Aging and Gait Function: Examination of Multiple Factors that Influence Gait Variability.

This investigation aimed to identify parameters of reduced functionality that are responsible for variations in the normal gait cycle. Sixteen older adults (55-85 years; nine males) and eighteen young adults (18-40 years; eight males) were enrolled. Assessments included walking trials, questionnaires, and assessed maximal and submaximal dorsiflexors (DF) and plantar flexors (PF) force. Multiple relationships were found between the muscular capabilities of the ankle and gait variability in older adults. For both the DF and PF muscles, the older adults produced significantly lower maximal force production and higher levels of force variability than younger adults; physical activity (PA) level was also significantly correlated. The reduction in muscular strength was concurrent with increased force variability and deficits in spatiotemporal gait parameters, suggesting an age-related worsening of the central motor control. Our results found that PA engagement could preserve gait quality and independence. These are essential considerations for further research on the cause and reduction of falls in older adults.

Feasibility and Acceptability of a Program to Promote Positive Affect, Well-Being and Gender Empowerment in Black Women Living with HIV.

While programs and interventions intended to increase positive affect among people living with HIV (PLWH) and other chronic diseases have been associated with improved health outcomes, including decreased depression, programs have not been tailored specifically for Black women. We tailored a program designed to increase positive affect and to decrease depressive symptoms in PLWH to a group format for Black WLWH. We also added skills to increase gender empowerment. We then tested the acceptability and feasibility of this program with 8 Black WLWH. The program was acceptable and relatively feasible, as assessed by women's participation and feedback about program clarity and helpfulness, which women rated above 9 on a 10-point scale. A few women suggested that optimal delivery point for some skills taught would be shortly after HIV diagnosis. A proof-of-concept program intended to bolster positive emotions and gender empowerment and decrease depression can be tailored for Black WLWH and is relatively feasible and acceptable. A randomized controlled trial is needed to assess the preliminary efficacy of this program on positive affect, depression, and other health outcomes for WLWH.

Assessment of automated cone-beam CT vessel identification software during transarterial hepatic embolisation: radiation dose, contrast medium volume, processing time, and operator perspectives compared to digital subtraction angiography.

AIM: To evaluate arterial cone-beam computed tomography (A-CBCT) automated analysis software for identification of vessels supplying tumours during transarterial hepatic embolisation (TAE). MATERIALS AND METHODS: This study was approved by the institutional review board, with waiver of consent. Consecutive TAE procedures using arterial mapping software (AMS), and performed between February 2014 and August 2014, were reviewed. Hepatic arteries were imaged using digital subtraction angiography (DSA) as well as A-CBCT processed with AMS. Interventional radiologists reported1 potential embolisation target vessels computed using AMS versus DSA alone,2 modification of the embolisation plan based on AMS, and3 operator confidence related to technical success. Imaging set-up, processing time, radiation dose, and contrast media volume were recorded. RESULTS: Thirty of 34 consecutive procedures were evaluated retrospectively. At least one additional embolisation target vessel was identified using AMS in 13 procedures (43%, 95% confidence interval [CI]: 26-61%) and embolisation plan modified in 11 (37%, 95% CI: 19-54%). Radiologists reported AMS increased operator confidence and reduced the number of DSA acquisitions in 25 (83%, 95% CI: 70-97%) and 15 cases (50%, 95% CI: 32-68%), respectively. The average A-CBCT acquisition and processing time was 4 minutes 53 seconds and 3 minutes 45 seconds, respectively. A-CBCT contributed to 11% of the radiation dose and 18% of the contrast media volume. CONCLUSION: Physicians report increased tumour supplying vessel detection and intraprocedural confidence using AMS during TAE without substantial impact on radiation dose, contrast media volume, and procedure time.

90Y Resin Microspheres Radioembolization for Colon Cancer Liver Metastases Using Full-Strength Contrast Material.

