Relaxation of the single-mode emission conditions in extended-cavity semiconductor lasers with a self-organizing photorefractive filter.
Commercial 1.55-microm extended-cavity semiconductor lasers provide single-mode operation that can be continuously tuned over a range larger than 100 nm without mode hopping. But such performance requires delicate factory adjustment and high mechanical stability of the external cavity. Furthermore, at high emission power the tuning range is limited to small values because of the annoying multimode operations that sometimes occur. We have shown that the alignment constraints can be relaxed by use of an intracavity photorefractive filter. Here we present new results obtained with a crystal with low absorption and high photorefractive gain. We demonstrate that, without inducing excessive additional loss, we can preserve single-mode emission at an output power higher than the maximum power obtained in the absence of a photorefractive crystal over the full tuning range of the laser.


Extraordinary optical transmission inside a waveguide: spatial mode dependence.
We study the influence of the input spatial mode on the extraordinary optical transmission (EOT) effect. By placing a metal screen with a 1D array of subwavelength holes inside a terahertz (THz) parallel-plate waveguide (PPWG), we can directly compare the transmission spectra with different input waveguide modes. We observe that the transmitted spectrum depends strongly on the input mode. A conventional description of EOT based on the excitation of surface plasmons is not predictive in all cases. Instead, we utilize a formalism based on impedance matching, which accurately predicts the spectral resonances for both TEM and non-TEM input modes.


Medical management of small abdominal aortic aneurysms.
Abdominal aortic aneurysm is a common condition that may be lethal when it is unrecognized. Current guidelines suggest repair as the aneurysm diameter reaches 5.0 to 5.5 cm. Most aortic aneurysms are detected incidentally when imaging is done for other purposes or through screening programs. Ninety percent of these aneurysms are below the threshold for intervention at the time of detection. A number of studies have sought to determine factors that lead to progression of aneurysmal disease that might be amenable to intervention during this period of observation. We review these studies and make recommendations for the medical management of small abdominal aortic aneurysms. On the basis of our current knowledge of the causes of aneurysm, a number of approaches have been proposed to prevent progression of aneurysmal disease. These include hemodynamic management, inhibition of inflammation, and protease inhibition. The American College of Cardiology/American Heart Association clinical practice guidelines rules of evidence have helped to define strength of evidence to support these approaches. Level A evidence (from large randomized trials) is available to indicate that observation of small aneurysms in men is safe up to a size of 5.5 cm and that propranolol does not inhibit aneurysm expansion. Level B evidence (from small randomized trials) suggests that roxithromycin or doxycycline will decrease the rate of aneurysm expansion. A number of studies agree that tobacco use is associated with an increased rate of aneurysm expansion. Level B and C evidence is available to suggest that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) may inhibit aneurysm expansion. There are animal data but no human data demonstrating that angiotensin-converting enzyme inhibitors or losartan, an angiotensin receptor blocker, will decrease the rate of AAA expansion. A pharmacological agent without important side effects that inhibited aneurysm expansion could change current approaches to aneurysm treatment. Additional studies are needed to clarify the potential role of doxycycline, roxithromycin, and statin therapy in the progression of aneurysmal disease.


Coordination of cluster ensembles via exact methods.
We present a novel optimization-based method for the combination of cluster ensembles for the class of problems with intracluster criteria, such as Minimum-Sum-of-Squares-Clustering (MSSC). We propose a simple and efficient algorithm-called EXAMCE-for this class of problems that is inspired from a Set-Partitioning formulation of the original clustering problem. We prove some theoretical properties of the solutions produced by our algorithm, and in particular that, under general assumptions, though the algorithm recombines solution fragments so as to find the solution of a Set-Covering relaxation of the original formulation, it is guaranteed to find better solutions than the ones in the ensemble. For the MSSC problem in particular, a prototype implementation of our algorithm found a new better solution than the previously best known for 21 of the test instances of the 40-instance TSPLIB benchmark data sets used in [1], [2], and [3], and found a worse-quality solution than the best known only five times. For other published benchmark data sets where the optimal MSSC solution is known, we match them. The algorithm is particularly effective when the number of clusters is large, in which case it is able to escape the local minima found by K-means type algorithms by recombining the solutions in a Set-Covering context. We also establish the stability of the algorithm with extensive computational experiments, by showing that multiple runs of EXAMCE for the same clustering problem instance produce high-quality solutions whose Adjusted Rand Index is consistently above 0.95. Finally, in experiments utilizing external criteria to compute the validity of clustering, EXAMCE is capable of producing high-quality results that are comparable in quality to those of the best known clustering algorithms.


