Hemodynamic effects of KRN2391 (potassium channel opener) in halothane-anesthetized dogs

The cardiovascular responses to an infusion of KRN2391, a potassium channel opener, was studied in halothane-anesthetized dogs. Intravenous administration of KRN2391 at 1.0 and 5.0 μg·kg⁻¹·min⁻¹ for 60 min produced dose-dependent decreases in mean arterial pressure (MAP) and systemic vascular resistance (SVR) associated with dose-dependent increases in the cardiac index (CI) and stroke volume index (SVI) but was not accompanied by an increase in heart rate (HR). The maximum decrease in MAP during the infusion of KRN2391 at 1.0 and 5.0 μg·kg⁻¹·min⁻¹ was −13±7% (P<0.01) and −37±10% (P<0.01), respectively. The maximum reduction in SVR after 1.0 and 5.0 μg·kg⁻¹·min⁻¹ was −20±11% (P<0.01) and −60±16% (P<0.01), respectively. A KRN2391 infusion of 1.0 and 5.0 μg·kg⁻¹·min⁻¹ increased Cl a maximum of 11±13% (P<0.05) and 65±33% (P<0.01), respectively. KRN2391 1.0 μg·kg⁻¹·min⁻¹ showed a tendency to increase SVI but this change was not significant, KRN2391 5.0 μg·kg⁻¹·min⁻¹, however, produced a significant increase in SVI. The present results demonstrate that the decrease in MAP and the increases in CI and SVI caused by KRN2391 are due to a reduction in the afterload. Therefore, we conclude that these cardiovascular profiles of KRN2391 may be benificial in perioperative uses including the control of systemic blood pressure and the treatment of hypertension during halothane anesthesia in clinical practice.     

Resolvin E1 inhibits dendritic cell migration in the skin and attenuates contact hypersensitivity responses

Resolvin E1 (RvE1) is a lipid mediator derived from ω3 polyunsaturated fatty acids that exerts potent antiinflammatory roles in several murine models. The antiinflammatory mechanism of RvE1 in acquired immune responses has been attributed to attenuation of cytokine production by dendritic cells (DCs). In this study, we newly investigated the effect of RvE1 on DC motility using two-photon microscopy in a contact hypersensitivity (CHS) model and found that RvE1 impaired DC motility in the skin. In addition, RvE1 attenuated T cell priming in the draining lymph nodes and effector T cell activation in the skin, which led to the reduced skin inflammation in CHS. In contrast, leukotriene B4 (LTB4) induced actin filament reorganization in DCs and increased DC motility by activating Cdc42 and Rac1 via BLT1, which was abrogated by RvE1. Collectively, our results suggest that RvE1 attenuates cutaneous acquired immune responses by inhibiting cutaneous DC motility, possibly through LTB4-BLT1 signaling blockade.Following the well-known epidemiological study conducted in Northwest Greenland in the 1970s (Dyerberg et al., 1978), several clinical assessments have indicated that a diet rich in ω3 polyunsaturated fatty acids (PUFAs) has beneficial effects in various inflammatory diseases, including asthma, psoriasis, inflammatory bowel diseases, and rheumatoid arthritis (Horrobin, 1987). Although it remains unclear how ω3 PUFAs exert such antiinflammatory effects, recent studies have identified several derivatives of ω3 PUFAs that possess strong antiinflammatory effects (Serhan et al., 2008; Tull et al., 2009). Resolvin E1 (RvE1) is one such antiinflammatory lipid mediator.RvE1 is known to exert its actions through two receptors, BLT1 and ChemR23 (Arita et al., 2007). RvE1 binds to BLT1, a G protein–coupled receptor for leukotriene B4 (LTB4), and inhibits BLT1 signals (Arita et al., 2007). In addition, RvE1 exhibits an agonistic activity toward ChemR23 (Arita et al., 2007), a G protein–coupled receptor for chemerin. The antiinflammatory effects of RvE1 have been demonstrated in acute innate immune inflammation, such as peritonitis (Arita et al., 2007) and colitis (Arita et al., 2005b). In these models, RvE1 exerted its antiinflammatory effects by inhibiting neutrophil infiltration into the inflammatory foci through a blockade of LTB4-BLT1 signaling in neutrophils (Haas-Stapleton et al., 2007). In contrast, few studies have been conducted on the effect of RvE1 on acquired immune responses, in which DCs and T cells play major roles in the development. In these studies, the attenuated cytokine production, such as IL-12 and IL-23, from DCs is considered as the major mechanism by which RvE1 exerts the antiinflammatory effects (Arita et al., 2005a; Haworth et al., 2008). However, the effect of RvE1 on DC motility has not been investigated in the context of acquired immunity.In the peripheral tissues such as the skin, DCs migrate in an amoeboid movement that requires actin polymerization via activation of the Rho family of small GTPases, such as Cdc42, Rac, and Rho A (Lämmermann and Germain, 2014). In acquired immunity such as contact hypersensitivity (CHS), upon uptake of foreign antigens, DCs migrate to the draining LNs (dLNs) via lymphatic vessels to establish sensitization by inducing the antigen-specific T cell differentiation (Honda et al., 2013). In elicitation, DC migration to form DC–T cell clustering is required for efficient antigen presentation in situ (Natsuaki et al., 2014). Thus, active DC motility is an essential factor for acquired immunity.In this study, we investigated the effects and underlying mechanisms of RvE1 on DC motility using a CHS model, which is a prototype of delayed-type hypersensitivity in the skin mediated by IFN-γ (Mori et al., 2008; Honda et al., 2013). RvE1 inhibited cutaneous DC migration into the dLNs and suppressed antigen-specific T cell induction in the sensitization phase. In addition, live imaging analysis revealed that RvE1 inhibited cutaneous DC motility and cluster formation in the skin, which subsequently attenuated activation of effector T cells in the skin in the elicitation phase of CHS. Intriguingly, LTB4 induced actin filament reorganization in DCs and increased DC motility by activating Cdc42 and Rac1 via BLT1, which was abrogated by RvE1. These results suggest that RvE1 exerts its antiinflammatory effects in cutaneous acquired immunity by inhibiting DC motility, possibly through an LTB4-BLT1 signaling blockade.     

