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Prion diseases, including sheep scrapie, are neurodegenerative diseases with the fundamental pathogenesis involving conversion of normal cellular prion protein (PrP C) to disease-associated prion protein (PrP Sc). Chemical inhibition of prion accumulation is widely investigated, often using rodent-adapted prion cell culture models. Using a PrP Sc -specific ELISA we discovered a monocationic phenyl-furan-benzimidazole (DB772), which has previously demonstrated anti-pestiviral activity and represents a chemical category previously untested for anti-prion activity, that inhibited PrP Sc accumulation and prion infectivity in primary sheep microglial cell cultures (PRNP 136VV/154RR/171QQ) and Rov9 cultures (VRQ-ovinized RK13 cells). We investigated potential mechanisms of this anti-prion activity by evaluating PrP C expression with quantitative RT-PCR and PrP ELISA, comparing the concentration-dependent anti-prion and anti-pestiviral effects of DB772, and determining the selectivity index. Results demonstrate at least an approximate two-log inhibition of PrP Sc accumulation in the two cell systems and confirmed that the inhibition of PrP Sc accumulation correlates with inhibition of prion infectivity. PRNP transcripts and total PrP protein concentrations within cell lysates were not decreased; thus, decreased PrP C expression is not the mechanism of PrP Sc inhibition. PrP Sc accumulation was multiple logs more resistant than pestivirus to DB772, suggesting that the anti-PrP Sc activity was independent of anti-pestivirus activity. The anti-PrP Sc selectivity index in cell culture was approximately 4.6 in microglia and 5.5 in Rov9 cells. The results describe a new chemical category that inhibits ovine PrP Sc accumulation in primary sheep microglia and Rov9 cells, and can be used for future studies into the treatment and mechanism of prion diseases.

Neospora caninum, an apicomplexan parasite closely related to Toxoplasma gondii, causes abortion, stillbirths, and congenital neurologic disease in multiple animal species. The present study focuses on the development of encephalitis and intracerebral parasite load that occurs 6 wk postinfection (PI). Utilizing BALB/c, C57BL/6, and B10.D2 mice, an initial investigation was undertaken to determine the relative resistance of inbred strains to N. caninum-induced encephalitis. Relative resistance was defined in terms of central nervous system lesion development and parasite load. Based on other protozoal infections in mice, it was hypothesized that BALB/c and C57BL/6 should be contrasting in their relative resistance to N. caninum, with BALB/c and congenic B10.D2 mice less susceptible than C57BL/6 mice. Contrary to expectation, BALB/c and C57BL/6 were both highly susceptible to the development of N. caninum-induced encephalitis, whereas B10.D2 mice were resistant. Both BALB/c mice and C57BL/6 mice had significantly higher numbers of brain lesions and intracerebral tachyzoites than B10.D2 mice. Resistance in B10.D2 was associated with a high interferon (IFN)-γ: interleukin (IL)-4 ratio from antigen-stimulated splenocytes, whereas susceptibility in C57BL/6 and BALB/c mice corresponded with a low splenocyte FFN-γ: IL-4 ratio. In vivo measurement of Neospora-specific isotype antibodies demonstrated predominately IgG2a in serum from B10.D2 mice and IgG1 in serum from BALB/c and C57BL/6 mice. In conclusion, susceptibility of mice to N. caninum is unique compared to other protozoal diseases. The present study also demonstrates that parasite load is a fundamental measurement for evaluating disease induced by N. caninum and that a type 1 cytokine response may be necessary for regulation of this parameter.

NEK7 is a serine-threonine kinase linked to mitosis. Beutler and colleagues show that NEK7 is required for assembly of the NLRP3 inflammasome and restricts NLRP3 activation to interphase of the cell cycle. The NLRP3 inflammasome responds to microbes and danger signals by processing and activating proinflammatory cytokines, including interleukin 1β (IL-1β) and IL-18. We found here that activation of the NLRP3 inflammasome was restricted to interphase of the cell cycle by NEK7, a serine-threonine kinase previously linked to mitosis. Activation of the NLRP3 inflammasome required NEK7, which bound to the leucine-rich repeat domain of NLRP3 in a kinase-independent manner downstream of the induction of mitochondrial reactive oxygen species (ROS). This interaction was necessary for the formation of a complex containing NLRP3 and the adaptor ASC, oligomerization of ASC and activation of caspase-1. NEK7 promoted the NLRP3-dependent cellular inflammatory response to intraperitoneal challenge with monosodium urate and the development of experimental autoimmune encephalitis in mice. Our findings suggest that NEK7 serves as a cellular switch that enforces mutual exclusivity of the inflammasome response and cell division.