Facile synthesis of N-acyl-aminoacyl-pCpA for preparation of mischarged fully ribo tRNA.
Chemical synthesis of N-acyl-aminoacyl-pdCpA and its ligation to tRNA(minus CA) is widely used for the preparation of unnatural aminoacyl-tRNA substrates for ribosomal translation. However, the presence of the unnatural deoxyribose can decrease incorporation yield in translation and there is no straightforward method for chemical synthesis of the natural ribo version. Here, we show that pCpA is surprisingly stable to treatment with strong organic bases provided that anhydrous conditions are used. This allowed development of a facile method for chemical aminoacylation of pCpA. Preparative synthesis of pCpA was also simplified by using t-butyl-dithiomethyl protecting group methodology, and a more reliable pCpA postpurification treatment method was developed. Such aminoacyl-pCpA analogues ligated to tRNA(minus CA) transcripts are highly active in a purified translation system, demonstrating utility of our synthetic method.


Differential effect of HOE642 on two separate monovalent cation transporters in the human red cell membrane.
Residual K(+) fluxes in red blood cells can be stimulated in conditions of low ionic strength. Previous studies have identified both the non-selective, voltage-dependent cation (NSVDC) channel and the K(+)(Na(+))/H(+) exchanger as candidate pathways mediating this effect, although it is possible that these pathways represent different modes of operation of a single system. In the present study the effects of HOE642, recently characterised as an inhibitor of the K(+)(Na(+))/H(+) exchanger, on NSVDC has been determined to clarify this question. Radioisotope flux measurements and conductance determinations showed that HOE642 exerted differential effects on the NSVDC channel and the K(+)(Na(+))/H(+) exchanger, confirming that the salt loss observed in low ionic strength solutions represents contributions from at least two independent ion transport pathways. The findings are discussed in the context of red blood cell apoptosis (eryptosis) and disease.


Prevalence of undiagnosed depression among persons with hypertension and associated risk factors: a cross-sectional study in urban Nepal.
Despite an increasing number of studies exploring prevalence of depression among hypertensive patients in high income countries, limited data is available from low and middle income countries, particularly Nepal. Our aim was to investigate the prevalence of undiagnosed (sub clinical) depression and associated risk factors among hypertensive patients attending a tertiary health care clinic in Nepal. The study was based on a cross-sectional study design, with 321 hypertensive patients attending the Out-Patient Department of a central hospital in Nepal. Blood measure was recorded via a mercury column sphygmomanometer. Depression levels were assessed using the Beck Depression Inventory-Ia (BDI) scale. Demographics and risk factors were assessed. The proportion of participants with undiagnosed depression was 15%. Multivariable analyses demonstrated an increase in BDI scores with increased aging. Approximately a 1 point increase in the BDI score was observed for each additional decade of aging in hypertensive patients. Additional factors associated with increased risk of depression included being female (4.28 point BDI score increase), smoking (5.61 point BDI score increase), being hypertensive with no hypertensive medication (4.46 point BDI score increase) and being illiterate (4.46 point BDI score increase). Among persons with hypertension in outpatient settings in Nepal, demographic (age, sex, education), behavioural (smoking,) and adherence factors (anti-hypertensive medication) were associated with undiagnosed depression. Screening programs in Nepal may assist early intervention in hypertensive patients with sub clinical depression.


