Implementation of a Perioperative Venous Thromboembolism Prophylaxis Program for Patients Undergoing Radical Cystectomy on an Enhanced Recovery After Surgery Protocol.

BACKGROUND: Novel venous thromboembolism (VTE) prophylaxis programs, including postdischarge pharmacologic prophylaxis, have been associated with decreased VTE rates. Such practices have not been widely adopted in managing radical cystectomy (RC) patients. OBJECTIVE: To evaluate the effect of a perioperative VTE prophylaxis program on VTE rates after RC. DESIGN, SETTING, AND PARTICIPANTS: Single-institution, nonrandomized, pre- and post-intervention analysis of 319 patients undergoing RC at Brigham and Women's Hospital between July 2011 and April 2017. Patient and outcome data were prospectively collected as part of the American College of Surgeons National Surgical Quality Improvement Program. INTERVENTION: Before June 2015, patients only received postoperative pharmacologic and mechanical VTE prophylaxis in the inpatient setting. Starting June 2015, a perioperative VTE prophylaxis program was implemented as part of an enhanced recovery after surgery (ERAS) protocol, including a 28-d course of postdischarge enoxaparin. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary outcome was 30-d postoperative VTE rate. Secondary outcomes were perioperative bleeding rates, 30-d complication, readmission, and mortality rates, and length of stay. Univariate analysis was performed comparing outcomes between pre- and post-intervention cohorts. RESULTS AND LIMITATIONS: Of the 319 patients who underwent RC, 210 (66%) were in the pre- and 109 (34%) in the post-intervention cohort. VTE rate was significantly lower in the post-intervention cohort (n=1, 0.9% vs n=13, 6.2%; p=0.04). Rates of perioperative bleeding (35% vs 33%; p=0.80) and 30-d readmissions related to bleeding (1% vs 3.7%; p=0.19) did not differ significantly. Single-institution data limits generalizability, and patient compliance with postdischarge enoxaparin was unknown. CONCLUSIONS: Implementation of a perioperative VTE prophylaxis program as part of an ERAS protocol that includes extended postdischarge pharmacologic prophylaxis was associated with decreased rate of VTE events after RC. Perioperative bleeding and readmissions related to bleeding did not increase with this intervention. PATIENT SUMMARY: This study evaluated whether clotting complication rates after radical cystectomy (RC) for bladder cancer can be reduced by implementing a new postoperative care pathway. This pathway reduced rates of clotting complications without increasing bleeding rates and should be considered for all patients undergoing RC.

Multilevel Analysis of Readmissions After Radical Cystectomy for Bladder Cancer in the USA: Does the Hospital Make a Difference?

BACKGROUND: Hospitals are increasingly being held responsible for their readmissions rates. The contribution of hospital versus patient factors (eg, case mix) to hospital readmissions is unknown. OBJECTIVE: To estimate the relative contribution of hospital and patient factors to readmissions after radical cystectomy (RC) for bladder cancer. DESIGN, SETTING, AND PARTICIPANTS: We identified individuals who underwent RC in 2014 in the Nationwide Readmissions Database (NRD). The NRD is a nationally representative (USA), all-payer database that includes readmissions at index and nonindex hospitals. Survey weights were used to generate national estimates. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The main outcome was readmission within 30 d after RC. Using a multilevel mixed-effects model, we estimated the statistical association between patient and hospital characteristics and readmission. A hospital-level random-effects term was used to estimate hospital-level readmission rates while holding patient characteristics constant. RESULTS AND LIMITATIONS: We identified a weighted sample of 7095 individuals who underwent RC at 341 hospitals in the USA. The 30-d readmission rate was 29.5% (95% confidence interval [CI] 27.8-31.2%), ranging from 1.4% (95% CI 0.6-2.2%) in the bottom quartile to 73.6% (95% CI 68.4-78.7) in the top. In our multilevel model, female sex and comorbidity score were associated with a higher likelihood of readmission. The hospital random-effects term, encompassing both measured and unmeasured hospital characteristics, contributed minimally to the model for readmission when patient characteristics were held constant at population mean values (pseudo-R2<0.01% for hospital effects). Surgical volume, bed size, hospital ownership, and academic status were not significantly associated with readmission rates when these terms were added to the model. CONCLUSIONS: After adjusting for patient characteristics, hospital-level effects explained little of the large between-hospital variability in readmission rates. These findings underscore the limitations of using 30-d post-discharge readmissions as a hospital quality metric. PATIENT SUMMARY: The chance of being readmitted after radical cystectomy varies substantially between hospitals. Little of this variability can be explained by hospital-level characteristics, while far more can be explained by patient characteristics and random variability.

