IntroductionPatient specific instruments (PSI) and computer-assisted surgery (CAS) are innovative technologies that offer the potential to improve the accuracy and reproducibility with which a total knee arthroplasty (TKA) is performed. It has not been established whether clinical, functional, or radiographic outcomes between PSI, CAS, and manual TKA differ in the hands of an experienced TKA surgeon. The purpose of this study was to evaluate clinical, functional and radiographic outcomes between TKA performed with PSI, CAS, and manual instruments at short-term follow-up. Our hypothesis was that at early follow-up, we would be unable to elucidate any significant differences between the groups using the most commonly utilized outcomes measures.Methods40 PSI, 38 CAS, and 40 manual TKA were performed by a single surgeon. The groups were similar in regards to age, sex, and preoperative diagnosis. The Knee Society Scoring System was used to evaluate patient clinical and functional outcome scores preoperatively ...

Efforts to identify pharmaceuticals to treat heritable metabolic liver diseases have been hampered by the lack of models. However, cells with hepatocyte characteristics can be produced from induced pluripotent stem cells (iPSCs). Here, we have used hepatocyte-like cells generated from homozygous familial hypercholesterolemia (hoFH) iPSCs to identify drugs that can potentially be repurposed to lower serum LDL-C. We found that cardiac glycosides reduce the production of apolipoprotein B (apoB) from human hepatocytes in culture and the serum of avatar mice harboring humanized livers. The drugs act by increasing the turnover of apoB protein. Analyses of patient medical records revealed that the treatment of patients with cardiac glycosides reduced serum LDL-C levels. These studies highlight the effectiveness of using iPSCs to screen for potential treatments for inborn errors of hepatic metabolism and suggest that cardiac glycosides could provide an approach for reducing hepatocyte production of apoB and treating hypercholesterolemia.

When comparing hepatic phenotypes between iPSC-derived hepatocyte-like cells from different liver disease patients, cell heterogeneity can confound interpretation. We proposed that homogeneous cell populations could be generated by fluorescence-activated cell sorting (FACS). Using cell-surface capture proteomics, we identified a total of 300 glycoproteins on hepatocytes. Analyses of the expression profiles during the differentiation of iPSCs revealed that SLC10A1, CLRN3, and AADAC were highly enriched during the final stages of hepatocyte differentiation. FACS purification of hepatocyte-like cells expressing SLC10A1, CLRN3, or AADAC demonstrated enrichment of cells with hepatocyte characteristics. Moreover, transcriptome analyses revealed that cells expressing the liver gene regulatory network were enriched while cells expressing a pluripotent stem cell network were depleted. In conclusion, we report an extensive catalog of cell-surface N-linked glycoproteins expressed in primary hepatocytes and identify cell-surface proteins that facilitate the purification of homogeneous populations of iPSC-derived hepatocyte-like cells.

The characterization of induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs) routinely includes analyses of chromosomal integrity. The belief is that pluripotent stem cells best suited to the generation of differentiated derivatives should display a euploid karyotype; although, this does not appear to have been formally tested. While aneuploidy is commonly associated with cell transformation, several types of somatic cells, including hepatocytes, are frequently aneuploid and variation in chromosomal content does not contribute to a transformed phenotype. This insight has led to the proposal that dynamic changes in the chromosomal environment may be important to establish genetic diversity within the hepatocyte population and such diversity may facilitate an adaptive response by the liver to various insults. Such a positive contribution of aneuploidy to liver function raises the possibility that, in contrast to existing dogma, aneuploid iPSCs may be capable of generating hepatocyte-like cells that display hepatic activities.

