labeled cells in L2 and the L4–6 dorsal root ganglia (source of obturator nerve in canines) of L7d+S Dec+Reinn animals, compared with controls.CONCLUSIONSNew neuronal pathways created by nerve transfer can restore bladder sensation and motor function in lower motor neuron–lesioned canines even 12 months after decentralization.

The high-pressure zone of the gastroesophageal junction acts as a multifunctional valve that comprises different groups of smooth muscles located in the distal esophagus and the proximal stomach, in addition to the extrinsic crural diaphragm, composed of skeletal muscle. In this review article, we evaluate the current literature with respect to human subjects, discussing the anatomic locations and physiologic and pharmacologic processes controlling these muscles. These muscles work individually and as a group to prevent reflux of gastric contents while allowing anterograde passage of food and liquid and retrograde passage of gas. We also reviewed new findings with respect to abnormalities that are permissive of reflux of gastric contents into the esophagus, which may lead to gastroesophageal reflux disease.

Aims Complete spinal cord injury does not block perceptual responses or inferior solitary nucleus activation after genital self-stimulation, even though the vagus is not thought to innervate pelvic structures. We tested if vagus nerve endings sprout after bladder decentralization to innervate genitourinary structures in canines with decentralized bladders. Methods Four reinnervation surgeries were performed in female hounds: bilateral genitofemoral nerve transfer to pelvic nerve with vesicostomy (GNF-V) or without (GFN-NV); and left femoral nerve transfer (FNT-V and FNT-NV). After 8 months, retrograde dyes were injected into genitourinary structures. Three weeks later, at euthanasia, reinnervation was evaluated as increased detrusor pressure induced by functional electrical stimulation (FES). Controls included un-operated, sham-operated, and decentralized animals. Results Increased detrusor pressure was seen in 8/12 GFNT-V, 4/5 GFNT-NV, 5/5 FNT-V, and 4/5 FNT-NV animals after FES, but not decentralized controls. Lumbar cord segments contained cells labeled from the bladder in all nerve transfer animals with FES-induced increased detrusor pressure. Nodose ganglia cells labeled from the bladder were observed in 5/7 nerve transfer animals (1/2 GNT-NV; 4/5 FNT-V), and from the clitoris were in 6/7 nerve transfer animals (2/2 GFNT-NV; 4/5 FNT-V). Dorsal motor nucleus vagus cells labeled from the bladder were observed in 3/5 nerve transfer animals (1/2 GFNT-NV; 2/3 FNT-V), and from the clitoris in 4/5 nerve transfer animals (1/2 GFNT-NV; 3/3 FNT-V). Controls lacked this labeling. Conclusions Evidence of vagal nerve sprouting to the bladder and clitoris was observed in canines with lower motoneuron lesioned bladders. Neurourol. Urodynam. © 2015 Wiley Periodicals, Inc.

During the past century, diverse studies have focused on the development of surgical strategies to restore function of a decentralized bladder after spinal cord or spinal root injury via repair of the original roots or by transferring new axonal sources. The techniques included end-to-end sacral root repairs, transfer of roots from other spinal segments to sacral roots, transfer of intercostal nerves to sacral roots, transfer of various somatic nerves to the pelvic or pudendal nerve, direct reinnervation of the detrusor muscle, or creation of an artificial reflex pathway between the skin and the bladder via the central nervous system. All of these surgical techniques have demonstrated specific strengths and limitations. The findings made to date already indicate appropriate patient populations for each procedure, but a comprehensive assessment of the effectiveness of each technique to restore urinary function after bladder decentralization is required to guide future research and potential clinical application.

In 1990, although the etiology and pathogenesis of the condition then referred to as “interstitial cystitis” (IC) was admitted to be largely or even completely unknown, the widely held implicit working assumptions held that it is a bladder disease. These assumptions implied that if we could discover and correct what was wrong with the bladder itself then we could cure the condition. These assumptions have proved to be largely off base. At that time, the previous suggestions that IC might have a primarily autoimmune or infectious etiology were largely abandoned. The autoimmune hypothesis still remains but has yet to be either been proven nor disproven conclusively.

Many studies examining the innervation of genitourinary structures focus on either afferent or efferent inputs, or on only one structure of the system. We aimed to clarify innervation of the bladder, external urethral sphincter (EUS) and clitoris. Retrograde dyes were injected into each end organ in female dogs. Spinal cord, mid-bladder, and spinal, caudal mesenteric, sympathetic trunk and pelvic plexus ganglia were examined for retrograde dye-labeled neurons. Neurons retrogradely labeled from the bladder were found primarily in L7-S2 spinal ganglia, spinal cord lateral zona intermedia at S1-S3 levels, caudal mesenteric ganglia, T11-L2 and L6-S2 sympathetic trunk ganglia, and pelvic plexus ganglia. The mid-bladder wall contained many intramural ganglia neurons labeled anterogradely from the pelvic nerve, and intramural ganglia retrogradely labeled from dye labeling sites surrounding ureteral orifices. Neurons retrogradely labeled from the clitoris were found only in L7 and S1 spinal ganglia, L7-S3 spinal cord lateral zona intermedia, and S1 sympathetic trunk ganglia, and caudal mesenteric ganglia. Neurons retrogradely labeled from the EUS were found in primarily at S1 and S2 spinal ganglia, spinal cord lamina IX at S1-S3, caudal mesenteric ganglia, and S1-S2 sympathetic trunk ganglia. Thus, direct inputs from the spinal cord to each end organ were identified, as well as multisynaptic circuits involving several ganglia, including intramural ganglia in the bladder wall. Knowledge of this complex circuitry of afferent and efferent inputs to genitourinary structures is necessary to understand and treat genitourinary dysfunction. Anat Rec, 2018. © 2018 Wiley Periodicals, Inc.