Intravesical Extrusion of a Single-Incision Midurethral Sling Anchor With a Simple Transurethral Resection Technique: A Case Report.

Single-incision midurethral slings were introduced in 2006 with the goal of providing shorter operative time, less postoperative pain, and decreased rates of injury to surrounding structures (eg, bladder and/or obturator nerve). Although unrecognized bladder injury during SIMS placement is a rare complication, it can lead to irritative voiding symptoms and recurrent urinary tract infections. We present the case of minimally invasive approach to remove an extruded sling.

Sensory nerve degeneration in a mouse model mimicking early manifestations of familial amyloid polyneuropathy due to transthyretin Ala97Ser.

AIMS: Sensory nerve degeneration and consequent abnormal sensations are the earliest and most prevalent manifestations of familial amyloid polyneuropathy (FAP) due to amyloidogenic transthyretin (TTR). FAP is a relentlessly progressive degenerative disease of the peripheral nervous system. However, there is a lack of mouse models to replicate the early neuropathic manifestations of FAP. METHODS: We established human TTR knock-in mice by replacing one allele of the mouse Ttr locus with human wild-type TTR (hTTRwt ) or human TTR with the A97S mutation (hTTRA97S ). Given the late onset of neuropathic manifestations in A97S-FAP, we investigated nerve pathology, physiology, and behavioural tests in these mice at two age points: the adult group (8 - 56 weeks) and the ageing group (> 104 weeks). RESULTS: In the adult group, nerve profiles, neurophysiology and behaviour were similar between hTTRwt and hTTRA97S mice. By contrast, ageing hTTRA97S mice showed small fibre neuropathy with decreased intraepidermal nerve fibre density and behavioural signs of mechanical allodynia. Furthermore, significant reductions in sural nerve myelinated nerve fibre density and sensory nerve action potential amplitudes in these mice indicated degeneration of large sensory fibres. The unaffected motor nerve physiology replicated the early symptoms of FAP patients, that is, sensory nerves were more vulnerable to mutant TTR than motor nerves. CONCLUSIONS: These results demonstrate that the hTTRA97S mouse model develops sensory nerve pathology and corresponding physiology mimicking A97S-FAP and provides a platform to develop new therapies for the early stage of A97S-FAP.

Magnetic Resonance Spectroscopy in Living-Donor Liver Transplantation.

OBJECTIVE: The purpose of this study is to evaluate the accuracy rate of the one breath-hold single voxel hydrogen-1 magnetic resonance spectroscopy (MRS) in comparison with intraoperative biopsy for liver fat quantification in living-donor liver transplantation. MATERIALS AND METHODS: A total of 80 living liver donors participated in this study. Each patient underwent both MRS and intraoperative biopsy for evaluation of liver fatty content. MRS was performed using 1.5-T magnetic resonance imaging and placed in segments 2-4, 5-8, and left lateral segment for each donor. Accuracy was assessed through receiver operating characteristic curve analysis. Sensitivity and specificity of MRS fat fractions were also calculated. RESULTS: Eighty living-donor liver transplantation donors were enrolled in this study. There was no fatty liver in 59 subjects (73.8%), 5% to 10% fatty liver in 17 subjects, 11% to 15% fatty liver in 3 subjects, and >16% fatty liver in 1 subject. MRS fat fraction showed excellent parameters to predict between normal liver and fatty liver groups (1.85% ± 0.98, 8.13% ± 3.52, respectively; P < .0001). Linear regression between MRS fat fraction and pathology grading showed high correlation (R(2) = 0.7092). Pearson correlation revealed high correlation between MRS and pathology results (r = 0.936), poor correlation between body mass index and pathology results (r = 0.390). The sensitivity and specificity for detection of liver steatosis in MRS fat fraction were 95.2% and 98.3%, respectively. CONCLUSION: (1)H MRS fat fraction is a highly precise and accurate method in quantification of hepatic steatosis for the living donor and can be finished in a single breath-hold.

