What is the gold standard for comprehensive interinstitutional communication of perioperative information for thyroid cancer patients? A comparison of existing electronic health records with the current American Thyroid Association recommendations.
Appropriate management of well-differentiated thyroid cancer requires treating clinicians to have access to critical elements of the patient's presentation, surgical management, postoperative course, and pathologic assessment. Electronic health records (EHRs) provide an effective method for the storage and transmission of patient information, although most commercially available EHRs are not intended to be disease-specific. In addition, there are significant challenges for the sharing of relevant clinical information when providers involved in the care of a patient with thyroid cancer are not connected by a common EHR. In 2012, the American Thyroid Association (ATA) defined the critical elements for optimal interclinician communication in a position paper entitled, "The Essential Elements of Interdisciplinary Communication of Perioperative Information for Patients Undergoing Thyroid Cancer Surgery." We present a field-by-field comparison of the ATA's essential elements as applied to three contemporary electronic reporting systems: the Thyroid Surgery e-Form from Memorial Sloan-Kettering Cancer Center (MSKCC), the Alberta WebSMR from the University of Calgary, and the Thyroid Cancer Care Collaborative (TCCC). The MSKCC e-form fulfills 21 of 32 intraoperative fields and includes an additional 14 fields not specifically mentioned in the ATA's report. The Alberta WebSMR fulfills 45 of 82 preoperative and intraoperative fields outlined by the ATA and includes 13 additional fields. The TCCC fulfills 117 of 120 fields outlined by the ATA and includes 23 additional fields. Effective management of thyroid cancer is a highly collaborative, multidisciplinary effort. The patient information that factors into clinical decisions about thyroid cancer is complex. For these reasons, EHRs are particularly favorable for the management of patients with thyroid cancer. The MSKCC Thyroid Surgery e-Form, the Alberta WebSMR, and the TCCC each meet all of the general recommendations for effective reporting of the specific domains that they cover in the management of thyroid cancer, as recommended by the ATA. However, the TCCC format is the most comprehensive. The TCCC is a new Web-based disease-specific database to enhance communication of patient information between clinicians in a Health Insurance Portability and Accountability Act (HIPAA)-compliant manner. We believe the easy-to-use TCCC format will enhance clinician communication while providing portability of thyroid cancer information for patients.


Long-term outcome of head injuries: a 23 year follow up study of children with head injuries.
The purpose of the 23 year follow up study was to determine the relationship between trauma variables including measures of head injury and very long-term sequelae. The study included 159 individuals with a mean age 31.40 years, of whom approximately 90% were admitted to hospital with a mild head injury during childhood (mean age 7.96). Extent of head injury was determined by unconsciousness, neurological status, skull fracture, EEG, post-traumatic seizures and a composite measure. The composite measure of neurological variables was the best predictor of long-term outcome. In addition, IQ recorded in the post-acute phase was a reliable predictor of long-term outcome. Of the sample, 32.7% reported physical complaints and 17.6% reported current psychological/psychiatric problems unrelated to the head injury. Subjective sequelae (physical, intellectual and emotional) specified as due to the head injury were reported by 31% of the sample, and the sequelae were found to be related to the extent of the head injury and initial IQ. There were no discernible relationships between attribute variables including premorbid status and age with subjective sequelae. There were, however, significant relationships between subjective sequelae and objective, psychosocial measures of adaptation including educational lag, unemployment, current psychological/psychiatric problems and relationships with family members. Finally, there appeared to be continuity of complaints elicited during the five year follow up of the original project and current sequelae. The severity of the head injury was identified as the primary contributory factor in the reconstitution process and in the prediction of long term outcomes.


Tularemia in range sheep: an overlooked syndrome?
Abortion and death caused by Francisella tularensis were well recognized in range flocks of domestic sheep in Idaho, Montana, and Wyoming in the first 6 decades of the 20th century. The current report describes 4 episodes of tularemia in 3 range flocks in Wyoming and South Dakota in 1997 and 2007 (1 flock was affected twice). Flock owners reported that ticks were unusually numerous and commonly present on sheep during outbreaks. Tularemia presented as late-term abortions (3 episodes) or listlessness and death in lambs and, to a lesser extent, ewes (1 episode). Lesions were multifocal pinpoint necrotic foci in tissues, particularly spleen, liver, and lung. An immunohistochemical procedure demonstrated F. tularensis, particularly in necrotic foci. The diagnosis was corroborated by bacterial isolation and, in individual cases, by serology, fluorescent antibody assay, and/or polymerase chain reaction detection of F. tularensis. Diagnosticians in endemic areas should include tularemia as a differential diagnosis when investigating late-term abortions or outbreaks of fatal illness in young lambs, particularly in years of high tick activity and when characteristic necrotic foci occur in spleen, liver, and lung.


A grounded theory: seeking relief from flatus as relevant client-nurse action and interaction.
Flatus problems are not uncommon among gastroenterological clients and those in other care settings. Yet what clients and nurses do productively about those problems in regard to their actions and interactions and why they do so has not previously been the focus of research. Holistic health management requires trustworthy qualitative evidence to guide best practice in this regard. This study systematically developed a substantive grounded theory that details and explains the trajectory of the basic social process: seeking relief from being discommoded (inconvenienced, troubled) by flatus in the situational context of client-nurse interactions. In the theory, there is also a focus on the context of nursing care situations, possible constraints, and likely outcomes. Grounded theory method was applied. Data were collected through semistructured individual interviews, nonparticipant observation, and document analysis regarding incidents and situations involving 38 participants-clients and registered nurses. The results show that clients, when trying to do something about the situation, can be severely discommoded by flatus problems and are hampered by embarrassment and the social taboo about admitting that one is bothered by flatus. The individual may or may not disclose the problem to a nurse, and nurses may or may not be attuned to these problems. There are ways for nurses to be helpful in these situations and possible remedies are identified in this article.


An assessment of fluoride related posts on Instagram.
Background: Social media is a driving force in the sharing of information. The purpose of this study is to describe fluoride related content on Instagram, a popular social media platform. Methods: Content categories were created and coded to better describe the nature of the posts.Data collection occurred in three sessions, two months apart. Only relevant posts that included images and had text written in the English language were included. Results: The most common topics were conspiracy theory, contained in 37.3% of posts, followed by dangers of fluoride to health (30.3%) and benefits of fluoride to teeth (28.7%). Of the posts reviewed, 96/300 (32.0%) contained pro-fluoride content while 139/300 (63.0%) posts featured anti-fluoride content. Content varied significantly between pro- and anti-fluoride posts. Conclusion: Our review of Instagram posts revealed that there were approximately 300 posts focused on fluoride related content. Of these posts, there was a higher number of anti-fluoride related content compared to pro-fluoride related content. With accessibility comes the potential for misinformation. Future efforts from medical providers need to focus on educating consumers about reliable sources for health information on the internet.


Hyperinflation and respiratory muscle interaction.
Hyperinflation clearly affects respiratory muscle interaction. It commonly increases the rib cage contribution to chest wall motion, whilst it reduces the abdominal contribution. This change is thought to result from the fact that hyperinflation severely reduces the mechanical advantage of the diaphragm, whilst it affects the mechanical advantage of the neck and rib cage muscles to a lesser extent. The mechanical disadvantage in the diaphragm induced by hyperinflation is presumably primarily the result of the length changes undergone by the diaphragm in acute hyperinflation. Changes in diaphragmatic geometry are generally considered to be less important in the reduction of the diaphragm's force-generating capacity. Further factors contributing to the mechanical disadvantage in the diaphragm include a reduction in the appositional component of diaphragmatic action (through reduction in the zone of apposition), and a reduction in the insertional component (through a shift in the alignment of the diaphragmatic fibres from axial to radial). In chronic hyperinflation, the diaphragm adapts to the chronically hyperinflated state. This adaptation to chronic foreshortening is similar to the adaptation occurring in the skeletal muscle. It is caused by a dropout of sarcomeres in series along the muscle fibres. It restores the force-generating capacity of the muscle, in part, but it reduces the capacity of the muscle to undergo length changes. The mechanical advantage of the parasternal intercostals and the scalenes is possibly less affected, because the length changes undergone by these muscles during hyperinflation are smaller. The factors determining the mechanical advantage of the parasternal intercostals are complex. Variables related to the mechanical advantage of the parasternal intercostals include: length changes; changes in angle between the parasternal intercostals and the sternum and between rib and sternum; and changes in mechanical arrangement among different parasternals. At present, it is difficult to develop an integrated view of these factors and of their change with hyperinflation. Finally, hyperinflation commonly results in recruitment of expiratory muscles. The functional significance of this expiratory muscle recruitment in patients is still debated.


Childhood Respiratory Risk Factor Profiles and Middle-Age Lung Function: A Prospective Cohort Study from the First to Sixth Decade.
Childhood risk factors for long-term lung health often coexist and their specific patterns may affect subsequent lung function differently. To identify childhood risk factor profiles and their influence on lung function and chronic obstructive pulmonary disease (COPD) in middle age, and potential pathways. Profiles of 11 childhood respiratory risk factors, documented at age 7, were identified in 8,352 participants from the Tasmanian Longitudinal Health Study using latent class analysis. We investigated associations between risk profiles and post-bronchodilator lung function and COPD at age 53, mediation by childhood lung function and adult asthma, and interaction with personal smoking. Six risk profiles were identified: 1) unexposed or least exposed (49%); 2) parental smoking (21.5%); 3) allergy (10%); 4) frequent asthma, bronchitis (8.7%); 5) infrequent asthma, bronchitis (8.3%); and 6) frequent asthma, bronchitis, allergy (2.6%). Profile 6 was most strongly associated with lower forced expiratory volume in 1 second (FEV1) (-261; 95% confidence interval, -373 to -148 ml); lower FEV1/forced vital capacity (FVC) (-3.4; -4.8 to -1.9%) and increased COPD risk (odds ratio, 4.9; 2.1 to 11.0) at age 53. The effect of profile 6 on COPD was largely mediated by adult active asthma (62.5%) and reduced childhood lung function (26.5%). Profiles 2 and 4 had smaller adverse effects than profile 6. Notably, the effects of profiles 2 and 6 were synergistically stronger for smokers. Profiles of childhood respiratory risk factors predict middle-age lung function levels and COPD risk. Specifically, children with frequent asthma attacks and allergies, especially if they also become adult smokers, are the most vulnerable group. Targeting active asthma in adulthood (i.e., a dominant mediator) and smoking (i.e., an effect modifier) may block causal pathways and lessen the effect of such established early-life exposures.


