Efficacy of MEM 1003, a novel calcium channel blocker, in delay and trace eyeblink conditioning in older rabbits

Eyeblink conditioning is a relatively simple form of associative learning that shows neurobiological and behavioral parallels across several species, including humans. Aged subjects acquire eyeblink conditioning more slowly than young ones. In addition, eyeblink conditioning effectively discriminates patients with Alzheimer's disease from healthy older adults. The present study evaluated the effect of a novel L-type Ca2+ channel antagonist, MEM 1003, on delay and trace eyeblink conditioning in older (mean 33.4 months old) female New Zealand white rabbits. In the delay conditioning paradigm, an 850 ms tone conditioning stimulus (CS) was followed 750 ms after its onset by a 100 ms corneal air puff. Several trace conditioning paradigms were evaluated, with a silent period of 300, 400 or 500 ms between the end of the tone CS and the delivery of the air puff. Learning was more difficult in the longer trace paradigms than in the delay paradigm. MEM 1003, at a dose of 2.0 mg/kg, s.c., given daily 30 min prior to training on each of the 15 training days, enhanced learning compared to vehicle injections in both delay and trace paradigms. However, higher or lower doses were ineffective. These results support previous work demonstrating that modulation of Ca2+ channel activity can reduce age-related cognitive impairments.     

White matter grade and ventricular volume on brain MRI as markers of longevity in the cardiovascular health study

High white matter grade (WMG) on magnetic resonance imaging (MRI) is a risk factor for dementia, stroke and disability. Higher ventricular size is a marker of brain "atrophy." In the Cardiovascular Health Study (CHS) (n=3245) mean age 75 years, 50% black and 40% men, we evaluated WM and ventricular grade (VG), total, cardiovascular and noncardiovascular mortality and longevity before and after adjusting for numerous determinants of longevity over an approximate 10-12 years of follow-up. A low WMG and VG was a marker for low total, cardiovascular and noncardiovascular mortality and for increased longevity over 10+ years of follow-up. We estimated that a 75-year-old with WMG below median would have about a 5-6 years greater longevity and for VG about 3 years, than above the median even after adjustment for numerous risk factors. Low WMG and VG on MRI is a powerful determinant of long-term survival among older individuals.     

The IL-1 type 1 receptor is required for the development of LPS-induced airways disease

BACKGROUND: The contribution of IL-1beta signaling through the IL-1 type 1 receptor (IL-1R1) to the development of persistent LPS-induced airway disease has not been investigated. OBJECTIVE: To determine the importance of signaling through the IL-1 type 1 receptor in the development of LPS-induced airway disease. METHODS: We exposed IL-1R1-deficient (C57BL/6(IL-1RI-/-)) mice to an aerosol of LPS or filtered air for 1 day, 1 week, or 4 weeks. RESULTS: After 4 weeks of LPS inhalation, C57BL/6(IL-1RI-/-) mice failed to develop significant submucosal thickening, whereas C57BL/6 mice had significantly thickened submucosa in small, medium, and large airways compared with those of unexposed control mice. Cell proliferation in the airways of both the 1-week and 4-week LPS-exposed C57BL/6(IL-1RI-/-) mice was significantly reduced compared with LPS-exposed C57BL/6 mice. mRNA for type III alpha-3 procollagen was significantly elevated over baseline in C57BL/6 yet remained unchanged compared with baseline in C57BL/6(IL-1RI-/-) mice after 1 week or 4 weeks of LPS inhalation. mRNA for tissue inhibitor of metalloprotease 1 in C57BL/6 mice in the 1-week and 4-week groups was significantly elevated over both control mice and C57BL/6(IL-1RI-/-) mice. CONCLUSION: These data support the hypothesis that signaling through the IL-1 receptor modulates extracellular matrix homeostasis in response to inhaled LPS. CLINICAL IMPLICATIONS: Attenuating IL-1R1-mediated signaling might be an effective therapy against the development of airway remodeling in chronic inflammatory diseases.     

Improved test-retest reliability of 50-ms paired-click auditory gating using magnetoencephalography source modeling

Used to study filtering abnormalities in schizophrenia, the paired-click paradigm suffers from poor test-retest reliability of the gating ratio, calculated from the P50 component of the ERP recorded at Cz approximately 50 ms following each of two stimuli. This study sought to improve reliability by assessing 50-ms gating at primary auditory cortices (PAC), the main generators of the P50 Cz component. MEG source modeling was used, taking advantage of the tangentially oriented PAC sources. Ten healthy subjects underwent three sessions, during which Cz-based and PAC-derived gating was measured. Unlike Cz P50, gating ratios at bilateral PACs achieved an intraclass coefficient of .8 or greater. Variability of gating within the same subject was also significantly smaller for bilateral PACs than for Cz P50. Paired-click gating ratio reliability can be improved by examining the individual PACs rather than composite scalp-recorded activity.     