Pharmacokinetic Analysis of Dynamic Contrast-Enhanced Magnetic Resonance Imaging for Distinguishing Hepatocellular Carcinoma From Cholangiocarcinoma in Pre-Liver Transplantation Evaluation.

OBJECTIVE: Liver transplantation for intrahepatic cholangiocarcinoma is notorious for rapid recurrence with poor survival rate postoperatively and has therefore been discontinued in most centers. The purpose of this study is to distinguish hepatocellular carcinoma (HCC) from cholangiocarcinoma in pretransplantation imaging evaluation by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). MATERIALS AND METHODS: From January 2014 to September 2015, 19 patients were included in the study, with a mean age of 62.8 years. All subjects underwent pretransplantation DCE-MRI and surgical excision or core biopsy. The DCE-MRI parameters were measured using the Tofts model 1999. Statistical analysis included nonparametric tests and area under the curve for the receiver operating characteristic. RESULTS: Fourteen HCCs and 5 cholangiocarcinomas were diagnosed by surgical pathology. The mean size of tumor was 6.4 cm (range, 1.5 cm to 13.7 cm). All DCE-MRI parameters were calculated as the ratio between the tumor and normal liver parenchyma and K(trans) (1/min) was used as a distinguishing parameter between the two tumors. K(trans) was higher in the cholangiocarcinoma group (1.89 ± 1.13) than in the HCC group (0.46 ± 0.35). Univariate analysis revealed that K(trans) has a high significant difference (P = .001). The optimal K(trans) value cutoffs were 1 or more (area under the curve = 0.971) for detection of HCCs or cholangiocarcinomas. CONCLUSION: The analysis of DCE-MRI with the kinetic model (Tofts, 1999) presents a new and practical approach indiscrimination of HCC from cholangiocarcinoma for pretransplantation imaging evaluation.

Causes of hospital readmissions after urologic cancer surgery.

OBJECTIVES: The Hospital Readmissions Reduction Program mandates reimbursement reductions to hospitals with higher than expected rates of readmissions. We examine causes and predictors of readmissions following major procedures in urologic oncology. MATERIALS AND METHODS: Using the American College of Surgeons National Surgical Quality Improvement Program database, patients undergoing radical prostatectomy (RP), radical (RN) or partial nephrectomy (PN), and radical cystectomy (RC) during the year 2012 were abstracted. Rates of unplanned readmission within 30 days after surgery, as well as causes of readmission, were identified. Multivariable logistic regression models were fitted to examine the association between patient perioperative factors and odds of readmission. RESULTS: Overall, we observed a 5.5% unplanned 30-day readmission rate. Readmission rates for patients treated with RP, RN, PN, and RC were 4.1%, 5.2%, 4.5%, and 15.9%, respectively. For each procedure, approximately two-third of readmissions occurred within the first 10 days following hospital discharge. Commonest causes of readmission after RP included thromboembolic (13.6%), wound (12.2%), renal/genitourinary (12.2%), and gastrointestinal (11.8%); after RN, wound (12.9%) and gastrointestinal (12.9%); after PN, renal/genitourinary (19.6%), cardiovascular (9.8%), and bleeding/hematoma (9.8%); and after RC, renal/genitourinary (15.5%), wound (14.8%), and sepsis/infection (14.1%). RC was significantly associated with readmission. Patients undergoing open RP or PN were more likely to be readmitted relative to their minimally invasive counterparts (odds ratio = 1.53, 95% CI: 1.12-2.08, P = 0.007 and odds ratio = 2.51, 95% CI: 1.38-4.55, P = 0.003, respectively). CONCLUSIONS: Readmissions are relatively common following major urologic oncology procedures. Compared with RP, RN, or PN, RC patients experience the highest burden of readmission. Venous thromboembolism is a common modifiable cause of readmission following urologic cancer surgery. Minimally invasive approach is associated with decreased odds of readmission following RP and PN.

