Centromere tethering confines chromosome domains.

The organization of chromosomes into territories plays an important role in a wide range of cellular processes, including gene expression, transcription, and DNA repair. Current understanding has largely excluded the spatiotemporal dynamic fluctuations of the chromatin polymer. We combine in vivo chromatin motion analysis with mathematical modeling to elucidate the physical properties that underlie the formation and fluctuations of territories. Chromosome motion varies in predicted ways along the length of the chromosome, dependent on tethering at the centromere. Detachment of a tether upon inactivation of the centromere results in increased spatial mobility. A confined bead-spring chain tethered at both ends provides a mechanism to generate observed variations in local mobility as a function of distance from the tether. These predictions are realized in experimentally determined higher effective spring constants closer to the centromere. The dynamic fluctuations and territorial organization of chromosomes are, in part, dictated by tethering at the centromere.

Dedifferentiation of cancer cells following recovery from a potentially lethal damage is mediated by H2S-Nampt.

Recently, we reported that cancer cells that recover from a potentially lethal damage gain new phenotypic features comprised of mitochondrial structural remodeling associated with increased glycolytic dependency and drug resistance. Here, we demonstrate that a subset of cancer cells, upon recovery from a potentially lethal damage, undergo dedifferentiation and express genes, which are characteristic of undifferentiated stem cells. While these cells are competent in maintaining differentiated progeny of tumor, they also exhibit transdifferentiation potential. Dedifferentiation is characterized by accumulation of hydrogen sulfide (H2S), which triggers up-regulation of nicotinamide phosphoribosyltransferase (Nampt) accompanied by changes in the redox state. The molecular events triggered by Nampt include elevated production of NAD(+) and up-regulation of H2S producing enzymes, cystathionine beta synthase (CBS) and cystathionase (CTH) with 3-mercaptopyruvate sulfurtransferase (MST) being detectable only in 3D spheroids. Suppression of Nampt, or inactivation of H2S producing enzymes, all reduce H2S production and reverse the ability of cells to dedifferentiate. Moreover, H2S induced stem cell markers in parental cancer cells in a manner similar to that observed in damage recovered cells. These data suggest of existence of a positive feedback loop between H2S and Nampt that controls dedifferentiation in cancer cells that recover from a potentially lethal damage.

Computer-aided diagnosis of hyperacute stroke with thrombolysis decision support using a contralateral comparative method of CT image analysis.

New and improved techniques have been continuously introduced into CT and MR imaging modalities for the diagnosis and therapy planning of acute stroke. Nevertheless, non-contrast CT (NCCT) is almost always used by every institution as the front line diagnostic imaging modality due to its high affordability and availability. Consequently, the potential reward of extracting as much clinical information as possible from NCCT images can be very great. Intravenous tissue plasminogen activator (tPA) has become the gold standard for treating acute ischemic stroke because it is the only acute stroke intervention approved by the FDA. ASPECTS scoring based on NCCT images has been shown to be a reliable scoring method that helps physicians to make sound decisions regarding tPA administration. In order to further reduce inter-observer variation, we have developed the first end-to-end automatic ASPECTS scoring system using a novel method of contralateral comparison. Due to the self-adaptive nature of the method, our system is robust and has good generalizability. ROC analysis based on evaluation of 103 subjects who presented to the stroke center of Chang Gung Memorial Hospital with symptoms of acute stroke has shown that our system's dichromatic classification of patients into thrombolysis indicated or thrombolysis contraindicated groups has achieved a high accuracy rate with AUC equal to 90.2 %. The average processing time for a single case is 170 s. In conclusion, our system has the potential of enhancing quality of care and providing clinical support in the setting of a busy stroke or emergency center.

Lower-extremity endovascular interventions for Medicare beneficiaries: comparative effectiveness as a function of provider specialty.