Increasing arousal enhances inhibitory control in calm but not excitable dogs.
The emotional-reactivity hypothesis proposes that problem-solving abilities can be constrained by temperament, within and across species. One way to test this hypothesis is with the predictions of the Yerkes-Dodson law. The law posits that arousal level, a component of temperament, affects problem solving in an inverted U-shaped relationship: Optimal performance is reached at intermediate levels of arousal and impeded by high and low levels. Thus, a powerful test of the emotional-reactivity hypothesis is to compare cognitive performance in dog populations that have been bred and trained based in part on their arousal levels. We therefore compared a group of pet dogs to a group of assistance dogs bred and trained for low arousal (N = 106) on a task of inhibitory control involving a detour response. Consistent with the Yerkes-Dodson law, assistance dogs, which began the test with lower levels of baseline arousal, showed improvements when arousal was artificially increased. In contrast, pet dogs, which began the test with higher levels of baseline arousal, were negatively affected when their arousal was increased. Furthermore, the dogs' baseline levels of arousal, as measured in their rate of tail wagging, differed by population in the expected directions. Low-arousal assistance dogs showed the most inhibition in a detour task when humans eagerly encouraged them, while more highly aroused pet dogs performed worst on the same task with strong encouragement. Our findings support the hypothesis that selection on temperament can have important implications for cognitive performance.


Case report of a rare complication of open-heart surgery masquerading as a gunshot wound: an autopsy diagnosis.
Poststernotomy mediastinitis is a rare feared sequelae of open-heart surgery with low incidence of 1% to 3% but a high mortality rate (10%-35%). Poststernotomy mediastinitis can in uncommon instances give rise to sternocutaneous fistulas in 0.25% to 10% of cases. Although scant reports have documented prosthetic valve endocarditis occurring in a setting of deep sternal wire infections, it is an infrequent but well-documented fatal complication of valvular replacement surgery. A 52-year-old male smoker with aortic valve replacement (2011), on Coumadin and Monocor, was found dead on September 2013 with a hole along a surgical scar over the sternum, masquerading as a gunshot wound. Chest radiograph revealed no foreign body, and no evidence of homicidal/suicidal or accidental cause was found at autopsy. Examination revealed a chronic fistulous tract from a deep sternal wire infection to the skin, in addition to a chronic sinus tract eroding into the root of the aorta with recent prosthetic valve endocarditis. To our knowledge, this is the first case report documenting poststernotomy mediastinitis causing a simultaneous occurrence of sternocutaneous fistula and prosthetic valve endocarditis. Either of these 2 exceptional but lethal complications would have sufficed as the cause of death.


Recent introgression between Taiga Bean Goose and Tundra Bean Goose results in a largely homogeneous landscape of genetic differentiation.
Several studies have uncovered a highly heterogeneous landscape of genetic differentiation across the genomes of closely related species. Specifically, genetic differentiation is often concentrated in particular genomic regions ("islands of differentiation") that might contain barrier loci contributing to reproductive isolation, whereas the rest of the genome is homogenized by introgression. Alternatively, linked selection can produce differentiation islands in allopatry without introgression. We explored the influence of introgression on the landscape of genetic differentiation in two hybridizing goose taxa: the Taiga Bean Goose (Anser fabalis) and the Tundra Bean Goose (A. serrirostris). We re-sequenced the whole genomes of 18 individuals (9 of each taxon) and, using a combination of population genomic summary statistics and demographic modeling, we reconstructed the evolutionary history of these birds. Next, we quantified the impact of introgression on the build-up and maintenance of genetic differentiation. We found evidence for a scenario of allopatric divergence (about 2.5 million years ago) followed by recent secondary contact (about 60,000 years ago). Subsequent introgression events led to high levels of gene flow, mainly from the Tundra Bean Goose into the Taiga Bean Goose. This scenario resulted in a largely undifferentiated genomic landscape (genome-wide FST = 0.033) with a few notable differentiation peaks that were scattered across chromosomes. The summary statistics indicated that some peaks might contain barrier loci while others arose in allopatry through linked selection. Finally, based on the low genetic differentiation, considerable morphological variation and incomplete reproductive isolation, we argue that the Taiga and the Tundra Bean Goose should be treated as subspecies.


Association of Mutations in the Basal Core Promoter and Pre-core Regions of the Hepatitis B Viral Genome and Longitudinal Changes in HBV Level in HBeAg Negative Individuals: Results From a Cohort Study in Northern Iran.
Although certain HBV mutations are known to affect the expression of Hepatitis e antigen, their association with HBV viral level or clinical outcomes is less clear. We evaluated associations between different mutations in the Basal Core promoter (BCP) and Pre-core (PC) regions of HBV genome and subsequent changes in HBV viral DNA level over seven years in a population of untreated HBeAg negative chronic hepatitis B (CHB) participants in Northeast of Iran. Participants in the current study were drawn from the Golestan Hepatitis B Cohort Study (GHBCS), a cohort of approximately 2590 HBsAg positive subjects (living in Gonbad city) embedded in the Golestan Cohort Study (GCS). At baseline, HBsAg was measured in all participants and revealed 2590 HBsAg positive cases. We randomly selected 304 participants who their blood sample were taken at both baseline and seven years later in follow-up and had not been treated for HBV during this time. HBV viral load were assessed at baseline and at year 7. The BCP and PC regions of the HBV DNA, at baseline, were amplified via hemi-nested PCR and sequenced by cycle sequencing. At year 7, liver stiffness was assessed by fibroscan; also, other parameters of liver disease were assessed following standard clinical protocols. Associations were assessed via tabulation, chi-square, t-tests and logistic regression. P values < 0.05 were considered statistically significant and all tests were two-sided. Among 304 HBsAg positive participants, 99 had detectable HBV DNA at study baseline. Of these, 61.6% had PC mutations (48.5% A1896 and 25.2% G1899). In contrast to other mutations, A1896 was associated with a higher proportion of detectable HBV DNA at year 7 (39.6%) compared to patients with the wild type (13.7%) (OR: 4.36, CI95% = 1.63-11.70; P Value = 0.002). Although participants with the A1896 mutation had higher year-7 HBV viral load than participants with G1896 (2.30 ± 1.66 IU/mL vs. 1.76 ± 1 IU/mL among patients with detectable HBV; P value = 0.052), no association was observed with either serum level ALT or liver stiffness. Interestingly, mutations in the basal core promoter (BCP) region had no significant effect on virus DNA detection. In this population with chronic HBeAg negative hepatitis B, an association was observed between the G1896A mutation in the Pre-core region of HBV and subsequent level of HBV DNA seven years later, which indicated that mutations in this region of HBV genome may contribute to disease progression in these patients and play an important role in HBV natural course of disease.


Comparative genomics reveals diverse capsular polysaccharide synthesis gene clusters in emerging Raoultella planticola.
Raoultella planticola is an emerging zoonotic pathogen that is associated with rare but life-threatening cases of bacteremia, biliary tract infections, and urinary tract infections. Moreover, increasing antimicrobial resistance in the organism poses a potential threat to public health. In spite of its importance as a human pathogen, the genome of R. planticola remains largely unexplored and little is known about its virulence factors. Although lipopolysaccharides has been detected in R. planticola and implicated in the virulence in earlier studies, the genetic background is unknown. Here, we report the complete genome and comparative analysis of the multidrug-resistant clinical isolate R. planticola GODA. The complete genome sequence of R. planticola GODA was sequenced using single-molecule real-time DNA sequencing. Comparative genomic analysis reveals distinct capsular polysaccharide synthesis gene clusters in R. planticola GODA. In addition, we found bla TEM-57 and multiple transporters related to multidrug resistance. The availability of genomic data in open databases of this emerging zoonotic pathogen, in tandem with our comparative study, provides better understanding of R. planticola and the basis for future work.


Cracked tooth syndrome: characteristics and distribution among adults in a Nigerian teaching hospital.
This study highlighted the characteristics and distribution of cracked tooth syndrome (CTS) and the associated factors in adult attendees in the University of Nigeria Teaching Hospital. Three hundred seventy patients aged 18 years to 77 years with CTS-like conditions were included and studied over 12 months. The following information was recorded: suspected tooth and the dental arch, restorative status of the tooth, age and sex of the patient, results of bite test and transillumination, and the pulpal and periapical status of the tooth. CTS was seen most often in the 41 to 50 years age band (36.4%), in molars (63.6%), and in the maxillary arch (51.5%). Also, it was more frequent in men (55.8%). About 82% of CTS occurred in amalgam-restored teeth. All cases had a positive response to the bite test and a normal response to the electric pulp test. Only 10% gave a positive history of masticatory accident as against none with history of bruxism habits. It was concluded that patients with unexplained pain in a vital, amalgam-restored tooth (especially in maxillary molars), with or without a history of a masticatory accident, may have a cracked or fractured tooth.


Production of tumor-associated antigen, TA-4, by the CaSki cervical carcinoma cell line.
Previous Japanese studies described the purification of TA-4 from homogenates of tumor tissues excised from squamous cell carcinomas of the uterine cervix, and the development of a radioimmunoassay to detect TA-4 in sera of patients with this disease. The aim of the present investigation was to determine if TA-4 was produced by the CaSki cell line, established in culture ten years ago from epidermoid carcinoma of the uterine cervix. The radioimmunoassay detected the TA-4 antigen in the CaSki cells, but not in cell lines derived from either choriocarcinoma or breast carcinoma. The TA-4 concentration in the CaSki cell lysate exceeded that in the CaSki culture fluid by more than twentyfold, and exceeded the concentration of human chorionic gonadotropin beta-like immunoreactive material by nearly two orders of magnitude. Antiserum to TA-4 was used to immunoprecipitate biosynthetically labeled TA-4 from CaSki cultures that had been incubated with [3H]leucine. After electrophoresis and autoradiography, the immunoprecipitated material showed a major band corresponding in apparent molecular weight (48,000 daltons) to TA-4 originally isolated from squamous cell carcinoma tumors. It is concluded that the CaSki cell line constitutes an ideal model with which to investigate the biosynthesis and regulation of TA-4, and a source for large-scale production of TA-4 for characterization studies as well as development of clinical diagnostic reagents.