Tissue-Engineered Skin Substitutes.

BACKGROUND: Skin substitutes are frequently used by plastic surgeons today to treat a wide variety of cutaneous defects. They provide methods to heal wounds while minimizing donor sites. They are commonly used in burns, acute wounds, and chronic wounds. METHODS: The authors reviewed the literature on both the development of skin substitutes and their use today. The authors focused their work on what are currently the more commonly used types of skin substitutes in the United States. There is a wide interest in human-derived placental products, which will be the subject of a future publication. RESULTS: Commonly used skin substitutes include semisynthetic dermal scaffolds, allogenic cell constructs, and cellular and decellularized allogenic or xenogenic sources. For semisynthetic dermal scaffolds and allogenic cell constructs, there have been large clinical trials demonstrating their efficacy. CONCLUSIONS: Skin substitutes represent great progress for plastic surgery and provide several advances and options with which to heal wounds. More studies are needed to guide surgeons into the most appropriate use of these materials. Future developments, including advances in scaffolds, stem cells, and tissue processing, are likely to produce even more clinical options for our patients.

Restoration of erectile function with intracavernous injections of endothelial progenitor cells after bilateral cavernous nerve injury in rats.

Endothelial progenitor cells (EPCs) are bone marrow-derived endothelial cells capable of circulating, proliferating, and differentiating into mature endothelial cells. Circulating EPCs can be directly recruited to some extent at sites of injury, and their administration could accelerate repair or endothelialization of the damaged tissue. We investigated the effects of intracavernous injections of EPCs into the corpora cavernosa of rats with erectile dysfunction (ED) caused by bilateral cavernous nerve (CN) injury. Overall, 24 male Sprague-Dawley rats were randomized into three groups: sham surgery, vehicle-only, or EPC treatment. Rats in the EPC treatment and vehicle-only groups were subjected to bilateral CN injury before injection of EPCs or vehicle, respectively, into the corpora cavernosa. Four weeks after surgery, erectile function was assessed by measuring maximum intracavernosal pressure (ICP), change in ICP, area under the ICP curve, and ratio of change in ICP and mean arterial pressure (MAP; ΔICP/MAP). Penile tissue was histomorphometrically analyzed for the expression of neural nitric oxide synthase (nNOS), neurofilament-1 (NF-1), von Willebrand factor (vWF), endothelial NOS (eNOS), and smooth muscle cell content. Maximum ICP and all other functional parameters of erectile function were significantly reduced in the vehicle-only group vs. the sham and EPC treatment groups (all p < 0.001). Smooth muscle cell content was decreased in the vehicle-only vs. the sham and EPC treatment groups (both p < 0.01). Expressions of vWF and eNOS in the dorsal artery were significantly higher in the EPC treatment than the vehicle-only group (p < 0.05). In conclusion, EPC treatment restored erectile function in a rat model of bilateral CN injury through recruitment of EPCs toward the dorsal artery and preservation of smooth muscle cells in the corpus cavernosum. These findings elucidate the therapeutic potential of EPCs for treating ED in humans.

Human herpes virus reactivations and dynamic cytokine profiles in patients with cutaneous adverse drug reactions --a prospective comparative study.

BACKGROUND: Sequential human herpes virus (HHV) reactivation is well known in drug reaction with eosinophilia and systemic symptom (DRESS), but such a phenomenon has seldom studied in other types of cutaneous adverse drug reactions (cADRs). Moreover, the association between viral reactivations and cytokine or chemokine changes is largely unknown. We aimed to evaluate the viral reactivation rates of HHV-6, HHV-7, Epstein-Barr virus (EBV), and cytomegalovirus (CMV) in different cADRs and their impacts on clinical prognosis. Cytokine and chemokine changes with viral reactivations were also examined. METHODS: A prospective study was conducted to monitor the viral statuses of patients with different cADRs by polymerase chain reaction and serum-specific antibody titers. Changes in plasma cytokine and chemokine levels were also evaluated by sequential blood samples. RESULTS: Among the various cADRs, HHV-6 reactivation was only observed in DRESS, but EBV and CMV could be detected in other cADRs. Many proinflammatory cytokines and chemokines, including interleukin (IL)-1ß, IL-2, IL-6, interferon-γ, tumor necrosis factor-α, were significantly lower in DRESS patients with HHV-6 reactivation when compared to those without HHV-6 reactivation. In addition, these mediators were significantly lower before and during HHV-6 reactivation, compared to cytokine levels after HHV-6 reactivation in the same patient. CONCLUSION: HHV-6 reactivation was only observed in DRESS patients, not in any other cADR. In DRESS patients, some proinflammatory cytokines were significantly lower before or during HHV-6 reactivation.

