Faculty Bibliography

The outcomes of 20 patients diagnosed with osteoarthritis or rheumatoid arthritis with body mass index less than 18.5 (considered underweight) who received total hip arthroplasty at a single institution were reviewed. Surgical complications in the first 30 days after surgery included 1 prolonged surgical site drainage and 3 posterior dislocations. Two patients experienced medical complications that included hematemesis, confusion, aspiration pneumonia, and death. Sixty-five percent of the patients received at least one blood transfusion. Harris hip scores improved from 35 to 81 (P < .05) at an average of 6.1 years (2-10.1 years) of follow-up. Total hip arthroplasty is effective in patients who are underweight; however, they appear to be at an increased risk of dislocation and blood transfusion

The strengths of 3 hip spacer constructs--Steinmann pins, a short intramedullary nail (both cement-incorporated), and a Charnley prosthesis--were determined and compared with the strength of a commercially available hip spacer. The hip prosthesis construct was more than twice as strong as the other 2 constructs and was equivalent in strength to the commercial spacer. For spacer applications in which limited weight-bearing is anticipated, the hip prosthesis construct appears more efficacious, but its pros and cons should be compared with those of the commercial product

Pancreatic carboxyl ester lipase (CEL) is in the plasma of many mammals, including humans and rats, but not mice. In vitro, CEL hydrolyzes cholesterol esters of apolipoprotein B-containing lipoproteins (apo B-Lp). To study the effect of CEL on metabolism of apo B-Lp and atherosclerosis in vivo, apo E-knockout (EKO) mice, which have high plasma levels of apo B-Lp and are prone to atherosclerosis, were made to secrete CEL into plasma by introducing a transgene containing a liver-specific promoter and rat CEL complementary DNA. Plasma CEL activity in EKO-CEL mice was comparable with that found in rats. Evidence of modification of apo B-Lp by plasma CEL in vivo was an increase in the free cholesterol to cholesterol ester ratio of apo B-Lp from mice on chow or a Western-type diet. In addition, plasma total cholesterol levels were elevated in EKO-CEL mice, with the elevation found exclusively in the apo B-Lp fraction. Associated with the increase in steady-state apo B-Lp levels was an increase in the plasma half-life of very low-density lipoproteins (VLDL) in EKO-CEL mice, measured by the clearance rate of injected VLDL. Interestingly, despite the increase of apo B-Lp, the atherosclerotic lesion did not differ between EKO and EKO-CEL mice on a Western-type diet. In summary, our results demonstrate that plasma CEL modulates apo B-Lp metabolism in vivo, resulting in reduced VLDL clearance and elevated plasma cholesterol levels.

The progression from insulin resistance to type 2 diabetes is caused by the failure of pancreatic beta cells to produce sufficient levels of insulin to meet the metabolic demand. Recent studies indicate that nutrient fluctuations and insulin resistance increase proinsulin synthesis in beta cells beyond the capacity for folding of nascent polypeptides within the endoplasmic reticulum (ER) lumen, thereby disrupting ER homeostasis and triggering the unfolded protein response (UPR). Chronic ER stress promotes apoptosis, at least in part through the UPR-induced transcription factor C/EBP homologous protein (CHOP). We assessed the effect of Chop deletion in multiple mouse models of type 2 diabetes and found that Chop-/- mice had improved glycemic control and expanded beta cell mass in all conditions analyzed. In both genetic and diet-induced models of insulin resistance, CHOP deficiency improved beta cell ultrastructure and promoted cell survival. In addition, we found that isolated islets from Chop-/- mice displayed increased expression of UPR and oxidative stress response genes and reduced levels of oxidative damage. These findings suggest that CHOP is a fundamental factor that links protein misfolding in the ER to oxidative stress and apoptosis in beta cells under conditions of increased insulin demand

The Wnt pathway constitutes one of the most attractive candidates for modulating skeletal tissue regeneration based on its functions during skeletal development and homeostasis. Wnts participate in every stage of skeletogenesis, from the self-renewal and proliferation of skeletal stem cells to the specification of osteochondroprogenitor cells and the maturation of chondrocytes and osteoblasts. We propose that the function of Wnts depend upon a skeletogenic cell's state of differentiation. In this review we summarize recent data with a focus on the roles of Wnt signaling in mesenchymal stem cell fate, osteoprogenitor cell differentiation, chondrocyte maturation, bone remodeling, and bone regeneration.

