ABVD followed by BV consolidation in risk-stratified patients with limited-stage Hodgkin lymphoma.
Approximately 90% of limited-stage Hodgkin lymphoma (HL) patients are projected to be cured with standard therapy, but many do not live their expected life span because of late treatment-related complications. New treatment paradigms are needed to reduce the use of radiation therapy (RT) as well as conventional chemotherapy drugs while improving upon current standard-of-care survival outcomes. In this phase 2 multicenter study, patients with non-bulky limited-stage HL received doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by brentuximab vedotin (BV) consolidation. Forty-one patients were enrolled, and patient characteristics included median age of 29 years (range, 19 to 67 years), 58% were female, 45% had unfavorable disease, and 98% had stage II disease. Based on positron emission tomography (PET)-based risk stratification, patients received 2 to 6 cycles of ABVD followed by 6 cycles of BV. After ABVD followed by BV, 95% of evaluable patients (37 out of 39; 95% confidence interval [CI], 83%-99%) achieved PET-negative status. In the intent-to-treat patient population, the estimated 3-year progression-free survival (PFS) rate was 92%, and the overall survival (OS) rate was 97%, with a median follow-up of 47 months. All 37 patients who achieved negative PET status after BV consolidation effectively avoided RT and remain in remission with estimated 3-year PFS and OS rates of 100%. In conclusion, BV demonstrates encouraging clinical activity when it follows ABVD therapy in limited-stage HL. Early incorporation of BV may reduce the use of RT as well as conventional chemotherapy drugs while achieving favorable survival outcomes in risk-stratified patients with non-bulky limited-stage HL. This trial was registered at www.clinicaltrials.gov as #NCT01578967.


Gene transfer of endothelial nitric oxide synthase to pulmonary allografts: impact on acute rejection.
Experiments were designed to study whether overexpression of nitric oxide (NO) from endothelial nitric oxide synthase (eNOS) affects acute rejection. Allogenic, orthotopic single-lung transplantation was performed after transbronchial adenoviral-mediated gene transfer (3 x 10(8) pfu) of either of eNOS or beta-galactosidase to donor lungs of rats (n = 6 each). No immunosuppression was used. After 4 days, transplanted lungs were prepared for enzyme activity, cGMP and histology. Calcium-dependent NOS activity, reflecting eNOS, was greater in eNOS-transduced lungs (587 +/- 97 vs 2.1 +/- 1.4 pmol/mg protein per h, P <0.001). In contrast, calcium-independent NOS activity, reflecting iNOS, was comparable. Concentrations of cGMP were higher in eNOS-transduced lungs (13.2 +/- 2.3 vs 4.9 +/- 0.5 pmol/mg protein). Positive immunostaining for eNOS was present in pneumocytes only in eNOS-transduced lungs. No difference in histological grade of rejection was observed. eNOS gene transfer to pulmonary allografts results in a functionally active transgene product and increased NO production. Increasing NO from eNOS does not affect histogically identified acute rejection.


Rhizoctonia solani Anastomosis Group 3 is Predominant in Potato Tubers in Poland.
Rhizoctonia solani is a species complex of 13 related but genetically distinct anastomosis groups (AGs). In potato, R. solani can infect the stems, stolons, and roots, resulting in quantitative losses. It can also cause qualitative losses through blemishes occurring on progeny tubers, such as black scurf and elephant hide (corky cracking). Knowledge of the AG in local populations is important because they differ in host range, fungicide sensitivity, and disease severity (2). To determine the AGs present in Poland, 54 tuber samples displaying typical R. solani symptoms were taken from six different fields in 2011. The fields were representative of five different administrative regions of Poland and from at least 10 different varieties. Rhizoctonia was isolated from tubers by placing symptomatic material on to tap water agar amended with streptomycin and penicillin and after 2 to 3 days Rhizoctonia colonies were identified and hyphal tips of these transferred to potato dextrose agar. Rhizoctonia was successfully isolated from 48 tubers displaying black scurf and two tubers displaying elephant hide symptoms. DNA was extracted from Rhizoctonia cultures using a Wizard Food kit (Promega) and the AG was determined using specific real-time PCR assays (1). All Rhizoctonia isolates were determined to be AG3 and this was confirmed for 10 selected isolates by observing hyphal fusion with a known AG3 tester isolate (Rs08) as described previously (3). Pairings were also conducted amongst the 10 Polish isolates, C2 reactions were typically observed indicating numerous vegetative compatible groups are present. This study shows that AG3 is likely to be the predominant AG in potato tubers in Poland. This is similar to other studies in Europe, which have all determined that AG3 accounts for at least 92% of isolates from potato (2,3). AG2-1, 4, and 5 have also been found in tubers worldwide and climate and certain crop rotations can influence the presence of these other AGs in potato tubers (2). However, climate and crop rotations in Poland are similar to other parts of Europe so the predominance of AG3 is expected. AG3 was also isolated from elephant hide symptoms; however, it was more frequently isolated from sclerotia. The ability of AG3 to prolifically produce sclerotia and thereby survive on seed tubers may explain its predominance in potato crops (4). Therefore, studies focusing on the management of Rhizoctonia potato disease in Poland should consider AG3 in the first instance. References: (1) G. E. Budge et al. Plant Pathol. 58:1071, 2009. (2) L. Tsror. J. Phytopathol. 158:649, 2010. (3) J. W. Woodhall et al. Plant Pathol. 56:286, 2007. (4) J. W. Woodhall et al. Plant Pathol. 57:5, 2008.


Automatic Selection of Control Features for Electroencephalography-Based Brain-Computer Interface Assisted Motor Rehabilitation: The GUIDER Algorithm.
Sensorimotor rhythms-based Brain-Computer Interfaces (BCIs) have successfully been employed to address upper limb motor rehabilitation after stroke. In this context, becomes crucial the choice of features that would enable an appropriate electroencephalographic (EEG) sensorimotor activation/engagement underlying the favourable motor recovery. Here, we present a novel feature selection algorithm (GUIDER) designed and implemented to integrate specific requirements related to neurophysiological knowledge and rehabilitative principles. The GUIDER algorithm was tested on an EEG dataset collected from 13 subacute stroke participants. The comparison between the automatic feature selection procedure by means of GUIDER algorithm and the manual feature selection executed by an expert neurophysiologist returned similar performance in terms of both feature selection and classification. Our preliminary findings suggest that the choices of experienced neurophysiologists could be reproducible by an automatic approach. The proposed automatic algorithm could be apt to support the professional end-users not expert in BCI such as therapist/clinicians and, to ultimately foster a wider employment of the BCI-based rehabilitation after stroke.


Impaired microRNA processing enhances cellular transformation and tumorigenesis.
MicroRNAs (miRNAs) are a new class of small noncoding RNAs that post-transcriptionally regulate the expression of target mRNA transcripts. Many of these target mRNA transcripts are involved in proliferation, differentiation and apoptosis, processes commonly altered during tumorigenesis. Recent work has shown a global decrease of mature miRNA expression in human cancers. However, it is unclear whether this global repression of miRNAs reflects the undifferentiated state of tumors or causally contributes to the transformed phenotype. Here we show that global repression of miRNA maturation promotes cellular transformation and tumorigenesis. Cancer cells expressing short hairpin RNAs (shRNAs) targeting three different components of the miRNA processing machinery showed a substantial decrease in steady-state miRNA levels and a more pronounced transformed phenotype. In animals, miRNA processing-impaired cells formed tumors with accelerated kinetics. These tumors were more invasive than control tumors, suggesting that global miRNA loss enhances tumorigenesis. Furthermore, conditional deletion of Dicer1 enhanced tumor development in a K-Ras-induced mouse model of lung cancer. Overall, these studies indicate that abrogation of global miRNA processing promotes tumorigenesis.


Disease evolution of patients with mycosis fungoides--a report of 30 cases.
Mycosis fungoides is the most common disease of the primary cutaneous T-cell lymphoma group. This is a retrospective study to evaluate the outcome of 30 patients with mycosis fungoides who were followed up for at least 3 years, 18 of them followed for 5 years and 9 of them followed for 7 years. A total of 10 patients achieved a sustained remission, 2 patients achieved a remission but then relapsed and three patients died from lymphoma-related death. It is concluded that the majority of the patients with T1 or T2 stage MF usually have a good prognosis. As a rule, those who do progress further in the disease have advanced stages at the moment of the diagnosis; the disease progression occurring during the first 3-5 years after diagnosis.


Will This Hospitalized Patient Develop Severe Alcohol Withdrawal Syndrome?: The Rational Clinical Examination Systematic Review.
Although severe alcohol withdrawal syndrome (SAWS) is associated with substantial morbidity and mortality, most at-risk patients will not develop this syndrome. Predicting its occurrence is important because the mortality rate is high when untreated. To assess the accuracy and predictive value of symptoms and signs for identifying hospitalized patients at risk of SAWS, defined as delirium tremens, withdrawal seizure, or clinically diagnosed severe withdrawal. MEDLINE and EMBASE (1946-January 2018) were searched for articles investigating symptoms and signs predictive of SAWS in adults. Reference lists of retrieved articles were also searched. Original studies that were included compared symptoms, signs, and risk assessment tools among patients who developed SAWS and patients who did not. Data were extracted and used to calculate likelihood ratios (LRs), sensitivity, and specificity. A meta-analysis was performed to calculate summary LR. Of 530 identified studies, 14 high-quality studies that included 71 295 patients and 1355 relevant cases of SAWS (1051 cases), seizure (53 cases), or delirium tremens (251 cases) were analyzed. A history of delirium tremens (LR, 2.9 [95% CI 1.7-5.2]) and baseline systolic blood pressure 140 mm Hg or higher (LR, 1.7 [95% CI, 1.3-2.3) were associated with an increased likelihood of SAWS. No single symptom or sign was associated with exclusion of SAWS. Six high-quality studies evaluated combinations of clinical findings and were useful for identifying patients in acute care facilities at high risk of developing SAWS. Of these combinations, the Prediction of Alcohol Withdrawal Severity Scale (PAWSS) was most useful, with an LR of 174 (95% CI, 43-696; specificity, 0.93) when patients had 4 or more individual findings and an LR of 0.07 (95% CI, 0.02-0.26; sensitivity, 0.99) when there were 3 or fewer findings. Assessment tools that use a combination of symptoms and signs are useful for identifying patients at risk of developing severe alcohol withdrawal syndrome. Most studies of these tools were not fully validated, limiting their generalizability.


