Reactive oxygen species (ROS) produced by tumor necrosis factor-a (TNF-a) have an important function in cell death by activating c-Jun N-terminal kinase. However, the exact mechanism of mitochondrial ROS production, after TNF-a stimulation, is not clearly understood. In this study, we determined that ROS modulator 1 (Romo1) and B-cell lymphoma-extra large (Bcl-X L ) are directly associated with TNF-a-induced ROS production. In response to TNF-a, TNF complex II, which consists of receptorinteracting protein 1, TNF receptor-associated protein with death domain, TNF receptor-associated factor 2, Fas-associated death domain protein, and pro-caspase-8, binds to the C-terminus of Romo1 located in the mitochondria. Concurrently, Romo1 recruits Bcl-X L to reduce the mitochondrial membrane potential, resulting in ROS production and apoptotic cell death. On the basis of these results, we suggest that Romo1 is a molecular bridge between TNF-a signaling and the mitochondria for ROS production that triggers TNF-a-mediated apoptosis, as well as a novel target in the development of anti-inflammatory agents that block the origin of ROS production. Tumor necrosis factor-a (TNF-a) is a major mediator of inflammation. There are two main pathways in TNF-a signaling. One is the pro-survival/pro-inflammatory pathway that activates NF-kB and MAPK through TNF-a-induced signaling complex I. 1 After binding of the trimeric TNF-a to the cell surface receptor TNF-R1, the silencer of death domain dissociates from TNF-R1 complexes, and the TNF receptor-associated protein with death domain (TRADD) -an adaptor protein -binds to the cytoplasmic domain of the receptor. 2 TRADD recruits additional proteins including TNF receptor-associated factor 2 (TRAF2), receptor-interacting protein 1 (RIP1), and cellular inhibitor of apoptosis proteins to form TNF-a-induced signaling complex I. 3,4 The other TNF-a signaling pathway is the proapoptotic pathway through TNF-ainduced signaling complex II, in which reactive oxygen species (ROS), a caspase cascade, and the mitochondria function as downstream mediators. If TRADD, TRAF2, and RIP1 dissociate from the receptor, they recruit Fas-associated death domain protein (FADD) and pro-caspase-8 to form TNF-a-induced signaling complex II, which is implicated in signaling apoptosis. 5,6 This TNF-a-induced cell death pathway is normally blocked by concomitant activation of NF-kB.ROS generation, after TNF-a binding, has been reported to be involved in both cell survival and cell death, and the main source of ROS generation that contributes to TNF-a-induced cell death is the mitochondrion. 7-9 However, another study reported that NADPH oxidase is the source of ROS generation after TNF-a treatment. 10 ROS are known to contribute to cell death by inducing mitochondrial membrane permeabilization and sustaining c-Jun N-terminal kinase (JNK) activation. 11,12 JNK is activated by the activation of apoptosis signal-regulating kinase-1 or by ROS-mediated inactivation of MKPs. 13,14 There are several reports regarding the mech...

The main limitation of medical treatment for premature ejaculation is recurrence after withdrawal of medication. We evaluated the effect of glans penis augmentation using injectable hyaluronic acid (HA) gel for the treatment of premature ejaculation via blocking accessibility of tactile stimuli to nerve receptors. In 139 patients of premature ejaculation, dorsal neurectomy (Group I, n ¼ 25), dorsal neurectomy with glandular augmentation (Group II, n ¼ 49) and glandular augmentation (Group III, n ¼ 65) were carried out, respectively. Two branches of dorsal nerve preserving that of midline were cut at 2 cm proximal to coronal sulcus. For glandular augmentation, 2 cc of HA was injected into the glans penis, subcutaneously. At 6 months after each procedure, changes of glandular circumference were measured by tapeline in Groups II and III. In each groups, ejaculation time, patient's satisfaction and partner's satisfaction were also assessed. There was no significant difference in preoperative ejaculation time among three groups. Preoperative ejaculation times were 89.2740.29, 101.54759.42 and 96.5752.32 s in Groups I, II and III, respectively. Postoperative ejaculation times were significantly increased to 235.6758.6, 324.247107.58 and 281.9793.2 s in Groups I, II and III, respectively (Po0.01). The percentage of postoperative satisfaction in both patient and his partner was 68% (17/25) and 44% (7/16) in Group I, 80% (39/49) and 66% (25/38) in Group II and 75% (49/65) and 62% (32/52) in Group III, respectively. Maximal glandular girth was significantly increased from 9.1670.59 to 10.9570.4 cm in Group II and 8.9570.54 to 11.6770.71 cm in Group III, respectively. These results suggest that glandular augmentation with injectable HA gel is a safe and effective modality to reduce sensory of glans penis. Long-term follow-up for residual volume and efficacy should be requested to establish its precise therapeutic potentials in premature ejaculation.