Candidate tumor suppressor B-cell translocation gene 3 impedes neoplastic progression by suppression of AKT.

BTG3 (B-cell translocation gene 3) is a p53 target that also binds and inhibits E2F1. Although it connects two major growth-regulatory pathways functionally and is downregulated in human cancers, whether and how BTG3 acts as a tumor suppressor remain largely uncharacterized. Here we present evidence that BTG3 binds and suppresses AKT, a kinase frequently deregulated in cancers. BTG3 ablation results in increased AKT activity that phosphorylates and inhibits glycogen synthase kinase 3ß. Consequently, we also observed elevated ß-catenin/T-cell factor activity, upregulation of mesenchymal markers, and enhanced cell migration. Consistent with these findings, BTG3 overexpression suppressed tumor growth in mouse xenografts, and was associated with diminished AKT phosphorylation and reduced ß-catenin in tissue specimens. Significantly, a short BTG3-derived peptide was identified, which recapitulates these effects in vitro and in cells. Thus, our study provides mechanistic insights into a previously unreported AKT inhibitory pathway downstream of p53. The identification of an AKT inhibitory peptide also unveils a new avenue for cancer therapeutics development.

Inguinal hernia repair outcomes that utilized the modified Kugel patch without the optional onlay patch: a case series of 163 consecutive patients.

PURPOSE: The purpose of this study was to evaluate the efficacy and safety of the anterior Kugel herniorrhaphy approach when the onlay patch is omitted. METHODS: The study population comprised patients who underwent anterior Kugel herniorrhaphy without the onlay patch from 1 May 2009, to 31 June 2012. The onlay patch was omitted if the posterior wall defect did not exceed the inner Posiflex(®) ring diameter. After reviewing the clinical follow-up records and conducting telephone interviews, the postoperative results were recorded and analyzed. RESULTS: A total of 163 patients underwent 175 hernia repairs. One patient developed recurrence after undergoing our herniorrhaphy method. The most common postoperative complaints were mild soreness, indescribable discomfort, and foreign body sensations (11 patients). The mean operative time and hospital stay were 67 min and 2 days, respectively. More serious complications included one scrotal hematoma, one hydrocele, and one wound infection that resulted in epididymitis. CONCLUSIONS: The onlay patch can be omitted with low recurrence and complication rates if the posterior wall defects do not exceed the inner Posiflex(®) ring diameter.

Human germ cell formation in xenotransplants of induced pluripotent stem cells carrying X chromosome aneuploidies.

Turner syndrome is caused by complete or partial loss of the second sex chromosome and is characterized by spontaneous fetal loss in >90% of conceptions. Survivors possess an array of somatic and germline clinical characteristics. Induced pluripotent stem cells (iPSCs) offer an opportunity for insight into genetic requirements of the X chromosome linked to Turner syndrome. We derived iPSCs from Turner syndrome and control individuals and examined germ cell development as a function of X chromosome composition. We demonstrate that two X chromosomes are not necessary for reprogramming or maintenance of pluripotency and that there are minimal differences in gene expression, at the single cell level, linked to X chromosome aneuploidies. Formation of germ cells, as assessed in vivo through a murine xenotransplantation model, indicated that undifferentiated iPSCs, independent of X chromosome composition, are capable of forming germ-cell-like cells (GCLCs) in vivo. In combination with clinical data regarding infertility in women with X chromosome aneuploidies, results suggest that two intact X chromosomes are not required for human germ cell formation, qualitatively or quantitatively, but rather are likely to be required for maintenance of human germ cells to adulthood.