OBJECTIVES: To assess safety and efficacy of 90Y resin microspheres administration using undiluted non-ionic contrast material (UDCM) {100% Omnipaque-300 (Iohexol)} in both the "B" and "D" lines. MATERIALS AND METHODS: We reviewed all colorectal cancer liver metastases patients treated with 90Y resin microspheres radioembolization (RAE) from 2009 to 2017. As of April 2013, two experienced operators started using UDCM (study group) instead of standard sandwich infusion (control group). Occurrence of myelosuppression (leukopenia, neutropenia, erythrocytopenia or/and thrombocytopenia), stasis, nontarget delivery (NTD), median fluoroscopy radiation dose (FRD), median infusion time (IT), liver progression-free (LPFS) and overall survivals (OS) was evaluated. Complications within 6 months post-RAE were reported according to CTCAE v3.0 criteria. RESULTS: Study and control groups comprised 23(28%) and 58(72%) patients, respectively. Median follow-up was 9.1 months. There was no statistically significant difference in myelosuppression incidence within 6 months post-RAE between groups. Median FRD and IT for study and control groups were 44.6 vs. 97.35 Gy/cm2 (p = 0.048) and 31 vs. 39 min (p = 0.006), respectively. A 38% lower stasis incidence in study group was not significant (p = 0.34). NTD occurred in 1/27(4%) study vs. 5/73(7%) control group procedures (p = 1). Grade 1-2 and grade 3-4 toxicities between study and control group patients were 36%(8/22) vs. 45%(26/58), p = 0.61 and 9%(2/22) vs. 16%(9/58), p = 0.72, respectively. There was no difference in LPFS and OS between groups. CONCLUSION: Administration of 90Y resin microspheres using UDCM in both lines is safe and effective, resulting in lower fluoroscopy radiation dose and shorter infusion time, without evidence of myelosuppression or increased stasis incidence.

Genome-wide studies of von Willebrand factor propeptide identify loci contributing to variation in propeptide levels and von Willebrand factor clearance.

UNLABELLED: Essentials Variants at ABO, von Willebrand Factor (VWF) and 2q12 contribute to the variation in plasma in VWF. We performed a genome-wide association study of plasma VWF propeptide in 3,238 individuals. ABO, VWF and 2q12 loci had weak or no association or linkage with plasma VWFpp levels. VWF associated variants at ABO, VWF and 2q12 loci primarily affect VWF clearance rates. SUMMARY: Background Previous studies identified common variants at the ABO and VWF loci and unknown variants in a chromosome 2q12 linkage interval that contributed to the variation in plasma von Willebrand factor (VWF) levels. Whereas the association with ABO haplotypes can be explained by differential VWF clearance, little is known about the mechanisms underlying the association with VWF single-nucleotide polymorphisms (SNPs) or with variants in the chromosome 2 linkage interval. VWF propeptide (VWFpp) and mature VWF are encoded by the VWF gene and secreted at the same rate, but have different plasma half-lives. Therefore, comparison of VWFpp and VWF association signals can be used to assess whether the variants are primarily affecting synthesis/secretion or clearance. Methods We measured plasma VWFpp levels and performed genome-wide linkage and association studies in 3238 young and healthy individuals for whom VWF levels had been analyzed previously. Results and conclusions Common variants in an intergenic region on chromosome 7q11 were associated with VWFpp levels. We found that ABO serotype-specific SNPs were associated with VWFpp levels in the same direction as for VWF, but with a much lower effect size. Neither the association at VWF nor the linkage on chromosome 2 previously reported for VWF was observed for VWFpp. Taken together, these results suggest that the major genetic factors affecting plasma VWF levels, i.e. variants at ABO, VWF and a locus on chromosome 2, operate primarily through their effects on VWF clearance.

Reprogramming of hepatic fat accumulation and 'browning' of adipose tissue by the short-chain fatty acid acetate.

BACKGROUND/OBJECTIVES: Short-chain fatty acids, produced by microbiome fermentation of carbohydrates, have been linked to a reduction in appetite, body weight and adiposity. However, determining the contribution of central and peripheral mechanisms to these effects has not been possible. SUBJECTS/METHODS: C57BL/6 mice fed with either normal or high-fat diet were treated with nanoparticle-delivered acetate, and the effects on metabolism were investigated. RESULTS: In the liver, acetate decreased lipid accumulation and improved hepatic function, as well as increasing mitochondrial efficiency. In white adipose tissue, it inhibited lipolysis and induced 'browning', increasing thermogenic capacity that led to a reduction in body adiposity. CONCLUSIONS: This study provides novel insights into the peripheral mechanism of action of acetate, independent of central action, including 'browning' and enhancement of hepatic mitochondrial function.