Antiallergy Drugs as Potent Inhibitors of Lipase with Structure-activity Relationships and Molecular Docking.
Inhibition activity of 8 synthetic molecules known as anti-allergy drugs on lipases has been investigated. The enzymatic inhibition produced by these molecules is described here for the first time. The used anti-allergy drugs are: Loratidine, primalan, zyrtec, histagan, periactin, ketotifene, rifex and bilastine. Lipase inhibition is studied using the spectrophotometric method. Molecular docking has been achieved for the first time for these drugs using AutoDock Vina program to discuss the nature of interactions, structure-activity relationship and the mechanism of inhibition. The biological evaluation of these molecules showed that most of these drugs are potent lipase inhibitors with competitive type inhibition. The best drug is loratidine with IC50=0.44mg/ml and Ki=0.86 mM and competitive type inhibition. Molecular docking studies of the studied molecules confirmed their competitive inhibitory type with their binding to the Catalytic Active Site (CAS) of lipases. Hence, these drugs could be used for obesity or candidiasis treatment taking advantage of the much-known details of their secondary effects as antiallergy drugs.


Comparison of physical activity levels between cancer survivors and non-cancer participants in the 2009 BRFSS.
The purpose of this study is to compare physical activity (PA) levels between cancer survivors and those without cancer diagnosis (non-cancer participants). Using data from the 2009 Behavioral Risk Factor Surveillance System, we conducted secondary data analysis to compare PA between 31,078 cancer survivors with history of single-site cancer diagnosis at least 2 years prior to the survey, including cancer survivors of prostate [n = 2,951], female breast [n = 5,695], colon [n = 1,436], cervix [n = 2,211], endometrium [n = 1,080], and ovary [n = 732], and 235,351 non-cancer participants between 40 and 79 years of age. Self-reported PA and cancer history data were collected through telephone interviews. Weekly moderate- to vigorous-intensity PA levels were calculated in moderate-to-intensity physical activity equivalent (MIE). Least-squares means of MIE were obtained from sex, age groups (40-64 years [middle-aged] and 65-79 years [older]), and cancer site-specific multivariable linear regression models, adjusting for age, age(2), race/ethnicity, household income, and education. Prostate cancer survivors reported participating in approximately 20 min/week more MIE, compared to their non-cancer counterparts (P < 0.10 for the middle-aged group; P < 0.01 for the older group). Middle-aged cervical and endometrial cancer survivors reported approximately 10 min/week less MIE (P < 0.05 and P < 0.15, respectively). Adjusted means of MIE were not different between cancer survivors of colon, female breast, or ovary and non-cancer participants. This study demonstrates higher PA levels among prostate cancer survivors and lower PA levels among middle-aged cervical and endometrial cancer survivors, compared to sex- and age group-matched general populations.


Changes in the diurnal rhythms of cortisol, melatonin, and testosterone after 2, 4, and 7 consecutive night shifts in male police officers.
Night work is associated with a large range of acute health problems and possibly also health consequences in the long run. Yet, only very few field studies specifically investigate the effects of consecutive night shift on key physiological regulatory systems. In this field study, we investigated the effects of consecutive night shifts on three hormones, melatonin, cortisol, and testosterone, among police officers at work. More specifically, the aim was to investigate how the diurnal rhythms of melatonin, cortisol, and testosterone responded to two, four, and seven consecutive night shifts and a corresponding number of days for recovery. The study was part of the "In the Middle of the Night" project and included 73 male police officers from five different police districts. The participants were exposed to three intervention conditions: "2+2": two consecutive night shifts followed by two consecutive day recovery days; "4+4": four consecutive night shifts followed by four consecutive recovery days; "7+7": seven consecutive night shifts followed by seven consecutive recovery days. On the last day with night shift and the last recovery day in each intervention, the participants collected saliva samples every 4th hour when awake. The diurnal rhythms of melatonin, cortisol, and testosterone were all affected differently by an increasing number of consecutive night shifts: the amplitude of the melatonin rhythm was suppressed by 4.9% per day (95% CI 1.4-8.2% per day; p = 0.006). The diurnal rhythm of cortisol phase was delayed with an increasing number of night shifts by 33 min/day (95% CI 18-48 min per day; p ≤ 0.001), but did not show any changes in amplitude. For the diurnal rhythm of testosterone, there was no effect of the number of consecutive night shifts and the diurnal rhythm completely followed the sleep/wake cycle. We found that there were no differences in the rhythms of melatonin, cortisol, and testosterone after 2, 4, and 7 recovery days, respectively. In conclusion, we found signs of desynchronization in terms of suppressed amplitude of melatonin and phase delay of salivary cortisol as a consequence of the increasing number of consecutive night shifts among police officers at work. Lack of synchronization has been suggested as a possible mechanism linking night work to disease, but this remains to be determined.


Long-term impairment of endothelium-dependent relaxations to aggregating platelets after reperfusion injury in canine coronary arteries.
Experiments were designed and performed to determine whether endothelial function remained chronically impaired after coronary artery reperfusion. Canine left anterior descending coronary arteries were exposed to ischemia (60 minutes) followed by reperfusion (12 weeks). Rings (3-4 mm wide) of the reperfused artery and of normal left circumflex (control) coronary artery segments were suspended in organ chambers containing physiological saline solution (37 degrees C, gassed with 95% O2-5% CO2) for isometric force measurement. Endothelium-independent contractions to KCl or prostaglandin F2 alpha and endothelium-independent relaxations to nitric oxide or isoproterenol were comparable in control and chronically reperfused arteries. However, chronically reperfused coronary arteries exhibited impaired endothelium-dependent relaxations to aggregating platelets. In addition, the reperfused coronary arteries exhibited impaired endothelium-dependent relaxations to the platelet-derived compounds adenosine diphosphate, serotonin, and thrombin. However, the endothelium-dependent relaxations to acetylcholine were comparable between control and reperfused arteries. Thus, after 12 weeks of reperfusion, previously occluded coronary arteries exhibited a selective impairment of endothelium-dependent relaxation evoked by aggregating platelets. In vivo, this phenomenon could favor platelet adhesion, aggregation, and platelet-induced contraction of coronary smooth muscle and thus facilitate ischemic events such as vasospasm and coronary thrombosis.


Multicenter, Phase III, Randomized, Double-Blind, Placebo-Controlled Trial of Pravastatin Added to First-Line Standard Chemotherapy in Small-Cell Lung Cancer (LUNGSTAR).
Purpose Treating small-cell lung cancer (SCLC) remains a therapeutic challenge. Experimental studies show that statins exert additive effects with agents, such as cisplatin, to impair tumor growth, and observational studies suggest that statins combined with anticancer therapies delay relapse and prolong life in several cancer types. To our knowledge, we report the first large, randomized, placebo-controlled, double-blind trial of a statin with standard-of-care for patients with cancer, specifically SCLC. Patients and Methods Patients with confirmed SCLC (limited or extensive disease) and performance status 0 to 3 were randomly assigned to receive daily pravastatin 40 mg or placebo, combined with up to six cycles of etoposide plus cisplatin or carboplatin every 3 weeks, until disease progression or intolerable toxicity. Primary end point was overall survival (OS), and secondary end points were progression-free survival (PFS), response rate, and toxicity. Results Eight hundred forty-six patients from 91 United Kingdom hospitals were recruited. The median age of recruited patients was 64 years of age, 43% had limited disease, and 57% had extensive disease. There were 758 deaths and 787 PFS events. No benefit was found for pravastatin, either in all patients or in several subgroups. For pravastatin versus placebo, the 2-year OS rate was 13.2% (95% CI, 10.0 to 16.7) versus 14.1% (95% CI, 10.9 to 17.7), respectively, with a hazard ratio of 1.01 (95% CI, 0.88 to 1.16; P = .90. The median OS was 10.7 months v 10.6 months, respectively. The median PFS was 7.7 months v 7.3 months, respectively. The median OS (pravastatin v placebo) was 14.6 months in both groups for limited disease and 9.1 months versus 8.8 months, respectively, for extensive disease. Adverse events were similar between groups. Conclusion Pravastatin 40 mg combined with standard SCLC therapy, although safe, does not benefit patients. Our conclusions are the same as those found in all four much smaller, randomized, placebo-controlled trials specifically designed to evaluate statin therapy in patients with cancer.


Detection of atmospheric pollutants: a correlation technique.
The objective of this effort was to derive suitable correlation functions for monitoring the atmosphere for specified pollutants by remote ir sensing techniques. The correlation function for a particular target pollutant is calculated by the simplex optimization method. This technique constrains the response of the gas detection system to less than some arbitrary constraint limit for background changes while optimizing system response to the target pollutant. The response to a target pollutant was 2 to 3 times greater than any background induced change over a period of 2 weeks. The technique is applicable to a wide range of spectral analytical problems and may apply to process control as well as remote sensing techniques, particularly in pollution monitoring applications.


Upregulation of a silent sodium channel after peripheral, but not central, nerve injury in DRG neurons.
After transection of their axons within the sciatic nerve, DRG neurons become hyperexcitable. Recent studies have demonstrated the emergence of a rapidly repriming tetrodotoxin (TTX)-sensitive sodium current that may account for this hyperexcitability in axotomized small (<27 microm diam) DRG neurons, but its molecular basis has remained unexplained. It has been shown previously that sciatic nerve transection leads to an upregulation of sodium channel III transcripts, which normally are present at very low levels in DRG neurons, in adult rats. We show here that TTX-sensitive currents in small DRG neurons, after transection of their peripheral axonal projections, reprime more rapidly than those in control neurons throughout a voltage range of -140 to -60 mV, a finding that suggests that these currents are produced by a different sodium channel. After transection of the central axonal projections (dorsal rhizotomy) of these small DRG neurons, in contrast, the repriming kinetics of TTX-sensitive sodium currents remain similar to those of control (uninjured) neurons. We also demonstrate, with two distinct antibodies directed against different regions of the type III sodium channel, that small DRG neurons display increased brain type III immunostaining when studied 7-12 days after transection of their peripheral, but not central, projections. Type III sodium channel immunoreactivity is present within somata and neurites of peripherally axotomized, but not centrally axotomized, neurons studied after <24 h in vitro. Peripherally axotomized DRG neurons in situ also exhibit enhanced type III staining compared with control neurons, including an accumulation of type III sodium channels in the distal portion of the ligated and transected sciatic nerve, but these changes are not seen in centrally axotomized neurons. These observations are consistent with a contribution of type III sodium channels to the rapidly repriming sodium currents observed in peripherally axotomized DRG neurons and suggest that type III channels may at least partially account for the hyperexcitibility of these neurons after injury.