Spatial distribution and cognitive impact of cerebrovascular risk-related white matter hyperintensities.
White matter hyperintensities (WMHs) are considered macroscale markers of cerebrovascular burden and are associated with increased risk of vascular cognitive impairment and dementia. However, the spatial location of WMHs has typically been considered in broad categories of periventricular versus deep white matter. The spatial distribution of WHMs associated with individual cerebrovascular risk factors (CVR), controlling for frequently comorbid risk factors, has not been systematically investigated at the population level in a healthy ageing cohort. Furthermore, there is an inconsistent relationship between total white matter hyperintensity load and cognition, which may be due to the confounding of several simultaneous risk factors in models based on smaller cohorts. We examined trends in individual CVR factors on total WMH burden in 13,680 individuals (aged 45-80) using data from the UK Biobank. We estimated the spatial distribution of white matter hyperintensities associated with each risk factor and their contribution to explaining total WMH load using voxel-wise probit regression and univariate linear regression. Finally, we explored the impact of CVR-related WMHs on speed of processing using regression and mediation analysis. Contrary to the assumed dominance of hypertension as the biggest predictor of WMH burden, we show associations with a number of risk factors including diabetes, heavy smoking, APOE ε4/ε4 status and high waist-to-hip ratio of similar, or greater magnitude to hypertension. The spatial distribution of WMHs varied considerably with individual cerebrovascular risk factors. There were independent effects of visceral adiposity, as measured by waist-to-hip ratio, and carriage of the APOE ε4 allele in terms of the unique spatial distribution of CVR-related WMHs. Importantly, the relationship between total WMH load and speed of processing was mediated by waist-to-hip ratio suggesting cognitive consequences to WMHs associated with excessive visceral fat deposition. Waist-to-hip ratio, diabetes, heavy smoking, hypercholesterolemia and homozygous APOE ε4 status are important risk factors, beyond hypertension, associated with WMH total burden and warrant careful control across ageing. The spatial distribution associated with different risk factors may provide important clues as to the pathogenesis and cognitive consequences of WMHs. High waist-to-hip ratio is a key risk factor associated with slowing in speed of processing. With global obesity levels rising, focused management of visceral adiposity may present a useful strategy for the mitigation of cognitive decline in ageing.


PREVALENCE AND INCIDENCE OF FOUR COMMON BEAN ROOT ROTS IN UGANDA.
Root rots are one of the main biotic constraints to common bean (Phaseolus vulgaris L.) production, causing losses estimated at 221 000 metric tons a year in sub-Saharan Africa. Until recently, root rots in Ugandan common bean agroecologies were mostly caused by Pythium and Fusarium spp., especially in high altitude areas. But now, severe root rots are observed in low and medium altitude agroecologies characterized by dry and warm conditions. The objective of our study was therefore to ascertain the current prevalence and incidence of common bean root rot diseases in Ugandan common bean agroecologies. Our results show that root rots were present in all seven agroecologies surveyed. Overall, the most rampant root rot was southern blight caused by Sclerotium rolfsii Sacc., followed by root rots caused by Fusarium spp., Pythium spp. and Rhizoctonia solani, respectively. Our study clearly showed the influence of environmental conditions on the prevalence and incidence of common bean root rots. While Fusarium and Pythium root rots are favoured under low air temperature and high air humidity in highland areas, high incidence of southern blight is favoured by warm and moist conditions of lowland areas. The prevalence and incidence of common bean root rots was mapped, providing a reliable baseline for future studies. Similarly, hotspots identified for common bean root rots will be a very useful resource for evaluation of germplasm and breeding lines for resistance to root rots.


Affirming the right to care, preserving the right to die: disorders of consciousness and neuroethics after Schiavo.
In this article, I attempt to untangle some of the cultural, philosophical, and ethical currents that informed the Schiavo case. My objective is to better apprehend what the Schiavo case means for end-of-life care in general and to assert that our discourse about the ethical issues attendant to brain injury will be impoverished if we limit our discussions about disorders of consciousness solely to the vegetative state. If we ignore emerging developments in neuroscience that are helping to elucidate the nature of these disorders and fail to broaden the conversation about brain injury, beyond the unmitigated futility of the permanent vegetative state, we will imperil others who might improve and be helped. Through such efforts we can help mitigate the tragedy of the Schiavo case and overcome the rhetoric that marked the national discourse in March 2005. Once the complexity of disorders of consciousness is appreciated, rhetorical statements about a right to die or a right to life are exposed as being incompatible with the challenge of providing care to such patients. This is especially true as neuroscience brings greater diagnostic refinement to their assessment and management, a topic addressed in this article, which specifically focuses on the clinical and ethical implications of the recently described minimally conscious state. Instead of staking out ideological positions that do not meet the needs of patients or families, we should strive to both preserve the right to die for those who are beyond hope while affirming the right to care to those who might benefit from coming advances in neuroscience. If we can achieve that delicate balance, we will be able to transcend the partisan debate that shrouded the life and death of Theresa Marie Schiavo and begin to articulate a palliative neuroethics of care for those touched by severe brain injury and disorders of consciousness.


