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Localized cartilage lesions in early osteoarthritis and acute joint injuries are usually treated surgically to restore function and relieve pain. However, a persistent clinical challenge remains in how to repair the cartilage lesions. We expressed doublecortin (DCX) in human adipose-derived stromal/stem cells (hASCs) and engineered hASCs into cartilage tissues using an in vitro 96-well pellet culture system. The cartilage tissue constructs with and without DCX expression were implanted in the knee cartilage defects of rabbits (n = 42) and monkeys (n = 12). Cohorts of animals were euthanized at 6, 12, and 24 months after surgery to evaluate the cartilage repair outcomes. We found that DCX expression in hASCs increased expression of growth differentiation factor 5 (GDF5) and matrilin 2 in the engineered cartilage tissues. The cartilage tissues with DCX expression significantly enhanced cartilage repair as assessed macroscopically and histologically at 6, 12, and 24 months after implantation in the rabbits and 24 months after implantation in the monkeys, compared to the cartilage tissues without DCX expression. These findings suggest that hASCs expressing DCX may be engineered into cartilage tissues that can be used to treat localized cartilage lesions. [ABSTRACT FROM AUTHOR]

Growth arrest-specific gene 6 (Gas6) is a cytokine that binds to receptor tyrosine kinases Tyro3, Axl, and Mer. Numerous studies have suggested that macrophage-derived Gas6 interacts with Axl to promote cancer progression, and Axl has been associated with poor clinical outcome. However, the expression and relevance of Gas6 in human breast cancer patients has not been studied. Analysis of tissue microarrays showed that Gas6 was highly expressed in ductal carcinoma in situ (DCIS) but markedly decreased in invasive breast cancer. Gas6 and Axl were weakly correlated, suggesting that their functions may not exclusively rely on each other. Analyses of publicly available databases showed significantly improved overall and relapse-free survival in patients with high Gas6 mRNA, particularly in luminal A breast cancers. These findings indicate that tumor-derived Gas6 is not overexpressed in invasive breast cancer, and may not be a negative prognostic factor in human breast cancer. [ABSTRACT FROM AUTHOR]

Energy expenditure decreases with age, but in the oldest-old, energy demand for maintenance of body functions increases with declining health. Uncoupling proteins have profound impact on mitochondrial metabolic processes; therefore, we focused attention on mitochondrial uncoupling protein genes. Alongside resting metabolic rate (RMR), two SNPs in the promoter region of UCP2 were associated with healthy aging. These SNPs mark potential binding sites for several transcription factors; thus, they may affect expression of the gene. A third SNP in the 3′-UTR of UCP3 interacted with RMR. This UCP3 SNP is known to impact UCP3 expression in tissue culture cells, and it has been associated with body weight and mitochondrial energy metabolism. The significant main effects of the UCP2 SNPs and the interaction effect of the UCP3 SNP were also observed after controlling for fat-free mass (FFM) and physical-activity related energy consumption. The association of UCP2/3 with healthy aging was not found in males. Thus, our study provides evidence that the genetic risk factors for healthy aging differ in males and females, as expected from the differences in the phenotypes associated with healthy aging between the two sexes. It also has implications for how mitochondrial function changes during aging. [ABSTRACT FROM AUTHOR]

Research has suggested that parenting behaviors and other parental factors impact the long-term outcome of children's posttraumatic stress disorder (PTSD) symptoms. In a sample of 62 children between the ages of one and six who experienced life-threatening traumas, PTSD was measured prospectively 2 years apart. Seven maternal factors were measured in a multi-method, multi-informant design. Both moderation and mediation models, with different theoretical and mechanism implications, were tested. Moderation models were not significant. Mediation models were significant when the mediator variable was maternal symptoms of PTSD or depression (measured at Time 1), self-report of maternal escape/avoidance coping (measured at Time 2), or self-report emotional sensitivity (measured at Time 2). Greater maternal emotional sensitivity was associated with greater Time 2 PTSD symptoms among children. Observational measures of emotional sensitivity as the mediator were not supported. Correlation of parents' and children's symptoms is a robust finding, however caution is warranted in attributing children's PTSD symptoms to insensitive parenting. [ABSTRACT FROM AUTHOR]

