Long-term social isolation enhances picrotoxin seizure susceptibility in mice: up-regulatory role of endogenous brain allopregnanolone in GABAergic systems

Allopregnanolone (ALLO, 3alpha,5alpha-tetrahydroprogesterone), a positive allosteric modulator of actions of gamma-aminobutyric acid GABA) at GABA(A) receptors, is synthesized in the brain from progesterone by the sequential action of two enzymes: a type I 5alpha-reductase and a 3alpha-hydroxysteroid oxidoreductase. We previously demonstrated that long-term social isolation of mice caused a significant decrease in brain ALLO content via suppression of type I 5alpha-reductase and its mRNA expression. In this study, to clarify a physiological role of endogenous brain ALLO, we investigated changes in seizure susceptibility of mice following protracted social isolation and compared with those of mice treated with SKF105111 (SKF), an inhibitor of types I and II 5alpha-reductase. Social isolation of mice for 7 weeks prior to the experiments caused a significant increase of seizure susceptibility to the GABA(A) receptor antagonist picrotoxin but not to the glycine receptor antagonist strychnine or the glutamate receptor agonist kainic acid. The change in the seizure susceptibility was completely reversed by 2.5 mg/kg ip ALLO, a dose that per se had no effect on picrotoxin-induced seizure. Treatment of mice with SKF (20 mg/kg ip) also reduced a threshold dose of picrotoxin, but not that of strychnine or kainic acid, which was required to elicit seizure in group-housed mice. The effect of SKF was attenuated by ALLO (2.5 mg/kg ip). In contrast, SKF treatment had no effect on picrotoxin-induced seizure in socially isolated mice. These findings suggest that endogenous brain ALLO plays a suppressive role in seizure susceptibility via a positive modulation of GABA(A) receptor function and that social isolation enhances seizure susceptibility in mice via reduction of GABA(A) receptor function caused by a decrease of endogenous ALLO.     

Effect of overproduction of nitric oxide in the brain stem on the cardiovascular response in conscious rats

To examine the role of nitric oxide in the brain stem on cardiovascular response in vivo, we have developed and applied a technique of endothelial nitric oxide synthase gene transfer into the nucleus tractus solitarii or the rostral ventrolateral medulla of rats in vivo. The blood pressure and heart rate were monitored using a radiotelemetry system in the conscious state. As a marker of sympathetic nerve activity, we measured 24-h urinary norepinephrine excretion. We found that overexpression of endothelial nitric oxide synthase in the nucleus tractus solitarii as well as in the rostral ventrolateral medulla causes hypotension and bradycardia via a decrease in sympathetic nerve activity. Furthermore, in the case of the local increases in nitric oxide in the rostral ventrolateral medulla, we suggest that this effect is mediated by an increase in gamma-aminobutyric acid. Moreover, in the stroke-prone spontaneously hypertensive rat, the increase in nitric oxide production evoked by the overexpression of endothelial nitric oxide synthase in the rostral ventrolateral medulla caused greater depressor and sympatho-inhibitory responses than in normotensive Wistar-Kyoto rats, suggesting that an abnormality of the L-arginine-nitric oxide pathway may be involved in the central mechanisms of hypertension in this model.     

IL-6 and Crohn's disease

Interleukin-6 (IL-6) is a pleiotropic cytokine with central roles in immune regulation, inflammation, hematopoiesis, and oncogenesis. Its biological activities are shared by IL-6-family of cytokines such as leukemia inhibitory factor and oncostatin M. When IL-6 binds to IL-6R, the IL-6/IL-6R complex then associates with gp130, the common signal transducer of cytokines related to IL-6. IL-6R does not have to be expressed on the cell surface for IL-6 signaling because soluble form of IL-6R (sIL-6R) can bind to IL-6 and function through gp130. Increased levels of IL-6 and sIL-6R have been demonstrated in both serum and intestinal tissues of the patients with active Crohn's disease. In animal model studies, anti-IL-6R monoclonal antibody (mAb) successfully prevented intestinal inflammation and systemic wasting disease by suppressing adhesion molecule expression by vascular endothelium. It also reduced colonic expression of tumor necrosis factor alpha, IL-1beta, and interferon gamma mRNA without affecting the production of transforming growth factor beta, IL-10, and IL-4. Moreover, the treatment displayed therapeutic efficacy against established colitis through the induction of lamina propria T-cell apoptosis. These results strongly suggest that specific targeting of IL-6/sIL-6R pathway will be a promising new approach for the treatment of Crohn's disease, and the clinical trial of humanized anti-IL-6R mAb has been carried out.     