Transcobalamin II receptor polymorphisms are associated with increased risk for neural tube defects.

OBJECTIVE: Women who have low cobalamin (vitamin B(12)) levels are at increased risk for having children with neural tube defects (NTDs). The transcobalamin II receptor (TCblR) mediates uptake of cobalamin into cells. Inherited variants in the TCblR gene as NTD risk factors were evaluated. METHODS: Case-control and family-based tests of association were used to screen common variation in TCblR as genetic risk factors for NTDs in a large Irish group. A confirmatory group of NTD triads was used to test positive findings. RESULTS: 2 tightly linked variants associated with NTDs in a recessive model were found: TCblR rs2336573 (G220R; p(corr)=0.0080, corrected for multiple hypothesis testing) and TCblR rs9426 (p(corr)=0.0279). These variants were also associated with NTDs in a family-based test before multiple test correction (log-linear analysis of a recessive model: rs2336573 (G220R; RR=6.59, p=0.0037) and rs9426 (RR=6.71, p=0.0035)). A copy number variant distal to TCblR and two previously unreported exonic insertion-deletion polymorphisms were described. CONCLUSIONS: TCblR rs2336573 (G220R) and TCblR rs9426 represent a significant risk factor in NTD cases in the Irish population. The homozygous risk genotype was not detected in nearly 1000 controls, indicating that this NTD risk factor may be of low frequency and high penetrance. 9 other variants are in perfect linkage disequilibrium with the associated single nucleotide polymorphisms. Additional work is required to identify the disease-causing variant. Our data suggest that variation in TCblR plays a role in NTD risk and that these variants may modulate cobalamin metabolism.

Prospective study of outcomes after percutaneous biliary drainage for malignant biliary obstruction.

BACKGROUND: Percutaneous biliary drainage (PBD) is used to relieve malignant bile duct obstruction (MBO) when endoscopic drainage is not feasible. Little is known about the effects of PBD on the quality of life (QoL) in patients with MBO. The aim of this study was to evaluate changes in QoL and pruritus after PBD and to explore the variables that impact these changes. MATERIALS AND METHODS: Eligible patients reported their QoL and pruritus before and after PBD using the Functional Assessment of Cancer Therapy-Hepatobiliary instrument (FACT-HS) and the Visual Analog Scale for Pruritus (VASP). Instruments were completed preprocedure and at 1 and 4 weeks following PBD. RESULTS: A total of 109 (60 male/49 female) patients enrolled; 102 (94%) had unresectable disease. PBD was technically successful (hepatic ducts cannulated at the conclusion of procedure) in all patients. There were 2 procedure-related deaths. All-cause mortality was 10% (N = 11) at 4 weeks and 28% (N = 31) at 8 weeks post-PBD with a median survival of 4.74 months. The mean FACT-HS scores declined significantly (P < .01) over time (101.3, 94.8, 94.7 at baseline, 1 week, 4 weeks, respectively). The VASP scores showed significant improvement at 1 week with continued improvement at 4 weeks (P < .01). CONCLUSIONS: PBD improves pruritus but not QoL in patients with MBO and advanced malignancy. There is high early mortality in this population.

Considerations for designing a prototype genetic test for use in translational research.

BACKGROUND: Translational research is needed to explore how people will respond to personal genetic susceptibility information related to common health conditions. Maximizing the rigor of this research will require that genetic test results be returned to study participants. Currently, there is no established method that guides the selection of genetic variants to be used in research with these objectives. METHODS AND RESULTS: To address this question, we designed a process to identify gene variants and health conditions to be included in a prototype genetic test for use in a larger research effort, the Multiplex Initiative. The intention of this exploration was to facilitate research that generates individual genetic test results that are returned to study participants. Inclusion criteria were developed as part of a transdisciplinary and iterative process that considered the weight of evidential support for genetic association with common health conditions, the appropriateness of use in human subjects research, and the recommendations of expert peer reviewers. CONCLUSIONS: The selection process was designed to identify gene variants for the limited purpose of translational research and, therefore, should not be seen as producing a valid clinical test. However, this example of an applied selection process may provide guidance for researchers who are designing studies to evaluate the implications of genetic susceptibility testing through the return of personalized genetic information. As the rate of genomic discoveries increases, such research will be essential in steering the translation of this information towards the greatest public health benefit.