Targeting Cancer Resistance via Multifunctional Gold Nanoparticles.
Resistance to chemotherapy is a major problem facing current cancer therapy, which is continuously aiming at the development of new compounds that are capable of tackling tumors that developed resistance toward common chemotherapeutic agents, such as doxorubicin (DOX). Alongside the development of new generations of compounds, nanotechnology-based delivery strategies can significantly improve the in vivo drug stability and target specificity for overcoming drug resistance. In this study, multifunctional gold nanoparticles (AuNP) have been used as a nanoplatform for the targeted delivery of an original anticancer agent, a Zn(II) coordination compound [Zn(DION)2]Cl2 (ZnD), toward better efficacy against DOX-resistant colorectal carcinoma cells (HCT116 DR). Selective delivery of the ZnD nanosystem to cancer cells was achieved by active targeting via cetuximab, NanoZnD, which significantly inhibited cell proliferation and triggered the death of resistant tumor cells, thus improving efficacy. In vivo studies in a colorectal DOX-resistant model corroborated the capability of NanoZnD for the selective targeting of cancer cells, leading to a reduction of tumor growth without systemic toxicity. This approach highlights the potential of gold nanoformulations for the targeting of drug-resistant cancer cells.


Pancreatic β-cell-specific ablation of TASK-1 channels augments glucose-stimulated calcium entry and insulin secretion, improving glucose tolerance.
Calcium entry through voltage-dependent Ca(2+) channels (VDCCs) is required for pancreatic β-cell insulin secretion. The 2-pore-domain acid-sensitive potassium channel (TASK-1) regulates neuronal excitability and VDCC activation by hyperpolarizing the plasma membrane potential (Δψp); however, a role for pancreatic β-cell TASK-1 channels is unknown. Here we examined the influence of TASK-1 channel activity on the β-cell Δψp and insulin secretion during secretagogue stimulation. TASK-1 channels were found to be highly expressed in human and rodent islets and localized to the plasma membrane of β-cells. TASK-1-like currents of mouse and human β-cells were blocked by the potent TASK-1 channel inhibitor, A1899 (250nM). Although inhibition of TASK-1 currents did not influence the β-cell Δψp in the presence of low (2mM) glucose, A1899 significantly enhanced glucose-stimulated (14mM) Δψp depolarization of human and mouse β-cells. TASK-1 inhibition also resulted in greater secretagogue-stimulated Ca(2+) influx in both human and mouse islets. Moreover, conditional ablation of mouse β-cell TASK-1 channels reduced K2P currents, increased glucose-stimulated Δψp depolarization, and augmented secretagogue-stimulated Ca(2+) influx. The Δψp depolarization caused by TASK-1 inhibition resulted in a transient increase in glucose-stimulated mouse β-cell action potential (AP) firing frequency. However, secretagogue-stimulated β-cell AP duration eventually increased in the presence of A1899 as well as in β-cells without TASK-1, causing a decrease in AP firing frequency. Ablation or inhibition of mouse β-cell TASK-1 channels also significantly enhanced glucose-stimulated insulin secretion, which improved glucose tolerance. Conversely, TASK-1 ablation did not perturb β-cell Δψp, Ca(2+) influx, or insulin secretion under low-glucose conditions (2mM). These results reveal a glucose-dependent role for β-cell TASK-1 channels of limiting glucose-stimulated Δψp depolarization and insulin secretion, which modulates glucose homeostasis.


The co-activator p300 associates physically with and can mediate the action of the distal enhancer of the FGF-4 gene.
Distal enhancers commonly regulate gene expression. However, the mechanisms of transcriptional mediation by distal enhancers remain largely unknown. To better understand distal enhancer-mediated transcription, we examined the regulation of the FGF-4 gene. The FGF-4 gene is regulated during early development by a powerful distal enhancer located downstream of the promoter in exon 3. Sox-2 and Oct-3 bind to the enhancer and are required for the activation of the FGF-4 gene. Previously, we implicated the co-activator p300 as a mediator of Sox-2/Oct-3 synergistic activation of a heterologous promoter, suggesting that p300 may play a role in mediating enhancer activation of the FGF-4 gene. In this study, we provide both functional and physical evidence that p300 plays an important role in the action of the FGF-4 enhancer. Specifically, we show that E1a, but not a mutant form of E1a that is unable to bind p300, inhibits enhancer activation of the FGF-4 promoter. We also demonstrate that Gal4/p300 fusion proteins can stimulate the FGF-4 promoter when bound to the FGF-4 enhancer. Additionally, we present evidence that p300 mediation of the FGF-4 enhancer requires acetyltransferase activity. Importantly, we also show that Sox-2 and p300 are physically associated with the endogenous FGF-4 enhancer but weakly associated with the endogenous FGF-4 promoter. These results are consistent with a model of transitory interaction between the distal enhancer and the FGF-4 promoter. Our results also suggest that intragenic distal enhancers may use mechanisms that differ from extragenic distal enhancers.


DNAzymes: from creation in vitro to application in vivo.
DNAzymes, also known as deoxyribozymes or DNA enzymes, refer to single-stranded DNA molecules with catalytic capabilities. DNAzymes are generated de novo by in vitro selection--a powerful and yet simple technique that has been routinely used to isolate extremely rare DNA or RNA sequences with a function of interest (e.g. ligand-binding or catalysis) from an extraordinarily large population of single-stranded DNA or RNA molecules. Since the report of the first DNAzyme nearly ten years ago, hundreds of DNA sequences have been isolated in many research laboratories around the world to facilitate many chemical transformations of biological importance. In recent years, considerable efforts have been undertaken to assess a variety of DNAzymes for innovation-driven applications ranging from biosensing to gene regulation. This article provides a review on several key aspects of DNAzyme-related research. We will first review in vitro selection techniques used for DNAzyme creation as well as some DNAzymes created for a few representative chemical transformations. We will then discuss recent progresses in studying and developing DNAzymes as reporter molecules for detection-oriented applications, and as therapeutic agents to regulate gene expression at the RNA level. Future outlook on efforts aimed to bring the wonder of catalytic DNA from laboratory curiosity to real world application are also discussed.


Blood pressure reduction in diabetes: lessons from ACCORD, SPRINT and EMPA-REG OUTCOME.
In patients with diabetes mellitus, the presence of hypertension substantially increases the risk of cardiovascular events, and reductions in blood pressure (BP) can reduce cardiovascular morbidity and mortality. Following evidence from trials randomizing patients to diastolic BP levels, previous guidelines recommended an office BP target of <130/80 mmHg in individuals with diabetes mellitus. However, the evidence for this systolic BP (SBP) target was derived from observational studies. When the results of the ACCORD-BP study showed that those individuals with diabetes mellitus and a target BP of <120 mmHg had a cardiovascular risk that is similar to those with <140 mmHg, all guidelines returned to a recommended SBP of <140 mmHg. However, the ACCORD-BP trial was limited by the low number of cardiovascular events observed, whereas the mean SBP in the 'conventional' arm was 133 mmHg. The SPRINT study, showing cardiovascular benefits in hypertensive patients without diabetes mellitus randomized to SBP <120 mmHg versus those randomized to <140 mmHg, came in contrast with the ACCORD-BP, but a detailed evaluation reveals many similarities between the two trials. Finally, the EMPA-REG OUTCOME study, with impressive cardiovascular mortality reduction with empagliflozin, suggested that reduction of SBP to around 130 mmHg is safe and might explain part of these beneficial results. In this Review, we evaluate the implications of the ACCORD-BP, SPRINT and EMPA-REG OUTCOME trials and previous studies for the optimal BP target in diabetes mellitus.


Isolated short CTG/CAG DNA slip-outs are repaired efficiently by hMutSbeta, but clustered slip-outs are poorly repaired.
Expansions of CTG/CAG trinucleotide repeats, thought to involve slipped DNAs at the repeats, cause numerous diseases including myotonic dystrophy and Huntington's disease. By unknown mechanisms, further repeat expansions in transgenic mice carrying expanded CTG/CAG tracts require the mismatch repair (MMR) proteins MSH2 and MSH3, forming the MutSbeta complex. Using an in vitro repair assay, we investigated the effect of slip-out size, with lengths of 1, 3, or 20 excess CTG repeats, as well as the effect of the number of slip-outs per molecule, on the requirement for human MMR. Long slip-outs escaped repair, whereas short slip-outs were repaired efficiently, much greater than a G-T mismatch, but required hMutSbeta. Higher or lower levels of hMutSbeta or its complete absence were detrimental to proper repair of short slip-outs. Surprisingly, clusters of as many as 62 short slip-outs (one to three repeat units each) along a single DNA molecule with (CTG)50*(CAG)50 repeats were refractory to repair, and repair efficiency was reduced further without MMR. Consistent with the MutSbeta requirement for instability, hMutSbeta is required to process isolated short slip-outs; however, multiple adjacent short slip-outs block each other's repair, possibly acting as roadblocks to progression of repair and allowing error-prone repair. Results suggest that expansions can arise by escaped repair of long slip-outs, tandem short slip-outs, or isolated short slip-outs; the latter two types are sensitive to hMutSbeta. Poor repair of clustered DNA lesions has previously been associated only with ionizing radiation damage. Our results extend this interference in repair to neurodegenerative disease-causing mutations in which clustered slip-outs escape proper repair and lead to expansions.


Assessing the evaluability of complex public health interventions: five questions for researchers, funders, and policymakers.
Evidence to support government programs to improve public health often is weak. Recognition of this "knowledge gap" has led to calls for more and better evaluation, but decisions about priorities for evaluation also need to be addressed in regard to financial restraint. Using England's Healthy Community Challenge Fund as a case study, this article presents a set of questions to stimulate and structure debate among researchers, funders, and policymakers and help make decisions about evaluation within and between complex public health interventions as they evolve from initial concept to dissemination of full-scale intervention packages. This approach can be used to identify the types of knowledge that might be generated from any evaluation, given the strength of evidence available in response to each of five questions, and to support a more systematic consideration of resource allocation decisions, depending on the types of knowledge required. The principles of this approach may be generalizable, and should be tested and refined for other complex public health and wider social interventions.


