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Background: The tumor suppressor protein merlin is thought to regulate cell proliferation and cell adhesion through interaction with protein partners. Loss of merlin is associated with Neurofibromatosis Type 2 (NF2) tumors. NHERF1 or EBP50 is a scaffolding protein that functions in apical organization of polarized cells. Merlin and NHERF1 have been shown to interact in vitro in vertebrates. We investigate how the Drosophila NHERF1 orthologue, Sip1, and Merlin function to regulate cell proliferation and adhesion. Results: We identify two conserved arginine residues (R325 and R335) in Merlin which, in addition to the FERM domain, are required for interaction with Sip1. Mutation of the arginine residues result in reduced Sip1 binding to Merlin and loss of Merlin growth suppressor function. Over-expression of MerlinR325A and/or MerlinR335L in Drosophila wings result in increased proliferation in the adult wing (increase in size), which is rescued by co-over-expression of constitutively active Merlin protein. Reduced Sip1 binding to Merlin also produces defects in adhesion in follicle epithelial cells. Conclusions: Sip1 facilitates the activation of Merlin as a tumor suppressor protein. Thus, our work provides insight into how Merlin functions as a tumor suppressor and in adhesion and this provides insight into the mechanism of NF2 pathogenesis. Developmental Dynamics 243:1554–1570, 2014. © 2014 Wiley Periodicals, Inc.

The signalling activities of Merlin and Moesin, two closely related members of the protein 4.1 Ezrin/Radixin/Moesin family, are regulated by conformational changes. These changes are regulated in turn by phosphorylation. The same sterile 20 kinase-Slik co-regulates Merlin or Moesin activity whereby phosphorylation inactivates Merlin, but activates Moesin. Thus, the corresponding coordinate activation of Merlin and inactivation of Moesin would require coordinated phosphatase activity. We find that Drosophila melanogaster protein phosphatase type 1 β (flapwing) fulfils this role, co-regulating dephosphorylation and altered activity of both Merlin and Moesin. Merlin or Moesin are detected in a complex with Flapwing both in-vitro and in-vivo. Directed changes in flapwing expression result in altered phosphorylation of both Merlin and Moesin. These changes in the levels of Merlin and Moesin phosphorylation following reduction of flapwing expression are associated with concomitant defects in epithelial integrity and increase in apoptosis in developing tissues such as wing imaginal discs. Functionally, the defects can be partially recapitulated by over expression of proteins that mimic constitutively phosphorylated or unphosphorylated Merlin or Moesin. Our results suggest that changes in the phosphorylation levels of Merlin and Moesin lead to changes in epithelial organization.

The first carpometacarpal (CMC) joint, also referred to as trapeziometacarpal joint, is the area of the hand most commonly symptomatic of osteoarthritis. Although there are a variety of surgical techniques that treat this condition, this article focuses on the technical aspects of arthroscopic hemitrapeziectomy with tendon interposition. Furthermore, this study evaluated the use of arthroscopy to treat CMC arthritis, with the expectation that an arthroscopic procedure would lead to low morbidity, quick recovery of function, rapid resolution of pain, and satisfactory results in patients' strength, range of motion, and pain relief. Early outcomes data indicate that all patients experienced statistically significant improvement in their pain scale rating at a mean of 11 months after the operation. All patients were satisfied with the outcome of their surgery. All patients would choose to have this surgery again. This study supports arthroscopic hemitrapeziectomy with tendon interposition as a safe and effective treatment for CMC arthritis.

Male sexual dysfunction can be classified in the following categories: erectile dysfunction (ED); orgasmic and ejaculatory dysfunction; priapism; and decreased libido. Of these various dysfunctions, more patients with ED are likely to seek medical attention. ED, or impotence, is defined as the inability to achieve or maintain an erection sufficient for satisfactory sexual function1. In recent years, there has been an escalated awareness of ED, partly attributed to the advent of ViagraTM and its associated promotion. The impact of ED can be appreciated by the estimation that its prevalence in men 40 to 70 years old is 52%, based on the Massachusetts Male Aging Study.2 Based on these data and United States population projections for the year 2005 of more than 50 million men 40 to 70 years old, ED will affect more than 25 million men, and millions more over the age of 70. The projected worldwide prevalence of ED for year 2025 will be staggering at 322 million men. Certain patients are found to have a significantly higher prevalence of ED; for example, diabetic men command a more than threefold increase in risk of ED than their nondiabetic counterparts. Indeed, diabetes mellitus is the single most common cause of ED.2 More than 50% of diabetic patients are afflicted with some degree of ED, and approximately 50% of the patients evaluated at our Center for Male Sexual Dysfunction are diabetic.

Objectives To perform a comparison to determine which of two methods of partial urethral ligation produces the most consistent outcome and fewest side effects. Such a study has not been previously reported. Partial urethral ligation is a means of causing reproducible bladder outlet obstruction. In the male rat model, partial urethral obstruction can be performed either by perineal incision and bulbous urethral ligation or retropubic incision and midprostatic obstruction. Methods Fifteen male Sprague-Dawley rats were studied. Five were selected for bulbous urethral obstruction through a perineal incision, five for midprostatic obstruction using a retropubic approach, and five for a sham operation through a perineal incision. Results The operative time was shorter and morbidity lower with the perineal approach compared with the retropubic approach. Inflammation or infection, or both, were seen in the prostate, bladder, proximal urethra, ureters, and kidneys in the rats in which a midprostatic obstruction was performed. The proximal urethra and prostate were mildly inflamed in those rats that underwent bulbous obstruction. Sham-operated rats exhibited mild prostatitis only. Conclusions The perineal approach to the bulbous urethra is the method of choice for creating a partial urethral obstruction model of bladder outlet obstruction in the male rat.