Radiofrequency ablation in the management of liver metastases from breast cancer.

OBJECTIVE: Systemic chemotherapy remains the standard treatment for patients with breast cancer hepatic metastases. Resection of metastases has survival advantages in a small percentage of selected patients. Radiofrequency ablation has been used in small numbers of selected patients. This small series was undertaken to review our experience with radiofrequency ablation in the management of patients with breast cancer hepatic metastases. CONCLUSION: Radiofrequency ablation of breast cancer hepatic metastases is safe and may be used to control hepatic deposits in patients with stable or no extrahepatic disease.

Concentric and eccentric shoulder rehabilitation biomechanics.

The use of an impulse-momentum (IM) exercise technique was investigated for end-stage shoulder rehabilitation. The objectives of this study were to: (a) quantify the net shoulder joint forces and moments while using an IM system and (b) test the influence of gender and muscle loading type (concentric or eccentric) on kinetic and kinematic parameters. Fourteen healthy adults (eight males, six females) performed a repeated measures experiment on an instrumented device utilizing a cabled shuttle system. While maintaining 90 degrees of shoulder abduction and 90 degrees of elbow flexion, the subjects externally rotated their upper arm from 0 degrees to 90 degrees (concentric acceleration) and then internally rotated their upper arm back from 90 degrees to the 0 degrees position (eccentric deceleration). Shoulder joint forces and moments as well as rotational work and power were calculated using inverse dynamics (free-body forces and moments calculated at intersegmental joint centres). Overall concentric peak forces and moments were greater than eccentric peak forces and moments (P < 0.0001). Joint forces and moments reached a maximum during the initial phase of concentric loading (0 degrees to 45 degrees) compared with any other rotational position in the loading cycle (concentric 45 degrees to 90 degrees or eccentric 90 degrees to 0 degrees). The results also indicate that males experienced higher (P < 0.0001) average resultant peak joint forces (concentric 0 degrees to 45 degrees = 108.0 N and eccentric 90 degrees to 45 degrees = 87.2 N) than females (concentric 0 degrees to 45 degrees = 74.7 N and eccentric 45 degrees to 0 degrees = 56.0 N). In addition, males experienced higher (P < 0.0001) average resultant peak joint moments (concentric 0 degrees to 45 degrees = 30.4 N m and eccentric 45 degrees to 0 degrees = 21.0 N m) than females (concentric 0 degrees to 45 degrees = 19.7 N m and eccentric 45 degrees to 0 degrees = 12.8 N m).

Rates and patterns of recurrence for percutaneous radiofrequency ablation and open wedge resection for solitary colorectal liver metastasis.

INTRODUCTION: The purpose of this study was to compare rates and patterns of disease progression following percutaneous, image-guided radiofrequency ablation (RFA) and nonanatomic wedge resection for solitary colorectal liver metastases. METHODS: We identified 30 patients who underwent nonanatomic wedge resection for solitary liver metastases and 22 patients who underwent percutaneous RFA because of prior major hepatectomy (50%), major medical comorbidities (41%), or relative unresectability (9%). Serial imaging studies were retrospectively reviewed for evidence of local tumor progression. RESULTS: Patients in the RFA group were more likely to have undergone prior liver resection, to have a disease-free interval greater than 1 year, and to have had an abnormal carcinoembryonic antigen (CEA) level before treatment. Two-year local tumor progression-free survival (PFS) was 88% in the Wedge group and 41% in the RFA group. Two patients in the RFA group underwent re-ablation, and two patients underwent resection to improve the 2-year local tumor disease-free survival to 55%. Approximately 30% of patients in each group presented with distant metastasis as a component of their first recurrence. Median overall survival from the time of resection was 80 months in the Wedge group vs 31 months in the RFA group. However, overall survival from the time of treatment of the colorectal primary was not significantly different between the two groups. CONCLUSIONS: Local tumor progression is common after percutaneous RFA. Surgical resection remains the gold standard treatment for patients who are candidates for resection. For patients who are poor candidates for resection, RFA may help to manage local disease, but close follow-up and retreatment are necessary to achieve optimal results.