Infections and Systemic Lupus Erythematosus: Binding or Sparring Partners?
Extensive work on experimental animal models clearly demonstrates that infectious agents can break immunological tolerance to self-antigens and induce autoimmune disorders, mainly systemic lupus erythematosus (SLE). The establishment of a causative link between infections and autoimmunity has been largely studied in a host of clinical studies, proving the role of infectious agents in the induction, as well as in the progression or exacerbation of SLE. However, we are far from a plain understanding of microbial-host interactions in the pathogenesis of SLE. Much serological, molecular and geoepidemiological evidence supports the relationship of different environmental infectious triggers in the inception of SLE-related autoimmune phenomena with adjuvant effects. The promotion of autoimmune responses through bystander activation or epitope spreading via multiple inflammatory pathways has been confirmed in animal models. Different viruses have been implicated in SLE pathogenesis, particularly Epstein-Barr virus, but also parvovirus B19, cytomegalovirus and retroviruses. SLE patients usually have an impaired immune response towards Epstein-Barr virus and dysregulation of the viral latency period. Furthermore, the accumulation of endogenous retroviral products might trigger the production of interferon and anti-DNA antibodies. In addition, protozoan infections might even protect from autoimmune processes and rescind an ongoing B cell activation. Herein, we discuss which type of infections induce, exacerbate or inhibit autoimmune disorders and analyze the principal infection-induced immunological mechanisms influencing the development of SLE.


Visualization of opiate receptor upregulation by light microscopy autoradiography.
Light microscopy autoradiography has been used to visualize neuroanatomical patterns of brain opiate receptor upregulation in response to chronic naltrexone administration. Slide-mounted brain sections of frozen rat brain were labeled in vitro with dihydro[3H]morphine, a relatively selective mu opioid ligand. The greatest relative increases in opiate receptor density were observed in the nucleus accumbens, the amygdala, striatal patches, nuclei of the thalamus and hypothalamus, layers I and III of neocortex, substantia nigra compacta, midbrain periaqueductal gray regions, and the parabrachial nuclei of the brainstem. The substantia nigra reticulata, surrounding areas of striatal patches, and the locus ceruleus, were not affected by this drug treatment. These findings demonstrate that chronically administered naltrexone differentially regulates opiate receptors throughout the brain. In particular, three brain systems appear to be target areas of receptor upregulation : (i) the dopamine A9/A10 systems, (ii) the limbic system, and (iii) structures that receive input from afferent sensory pathways. Two possible mechanisms to account for this finding are (i) that the drug does not have uniform effects throughout the brain or (ii) that the receptors themselves may be associated with different functional systems. Receptor density changes are paralleled by increases in methionine-enkephalin content in the striatum, nucleus accumbens, periaqueductal gray, and hypothalamic areas of chronic naltrexone-treated rats relative to control rats. Thus opiate receptors and opioid peptides appear to be subject to regulatory mechanisms similar to those that modulate other neurotransmitters and their receptors. These results document in a visual manner brain patterns of opiate receptor upregulation .


REM sleep behavior disorder preceding other aspects of synucleinopathies by up to half a century.
Idiopathic REM sleep behavior disorder (RBD) may be the initial manifestation of synucleinopathies (Parkinson disease [PD], multiple system atrophy [MSA], or dementia with Lewy bodies [DLB]). We used the Mayo medical records linkage system to identify cases presenting from 2002 to 2006 meeting the criteria of idiopathic RBD at onset, plus at least 15 years between RBD and development of other neurodegenerative symptoms. All patients underwent evaluations by specialists in sleep medicine to confirm RBD, and behavioral neurology or movement disorders to confirm the subsequent neurodegenerative syndrome. Clinical criteria were met by 27 patients who experienced isolated RBD for at least 15 years before evolving into PD, PD dementia (PDD), DLB, or MSA. The interval between RBD and subsequent neurologic syndrome ranged up to 50 years, with the median interval 25 years. At initial presentation, primary motor symptoms occurred in 13 patients: 9 with PD, 3 with PD and mild cognitive impairment (MCI), and 1 with PDD. Primary cognitive symptoms occurred in 13 patients: 10 with probable DLB and 3 with MCI. One patient presented with primary autonomic symptoms, diagnosed as MSA. At most recent follow-up, 63% of patients progressed to develop dementia (PDD or DLB). Concomitant autonomic dysfunction was confirmed in 74% of all patients. These cases illustrate that the alpha-synuclein pathogenic process may start decades before the first symptoms of PD, DLB, or MSA. A long-duration preclinical phase has important implications for epidemiologic studies and future interventions designed to slow or halt the neurodegenerative process.


Preferences of Information Dissemination on Treatment for Bipolar Disorder: Patient-Centered Focus Group Study.
Patient education has taken center stage in successfully shared decision making between patients and health care providers. However, little is known about how patients with bipolar disorder typically obtain information on their illness and the treatment options available to them. This study aimed to obtain the perspectives of patients with bipolar disorder and their family members on the preferred and most effectively used information channels on bipolar disorder and the available treatment options. We conducted nine focus groups in Montana, New Mexico, and California, in which we surveyed 84 individuals including patients with bipolar disorder and family members of patients with bipolar disorder. The participants were recruited using National Alliance on Mental Illness mailing lists and websites. Written verbatim responses to semistructured questionnaires were analyzed using summative content analysis based on grounded theory. Two annotators coded and analyzed the data on the sentence or phrase level to create themes. Relationships between demographics and information channel were also examined using the Chi-square and Fisher exact tests. The focus group participants mentioned a broad range of information channels that were successfully used in the past and could be recommended for future information dissemination. The majority of participants used providers (74%) and internet-based resources (75%) as their main information sources. There was no association between internet use and basic demographics such as age or geographical region of the focus groups. Patients considered time constraints and the fast pace in which an overwhelming amount of information is often presented by the provider as major barriers to successful provider-patient interactions. If Web-based channels were used, the participants perceived information obtained through Web-based channels as more helpful than information received in the provider's office (P<.05). Web-based resources are increasingly used by patients with bipolar disorder and their family members to educate themselves about the disease and its treatment. Although provider-patient interactions are frequently perceived to be burdened with time constraints, Web-based information sources are considered reliable and helpful. Future research should explore how high-quality websites could be used to empower patients and improve provider-patient interactions with the goal of enhancing shared decision making between patients and providers.


Extinction efficiencies for metallic fibers in the infrared: erratum.
In this erratum, a correction of a previously computed extinction spectrum of a sample of silver fibers in the infrared [Appl. Opt.48, 5095 (2009)APOPAI0003-693510.1364/AO.48.005095] is reported. The spectrum was inaccurately computed through use of an approximation relating the E-field aligned values to those of the orientationally averaged extinction efficiency. This approximation is very close for spectral points in the vicinity of the primary resonance but not necessarily for those well away from this resonance. Here, the exact theory has been used to produce the spectra.


Visualizing Multiple Variables Across Scale and Geography.
Comparing multiple variables to select those that effectively characterize complex entities is important in a wide variety of domains - geodemographics for example. Identifying variables that correlate is a common practice to remove redundancy, but correlation varies across space, with scale and over time, and the frequently used global statistics hide potentially important differentiating local variation. For more comprehensive and robust insights into multivariate relations, these local correlations need to be assessed through various means of defining locality. We explore the geography of this issue, and use novel interactive visualization to identify interdependencies in multivariate data sets to support geographically informed multivariate analysis. We offer terminology for considering scale and locality, visual techniques for establishing the effects of scale on correlation and a theoretical framework through which variation in geographic correlation with scale and locality are addressed explicitly. Prototype software demonstrates how these contributions act together. These techniques enable multiple variables and their geographic characteristics to be considered concurrently as we extend visual parameter space analysis (vPSA) to the spatial domain. We find variable correlations to be sensitive to scale and geography to varying degrees in the context of energy-based geodemographics. This sensitivity depends upon the calculation of locality as well as the geographical and statistical structure of the variable.


Correction of both prothrombin time and primary haemostasis by recombinant factor VII during therapeutic alcohol injection of hepatocellular cancer in liver cirrhosis.
We evaluated the efficacy of recombinant factor VII to correct impaired haemostasis in a patient with liver cirrhosis requiring an invasive procedure. A test intravenous bolus of 80 microg/kg of recombinant factor VII was given to a Jehovah's Witness, with a solitary 4.4-cm hepatocellular carcinoma and underlying hepatitis C virus cirrhosis, in an attempt to correct his haemostatic disorders and safely inject the tumour with alcohol. An extensive portal block had precluded consideration of liver transplantation. Haemostasis was evaluated by clotting assays, bleeding time and thromboelastography 10 min before and 10 min and 1, 2, 4, 8 and 24 h after factor VII infusion. Parameters of both coagulation (prothrombin time) and platelet function (bleeding time and the alpha and ma parameters of thrombelastography) were improved 10 min after factor VII infusion; improvements lasted 4 to 8 h or more. Platelet count did not change and there was no evidence of disseminated intravascular coagulation. The improvements in haemostatic parameters correlated significantly with the increases in factor VII plasma concentrations (p<0.04). Factor VII clearance was 25.1 U/h/kg and its half-life was 5.8 h. The same dose of recombinant factor VII was given to the patient 1 week later, just before the alcohol injections. The patient had no subsequent bleeding or other complication, with no change in haemoglobin levels over 24 h. Thus, recombinant factor VII represents a therapeutic advance, as it can correct fully both coagulation and platelet function defects in cirrhosis and allow invasive procedures to be performed safely.