Various measures incorporated in geriatric assessment have found their way into frailty indices (FIs), which have been used as indicators of survival/mortality and longevity. Our goal is to understand the genetic basis of healthy aging to enhance its evidence base and utility. We constructed a FI as a quantitative measure of healthy aging and examined its characteristics and potential for genetic analyses. Two groups were selected from two separate studies. One group (OLLP for offspring of long-lived parents) consisted of unrelated participants at least one of whose parents was age 90 or older, and the other group of unrelated participants (OSLP for offspring of short-lived parents), both of whose parents died before age 76. FI scores were computed from 34 common health variables and compared between the two groups. The FI was better correlated than chronological age with mortality. The mean FI value of the OSLP was 31 % higher than that of the OLLP ( P = 0.0034). The FI increased exponentially, at an instantaneous rate that accelerated 2.0 % annually in the OLLP ( P = 0.024) and 2.7 % in the OSLP ( P < < 0.0001) consequently yielding a 63 % larger accumulation in the latter group ( P = 0.0002). The results suggest that accumulation of health deficiencies over the life course is not the same in the two groups, likely due to inheritance related to parental longevity. Consistent with this, sib pairs were significantly correlated regarding FI scores, and heritability of the FI was estimated to be 0.39. Finally, hierarchical clustering suggests that the OLLP and OSLP differ in their aging patterns. Variation in the FI is, in part, due to genetic variation; thus, the FI can be a phenotypic measure suitable for genetic analyses of healthy aging. [ABSTRACT FROM AUTHOR]

Leukocyte telomere length is widely considered a biomarker of human age and in many studies indicative of health or disease. We have obtained quantitative estimates of telomere length from blood leukocytes in a population sample, confirming results of previous studies that telomere length significantly decreases with age. Telomere length was also positively associated with several measures of healthy aging, but this relationship was dependent on age. We screened two genes known to be involved in telomere maintenance for association with the age-related decline in telomere length observed in our population to identify candidate longevity-associated genes. A single-nucleotide polymorphism located in the SIRT1 gene and another in the 3′ flanking region of XRCC6 had significant effects on telomere length. At each bi-allelic locus, the minor variant was associated with longer telomeres, though the mode of inheritance fitting best differed between the two genes. No statistical interaction was detected for telomere length between the SIRT1 and XRCC6 variants or between these polymorphisms and age. The SIRT1 locus was significantly associated with longevity ( P < 0.003). The frequency of the minor allele was higher in long-lived cases than in young controls, which coincides with the protective role of the minor variant for telomere length. In contrast, the XRCC6 variant was not associated with longevity. Furthermore, it did not affect the association of SIRT1 with exceptional survival. The association of the same variant of SIRT1 with longevity was near significant ( P < 0.07) in a second population. These results suggest a potential role of SIRT1 in linking telomere length and longevity. Given the differences between this gene and XRCC6, they point to the distinct impact that alternate pathways of telomere maintenance may have on aging and exceptional survival. [ABSTRACT FROM AUTHOR]

Single nucleotide polymorphism (SNP) interaction plays a critical role for complex diseases. The primary limitation of logistic regressions (LR) in testing SNP–SNP interactions is that coefficient estimates may not be valid because of numerous terms in a model. Multivariate adaptive regression splines (MARS) have useful features to effectively reduce the number of terms in a model. To study how MARS can address these drawbacks possibly better than LR, the power of MARS and LR with SNPs using the reference-coding and additive-mode scheme was compared using simulated data of ten SNPs for 400 subjects based on 1,000 replications for five interaction models. In overall scenarios, MARS performed better than LR. In the model with a dominant two-way interaction, the power range was 76–96% for MARS and 1–8% for LR in both coding schemes. In the dominant three-way interaction model, the power was 57–85% for MARS and less than 4% for LR. In the prostate cancer example, we evaluated the association between ten SNPs and prostate cancer risk in 649 Caucasians. The best model with one two-way and one three-way interaction was selected using MARS. The findings supported that MARS may provide a useful tool for exploring SNP–SNP interactions. [ABSTRACT FROM AUTHOR]