Effects of FK506 on acute allograft rejection in transplanted rat heart: the role of mitogen-activated protein kinases, AP-1 and NF-kappaB

To scrutinize the effect of the immunosuppressant on acute allograft rejection as related to the intracellular signal transduction, heterotopic cardiac transplantation was performed from DA rat to Lewis rat with/without FK506. In the experimental group, recipients were given FK506 intramuscularly for 5 days. The control group received placebo. Allograft survivals were compared between two groups. For the assay of mitogen-activated protein kinase (MAPKs) families, activator protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB) in the left ventricular free wall (LV) and septum (SEP) of the grafts, rats were sacrificed on POD 5 (n=5 in each group). Extracellular signal-regulated kinase (ERK) and p38MAPK were measured using Western blot analysis. AP-1 and NF-kappaB DNA binding activities were measured by electrophoretic mobility shift assay. FK506 prolonged allograft survival (6.5 vs 31 days), and suppressed activation of myocardial MAPKs (ERK: 66% in LV and 67% in SEP, p38MAPK: 62% in LV and 72% in SEP), AP-1 (24% in LV and 18% in SEP), and NF-kappaB (41% in LV and 20% in SEP) (the mean value of activities in the control group was represented as 100%). These results suggest that the signal transduction pathways may play important roles in acute allograft rejection in rat cardiac transplantation.     

Differentiating between atypical adenomatous hyperplasia and bronchioloalveolar carcinoma using the computed tomography number histogram

BACKGROUND: Both atypical adenomatous hyperplasia (AAH) and bronchioloalveolar carcinoma (BAC) appear as ground glass opacity (GGO) lesions by computed tomography (CT) and are sometimes difficult to differentiate. To aid distinction between the two, we examined their CT number histograms. METHODS: Histograms of pixel CT numbers were made for AAH (n = 9) and nonmucinous BAC (n = 8), and the peak and mean CT numbers on the histogram were quantified. RESULTS: Although there was no significant difference in lesion size between AAH and BAC, all AAHs were less than or equal to 1 cm in diameter. All AAHs and BACs manifested one histogram peak. Both the peak and mean CT numbers on the histogram were significantly lower for AAH than for BAC (p < 0.001). However, the degree of overlap between AAH and BAC was less for the peak CT number than for the mean CT number. CONCLUSIONS:The peak CT number on the histogram can help the radiologic differentiation between AAH and BAC. GGO lesions less than or equal to 1 cm in diameter that are diagnosed as AAH from the CT number histogram can be safely followed by CT.     

Computed tomography findings of Caplan syndrome

We report a case of Caplan syndrome complicated with tuberculosis, which was clinically followed up for 18 years and underwent autopsy. Initial chest radiograph showed 2 large nodules against the background of smaller pneumoconiotic nodules. One of the large nodules showed cavitation during follow-up. Computed tomography (CT) was helpful in identifying calcification in another large nodule. Autopsy confirmed the 2 large nodules as burned-out rheumatoid nodules and revealed additional rheumatoid nodules that were indistinguishable from silicotic nodules by CT.     