Model-based 2.5-d deconvolution for extended depth of field in brightfield microscopy.
Due to the limited depth of field of brightfield microscopes, it is usually impossible to image thick specimens entirely in focus. By optically sectioning the specimen, the in-focus information at the specimen's surface can be acquired over a range of images. Commonly based on a high-pass criterion, extended-depth-of-field methods aim at combining the in-focus information from these images into a single image of the texture on the specimen's surface. The topography provided by such methods is usually limited to a map of selected in-focus pixel positions and is inherently discretized along the axial direction, which limits its use for quantitative evaluation. In this paper, we propose a method that jointly estimates the texture and topography of a specimen from a series of brightfield optical sections; it is based on an image formation model that is described by the convolution of a thick specimen model with the microscope's point spread function. The problem is stated as a least-squares minimization where the texture and topography are updated alternately. This method also acts as a deconvolution when the in-focus PSF has a blurring effect, or when the true in-focus position falls in between two optical sections. Comparisons to state-of-the-art algorithms and experimental results demonstrate the potential of the proposed approach.


Characterisation of human AV-nodal properties using a network model.
Characterisation of the AV-node is an important step in determining the optimal form of treatment for supraventricular tachycardias. To integrate and analyse patient-specific measurements, mathematical modelling has emerged as a valuable tool. Here we present a model of the human AV-node, consisting of a series of interacting nodes, each with separate dynamics in refractory time and conduction delay. The model is evaluated in several scenarios, including atrial fibrillation (AF) and clinical pacing, using simulated and measured data. The model is able to replicate signals derived from clinical ECG data as well as from invasive measurements, both under AF and pacing. To quantify the uncertainty in parameter estimation, 1000 parameter sets were sampled, showing that model output similar to data corresponds to limited regions in the model parameter space. The model is the first human AV-node model to capture both spatial and temporal dynamics while being efficient enough to allow interactive use on clinical timescales, as well as parameter estimation and uncertainty quantification. As such, it fills a new niche in the current set of published models and forms a valuable tool for both understanding and clinical research.


Use of in vitro vancomycin testing results to predict susceptibility to oritavancin, a new long-acting lipoglycopeptide.
Oritavancin is a recently approved lipoglycopeptide antimicrobial agent with activity against Gram-positive pathogens. Its extended serum elimination half-life and concentration-dependent killing enable single-dose treatment of acute bacterial skin and skin structure infections. At the time of regulatory approval, new agents, including oritavancin, are not offered in the most widely used susceptibility testing devices and therefore may require application of surrogate testing using a related antimicrobial to infer susceptibility. To evaluate vancomycin as a predictive susceptibility marker for oritavancin, 26,993 recent Gram-positive organisms from U.S. and European hospitals were tested using reference MIC methods. Organisms included Staphylococcus aureus, coagulase-negative staphylococci (CoNS), beta-hemolytic streptococci (BHS), viridans group streptococci (VGS), and enterococci (ENT). These five major pathogen groups were analyzed by comparing results with FDA-approved susceptible breakpoints for both drugs, as well as those suggested by epidemiological cutoff values and supported by pharmacokinetic/pharmacodynamic analyses. Vancomycin susceptibility was highly accurate (98.1 to 100.0%) as a surrogate for oritavancin susceptibility among the indicated pathogen species. Furthermore, direct MIC comparisons showed high oritavancin potencies, with vancomycin/oritavancin MIC90 results of 1/0.06, 2/0.06, 0.5/0.12,1/0.06, and >16/0.06 μg/ml for S. aureus, CoNS, BHS, VGS, and ENT, respectively. In conclusion, vancomycin demonstrated acceptable accuracy as a surrogate marker for predicting oritavancin susceptibility when tested against the indicated pathogens. In contrast, 93.3% of vancomycin-nonsusceptible enterococci had oritavancin MIC values of ≤0.12 μg/ml, indicating a poor predictive value of vancomycin for oritavancin resistance against these organisms. Until commercial oritavancin susceptibility testing devices are readily available, isolates that when tested show vancomycin susceptibility can be inferred to be susceptible to oritavancin by using FDA-approved breakpoints.


Videolaparoscopic management of percutaneous liver biopsy complications.
Percutaneous liver biopsy is a routine procedure in the diagnosis, management, and follow-up of several liver disorders. Mortality and morbidity rates from percutaneous liver biopsy are low. This report of three cases of serious percutaneous liver biopsy complication and their management highlights the role played by videolaparoscopy as a diagnostic and therapeutic procedure in two different types of PLB complication: hemobilia and bile peritonitis. In two patients, intrahepatic arteriobiliary fistula developed with gastrointestinal hemorrhage (hemobilia). Both were treated with cholecystectomy and ligation of the right branch of the hepatic artery. In the third case, the percutaneous liver biopsy needle punctured the gallbladder, leading to bile peritonitis and acute abdomen, and the patient underwent videolaparoscopic cholecystectomy with aspiration and lavage of the abdominal cavity. Videolaparoscopic procedures are an adequate alternative for the management of serious percutaneous liver biopsy complications such as hemobilia and bile peritonitis. The advantages of a videolaparoscopy include low morbidity rates, quick recovery, good cosmetic result, and ability to resolve the complications of percutaneous liver biopsy.


Hypertension in rural communities in Delta State, Nigeria: Prevalence, risk factors and barriers to health care.
Hypertension is a global health challenge and its prevalence is increasing rapidly amongst adults in many African countries. Some studies on the prevalence and risk factors of hypertension have been conducted in Nigeria, but none within Delta State. We assessed the prevalence of hypertension and associated risk factors amongst adults in three villages in the Ibusa community in Delta State, Nigeria. Homesteads were randomly selected and all consenting adults (≥ 18 years of age) were recruited for this cross-sectional study (134 individuals: 48 men, 86 women). Sociodemographic data and anthropometric measurements (weight, height and abdominal circumference) were recorded. Diagnosis of hypertension was based on blood pressure ≥ 140/90 mmHg. Hypertension prevalence in this rural community was 44%. Results from one village (Ogboli: 82%) and ethnic group (Ibo: 50%) were significantly higher than in others in the same variable category. Multivariate logistic regression analysis suggested increasing age, increasing body mass index and high salt intake as prominent risk factors for hypertension. Lack of funds and equipment shortage in clinics were most often reported as barriers to healthcare. A nutritional education programme to promote low-cholesterol and low-salt diets is recommended to specifically target people in higher-risk areas and of higher-risk ethnicity. Local barriers to accessing health care need to be addressed.


Socioeconomic Status and Reading Disability: Neuroanatomy and Plasticity in Response to Intervention.
Although reading disability (RD) and socioeconomic status (SES) are independently associated with variation in reading ability and brain structure/function, the joint influence of SES and RD on neuroanatomy and/or response to intervention is unknown. In total, 65 children with RD (ages 6-9) with diverse SES were assigned to an intensive, 6-week summer reading intervention (n = 40) or to a waiting-list control group (n = 25). Before and after, all children completed standardized reading assessments and magnetic resonance imaging to measure cortical thickness. At baseline, higher SES correlated with greater vocabulary and greater cortical thickness in bilateral perisylvian and supramarginal regions-especially in left pars opercularis. Within the intervention group, lower SES was associated with both greater reading improvement and greater cortical thickening across broad, bilateral occipitotemporal and temporoparietal regions following the intervention. Additionally, treatment responders (n = 20), compared with treatment nonresponders (n = 19), exhibited significantly greater cortical thickening within similar regions. The waiting control and nonresponder groups exhibited developmentally typical, nonsignificant cortical thinning during this time period. These findings indicate that effective summer reading intervention is coupled with cortical growth, and is especially beneficial for children with RD who come from lower-SES home environments.


Chemotherapy-induced peripheral neuropathy: an algorithm to guide nursing management.
Oncology nurses play a critical role in the assessment and management of chemotherapy-induced peripheral neuropathy (CIPN). Baseline and ongoing evaluation of physical function is a critical but often overlooked aspect of assessment of CIPN. The diversity of symptoms and the complexity associated with neuromuscular assessment lead to challenges in evaluation and management of CIPN. To meet this challenge, the authors devised a feasible algorithm to guide oncology nurses in the assessment and management of CIPN using techniques that can easily be implemented in a variety of clinical settings. Managing pain, maintaining safety, and maximizing physical function are the primary goals for nursing management of CIPN.


Working women and the menopause.
Women are living longer, working more and retiring later. About 45% of the over 50-year-old workforce in virtually all forms of employment are women, all of whom will experience the menopause and its symptoms, which in some women will be mild to moderate, whilst in others they may be severe and debilitating. About half of these women will find it somewhat, or fairly difficult, to cope with their work, about half will not be affected and only about 5% will be severely compromised. Poor concentration, tiredness, poor memory, depression, feeling low, lowered confidence, sleepiness and particularly hot flushes are all cited as contributing factors. As with any longstanding health-related condition, the need for support and understanding from line management is crucial and can make a major difference to how a woman will deal with the adverse impact the menopausal symptoms may have on her productivity, her job satisfaction and her efficiency. A number of plausible strategies have been proposed that can be realistically implemented in the workplace and which could certainly make a significant difference. Careful thought, planning, consideration and effort may be required but, if instituted, they will, in the final analysis, benefit both employer and employee.


Instructional methods used by health sciences librarians to teach evidence-based practice (EBP): a systematic review.
Librarians often teach evidence-based practice (EBP) within health sciences curricula. It is not known what teaching methods are most effective. A systematic review of the literature was conducted searching CINAHL, EMBASE, ERIC, LISTA, PubMed, Scopus, and others. Searches were completed through December 2014. No limits were applied. Hand searching of Medical Library Association annual meeting abstracts from 2009-2014 was also completed. Studies must be about EBP instruction by a librarian within undergraduate or graduate health sciences curricula and include skills assessment. Studies with no assessment, letters and comments, and veterinary education studies were excluded. Data extraction and critical appraisal were performed to determine the risk of bias of each study. Twenty-seven studies were included for analysis. Studies occurred in the United States (20), Canada (3), the United Kingdom (1), and Italy (1), with 22 in medicine and 5 in allied health. Teaching methods included lecture (20), small group or one-on-one instruction (16), computer lab practice (15), and online learning (6). Assessments were quizzes or tests, pretests and posttests, peer-review, search strategy evaluations, clinical scenario assignments, or a hybrid. Due to large variability across studies, meta-analysis was not conducted. Findings were weakly significant for positive change in search performance for most studies. Only one study compared teaching methods, and no one teaching method proved more effective. Future studies could conduct multisite interventions using randomized or quasi-randomized controlled trial study design and standardized assessment tools to measure outcomes.


