Hyperpolarization-Activated Cyclic Nucleotide-Gated Non-selective (HCN) Ion Channels Regulate Human and Murine Urinary Bladder Contractility

Purpose: Hyperpolarization-activated cyclic nucleotide gated non-selective (HCN) channels have been demonstrated in the urinary bladder in various species. Since they play a major role in governing rhythmic activity in pacemaker cells like in the sinoatrial node, we explored the role of these channels in human and murine detrusor smooth muscle.Methods: In an organ bath, human and murine detrusor smooth muscle specimens were challenged with the HCN channel blocker ZD7288. In human tissue derived from macroscopically tumor-free cancer resections, the urothelium was removed. In addition, HCN1-deficient mice were used to identify the contribution of this particular isoform. Expression of HCN channels in the urinary bladder was analyzed using histological and ultrastructural analyses as well as quantitative reverse transcriptase polymerase chain reaction (RT-PCR).Results: We found that the HCN channel blocker ZD7288 (50 μM) both induced tonic contractions and increased phasic contraction amplitudes in human and murine detrusor specimens. While these responses were not sensitive to tetrodotoxin, they were significantly reduced by the gap junction inhibitor 18β-glycyrrhetic acid suggesting that HCN channels are located within the gap junction-interconnected smooth muscle cell network rather than on efferent nerve fibers. Immunohistochemistry suggested HCN channel expression on smooth muscle tissue, and immunoelectron microscopy confirmed the scattered presence of HCN2 on smooth muscle cell membranes. HCN channels seem to be down-regulated with aging, which is paralleled by an increasing effect of ZD7288 in aging detrusor tissue. Importantly, the anticonvulsant and HCN channel activator lamotrigine relaxed the detrusor which could be reversed by ZD7288.Conclusion: These findings demonstrate that HCN channels are functionally present and localized on smooth muscle cells of the urinary bladder. Given the age-dependent decline of these channels in humans, activation of HCN channels by compounds such as lamotrigine opens up the opportunity to combat detrusor hyperactivity in the elderly by drugs already approved for epilepsy

Las indicaciones quirúrgicas en el tratamiento de las complicaciones de la úlcera péptica gástrica y duodenal

In this paper we shall deal only with the surgical indications in the treatment of complications of peptic ulcer disease, gastric and duodenal. First, we state that the ulcer is a very common disease, and whose primary treatment should be medical, but its complications should be treated surgically. The incidence of this condition is such that, in reality, is of serious character, and sin not exaggerated if we place between social conditions and the mechanization century.En el presente trabajo nos ocuparemos solamente de las indicaciones quirúrgicas en el tratamiento de las complicaciones de la úlcera péptica, gástrica y duodenal. Antes que nada, enunciemos que el ulcus es una enfermedad muy frecuente, y cuyo tratamiento fundamental debe ser médico, solamente sus complicaciones deberán ser tratadas quirúrgicamente. La incidencia de esta afección es tal, que, en realidad, reviste caracteres serios, y no pecamos de exagerados si la colocamos entre las enfermedades sociales y del siglo del maquinismo

Molecular Research in Penile Cancer—Lessons Learned from the Past and Bright Horizons of the Future?

Penile cancer is a rare tumor. There is a limited understanding of the biological mediators of prognostic and therapeutic importance in penile cancer. However, there exists some fundamental understanding of the major pathways involved in the development of penile pre-neoplastic lesions and neoplasms. The aim of the present review is to highlight our current state of molecular knowledge in penile cancer to foster the necessary tools for researchers to pave major advancements in our current treatment paradigms and cancer specific outcomes

Chemotherapy in penile cancer

Penile cancer is an aggressive disease and after systemic progression it is virtually incurable. While this squamous cell cancer responds to chemotherapy, successful treatment of lymphatic metastases can only be achieved with aggressive surgical treatment in combination with chemotherapy. However, because penile carcinoma is relatively rare there is a paucity of clinical data on the chemotherapy for this aggressive disease. Recent advances have included the establishment of less toxic regimens incorporating taxanes, while cisplatinum remains central to all regimens. Multi-institutional studies are urgently needed to advance the multimodal care for patients with penile cancer

International case series of metastasis to penis

Abstract Objectives To evaluate clinical characteristics associated with survival in patients with metastases to the penis. Methods After approval by the IRB, records of collaborating centres in Leuven, London, Rostock, Amsterdam and Tampa were screened for men presenting with metastatic disease to penis. Multivariate logistic regression analyses were used to identify covariables associated with survival. We analysed clinical data on 34 patients. Results Primary sites were most frequently prostate (n = 14, 41%) and bladder (n = 9, 26%). Twenty‐eight of 34 (82%) presented with metachronous penile metastases, and 11 (32%) patients had penile metastases as the sole metastatic site. Penile metastatic locations were most frequently in the corpora (n = 18; 53%). Seven (21%) patients with penile metastases had priapism on presentation. Systemic therapy was frequent and variable (chemotherapy n = 12; immunotherapy n = 5; hormones n = 3). Local management included either surgery (n = 10) or RT (n = 8). Twelve‐ and 24‐month overall survival rate were 67% and 35%, respectively. No clinical parameter including primary histology, synchronous or metachronous metastases or priapism showed statistical survival benefit or detriment. Conclusion Metastasis to penis arises most frequently from pelvic primaries. Priapism does not appear to correlate with survival in this large, well‐defined series