Optilume® drug-coated balloon dilation in complex female urethral stricture.

The treatment of female urethral stricture disease is in flux in terms of developing guidelines for surgical treatment. Urethral strictures in women are rare, but frequently result because of urethral instrumentation or surgery. Stricture sites vary from proximal, intrasphincteric, distal or at the meatus. Stricture formation after previous urethral surgery may pose a special challenge. We describe the first Optilume® urethral drug-coated balloon dilation for female urethral stricture disease involving the sphincter. After six months follow-up the patient remains stricture free with full continence and complete bladder emptying.

Urethro-cavernosal-spongiosal fistula after intralesional mitomycin C for recurrent urethral stricture disease.

Intralesional mitomycin C after direct visual internal urethrotomy for recurrent urethral stricture disease in patients suboptimal for open urethroplasty is an established option. We report a case of urethro-cavernosal-spongiosal fistula after intralesional mitomycin C into an area of previous dorsal inlay urethroplasty. The patient presented with pus draining from the urethral meatus ten days after treatment. Sterile abscesses developed within the corporal and spongious bodies, draining freely into the urethra. Complete spontaneous healing followed short-term transurethral catheterization and antibiotic prophylaxis.

World record: Single AMS 800 artificial urinary sphincter functioning uninterrupted for 29 years in male paraplegic patient.

Lapides has revolutionized the treatment of neurogenic patients by introducing routine intermittent catheterization in 1971. This drastically lowered mortality from urosepsis. Scott introduced the artificial urinary sphincter (AUS) in 1972. This gave a completely new perspective for incontinent patients by dramatically increasing the quality of life. In patients with neurogenic urinary incontinence, the principles of care are preserving renal function, maintaining a low-pressure reservoir, allowing unobstructed urine flow and providing continence. We describe a male patient that received an AUS with a bladder neck cuff that functioned without revision for 29 years. After 30 years, AUS exchange proved successful.

Excessive fibrosis and non-function after ATOMS (adjustable transobturator male system): A case of capsular contracture?

The adjustable transobturator male system (ATOMS) treats post-prostatectomy urinary incontinence by compression of the proximal bulbous urethra. It reminds of the Kaufman prosthesis described in 1978. We describe a case where an excessive fibrotic reaction occurred around the cushion. Furthermore, the bulbous urethra underneath, developed severe atrophy devoid of any visible blood supply. We suspect ongoing shear forces around the cushion while sitting resulting in a chain reaction of acute through chronic inflammation and progressive fibrosis and encapsulation. Does the encapsulation lead to capsular contracture resulting in non-function?

Intrapelvic bulboprostatic repair after urethral distraction injury and failed bulbomembranous anastomosis.

A failed end-to-end anastomosis after membranous urethral distraction injury post-trauma is a surgical challenge. We present a case of a young man after complex pelvic injury. Revision urethroplasty was done utilizing nerve and vessel sparing techniques. Intrasphincteric dissection enabled bulbous urethral pull-through with intrapelvic anastomosis with good success. Low dose tadalafil was given to optimize penile rehabilitation.

Lrp12/Mig13a reveals changing patterns of preplate neuronal polarity during corticogenesis that are absent in reeler mutant mice.

During corticogenesis, the earliest generated neurons form the preplate, which evolves into the marginal zone and subplate. Lrp12/Mig13a, a mammalian gene related to the Caenorhabditis elegans neuroblast migration gene mig-13, is expressed in a subpopulation of preplate neurons that undergo ventrally directed tangential migrations in the preplate layer and pioneer axon projections to the anterior commissure. As the preplate separates, Lrp12/Mig13a-positive neurons polarize in the radial plane and form a pseudocolumnar pattern, prior to moving to a deeper position within the emerging subplate layer. These changes in neuronal polarity do not occur in reeler mutant mice, revealing the earliest known defect in reeler cortical patterning and suggesting that the alignment of preplate neurons into a pseudolayer facilitates the movement of later-born radially migrating neurons into the emerging cortical plate.

Beta-catenin-mediated Wnt signaling regulates neurogenesis in the ventral telencephalon.