Vascular endothelial growth factor A improves quality of matured porcine oocytes and developing parthenotes.

Vascular endothelial growth factor is a multipotent angiogenic factor implicated in cell survival and proliferation. The objective was to determine effects of exogenous recombinant human VEGFA (or VEGFA165) in culture media on porcine oocyte maturation and parthenote development. Adding 5 ng/mL VEGFA to the culture medium improved the maturation rate of denuded oocytes (P < 0.05), although 5, 50, or 500 ng/mL did not significantly affect nuclear maturation of oocytes. Parthenotes from oocytes cultured either in in vitro maturation or in vitro culture medium supplemented with 5 or 50 ng/mL VEGFA had an improved blastocyst rate and increased total numbers of cells (P < 0.05). Moreover, those treated with 5 ng/mL of VEGFA had a higher hatched blastocyst rate (average of 121 cells per blastocyst). All VEGFA-treated oocytes had reduced apoptotic indices (P < 0.05), except for those with a higher dose (500 ng/mL) of VEGFA which had more apoptotic cells (P < 0.05). Adding 5 ng/mL VEGFA to oocytes during the last 22 h of in vitro maturation improved (P < 0.05) blastocyst rates and total numbers of cells, with reduced apoptosis indices similar to that of long-term (44 h) culture. Furthermore, Axitinib (VEGFR inhibitor) reversed the effects of VEGFA on parthenote development (P < 0.05). Follicular fluids from medium (2-6 mm) to large (>6 mm) follicles contained 5.3 and 7.0 ng/mL vascular endothelial growth factor protein, respectively, higher (P < 0.05) than concentrations in small (<2 mm) follicles (0.4 ng/mL). Also, VEGFA and its receptor (VEGFR-2) were detected (immunohistochemistry) in growing follicles and developing blastocysts. In addition, VEGFA inhibited caspase-3 activation in matured oocytes (P < 0.05). In conclusion, this is apparently the first report that VEGFA has proliferative and cytoprotective roles in maturing porcine oocytes and parthenotes. Furthermore, an optimal VEGFA concentration promoted porcine oocyte maturation and subsequent development.

Magnetic resonance fat quantification in living donor liver transplantation.

OBJECTIVE: Hepatic steatosis can cause substantial problems for both donors and recipients in living donor liver transplantation (LDLT). The aim of this study is to evaluate the accuracy of the magnetic resonance IDEAL (iterative decomposition of water and fat with echo asymmetry and least squares estimation) sequence in quantifying the liver fat during LDLT. MATERIALS AND METHODS: A total of 63 liver donors (29 men and 34 women ranging from 18 to 47 years old with a mean age of 30) who received both magnetic resonance imaging (MRI) and intraoperative liver biopsy were enrolled in this study. MR IDEAL IQ sequences were performed by 1.5-T MRI (Discovery 450; GE Healthcare, Milwaukee, Wis, United States) to estimate the liver fatty content. Accuracy was assessed through linear regression between fat fraction image and pathology grading. Sensitivity and specificity of MR IDEAL IQ fat fractions were also calculated. RESULTS: A total of 63 LDLTs were performed and with pathology grading. No fatty content was found in 48 donors (76.2%; group 1), 5% to 10% fatty liver in 11 donors (17.4%; group 2), 11% to 15% fatty liver in 2 donors (3.2%; group 3), and >16% fatty change in 2 donors (3.2%; group 4). MR IDEAL fat fraction results were excellent in prediction of the normal and fatty content and with good correlation with the pathology grading (2.9 ± 0.9, 8.3 ± 4.2, P < .0001). Linear regression between IDEAL image and pathology grading indicated a high accuracy rate (R(2) = 0.813, R(2) = 0.9286) for all 4 groups. The sensitivity and specificity for detection of liver steatosis in MRI fat fraction image were 100% and 77.1% (P < .0001, 95% confidence interval 0.000-1.000). CONCLUSION: MR IDEAL IQ sequencing is a highly precise and accurate method in quantifying hepatic steatosis for the living donor.