Prospective, blinded comparison of helical CT and CT arterial portography in the assessment of hepatic metastasis from colorectal carcinoma.

OBJECTIVE: This prospective blinded comparison of helical CT and helical CT arterial portography aimed to detect liver metastasis from colorectal carcinoma. METHODS AND MATERIALS: 50 patients with colorectal carcinoma were evaluated comparing helical CT with helical CT arterial portography. Each imaging study was evaluated on a 5-point ROC scale by radiologists blinded to the other imaging findings, and the results were compared, with the surgical and pathologic findings as the gold standard. RESULTS: Of the 127 lesions found at pathology identified as metastatic colorectal cancer, helical CT correctly identified 85 (69%) and CT portography 96 (76%). When subgroups with lesions <3 cm (48 patients) and patients with maximum tumor size <3 cm (18 patients) were considered, CT portography was always better than helical CT in terms of sensitivity, specificity, positive predictive value, and negative predictive value. ROC analysis adjusting for multiple lesions per patient revealed significantly greater area under the curve (AUC) for the subgroup of lesions <3 cm (CT-AUC of 77% and CT portography AUC of 81%; P = 0.002). CONCLUSIONS: For identification of large metastases, helical CT and CT portography have similar yield. However, for detection of small liver metastases, CT portography remains superior for lesion detectability.

Routine urine culture at the time of percutaneous urinary drainage: does every patient need one?

PURPOSE: To determine the clinical variables associated with bacteriuria in patients undergoing primary percutaneous antegrade urinary drainage procedures in order to predict the utility of routinely obtaining urine cultures at the time of the procedure. METHODS: Between October 1995 and March 1998 urine cultures were prospectively obtained in all patients undergoing a primary percutaneous antegrade urinary drainage procedure. One hundred and eighty-seven patients underwent 264 procedures. Results were available in 252 cases. Culture results were correlated with clinical, laboratory, and demographic variables. Anaerobic cultures were not uniformly performed. RESULTS: Urine cultures were positive in 24 of 252 (9.5%) cases. An indwelling or recently removed ipsilateral device (catheter or stent) and a history of previous cystectomy with urinary diversion were significant predictors of a positive culture. Patients without either of these predictors, and without clinical or laboratory evidence of infection, were rarely found to have positive cultures. CONCLUSION: The likelihood of a positive urine culture can be predicted on the basis of the aforementioned clinical variables. In the absence of these clinical indicators routine urine cultures are neither useful nor cost-effective.

Upper urinary tract metastases from adenocarcinoma of the colon.

An unusual presentation of colorectal metastasis to the upper urinary tract is reported. The metastasis manifested as a filling defect seen during antegrade pyelography. Cytologic evaluation of aspirated material demonstrated metastatic colonic adenocarcinoma. A dilated collecting system may be caused by intraluminal material including tumor and blood clots. Whenever fixed filling defects are encountered, urine cytology should be sent even in the absence of renal parenchymal involvement by tumor. The cytological evaluation may allow for prompt diagnosis and treatment.

Interpreting epidemiological research: blinded comparison of methods used to estimate the prevalence of inherited mutations in BRCA1.

While sequence analysis is considered by many to be the most sensitive method of detecting unknown mutations in large genes such as BRCA1, most published estimates of the prevalence of mutations in this gene have been derived from studies that have used other methods of gene analysis. In order to determine the relative sensitivity of techniques that are widely used in research on BRCA1, a set of blinded samples containing 58 distinct mutations were analysed by four separate laboratories. Each used one of the following methods: single strand conformational polymorphism analysis (SSCP), conformation sensitive gel electrophoresis (CSGE), two dimensional gene scanning (TDGS), and denaturing high performance liquid chromatography (DHPLC). Only the laboratory using DHPLC correctly identified each of the mutations. The laboratory using TDGS correctly identified 91% of the mutations but produced three apparent false positive results. The laboratories using SSCP and CSGE detected abnormal migration for 72% and 76% of the mutations, respectively, but subsequently confirmed and reported only 65% and 60% of mutations, respectively. False negatives therefore resulted not only from failure of the techniques to distinguish wild type from mutant, but also from failure to confirm the mutation by sequence analysis as well as from human errors leading to misreporting of results. These findings characterise sources of error in commonly used methods of mutation detection that should be addressed by laboratories using these methods. Based upon sources of error identified in this comparison, it is likely that mutations in BRCA1 and BRCA2 are more prevalent than some studies have previously reported. The findings of this comparison provide a basis for interpreting studies of mutations in susceptibility genes across many inherited cancer syndromes.