Central nervous system manifestations of cardiac myxoma.
Neurologic complications can be the initial manifestation of atrial myxoma. Prompt diagnosis is of paramount significance to prevent recurrent complications. To identify patients with neurologic complications attributed to atrial myxoma. With institutional review board approval, we retrospectively reviewed the medical records of 74 consecutive patients with pathologically confirmed cardiac myxoma at the Mayo Clinic from January 1, 1993, through December 31, 2004. Discharge and follow-up modified Rankin score. Nine of the 74 patients with cardiac myxoma (12%) presented with neurologic manifestations in the setting of atrial myxoma. Mean age was 48.5 years (range, 17-70 years). There were 6 females and 3 males. Among patients with myxoma and neurologic symptoms, ischemic cerebral infarct was the most common neurologic manifestation (8 patients [89%]). No patients had concomitant cardiac symptoms. The size of the atrial myxoma was variable, with a mean diameter of 2.7 (range, 0.4-6.5) cm. Most of the atrial myxomas causing neurologic symptoms demonstrated a mobile component on transesophageal echocardiography (8 patients [89%]). Two patients (22%) had pathologic evidence of systemic myxomatous emboli. One patient with intracerebral hemorrhage had pathologically confirmed intracranial metastatic myxoma and myxoma-induced aneurysmal dilatation. Neurologic complications are associated with cardiac myxoma in some patients with myxoma and, when they occur, frequently present with cerebral infarction. The mobility, not the size, of the myxoma appears to be related to embolic potential. Potential delayed neurologic complications relevant to patients with tumor embolization include myxoma-induced cerebral aneurysm and myxomatous metastasis, which can mimic the clinical picture of central nervous system vasculitis or infective endocarditis.


Magnetodielectric detection of magnetic quadrupole order in Ba(TiO)Cu4(PO4)4 with Cu4O12 square cupolas.
In vortex-like spin arrangements, multiple spins can combine into emergent multipole moments. Such multipole moments have broken space-inversion and time-reversal symmetries, and can therefore exhibit linear magnetoelectric (ME) activity. Three types of such multipole moments are known: toroidal; monopole; and quadrupole moments. So far, however, the ME activity of these multipole moments has only been established experimentally for the toroidal moment. Here we propose a magnetic square cupola cluster, in which four corner-sharing square-coordinated metal-ligand fragments form a noncoplanar buckled structure, as a promising structural unit that carries an ME-active multipole moment. We substantiate this idea by observing clear magnetodielectric signals associated with an antiferroic ME-active magnetic quadrupole order in the real material Ba(TiO)Cu4(PO4)4. The present result serves as a useful guide for exploring and designing new ME-active materials based on vortex-like spin arrangements.


Untreated for 20 Years: A 14 Kilogram Subcutaneous Lipoma.
Lipomas are the most common benign mesenchymal tumors found in humans, with a prevalance rate of 2.1 per 1000 tumors. Most of them are small, weighing only a few grams and measuring less than 2 centimeters in diameter. However, those weighing upwards of 200 grams and exceeding 10 centimeters have only been described in different anatomic locations on occasion in the literature. A 54-year-old man presented with a large soft tissue growth over the lower back, present for the past 20 years and rapidly enlarging over the past 3 years. A diagnosis of giant lipoma was made. Six hours and several surgical teams were required to remove the 14 kilogram mass. During excision, the skin flaps overlying the mass were preserved and were ultimately used to reconstruct the surgical site defect in a layered fashion once intraoperative frozen pathology confirmed the pre-operative diagnosis. Benign lipomas of the size reported in this case have rarely been described in the literature, as lipomatous masses of this size are often found to instead be either atypical lipomatous tumors or high-grade liposarcomas. In this case, we describe one of the largest of these giant benign lipomas ever reported to date. The case also illustrates the use of an interdisciplanary, multi-team approach to undertake the high-risk operation of removing such a mass from a patient safely. Finally, the case describes aninteresting approach toward reconstructing the large soft tissue defect that remained once the tumor had been removed from the patient.


Nonprocessive motor dynamics at the microtubule membrane tube interface.
Key cellular processes such as cell division, membrane compartmentalization, and intracellular transport rely on motor proteins. Motors have been studied in detail on the single motor level such that information on their step size, stall force, average run length, and processivity are well known. However, in vivo, motors often work together, so that the question of their collective coordination has raised great interest. Here, we specifically attach motors to giant vesicles and examine collective motor dynamics during membrane tube formation. Image correlation spectroscopy reveals directed motion as processive motors walk at typical speeds (< or = 500 nm/s) along an underlying microtubule and accumulate at the tip of the growing membrane tube. In contrast, nonprocessive motors exhibit purely diffusive behavior, decorating the entire length of a microtubule lattice with diffusion constants at least 1000 times smaller than a freely-diffusing lipid-motor complex in a lipid bilayer (1 microm(2)/s); fluorescence recovery after photobleaching experiments confirm the presence of the slower-moving motor population at the microtubule-membrane tube interface. We suggest that nonprocessive motors dynamically bind and unbind to maintain a continuous interaction with the microtubule. This dynamic and continuous interaction is likely necessary for nonprocessive motors to mediate bidirectional membrane tube dynamics reported previously.


FusionMap: detecting fusion genes from next-generation sequencing data at base-pair resolution.
Next generation sequencing technology generates high-throughput data, which allows us to detect fusion genes at both transcript and genomic levels. To detect fusion genes, the current bioinformatics tools heavily rely on paired-end approaches and overlook the importance of reads that span fusion junctions. Thus there is a need to develop an efficient aligner to detect fusion events by accurate mapping of these junction-spanning single reads, particularly when the read gets longer with the improvement in sequencing technology. We present a novel method, FusionMap, which aligns fusion reads directly to the genome without prior knowledge of potential fusion regions. FusionMap can detect fusion events in both single- and paired-end datasets from either RNA-Seq or gDNA-Seq studies and characterize fusion junctions at base-pair resolution. We showed that FusionMap achieved high sensitivity and specificity in fusion detection on two simulated RNA-Seq datasets, which contained 75 nt paired-end reads. FusionMap achieved substantially higher sensitivity and specificity than the paired-end approach when the inner distance between read pairs was small. Using FusionMap to characterize fusion genes in K562 chronic myeloid leukemia cell line, we further demonstrated its accuracy in fusion detection in both single-end RNA-Seq and gDNA-Seq datasets. These combined results show that FusionMap provides an accurate and systematic solution to detecting fusion events through junction-spanning reads. FusionMap includes reference indexing, read filtering, fusion alignment and reporting in one package. The software is free for noncommercial use at (http://www.omicsoft.com/fusionmap).


Skin tumor-promoting activity of benzoyl peroxide, a widely used free radical-generating compound.
Benzoyl peroxide, a widely used free radical-generating compound, promoted both papillomas and carcinomas when it was topically applied to mice after 7,12-dimethylbenz[a]anthracene initiation. Benzoyl peroxide was inactive on the skin as a complete carcinogen or as a tumor initiator. A single topical application of benzoyl peroxide produced a marked epidermal hyperplasia and induced a large number of dark basal keratinocytes, effects similar to those produced by the potent tumor promoter 12-O-tetradecanoyl phorbol-13-acetate. Benzoyl peroxide, like other known tumor promoters, also inhibited metabolic cooperation (intercellular communication) in Chinese hamster cells. In view of these results caution should be recommended in the use of this and other free radical-generating compounds.


Identification of the maize gravitropism gene lazy plant1 by a transposon-tagging genome resequencing strategy.
Since their initial discovery, transposons have been widely used as mutagens for forward and reverse genetic screens in a range of organisms. The problems of high copy number and sequence divergence among related transposons have often limited the efficiency at which tagged genes can be identified. A method was developed to identity the locations of Mutator (Mu) transposons in the Zea mays genome using a simple enrichment method combined with genome resequencing to identify transposon junction fragments. The sequencing library was prepared from genomic DNA by digesting with a restriction enzyme that cuts within a perfectly conserved motif of the Mu terminal inverted repeats (TIR). Paired-end reads containing Mu TIR sequences were computationally identified and chromosomal sequences flanking the transposon were mapped to the maize reference genome. This method has been used to identify Mu insertions in a number of alleles and to isolate the previously unidentified lazy plant1 (la1) gene. The la1 gene is required for the negatively gravitropic response of shoots and mutant plants lack the ability to sense gravity. Using bioinformatic and fluorescence microscopy approaches, we show that the la1 gene encodes a cell membrane and nuclear localized protein. Our Mu-Taq method is readily adaptable to identify the genomic locations of any insertion of a known sequence in any organism using any sequencing platform.


Exposure to psychosocial job strain during pregnancy and odds of asthma and atopic dermatitis among 7-year old children - a prospective cohort study.
Few epidemiological studies have studied maternal stress exposure during pregnancy and odds of asthma and atopic dermatitis (AD) among offspring, and none have extended the focus to psychosocial job strain. The aim of this study was to assess the association between maternal job strain during pregnancy and asthma as well as AD among 7-year-old children. The study is based on the Danish National Birth Cohort and includes prospective data from 32 104 pregnancies. Job strain was assessed early in pregnancy by use of two questions on demands and control. We categorized participants into four job strain categories: low strain (low demands, high control), active (high demands, high control), passive (low demands, low control), and high strain (high demands, low control). Information on asthma and AD until age seven was collected using maternal self-report. Multinomial logistic regression models were used to estimate odds ratios (OR) with 95% confidence intervals (95% CI) adjusted for several covariates. Maternal exposure to self-reported high strain during pregnancy was associated with 15% higher odds of atopic dermatitis among 7-year-old children (OR adj1.15, 95% CI 1.02-1.31). Furthermore, an association between the active jobs and asthma among 7-year-old children was found (OR adj1.13, 95% CI 1.03-1.24). Maternal exposure to high strain and active jobs during pregnancy was associated with asthma and atopic dermatitis among 7-year-old children.