Etching patterns of Co-Cr alloys for bonded cast restorations.
Resin-bonded bridges may replace missing teeth and act as splints in periodontal treatment. The objective of this study was to investigate the etch pattern after electrolytic etching of selected Co-Cr alloys in hydrochloric acid and to assess the changes in alloy composition after different etching times. The alloys investigated were Vitallium, Wironit, Wironium, Nobilium Hard, and Niranium NN. Alloy specimens were electrolytically etched in a hydrochloric acid solution for 1, 2, 5, and 10 min. The etched specimens were examined in a light microscope and a scanning electron microscope (SEM). Different etching patterns were revealed in the various alloys. Microprobe analyses after the etching of Vitallium showed generally that Co was released and that Cr content increased at the surface.


Digitally reconfigurable complex two-dimensional dual-lattice structure by optical phase engineering.
We present a method to combine two periodic lattice wave fields to generate a complex dual-lattice wave field which could be employed for microfabrication of corresponding two-dimensional dual-lattice structures. Since the addition of two periodic lattice wave fields is coherent in nature, the resultant dual-lattice structure is highly dependent on the relative phase difference between constituent wave fields. We show that it is possible to have control over the dual-lattice pattern by precisely controlling this relative phase difference. This control is enabled by making use of digitally addressable phase-only spatial light modulator (SLM). We provide the computational method for calculation of the corresponding phase mask to be displayed on the SLM and also verify the results experimentally by employing a simple 4f Fourier filter-based geometry. The method is completely scalable and reconfigurable in terms of the choice of periodic lattice wave fields and has the potential to form gradient phase masks which could be useful for fabrication of graded-index optical components.


The emergent connectome in Caenorhabditis elegans embryogenesis.
The relatively new field of connectomics provides us with a unique window into nervous system function. In the model organism Caenorhabditis elegans, this promise is even greater due to the relatively small number of cells (302) in its nervous system. While the adult C. elegans connectome has been characterized, the emergence of these networks in development has yet to be established. In this paper, we approach this problem using secondary data describing the birth times of terminally-differentiated cells as they appear in the embryo and a connectomics model for nervous system cells in the adult hermaphrodite. By combining these two sources of data, we can better understand patterns that emerge in an incipient connectome. This includes identifying at what point in embryogenesis the cells of a connectome first comes into being, potentially observing some of the earliest neuron-neuron interactions, and making comparisons between the formally-defined connectome and developmental cell lineages. An analysis is also conducted to root terminally-differentiated cells in their developmental cell lineage precursors. This reveals subnetworks with different properties at 300 min of embryogenesis. Additional investigations reveal the spatial position of neuronal cells born during pre-hatch development, both within and outside the connectome model, in the context of all developmental cells in the embryo. Overall, these analyses reveal important information about the birth order of specific cells in the connectome, key building blocks of global connectivity, and how these structures correspond to key events in early development.


Identification of a protein that recognizes a distal negative regulatory element within the mouse mammary tumor virus long terminal repeat.
The mouse mammary tumor virus (MMTV) long terminal repeat contains a distal negative regulatory element (dNRE) that selectively represses activity of the proviral promoter in the absence of steroid hormone receptor-mediated activation. A protein, termed MMTV NRE-binding protein 1 (MNBP-1), that recognizes long terminal repeat sequences between -433 and -418 was identified by gel electrophoresis mobility shift assays and methylation interference footprinting in nuclear extracts of HeLa and Ltk(-) cells. Mutations within the defined binding site affect dNRE-mediated promoter repression in vivo. MNBP-1 has an apparent molecular mass of approximately 100 kDa as determined by gel filtration chromatography.


Concomitant conus medullaris ependymoma and filum terminale lipoma: case report.
Ependymomas of the conus medullaris-cauda equina-filum terminale region are typically solitary lesions. In this report, we describe the clinical presentation, radiographic findings, operative details, and pathological features of a patient with a conus medullaris ependymoma and a filum terminale lipoma. A 40-year-old woman presented with increasing low back pain and bowel and bladder dysfunction. Magnetic resonance imaging revealed a partially cystic enhancing lesion at the conus medullaris and a T1-weighted hyperintense mass within the filum terminale. An L2-L3 laminotomy/laminoplasty was performed for gross total resection of the mass. Histopathological examination demonstrated a conus medullaris ependymoma and filum terminale lipoma. The patient experienced complete resolution of her preoperative symptoms. Spinal cord ependymomas are almost exclusively single lesions and their coexistence with other pathological entities is rare. In this report, we describe a patient with a concomitant conus medullaris ependymoma and filum terminale lipoma.


[Data on mortality from external causes and events of undetermined intent, Paraná State, Brazil, 1979 to 2005].
This study analyzed the quality of data from the Mortality Information System (SIM) for deaths due to external causes in the State of Paraná, Brazil, 1979 to 2005, focusing on events of undetermined intent. Deaths were grouped in motor vehicle accidents, homicides, suicides, and events of undetermined intent, and proportional mortality and relative annual variation of rates over the three-year period were analyzed. Motor vehicle accidents (more than 30% of the total) were the most frequent causes of death throughout the period, and since 1997 homicides have become the second most frequent cause. Deaths due to events of undetermined intent caused by weapons (firearms or knives) decreased from 4.8% in 1981 to 0.3% in 2005. Mortality rates for events of undetermined intent (overall) decreased from 14.9 deaths per 100,000 inhabitants in 1979-81 to 2.0 in 2003-05. Annual percentage variation was -13.1% from 1980 to 1985, -6% from 1996 to 2000, and -11% from 2000 to 2004. The findings show the good quality of SIM data on external causes in the State of Paraná, allowing analyses with the potential to support programs to prevent injuries as well as health promotion measures.


Micromechanics of Amorphous Metal/Polymer Hybrid Structures with 3D Cellular Architectures: Size Effects, Buckling Behavior, and Energy Absorption Capability.
By designing advantageous cellular geometries and combining the material size effects at the nanometer scale, lightweight hybrid microarchitectured materials with tailored structural properties are achieved. Prior studies reported the mechanical properties of high strength cellular ceramic composites, obtained by atomic layer deposition. However, few studies have examined the properties of similar structures with metal coatings. To determine the mechanical performance of polymer cellular structures reinforced with a metal coating, 3D laser lithography and electroless deposition of an amorphous layer of nickel-boron (NiB) is used for the first time to produce metal/polymer hybrid structures. In this work, the mechanical response of microarchitectured structures is investigated with an emphasis on the effects of the architecture and the amorphous NiB thickness on their deformation mechanisms and energy absorption capability. Microcompression experiments show an enhancement of the mechanical properties with the NiB thickness, suggesting that the deformation mechanism and the buckling behavior are controlled by the brittle-to-ductile transition in the NiB layer. In addition, the energy absorption properties demonstrate the possibility of tuning the energy absorption efficiency with adequate designs. These findings suggest that microarchitectured metal/polymer hybrid structures are effective in producing materials with unique property combinations.


Autism Spectrum Disorder from the Womb to Adulthood: Suggestions for a Paradigm Shift.
The wide spectrum of unique needs and strengths of Autism Spectrum Disorders (ASD) is a challenge for the worldwide healthcare system. With the plethora of information from research, a common thread is required to conceptualize an exhaustive pathogenetic paradigm. The epidemiological and clinical findings in ASD cannot be explained by the traditional linear genetic model, hence the need to move towards a more fluid conception, integrating genetics, environment, and epigenetics as a whole. The embryo-fetal period and the first two years of life (the so-called 'First 1000 Days') are the crucial time window for neurodevelopment. In particular, the interplay and the vicious loop between immune activation, gut dysbiosis, and mitochondrial impairment/oxidative stress significantly affects neurodevelopment during pregnancy and undermines the health of ASD people throughout life. Consequently, the most effective intervention in ASD is expected by primary prevention aimed at pregnancy and at early control of the main effector molecular pathways. We will reason here on a comprehensive and exhaustive pathogenetic paradigm in ASD, viewed not just as a theoretical issue, but as a tool to provide suggestions for effective preventive strategies and personalized, dynamic (from womb to adulthood), systemic, and interdisciplinary healthcare approach.


Ubiquitylation of DNA polymerase λ.
DNA polymerase (pol) λ, one of the 15 cellular pols, belongs to the X family. It is a small 575 amino-acid protein containing a polymerase, a dRP-lyase, a proline/serine rich and a BRCT domain. Pol λ shows various enzymatic activities including DNA polymerization, terminal transferase and dRP-lyase. It has been implicated to play a role in several DNA repair pathways, particularly base excision repair (BER), non-homologous end-joining (NHEJ) and translesion DNA synthesis (TLS). Similarly to other DNA repair enzymes, pol λ undergoes posttranslational modifications during the cell cycle that regulate its stability and possibly its subcellular localization. Here we describe our knowledge about ubiquitylation of pol λ and the impact of this modification on its regulation.


Hypomagnesemia in patients with type 2 diabetes.
Hypomagnesemia has been reported to occur at an increased frequency among patients with type 2 diabetes compared with their counterparts without diabetes. Despite numerous reports linking hypomagnesemia to chronic diabetic complications, attention to this issue is poor among clinicians. This article reviews the literature on the metabolism of magnesium, incidence of hypomagnesemia in patients with type 2 diabetes, implicated contributing factors, and associated complications. Hypomagnesemia occurs at an incidence of 13.5 to 47.7% among patients with type 2 diabetes. Poor dietary intake, autonomic dysfunction, altered insulin metabolism, glomerular hyperfiltration, osmotic diuresis, recurrent metabolic acidosis, hypophosphatemia, and hypokalemia may be contributory. Hypomagnesemia has been linked to poor glycemic control, coronary artery diseases, hypertension, diabetic retinopathy, nephropathy, neuropathy, and foot ulcerations. The increased incidence of hypomagnesemia among patients with type 2 diabetes presumably is multifactorial. Because current data suggest adverse outcomes in association with hypomagnesemia, it is prudent to monitor magnesium routinely in this patient population and treat the condition whenever possible.