Aims Detrusor underactivity, resulting in either prolonged or inefficient voiding, is a common clinical problem for which treatment options are currently limited. The aim of this report is to summarize current understanding of the clinical observation and its underlying pathophysiological entities.

Background Proper function of the gastro-esophageal high pressure zone is essential for the integrity of the antireflux barrier. Mechanisms include tonic contractions and the decreased tone during transient lower esophageal sphincter relaxations. Methods We characterized the pharmacology of nicotinic receptors mediating relaxations of the human upper gastric sphincter (clasp and sling fibers) using currently available subtype selective nicotinic antagonists in tissue from organ transplant donors. Donors with either a history of gastro-esophageal reflux disease or histologic evidence of Barrett's esophagus were excluded. Clasp and sling muscle fiber strips were used for one of three paradigms. For paradigm 1, each strip was exposed to carbachol, washed, exposed to nicotinic antagonists then re-exposed to carbachol. In paradigm 2, strips were exposed to a near maximally effective bethanechol concentration then nicotine was added. Strips then were washed, exposed to nicotinic antagonists then re-exposed to bethanechol followed by nicotine. In paradigm 3, strips were exposed to bethanechol then choline or cytisine. Key Results 100 μM methyllycaconitine has no inhibitory effects on relaxations, eliminating homomeric α7 subtypes. Subtypes composed of α4β2 subunits are also eliminated because choline acts as an agonist and dihydro-beta-erythroidine is ineffective. Conclusions & Inferences Because mecamylamine blocks the relaxations and both choline and cytisine act as agonists in both clasp and sling fibers, the nicotinic receptor subtypes responsible for these relaxations could be composed of α3β4β2, α2β4, or α4β4 subunits.

Anatomical variations in lumbosacral plexus or nerves to genitourinary structures in dogs are under described, despite their importance during surgery and potential contributions to neuromuscular syndromes. Gross dissection of 16 female mongrel hound dogs showed frequent variations in lumbosacral plexus classification, sympathetic ganglia, ventral rami input to nerves innervating genitourinary structures and pudendal nerve (PdN) branching. Lumbosacral plexus classification types were mixed, rather than pure, in 13 (82%) of dogs. The genitofemoral nerve (GFN) originated from ventral ramus of L4 in 67% of nerves, differing from the expected L3. Considerable variability was seen in ventral rami origins of pelvic (PN) and Pd nerves, with new findings of L7 contributions to PN, joining S1 and S2 input (23% of sides in 11 dogs) or S1–S3 input (5%), and to PdN, joining S1–S2, unilaterally, in one dog. L7 input was confirmed using retrograde dye tracing methods. The PN also received CG1 contributions, bilaterally, in one dog. The PdN branched unusually in two dogs. Lumbosacral sympathetic ganglia had variant intra-, inter- and multisegmental connectivity in 6 (38%). Thus, the anatomy of mongrel dogs had higher variability than previously described for purebred dogs. Knowledge of this variant innervation during surgery could aid in the preservation of nerves and reduce risk of urinary and sexual dysfunctions.

ObjectiveWe aimed to refine electroneurogram techniques for monitoring hypogastric nerve activity during bladder filling, and then examined nerve activity in normal intact versus acutely decentralized bladders.MethodsEffects of electrical stimulation of hypogastric nerves or lumbar ventral roots on detrusor pressure were examined, as were effects of isoflurane versus propofol anesthetics on hypogastric nerve stimulation evoked pressure. Hypogastric nerve activity was then recorded using custom-made bipolar cuff electrodes during bladder filling before and after its transection between the spinal cord and electrode to eliminate efferent nerve signals.ResultsElectrical stimulation of hypogastric nerves evoked low amplitude detrusor pressures that did not differ between the two anesthetics. Upper lumbar (L2) ventral root stimulation evoked detrusor pressures were suppressed, yet not eliminated, after transection of hypogastric nerves and all spinal roots below L5. Afferent and efferent hypogastric nerve activity did not change with bladder filling in neuronally intact bladders yet decreased in decentralized bladders. No change in afferent activity was observed during bladder filling in either intact or decentralized bladders.ConclusionsThese findings indicate that a more complete decentralized bladder model should include transection of lumbosacral spinal roots innervating the bladder as well as hypogastric nerves. These refined electroneurogram recording methods may be suitable for evaluating the effectiveness of nerve transfer surgeries for bladder reinnervation by monitoring sensory activity in the transferred nerve.