The authors created the glans penis augmentation by injectable hyaluronic acid gel and reported the 6-month result for premature ejaculation. In a total of 38 patients, long-term effects of 5 years were compared to those of 6 months in terms of residual volume of implants and efficacy on premature ejaculation. Maximal glandular circumference measured by tapeline significantly decreased by 15% (Po0.05) but mean patient's visual estimation (Gr 0-Gr 4) did not decrease (3.60 vs 3.56, P40.05). Compared to 6-month follow-up, intravaginal ejaculatory latency time and vibratory threshold decreased at 5 years (Po0.05), but still well increased considering those of preaugmentation. Hence, 76% of patients and 63% of partners were still satisfied. There was no serious adverse reaction. In the 5-year long-term follow-up of glans penis augmentation by filler, the implants were well maintained and effective for glans penis hypersensitivity in premature ejaculation patients.

Although augmentation phalloplasty is not an established procedure, some patients still need enlargement of their penis. Current penile augmentation is girth enhancement of penile body by dermofat graft. We performed this study to identify the efficacy and the patient's satisfaction of human glans penis augmentation with injectable hyaluronic acid gel. In 100 patients of subjective small penis (Group I) and 87 patients of small glans after dermofat graft (Group II), 2 cm 3 of hyaluronic acid gel was injected into the glans penis, subcutaneously. At 1 y after injection, changes of glandular diameter were measured by tapeline. Patient's visual estimation of glandular size (Gr 0-4) and patient's satisfaction (Grade (Gr) 0-4) were evaluated, respectively. Any adverse reactions were also evaluated. The mean age of patients was 42.2 (30-70) y in Group I and 42.13 (28-61) y in Group II. The maximal glandular circumference was significantly increased compared to basal circumference of 9.13 7 0.64 cm in Group I (Po0.01) and 9.49 7 1.05 cm in Group II (Po0.01) at 1 y after injection. Net increase of maximal glandular circumference after glans augmentation was 14.93 7 0.80 mm in Group I and 14.78 7 0.89 mm in Group II. In patient's visual estimation, more than 50% of injected volume was maintained in 95% of Group 1 and 100% of Group II. The percentage of postoperative satisfaction (Gr 4, 5) was 77% in Group 1 and 69% in Group II. There was no abnormal reaction in area feeling, texture, and color. In most cases, initial discoloration by glandular swelling recovered to normal within 2 weeks. There were no signs of inflammation and no serious adverse reactions in all cases. These results suggest that injectable hyaluronic acid gel is a safe and effective material for augmentation of glans penis.

Recently, injectable hyaluronic acid gel has been widely used in soft-tissue augmentation. We performed this study to identify the feasibility of hyaluronic acid gel for the augmentation of the glans penis. In experiment I, 0.2 cm 3 of hyaluronic acid gel (HA) was injected into the dermis of the glans penis of 25 New Zealand white rabbits via a 30 G needle. At 3, 7, 14, 30, and 90 days after injection, histological changes of glans were studied, respectively. In experiment II, 0.5 cm 3 of HA was injected into the dermis of the glans penis of 14 Beagle dogs via a 27 G needle. At 6 months after injection, histological changes of the glans penis were also evaluated. At the time of autopsy, the lung, liver, and spleen were studied for systemic adverse reaction in each separate experiment. In experiment I, various sized cavities filled with amorphous basophilic materials were noted in the lamina propria and corpus spongiosum of the glans penis. All implants were positively stained on alcian blue. The intensity decreased in a time-dependent manner. Until 14 days, minimal inflammatory reactions were noted, but no signs of inflammation were identified at 90 days. With the gradual decrease of inflammation, fibrosis and deposition of collagen were noted. In experiment II, implants were well maintained at 6 months after injection in the lamina propria. Grade 1 of the inflammatory reaction was noted in one case. In both the experiments, all the specimens were free from any foreign body reaction and systemic adverse reactions. In conclusion, these results suggest that hyaluronic acid gel can be easily injected into the lamina propria of the glans penis and reside until 6 months. Injectable hyaluronic acid gel has a potential as a new bioimplant for the augmentation of the glans penis.