PURPOSE:The purpose of this study was to evaluate clinical, functional, and radiographic outcomes following total knee arthroplasty (TKA) performed with patient-specific instrumentation (PSI), computer-assisted surgery (CAS), and manual instruments at short-term follow-up.METHODS:122 TKAs were performed by a single surgeon: 42 with PSI, 38 with CAS, and 40 with manual instrumentation. Preoperative, 1-month, and 6-month clinical and functional outcomes were measured using the Knee Society scoring system (knee score, function score, range of motion, and pain score). Improvements in clinical and functional outcomes from the preoperative to postoperative period were analyzed. Preoperative and postoperative radiographs were measured to evaluate limb and component alignment.RESULTS:Preoperative, 1-month postoperative, and 6-month postoperative knee scores, function scores, range of motion, and pain scores were highest in the PSI group compared to CAS and manual instrumentation. At 6-month follow-up, PSI TKA was associated with a statistically significant improvement in functional score when compared to manual TKA. Otherwise, there were no statistically significant differences in improvements among PSI, CAS, and manual TKA groups.CONCLUSION:The higher preoperative scores in the PSI group limits the ability to draw definitive conclusions from the raw postoperative scores, but analyzing the changes in scores revealed that PSI was associated with a statistically significant improvement in Knee Society Functional score at 6-month post-TKA as compared to CAS or manual TKA. This may be attributable to improvements in component rotation and positioning, improved component size accuracy, or other factors that are not discernible on plain radiograph.

Conventional uncemented femoral implants provide dependable long-term fixation in patients with a wide range of clinical function. However, challenges with proximal-distal femoral mismatch, preservation of bone stock, and minimally invasive approaches have led to exploration into various other implant designs. Short-stem designs focusing on a stable metaphyseal fit have emerged to address these challenges in total hip arthroplasty (THA). The purpose of this study was to present the 5-year clinical and radiographic results of a computed tomography-based, custom-made, metaphyseal-engaging short-stem femoral implant.Sixty-one patients with an average age of 61 years (range, 22-75 years) and average body mass index of 28.9 kg/m(2) (range, 20.3-44.1 kg/m(2)) at follow-up underwent 69 THAs with the metaphyseal-engaging short stem. Clinical performance was evaluated using the Harris Hip Score and Western Ontario and McMaster Universities Arthritis Index score, and radiographs were reviewed for stability and bony ingrowth. Harris Hip Score averaged 55 (range, 20-90) preoperatively and 96 (range, 55-100) postoperatively. Western Ontario and McMaster Universities Arthritis Index score averaged 51 (range, 13-80) preoperatively and 3 (range, 0-35) postoperatively. No cases of subsidence were observed, and no revision surgeries were performed. Bone remodeling was typified by endosteal condensation and cortical hypertrophy in Gruen zones 2, 3, 5, and 6. At 5-year follow-up, the uncemented, metaphyseal-engaging short stem was stable and exhibited proximal bone remodeling closer to the metaphysis than conventional stems. Short-stem, metaphyseal-engaging femoral implants can meet the goals of a successful THA.

The purpose of this study was to determine whether differences in clinical, functional, or radiographic outcomes existed at 5-year follow-up between patients who underwent computer-assisted or manual total knee arthroplasty (TKA). Seventy-eight consecutive TKAs were performed by a single surgeon who had extensive experience performing computer-assisted and manual TKA. The manual group (n=40) and computer-assisted group (n=38) were similar with regard to age, sex, diagnosis, body mass index, surgical technique, implants, perioperative management, Knee Society scores, and anteroposterior mechanical axis. Sixty-three (manual group, n=34; computer-assisted group, n=29) patients were available for final follow-up. At 5-year follow-up, no statistically significant differences were found in Knee Society knee score (P=.289), function score (P=.272), range of motion (P=.284), pain score (P=.432), or UCLA activity score (P=.109) between the 2 groups. Postoperative radiographs showed a significant difference in the mechanical axis (P=.004) between the 2 groups; however, both groups achieved a neutral mechanical axis of ±3° (computer-assisted group mean, 2.0°; manual group mean, -0.24°).When TKA was performed by an experienced surgeon, no significant difference was identified at 5-year follow-up between patients who underwent computer-assisted vs manual TKA.

Introduction: The use of computer-assisted surgery (CAS) offers the experienced surgeon the ability to improve limb and implant alignment and reduce outliers. Two recent high quality meta-analyses have demonstrated that CAS can produce more accurate and precise limb alignment results. It has not been clearly established within the literature whether these benefits translate to improved patient outcomes. A previous case-controlled study by this author demonstrated no significant difference in clinical, functional, or radiographic outcomes between CAS and manual TKA at short term follow-up. We attributed these results to the improvements in the performance of manual TKA that had been realized through the learning effects afforded by working extensively with an intraoperative navigation system. The purpose of the present study was to determine whether any differences in clinical, functional, or radiographic outcomes could be elicited between patients who underwent either CAS or manual TKA at 5 year follow-up.