Development and Validation of Osteoporosis Risk-Assessment Model for Korean Men.
The aim of the present study was to develop an osteoporosis risk-assessment model to identify high-risk individuals among Korean men. The study used data from 1340 and 1110 men ≥50 years who participated in the 2009 and 2010 Korean National Health and Nutrition Examination Survey, respectively, for development and validation of an osteoporosis risk-assessment model. Osteoporosis was defined as T score ≤-2.5 at either the femoral neck or lumbar spine. Performance of the candidate models and the Osteoporosis Self-assessment Tool for Asian (OSTA) was compared with sensitivity, specificity, and area under the receiver operating characteristics curve (AUC). A net reclassification improvement was further calculated to compare the developed Korean Osteoporosis Risk-Assessment Model for Men (KORAM-M) with OSTA. In the development dataset, the prevalence of osteoporosis was 8.1%. KORAM-M, consisting of age and body weight, had a sensitivity of 90.8%, a specificity of 42.4%, and an AUC of 0.666 with a cut-off score of -9. In the validation dataset, similar results were shown: sensitivity 87.9%, specificity 39.7%, and AUC 0.638. Additionally, risk categorization with KORAM-M showed improved reclassification over that of OSTA up to 22.8%. KORAM-M can be simply used as a pre-screening tool to identify candidates for dual energy X-ray absorptiometry tests.


Understanding how to improve collaboration between hospitals and primary care in postdischarge care transitions: a qualitative study of primary care leaders' perspectives.
There is limited collaboration between hospitals and primary care despite parallel efforts to improve postdischarge care transitions. To understand what primary care leaders perceived as barriers and facilitators to collaboration with hospitals. Qualitative study with in-depth, semistructured interviews of 22 primary care leaders in 2012 from California safety-net clinics. Major barriers to collaboration included lack of institutional financial incentives for collaboration, competing priorities (e.g., regulatory requirements, strained clinic capacity, financial strain) and mismatched expectations about role and capacity of primary care to improve care transitions. Facilitators included relationship building through interpersonal networking and improving communication and information transfer via electronic health record (EHR) implementation. Efforts to improve care transitions should focus on aligning financial incentives, standardizing regulations around EHR interoperability and data sharing, and enhancing opportunities for interpersonal networking.


Act quickly, decide later: long-latency visual processing underlies perceptual decisions but not reflexive behavior.
Humans largely guide their behavior by their visual representation of the world. Recent studies have shown that visual information can trigger behavior within 150 msec, suggesting that visually guided responses to external events, in fact, precede conscious awareness of those events. However, is such a view correct? By using a texture discrimination task, we show that the brain relies on long-latency visual processing in order to guide perceptual decisions. Decreasing stimulus saliency leads to selective changes in long-latency visually evoked potential components reflecting scene segmentation. These latency changes are accompanied by almost equal changes in simple RTs and points of subjective simultaneity. Furthermore, we find a strong correlation between individual RTs and the latencies of scene segmentation related components in the visually evoked potentials, showing that the processes underlying these late brain potentials are critical in triggering a response. However, using the same texture stimuli in an antisaccade task, we found that reflexive, but erroneous, prosaccades, but not antisaccades, can be triggered by earlier visual processes. In other words: The brain can act quickly, but decides late. Differences between our study and earlier findings suggesting that action precedes conscious awareness can be explained by assuming that task demands determine whether a fast and unconscious, or a slower and conscious, representation is used to initiate a visually guided response.


Vitamin D deficiency inhibits pancreatic secretion of insulin.
The effects of a vitamin D deficiency on insulin and glucagon release was determined in the isolated perfused rat pancreas by radioimmunoassay of the secreted proteins. During a 30-minute period of perfusion with glucose and arginine, pancreases from vitamin D-deficient rats exhibited a 48 percent reduction in insulin secretion compared to that for pancreases from vitamin D-deficient rats that had been replenished with vitamin D. Vitamin D status had no effect on pancreatic glucagon secretion. This result, along with the previously demonstrated presence in the pancreas of a vitamin D-dependent calcium-binding protein and cytosol receptor for the hormonal form of vitamin D, 1,25-dihydroxyvitamin D3, indicates an important role for vitamin D in the endocrine functioning of the pancreas.


Vocal individuality and species divergence in the contact calls of banded penguins.
Penguins produce contact calls to maintain social relationships and group cohesion. Such vocalisations have recently been demonstrated to encode individual identity information in the African penguin. Using a source-filter theory approach, we investigated whether acoustic cues of individuality can also be found in other Spheniscus penguins and the acoustic features of contact calls have diverged within this genus. We recorded vocalisations from two ex-situ colonies of Humboldt penguin and Magellanic penguin (sympatric and potentially interbreeding in the wild) and one ex-situ group of African penguins (allopatric although capable of interbreeding with the other two species in captivity). We measured 14 acoustic parameters from each vocalisation. These included temporal (duration), source-related (fundamental frequency, f0), and filter-related (formants) parameters. They were then used to carry out a series of stepwise discriminant function analyses (with cross-validation) and General Linear Model comparisons. We showed that contact calls allow individual discrimination in two additional species of the genus Spheniscus. We also found that calls can be classified according to species in a manner far greater than that attributable by chance, even though there is limited genetic distance among African, Humboldt, and Magellanic penguins. Our results provide further evidence that the source-filter theory is a valuable framework for investigating the biologically meaningful information contained in bird vocalisations. Our findings also provide novel insights into penguin vocal communication and suggest that contact calls of the penguin family are affected by selection for individuality.


Genetic variance in the spinocerebellar ataxia type 2 (ATXN2) gene in children with severe early onset obesity.
Expansion of a CAG repeat in the coding region of exon 1 in the ATXN2 gene located in human chromosome 12q24.1 causes the neurodegenerative disease spinocerebellar ataxia type 2 (SCA2). In contrast to other polyglutamine (polyQ) disorders, the SCA2 repeat is not highly polymorphic in central European (CEU) controls with Q22 representing 90% of alleles, and Q23 contributing between 5-7% of alleles. Recently, the ATXN2 CAG repeat has been identified as a target of adaptive selection in the CEU population. Mouse lines deficient for atxn2 develop marked hyperphagia and obesity raising the possibility that loss-of-function mutations in the ATXN2 gene may be related to energy balance in humans. Some linkage studies of obesity related phenotypes such as antipsychotic induced weight gain have reported significant lod scores on chromosome 12q24. We tested the hypothesis that rare loss-of-function ATXN2 variants cause obesity analogous to rare mutations in the leptin, leptin receptor and MC4R genes. We sequenced the coding region of ATXN2 including intron-exon boundaries in 92 severely obese children with a body mass index (BMI) >3.2 standard deviations above age- and gender-adjusted means. We confirmed five previously identified single nucleotide polymorphisms (SNPs) and three new SNPs resulting in two synonymous substitutions and one intronic polymorphism. Alleles encoding >Q22 were overrepresented in our sample of obese children and contributed 15% of alleles in children identified by their parents as white. SNP rs695872 closely flanking the CAG repeat showed a greatly increased frequency of C/C homozygotes and G/C heterozygotes compared with reported frequencies in the CEU population. Although we did not identify variants leading to novel amino acid substitutions, nonsense or frameshift mutations, this study warrants further examination of variation in the ATXN2 gene in obesity and related phenotypes in a larger case-control study with emphasis on rs695872 and CAG repeat structure.


Is turbulent mixing a self-convolution process?
Experimental results for the evolution of the probability distribution function (PDF) of a scalar mixed by a turbulent flow in a channel are presented. The sequence of PDF from an initial skewed distribution to a sharp Gaussian is found to be nonuniversal. The route toward homogeneization depends on the ratio between the cross sections of the dye injector and the channel. In connection with this observation, advantages, shortcomings, and applicability of models for the PDF evolution based on a self-convolution mechanism are discussed.


Mechanisms underlying allergy vaccination with recombinant hypoallergenic allergen derivatives.
Hundred years ago therapeutic vaccination with allergen-containing extracts has been introduced as a clinically effective, disease-modifying, allergen-specific and long-lasting form of therapy for allergy, a hypersensitivity disease affecting more than 25% of the population. Today, the structures of most of the disease-causing allergens have been elucidated and recombinant hypoallergenic allergen derivatives with reduced allergenic activity have been engineered to reduce side effects during allergen-specific immunotherapy (SIT). These recombinant hypoallergens have been characterized in vitro, in experimental animal models and in clinical trials in allergic patients. This review provides a summary of the molecular, immunological and preclinical evaluation criteria applied for this new generation of allergy vaccines. Furthermore, we summarize the mechanisms underlying SIT with recombinant hypoallergens which are thought to be responsible for their therapeutic effect.


Histomorphological Alterations in the Prostate Gland and Epithelium of Seminiferous Tubule of Sprague-Dawley Rats Treated with Methanolic Extract of Momordica charantia Seeds.
There is yet a dearth of literature on the antifertility effect of Momordica charantia on the male reproductive system. The aim of this study was to determine the effect of graded oral doses of methanolic seed extract of Momordica charantia on the histology of prostate gland and seminiferous tubules of rats. Forty male Sprague-Dawley rats, weighing 176±7 g were assigned randomly into four main groups A to D of 10 rats per group. Groups A to C received daily oral doses of15, 25 or 50 mg/100 g body weight of the seed extract for 56 days. Group D (control) received physiological saline. In each group, five rats were sacrificed on day 57, the remaining half on day 113 (56 days after withdrawal of the extract). The testes and prostate were processed for histological examination. There was a dose-related alteration in the cytoarchitecture of seminiferous tubules with marked reduction in spermatogenic series. The prostate gland showed dilatation as well as increased intraluminal secretions with increasing dose. Moreover, there was a significant recovery of prostate tissue as the sections were similar to their control counterpart. the findings of the present study indicate that methanolic extract of Momordica charantia seeds caused reversible histological alterations in the prostate and testes of Sprague-Dawley rats.