A telephone survey was conducted to identify predictors of treatment engagement in 83 cohabitating female partners of 83 Vietnam theater veterans with combat-related post-traumatic stress disorder (PTSD). The survey assessed veterans for their trauma history and PTSD symptoms. Partners were assessed for caregiver burden, patient–partner involvement, PTSD treatment engagement, self-efficacy relating to PTSD, beliefs about benefits of PTSD treatment, and PTSD treatment barriers. Significant predictors of partner PTSD treatment engagement were the couple’s income, patient–partner involvement, and partner caregiver burden. These findings have implications for family interventions that may increase partner PTSD treatment engagement and improve PTSD treatment outcome. [ABSTRACT FROM AUTHOR]

Rules of thumb for power in multiple regression research abound. Most such rules dictate the necessary sample size, but they are based only upon the number of predictor variables, usually ignoring other critical factors necessary to compute power accurately. Other guides to power in multiple regression typically use approximate rather than precise equations for the underlying distribution; entail complex preparatory computations; require interpolation with tabular presentation formats; run only under software such as Mathmatica or SAS that may not be immediately available to the user; or are sold to the user as parts of power computation packages. In contrast, the program we offer herein is immediately downloadable at no charge, runs under Windows, is interactive, self-explanatory, flexible to fit the user's own regression problems, and is as accurate as single precision computation ordinarily permits. [ABSTRACT FROM AUTHOR]

Regulatory T (Treg) cells mediate homeostatic peripheral tolerance by suppressing autoreactive T cells. Failure of host antitumor immunity may be caused by exaggerated suppression of tumor-associated antigen—reactive lymphocytes mediated by Treg cells; however, definitive evidence that Treg cells have an immunopathological role in human cancer is lacking. Here we show, in detailed studies of CD4+CD25+FOXP3+ Treg cells in 104 individuals affected with ovarian carcinoma, that human tumor Treg cells suppress tumor-specific T cell immunity and contribute to growth of human tumors in vivo. We also show that tumor Treg cells are associated with a high death hazard and reduced survival. Human Treg cells preferentially move to and accumulate in tumors and ascites, but rarely enter draining lymph nodes in later cancer stages. Tumor cells and microenvironmental macrophages produce the chemokine CCL22, which mediates trafficking of Treg cells to the tumor. This specific recruitment of Treg cells represents a mechanism by which tumors may foster immune privilege. Thus, blocking Treg cell migration or function may help to defeat human cancer. [ABSTRACT FROM AUTHOR]

Pseudarthrosis remains a significant problem in spinal fusion. The objective of our study was to investigate the effects of autologous growth factors (AGF) in instrumented transforaminal lumbar interbody spinal fusion (TLIF). A prospective review was carried out of 23 patients who underwent TLIF with application of AGF, with a minimum 2-year follow-up. Comparison with our historical cohort (without AGF application) was performed. Mean age at surgery was 44.3 years in the AGF treatment group. Twelve had a positive smoking history. Fourteen had undergone previous spinal surgeries. Thirteen received one-level fusions and ten received two-level fusions. The radiographic results showed a fusion rate of 100% in one-level fusions and 90% in two-level fusions. There was no significant difference in pseudarthrosis rates between the AGF treatment group and historical cohort. Excluding the cases with pseudarthrosis, there was faster bony healing in patients who had been treated with AGF application. This study indicates that although AGF may demonstrate faster fusions, it does not result in an overall increase in spinal fusion rates. Further studies are needed before AGF can routinely be used as an adjunct in spinal fusion. [ABSTRACT FROM AUTHOR]