Introduction Patient specific instruments (PSI) and computer-assisted surgery (CAS) are innovative technologies that offer the potential to improve the accuracy and reproducibility with which a total knee arthroplasty (TKA) is performed. It has not been established whether clinical, functional, or radiographic outcomes between PSI, CAS, and manual TKA differ in the hands of an experienced TKA surgeon. The purpose of this study was to evaluate clinical, functional and radiographic outcomes between TKA performed with PSI, CAS, and manual instruments at short-term follow-up. Our hypothesis was that at early follow-up, we would be unable to elucidate any significant differences between the groups using the most commonly utilized outcomes measures. Methods 40 PSI, 38 CAS, and 40 manual TKA were performed by a single surgeon. The groups were similar in regards to age, sex, and preoperative diagnosis. The Knee Society Scoring System was used to evaluate patient clinical and functional outcome scores preoperatively and at 1 and 6 months postoperatively. Long-standing AP radiographs were obtained pre and postoperative to evaluate mechanical axis alignment. Results PSI, CAS, and manual TKA produced similar interval improvements in clinical and functional outcomes at both 1 and 6-months postoperative. Knee Society Knee scores were on average 88.5, 72.5, and 69.3 for PSI, CAS, and manual TKA at 1 month and 99.4, 83.4, and 84.6 at 6 months postoperative. Knee Society Function scores were on average 65.9, 49.3, and 48.4 for PSI, CAS, and manual TKA at 1 month and 86.3, 66.2, and 61.2 at 6 months postoperative. Although PSI tended to have higher absolute Knee and Function scores at 1 and 6 months postoperative, the interval change from preoperative to postoperative between each group was similar. Postoperative mechanical axis alignment was not significantly different between PSI, CAS, and manual TKA (1.0âi?½°, 2.0âi?½°, and −0.2âi?½°, respectively). Discussion This study suggests that in the hands of an experienced arthroplasty surgeon, PSI, CAS and manual TKA produce similar interval improvements in clinical, functional, and radiographic outcomes at short-term follow-up. These results may reflect the ability of an arthroplasty-trained academic surgeon to perform a TKA accurately with multiple technologies. These findings may also represent the lack of sensitivity and inability of commonly utilized evaluation tools, like plain radiographs and the Knee Society Scoring System, to adequately differentiate small differences in outcomes and limb alignment, if differences do indeed exist. Long-term follow-up will help establish whether these TKA technologies continue to demonstrate equivalent clinical and functional interval improvements.

Computer-assisted surgery (CAS) is a tool developed to allow accurate limb and implant alignment in total knee arthroplasty [TKA]. The strength of the technology is that it allows the surgeon to assess soft tissue balance and ligament laxity in flexion and extension. The accuracy of this ligament balancing technology depends upon an accurate determination of femoral component size. This size is established with intraoperative surface registration techniques. Customised instrumentation (CI) is a measured resection technique in which component size is established on preoperative 3D MRI reconstructions. The purpose of this study is to determine how these two computer-based technologies compare with regard to the accuracy with which femoral component size is established in TKA. 67 TKA were performed using CI and 30 TKA were performed using CAS by a single surgeon. CI-predicted and CAS-predicted femoral component size were compared to actual component selection. The process by which CI and CAS perform an anatomic registration was evaluated. The CI and CAS systems accurately predicted surgeon-selected femoral component size in 89% and 43% of cases, respectively (p The CI system was both more accurate and more precise than the CAS navigation system in predicting femoral component size in TKA. CI utilises preoperative MR imaging to generate femoral component sizing based on optimizing medial-lateral fit with a measured posterior femoral bone resection. CAS utilises surface registration techniques based on anatomic site registration that may be subject to intraoperative measurement error due to difficult visualization (femoral epicondyles), inherent subjectivity (Whiteside9s line) or anatomic variation (hypoplastic posterior condyles). CI bases implant sizing solely on reproducing an anatomical fit and a measured resection technique, whereas CAS attempts to balance an anatomic fit with optimal soft tissue balancing. In this study, the surgeon9s final component selection was more likely to be in accordance with the CI rather than the CAS sizing algorithm. The CI system was capable of accurate femoral component placement in TKA. This study suggests that intraoperative surface registration may not be as accurate as preoperative 3D MRI reconstructions for establishing optimal femoral component sizing. Surgeons using intraoperative navigation based surface registration need to be aware of this when making femoral component size selection, establishing ligament balance, and determining femoral rotation.