Clinical features and pathophysiological mechanism of the hemianoptic complication after the occipital transtentorial approach

Objective

To obtain detailed insight into neuro-ophthalmological characteristics and pathophysiology of hemianoptic complications after occipital transtentorial surgery.

Methods

We reviewed the cases of 14 patients surgically treated by the occipital transtentorial approach. Treated lesions included 6 posterior third ventricle tumors, including pineal and tectal lesions, 3 falco-tentorial meningiomas, and 5 superior cerebellar lesions. The surgeries were performed by the unilateral occipital transtentorial approach with patients in the prone position.

Results

Visual functions were preoperatively normal in all patients. After surgery, 11 patients (79%) showed hemianoptic complications detected by a confrontation test in the immediate postoperative period. The condition began to improve in the early postoperative days. The visual field recovered completely in 6 patients within 10 days, 2 patients recovered within 3 months, and 3 patients complained of permanent visual field defects. Optometric neuro-ophthalmic evaluation in the early postoperative period failed to detect complete homonymous hemianopsia, but homonymous inferior quadrantanopia and scotomatous defects were observed in 6 patients. These visual field defects were permanent in 3 patients. Postoperative MRI showed no morphological abnormality except these three patients. Atrophic change of the occipital lobe with preservation of striate cortex was associated with persistent visual field defects in two patients. Cerebral blood flow evaluation by single photon emission computed tomography suggested that temporary local hyperperfusion of the retracted occipital region when visual field defect was present.

Conclusion

Hemianoptic visual field defects can recover via inferior quadrantanopia or scotomatous defect. All of these defects are attributable to injury to the optic radiation as well to the occipital lobe. Hyperperfusion of the retracted occipital region may underlie the pathophysiology of hemianoptic complications after the occipital transtentorial approach.     

Enhanced Apoptosis in Pilocytic Astrocytoma: A Comparative Study of Apoptosis and Proliferation in Astrocytic Tumors

Both cell proliferation and cell death occur simultaneously in tumor tissue, and extent of tumor growth reflects the net balance of these events. We correlated cell proliferation, spontaneous cell death, and alterations in tumor suppressor proteins with one another and with survival of patients with primary astrocytic tumors. In 39 astrocytic tumor specimens (6 pilocytic astrocytomas, 14 fibrillary astrocytomas, 9 anaplastic astrocytomas, and 10 glioblastomas), we determined the MIB-1 labeling index, the apoptotic ratio according to nick end labeling with morphologic confirmation, the p53 labeling index, and the presence of p53 or PTEN mutations.MIB-1 labeling indices of pilocytic astrocytomas, fibrillary astrocytomas, anaplastic astrocytomas, and glioblastomas were 0.30±0.32; 1.84±1.87; 19.3±6.42; and 28.0±14.5 (mean±SD), respectively. Corresponding apoptotic ratios were 17.9±5.16; 3.96±3.57; 1.18±0.93; and 2.11± 1.60 (mean±SD). The apoptotic ratio in pilocytic astrocytomas was significantly higher than in other astrocytic tumors (fibrillary astrocytomas, p<0.05; anaplastic astrocytomas and glioblastomas, p<0.01). MIB-1 showed a significant negative correlation with apoptosis (p<0.01). MIB-1 and apoptosis showed significant negative and positive correlations with patient survival (p<0.01). Mutations of p53 and PTEN show no correlation with survival and apoptotic ratio.The apoptotic ratio can clearly distinguish pilocytic astrocytomas from other tumors, and this biological feature may reflect less aggressive growth of pilocytic astrocytomas.     

Survival results of neoadjuvant chemotherapy for advanced squamous cell carcinoma of the head and neck

BACKGROUND: We carried out an open, randomized multi-center clinical trial for advanced head and neck cancer between April 1991 and December 1992. In this report, we update the results and analyze the 5-year survival results. METHODS: Thirty-two patients with previously untreated stage III and IV resectable squamous cell carcinoma of the oral cavity and pharynx were entered into the study. The PEM regimen consisted of cisplatin 60 mg/m2 2 h infusion on day 1, etoposide 40 mg/m2 1 h infusion on days 1, 2 and 3 and mitomycin-C 7 mg/m2 i.v. bolus on day 1. RESULTS: Among the 32 patients entered into this trial, eight were disqualified from the analysis. Of the remaining 24 patients, 13 were given neoadjuvant chemotherapy (NAC) and 11 underwent surgery alone. Among the 13 patients who received NAC, four achieved a complete response (31%) and three a partial response (23%), with an overall response rate of 54%. Myelosuppression was a major side effect. Thrombocytopenia and anemia were dose-limiting toxicities. Other adverse reactions, including mucositis, were all mild and transient. The overall 5-year survival after NAC and without NAC were 83 and 62%, respectively. The survival difference was not statistically significant (p = 0.33). CONCLUSIONS: NAC does not appear to play a role in the treatment of cancer of the oral cavity and pharynx with our PEM regimen. However, the degree of toxicity was limited in our trial and therefore attempts to increase the dosage and/or revise the administration schedule for cancer of the pharynx and T1 to T3 tumor disease appear warranted.