Fast inactivation of voltage-dependent calcium channels. A hinged-lid mechanism?
We recently described domains II and III as important determinants of fast, voltage-dependent inactivation of R-type calcium channels (Spaetgens, R. L., and Zamponi, G. W. (1999) J. Biol. Chem. 274, 22428-22438). Here we examine in greater detail the structural determinants of inactivation using a series of chimeras comprising various regions of wild type alpha(1C) and alpha(1E) calcium channels. Substitution of the II S6 and/or III S6 segments of alpha(1E) into the alpha(1C) backbone resulted in rapid inactivation rates that closely approximated those of wild type alpha(1E) channels. However, neither individual or combined substitution of the II S6 and III S6 segments could account for the 60 mV more negative half-inactivation potential seen with wild type alpha(1E) channels, indicating that the S6 regions contribute only partially to the voltage dependence of inactivation. Interestingly, the converse replacement of alpha(1E) S6 segments of domains II, III, or II+III with those of alpha(1C) was insufficient to significantly slow inactivation rates. Only when the I-II linker region and the domain II and III S6 regions of alpha(1E) were concomitantly replaced with alpha(1C) sequence could inactivation be abolished. Conversely, introduction of the alpha(1E) domain I-II linker sequence into alpha(1C) conferred alpha(1E)-like inactivation rates, indicating that the domain I-II linker is a key contributor to calcium channel inactivation. Overall, our data are consistent with a mechanism in which inactivation of voltage-dependent calcium channels may occur via docking of the I-II linker region to a site comprising, at least in part, the domain II and III S6 segments.


Enhanced mucosal imaging.
The continued application of innovative imaging systems to endoscopic procedures has vastly improved the detection of indiscriminant tissue anomalies. This article describes the fundamental principles of these technologies and reviews the advances of each over the past 18 months, considering their utility in the diagnosis and surveillance of various gastrointestinal diseases. Through a combination of novel optics, processors and filters, real-time high-resolution contrast endoscopy provides increased visual data without greater procedure duration or difficulty. Optical contrast techniques incorporated into endoscopes, such as narrow band imaging (Olympus), i-Scan (Pentax), and Fujinon Intelligent Chromo Endoscopy, have become standard of care for many endoscopists. These technologies, as well as autofluorescence imaging, potentially improve detection of mucosal abnormalities, serving as 'red flag' tools for the evaluation of wide areas of mucosa. In addition, a number of promising devices allow virtual histology and in-vivo diagnosis, thereby directing biopsies and potentially guiding concurrent interventions. One such technology, confocal laser endomicroscopy, continues to establish its role in clinical practice. Because of inherent shortcomings affecting each modality's sensitivity and specificity, the coupling of various devices, as with endoscopic trimodal imaging, has shown great promise; however, most are not widely available and not definitively proven to be superior to more established techniques. Emerging technologies, including in-vivo molecular tagging, provide a powerful means of detecting disease without reliance on morphologic diagnostic criteria. Endoscopy continues to evolve from a field that previously allowed only macroscopic imaging dependent on subsequent pathology to one that allows real-time in-vivo diagnosis. Although the promise of enhanced endoscopic technologies seems limitless, practical and technological considerations slow their adoption into the standard of care.