Radical perineal prostatectomy was historically the surgical treatment of choice for localized adenocarcinoma of the prostate until the 1980s when radical retropubic prostatectomy began to gain popularity. Nevertheless, the perineal approach possesses advantages that prompt resurgence in the interest of this classic operation. We review the relevant anatomy and our modified technique of performing a successful radical perineal prostatectomy.The English literature pertaining to the different surgical approaches to radical perineal prostatectomy was reviewed through PubMed. Attention was paid to its indications, anatomical significance and various surgical techniques.Studies demonstrate no difference in the incidence of positive surgical margins and biochemical recurrence between radical retropubic and perineal prostatectomies. Furthermore, the perineal approach avoids the dorsal venous complex and better facilitates the vesicourethral anastomosis in the face of minimal pain and requirement for transfusion. We use a modified Belt approach, aiming to yield the most optimal outcome with minimal morbidity. A meticulous anatomical approach is warranted if complications such as rectal injury, incontinence and erectile dysfunction are to be minimized.With careful preoperative evaluation, selected patients should benefit from radical perineal prostatectomy for the management of localized prostate cancer. Familiarity with this specialized technique should be an immeasurable addition to any armamentarium in the therapy of prostatic diseases.

Renal cell carcinoma is increasingly being diagnosed at an earlier stage owing to medical advances. Since the pathologic stage is the most crucial predictor of patient outcome, an accurate and universal tumor staging system is of outmost importance. The TNM staging system, after multiple revisions, has evolved into a more precise system that correlates with cancer specific survival. Renal cell carcinoma staging systems have important clinical implications pertaining to nephron sparing surgery and the need for adrenalectomy or lymphadenectomy.

The tumor suppressor protein merlin is thought to regulate cell proliferation and cell adhesion through interaction with protein partners. Loss of merlin is associated with Neurofibromatosis Type 2 (NF2) tumors. NHERF1 or EBP50 is a scaffolding protein that functions in apical organization of polarized cells. Merlin and NHERF1 have been shown to interact in vitro in vertebrates. We investigate how the Drosophila NHERF1 orthologue, Sip1, and Merlin function to regulate cell proliferation and adhesion.We identify two conserved arginine residues (R325 and R335) in Merlin which, in addition to the FERM domain, are required for interaction with Sip1. Mutation of the arginine residues result in reduced Sip1 binding to Merlin and loss of Merlin growth suppressor function. Over-expression of Merlin(R325A) and/or Merlin(R335L) in Drosophila wings result in increased proliferation in the adult wing (increase in size), which is rescued by co-over-expression of constitutively active Merlin protein. Reduced Sip1 binding to Merlin also produces defects in adhesion in follicle epithelial cells.Sip1 facilitates the activation of Merlin as a tumor suppressor protein. Thus, our work provides insight into how Merlin functions as a tumor suppressor and in adhesion and this provides insight into the mechanism of NF2 pathogenesis.

MPP+ has been reported to inhibit reduced nicotinamide adenine dinucleotide (NADH) dehydrogenase in mitochondria, which results in the formation of O2(.-). The current report demonstrates that H2O2 and HO. are also products of MPP+ interaction with NADH dehydrogenase. It is possible that MPP. formation precedes the formation of some of these active oxygen species. Reducing equivalents for radical formation come from NADH. MPP+ may be capable of interacting with submitochondrial particles at a site other than the rotenone site, which results in some formation of oxygen radicals. Plasma amine oxidase incubations with MPDP+ resulted in O2.- H2O2, and perhaps HO. formation. This is probably due to MPP. formation from the oxidation of MPDP+. This study presents new findings that indicate the potential importance of oxygen radical formation in mitochondria during MPTP toxicity.

Until recently, erectile dysfunction (ED) was treated by either sexual counseling or penile prosthesis implantation. The advent of intracavernous and transurethral agents has expanded the number of therapeutic options available to ED patients. Furthermore, the approval of oral sildenafil for the treatment of ED in 1998 has prompted an increased awareness of the disease process. With ED now amenable to pharmacologic solutions, research is continuously underway to elucidate the mechanisms underlying the pathophysiologic basis of ED. The hemodynamic changes associated with each erectile event require the integrity of the penile vasculature and neural pathways. Studies that scrutinize the pathophysiology of ED have revealed various modulators or agents that may play a significant role in penile erection. These agents have been demonstrated to mediate their effects through modulation with gap junctions and potassium channels. These findings are facilitated through studies on animal models, specifically aged and diabetes-induced rats. There also appears to be a central control of the cardiac, respiratory, and penile functions that ultimately effects penile tumescence via an intricate cascade of coordinated events. With investigators striving to shed light on the pathophysiologic process of ED, the future does look bright for ED patients as more therapeutic agents, such as new oral agents and gene therapy, are on the horizon.

Leydig cell tumors of the testis are the underlying cause in about 10% of the cases of precocious puberty in boys. Leydig cell hyperplasia is a less well-characterized cause, with an undocumented frequency. We describe a boy with precocious puberty associated with ipsilateral testicular enlargement and focal Leydig cell hyperplasia with spermatogenesis limited to the local adjacent testicular tissue.