Elevated levels of low-density lipoprotein cholesterol (LDL-C) in plasma are a major contributor to cardiovascular disease, which is the leading cause of death worldwide. Genome-wide association studies (GWAS) have identified 95 loci that associate with control of lipid/cholesterol metabolism. Although GWAS results are highly provocative, direct analyses of the contribution of specific allelic variations in regulating LDL-C has been challenging due to the difficulty in accessing appropriate cells from affected patients. The primary cell type responsible for controlling cholesterol and lipid flux is the hepatocyte. Recently, we have shown that cells with hepatocyte characteristics can be generated from human induced pluripotent stem cells (iPSCs). This finding raises the possibility of using patient-specific iPSC-derived hepatocytes to study the functional contribution of GWAS loci in regulating lipid metabolism. To test the validity of this approach, we produced iPSCs from JD a patient with mutations in the low-density lipoprotein receptor (LDLR) gene that result in familial hypercholesterolemia (FH). We demonstrate that (1) hepatocytes can be efficiently generated from FH iPSCs; (2) in contrast to control cells, FH iPSC-derived hepatocytes are deficient in LDL-C uptake; (3) control but not FH iPSC-derived hepatocytes increase LDL uptake in response to lovastatin; and (4) FH iPSC-derived hepatocytes display a marked elevation in secretion of lipidated apolipoprotein B-100. Conclusion: Cumulatively, these findings demonstrate that FH iPSC-derived hepatocytes recapitulate the complex pathophysiology of FH in culture. These results also establish that patient-specific iPSC-derived hepatocytes could be used to definitively determine the functional contribution of allelic variation in regulating lipid and cholesterol metabolism and could potentially provide a platform for the identification of novel treatments of cardiovascular disease. (HEPATOLOGY 2012;56:2163-2171)

Various methods of skin closure exist in joint replacement surgery. Although subcuticular skin closure techniques offer an aesthetic advantage over conventional skin stapling, no measurable differences have been reported. Furthermore, newer barbed sutures, such as the V-Loc absorbable suture (Covidien, Mansfield, Massachusetts), theoretically distribute tension evenly through the wound and help decrease knot-related complications. The purpose of this study was to evaluate whether wound complication rates were (1) lower in V-Loc closure cases as theoretically suggested, (2) lower for subcuticular closure vs staples, and (3) significantly different for knee and hip joint reconstruction.A retrospective chart review was conducted of 278 consecutive cases of primary joint reconstruction performed by a single surgeon (L.P.). The study group comprised 106 men and 161 women. Average patient age at surgery was 63 years (range, 18-92 years), and average body mass index of the cohort was 33.7 kg/m(2) (range, 25-51 kg/m(2)). Skin was closed via staple gun or subcuticular stitch (3-0 Biosyn [Covidien] vs V-Loc). Seven (3.9%) wound complications occurred in 181 cases closed with staples. Four (7.8%) wound complications occurred in 51 cases closed via subcuticular Biosyn suture. Six (13.0%) wound complications occurred in 46 cases closed with V-Loc suture. The staple group had a lower rate of complications when compared with the suture group as a whole (P=.033) and when compared specifically with the V-Loc suture group (P=.017).

INTRODUCTION:Patient-specific guides (PSG) and computer-assisted navigation (CAN) are technologies that have been developed to improve the accuracy and reproducibility of total knee arthroplasty (TKA). The purpose of this study is to compare the methodology by which a PSG system and an intraoperative navigation system (CAN) perform an anatomical registration and correctly predict femoral component size in TKA.METHODS:One hundred and eleven PSG TKA were performed, 30 of which were concurrently evaluated with CAN. PSG-predicted and CAN-predicted femoral component size were compared with the actual component selection. The process by which PSG and CAN determines component sizing was evaluated.RESULTS:The PSG system was both more accurate and more precise than the CAN navigation system in predicting femoral component size in TKA.CONCLUSION:In this study, the surgeon's final component selection was more likely to be in accordance with the PSG rather than the CAN sizing algorithm. This study suggests that intraoperative surface registration may not be as accurate as preoperative three-dimensional magnetic resonance imaging reconstructions for establishing optimal femoral component sizing.