Population studies: return of research results and incidental findings Policy Statement.
The Public Population Project in Genomics and Society (P³G) is a not-for profit international consortium with members from more than 40 countries. Its objective is to lead, catalyze, and co-ordinate international efforts and expertise in order to optimize the use of population studies, biobanks, research databases, and other similar health and social science research infrastructures. The year 2011-2012 witnessed a plethora of special issues of journals on the return of results but few discussed the particular situation of population studies that serve as resources for future unspecified research. P³G considers it important to propose a policy that distinguishes between the contexts of population research and disease (clinical) research involving patients and then delineates actual and future obligations. The objectives of this Policy Statement are to: (1) delineate the particular characteristics of population studies, (2) distinguish the circumstances surrounding access by researchers to such studies, and (3) develop a framework for the return of research results and incidental findings.


Clinical importance of DNA content in rectal cancer measured by flow cytometry.
The DNA content of 369 rectal cancers was measured by flow cytometry. One hundred and four (28%) were diploid, 252 (68%) were aneuploid, and 13 (3.5%) were tetraploid. Diploid cancers were associated with an improved 5 year survival (p less than 0.001) and were more likely to present at an early stage. DNA content, however, did not confer independent prognostic information in a Cox model based on four discrete pathological variables. Patients were classified by a new system of prognostic grouping and those with a very good or a very poor outlook were removed leaving 137 prognostic group III patients. No further substratification of this group by DNA content or by four additional pathological variables could be achieved. As the new prognostic system is not improved by the addition of ploidy, routine adoption of flow cytometry in the assessment of rectal cancer cannot be recommended.


Inhibition of mitochondrial aconitase by succination in fumarate hydratase deficiency.
The gene encoding the Krebs cycle enzyme fumarate hydratase (FH) is mutated in hereditary leiomyomatosis and renal cell cancer (HLRCC). Loss of FH activity causes accumulation of intracellular fumarate, which can directly modify cysteine residues to form 2-succinocysteine through succination. We undertook a proteomic-based screen in cells and renal cysts from Fh1 (murine FH)-deficient mice and identified 94 protein succination targets. Notably, we identified the succination of three cysteine residues in mitochondrial Aconitase2 (ACO2) crucial for iron-sulfur cluster binding. We show that fumarate exerts a dose-dependent inhibition of ACO2 activity, which correlates with increased succination as determined by mass spectrometry, possibly by interfering with iron chelation. Importantly, we show that aconitase activity is impaired in FH-deficient cells. Our data provide evidence that succination, resulting from FH deficiency, targets and potentially alters the function of multiple proteins and may contribute to the dysregulated metabolism observed in HLRCC.


Phone behaviour and its relationship to loneliness in older adults.
Loneliness and social isolation are two important health outcomes among older adults. Current assessment of these outcomes relies on self-report which is susceptible to bias. This paper reports on the relationship between loneliness and objective measures of isolation using a phone monitoring device. Phone monitors were installed in the homes of 26 independent elderly individuals from the ORCATECH Life Laboratory cohort (age 86 ± 4.5, 88% female) and used to monitor the daily phone usage for an average of 174 days. Loneliness was assessed using the 20-item University of California Los Angeles (UCLA) Loneliness scale. A mixed effects negative binomial regression was used to model the relationship between loneliness and social isolation, as assessed using the total number of calls, controlling for cognitive function, pain, age, gender, and weekday. A secondary analysis examined the differential effect of loneliness on incoming and outgoing calls. The average UCLA Loneliness score was 35.3 ± 7.6, and the median daily number of calls was 4. Loneliness was negatively associated with telephone use (IRR = 0.99, p < 0.05). Daily phone use was also associated with gender (IRR = 2.03, p < 0.001) and cognitive status (IRR = 1.51, p < 0.001). The secondary analysis revealed that loneliness was significantly related to incoming (IRR = 0.98, p < 0.01) but not outgoing calls. These results demonstrate the close relationship between loneliness and social isolation, showing that phone behaviour is associated with emotional state and cognitive function. Because phone behaviour can be monitored unobtrusively, it may be possible to sense loneliness levels in older adults using objective assessments of key aspects of behaviour.