Patients' affective processes within initial experiential dynamic therapy sessions.
Research has indicated that patients' in-session experience of previously avoided affects may be important for effective psychotherapy. The aim of this study was to investigate patients' in-session levels of affect experiencing in relation to their corresponding levels of insight, motivation, and inhibitory affects in initial Experiential Dynamic Therapy (EDT) sessions. Four hundred sixty-six 10-min video segments from 31 initial sessions were rated using the Achievement of Therapeutic Objectives Scale. A series of multilevel growth models, controlling for between-therapist variability, were estimated to predict patients' adaptive affect experiencing (Activating Affects) across session segments. In line with our expectations, higher within-person levels of Insight and Motivation related to higher levels of Activating Affects per segment. Contrary to expectations, however, lower levels of Inhibition were not associated with higher levels of Activating Affects. Further, using a time-lagged model, we did not find that the levels of Insight, Motivation, or Inhibition during one session segment predicted Activating Affects in the next, possibly indicating that 10-min segments may be suboptimal for testing temporal relationships in affective processes. Our results suggest that, to intensify patients' immediate affect experiencing in initial EDT sessions, therapists should focus on increasing insight into defensive patterns and, in particular, motivation to give them up. Future research should examine the impact of specific inhibitory affects more closely, as well as between-therapist variability in patients' in-session adaptive affect experiencing. (PsycINFO Database Record


Peribulbar versus retrobulbar anaesthesia for cataract surgery.
Cataract is a major cause of blindness worldwide. Unless medically contraindicated, cataract surgery is usually performed under local (regional) anaesthesia. Local anaesthesia involves the blockage of a nerve subserving a given part of the body by infiltration of the area around the nerve with local anaesthetic. The two main approaches in the eye are retrobulbar and peribulbar. There is debate over whether the peribulbar approach provides more effective and safer anaesthesia for cataract surgery than retrobulbar block. The objective of this review was to assess the effects of peribulbar anaesthesia (PB) compared to retrobulbar anaesthesia (RB) on pain scores, ocular akinesia, patient acceptability and ocular and systemic complications. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2007, Issue 4); MEDLINE (1960 to December 2007); and EMBASE (1980 to December 2007). We included randomized controlled clinical trials comparing peribulbar anaesthesia and retrobulbar anaesthesia for cataract surgery. Two authors independently assessed trial quality and extracted data. We contacted trial authors for additional information, study methodology and missing data. We carried out a descriptive narrative of results as the methods used by the included stories for reporting the outcomes varied. We performed a subgroup analysis for globe akinesia. We included six trials involving 1438 participants. Two of the six trials had a low risk of bias; the remaining four had a moderate risk of bias. There was no evidence of any difference in pain perception during surgery with either retrobulbar or peribulbar anaesthesia. Both were largely effective. There was no evidence of any difference in complete akinesia or the need for further injections of local anaesthetic. Conjunctival chemosis was more common after peribulbar block (relative risk (RR) 2.11, 95% confidence Interval (CI) 1.46 to 3.05) and lid haematoma was more common after retrobulbar block (RR 0.36, 95% CI 0.15 to 0.88). Retrobulbar haemorrhage was uncommon and occurred only once, in a patient who had a retrobulbar block. There is little to choose between peribulbar and retrobulbar block in terms of anaesthesia and akinesia during surgery in terms of acceptability to patients, need for additional injections and development of severe complications. Severe local or systemic complications were rare in PB and RB.


Hepatitis viruses: not always what it seems to be.
The classic hepatotropic viruses, hepatitis A through E, are not the only viral agents able to infect the liver. Other systemic viruses may cause hepatic injury that can range from mild and transient elevation of aminotransferases to acute hepatitis and occasionally acute liver failure and fulminant hepatitis. The clinical presentation may be indistinguishable from that associated with classic hepatotropic viruses. These agents include cytomegalovirus; Epstein-Barr virus; herpes simplex virus; varicella-zoster virus; human herpesvirus 6, 7, and 8; human parvovirus B19; adenoviruses among others. Wide spectrums of clinical syndromes are associated with cytomegalovirus disease. Unique clinical syndromes may present in neonates, young adults and immunocompromised hosts infected with cytomegalovirus. Cases of fulminant hepatitis have been reported in both immunocompromised and immunocompetent hosts infected with Epstein Barr virus. Occasionally, these patients with acute hepatic failure may need liver transplantation. Herpes simplex viruses may involve the liver in neonatal infections, pregnancy, immunocompromised hosts and occasionally, immunocompetent adults. Varicella-Zoster virus has also been associated with severe acute hepatitis and fulminant hepatitis in adults. The drug of choice for these conditions is intravenous acyclovir. These may also need liver transplantation in the more severe forms of clinical presentation. Typical liver biopsy findings can be useful in determining the diagnosis of these viral infections. Human herpesviruses 6, 7, and 8, human parvovirus B19, and adenoviruses can also be present with features of acute liver injury and occasionally as fulminant hepatitis. The clinical syndromes are less well delineated than those associated with herpesviruses. It is important to consider these viruses as possible etiologic agents in patients who have acute liver injury and their serologic markers for the classic hepatotropic viruses are not indicative of an active infection.


Zidovudine, didanosine, or both as the initial treatment for symptomatic HIV-infected children. AIDS Clinical Trials Group (ACTG) Study 152 Team.
Zidovudine has been the drug of choice for the initial treatment of symptomatic children infected with the human immunodeficiency virus (HIV). This trial was designed to assess the efficacy and safety of treatment with zidovudine alone as compared with either didanosine alone or combination therapy with zidovudine plus didanosine. In this multicenter, double-blind study, symptomatic HIV-infected children 3 months through 18 years of age were stratified according to age (<30 months or > or =30 months) and randomly assigned to receive zidovudine, didanosine, or zidovudine plus didanosine. The primary end point was length of time to death or to progression of HIV disease. Of the 831 children who could be evaluated, 92 percent had never received antiretroviral therapy and 90 percent had acquired HIV perinatally. An interim analysis (median follow-up, 23 months) showed a significantly higher risk of HIV-disease progression or death in patients receiving zidovudine alone than in those receiving combination therapy (relative risk, 0.61; 95 percent confidence interval, 0.42 to 0.88; P=0.007). The study arm with zidovudine alone was stopped and unblinded; the other two treatment arms were continued. At the end of the study, didanosine alone had an efficacy similar to that of zidovudine plus didanosine (median follow-up, 32 months) (relative risk of disease progression or death, 0.98; 95 percent confidence interval, 0.70 to 1.37; P=0.91). A significantly lower risk of anemia or neutropenia was seen in patients receiving didanosine alone (P=0.036). In symptomatic HIV-infected children, treatment with either didanosine alone or zidovudine plus didanosine was more effective than treatment with zidovudine alone. The efficacy of didanosine alone was similar to that of the combination therapy and was associated with less hematologic toxicity.


Memory errors reveal a bias to spontaneously generalize to categories.
Much evidence suggests that, from a young age, humans are able to generalize information learned about a subset of a category to the category itself. Here, we propose that-beyond simply being able to perform such generalizations-people are biased to generalize to categories, such that they routinely make spontaneous, implicit category generalizations from information that licenses such generalizations. To demonstrate the existence of this bias, we asked participants to perform a task in which category generalizations would distract from the main goal of the task, leading to a characteristic pattern of errors. Specifically, participants were asked to memorize two types of novel facts: quantified facts about sets of kind members (e.g., facts about all or many stups) and generic facts about entire kinds (e.g., facts about zorbs as a kind). Moreover, half of the facts concerned properties that are typically generalizable to an animal kind (e.g., eating fruits and vegetables), and half concerned properties that are typically more idiosyncratic (e.g., getting mud in their hair). We predicted that-because of the hypothesized bias-participants would spontaneously generalize the quantified facts to the corresponding kinds, and would do so more frequently for the facts about generalizable (rather than idiosyncratic) properties. In turn, these generalizations would lead to a higher rate of quantified-to-generic memory errors for the generalizable properties. The results of four experiments (N = 449) supported this prediction. Moreover, the same generalizable-versus-idiosyncratic difference in memory errors occurred even under cognitive load, which suggests that the hypothesized bias operates unnoticed in the background, requiring few cognitive resources. In sum, this evidence suggests the presence of a powerful bias to draw generalizations about kinds.


Disposable platform provides visual and color-based point-of-care anemia self-testing.
Anemia, or low blood hemoglobin (Hgb) levels, afflicts 2 billion people worldwide. Currently, Hgb levels are typically measured from blood samples using hematology analyzers, which are housed in hospitals, clinics, or commercial laboratories and require skilled technicians to operate. A reliable, inexpensive point-of-care (POC) Hgb test would enable cost-effective anemia screening and chronically anemic patients to self-monitor their disease. We present a rapid, stand-alone, and disposable POC anemia test that, via a single drop of blood, outputs color-based visual results that correlate with Hgb levels. We tested blood from 238 pediatric and adult patients with anemia of varying degrees and etiologies and compared hematology analyzer Hgb levels with POC Hgb levels, which were estimated via visual interpretation using a color scale and an optional smartphone app for automated analysis. POC Hgb levels correlated with hematology analyzer Hgb levels (r = 0.864 and r = 0.856 for visual interpretation and smartphone app, respectively), and both POC test methods yielded comparable sensitivity and specificity for detecting any anemia (n = 178) (<11 g/dl) (sensitivity: 90.2% and 91.1%, specificity: 83.7% and 79.2%, respectively) and severe anemia (n = 10) (<7 g/dl) (sensitivity: 90.0% and 100%, specificity: 94.6% and 93.9%, respectively). These results demonstrate the feasibility of this POC color-based diagnostic test for self-screening/self-monitoring of anemia. Not applicable. This work was funded by the FDA-funded Atlantic Pediatric Device Consortium, the Georgia Research Alliance, Children's Healthcare of Atlanta, the Georgia Center of Innovation for Manufacturing, and the InVenture Prize and Ideas to Serve competitions at the Georgia Institute of Technology.


Sister-chromatid cohesion mediated by the alternative RF-CCtf18/Dcc1/Ctf8, the helicase Chl1 and the polymerase-alpha-associated protein Ctf4 is essential for chromatid disjunction during meiosis II.
Cohesion between sister chromatids mediated by a multisubunit complex called cohesin is established during DNA replication and is essential for the orderly segregation of chromatids during anaphase. In budding yeast, a specialized replication factor C called RF-C(Ctf18/Dcc1/Ctf8) and the DNA-polymerase-alpha-associated protein Ctf4 are required to maintain sister-chromatid cohesion in cells arrested for long periods in mitosis. We show here that CTF8, CTF4 and a helicase encoded by CHL1 are required for efficient sister chromatid cohesion in unperturbed mitotic cells, and provide evidence that Chl1 functions during S-phase. We also show that, in contrast to mitosis, RF-C(Ctf18/Dcc1/Cft8), Ctf4 and Chl1 are essential for chromosome segregation during meiosis and for the viability of meiotic products. Our finding that cells deleted for CTF8, CTF4 or CHL1 undergo massive meiosis II non-disjunction suggests that the second meiotic division is particularly sensitive to cohesion defects. Using a functional as well as a cytological assay, we demonstrate that CTF8, CHL1 and CTF4 are essential for cohesion between sister centromeres during meiosis but dispensable for cohesin's association with centromeric DNA. Our finding that mutants in fission yeast ctf18 and dcc1 have similar defects suggests that the involvement of the alternative RF-C(Ctf18/Dcc1/Ctf8) complex in sister chromatid cohesion might be highly conserved.