Review on RAF1 (v-raf-1 murine leukemia viral oncogene homolog 1), with data on DNA, on the protein encoded, and where the gene is implicated.

Review on NOTCH1 (Notch homolog 1, translocation-associated (Drosophila)), with data on DNA, on the protein encoded, and where the gene is implicated.

BACKGROUND:It is not known if surgeons who place women of reproductive age on thyroid hormone replacement (levothyroxine, LT4) routinely inform them of the increased LT4 demands with future pregnancy. In addition, it is not clear whether reading the 2007 Endocrine Society's "Guidelines on the Management of Thyroid Dysfunction during Pregnancy and Postpartum" influences the role of the surgeon in patient education. The objective of this study was to identify the role of the surgeon in patient education at the time of initiation of LT4 therapy.METHODS:A two-sided one-page survey was distributed to the 260 surgeons attending the 2009 American Association of Endocrine Surgeons' meeting. Of those distributed, 109 (42%) surgeons returned the survey.RESULTS:Although only 26/109 (23%) read the 2007 Endocrine Society's "Guidelines on the Management of Thyroid Dysfunction during Pregnancy and Postpartum," reading the guidelines was associated with a significantly greater likelihood of informing patients of higher LT4 requirements with pregnancy (p < 0.0001). Eighty-five percent of those who read the guidelines "often" or "always" informed patients of higher LT4 requirements with future pregnancy, whereas only 44% of those who did not read the guidelines provided the same level of education. After controlling for surgeon sex, academic versus private practice, years in practice, and number of surgeries performed in 2008, the only independent predictor of patient education was reading the guidelines (p = 0.006). On multivariable analysis, surgeon volume was associated with reading the guidelines (p = 0.006). The mean number of thyroid surgeries performed by those who read the guidelines versus those who did not was 164.46 +/- 16.98 versus 115.01 +/- 8.27 (p = 0.005).CONCLUSION:Surgeons who read the Endocrine Society's "Guidelines on the Management of Thyroid Dysfunction during Pregnancy and Postpartum" were significantly more likely to inform patients of the need for higher LT4 doses with pregnancy. Thyroid surgery volume was associated with guideline awareness.

BACKGROUND:Pheochromocytoma is a neuroendocrine (NE) tumor of the adrenal medulla for which surgical resection is the only therapy. However, 10-46% of tumors are metastatic or have malignant features, and are often inoperable. Our lab has demonstrated the importance of the Notch1 signaling pathway in NE neoplasia, indicating that this pathway could be a target for emergent treatments in pheochromocytoma. It has recently become clear that histone deacetylase (HDAC) inhibitors influence Notch1 signaling. We hypothesized that the HDAC inhibitor Sodium Butyrate (NaB) might activate Notch1 in pheochromocytoma resulting in altered tumor cell proliferation.METHODS:Pheochromocytoma (PC-12) cells were treated with increasing concentrations of NaB. MTT cellular proliferation assay was used to determine the effect of NaB on PC-12 cell growth. Expression of Notch1, NE markers, and cell cycle proteins was studied using Western analysis.RESULTS:Untreated PC-12 cells lack Notch1 activity. Treatment with NaB led to a dose-dependent induction of Notch1 signaling, reduction of NE markers ASCL1 and CgA, and a significant reduction in cellular proliferation. Levels of expression of cyclin D1, p21, cleaved PARP, and cleaved caspase 3 proteins indicated the presence of cell cycle arrest and apoptosis following NaB treatment.CONCLUSION:NaB activated Notch1 signaling, inhibited cellular proliferation, reduced NE markers, and induced cell cycle arrest and apoptosis in pheochromocytoma cells. This data indicates that activation of Notch1 signaling is a promising potential therapy or palliative measure for pheochromocytoma that warrants further investigation.

The clinical significance of papillary thyroid microcarcinoma (PTMC) is debated, and therefore the rise in incidence of PTMC creates management dilemmas. The following study evaluates factors influencing decisions to treat.