Epidemiological evidence for a health risk from mobile phone base stations.
Human populations are increasingly exposed to microwave/radiofrequency (RF) emissions from wireless communication technology, including mobile phones and their base stations. By searching PubMed, we identified a total of 10 epidemiological studies that assessed for putative health effects of mobile phone base stations. Seven of these studies explored the association between base station proximity and neurobehavioral effects and three investigated cancer. We found that eight of the 10 studies reported increased prevalence of adverse neurobehavioral symptoms or cancer in populations living at distances < 500 meters from base stations. None of the studies reported exposure above accepted international guidelines, suggesting that current guidelines may be inadequate in protecting the health of human populations. We believe that comprehensive epidemiological studies of long-term mobile phone base station exposure are urgently required to more definitively understand its health impact.


Self-sustained enzymatic cascade for the production of 2,5-furandicarboxylic acid from 5-methoxymethylfurfural.
2,5-Furandicarboxylic acid is a renewable building block for the production of polyfurandicarboxylates, which are biodegradable polyesters expected to substitute their classical counterparts derived from fossil resources. It may be produced from bio-based 5-hydroxymethylfurfural or 5-methoxymethylfurfural, both obtained by the acidic dehydration of biomass-derived fructose. 5-Methoxymethylfurfural, which is produced in the presence of methanol, generates less by-products and exhibits better storage stability than 5-hydroxymethylfurfural being, therefore, the industrial substrate of choice. In this work, an enzymatic cascade involving three fungal oxidoreductases has been developed for the production of 2,5-furandicarboxylic acid from 5-methoxymethylfurfural. Aryl-alcohol oxidase and unspecific peroxygenase act on 5-methoxymethylfurfural and its partially oxidized derivatives yielding 2,5-furandicarboxylic acid, as well as methanol as a by-product. Methanol oxidase takes advantage of the methanol released for in situ producing H2O2 that, along with that produced by aryl-alcohol oxidase, fuels the peroxygenase reactions. In this way, the enzymatic cascade proceeds independently, with the only input of atmospheric O2, to attain a 70% conversion of initial 5-methoxymethylfurfural. The addition of some exogenous methanol to the reaction further improves the yield to attain an almost complete conversion of 5-methoxymethylfurfural into 2,5-furandicarboxylic acid. The synergistic action of aryl-alcohol oxidase and unspecific peroxygenase in the presence of 5-methoxymethylfurfural and O2 is sufficient for the production of 2,5-furandicarboxylic acid. The addition of methanol oxidase to the enzymatic cascade increases the 2,5-furandicarboxylic acid yields by oxidizing a reaction by-product to fuel the peroxygenase reactions.


Down-regulation of EBV-LMP1 radio-sensitizes nasal pharyngeal carcinoma cells via NF-κB regulated ATM expression.
The latent membrane protein 1 (LMP1) encoded by EBV is expressed in the majority of EBV-associated human malignancies and has been suggested to be one of the major oncogenic factors in EBV-mediated carcinogenesis. In previous studies we experimentally demonstrated that down-regulation of LMP1 expression by DNAzymes could increase radiosensitivity both in cells and in a xenograft NPC model in mice. In this study we explored the molecular mechanisms underlying the radiosensitization caused by the down-regulation of LMP1 in nasopharyngeal carcinoma. It was confirmed that LMP1 could up-regulate ATM expression in NPCs. Bioinformatic analysis of the ATM ptomoter region revealed three tentative binding sites for NF-κB. By using a specific inhibitor of NF-κB signaling and the dominant negative mutant of IkappaB, it was shown that the ATM expression in CNE1-LMP1 cells could be efficiently suppressed. Inhibition of LMP1 expression by the DNAzyme led to attenuation of the NF-κB DNA binding activity. We further showed that the silence of ATM expression by ATM-targeted siRNA could enhance the radiosensitivity in LMP1 positive NPC cells. Together, our results indicate that ATM expression can be regulated by LMP1 via the NF-κB pathways through direct promoter binding, which resulted in the change of radiosensitivity in NPCs.