Reversibility of Defective Hematopoiesis Caused by Telomere Shortening in Telomerase Knockout Mice.
Telomere shortening is common in bone marrow failure syndromes such as dyskeratosis congenita (DC), aplastic anemia (AA) and myelodysplastic syndromes (MDS). However, improved knowledge of the lineage-specific consequences of telomere erosion and restoration of telomere length in hematopoietic progenitors is required to advance therapeutic approaches. We have employed a reversible murine model of telomerase deficiency to compare the dependence of erythroid and myeloid lineage differentiation on telomerase activity. Fifth generation Tert-/- (G5 Tert-/-) mice with shortened telomeres have significant anemia, decreased erythroblasts and reduced hematopoietic stem cell (HSC) populations associated with neutrophilia and increased myelopoiesis. Intracellular multiparameter analysis by mass cytometry showed significantly reduced cell proliferation and increased sensitivity to activation of DNA damage checkpoints in erythroid progenitors and in erythroid-biased CD150hi HSC, but not in myeloid progenitors. Strikingly, Cre-inducible reactivation of telomerase activity restored hematopoietic stem and progenitor cell (HSPC) proliferation, normalized the DNA damage response, and improved red cell production and hemoglobin levels. These data establish a direct link between the loss of TERT activity, telomere shortening and defective erythropoiesis and suggest that novel strategies to restore telomerase function may have an important role in the treatment of the resulting anemia.


The role of drug transporters in the kidney: lessons from tenofovir.
Tenofovir disoproxil fumarate, the prodrug of nucleotide reverse transcriptase inhibitor tenofovir, shows high efficacy and relatively low toxicity in HIV patients. However, long-term kidney toxicity is now acknowledged as a modest but significant risk for tenofovir-containing regimens, and continuous use of tenofovir in HIV therapy is currently under question by practitioners and researchers. Co-morbidities (hepatitis C, diabetes), low body weight, older age, concomitant administration of potentially nephrotoxic drugs, low CD4 count, and duration of therapy are all risk factors associated with tenofovir-associated tubular dysfunction. Tenofovir is predominantly eliminated via the proximal tubules of the kidney, therefore drug transporters expressed in renal proximal tubule cells are believed to influence tenofovir plasma concentration and toxicity in the kidney. We review here the current evidence that the actions, pharmacogenetics, and drug interactions of drug transporters are relevant factors for tenofovir-associated tubular dysfunction. The use of creatinine and novel biomarkers for kidney damage, and the role that drug transporters play in biomarker disposition, are discussed. The lessons learnt from investigating the role of transporters in tenofovir kidney elimination and toxicity can be utilized for future drug development and clinical management programs.


Use of Statins Among Patients Taking Levothyroxine: an Observational Drug Utilization Study Across Sites.
Treatment with levothyroxine (LT4) that normalize serum thyrotropin (TSH) is expected to restore lipid metabolism. To assess statin utilization in LT4-treated patients through an observational drug utilization study. Three sites were involved: (1) 10 723 outpatients placed on LT4 during 2006-2019 identified from the Clinical Research Data Warehouse of the University of Chicago; (2) ~1.4 million LT4 prescriptions prepared by primary care physicians during January-December 2018, identified from the IQVIA™ database of medical prescriptions in Brazil; (30 ~5.4 million patient interviews during 2009-2019, including ~0.32 million patients on LT4, identified from the Fleury Group database in Brazil. On site 1, initiation of therapy with LT4 increased the frequency of statin utilization (19.1% vs 24.6%), which occurred ~1.5 years later (median 76 weeks) and, among those patients that were on statins, increased intensity of treatment by 33%, despite normalization of serum TSH levels; on site 2, after matching for sex and age, the frequency of statins prescription was higher for those patients using LT4: females, 2.1 vs 3.4% (odds ratio [OR] 1.656 [1.639-1.673]); males, 3.1 vs 4.4% (OR 1.435 [1.409-1.462]); and, on site 3, after matching for sex and age, the frequency of statin utilization was higher in those patients using LT4: females, 10 vs 18% (OR 2.02 [2.00-2.04]); males, 15 vs 25% (OR 1.92 [1.88-1.96]); all P values were <.0001. Prescription and utilization of statins were higher in patients taking LT4. The reasons for this association should be addressed in future studies.


Synthesis of Self-Healing Polymers by Scandium-Catalyzed Copolymerization of Ethylene and Anisylpropylenes.
Self-healing materials are of fundamental interest and practical importance. Herein we report the synthesis of a new class of self-healing materials, formed by the copolymerization of ethylene and anisyl-substituted propylenes using a sterically demanding half-sandwich scandium catalyst. The copolymerization proceeded in a controlled fashion, affording unique multi-block copolymers composed of relatively long alternating ethylene- alt-anisylpropylene sequences and short ethylene-ethylene units. By controlling the molecular weight and varying the anisyl substituents, a series of copolymers that show a wide range of glass-transition temperatures ( Tg) and mechanical properties have been obtained. The copolymers with Tg below room temperature showed high elastic modulus, high toughness, and remarkable self-healability, being able to autonomously self-heal upon mechanical damage not only in a dry environment but also in water and aqueous acid and alkaline solutions, while those with Tg around or above room temperature exhibited excellent shape-memory property. The unique mechanical properties may be ascribed to the phase separation of the crystalline ethylene-ethylene nanodomains from the ethylene- alt-anisylpropylene matrix.


Evaluation of 11 PCR assays for species-level identification of Campylobacter jejuni and Campylobacter coli.
We examined the sensitivity and specificity of 11 PCR assays described for the species identification of Campylobacter jejuni and Campylobacter coli by using 111 type, reference, and field strains of C. jejuni, C. coli, and Campylobacter lari. For six assays, an additional 21 type strains representing related Campylobacter, Arcobacter, and Helicobacter species were also included. PCR tests were initially established in the laboratory by optimizing conditions with respect to five type and reference strains of C. jejuni, C. coli, and C. lari. One PCR test for C. coli failed to give appropriate results during this initial setup phase and was not evaluated further. The remaining 10 assays were used to examine heated lysate and purified DNA templates as appropriate of well-characterized type, reference, and field strains of C. jejuni (n = 62), C. coli (n = 34), and C. lari (n = 15). The tests varied considerably in their sensitivity and specificity for their respective target species. No assay was found to be 100% sensitive and/or specific for all C. jejuni strains tested, but four assays for C. coli gave appropriate responses for all strains examined. Between one and six strains of C. jejuni gave amplicons in four of seven C. jejuni PCR tests only where purified DNA was used as the template; corresponding results were seen with one strain of C. coli in each of three assays for the latter species. Our findings indicate that a polyphasic strategy for PCR-based identification should be used to identify C. jejuni and C. coli strains. The data may assist laboratories in selecting assays suited for their needs and in designing evaluations of future PCR tests aimed to identify these species.


Service improvement in health care: a literature review.
Service improvements in health care can improve provision, make cost savings, streamline services and reduce clinical errors. However, on its own it may not be adequate for improving patient outcomes and quality of care. The complexity of healthcare provision makes service improvement a challenge, and there is little evidence on whether improvement initiatives change healthcare practices and improve care. To understand the concept of service development within health care, it is necessary to explore the national context and how the NHS has adopted improvement initiatives. To equip the nursing workforce with the skills necessary to make positive change, higher education institutions have developed courses that include the topic within their pre-registration programmes. However, service improvement is a learned skill that nurses need to practise in order to become competent.


Modulation of intracellular reactive oxygen species level in chondrocytes by IGF-1, FGF, and TGF-beta1.
Growth factors are important in the development, maintenance and repair of cartilage. The principal aim of this study was to test the capacity of three growth factors with established roles in cartilage, namely insulin-like growth factor (IGF)-1, fibroblast growth factor (FGF) and transforming growth factor (TGF)-beta 1, to alter intracellular reactive oxygen species (ROS) levels. Explants of articular cartilage from young, mature, and aged rats were pretreated with IGF-1, FGF, or TGF-beta 1 and intracellular ROS levels were quantified using the free radical sensing probe dihydrorhodamine 123 (DHR 123), confocal microscopy, and densitometric image analysis. Viability of chondrocytes following ROS stress and growth factor treatment was assessed using the live/dead cytotoxicity assay, and the activities of the antioxidant enzymes--catalase (CAT), total superoxide dismutase (SOD), and glutathione peroxidase (GPX)--were measured spectrophotometrically by decay of the substrate from the reaction mixture. The effect of IGF-1 on ROS levels in cultured human chondrocytes also was examined. In rat cartilage, FGF did not significantly affect ROS levels or antioxidant enzyme activity in any age group. TGF-beta1 significantly increased cellular ROS levels in mature and old cartilage whereas in marked contrast, IGF-1 significantly and age-dependently reduced ROS levels. IGF-1 also had a potent antioxidant effect on cultured human chondrocytes. Pretreatment of rat cartilage with IGF-1 significantly enhanced the activity of GPX, without altering the activity of SOD or CAT, and protected chondrocytes against ROS-induced cell death. TGF-beta 1 had no significant effect on the activity of the antioxidant enzymes. Despite promoting ROS production, TGF-beta 1 was not cytotoxic. We concluded that TGF-beta 1 exhibits an acute pro-oxidant effect in cartilage that is not cytotoxic, suggesting a role in physiological cell signalling. In marked contrast, IGF-1 is a potent antioxidant in mature and aged rat and human chondrocytes, protecting cells against ROS-induced cell death probably through the enhancement of the activity of the antioxidant enzyme GPX.


Direct quantification of cancerous exosomes via surface plasmon resonance with dual gold nanoparticle-assisted signal amplification.
Sensitive detection of cancerous exosomes is critical to early diseases diagnosis and prognosis. Herein, a sensitive aptasensor was demonstrated for exosomes detection by surface plasmon resonance (SPR) with dual gold nanoparticle (AuNP)-assisted signal amplification. Dual nanoparticle amplification was achieved by controlled hybridization attachment of AuNPs resulting from electronic coupling between the Au film and AuNPs, as well as coupling effects in plasmonic nanostructures. By blocking the Au film surface with 11-Mercapto-1 -undecanol (MCU), nonspecific adsorption of AuNPs onto the SPR chip surface was suppressed and regeneration of the SPR sensor was realized. This method was highly sensitive and we have achieved the limit of detection (LOD) down to 5 × 103 exosomes/mL, which showed a 104-fold improvement in LOD compared to commercial ELISA. Moreover, the SPR sensor had the capability to differentiate the exosomes secreted by MCF-7 breast cancer cells and MCF-10A normal breast cells. Furthermore, the SPR sensor could effectively detect the exosomes in 30% fetal bovine serum. The work provides a sensitive and efficient quantification approach to detect cancerous exosomes and offers an avenue toward future diagnosis and comprehensive studies of exosomes.


