Two cases of femoral nerve palsy after radical prostatectomy

We report two cases of femoral nerve palsy after radical prostatectomy due to compression ascribed to the use of a ring retractor. The first case is in a 69-year-old man who fell when getting out of bed on the first postoperative day. Physical examination revealed hypoesthesia around the patella and weakness of the quadriceps muscle. The second case is in a 66-year-old man who complained of numbness of the anteromedial aspects of the right thigh and inability to extend his right knee on the first postoperative day. Postoperative femoral nerve palsy is not a well-recognized complication in urology. The literature was reviewed and the management of postoperative femoral nerve palsy was discussed.     

In vivo imaging reveals PKA regulation of ERK activity during neutrophil recruitment to inflamed intestines

Many chemical mediators regulate neutrophil recruitment to inflammatory sites. Although the actions of each chemical mediator have been demonstrated with neutrophils in vitro, how such chemical mediators act cooperatively or counteractively in vivo remains largely unknown. Here, by in vivo two-photon excitation microscopy with transgenic mice expressing biosensors based on Förster resonance energy transfer, we time-lapse–imaged the activities of extracellular signal–regulated kinase (ERK) and protein kinase A (PKA) in neutrophils in inflamed intestinal tissue. ERK activity in neutrophils rapidly increased during spreading on the endothelial cells and showed positive correlation with the migration velocity on endothelial cells or in interstitial tissue. Meanwhile, in the neutrophils migrating in the interstitial tissue, high PKA activity correlated negatively with migration velocity. In contradiction to previous in vitro studies that showed ERK activation by prostaglandin E₂ (PGE₂) engagement with prostaglandin receptor EP4, intravenous administration of EP4 agonist activated PKA, inhibited ERK, and suppressed migration of neutrophils. The opposite results were obtained using nonsteroidal antiinflammatory drugs (NSAIDs). Therefore, NSAID-induced enteritis may be caused at least partially by the inhibition of EP4 receptor signaling of neutrophils. Our results demonstrate that ERK positively regulates the neutrophil recruitment cascade by promoting adhesion and migration steps.Once inflammation occurs in tissues, in response to the gradient of chemoattractants such as leukotriene B₄ (LTB₄), IL-8, and formyl-methionyl-leucyl-phenylalanine (fMLP), neutrophils begin to emigrate from inside the venules to the inflammatory sites (Phillipson and Kubes, 2011). Using various in vivo microscopy approaches, it has been demonstrated that the neutrophil recruitment involves four steps: rolling, adhesion, crawling, and transmigration (Borregaard, 2010; Megens et al., 2011; Germain et al., 2012; Sanz and Kubes, 2012; Kolaczkowska and Kubes, 2013). Thereafter, neutrophils that have emigrated into the interstitial tissue migrate toward the inflammatory sites by the gradient of chemoattractants. Most chemoattractant receptors expressed on neutrophils are coupled with the heterotrimeric G_i protein, which inhibits protein kinase A (PKA) and activates p42/44 extracellular signal-regulated kinase (ERK) through both the α and βγ subunits of G_i (Alblas et al., 1993; Howe and Marshall, 1993; Winitz et al., 1993). The G_i-mediated ERK activation is required for adhesion and migration of neutrophils upon the engagement of the chemoattractants with the cognate receptors (Pillinger et al., 1996; Zarbock et al., 2007). However, this model was recently challenged by Liu et al. (2012), who proposed that fMLP-stimulated neutrophil migration is regulated negatively by ERK.Prostaglandins at the inflammatory sites play pleiotropic roles in inflammation (Hata and Breyer, 2004; Narumiya, 2009). For example, prostaglandin E₂ (PGE₂), which is a major cyclooxygenase product in several physiological settings, regulates multiple functions of different immune cells (Ricciotti and FitzGerald, 2011; Kalinski, 2012). The main signal transduction of the four PGE₂-sensitive (EP) receptors, EP1 to EP4, consists of a rise in intracellular cAMP concentration and subsequent PKA activation via G_s in EP2 and EP4, a rise in intracellular free calcium ion concentration in EP1, and a decrease in intracellular cAMP concentration and ERK activation via G_i in EP3 (Narumiya et al., 1999). Further complexity arises from the strength of the coupling to G_s and sensitivity to the metabolic inactivation: Although both EP2 and EP4 receptors couple to G_s, the EP2 receptor transduces signals primarily through PKA, whereas the EP4 receptor primarily utilizes phosphatidylinositol 3-kinase (PI3K) and ERK (Fujino et al., 2003). EP4 signaling is rapidly desensitized after its PGE₂ interaction, whereas EP2 is resistant to ligand-induced desensitization (Nishigaki et al., 1996). Reflecting these differences in molecular properties, EP2 and EP4 are regarded as pro- and antiinflammatory receptors, respectively (Kabashima et al., 2002; Hata and Breyer, 2004).Upon activation of G_s-coupled receptors in many cell types, PKA suppresses ERK mitogen-activated protein kinase (MAPK) via phosphorylation and inhibition of c-Raf, a MAPK kinase (Häfner et al., 1994; Pillinger et al., 1996). In neutrophils, for example, PKA has been shown to suppress respiratory burst by inhibition of the ERK signaling (Bengis-Garber and Gruener, 1996). However, in neuronal cells, an increase in cytoplasmic cAMP can activate ERK in a Rap1-dependent manner (Vossler et al., 1997). Therefore, the regulation of ERK activity by G_s-coupled receptors is dependent on the cell context.In the inflammatory tissues, neutrophils perceive several extracellular signals, which activate or inactivate ERK and PKA. Under this circumstance, it is hardly predictable which signaling pathway will be dominant in neutrophils during the course of inflammation. Although the recent advent of in vivo microscopy has enabled us to visualize the neutrophil recruitment to inflammatory sites (Megens et al., 2011; Germain et al., 2012; Sanz and Kubes, 2012), the activity change of signaling molecules has not been examined because of technical constraints. To overcome this problem, we generated transgenic mice expressing functional Förster resonance energy transfer (FRET) biosensors for ERK and showed that ERK activity correlated with migration velocity in the neutrophils of inflamed subcutaneous tissue (Kamioka et al., 2012). However, we failed to observe extravasation of neutrophils or activity change of PKA because of technical difficulty. Here, in vivo observation of the intestines of the transgenic mice enabled us to examine the role of ERK and PKA in the neutrophil recruitment to the inflammatory sites by two-photon excitation microscopy (2PM). In contradiction to a previous study that showed activation of ERK by EP4 engagement to PGE₂ (Fujino et al., 2003), we show that PGE₂ stimulates PKA in an EP4-dependent manner and suppresses neutrophil migration via down-regulation of ERK in the inflamed intestine.     