PURPOSE: Lower-extremity endovascular interventions are increasingly being performed by vascular surgeons (VSs) and interventional cardiologists (ICs) in addition to interventional radiologists (IRs). Regardless of specialty, well trained, experienced, and dedicated operators are expected to offer the best outcomes. To examine specialty-specific trends, outcomes of percutaneous lower-extremity revascularizations in Medicare beneficiaries were compared according to physician specialty types providing the service. MATERIALS AND METHODS: Medicare Standard Analytical Files that contain longitudinal data of all services (physician, inpatient, outpatient) provided to a 5% sample of Medicare beneficiaries were studied. All claims for percutaneous angioplasty, atherectomy, and stent implantation of lower-extremity arteries during the years 2005­2007 were extracted, and the following outcomes were assessed: mortality, transfusion, intensive care unit (ICU) use, length of stay, and subsequent revascularization or amputation. Outcomes were compared by using regression models adjusted for age, sex, race, emergency department admission, and comorbid conditions. RESULTS: Most outcomes were significantly worse if the service was provided by vascular surgeons compared with other vascular specialists. The in-hospital mortality rate for procedures performed by VSs was 19% higher than for those performed by others, but this difference was not significant (P =.351). Adjusted average 1-year procedure costs were significantly lower for IRs ($17,640) than for VSs ($19,012) or ICs ($19,096). CONCLUSIONS: Medicare data show that endovascular lower-extremity revascularization by vascular surgeons results in more transfusion and ICU use, longer hospital stay, more repeat revascularization procedures or amputations, and higher costs compared with procedures performed by interventional radiologists.

A targeted amplicon sequencing panel to simultaneously identify mosquito species and Plasmodium presence across the entire Anopheles genus.

Anopheles is a diverse genus of mosquitoes comprising over 500 described species, including all known human malaria vectors. While a limited number of key vector species have been studied in detail, the goal of malaria elimination calls for surveillance of all potential vector species. Here, we develop a multilocus amplicon sequencing approach that targets 62 highly variable loci in the Anopheles genome and two conserved loci in the Plasmodium mitochondrion, simultaneously revealing both the mosquito species and whether that mosquito carries malaria parasites. We also develop a cheap, nondestructive, and high-throughput DNA extraction workflow that provides template DNA from single mosquitoes for the multiplex PCR, which means specimens producing unexpected results can be returned to for morphological examination. Over 1000 individual mosquitoes can be sequenced in a single MiSeq run, and we demonstrate the panel's power to assign species identity using sequencing data for 40 species from Africa, Southeast Asia, and South America. We also show that the approach can be used to resolve geographic population structure within An. gambiae and An. coluzzii populations, as the population structure determined based on these 62 loci from over 1000 mosquitoes closely mirrors that revealed through whole genome sequencing. The end-to-end approach is quick, inexpensive, robust, and accurate, which makes it a promising technique for very large-scale mosquito genetic surveillance and vector control.

Genetic surveillance in the Greater Mekong subregion and South Asia to support malaria control and elimination.

Background: National Malaria Control Programmes (NMCPs) currently make limited use of parasite genetic data. We have developed GenRe-Mekong, a platform for genetic surveillance of malaria in the Greater Mekong Subregion (GMS) that enables NMCPs to implement large-scale surveillance projects by integrating simple sample collection procedures in routine public health procedures. Methods: Samples from symptomatic patients are processed by SpotMalaria, a high-throughput system that produces a comprehensive set of genotypes comprising several drug resistance markers, species markers and a genomic barcode. GenRe-Mekong delivers Genetic Report Cards, a compendium of genotypes and phenotype predictions used to map prevalence of resistance to multiple drugs. Results: GenRe-Mekong has worked with NMCPs and research projects in eight countries, processing 9623 samples from clinical cases. Monitoring resistance markers has been valuable for tracking the rapid spread of parasites resistant to the dihydroartemisinin-piperaquine combination therapy. In Vietnam and Laos, GenRe-Mekong data have provided novel knowledge about the spread of these resistant strains into previously unaffected provinces, informing decision-making by NMCPs. Conclusions: GenRe-Mekong provides detailed knowledge about drug resistance at a local level, and facilitates data sharing at a regional level, enabling cross-border resistance monitoring and providing the public health community with valuable insights. The project provides a rich open data resource to benefit the entire malaria community. Funding: The GenRe-Mekong project is funded by the Bill and Melinda Gates Foundation (OPP11188166, OPP1204268). Genotyping and sequencing were funded by the Wellcome Trust (098051, 206194, 203141, 090770, 204911, 106698/B/14/Z) and Medical Research Council (G0600718). A proportion of samples were collected with the support of the UK Department for International Development (201900, M006212), and Intramural Research Program of the National Institute of Allergy and Infectious Diseases.

Uterine artery embolization for treatment of leiomyomata: long-term outcomes from the FIBROID Registry.