Retinoic acid is required in the mouse embryo for left-right asymmetry determination and heart morphogenesis.
Determination of the left-right position (situs) of visceral organs involves lefty, nodal and Pitx2 genes that are specifically expressed on the left side of the embryo. We demonstrate that the expression of these genes is prevented by the addition of a retinoic acid receptor pan-antagonist to cultured headfold stage mouse embryos, whereas addition of excess retinoic acid leads to their symmetrical expression. Interestingly, both treatments lead to randomization of heart looping and to defects in heart anteroposterior patterning. A time course analysis indicates that only the newly formed mesoderm at the headfold-presomite stage is competent for these retinoid effects. We conclude that retinoic acid, the active derivative of vitamin A, is essential for heart situs determination and morphogenesis.


Draft Opioid-Prescribing Guidelines for Uncomplicated Normal Spontaneous Vaginal Birth.
Women who experience an uncomplicated vaginal delivery have acute intrapartum pain and variable pain in the immediate postpartum period. Although the Centers for Disease Control and Prevention (CDC) has urged clinicians to improve opioid-prescribing behavior, there are no published clinical practice guidelines for prescribing opioids during labor and delivery and at discharge for patients with uncomplicated normal spontaneous vaginal delivery. To address the knowledge gap regarding guidelines for pain management in this population, we used the national Premiere Health Care Database for deliveries of uncomplicated vaginal births from January 1, 2014, to December 31, 2016, to determine the prevalence of opioid administration. Among the 49,133 women who met inclusion criteria, 78.2% were administered opioids during hospitalization and 29.8% were administered opioids on the day of discharge. Descriptive statistics were generated to document the characteristics of the patients receiving opioids as well as the characteristics of hospitals administering opioids during inpatient labor and delivery and on discharge. Patient-level variables included age group, marital status, race, ethnicity, payer type, and length of stay. Hospital-level variables included bed size, geographic region, teaching status, and urbanicity status. These data were then presented in an electronic Delphi survey to 14 participants. The survey participants were obstetrician-gynecologists identified by the American College of Obstetricians and Gynecologists as being thought leaders in the obstetrics field and who had also demonstrated an active interest in the opioid epidemic and its effect on women's health. After the panelists viewed the opioid administration data, they were presented with an adapted version of the CDC's guidelines for opioid prescribing for chronic pain management. The eight adapted guidelines were constructed to be more relevant and appropriate for the inpatient normal spontaneous vaginal delivery population. After three rounds of the surveying process, seven of the eight adapted guidelines were endorsed by the survey participants. These seven draft consensus guidelines could now be used as a starting point to develop more broadly endorsed and studied guidelines for appropriately managing pain control for women with uncomplicated spontaneous vaginal birth.


Evolution of the hypoxia-sensitive cells involved in amniote respiratory reflexes.
The evolutionary origins of the hypoxia-sensitive cells that trigger amniote respiratory reflexes - carotid body glomus cells, and 'pulmonary neuroendocrine cells' (PNECs) - are obscure. Homology has been proposed between glomus cells, which are neural crest-derived, and the hypoxia-sensitive 'neuroepithelial cells' (NECs) of fish gills, whose embryonic origin is unknown. NECs have also been likened to PNECs, which differentiate in situ within lung airway epithelia. Using genetic lineage-tracing and neural crest-deficient mutants in zebrafish, and physical fate-mapping in frog and lamprey, we find that NECs are not neural crest-derived, but endoderm-derived, like PNECs, whose endodermal origin we confirm. We discover neural crest-derived catecholaminergic cells associated with zebrafish pharyngeal arch blood vessels, and propose a new model for amniote hypoxia-sensitive cell evolution: endoderm-derived NECs were retained as PNECs, while the carotid body evolved via the aggregation of neural crest-derived catecholaminergic (chromaffin) cells already associated with blood vessels in anamniote pharyngeal arches.


Short-term outcome of periviable small-for-gestational-age babies: is our counseling up to date?
There are limited data for counseling on and management of periviable small-for-gestational-age (SGA) fetuses. We therefore aimed to investigate the short-term outcome of periviable SGA fetuses in relation to the likely underlying cause. This was a retrospective study of data from three London tertiary fetal medicine centers obtained between 2000 and 2015. We included viable singleton pregnancies with a severely small fetus, defined as those with an abdominal circumference ≤ 3rd percentile, identified between 22 + 0 and 25 + 6 weeks' gestation. Data obtained included fetal biometry, presence of placental anomalies, uterine and fetal Doppler and neonatal outcome. We excluded cases with structural abnormalities, proven or suspected abnormal karyotype or genetic syndromes. Cases were classified according to the suspected underlying cause of the small fetal size into one of the following categories: uteroplacental insufficiency, evidence of placental damage with normal uterine artery Doppler, viral infection, or unclassied. There were 245 cases included in the study. Of these, at diagnosis of SGA, 201 (82%) were categorized as uteroplacental cause, 13 (5%) as suspected placental cause, one (0.4%) as suspected viral cause and 30 (12%) could not be assigned to any of these categories. Overall, 101 (41%) cases survived the neonatal period; 89 (36%) underwent in-utero fetal demise, 22 (9%) died neonatally and 33 (14%) pregnancies were terminated. The diagnosis-to-delivery interval was 8.1 weeks in those that survived and 4.5 weeks in those that died neonatally. Almost 90% of periviable SGA cases are associated with uteroplacental insufficiency or intraplacental damage. Survival is related to gestational age at delivery, with outcomes better than might be assumed at diagnosis and some pregnancies reaching term. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.


Inhibition of NEDD8 and FAT10 ligase activities through the degrading enzyme NEDD8 ultimate buster 1: A potential anticancer approach.
The capabilities of tumour cells to survive through deregulated cell cycles and evade apoptosis are hallmarks of cancer. The ubiquitin-like proteins (UBL) proteasome system is important in regulating cell cycles via signaling proteins. Deregulation of the proteasomal system can lead to uncontrolled cell proliferation. The Skp, Cullin, F-box containing complex (SCF complex) is the predominant E3 ubiquitin ligase, and has diverse substrates. The ubiquitin ligase activity of the SCF complexes requires the conjugation of neural precursor cell expressed, developmentally down-regulated 8 (NEDD8) to cullin proteins. A tumour suppressor and degrading enzyme named NEDD8 ultimate buster 1 (NUB1) is able to recruit HLA-F-adjacent transcript 10 (FAT10)- and NEDD8-conjugated proteins for proteasomal degradation. Ubiquitination is associated with neddylation and FAT10ylation. Although validating the targets of UBLs, including ubiquitin, NEDD8 and FAT10, is challenging, understanding the biological significance of such substrates is an exciting research prospect. This present review discusses the interplay of these UBLs, as well as highlighting their inhibition through NUB1. Knowledge of the mechanisms by which NUB1 is able to downregulate the ubiquitin cascade via NEDD8 conjugation and the FAT10 pathway is essential. This will provide insights into potential cancer therapy that could be used to selectively suppress cancer growth.


Biochemical characterization of RNA and protein synthesis in erythrocyte development.
Newts (Triturus cristatus) made anemic with acetylphenylhydrazine (APH) fail to regenerate erythrocytes (RBC's) immediately and exhibit a latent period of 1.5-2 wk during which animals lack RBC's and are aplastic. With the establishment of erythroid regeneration at 10-14 days, relatively homogeneous populations of successive erythropoietic stages occur in the blood. This feature makes possible biochemical analyses of events in early, intermediate, and late developmental stages, respectively, each of which can be obtained in vivo with minimal contamination by other stages. Previous studies have described a primitive cell population referred to as "erythroid precursor cells" (EPC's) which precedes the appearance of definitive erythroid elements. The present studies show that EPC's and early erythroid cells are engaged mainly in ribosomal production, including synthesis of rRNA and ribosomal proteins. Moreover, EPC's and early erythroid cells also synthesize tRNA and a presumed Hb-mRNA which has been identified by its sedimentation rate at 9-12 s and its content of polyadenylic acid. In intermediate stages, there occurs a fourfold decrease in the level of RNA synthesis and, while rRNA continues to be formed, there is a disproportionate accumulation of the two major cytoplasmic rRNA species in favor of the large ribosomal subunit RNA. In late developmental stages, the level of RNA synthesis is markedly diminished with little or no evidence of formation of defined RNA classes. Correlated radioautographic and biochemical studies with radioactive delta-aminolevulinic acid and leucine indicate that EPC's and other early erythroid elements synthesize not only hemoglobin but also ferritin and ribosomal proteins. It is concluded that: (a) erythroid RNA synthesis is most pronounced in the early developmental stages, being manifested predominantly by rRNA production but including tRNA and Hb-mRNA; (b) intermediate developmental stages show both "ribosomal wastage" and decreased growth rate, marking a pivotal point between the transcriptional activities of early stages and translational activities of late stages; (c) EPC's represent a cell population already committed to RBC formation and are excluded from a role as the pluripotential stem cell.


Diffraction of conic and Gaussian beams by a spiral phase plate.
An analytical expression for the spatial spectrum of the conic wave diffracted by a spiral phase plate (SPP) with arbitrary integer singularity of order n is obtained. Conic wave diffraction by the SPP is equivalent to plane-wave diffraction by a helical axicon. A comparison of the conic wave and Gaussian beam diffraction on a SPP is made. It is shown that in both cases a light ring is formed, with the intensity function growing in proportion to rho(2n) at small values of radial variable rho and decreasing as n(2)rho(-4) at large rho. By use of direct e-beam writing on the resist, a 32 level SPP of the 2nd order and diameter 5 mm is manufactured. By use of this SPP, a He-Ne laser beam is transformed into a beam with phase singularity and ringlike intensity distribution. A four-order binary diffractive optical element (DOE) with its transmittance proportional to a linear superposition of four angular harmonics is also manufactured. With this DOE, simultaneous optical trapping of several polystyrene beads of diameter 5 microm is performed.