Suppression of dendritic cell function in cancer patients is thought to contribute to the inhibition of immune responses and disease progression. Molecular mechanisms of this suppression remain elusive, however. Here, we show that a fraction of blood monocyte-derived myeloid dendritic cells (MDCs) express B7-H1, a member of the B7 family, on the cell surface. B7-H1 could be further upregulated by tumor environmental factors. Consistent with this finding, virtually all MDCs isolated from the tissues or draining lymph nodes of ovarian carcinomas express B7-H1. Blockade of B7-H1 enhanced MDC-mediated T-cell activation and was accompanied by downregulation of T-cell interleukin (IL)-10 and upregulation of IL-2 and interferon (IFN)-?. T cells conditioned with the B7-H1-blocked MDCs had a more potent ability to inhibit autologous human ovarian carcinoma growth in non-obese diabetic-severe combined immunodeficient (NOD-SCID) mice. Therefore, upregulation of B7-H1 on MDCs in the tumor microenvironment downregulates T-cell immunity. Blockade of B7-H1 represents one approach for cancer immunotherapy. [ABSTRACT FROM AUTHOR]

The purpose of this study was to determine ability of cyst aspiration and core biopsy to differentiate malignancies, and benign lesions needing intervention from benign complex cysts in the group of Bosniak 2F and 3 renal cysts. One hundred ninety-nine indeterminate complex renal cysts were biopsied under CT or US guidance using a coaxial system (19-G sheath, 20- or 21-G Chiba or Franseen or 18-G spring biopsy needle). Cytology, amylase, lipase, LDH, fat, protein, urea nitrogen, creatine, and culture and sensitivity were assessed in all patients, histopathology in 116, and flow cytometry in 32. In 179 patients (87.9%) a definitive diagnosis was made; in 20 the specimen was inadequate. Twenty of 28 malignancies were correctly diagnosed (sensitivity 0.71); 27 of 31 benign lesions needing intervention (sensitivity 0.87) and 128 of 140 benign complex cysts (sensitivity 0.91). All inconclusive biopsies were explored revealing six malignancies. There were four CT biopsy misdiagnoses: two renal cell carcinomas; one angiomyolipoma; and one abscess. Guided cyst puncture aspiration and core biopsy significantly altered management of Bosniak 3 and 2F renal cysts obviating surgery or invasive procedures in 70% of the patients with an affirmed diagnosis of benign complex cyst and rendering timely surgical and other interventions in the remaining patients. Long-term follow-up (mean 5.6 years) revealed no further misdiagnosis. [ABSTRACT FROM AUTHOR]

Poorer outcomes of treatment are reported in patients with spinal disorders who receive worker's compensation. The reason for their suboptimal outcomes is unclear. No study has examined the relationship between worker's compensation and SF-36 health status of patients with neck pain. The aim of our study was to compare the self-perceived health status of patients with neck pain receiving worker's compensation, with that of patients not receiving worker's compensation. A cross-sectional study was conducted on 2356 patients with neck pain who were evaluated at the 27 centers comprising the National Spine Network, between January 1998 and April 2000. The outcome measures used were the eight individual and two component scores of the SF-36 health survey. Of the 2356 patients, 171 (7%) were receiving worker's compensation. Bivariate analyses revealed seven individual scores (except General Health) and two summary scores of the SF-36 were significantly lower in patients receiving worker's compensation. After controlling for confounding covariates, worker's compensation status was a significant predictor of lower SF-36 scores for Physical Functioning (P<0.05). The results of this study indicate that worker's compensation status is associated with poorer Physical Functioning in patients presenting with neck pain. Another significant finding of the study is that confounding factors can exert major effects on the SF-36 scores obtained on normal validated instruments. [ABSTRACT FROM AUTHOR]