Hypoxia inducible factor 2α/insulin-like growth factor receptor signal loop supports the proliferation and Oct-4 maintenance of mouse germline stem cells.

Hypoxia inducible factor 2α (HIF-2α) is critical for primordial germ cell (PGC) survival as knockout of HIF-2α (HIF-2α(-/-)) decreases both expression of Oct-4 and PGC number in genital ridge. Hypoxia is known to stabilize HIF-2α protein from proteasomal degradation. However, little is known about the hypoxia-associated endocrinal signaling in HIF-2α expression. The current work demonstrates a role for an endocrine insulin-like growth factor-I receptor (IGF-IR)-PI3K/Akt-mTOR-HIF-2α regulatory loop in the proliferation and Oct-4 maintenance of PGC-like alkaline phosphatase positive mouse germline stem cells (AP(+)GSCs). We found that hypoxia greatly increased the cell proliferation and the levels of nuclear Oct-4/HIF-2α protein of AP(+)GSCs. The hypoxic-AP(+)GSCs presented stronger stemness ability for germ cell differentiation than normoxic, with expressions of c-KIT (differentiation germ cell marker), VASA (differentiation germ cell marker) and SCP3 (meiotic marker) using a renal capsule transplantation assay. Meanwhile, hypoxia significantly increased the expression levels of secreted-IGF-I and IGF-IR. The IGF-I dose dependently increased the HIF-2α expression levels in AP(+)GSCs; and, the inhibition of IGF-IR by RNA interference (shIGF-IR) or LY294002 (PI3K inhibitor)/Rapamycin (mTOR inhibitor) effectively suppressed the IGF-I- and/or hypoxia-induced HIF-2α and Oct-4 expression, suggesting that the IGF-IR and its downstream Akt/mTOR signaling are involved in the IGF-I/hypoxia effects. Additionally, knockdown of HIF-2α dramatically suppressed Oct-4 and IGF-IR protein levels in AP(+)GSC cells. In conclusion, the present study demonstrates a regulatory loop of IGF-IR-PI3K/Akt-mTOR-HIF-2α in proliferation and Oct-4 maintenance of PGC-like AP(+)GSCs under hypoxia. This finding provides insights into the niche endocrinology underlying early germ cell development.

Clinical feasibility of a novel biphasic osteochondral composite for matrix-associated autologous chondrocyte implantation.

OBJECTIVE: Matrix-associated autologous chondrocyte implantation has been used to treat cartilage defects. We developed a biphasic cylindrical osteochondral composite construct for such use, and conducted this study to determine its feasibility for treating osteochondral lesions in human knees. METHOD: Ten patients with symptomatic osteochondral lesions at femoral condyles were treated by replacing pathological tissue with the construct of dl-poly-lactide-co-glycolide, whose lower body was impregnated with ß-tricalcium phosphate and served as osseous phase. The construct had a chamber to load double-minced autologous cartilage, serving as source of chondrocytes. Osteochondral lesion was drill-fashioned a pit of identical dimension as the construct. Chondrocyte-laden construct was press-fit to fill the pit. Postoperative outcome was evaluated using Knee Injury and Osteoarthritis Outcome Score (KOOS) scale up to 24 months. Magnetic resonance image was taken, and sample tissue was collected with second-look arthroscopic needle biopsy at 12 months. Outcome parameters were primarily safety of surgery, and secondarily postoperative change in KOOS and regeneration of hyaline cartilage and cancellous bone. RESULTS: No patient experienced serious adverse events. Postoperative mean KOOS in "symptoms" subscale had not changed significantly from pre-operation until 24 months; whereas those in the other four subscales were significantly higher than pre-operation at 12 and 24 months. Second-look arthroscopy showed completely filled grafted sites, with regenerate cartilaginous surfaces flushed with surrounding native joint surface. Microscopically, regenerated cartilage appeared hyaline. CONCLUSION: This novel construct for chondrocyte implantation is safe for surgical application in knee. It repairs osteochondral lesions of femoral condyles by successful regeneration of hyaline cartilage.

