Citations

Abstract Background: Ovarian cancer is a leading cause of cancer-related death among women. In an effort to understand contributors to disease outcome, we evaluated single-nucleotide polymorphisms (SNP) previously associated with ovarian cancer recurrence or survival, specifically in angiogenesis, inflammation, mitosis, and drug disposition genes. Methods: Twenty-seven SNPs in VHL, HGF, IL18, PRKACB, ABCB1, CYP2C8, ERCC2, and ERCC1 previously associated with ovarian cancer outcome were genotyped in 10,084 invasive cases from 28 studies from the Ovarian Cancer Association Consortium with over 37,000-observed person-years and 4,478 deaths. Cox proportional hazards models were used to examine the association between candidate SNPs and ovarian cancer recurrence or survival with and without adjustment for key covariates. Results: We observed no association between genotype and ovarian cancer recurrence or survival for any of the SNPs examined. Conclusions: These results refute prior associations between these SNPs and ovarian cancer outcome and underscore the importance of maximally powered genetic association studies. Impact: These variants should not be used in prognostic models. Alternate approaches to uncovering inherited prognostic factors, if they exist, are needed. Cancer Epidemiol Biomarkers Prev; 22(5); 987–. ©2013 AACR.

Aberrant connectivity is implicated in many neurological and psychiatric disorders, including Alzheimer’s disease and schizophrenia. However, other than a few disease-associated candidate genes, we know little about the degree to which genetics play a role in the brain networks; we know even less about specific genes that influence brain connections. Twin and family-based studies can generate estimates of overall genetic influences on a trait, but genome-wide association scans (GWASs) can screen the genome for specific variants influencing the brain or risk for disease. To identify the heritability of various brain connections, we scanned healthy young adult twins with high-field, high-angular resolution diffusion MRI. We adapted GWASs to screen the brain’s connectivity pattern, allowing us to discover genetic variants that affect the human brain’s wiring. The association of connectivity with the SPON1 variant at rs2618516 on chromosome 11 (11p15.2) reached connectome-wide, genome-wide significance after stringent statistical corrections were enforced, and it was replicated in an independent subsample. rs2618516 was shown to affect brain structure in an elderly population with varying degrees of dementia. Older people who carried the connectivity variant had significantly milder clinical dementia scores and lower risk of Alzheimer’s disease. As a posthoc analysis, we conducted GWASs on several organizational and topological network measures derived from the matrices to discover variants in and around genes associated with autism ( MACROD2 ), development ( NEDD4 ), and mental retardation ( UBE2A ) significantly associated with connectivity. Connectome-wide, genome-wide screening offers substantial promise to discover genes affecting brain connectivity and risk for brain diseases.

Four rating systems were developed by the American Orthopaedic Foot and Ankle Society to provide a standard method of reporting clinical status of the ankle and foot. The systems incorporate both subjective and objective factors into numerical scales to describe function, alignment, and pain.

The objective documentation of foot function before and after therapeutic intervention will be greatly enhanced by the utilization of devices capable of measuring dynamic foot pressure distribution. Efforts to develop this technology date back to the late 19th century, but only with recent advances in computers has it been possible to produce quantitatively accurate high resolution foot pressure distribution with high sampling rates and easily interpreted graphic displays. Over the years, a variety of methods have been employed to study foot pressure. Many of these techniques have already improved our understanding of the foot and its function, and have had an impact on the way we practice. Effective clinical utilization of these new investigative tools depends on an understanding of their scientific basis, capabilities and limitations.

Magnetic resonance imaging (MRI), a useful technique of studying soft tissues of the body, can be very effective in assessing the integrity of tendons. Usually a patient with a complete tear of the posterior tibial tendon has characteristic physical findings. In the patient presented, MRI demonstrated a complete disruption of the posterior tibial tendon, despite the absence of the commonly associated clinical findings. In view of the difficulties encountered with attempted tenography of the completely torn posterior tibial tendon, MRI provides a sensitive alternative diagnostic technique.