Development of the telencephalon involves the coordinated growth of diversely patterned brain structures. Previous studies have demonstrated the importance of beta-catenin-mediated Wnt signaling in proliferation and fate determination during cerebral cortical development. We found that beta-catenin-mediated Wnt signaling critically maintained progenitor proliferation in the subcortical (pallidal) telencephalon. Targeted deletion of beta-catenin in mice severely impaired proliferation in the medial ganglionic eminence without grossly altering differentiated fate. Several lines of evidence suggest that this phenotype is primarily the result of a loss of canonical Wnt signaling. As previous studies have suggested that the ventral patterning factor Sonic Hedgehog (Shh) also stimulates dorsal telencephalic proliferation, we propose a model whereby Wnt and Shh signaling promote distinct dorsal-ventral patterning while also having broader effects on proliferation that serve to coordinate the growth of telencephalic subregions.

Environmental signals elicit multiple responses in dorsal telencephalic progenitors by threshold-dependent mechanisms.

Environmental signals including epidermal growth factor family members, Shh, fibroblast growth factor, and bone morphogenetic protein (BMP) can affect multiple processes during the development of the central nervous system, raising questions about the mechanisms that determine how these pleiotropic signals are interpreted to elicit appropriate responses at specific times and locations. Here we address the idea that different thresholds of stimulation determine how progenitors in the dorsal telencephalon interpret these signals. One mechanism for achieving different thresholds of signaling is illustrated by the developmental increase in the level of epidermal growth factor receptor (EGFR) expression among a subset of progenitors in the late embryonic telencephalon. Another mechanism is illustrated by the antagonistic interaction of BMP with Shh, which can influence EGFR expression and neuron subtype choice. We focus on the similarities and differences in the control of these responses and address the possibility that the gamma-aminobutyric acidergic neuron specification might be linked to progenitor expression of a higher level of EGFRs.

Shh maintains Nkx2.1 in the MGE by a Gli3-independent mechanism.

Gamma-aminobutyric acidergic (GABAergic) interneurons perform crucial roles in cortical development and function. These roles are executed by diverse subgroups of interneurons, and dysfunction of particular subgroups may contribute to a variety of neuropsychiatric diseases. In rodents, most cortical interneurons originate in the pallidal telencephalon that also gives rise to the GABAergic neurons of the striatum and other ventral structures. In this paper, we examine the evidence for distinct origins of interneuron subgroups and then discuss the role of the homeobox gene thyroid transcription factor1 (Ttf-1 or Nkx2.1) in the specification of interneurons from the medial ganglionic eminence (MGE). Nkx2.1 is induced in the pallidal telencephalon by the action of sonic hedgehog (Shh) that antagonizes formation of the dorsalizing Gli3 repressor (Gli3R) protein. Recent evidence suggests that Shh is also required to maintain Nkx2.1 expression, and thus MGE interneuron specification, during embryonic neurogenesis. Here we provide evidence that, in contrast to the initial induction of Nkx2.1 during telencephalic patterning, the Nkx2.1 maintenance function of Shh does not require blocking the formation of the Gli3R. The plastic nature of Nkx2.1 expression during the age range of interneuron genesis suggests that factors regulating this gene can be critical determinants of the balance of excitation and inhibition in the postnatal cerebral cortex.

Sonic hedgehog and bone morphogenetic protein regulate interneuron development from dorsal telencephalic progenitors in vitro.

Cortical progenitors are competent to produce interneurons, but do not generate large numbers of interneurons in vivo under normal circumstances. This could reflect the absence of an inductive signal in the environment of the dorsal telencephalon and/or the presence of an inhibitory signal. To determine whether either or both mechanisms regulate interneuron generation, progenitors in dorsomedial and dorsolateral wall explants of mouse telencephalon were marked with a retrovirus and cultured under several conditions. When cultured separately, progenitors in dorsomedial wall explants produced fewer GABAergic interneurons than progenitors in dorsolateral wall explants. When cocultured with ventral telencephalic cells, however, dorsomedial wall progenitors produced more GABAergic interneurons than in dorsomedial wall explants alone. The inductive effect of ventral telencephalon depended on sonic hedgehog (Shh) and could be mimicked by exogenous Shh. In contrast, exogenous bone morphogenetic protein 4 (BMP4) reduced the production of interneurons in dorsolateral wall explants and inhibited the induction by exogenous Shh. Moreover, inhibiting BMP signaling in dorsomedial wall progenitors with a dominant-negative BMP receptor Ib (dnBMPIb) virus increased their production of interneurons, even if Shh was blocked. Shh and dnBMPRIb increased proliferation and the generation of interneurons, but FGF2 did not induce interneurons, although it increased proliferation. This suggests that proliferation per se does not control the production of interneurons. Our findings suggest that the generation of interneurons by dorsal telencephalic progenitors is normally limited by excess levels of BMPs. Shh may promote the generation of interneurons by antagonizing BMP, but may not be required directly for the generation of interneurons.