Identification of proteins that interact with BRCA1 by Far-Western library screening.

Protein-protein interactions control numerous biological processes. In the case of a protein with no known function, identification of interacting proteins may lend insight into its cellular function. Protein-protein interactions are often detected by yeast two-hybrid screening which is based on a transcriptional read-out. One limitation of this technique is that transcription factors, when used as bait, frequently impair the effectiveness of this screen because they give rise to high levels of false positives. The carboxyl terminus of the breast cancer tumor suppressor gene, BRCA1, contains two BRCT motifs, a motif found in several DNA repair and cell cycle checkpoint proteins. This region of BRCA1 also exhibits an intrinsic transcriptional transactivation activity when bound to DNA as a fusion protein, thereby limiting its use in yeast two-hybrid screen. In order to isolate proteins that interact with this domain of BRCA1, we utilized a Far-Western screen, a method based on direct protein binding. We used recombinant histidine-tagged BRCT as the primary protein probe. We isolated eight cDNAs that bind to the BRCT domain of BRCA1. Further analysis demonstrated that two of the clones encode for proteins that interact directly with the BRCT domain of BRCA1.

Association and aggregation analysis using kin-cohort designs with applications to genotype and family history data from the Washington Ashkenazi Study.

When a rare inherited mutation in a disease gene, such as BRCA1, is found through extensive study of high-risk families, it is critical to estimate not only age-specific penetrance of the disease associated with the mutation, but also the residual effect of family history once the mutation is taken into account. The kin-cohort design, a cross-sectional survey of a suitable population that collects DNA and family history data, provides an efficient alternative to cohort or case-control designs for estimating age-specific penetrance in a population not selected because of high familial risk. In this report, we develop a method for analyzing kin-cohort data that simultaneously estimate the age-specific cumulative risk of the disease among the carriers and non-carriers of the mutations and the gene-adjusted residual familial aggregation or correlation of the disease. We employ a semiparametric modeling approach, where the marginal cumulative risks corresponding to the carriers and non-carriers are treated non-parametrically and the residual familial aggregation is described parametrically by a class of bivariate failure time models known as copula models. A simple and robust two-stage method is developed for estimation. We apply the method to data from the Washington Ashkenazi Study [Struewing et al., 1997, N Engl J Med 336:1401-1408] to study the residual effect of family history on the risk of breast cancer among non-carriers and carriers of specific BRCA1/BRCA2 germline mutations. We find that positive history of a single first-degree relative significantly increases risk of the non-carriers (RR = 2.0, 95% CI = 1.6-2.6) but has little or no effect on the carriers.

Portal vein embolization with use of polyvinyl alcohol particles.

Preoperative portal vein embolization has been used as method of inducing compensatory hypertrophy in the future remnant liver since it was first described in the late 1980s. Many different vascular embolic agents have been successfully used for this procedure, and there is no general consensus regarding which is the best agent. Polyvinyl alcohol (PVA) particles commonly used for arterial embolization come in many sizes, are readily available, and are easy to administer via conventional catheters. We describe an easy, safe, and effective method of the use of PVA particles for portal vein embolization.

Ego development, self-perception, and self-complexity in adolescence: a study of female psychiatric inpatients.

A study of two groups of female psychiatric inpatients, differing in level of ego development, explored domains of self-perception that best predicted global self-worth and symptom clusters that best predicted second-order factors of self perception. Findings revealed quantitative and qualitative differences in self-complexities, and more positive self-perceptions among the higher ego-level group in scholastic competence, job competence, and behavioral conduct. Results are discussed from a developmental perspective.