Cirugía urológica en pacientes de 80 años y más: ¿es la edad un factor de riesgo para el desarrollo de complicaciones postoperatorias? / Urological surgery in patients 80 years and older: is age a risk factor for the development of postoperative complications?

La expectativa de vida ha ido aumentando en Chile y en el mundo, lo que ha causado un gran impacto a nivel del número de cirugías que se realiza en la población añosa. El objetivo de este trabajo es describir la experiencia de nuestro centro en cirugías urológicas en pacientes mayores de 80 años y analizar que factores aumentan el riesgo de complicaciones postquirúrgicas.Materiales y método: Análisis retrospectivo de 138 cirugías urológicas realizadas en 120 pacientes mayores de 80 años, durante los años 2000 a 2012. Se obtuvo información sociodemográfica, riesgo quirúrgico (ASA), tipo y duración de cirugía realizada, complicaciones post-operatorias (escala de Clavien) y tiempo de hospitalización. Los datos obtenidos fueron analizados mediante el programa SPSS v17. Se realizó análisis multivariado y se estableció el riesgo relativo para el desarrollo de complicaciones. Se consideró signi ficativo p<0,05. Resultado: La edad promedio de los pacientes fue de 84+/-3.7 años, 86.2 por ciento fueron hombres. El 96.7 por ciento presentaba algún tipo de comorbilidad, con predominio de hipertensión arterial (60,84 por ciento) y diabetes mellitus tipo 2 (24,16 por ciento). La mayoría de las intervenciones fue de complejidad intermedia (77.27 por ciento), donde la anestesia regional (56,8 por ciento) y la vía endo urológica (84,78 por ciento) fueron las más utilizadas, con un tiempo operatorio promedio de 62+/-52.4 minutos. El riesgo quirúrgico prevalente fue ASA2 (62.7 por ciento). El promedio de hospitalización fue de 2,8+/-2.7 días. El 15.21 por ciento de los pacientes presentó algún tipo de complicación, con predominio de clasifi cación tipo 1 de Clavien (38 por ciento). En el análisis multivariado se evidenció como factores de riesgo signi ficativos para complicaciones, edad mayor a 90 años (p=0.03), presencia de insu ciencia renal (p=0.01), portar 4 o más comorbilidades (p=0.04), cirugía mayor a 3 horas (p=0.03) y tener riesgo quirúrgico ASA3 (p=0.04)...

Life expectancy has been increasing in Chile and in the World. This has caused a great impact over the number of surgeries being performed in the elderly population. The aim of this paper is to describe the experience of our center in urological surgery in patients older than 80 years and analyze which factors increase the risk of postoperative complications.Materials and methods: Retrospective analysis of 138 urological surgeries performed in 120 patients older than 80 years, during the years 2000-2012. Sociodemographic information, surgical risk (ASA), type and duration of surgery, postoperative complications (Clavien scale) and length of hospitalization was obtained. The data were analyzed using SPSS v17. Multivariate analysis was performed and the relative risk for developing complications was established. Signi cance was p <0.05. Average age of the patients was 84 +/- 3.7 years, 86.2percentwere men. The 96.7 percenct had some kind of comorbidity, with prevalence of hypertension (60.84 percent) and diabetes mellitus type 2 (24.16 percent). Most of the interventions was of intermediate complexity (77.27percent), where regional anesthesia (56.8 percent) and endourological aproach (84.78 percent) were the most used, with average operative time of 62 +/- 52.4 minutes. Most common Surgical risk was ASA2 (62.7 percent). Average hospital stay was 2.8 +/- 2.7 days. 15.21 percent of patients had some type of complication, with a predominance of type 1 Clavien classication (38 percent). The multivariate analysis showed signi cant risk factors for complications: age greater than 90 years (p = 0.03), renal failure (p = 0.01), carrying 4 or more comorbidities (p = 0.04), surgery Langer than 3 hours (p = 0.03) and ASA3 surgical risk (p =.04). No mortality was reported in our series. In this study, although most of our patients underwent endourological procedures, we evidence that surgery in patients older than 80 years is feasible...