Cell type-specific differences in chloride-regulatory mechanisms and GABA(A) receptor-mediated inhibition in rat substantia nigra.

The regulation of intracellular chloride has important roles in neuronal function, especially by setting the magnitude and direction of the Cl- flux gated by GABA(A) receptors. Previous studies have shown that GABA(A)-mediated inhibition is less effective in dopaminergic than in GABAergic neurons in substantia nigra. We studied whether this phenomenon may be related to a difference in Cl-regulatory mechanisms. Light-microscopic immunocytochemistry revealed that the potassium-chloride cotransporter 2 (KCC2) was localized only in the dendrites of nondopaminergic (primarily GABAergic) neurons in the substantia nigra, whereas the voltage-sensitive chloride channel 2 (ClC-2) was observed only in the dopaminergic neurons of the pars compacta. Electron-microscopic immunogold labeling confirmed that KCC2 is localized in the dendritic plasma membrane of GABAergic neurons close to inhibitory synapses. Confocal microscopy showed that ClC-2 was selectively expressed in the somatic and dendritic cell membranes of the dopaminergic neurons. Gramicidin-perforated-patch recordings revealed that the GABA(A) IPSP reversal potential was significantly less negative and had a much smaller hyperpolarizing driving force in dopaminergic than in GABAergic neurons. The GABA(A) reversal potential was significantly less negative in bicarbonate-free buffer in dopaminergic but not in GABAergic neurons. The present study suggests that KCC2 is responsible for maintaining the low intracellular Cl- concentration in nigral GABAergic neurons, whereas a sodium-dependent anion (Cl--HCO3-) exchanger and ClC-2 are likely to serve this role in dopaminergic neurons. The relatively low efficacy of GABAA-mediated inhibition in nigral dopaminergic neurons compared with nigral GABAergic neurons may be related to their lack of KCC2.

Wnt regulation of progenitor maturation in the cortex depends on Shh or fibroblast growth factor 2.

In the embryonic mouse cerebral cortex, progenitors in the ventricular zone (VZ) undergo a developmental change between embryonic day 13 (E13) and E15. This results in the generation of a secondary proliferative population and the appearance of a second germinal layer, the subventricular zone (SVZ). We have shown previously that bone morphogenetic proteins (BMPs) and fibroblast growth factor 2 (FGF2) act antagonistically to regulate the development of a subset of SVZ progenitors that normally express a high level of epidermal growth factor (EGF) receptors and divide in response to EGF. In the present study, we show that Wnt 7a, Wnt 7b, and Sonic hedgehog (Shh) promote progenitor maturation in explant cultures, as reported for FGF2. Wnts 7a and 7b also stimulate the proliferation of neurogenic progenitors and increase the number of cells that can generate primary neurospheres. To determine whether Wnts, FGF2, and Shh act independently or in a common pathway, each factor was inhibited in cortical explants. This revealed that endogenous Wnts, FGF2, and Shh normally contribute to progenitor maturation. Moreover, Wnt 7a depends on FGF2 or Shh to promote maturation but not proliferation. Maturation induced by blocking BMPs also depends on Shh. In contrast, FGF2 promotes maturation by a Shh-independent mechanism. In vivo, progenitors infected with a Wnt 7a retrovirus at E10.5 were found preferentially in the SVZ at E16.5. These findings suggest that Wnts depend on Shh or FGF2 to promote progenitor maturation to an SVZ state in the embryonic cortex.

Unexpected mobility variation among individual secretory vesicles produces an apparent refractory neuropeptide pool.

Most stored neuropeptide cannot be released from nerve terminals suggesting the existence of a refractory pool of dense core vesicles (DCVs). Past fluorescence photobleaching recovery, single particle tracking and release experiments suggested that the refractory neuropeptide pool corresponds to a distinct immobile fraction of cytoplasmic DCVs. However, tracking of hundreds of individual green fluorescent protein-labeled neuropeptidergic vesicles by wide-field or evanescent-wave microscopy shows that a separate immobile fraction is not evident. Instead, the DCV diffusion coefficient (D) distribution is unusually broad and asymmetric. Furthermore, the distribution shifts with a release facilitator. This unexpected variation, which could reflect heterogeneity among vesicles or in their medium, is shown to generate the appearance of a regulated refractory neuropeptide pool.