Equine model for soft-tissue regeneration.

Soft-tissue regeneration methods currently yield suboptimal clinical outcomes due to loss of tissue volume and a lack of functional tissue regeneration. Grafted tissues and natural biomaterials often degrade or resorb too quickly, while most synthetic materials do not degrade. In previous research we demonstrated that soft-tissue regeneration can be supported using silk porous biomaterials for at least 18 months in vivo in a rodent model. In the present study, we scaled the system to a survival study using a large animal model and demonstrated the feasibility of these biomaterials for soft-tissue regeneration in adult horses. Both slow and rapidly degrading silk matrices were evaluated in subcutaneous pocket and intramuscular defect depots. We showed that we can effectively employ an equine model over 6 months to simultaneously evaluate many different implants, reducing the number of animals needed. Furthermore, we were able to tailor matrix degradation by varying the initial format of the implanted silk. Finally, we demonstrate ultrasound imaging of implants to be an effective means for tracking tissue regeneration and implant degradation.

Young developmental age cardiac extracellular matrix promotes the expansion of neonatal cardiomyocytes in vitro.

A major limitation to cardiac tissue engineering and regenerative medicine strategies is the lack of proliferation of postnatal cardiomyocytes. The extracellular matrix (ECM) is altered during heart development, and studies suggest that it plays an important role in regulating myocyte proliferation. Here, the effects of fetal, neonatal and adult cardiac ECM on the expansion of neonatal rat ventricular cells in vitro are studied. At 24h, overall cell attachment was lowest on fetal ECM; however, ~80% of the cells were cardiomyocytes, while many non-myocytes attached to older ECM and poly-l-lysine controls. After 5 days, the cardiomyocyte population remained highest on fetal ECM, with a 4-fold increase in number. Significantly more cardiomyocytes stained positively for the mitotic marker phospho-histone H3 on fetal ECM compared with other substrates at 5 days, suggesting that proliferation may be a major mechanism of cardiomyocyte expansion on young ECM. Further study of the beneficial properties of early developmental aged cardiac ECM could advance the design of novel biomaterials aimed at promoting cardiac regeneration.

Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain.

Converging lines of evidence implicate the beta-amyloid peptide (Ass) as causative in Alzheimer's disease. We describe a novel class of compounds that reduce A beta production by functionally inhibiting gamma-secretase, the activity responsible for the carboxy-terminal cleavage required for A beta production. These molecules are active in both 293 HEK cells and neuronal cultures, and exert their effect upon A beta production without affecting protein secretion, most notably in the secreted forms of the amyloid precursor protein (APP). Oral administration of one of these compounds, N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester, to mice transgenic for human APP(V717F) reduces brain levels of Ass in a dose-dependent manner within 3 h. These studies represent the first demonstration of a reduction of brain A beta in vivo. Development of such novel functional gamma-secretase inhibitors will enable a clinical examination of the A beta hypothesis that Ass peptide drives the neuropathology observed in Alzheimer's disease.

Method in Catholic bioethics.

Method in Catholic bioethics is distinguished by a specific philosophical and theological anthropology. Human beings are not to be considered simply as selves, but as selves in relation to God and each other. This essay reflects on that claim by reviewing four areas of concern from Catholic social teaching: common good, human dignity, option for the poor, and stewardship.

Assisted suicide and equal protection: in defense of the distinction between killing and letting die.

The author argues that the distinction between intentionally killing oneself and intentionally letting oneself die is both coherent "as a matter of principle" and morally relevant. This principled distinction then provides a benchmark for courts considering equal protection arguments to distinguish one patient seeking to commit suicide from another wishing to free herself of unwanted life-sustaining medical treatment, and to conclude that these two individuals are not similarly situated for purposes of the Equal Protection Clause. These two situations are morally distinct--the deaths are caused by different means and those involved have different intentions. The intention of the doctor and patient to hasten the patient's death is material, and the intention relates to understanding what it means to treat people equally. Doctors who participate in assisted suicide intend their patients to die by their own acts, i.e., intentional killing. The author concludes that those who ask their doctors to commit assisted suicide and those who forego treatment are not similarly situated for purposes of the Equal Protection Clause. The afterward comments on the Supreme Court's recent assisted suicide decision. It affirms the author's analysis.

The structure of lipooligosaccharide produced by Neisseria gonorrhoeae, strain 15253, isolated from a patient with disseminated infection. Evidence for a new glycosylation pathway of the gonococcal lipooligosaccharide.

We studied the structure of the lipooligosaccharide (LOS) that is produced by Neisseria gonorrhoeae, strain 15253. This strain, recovered from a patient with disseminated infection, produces predominantly a single LOS component, and its oligosaccharide (OS) structure is different from those of previously studied LOSs. Definition of this OS structure provides additional information on the LOS biosynthesis. We determined that the 15253 OS has an unusual structure: 2 lactosyl residues at its nonreducing ends shown below, [formula: see text] where KDO is 2-keto-3-deoxy-mannooctulosonic acid and Hep is heptose. Comparison of this OS structure with those determined previously indicates the presence of a new glycosylation pathway for gonococcal OS biosynthesis: elongation of a GlcNAc-linked heptose, in contrast to elongation of the other heptose by sequential addition of glycoses which results in the antigenic similarity with human glycolipids. The current study provides not only additional structural information on LOS expressed during different clinical states of infection but also evidence for the diversity of gonococcal LOS biosynthesis. This evidence may be helpful in understanding the pathogenesis involving gonococcal LOS.

Neuraminic acid is alpha 2-->3 linked in the lipooligosaccharide of Neisseria meningitidis serogroup B strain 6275.

We have analyzed the sialylated lipooligosaccharide of Neisseria meningitidis 6275. Sialylated oligosaccharide released from strain 6275 lipooligosaccharide by mild hydrolysis was determined to contain N-acetylneuraminic acid linked alpha 2-->3 to terminal galactose as shown below. [formula: see text]