Transurethral resection in saline (TURis): a newly developed TUR system preventing obturator nerve reflex

PURPOSE: We developed an innovative transurethral resection system (TURis) consisting of a uniquely-designed generator and a resectoscope. The obturator nerve is protected from troublesome reflexes during TURis because the high frequency current delivery route is via the resection loop to the sheath of the resectscope and not via a patient plate. After extensive preclinical evaluation and verification of the system using an animal model to ensure efficacy as well as operational safety, TURis was conducted for treatment of superficial bladder cancer and benign prostatic hyperplasia. MATERIALS AND METHODS: In preclinical experiments swine bladder wall was transurethrally resected using the system in a saline environment. The results were compared with data obtained from an identical resection using the conventional system using sorbitol solution irrigation. Electrolytic contents were measured after TUR for comparative evaluation vis-a-vis corresponding pre-TUR data. Also, the depth of heat degeneration was measured in the resected tissue. From December, 2000 to June, 2002, TURis was performed in 25 cases of superficial bladder cancer and 30 cases of benign prostatic hyperplasia (BPH), using saline irrigation. All 55 cases were performed under spinal anesthesia without an obturator nerve block. The output power was set at 280 W for cut and 120 W for coagulation. A smaller electrode than those used in conventional TUR was used to improve the cutting efficacy. Occurrence of obturator nerve reflexes, difference of hematocrit and electrolytic contents before and after TURis, operation time and total volume of irrigated saline were evaluated. RESULTS: TURis in animal model: No adductor contraction of a lower limb was observable except for minimal creeping during the resection of a site close to the urethra. There were no apparent anomalies relative to the blood electrolyte content after TURis. No difference was observed in the mean depth of heat-degeneration tissue change compared with the conventional system. TURis for bladder cancer and BPH: No additional skills were required for TURis compared to conventional TUR. No obturator nerve reflex was observed except for a clinically insignificant thigh movement in one case of bladder cancer. The post-TURis blood tests manifested no significant anomalies in blood electrolyte content. Mean operation time for bladder cancer and BPH were 32 and 42 minutes respectively. Mean volumes of saline consumed during TURis were 6,083 ml for bladder cancer and 16,100 ml for BPH. CONCLUSIONS: TURis worked effectively in a saline-irrigated environment. It does not need a patient plate and obturator nerve block even in cases of bladder cancer on the lateral wall. In addition, saline was both safe and cost-effective compared to non-electrolytic solution as irrigant for TUR of BPH. This suggests that TURis may have more applications than conventional TUR.     

Cholangitis and liver abscess after percutaneous ablation therapy for liver tumors: incidence and risk factors

PURPOSE: To determine the risk factors of cholangitis and liver abscess occurring after percutaneous ablation therapy for liver tumors. MATERIALS AND METHODS: Between October 1995 and September 2002, 358 patients with 455 liver tumors underwent a total of 683 ablation procedures, such as percutaneous ethanol injection (PEI), percutaneous microwave coagulation (PMC), and radiofrequency (RF) ablation therapy. With a retrospective review of medical records, the rates and outcomes of cholangitis and/or liver abscess occurring after ablation therapy were evaluated. The relationship between cholangitis and/or liver abscess and multiple variables (age, disease, Child-Pugh class, size of nodules, multiplicity of nodules, history of transcatheter arterial embolization, presence of bilioenteric anastomosis, and lack of prophylactic antibiotics administration) were statistically analyzed. RESULTS: Cholangitis and/or liver abscess occurred in 10 sessions (1.5%) in 10 patients: six sessions after PEI, three sessions after PMC, and one session after RF ablation. Both cholangitis and liver abscess were noted in seven sessions, cholangitis was noted in two, and liver abscess was noted in one. Six patients recovered, but two developed recurrent cholangitis and liver abscess, one developed lung abscess complicated with liver abscess, and one died of septic shock associated with cholangitis. On stepwise regression analysis, bilioenteric anastomosis was the sole significant predictor of cholangitis and/or liver abscess formation (P <.001; odds ratio = 36.4; 95% CI = 9.67-136.9). CONCLUSION: Bilioenteric anastomosis strongly correlated with the development of cholangitis and/or liver abscess after percutaneous ablation therapy. Close posttreatment attention should be paid to this subgroup of patients.