Inhibition of iridovirus protein synthesis and virus replication by antisense morpholino oligonucleotides targeted to the major capsid protein, the 18 kDa immediate-early protein, and a viral homolog of RNA polymerase II

Frog virus 3 (FV3) is a large DNA virus that encodes approximately 100 proteins. Although the general features of FV3 replication are known, the specific roles that most viral proteins play in the virus life cycle have not yet been elucidated. To address the question of viral gene function, antisense morpholino oligonucleotides (asMOs) were used to transiently knock-down expression of specific viral genes and thus infer their role in virus replication. We designed asMOs directed against the major capsid protein (MCP), an 18 kDa immediate-early protein (18K) that was thought to be a viral regulatory protein, and the viral homologue of the largest subunit of RNA polymerase II (vPol-IIalpha). All three asMOs successfully inhibited translation of the targeted protein, and two of the three asMOs resulted in marked phenotypic changes. Knock-down of the MCP resulted in a marked reduction in viral titer without a corresponding drop in the synthesis of other late viral proteins. Transmission electron microscopy (TEM) showed that in cells treated with the anti-MCP MO assembly sites were devoid of viral particles and contained numerous aberrant structures. In contrast, inhibition of 18K synthesis did not block virion formation, suggesting that the 18K protein was not essential for replication of FV3 in fathead minnow (FHM) cells. Finally, consistent with the view that late viral gene expression is catalyzed by a virus-encoded or virus-modified Pol-II-like protein, knock-down of vPol-IIalpha triggered a global decline in late gene expression and virus yields without affecting the synthesis of early viral genes. Collectively, these results demonstrate the utility of using asMOs to elucidate the function of FV3 proteins.     

Soft tissue tumors of the urinary bladder, Part I: myofibroblastic proliferations, benign neoplasms, and tumors of uncertain malignant potential

Most bladder tumors arise from the urothelium. However, there are several uncommon but significant bladder lesions that must be differentiated from urothelial carcinomas. These include both benign and malignant spindle cell lesions. The first half of this 2-part review will describe benign myofibroblastic proliferations including inflammatory myofibroblastic tumor and postoperative spindle cell nodule; benign neoplasms including leiomyoma, hemangioma, neurofibroma, and schwannoma; and tumors of uncertain malignant potential including paraganglioma, granular cell tumor, and perivascular epithelioid cell tumor. Common clinical presentations, morphological characteristics, and immunohistochemical features are described to aid the practicing pathologist in the identification of these entities. This review also describes current theories as to the pathogenesis of inflammatory myofibroblastic tumor and postoperative spindle cell nodule and details the current molecular markers identifying several of these lesions.     

CD8+ T cells promote inflammation and apoptosis in the liver after sepsis: role of Fas-FasL

Although studies blocking the Fas pathway indicate it can decrease organ damage while improving septic (cecal ligation and puncture, CLP) mouse survival, little is known about how Fas-Fas ligand (FasL) interactions mediate this protection at the tissue level. Here, we report that although Fas expression on splenocytes and hepatocytes is up-regulated by CLP and is inhibited by in vivo short interfering RNA, FasL as well as the frequency of CD8(+) T cells are differentially altered by sepsis in the spleen (no change in FasL, decreased percentage of CD8(+) and CD4(+) T cells) versus the liver (increased FasL expression on CD8(+) T cells and increase in percentage/number). Adoptive transfer of CLP FasL(+/+) versus FasL(-/-) mouse liver CD8(+) T cells to severe combined immunodeficient or RAG1(-/-) recipient mice indicated that these cells could induce inflammation. The FasL-mediated cytotoxic capacity of these septic mouse liver CD8(+) T cells was shown by their ability to damage directly cultured hepatocytes. Finally, although CD8(-/-) mice exhibited a reduction in both CLP-induced liver active caspase-3 staining and blood interleukin-6 levels, only FasL(-/-) (but not CD8(-/-)) protected the septic mouse spleen from increasing apoptosis. Thus, although truncating Fas-FasL signaling ameliorates many untoward effects of sepsis, the pathological mode of action is distinct at the tissue level.     

Bacteremia, fever, and splenomegaly caused by a newly recognized bartonella species

Bartonella species cause serious human infections globally, including bacillary angiomatosis, Oroya fever, trench fever, and endocarditis. We describe a patient who had fever and splenomegaly after traveling to Peru and also had bacteremia from an organism that resembled Bartonella bacilliformis, the causative agent of Oroya fever, which is endemic to Peru. However, genetic analyses revealed that this fastidious bacterium represented a previously uncultured and unnamed bartonella species, closely related to B. clarridgeiae and more distantly related to B. bacilliformis. We characterized this isolate, including its ability to cause fever and sustained bacteremia in a rhesus macaque. The route of infection and burden of human disease associated with this newly described pathogen are currently unknown.