As axons myelinate, establish a stable neurofilament network, and expand in caliber, neurofilament proteins are extensively phosphorylated along their C-terminal tails, which is recognized by the monoclonal antibody, RT-97. Here, we demonstrate in vivo that RT-97 immunoreactivity (IR) is generated by phosphorylation at KSPXK or KSPXXXK motifs and requires flanking lysines at specific positions. extracellular signal regulated kinase 1,2 (ERK1,2) and pERK1,2 levels increase in parallel with phosphorylation at the RT-97 epitope during early postnatal brain development. Purified ERK1,2 generated RT-97 on both KSP motifs on recombinant NF-H tail domain proteins, while cdk5 phosphorylated only KSPXK motifs. RT-97 epitope generation in primary hippocampal neurons was regulated by extensive cross-talk among ERK1,2, c-Jun N-terminal kinase 1,2 (JNK1,2) and cdk5. Inhibition of both ERK1,2 and JNK1,2 completely blocked RT-97 generation. Cdk5 influenced RT-97 generation indirectly by modulating JNK activation. In mice, cdk5 gene deletion did not significantly alter RT-97 IR or ERK1,2 and JNK activation. In mice lacking the cdk5 activator P35, the partial suppression of cdk5 activity increased RT-97 IR by activating ERK1,2. Thus, cdk5 influences RT-97 epitope generation partly by modulating ERKs and JNKs, which are the two principal kinases regulating neurofilament phosphorylation. The regulation of a single target by multiple protein kinases underscores the importance of monitoring other relevant kinases when the activity of a particular one is blocked.

OBJECTIVES: An epithelial ovarian cancer cell line constitutively expressing the androgen receptor was created to evaluate the mechanism and effects of androgen receptor activation on epithelial ovarian cancer cell invasion. METHODS: Immunocytochemistry and Western blot analyses confirmed androgen receptor expression. Boyden chamber invasion assays were performed using cells treated with the androgen receptor ligands medroxyprogesterone acetate or dihydrotestosterone. The matrix metalloproteinases associated with invasion were investigated using zymographic assays. RESULTS: Androgen receptor-mediated invasion is ligand dependent. While both medroxyprogesterone acetate and dihydrotestosterone signal through androgen receptor, medroxyprogesterone acetate is more effective at stimulating invasion of epithelial ovarian cancer cells. Unlike the wild-type epithelial ovarian cancer cells, this increase in invasion in androgen receptor + epithelial ovarian cancer cells does not seem to be dependent on matrix metalloproteinase 2 or 9 activation. CONCLUSION: Although classified as a progestin, medroxyprogesterone acetate has significant androgenic activity unique from the pure androgen dihydrotestosterone. Our studies suggest that pharmacologic doses of medroxyprogesterone acetate may actually increase the invasive potential of epithelial ovarian cancer cells.

We have used an atomic force microscope to examine a clinically derived sample of single-molecule gene transcripts, in the form of double-stranded cDNA, (c: complementary) obtained from human cardiac muscle without the use of polymerase chain reaction (PCR) amplification. We observed a log-normal distribution of transcript sizes, with most molecules being in the range of 0.4-7.0 kilobase pairs (kb) or 130-2300 nm in contour length, in accordance with the expected distribution of mRNA (m: messenger) sizes in mammalian cells. We observed novel branching structures not previously known to exist in cDNA, and which could have profound negative effects on traditional analysis of cDNA samples through cloning, PCR and DNA sequencing

Notch-mediated cell-cell communication regulates numerous developmental processes and cell fate decisions. Through a mosaic genetic screen in Drosophila melanogaster, we identified a role in Notch signaling for a conserved thiol oxidase, endoplasmic reticulum (ER) oxidoreductin 1-like (Ero1L). Although Ero1L is reported to play a widespread role in protein folding in yeast, in flies Ero1L mutant clones show specific defects in lateral inhibition and inductive signaling, two characteristic processes regulated by Notch signaling. Ero1L mutant cells accumulate high levels of Notch protein in the ER and induce the unfolded protein response, suggesting that Notch is misfolded and fails to be exported from the ER. Biochemical assays demonstrate that Ero1L is required for formation of disulfide bonds of three Lin12-Notch repeats (LNRs) present in the extracellular domain of Notch. These LNRs are unique to the Notch family of proteins. Therefore, we have uncovered an unexpected requirement for Ero1L in the maturation of the Notch receptor