X-ray structure of a prokaryotic pentameric ligand-gated ion channel.
Pentameric ligand-gated ion channels (pLGICs) are key players in the early events of electrical signal transduction at chemical synapses. The family codes for a structurally conserved scaffold of channel proteins that open in response to the binding of neurotransmitter molecules. All proteins share a pentameric organization of identical or related subunits that consist of an extracellular ligand-binding domain followed by a transmembrane channel domain. The nicotinic acetylcholine receptor (nAChR) is the most thoroughly studied member of the pLGIC family (for recent reviews see refs 1-3). Two sources of structural information provided an architectural framework for the family. The structure of the soluble acetylcholine-binding protein (AChBP) defined the organization of the extracellular domain and revealed the chemical basis of ligand interaction. Electron microscopy studies of the nAChR from Torpedo electric ray have yielded a picture of the full-length protein and have recently led to the interpretation of an electron density map at 4.0 A resolution. Despite the wealth of experimental information, high-resolution structures of any family member have so far not been available. Until recently, the pLGICs were believed to be only expressed in multicellular eukaryotic organisms. The abundance of prokaryotic genome sequences, however, allowed the identification of several homologous proteins in bacterial sources. Here we present the X-ray structure of a prokaryotic pLGIC from the bacterium Erwinia chrysanthemi (ELIC) at 3.3 A resolution. Our study reveals the first structure of a pLGIC at high resolution and provides an important model system for the investigation of the general mechanisms of ion permeation and gating within the family.


Changes in Expression of Genes Representing Key Biologic Processes after Neoadjuvant Chemotherapy in Breast Cancer, and Prognostic Implications in Residual Disease.
The primary aim was to derive evidence for or against the clinical importance of several biologic processes in patients treated with neoadjuvant chemotherapy (NAC) by assessing expression of selected genes with prior implications in prognosis or treatment resistance. The secondary aim was to determine the prognostic impact in residual disease of the genes' expression. Expression levels of 24 genes were quantified by NanoString nCounter on formalin-fixed paraffin-embedded residual tumors from 126 patients treated with NAC and 56 paired presurgical biopsies. The paired t test was used for testing changes in gene expression, and Cox regression and penalized elastic-net Cox Regression for estimating HRs. After NAC, 12 genes were significantly up- and 8 downregulated. Fourteen genes were significantly associated with time to recurrence in univariable analysis in residual disease. In a multivariable model, ACACB, CD3D, MKI67, and TOP2A added prognostic value independent of clinical ER(-), PgR(-), and HER2(-) status. In ER(+)/HER2(-) patients, ACACB, PAWR, and ERBB2 predicted outcome, whereas CD3D and PAWR were prognostic in ER(-)/HER2(-) patients. By use of elastic-net analysis, a 6-gene signature (ACACB, CD3D, DECORIN, ESR1, MKI67, PLAU) was identified adding prognostic value independent of ER, PgR, and HER2. Most of the tested genes were significantly enriched or depleted in response to NAC. Expression levels of genes representing proliferation, stromal activation, metabolism, apoptosis, stemcellness, immunologic response, and Ras-ERK activation predicted outcome in residual disease. The multivariable gene models identified could, if validated, be used to identify patients needing additional post-neoadjuvant treatment to improve prognosis. Clin Cancer Res; 22(10); 2405-16. ©2016 AACR.


Crystal structures of complexes of the branched-chain aminotransferase from Deinococcus radiodurans with α-ketoisocaproate and L-glutamate suggest the radiation resistance of this enzyme for catalysis.
Branched-chain aminotransferases (BCAT), which utilize pyridoxal 5'-phosphate (PLP) as a cofactor, reversibly catalyze the transfer of the α-amino groups of three of the most hydrophobic branched-chain amino acids (BCAA), leucine, isoleucine, and valine, to α-ketoglutarate to form the respective branched-chain α-keto acids and glutamate. The BCAT from Deinococcus radiodurans (DrBCAT), an extremophile, was cloned and expressed in Escherichia coli for structure and functional studies. The crystal structures of the native DrBCAT with PLP and its complexes with L-glutamate and α-ketoisocaproate (KIC), respectively, have been determined. The DrBCAT monomer, comprising 358 amino acids, contains large and small domains connected with an interdomain loop. The cofactor PLP is located at the bottom of the active site pocket between two domains and near the dimer interface. The substrate (L-glutamate or KIC) is bound with key residues through interactions of the hydrogen bond and the salt bridge near PLP inside the active site pocket. Mutations of some interaction residues, such as Tyr71, Arg145, and Lys202, result in loss of the specific activity of the enzymes. In the interdomain loop, a dynamic loop (Gly173 to Gly179) clearly exhibits open and close conformations in structures of DrBCAT without and with substrates, respectively. DrBCAT shows the highest specific activity both in nature and under ionizing radiation, but with lower thermal stability above 60 °C, than either BCAT from Escherichia coli (eBCAT) or from Thermus thermophilus (HB8BCAT). The dimeric molecular packing and the distribution of cysteine residues at the active site and the molecular surface might explain the resistance to radiation but small thermal stability of DrBCAT.


Estrogen prevents oxidative damage to the mitochondria in Friedreich's ataxia skin fibroblasts.
Estrogen and estrogen-related compounds have been shown to have very potent cytoprotective properties in a wide range of disease models, including an in vitro model of Friedreich's ataxia (FRDA). This study describes a potential estrogen receptor (ER)-independent mechanism by which estrogens act to protect human FRDA skin fibroblasts from a BSO-induced oxidative insult resulting from inhibition of de novo glutathione (GSH) synthesis. We demonstrate that phenolic estrogens, independent of any known ER, are able to prevent lipid peroxidation and mitochondrial membrane potential (ΔΨm) collapse, maintain ATP at near control levels, increase oxidative phosphorylation and maintain activity of aconitase. Estrogens did not, however, prevent BSO from depleting GSH or induce an increased expression level of GSH. The cytoprotective effects of estrogen appear to be due to a direct overall reduction in oxidative damage to the mitochondria, enabling the FRDA fibroblast mitochondria to generate sufficient ATP for energy requirements and better survive oxidative stress. These data support the hypothesis that phenol ring containing estrogens are possible candidate drugs for the delay and/or prevention of FRDA symptoms.


Emerging concepts regarding B cells and autoantibodies in murine lupus nephritis. B cells have multiple roles; all autoantibodies are not equal.
Despite observations linking the severity of lupus nephritis to the quantity and location of glomerular immune deposits, it had been difficult to decipher the primary role of B cells and autoantibodies in this process. Newer technologies have provided the means to evaluate the roles of whole B cell populations and individual immunoglobulins in lupus lesions. In this review, recent advances in this area are summarized, with particular emphasis on work from the authors' laboratories. The results implicate a primary role for B cells and immunoglobulins in lupus nephritis, including glomerular, interstitial, and vascular lesions. Multiple antibody-ligand interactions participate in glomerular immune deposit formation in individuals with lupus nephritis. Recent evidence suggests that in situ formation of immune deposits by either cross-reactivity of autoantibodies with intrinsic glomerular antigens (i.e., anti-DNA antibodies with laminin) or direct interaction of autoantibodies with circulating autoantigens lodged within glomeruli (i.e., anti-DNA antibodies with histone/DNA). The predominant autoantibody-glomerular antigen interaction(s) in a given individual influences the principal location of immune deposition, which in turn influences the pathologic and clinical expression of disease. It is believed that these phenomena contribute to the phenotypic diversity commonly observed among individuals with lupus nephritis. Furthermore, these consequences are dependent on properties unique to both subsets of lupus autoantibodies and to their target antigen ligands within the glomerulus. Thus, the autoantibody variable or antigen binding region, along with the nature and location of the target glomerular antigen (or site of circulating antigen deposition), are influential in initiating these perturbations.


Methamphetamine use and risk for HIV among young men who have sex with men in 8 US cities.
To examine methamphetamine use and its association with sexual behavior among young men who have sex with men. Cross-sectional observational analysis. Eight US cities. As part of the Adolescent Trials Network for HIV/AIDS Interventions, adolescent boys and young men who have sex with men, aged 12 to 24 years, were recruited from social venues (e.g., clubs, parks, and street corners) between January 3, 2005, and August 21, 2006, to complete a study survey. Reported methamphetamine use in the past 90 days and reported sexual risk behavior compared with individuals reporting no hard drug use and individuals reporting hard drug use in the past 90 days. Among 595 adolescent boys and young men, 64 reported recent methamphetamine use, and 444 reported no recent hard drug use (87 reported use of hard drugs other than methamphetamine). Recent methamphetamine use was associated with a history of sexually transmitted diseases (51.6%), 2 or more sex partners in the past 90 days (85.7%), sex with an injection drug user (51.6%), and sex with someone who has human immunodeficiency virus (32.8%) compared with individuals reporting no recent hard drug use (21.1%, 63.1%, 10.7%, and 11.1%, respectively; P < .05 for all [n = 441]). Recent users of methamphetamine were more likely to have a history of homelessness (71.9%) and were less likely to be currently attending school (35.9%) compared with individuals reporting no recent hard drug use (28.4% and 60.4%, respectively; P < .001 for both). Adolescent boys and young men who have sex with men and use methamphetamine seem to be at high risk for human immunodeficiency virus. Prevention programs among this age group should address issues like housing, polydrug use, and educational needs.


Hip and Trunk Muscle Activity During the Star Excursion Balance Test in Healthy Adults.
Dynamic balance is a measure of core stability. Deficits in the dynamic balance have been related to injuries in the athletic populations. The Star Excursion Balance Test (SEBT) is suggested to measure and improve dynamic balance when used as a rehabilitative tool. To determine the electromyographic activity of the hip and the trunk muscles during the SEBT. Descriptive. University campus. Twenty-two healthy adults (11 males and 11 females; 23.3 [3.8] y, 170.3 [7.6] cm, 67.8 [10.3] kg, and 15.1% [5.0%] body fat). Surface electromyographic data were collected on 22 healthy adults of the erector spinae, external oblique, and rectus abdominis bilaterally, and gluteus medius and gluteus maximus muscle of the stance leg. A 2-way repeated measures analysis of variance was used to determine the interaction between the percentage maximal voluntary isometric contraction (%MVIC) and the reach directions. The %MVIC for each muscle was compared across the 8 reach directions using the Sidak post hoc test with α at .05. %MVIC. Significant differences were observed for all the 8 muscles. Highest electromyographic activity was found for the tested muscles in the following reach directions-ipsilateral external oblique (44.5% [38.4%]): anterolateral; contralateral external oblique (52.3% [40.8%]): medial; ipsilateral rectus abdominis (8% [6.6%]): anterior; contralateral rectus abdominis (8% [5.3%]): anteromedial; ipsilateral erector spinae (46.4% [20.2%]): posterolateral; contralateral erector spinae (33.5% [11.3%]): posteromedial; gluteus maximus (27.4% [11.7%]): posterior; and gluteus medius (54.6% [26.1%]): medial direction. Trunk and hip muscle activation was direction dependent during the SEBT. This information can be used during rehabilitation of the hip and the trunk muscles.