Ileal pouch-anal anastomosis (IPAA) is the procedure of choice for patients with ulcerative colitis and familial adenomatous polyposis. This two-stage procedure with a temporary diverting ileostomy avoids the catastrophic consequences of anastomotic leakage. We set out to determine the incidence and effect of asymptomatic pouch sinuses detected prior to ileostomy closure on the outcome of IPAA. A total 1600 IPAAs performed at the Mayo Clinic were reviewed. Forty-one (2.6%) asymptomatic sinuses were treated expectantly. There were 22 males and 19 females who had a median age of 32 years (range 14 to 58 years). The median time to ileostomy closure was 5.9 months (range 4 to 11 months). Five patients required further surgery following closure of ileostomy. The pouch function in these five patients was similar to that in the remainder of the group. Patients with a persistent sinus at the time of ileostomy closure had the same function as the main cohort. This group had a median of five (range 2 to 12) stools during the day and two (range 0 to 4) at night. The total number of stools per 24 hours was seven (range 2 to 14). Frequent incontinence occurred in 9.7% and 7.3% during the day and at night, respectively. Only 2.4% ( 1 41 ) were disappointed with the results of the operation and 80.4% ( 33 41 ) found their quality of life improved. Functional outcomes were comparable to those achieved with uncomplicated IPAA. Radiologically detected asymptomatic sinuses can be treated expectantly with a low rate of pouch loss and subsequent surgery. This is not considered a serious setback inasmuch as long-term function and quality of life are comparable to that achieved with IPAA without sinus tracts.

LUCKY the opera company with Luc Bondy's new production of Macbeth in its repertoire. Lucky, too, the company which has Richard Armstrong to conduct it. But Scottish Opera last night was three times - no, four times - lucky, because Richard Zeller and Kathleen Broderick were cast as the Macbeths. It was an evening that spared us no shocks. At the beginning the mini-skirted witches, dancing a mock can-can, gave only a frivolous foretaste of what was to follow. Lady Macbeth's knife fixation quickly tightened the screw, leading not only to the killing of Duncan - his corpse bloodily displayed for all to see - but to an almost cinematic dispatch of Banquo, slaughtered by the kitchen staff in front of the banqueting table on which Lady Macbeth had placed the knives and at which his ghost would subsequently sit. This was a striking device but there were others to follow, even if the second half of the performance could not quite sustain the consistent flow of the first. But the pacing of Armstrong's conducting, his sharp ear for Verdian detail, ensured that attention was constantly gripped by the musical unfurling of the grisly story. Zeller's Macbeth, seduced into action by Broderick's elegant femme fatale, was a telling portrayal, but praise, too, to Carsten Stabell's doomed Banquo, and to the Scottish Opera Chorus who were seen and heard to stunning effect.

A comparative discussion of a selected international estate planning problem by distinguished practitioners in major industrial countries is based upon several fact situations and questions. The discussion is provided for estate planning clients with contacts in Belgium, Canada, Denmark, France, Ireland, Italy, the Netherlands, Spain, Switzerland, the UK, and the US. Belgium imposes 3 transfer taxes that can be relevant in the case at issue. There also are gift taxes upon registration of all documents that evidence gifts. Further, inheritance taxes apply to property distributed at death by inhabitants of the kingdom. Other questions involve the effects of tax treaties. All of the aforementioned aspects of international estate taxation are reviewed for each country; in addition, planning opportunities pertinent to each situation offer ways to maximize the amount of the aftertax estate that remains for the beneficiaries. There are significant differences in the treatment of this estate in accordance with the various countries reviewed.

A comparative discussion of a selected international estate planning problem by distinguished practitioners in major industrial countries is based upon several fact situations and questions. The discussion is provided for estate planning clients with contacts in Belgium, Canada, Denmark, France, Ireland, Italy, the Netherlands, Spain, Switzerland, the UK, and the US. Belgium imposes 3 transfer taxes that can be relevant in the case at issue. There also are gift taxes upon registration of all documents that evidence gifts. Further, inheritance taxes apply to property distributed at death by inhabitants of the kingdom. Other questions involve the effects of tax treaties. All of the aforementioned aspects of international estate taxation are reviewed for each country; in addition, planning opportunities pertinent to each situation offer ways to maximize the amount of the aftertax estate that remains for the beneficiaries. There are significant differences in the treatment of this estate in accordance with the various countries reviewed.