The topoisomerase I inhibitor 9-dimethylaminomethyl-10-hydroxycamptothecin (topotecan) was evaluated against a panel of xenografts comprising four lines of adult colon adenocarcinoma, three colon tumors derived from adolescents, six childhood rhabdomyosarcomas from previously untreated patients as well as sublines selected in vivo for resistance to vincristine and melphalan, and three lines of childhood osteogenic sarcoma. Efficacy was determined at maximal tolerated dose levels using intermittent i.p. administration [every 4 days for 4 doses (q4dx4)] or daily p.o. or i.p. administration 5 days per week for up to 20 courses. On a q4dx4 schedule, the maximum tolerated dose (MTD) was 12.5 mg/kg per administration, which caused marked weight loss and lethality in approximately 5% of the tumor-bearing mice. This schedule caused significant growth inhibition (but no tumor regression) in advanced adult colon adenocarcinomas. The minimal treated/control (T/C) ratios were 0.49, 0.54, and 0.3 for three of the tumor lines and were achieved at 18-21 days after the initiation of treatment. In contrast, rhabdomyosarcomas were considerably more sensitive, with T/C ratios being < 0.1 for three lines, whereas topotecan was less active against two other rhabdomyosarcoma xenografts (minimal T/C ratios, 0.17 and 0.14). As inhibitors of topoisomerase I have been demonstrated to have activity in the replication phase of the cell cycle (S-phase-specific), prolonged administration schedules were examined. Mice received topotecan 5 days per week for 3 weeks either by i.p. injection or by oral gavage (p.o.). In selected experiments, p.o. administration was continued for up to 20 weeks. Oral administration for 3 weeks (2 mg/kg per dose) resulted in complete regression of all six lines of rhabdomyosarcoma, with two lines demonstrating no regrowth during the period of observation (> or = 84 days). Similar results were obtained after i.p. administration, suggesting significant schedule dependency for these tumors. For colon tumors, the daily administration schedule (i.p. or p.o.) demonstrated some advantage over the intermittent schedule, resulting in partial regressions and significant inhibition of the growth of several colon adenocarcinoma lines. In rhabdomyosarcoma Rh12 and VRC5 colon adenocarcinoma, both of which demonstrated intermediate sensitivity to topotecan, and in osteosarcoma OS33, protracted p.o. administration for 13-20 weeks (1.0-1.5 mg/kg per dose given daily x 5 days) caused complete regression without regrowth in Rh12 and OS33 tumors and partial regression of all VRC5 tumors. No toxicity was observed using this schedule of administration. Topotecan demonstrated significant activity against all three osteosarcoma xenografts examined, with optimal schedules causing complete regression in two lines.(ABSTRACT TRUNCATED AT 400 WORDS) [ABSTRACT FROM AUTHOR]

N-(5-indanylsulfonyl)-N'-(4-chlorophenyl)-urea (LY186641), a novel anticancer compound, was evaluated against six lines of rhabdomyosarcoma xenografts, each of which was established from tissue biopsies from untreated patients, and additional sublines selected as xenografts for primary resistance to vincristine, melphalan, and ifosfamide. LY186641 was given by oral gavage twice daily for 10 consecutive days or as 5-day courses repeated at 7-day intervals. At the optimal schedule, complete regressions of advanced tumors were obtained in each of the six rhabdomyosarcoma lines. There was no apparent cross-resistance in RMS lines selected for vincristine resistance or against multiple-drug-resistance KB cells in vitro. There was slight cross-resistance in xenografts selected for melphalan resistance, but not in an ifosfamide-resistant line. These results indicate that LY186641 may have significant clinical activity in the treatment of childhood rhabdomyosarcoma. [ABSTRACT FROM AUTHOR]

Preeclampsia is a pregnancy-related hypertensive disorder accounting for 14% of global maternal deaths annually. Preeclampsia — maternal hypertension and proteinuria — is promoted by placental ischemia resulting from reduced uteroplacental perfusion. Here, we assess longitudinal changes in placental oxygenation during preeclampsia using spectral photoacoustic imaging. Spectral photoacoustic images were acquired of the placenta of normal pregnant (NP) and preeclamptic reduced uterine perfusion pressure (RUPP) Sprague Dawley rats on gestational days (GD) 14, 16, and 18, corresponding to mid- to late gestation (n = 10 per cohort). Two days after implementation of the RUPP surgical model, placental oxygen saturation decreased 12% in comparison with NP. Proteinuria was determined from a 24-hour urine collection prior to imaging on GD18. Blood pressure measurements were obtained on GD18 after imaging. Placental hypoxia in the RUPP was confirmed with histological staining for hypoxia-inducible factor (HIF)-1α, a cellular transcription regulator which responds to local oxygen levels. Using in vivo, longitudinal imaging methods we determined that the placenta in the reduced uterine perfusion pressure rat model of preeclampsia is hypoxic, and that this hypoxia is maintained through late gestation. Future work will utilize these methods to assess the impact of novel therapeutics on placental ischemia and the progression of preeclampsia. [ABSTRACT FROM AUTHOR]