SummaryBackgroundKisspeptin is a novel hypothalamic peptide which stimulates endogenous gonadotrophin releasing hormone (GnRH) secretion. A single subcutaneous bolus injection of kisspeptin‐54 increases circulating luteinizing hormone (LH) levels in women, but its acute effects on LH pulsatility are not known.AimsTo investigate the effects of a single subcutaneous (sc) injection of kisspeptin‐54 administration on LH pulsatility in healthy female volunteers.MethodsSix healthy female adult volunteers underwent 10‐minute blood sampling for serum LH measurement for 8 h during the follicular phase of menstrual cycle. Sc bolus injection of saline or kisspeptin‐54 (0·15, 0·30 or 0·60 nmol/kg) was administered 4 h after commencing the study. A previously described, blinded deconvolution method was used to detect LH pulses.ResultsMean number of LH pulses was increased significantly following 0·30 and 0·60 nmol/kg kisspeptin‐54 when compared with saline (mean increase in number of LH pulses per 4 h, following injection: −0·17 ± 0·54, saline; +2·33 ± 0·56, 0·30 nmol/kg kisspeptin‐54, P < 0·05 vs saline; +2·33 ± 0·80, 0·60 nmol/kg kisspeptin‐54, P < 0·05 vs saline). LH pulse secretory mass increased following injection of 0·60 nmol/kg in five of six subjects, but the mean change in all subjects was non‐significant when compared with saline (mean increase in pulse secretory mass in IU/l following injection: +0·35 ± 0·40, saline; +2·61 ± 1·17, 0·60 nmol/kg kisspeptin‐54, P = 0·10 vs saline).ConclusionsA single injection of kisspeptin‐54 temporarily stimulates the number of LH pulses in healthy women. Further studies are required to investigate the therapeutic potential of kisspeptin‐54 injection to restore LH pulsatility in patients with reproductive disorders caused by impaired GnRH secretion.

AbstractSulindac is a prescription‐based non‐steroidal anti‐inflammatory drug (NSAID) that continues to be actively investigated as a candidate cancer chemoprevention agent. To further current understanding of sulindac bioavailability, metabolism, and disposition, we developed a population pharmacokinetic model for the parent compound and its active metabolites, sulindac sulfide, and exisulind. This analysis was based on data from 24 healthy subjects who participated in a bioequivalence study comparing two formulations of sulindac. The complex disposition of sulindac and its metabolites was described by a seven‐compartment model featuring enterohepatic recirculation and is the first reported population pharmacokinetic model for sulindac. The derived model was used to explore effects of clinical variables on sulindac pharmacokinetics and revealed that body weight, creatinine clearance, and gender were significantly correlated with pharmacokinetic parameters. Moreover, the model quantifies the relative bioavailability of the sulindac formulations and illustrates the utility of population pharmacokinetics in bioequivalence assessment. This novel population pharmacokinetic model provides new insights regarding the factors that may affect the pharmacokinetics of sulindac and the exisulind and sulindac sulfide metabolites in generally healthy subjects, which have implications for future chemoprevention trial design for this widely available agent.

The purpose of this study is to evaluate the rate of union after four-corner arthrodesis with a locking, dorsal circular plate comprised of polyether-ether-ketone. A retrospective review was conducted of all patients who underwent four-corner arthrodesis with a locking, dorsal circular plate at our institution from January 2005 to May 2009. The primary outcome measure was radiographic and clinical union. During the study period, 26 consecutive wrists underwent four-corner arthrodesis with a locking, dorsal circular plate. Twenty-three wrists were included. The mean clinical follow-up was 16 months (range 3–37). Union was achieved in 22 of 23 wrists at a mean time of 3 months (range 1–12). There was one partial union that underwent successful revision arthrodesis. In summary, four-corner fusion with a polyether-ether-ketone locking, dorsal circular plate results in high union rates. The use of a radiolucent plate allows for more accurate assessment of union with the biomechanical advantages of a fixed angle construct.