Aminopeptidase N is involved in cell motility and angiogenesis: its clinical significance in human colon cancer

BACKGROUND & AIMS: The molecular basis of cell motility is highly complex and is controlled by a number of molecular systems, whereas angiogenesis is an important biological component of tumor progression. The aims of this study were to investigate the possible involvement of proteins at the cell surface in controlling cell motility and angiogenesis, and to identify the cell surface molecules involved in gastrointestinal tumors. METHODS: We addressed these issues using functional monoclonal antibodies, which inhibit cell motility, endothelial cell migration, and tube formation. Furthermore, we investigated the relationship between this antigen and colon cancer, and showed the prognostic significance in human colon cancer. RESULTS: We established a murine monoclonal antibody MH8-11, which inhibits cell motility and in vitro angiogenesis. This epitope was a 165-kilodalton protein, and the sequencing analysis revealed that it was almost identical to aminopeptidase N (APN)/cluster of differentiation (CD) 13. APN/CD13 expression was associated with tumor status (P = 0.025). The disease-free and overall survival rate for patients with positive APN/CD13 expression tumors was significantly lower than that for patients with negative APN/CD13 expression tumors (P = 0.014, 0.033, respectively). Among 47 node-positive patients, the survival rate of patients with negative APN/CD13 expression was better than that of those with positive APN/CD13 expression. CONCLUSIONS: Our data suggest that APN/CD13 is involved in cell motility and angiogenesis, and APN/CD13 expression may be a useful indicator of a poor prognosis for node-positive patients with colon cancer.     

Treatment of Advanced Renal Cell Carcinoma with a Combination of Human Lymphoblastoid Interferon–Alpha and Cimetidine

Human lymphoblastoid interferon (IFN)–alpha was administered intramuscularly at doses of 5 megaunits/day 5 to 7 days a week to 32 advanced renal cell carcinoma patients. To augment the antitumor effect of IFN, cimetidine was also administered orally in doses oi 800 mg/day. This combination therapy resulted in a complete response (CR) in 6 patients (19%), a partial response (PR) in 7 (22%), a stable disease (SD) in 11 (34%), and a progressive disease (PD) in 8 (25%). The response rate (CR+PR) was 41%. The pulmonary metastases were more receptive to IFN therapy than those at other sites. The median times to response were 2 months for PR, and 4.5 months for CR. The survival of the responder patients was significantly longer than the nonresponder patients. These results suggest that IFN–alpha and cimetidine combination therapy may be of use in the management of advanced renal cell carcinoma.     

Recommended Dose of Flutamide with LH-RH Agonist Therapy in Patients with Advanced Prostate Cancer