OBJECTIVE: To assess long-term clinical outcomes of uterine artery embolization across a wide variety of practice settings in a large patient cohort. METHODS: The Fibroid Registry for Outcomes Data (FIBROID) for Uterine Embolization was a 3-year, single-arm, prospective, multi-center longitudinal study of the short- and long-term outcomes of uterine artery embolization for leiomyomata. Two thousand one hundred twelve patients with symptomatic leiomyomata were eligible for long-term follow-up at 27 sites representing a geographically diverse set of practices, including academic centers, community hospitals, and closed-panel health maintenance organizations. At 36 months after treatment, 1,916 patients remained in the study, and of these, 1,278 patients completed the survey. The primary measures of outcome were the symptom and health-related quality-of-life scores from the Uterine Fibroid Symptom and Quality of Life questionnaire. RESULTS: Mean symptom scores improved 41.41 points (P<.001), and the quality of life scores improved 41.47 points (P<.001), both moving into the normal range for this questionnaire. The improvements were independent of practice setting. During the 3 years of the study, Kaplan-Meier estimates of hysterectomy, myomectomy, or repeat uterine artery embolization were 9.79%, 2.82%, and 1.83% of the patients, respectively. CONCLUSION: Uterine artery embolization results in a durable improvement in quality of life. These results are achievable when the procedure is performed in any experienced community or academic interventional radiology practice. LEVEL OF EVIDENCE: III.

Duplex Doppler Imaging of Dialysis Fistulae and Grafts.

Arteriovenous fistulae and grafts for hemodialysis access are a lifeline in patients with end-stage renal disease. A significant cause of morbidity and mortality in this population is dialysis access dysfunction. Duplex ultrasound imaging is an excellent modality to evaluate arteriovenous fistulae and grafts, the 2 main types of long-term hemodialysis access. This review provides a detailed Doppler ultrasound protocol for evaluation of fistulae or grafts to familiarize imagers with their normal appearance, highlighting common dialysis access complications.

Altered Doppler flow patterns in cirrhosis patients: an overview.

Doppler ultrasonography of the hepatic vasculature is an integral part of evaluating precirrhotic and cirrhotic patients. While the reversal of the portal venous flow is a well-recognized phenomenon, other flow patterns, although not as easily understood, may play an important role in assessing the disease status. This article discusses the different characteristic flow patterns observed from the portal vein, hepatic artery, and hepatic vein in patients with liver cirrhosis or related complications and procedures. Knowledge of these different flow patterns provides additional information that may reinforce the diagnosis of cirrhosis, help in staging, and offer prognostic information for determining the direction of therapy. Doppler ultrasonography is invaluable when liver transplantation is being considered and aids in the diagnosis of cirrhosis and portal hypertension.

The FIBROID Registry: symptom and quality-of-life status 1 year after therapy.

OBJECTIVES: To investigate the change in symptom severity and health-related quality of life among patients treated with uterine artery embolization for leiomyomata. METHODS: Using the Fibroid Registry for Outcomes Data (FIBROID), a multicenter, prospective, voluntary registry of patients undergoing uterine embolization for leiomyomata, we studied changes in symptom status, health-related quality of life, subsequent care, menstrual status, and satisfaction with outcome. Health-related quality-of-life and symptom status were measured using the Uterine Fibroid Symptom and Quality of Life, a leiomyoma-specific questionnaire. Summary statistics were used to describe the data set and multivariate analyses to determine predictors of outcome at 12 months. RESULTS: Of 2,112 eligible patients, follow-up data were obtained on 1,797 (85.1%) at 6 months and 1,701 (80.5%) at 12 months. At 12 months, the mean symptom score had improved from 58.61 to 19.23 (P < .001), whereas 5.47% of patients had no improvement. The mean health-related quality-of-life score improved from 46.95 to 86.68 (P < .001), whereas 5.0% did not improve. In the first year after embolization, hysterectomy was performed in 2.9% of patients, with 3.6% requiring gynecologic interventions by 6 months and an additional 5.9% between 6 and 12 months. Amenorrhea as a result of embolization occurred in 7.3% of patients. Of these, 86% were age 45 or older. Most patients were satisfied with their outcome (82% strongly agree or agree). Predictors of a greater symptom change score include smaller leiomyoma size, submucosal location, and presenting symptom of heavy menstrual bleeding. CONCLUSION: Uterine embolization results in substantial symptom improvement for most patients, with hysterectomy required in only 2.9% of patients in the first 12 months after therapy.