Lesion detection in women breast's dynamic contrast-enhanced magnetic resonance imaging using deep learning.
Breast cancer is one of the most common cancers in women and the second foremost cause of cancer death in women after lung cancer. Recent technological advances in breast cancer treatment offer hope to millions of women in the world. Segmentation of the breast's Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) is one of the necessary tasks in the diagnosis and detection of breast cancer. Currently, a popular deep learning model, U-Net is extensively used in biomedical image segmentation. This article aims to advance the state of the art and conduct a more in-depth analysis with a focus on the use of various U-Net models in lesion detection in women's breast DCE-MRI. In this article, we perform an empirical study of the effectiveness and efficiency of U-Net and its derived deep learning models including ResUNet, Dense UNet, DUNet, Attention U-Net, UNet++, MultiResUNet, RAUNet, Inception U-Net and U-Net GAN for lesion detection in breast DCE-MRI. All the models are applied to the benchmarked 100 Sagittal T2-Weighted fat-suppressed DCE-MRI slices of 20 patients and their performance is compared. Also, a comparative study has been conducted with V-Net, W-Net, and DeepLabV3+. Non-parametric statistical test Wilcoxon Signed Rank Test is used to analyze the significance of the quantitative results. Furthermore, Multi-Criteria Decision Analysis (MCDA) is used to evaluate overall performance focused on accuracy, precision, sensitivity, F[Formula: see text]-score, specificity, Geometric-Mean, DSC, and false-positive rate. The RAUNet segmentation model achieved a high accuracy of 99.76%, sensitivity of 85.04%, precision of 90.21%, and Dice Similarity Coefficient (DSC) of 85.04% whereas ResNet achieved 99.62% accuracy, 62.26% sensitivity, 99.56% precision, and 72.86% DSC. ResUNet is found to be the most effective model based on MCDA. On the other hand, U-Net GAN takes the least computational time to perform the segmentation task. Both quantitative and qualitative results demonstrate that the ResNet model performs better than other models in segmenting the images and lesion detection, though computational time in achieving the objectives varies.


Serum resistin concentrations are associated with HbA1c in obese non-diabetics, but not in obese diabetics: a cross-sectional human study.
Glycosylated hemoglobin (HbA1c) and resistin may be influenced by diabetes, but their associations remain unclear. We hypothesized that serum resistin might be parallel to Hb1c. We measured serum resistin in 134 obese non-diabetic (73 women and 61 men), and 65 obese diabetic (33 women and 32 men) humans, and examined their relationships with HbA1c. The presence of diabetes was the only differentiating factor between the groups. Resistin, non-diabetic vs. diabetic, median and interquartile range, respectively: resistin (ng/mL) 26.08, 16.09 and 22.14,14.54, p>0.5. To investigate the influence of HbA1c on resistin, both groups were divided into tertiles based on HbA1c. In diabetics, resistin was similar in high, intermediate, and low HbA1c subgroups, p>0.05, and resistin was not influenced by HbA1c: r=-0.1785; p=0.15. In non-diabetics, resistin differed between HbA1c tertiles, p<0.001, and was influenced by HbA1c, r = -0.3599; p=0.0003. Resistin concentrations are similar in diabetic and non-diabetic humans with the same range of obesity. However, resistin is associated with HbA1c only in non-diabetic obese individuals which may point to the fact that resistin is a marker of glycaemic balance in obesity but not in diabetes.


Biosimilars: Considerations for Oncology Nurses .
Biosimilars are developed to be highly similar to and treat the same conditions as licensed biologics. As they are approved and their use becomes more widespread, oncology nurses should be aware of their development and unique considerations. This article reviews properties of biosimilars; their regulation and approval process; the ways in which their quality, safety, and efficacy are evaluated; their postmarketing safety monitoring; and their significance to oncology nurses and oncology nursing. . A search of PubMed and regulatory agency websites was conducted for references related to the development and use of biosimilars in oncology. . Because biologics are large, structurally complex molecules, biosimilars cannot be considered generic equivalents to licensed biologic products. Consequently, regulatory approval for biosimilars is different from approval for small-molecule generics. Oncology nurses are in a unique position to educate themselves, other clinicians, and patients and their families about biosimilars to ensure accurate understanding, as well as optimal and safe use, of biosimilars.


Quantification of Endogenous Cholesterol in Human Serum on Paper Using Direct Analysis in Real Time Mass Spectrometry.
Blood testing for endogenous small metabolites to determine physiological and biochemical states is routine for laboratory analysis. Here we demonstrate that by combining the commercial direct analysis in real time (DART) ion source with an ion trap mass spectrometer, native cholesterol in its free alcohol form is readily detected from a few hundred nanoliters of human serum loaded onto chromatography paper. Deuterium-labeled cholesterol was used as the internal standard to obtain the absolute quantity of the endogenous cholesterol. The amount of the cholesterol measured by this paper-loaded DART mass spectrometry (pDART-MS) is statistically comparable with that obtained by using commercially available fluorometric-enzymatic assay and liquid chromatography/mass spectrometry. Furthermore, sera from 21 participants at three different time points in an ultramarathon were collected to obtain their cholesterol levels. The test requires only very minimal sample preparation, and the concentrations of cholesterol in each sample were acquired within a minute.


Venation networks and the origin of the leaf economics spectrum.
The leaf economics spectrum describes biome-invariant scaling functions for leaf functional traits that relate to global primary productivity and nutrient cycling. Here, we develop a comprehensive framework for the origin of this leaf economics spectrum based on venation-mediated economic strategies. We define a standardized set of traits - density, distance and loopiness - that provides a common language for the study of venation. We develop a novel quantitative model that uses these venation traits to model leaf-level physiology, and show that selection to optimize the venation network predicts the mean global trait-trait scaling relationships across 2548 species. Furthermore, using empirical venation data for 25 plant species, we test our model by predicting four key leaf functional traits related to leaf economics: net carbon assimilation rate, life span, leaf mass per area ratio and nitrogen content. Together, these results indicate that selection on venation geometry is a fundamental basis for understanding the diversity of leaf form and function, and the carbon balance of leaves. The model and associated predictions have broad implications for integrating venation network geometry with pattern and process in ecophysiology, ecology and palaeobotany.


Physiological implications of the specificity of acetohydroxy acid synthase isozymes of enteric bacteria.
The rates of formation of the two alternative products of acetohydroxy acid synthase (AHAS) have been determined by a new analytical method (N. Gollop, Z. Barak, and D. M. Chipman, Anal. Biochem., 160:323-331, 1987). For each of the three distinct isozymes of AHAS in Escherichia coli and Salmonella typhimurium, a specificity ratio, R, was defined: Formula: see text, which is constant over a wide range of substrate concentrations. This is consistent with competition between pyruvate and 2-ketobutyrate for an active acetaldehyde intermediate formed irreversibly after addition of the first pyruvate moiety to the enzyme. Isozyme I showed no product preference (R = 1), whereas isozymes II and III form acetohydroxybutyrate (AHB) at approximately 180- and 60-fold faster rates, respectively, than acetolactate (AL) at equal pyruvate and 2-ketobutyrate concentrations. R values higher than 60 represent remarkably high specificity in favor of the substrate with one extra methylene group. In exponentially growing E. coli cells (under aerobic growth on glucose), which contain about 300 microM pyruvate and only 3 microM 2-ketobutyrate, AHAS I would produce almost entirely AL and only 1 to 2% AHB. However, isozymes II and III would synthesize AHB (on the pathway to Ile) and AL (on the pathway to valine-leucine) in essentially the ratio required for protein synthesis. The specificity ratio R of any AHAS isozyme was affected neither by the natural feedback inhibitors (Val, Ile) nor by the pH. On the basis of the specificities of the isozymes, the known regulation of AHAS I expression by the catabolite repression system, and the reported behavior of bacterial mutants containing single AHAS isozymes, we suggest that AHAS I enables a bacterium to cope with poor carbon sources, which lead to low endogenous pyruvate concentrations. Although AHAS II and III are well suited to producing the branched-chain amino acid precursors during growth on glucose, they would fail to provide appropriate quantities of AL when the concentration of pyruvate is relatively low.


Indoleamine 2,3-dioxygenase controls conversion of Foxp3+ Tregs to TH17-like cells in tumor-draining lymph nodes.
The immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) is expressed by a subset of murine plasmacytoid DCs (pDCs) in tumor-draining lymph nodes (TDLNs), where it can potently activate Foxp3+ regulatory T cells (Tregs). We now show that IDO functions as a molecular switch in TDLNs, maintaining Tregs in their normal suppressive phenotype when IDO was active, but allowing inflammation-induced conversion of Tregs to a polyfunctional T-helper phenotype similar to proinflammatory T-helper-17 (TH17) cells when IDO was blocked. In vitro, conversion of Tregs to the TH17-like phenotype was driven by antigen-activated effector T cells and required interleukin-6 (IL-6) produced by activated pDCs. IDO regulated this conversion by dominantly suppressing production of IL-6 in pDCs, in a GCN2-kinase dependent fashion. In vivo, using a model of established B16 melanoma, the combination of an IDO-inhibitor drug plus antitumor vaccine caused up-regulation of IL-6 in pDCs and in situ conversion of a majority of Tregs to the TH17 phenotype, with marked enhancement of CD8+ T-cell activation and antitumor efficacy. Thus, Tregs in TDLNs can be actively reprogrammed in situ into T-helper cells, without the need for physical depletion, and IDO serves as a key regulator of this critical conversion.