Background: In a recent study by the Casodex Combination Study Group, USA, patients in a flutamide (750mg/day) plus LH-RH agonist group showed a high treatment failure rate, mainly due to flutamide-induced diarrhea and hepatotoxicity. Our current study was conducted to determine the optimal dose of flutamide for use in this type of Combination therapy.
Methods: In a randomized, multicenter study, 30 patients (hormone untreated; stage C or D) were divided into 2 groups: flutamide 250mg (125mg × 2; 14 patients) and flutamide 375mg (125mg × 3; 16 patients), and each dose combined with either goserelin acetate (3.6 mg every 4 weeks) or leuprolide acetate (3.75 mg every 4 weeks). Goserelin and leuprolide were administered to patients in a 1:1 ratio. Flutamide monotherapy at a daily dose of 375 mg was determined to be the optimal dose in Japan in our previous phase II study. The endpoints of this pilot study were the objective response and adverse events during the 12-week treatment.
Results: The objective response rate was 83.3% in the flutamide 250mg group and 85.7% in the flutamide 375 mg group according to the Japanese response criteria for prostate cancer. Elevated PSA levels fell to within the normal range in 83.3% of the patients in the former group and in 93.3% of the patients in the latter group. One patient administered 250 mg of flutamide experienced diarrhea, while the serum GOT and/or GPT were elevated in 3 patients administered 250 mg of flutamide and 4 patients administered 375 mg of flutamide.
Conclusions: Based on the findings of this pilot study of maximal androgen-depletion therapy for advanced prostate cancer, 375mg/day of flutamide is recommended in combination with an LH-RH agonist. Assessment of the effects of our recommended regimen on longer term survival, quality of life and antiandrogen withdrawal syndrome of patients treated requires additional patients and time for foIIow-up.     

Relationship between Levels of Soluble Interleukin-2 Receptors and the Types and Activity of Vitiligo

Levels of serum-soluble interleukin-2 receptors (serum sIL-2R) are thought to indicate the activation of immunocompetent cells, mainly lymphocytes. Elevated levels of serum sIL-2R have been observed in various infectious and autoimmune diseases and also after organ transplantation. It has been hypothesized that autoimmune mechanisms are involved in the pathogenesis of vitiligo. Therefore, we studied serum sIL-2R levels in relation to disease types and activity of vitiligo. We used sera separated from venous blood samples from 12 patients with dermatomally distributed type B vitiligo, 17 patients with non-dermatomally distributed type A vitiligo during the active stage, 9 patients with type A vitiligo during the inactive stage, and 12 normal control subjects. Serum sIL-2R levels were similar in type B vitiligo patients and the controls but were significantly elevated in patients with active type A vitiligo compared with controls and inactive type A vitiligo patients. It is suggested that the immune system is activated in patients with type A vitiligo during the active stage and that autoimmune mechanisms may play a role only in type A vitiligo.     

Induction of regulatory T cells from mature T cells by allogeneic thymic epithelial cells in vitro

The ability of thymic epithelial cells (TEC) to re‐educate mature T cells to be regulatory T cells has not been addressed. In the present study, this issue was directly investigated by co‐culturing of mature T cells and allo‐TECs. B6 macrophage cell line 1C21‐cultured BALB/c splenocytes responded to B6 antigens in vitro. However, BALB/c splenocytes precultured with B6‐derived TECs 1‐4C18 or 1C6 did not proliferate to B6 antigens, but responded to rat antigens. Exogenous interleukin‐2 (IL‐2) failed to revise the unresponsiveness of these T cells. Allo‐TEC‐cultured T cells predominantly expressed Th2 cytokines (IL‐4 and IL‐10). B6 TEC‐cultured BALB/c splenocytes markedly inhibited the immune responses of naïve BALB/c splenocytes to B6 antigens, but not to rat or the third‐party mouse antigens. BALB/c nude mice that received naïve syngeneic splenocytes rejected B6 or rat skin grafts by 17 days postskin grafting; however, co‐injection of B6 TEC‐cultured BALB/c splenocytes significantly delayed B6 skin graft rejection (P < 0.01), with the unchanged rejection of rat skin grafts. These studies demonstrate that allo‐TECs are able to ‘educate’ mature T cells to be regulatory cells, and suggest that regulatory cells derived from mature T cells by TECs may play an important role in T cell tolerance to allo‐ and auto‐antigens.     

Juvenile temporal arteritis is a manifestation of Kimura disease.

An asymptomatic nodule appeared in the right temporal region of an 81-year-old woman. Histopathologic examination confirmed significant thickening of the vascular wall, constriction of the vessel lumen, and infiltration of numerous eosinophils and lymphocytes. Giant cells were not seen. Lymphoid follicles and capillaries surrounded the large vessel. Elastica van Gieson staining revealed a laceration of the internal elastic lamina. Based on these clinical and histologic findings, the patient was diagnosed as having juvenile temporal arteritis (JTA), a disease first proposed by Lie and his colleagues in 1975. Three years later, a new eruption, again asymptomatic, appeared in the posterior region of the patient's right ear. Subsequently, she was referred to our department. Histologic examination of the new lesion confirmed the infiltration of lymphocytes and eosinophils, which was accompanied by numerous lymphoid follicles, and the proliferation of endothelial cells and capillaries from the deep dermis to the subcutaneous tissue. The patient was diagnosed as having Kimura disease, which is a persistent and recurrent illness. We hypothesized that JTA was a partial expression of Kimura disease and investigated whether past cases of JTA could be considered Kimura disease. As a result, we found that most cases of JTA could indeed be considered Kimura disease. Furthermore, we examined the vascular changes in the routinely and elastic fiber-stained sections of three cases with Kimura disease and two cases with angiolymphoid hyperplasia with eosinophilia. The results showed occlusive vascular changes in most samples from these cases, supporting the hypothesis that JTA is an accessory lesion of Kimura disease.