Prospective data collection of a new procedure by a specialty society: the FIBROID registry.

OBJECTIVE: To describe registry methods and baseline patient demographics from a national sample of women undergoing uterine artery embolization for uterine leiomyomata. METHODS: Interventional radiology practices were recruited to submit data by a secure Web site on women undergoing uterine artery embolization for symptomatic leiomyomata. Baseline data included patient demographics, prior medical, surgical, and obstetrical history, uterine anatomy, and quality-of-life measures. Subsequent data collected included details of the uterine artery embolization procedure and hospital stay and outcomes at 30 days; patients were also offered the opportunity to participate in longer-term follow-up. Characteristics of white and African-American women were compared using t tests, chi(2), or Wilcoxon rank-sum tests as appropriate. RESULTS: As of December 31, 2002, 3,319 uterine artery embolization cases had been entered into the registry by 72 sites; number of patients entered by individual sites ranged from 1 to 514. Of these patients, 95.4% consented to participation in the short-term outcomes registry. Forty-eight percent of patients were African American, and 44.4% were white and non-Hispanic. Heavy menstrual bleeding was the single most bothersome symptom in 64.3% of patients. Compared with white non-Hispanic women, African-American women were significantly younger, more likely to be obese, had larger uteri and more numerous leiomyomata, more severe symptoms, and poorer quality-of-life scores before treatment. CONCLUSION: It is feasible to collect prospective data on new technologies. The FIBROID Registry prospectively collected data on more than 3,000 women undergoing uterine artery embolization for symptomatic leiomyomata. Baseline patient characteristics of this patient population seem to be similar to those of women undergoing other procedures for leiomyomata. LEVEL OF EVIDENCE: III.

The Fibroid Registry for outcomes data (FIBROID) for uterine embolization: short-term outcomes.

OBJECTIVE: To investigate the short-term safety of uterine embolization for leiomyomata in a large cohort of patients treated in a variety of clinical settings. METHODS: Examining the FIBROID Registry, a multicenter prospective voluntary registry of patients undergoing uterine embolization for leiomyomata, we studied the frequency of adverse events and predictors of adverse events within 30 days of the procedure. We also report on the technical aspects of the procedure, including details of periprocedural care, technique, and short-term recovery. All adverse events were recorded and classified using standard definitions, both in terms of type and severity. Summary statistics were used to describe the data set, and univariate and multivariate analyses were used to determine which factors might influence the incidence of adverse events. RESULTS: Of the 3,160 patients enrolled at 72 contributing sites, major in-hospital complications occurred in 0.66%, and postdischarge major events occurred in 4.8% within the first 30 days. The most common adverse event after discharge was inadequate pain relief requiring additional hospital treatment (2.4%). Thirty-one patients required additional surgical intervention within 30 days after treatment, 3 of whom required hysterectomy (0.1%). There were no deaths. Multivariate analysis showed modest increased odds for an adverse event for African Americans, smokers, and those with prior leiomyoma procedures. There were no differences in outcome based on the practice site experience, practice type, or any procedure-related factors. CONCLUSION: Uterine embolization for leiomyomata is a low-risk procedure with little variability in short-term outcome based on either patient demographics or practice setting. LEVEL OF EVIDENCE: II-3.

Chemotherapy-related complications in the kidneys and collecting system: an imaging perspective.

UNLABELLED: Nephrotoxicity is a common adverse effect of many chemotherapeutic agents. The agents most commonly associated with chemotherapy-associated nephrotoxicity are methotrexate, semustine, streptozocin, mithramycin, and cisplatin. Certain chemotherapeutic agents have adverse effects on the kidneys and urothelium that can be visualized radiographically, including cystic change, interstitial nephritis, papillary necrosis, urothelial changes, haemorrhagic cystitis, acute tubular necrosis, and infarction. This review focuses on imaging features identifying complications of chemotherapy in the kidneys and collecting system and provides didactic cases to alert referring clinicians. TEACHING POINTS: • Nephrotoxicity is a common adverse effect of many chemotherapeutic agents. • Chemotherapies have adverse renal and urothelial effects that can be visualized radiographically. • Crizotinib use can result in the development of complex renal cysts.