Dysbiosis and zonulin upregulation alter gut epithelial and vascular barriers in patients with ankylosing spondylitis.
Dysbiosis has been recently demonstrated in patients with ankylosing spondylitis (AS) but its implications in the modulation of intestinal immune responses have never been studied. The aim of this study was to investigate the role of ileal bacteria in modulating local and systemic immune responses in AS. Ileal biopsies were obtained from 50 HLA-B27+ patients with AS and 20 normal subjects. Silver stain was used to visualise bacteria. Ileal expression of tight and adherens junction proteins was investigated by TaqMan real-time (RT)-PCR and immunohistochemistry. Serum levels of lipopolysaccharide (LPS), LPS-binding protein (LPS-BP), intestinal fatty acid-BP (iFABP) and zonulin were assayed by ELISA. Monocyte immunological functions were studied in in vitro experiments. In addition the effects of antibiotics on tight junctions in human leukocyte antigen (HLA)-B27 transgenic (TG) rats were assessed. Adherent and invasive bacteria were observed in the gut of patients with AS with the bacterial scores significantly correlated with gut inflammation. Impairment of the gut vascular barrier (GVB) was also present in AS, accompanied by significant upregulation of zonulin, and associated with high serum levels of LPS, LPS-BP, iFABP and zonulin. In in vitro studies zonulin altered endothelial tight junctions while its epithelial release was modulated by isolated AS ileal bacteria. AS circulating monocytes displayed an anergic phenotype partially restored by ex vivo stimulation with LPS+sCD14 and their stimulation with recombinant zonulin induced a clear M2 phenotype. Antibiotics restored tight junction function in HLA-B27 TG rats. Bacterial ileitis, increased zonulin expression and damaged intestinal mucosal barrier and GVB, characterises the gut of patients with AS and are associated with increased blood levels of zonulin, and bacterial products. Bacterial products and zonulin influence monocyte behaviour.


Which antihypertensive drugs are the most nephroprotective and why?
Hypertension is a major independent risk factor for kidney disease and for faster renal function loss. Choice of antihypertensive strategies with highest nephroprotective effect is crucial to prevent or reverse progression to end stage renal disease (ESRD). The present review focuses on the role of hypertension in the progression of chronic kidney disease (CKD), the renoprotective effects of different antihypertensive therapies, and the blood pressure levels that should be targeted in different patient populations. To this end, the PubMed (1975 - 2010) database was searched for English-language articles, using the following keywords: hypertension, kidney disease, ACE-inhibitor, angiotensin receptor blocker, aldosterone antagonist, renin inhibitor, proteinuria. A comprehensive review of data on the association between hypertension and progression of chronic nephropathies and on the antihypertensive treatments with highest nephroprotective effects. Blood pressure should be targeted to 140/90 mmHg or less in patients with hypertension but no renal injury and 130/80 mmHg or less in those with CKD. Amongst different antihypertensive drugs, renin angiotensin aldosterone system (RAAS) inhibitors have an incremental nephroprotective effect in proteinuric patients. Maximal RAAS inhibition should be aimed to optimize renoprotection in hypertensive patients with CKD and proteinuria.


Deriving the exact nonadiabatic quantum propagator in the mapping variable representation.
We derive an exact quantum propagator for nonadiabatic dynamics in multi-state systems using the mapping variable representation, where classical-like Cartesian variables are used to represent both continuous nuclear degrees of freedom and discrete electronic states. The resulting Liouvillian is a Moyal series that, when suitably approximated, can allow for the use of classical dynamics to efficiently model large systems. We demonstrate that different truncations of the exact Liouvillian lead to existing approximate semiclassical and mixed quantum-classical methods and we derive an associated error term for each method. Furthermore, by combining the imaginary-time path-integral representation of the Boltzmann operator with the exact Liouvillian, we obtain an analytic expression for thermal quantum real-time correlation functions. These results provide a rigorous theoretical foundation for the development of accurate and efficient classical-like dynamics to compute observables such as electron transfer reaction rates in complex quantized systems.


Left Ventricular Long-Axis Function Assessed with Cardiac Cine MR Imaging Is an Independent Predictor of All-Cause Mortality in Patients with Reduced Ejection Fraction: A Multicenter Study.
Purpose To evaluate the prognostic value of a simple index of left ventricular (LV) long-axis function-lateral mitral annular plane systolic excursion (MAPSE)-in a large multicenter population of patients with reduced ejection fraction (EF) who were undergoing cardiac magnetic resonance (MR) imaging. Materials and Methods This retrospective study included 1040 consecutive patients (mean age, 59.5 years ± 15.8) at four U.S. medical centers who were undergoing cardiac MR imaging for assessment of LV dysfunction with EF less than 50%. Lateral MAPSE was measured in the four-chamber cine view. The primary end point was all-cause death. Cox proportional hazards regression modeling was used to examine the independent association between lateral MAPSE and death. The incremental prognostic value of lateral MAPSE was assessed in nested models. Results During a median follow-up of 4.4 years, 132 patients died. With Kaplan-Meier analysis, the risk of death increased significantly with decreasing tertiles of lateral MAPSE (log-rank P = .0001). Patients with relatively preserved lateral MAPSE (>9 mm) had very few deaths, regardless of whether their EF was above or below 35%. Patients with late gadolinium enhancement (LGE) and low lateral MAPSE had significantly reduced survival compared to those with LGE and high lateral MAPSE (log-rank P < .0001). Lateral MAPSE was independently associated with risk of death after adjustment for clinical and imaging risk factors, which were univariate predictors (age, body mass index, diabetes, LV end-diastolic volume index, LGE, EF) (hazard ratio = 2.051 per mm decrease; 95% confidence interval [CI]: 1.520, 2.768; P < .001). Inclusion of lateral MAPSE in this model resulted in significant improvement in model fit (likelihood ratio test P < .0001) and C statistic (increasing from 0.675 to 0.844; P < .0001). Continuous net reclassification improvement was 1.036 (95% CI: 0.878, 1.194). Conclusion Lateral MAPSE measured during routine cine cardiac MR imaging is a significant independent predictor of mortality in patients with LV dysfunction, incremental to common clinical and cardiac MR risk factors-including EF and LGE. © RSNA, 2017.


The POU domain of SCIP/Tst-1/Oct-6 is sufficient for activation of an acetylcholine receptor promoter.
In the PC12 neuroendocrine line, the neuronal nicotinic acetylcholine receptor alpha3 gene promoter is activated by SCIP/Tst-1/Oct-6, a POU domain transcription factor proposed to be important for regulating the development of specific neural cell populations. In this study, we have investigated the SCIP polypeptide domains involved in alpha3 promoter activation. The characteristics of activation by a chimeric effector in which the GAL4 DNA binding domain was substituted for the SCIP POU domain were dramatically different from those of wild-type SCIP. At low effector masses, the chimeric polypeptide weakly activated alpha3 in a GAL4 binding-site-dependent manner but then squelched transcription at higher masses. In contrast, wild-type SCIP activation was not modulated by the presence of multimerized SCIP binding sites, and squelching was not observed. Analysis of wild-type SCIP truncations revealed that deletion of the previously characterized SCIP amino-terminal activation domain did not destroy activity of the factor. Surprisingly, a truncation expressing nothing more than the POU domain was nearly as active as wild-type SCIP. Moreover, cotransfection of a GAL4-VP16 effector with an effector expressing just the SCIP POU domain resulted in synergistic activation of the promoter. Synergistic activation did not depend on an Sp1 motif that is the only functional alpha3 cis element outside the transcription start site region. Our results show that the DNA binding domain of a POU factor is capable of transcriptional activation probably through protein-protein interactions with components of the basal transcription complex.


The SANT domain of p400 ATPase represses acetyltransferase activity and coactivator function of TIP60 in basal p21 gene expression.
The TIP60 histone acetyltransferase plays diverse roles in DNA damage responses, DNA double-strand break repair, and transcriptional regulation. TIP60 resides within a multisubunit complex that has been shown to be targeted by transcription factors and to be involved in histone acetylation and transcriptional activation. p400, an SWI2/SNF2-related ATPase that serves as an ATP-dependent chromatin remodeling enzyme, exists as an integral subunit of a TIP60 complex but also resides within a distinct complex that presumably lacks TIP60 and appears to be involved in the transcriptional repression of basal p53 target gene expression. Here, we describe a TIP60-containing p400 complex population in which the acetyltransferase activity of TIP60 is repressed by interactions with p400. We further show that an SWI3-ADA2-N-CoR-TFIIIB (SANT) domain of p400 binds directly to the histone acetyltransferase (HAT) domain of TIP60 and blocks both its enzymatic activity and its coactivator function in regulating basal p21 gene expression. Our results thus suggest that p400 represses basal p21 gene expression through dual mechanisms that include the direct inhibition of TIP60 enzymatic activity described here and the previously described ATP-dependent positioning of H2A.Z at the promoter.


Online and social networking interventions for the treatment of depression in young people: a systematic review.
Major depression accounts for the greatest burden of all diseases globally. The peak onset of depression occurs between adolescence and young adulthood, and for many individuals, depression displays a relapse-remitting and increasingly severe course. Given this, the development of cost-effective, acceptable, and population-focused interventions for depression is critical. A number of online interventions (both prevention and acute phase) have been tested in young people with promising results. As these interventions differ in content, clinician input, and modality, it is important to identify key features (or unhelpful functions) associated with treatment outcomes. A systematic review of the research literature was undertaken. The review was designed to focus on two aspects of online intervention: (1) standard approaches evaluating online intervention content in randomized controlled designs (Section 1), and (2) second-generation online interventions and services using social networking (eg, social networking sites and online support groups) in any type of research design (Section 2). Two specific literature searches were undertaken. There was no date range specified. The Section 1 search, which focused on randomized controlled trials, included only young people (12-25 years) and yielded 101 study abstracts, of which 15 met the review inclusion criteria. The Section 2 search, which included all study design types and was not restricted in terms of age, yielded 358 abstracts, of which 22 studies met the inclusion criteria. Information about the studies and their findings were extracted and tabulated for review. The 15 studies identified in Section 1 described 10 trials testing eight different online interventions, all of which were based on a cognitive behavioral framework. All but one of the eight identified studies reported positive results; however, only five of the 15 studies used blinded interviewer administered outcomes with most trials using self-report data. Studies varied significantly in presentation of intervention content, treatment dose, and dropout. Only two studies included moderator or clinician input. Results for Section 2 were less consistent. None of the Section 2 studies reported controlled or randomized designs. With the exception of four studies, all included participants were younger than 25 years of age. Eight of the 16 social networking studies reported positive results for depression-related outcomes. The remaining studies were either mixed or negative. Findings for online support groups tended to be more positive; however, noteworthy risks were identified. Online interventions with a broad cognitive behavioral focus appear to be promising in reducing depression symptomology in young people. Further research is required into the effectiveness of online interventions delivering cognitive behavioral subcomponents, such as problem-solving therapy. Evidence for the use of social networking is less compelling, although limited by a lack of well-designed studies and social networking interventions. A range of future social networking therapeutic opportunities are highlighted.