The following discussion on the physiology of the esophagus includes commentaries on the function of the muscularis mucosa and submucosa as a mechanical antireflux barrier in the esophagus; the different mechanisms of neurological control in the esophageal striated and smooth muscle; new insights from animal models into the neurotransmitters mediating lower esophageal sphincter (LES) relaxation, peristalsis in the esophageal body (EB), and motility of esophageal smooth muscle; differentiation between in vitro properties of the lower esophageal circular muscle, clasp muscle, and sling fibers; alterations in the relationship between pharyngeal contraction and relaxation of the upper esophageal sphincter (UES) in patients with dysphagia; the mechanical relationships between anterior hyoid movement, the extent of upper esophageal opening, and aspiration; the application of fluoroscopy and manometry with biomechanics to define the stages of UES opening; and nonpharmacological approaches to alter the gastroesophageal junction (GEJ).

Object Nerve transfers are an effective means of restoring control to paralyzed somatic muscle groups and have recently been shown to be effective in denervated detrusor muscle in a canine model. A cadaveric study was performed to examine the anatomical feasibility of transferring femoral muscular nerve branches to vesical branches of the pelvic nerve as a method of potentially restoring innervation to control the detrusor muscle in humans. Methods Twenty cadavers were dissected bilaterally to expose pelvic and femoral muscular nerve branches. Ease of access and ability to transfer the nerves were assessed, as were nerve cross-sectional areas. Results The pelvic nerve was accessed at the base of the bladder, inferior to the ureter, and accompanied by inferior vesical vessels. Muscular branches of the femoral nerve to the vastus medialis and intermedius muscles (L-3 and L-4 origins) were followed distally for 17.4 ± 0.8 cm. Two muscle branches were split from the femoral nerve trunk, and tunneled inferior to the inguinal ligament. One branch was moved medially toward the base of the bladder and linked to the ipsilateral pelvic nerve. The second branch was tunneled superior to the bladder and linked to the contralateral pelvic nerve. The cross-sectional area of the pelvic nerve vesical branch was 2.60 ± 0.169 mm2 (mean ± SEM), and the femoral nerve branch at the suggested transection site was 4.40 ± 0.41 mm2. Conclusions Use of femoral nerve muscular branches from the vastus medialis and intermedius muscles for heterotopic nerve transfer of bilateral pelvic nerves is surgically feasible, based on anatomical location and cross-sectional areas.

Object Nerve transfers are effective for restoring control to paralyzed somatic muscle groups and, recently, even to denervated detrusor muscle in a canine model. A pilot project was performed in cadavers to examine the feasibility of transferring somatic nerves to vesical branches of the pelvic nerve as a method for potentially restoring innervation to control the detrusor muscle in humans. Methods Eleven cadavers were dissected bilaterally to expose intercostal, ilioinguinal, and iliohypogastric nerves, along with vesical branches of the pelvic nerve. Ease of access and ability to transfer the former 3 nerves to the pelvic vesical nerves were assessed, as were nerve cross-sectional areas. Results The pelvic vesical nerves were accessed at the base of the bladder, inferior to the ureter and accompanied by inferior vesical vessels. The T-11 and T-12 intercostal nerves were too short for transfer to the pelvic vesical nerves without grafting. Ilioinguinal and iliohypogastric nerves (L-1 origin) were identified retroperitoneally and, with full dissection, were easily transferred to the pelvic vesical nerves intraabdominally. The mean cross-sectional area of the dominant pelvic vesical branch was 2.60 ± 0.169 mm2; ilioinguinal and iliohypogastric branches at the suggested transection site were 2.38 ± 0.32 mm2 (the means are expressed ± SEM). Conclusions Use of the ilioinguinal or iliohypogastric nerves for heterotopic transfer to pelvic vesical nerves is surgically feasible, based on anatomical location and cross-sectional areas.

Object Nerve transfers are an effective means of restoring control to paralyzed somatic muscle groups and, recently, even denervated detrusor muscle. The authors performed a cadaveric pilot project to examine the feasibility of restoring control to the urethral and anal sphincters using a femoral motor nerve branch to reinnervate the pudendal nerve through a perineal approach. Methods Eleven cadavers were dissected bilaterally to expose the pudendal and femoral nerve branches. Pertinent landmarks and distances that could be used to locate these nerves were assessed and measured, as were nerve cross-sectional areas. Results A long motor branch of the femoral nerve was followed into the distal vastus medialis muscle for a distance of 17.4 ± 0.8 cm, split off from the main femoral nerve trunk, and transferred medially and superiorly to the pudendal nerve in the Alcock canal, a distance of 13.7 ± 0.71 cm. This was performed via a perineal approach. The cross-sectional area of the pudendal nerve was 5.64 ± 0.49 mm2, and the femoral nerve motor branch at the suggested transection site was 4.40 ± 0.41 mm2. Conclusions The use of a femoral nerve motor branch to the vastus medialis muscle for heterotopic nerve transfer to the pudendal nerve is surgically feasible, based on anatomical location and cross-sectional areas.