Cholestatic liver disease in children.
Inherited syndromes of intrahepatic cholestasis and biliary atresia are the most common causes of chronic liver disease and the prime indication for liver transplantation in children. Our understanding of the pathogenesis of these diseases has increased substantially by the discovery of genetic mutations in children with intrahepatic cholestasis and the findings that inflammatory circuits are operative at the time of diagnosis of biliary atresia. Building on this solid foundation, recent studies provide new insight into genotype-phenotype relationships and how mutations produce altered bile composition and cholestasis. New evidence exists that although liver transplantation is curative for patients with end-stage liver disease owing to cholestasis, some patients may develop recurrence of cholestasis because of the emergence of autoantibodies that disrupt canalicular function in the new graft. Progress is also evident in biliary atresia, with recent studies identifying candidate modifier genes and directly implicating lymphocytes and inflammatory signals in the pathogenesis of bile duct injury and obstruction.


Engineering root exudation of Lotus toward the production of two novel carbon compounds leads to the selection of distinct microbial populations in the rhizosphere.
The culture of opine-producing transgenic Lotus plants induces the increase in the rhizosphere of bacterial communities that are able to utilize these molecules as sole carbon source. We used transgenic Lotus plants producing two opines, namely mannopine and nopaline, to characterize the microbial communities directly influenced by the modification of root exudation. We showed that opine-utilizers represent a large community in the rhizosphere of opine-producing transgenic Lotus. This community is composed of at least 12 different bacterial species, one third of which are able to utilize the opine mannopine and two thirds the opine nopaline. Opine utilizers are diverse, belonging to the Gram-positive and -negative bacteria. We described two novel mannopine-utilizing species, Rhizobium and Duganella spp., and five novel nopaline-utilizing species, Duganella, Afipia, Phyllobacterium, Arthrobacter, and Bosea spp. Although opine utilizers mostly belong to the alpha-Proteobacteria, Rhizobiaceae family, there is little overlap between the populations able to utilize each of the two opines produced by the plants. Noticeably, in the rhizosphere of transgenic Lotus, only the opine mannopine favors the growth of Agrobacterium tumefaciens, the bacterium from which opines have been characterized. The diversity of opine utilizers from the rhizosphere of Lotus plants is greater than that observed from any other environment. Therefore, transgenic plants with engineered exudation constitute an excellent tool to isolate and characterize specific microbial populations.


Antibiotics and sweeteners in the aquatic environment: biodegradability, formation of phototransformation products, and in vitro toxicity.
In the present study, in vitro toxicity as well as biopersistence and photopersistence of four artificial sweeteners (acesulfame, cyclamate, saccharine, and sucralose) and five antibiotics (levofloxacin, lincomycin, linezolid, marbofloxacin, and sarafloxacin) and of their phototransformation products (PTPs) were investigated. Furthermore, antibiotic activity was evaluated after UV irradiation and after exposure to inocula of a sewage treatment plant. The study reveals that most of the tested compounds and their PTPs were neither readily nor inherently biodegradable in the Organisation for Economic Co-operation and Development (OECD)-biodegradability tests. The study further demonstrates that PTPs are formed upon irradiation with an Hg lamp (UV light) and, to a lesser extent, upon irradiation with a Xe lamp (mimics sunlight). Comparing the nonirradiated with the corresponding irradiated solutions, a higher chronic toxicity against bacteria was found for the irradiated solutions of linezolid. Neither cytotoxicity nor genotoxicity was found in human cervical (HeLa) and liver (Hep-G2) cells for any of the investigated compounds or their PTPs. Antimicrobial activity of the tested fluoroquinolones was reduced after UV treatment, but it was not reduced after a 28-day exposure to inocula of a sewage treatment plant. This comparative study shows that PTPs can be formed as a result of UV treatment. The study further demonstrated that UV irradiation can be effective in reducing the antimicrobial activity of antibiotics, and consequently may help to reduce antimicrobial resistance in wastewaters. Nevertheless, the study also highlights that some PTPs may exhibit a higher ecotoxicity than the respective parent compounds. Consequently, UV treatment does not transform all micropollutants into harmless compounds and may not be a large-scale effluent treatment option.


Lightweight versus heavyweight mesh in laparoscopic inguinal hernia repair: a meta-analysis.
Reinforcement of inguinal hernia repair with prosthetic mesh is standard practice but can cause considerable pain and stiffness around the groin and affect physical functioning. This has led to various types of mesh being engineered, with a growing interest in lighter-weight mesh. Minimally invasive approaches have also significantly reduced postoperative recovery from inguinal hernia repair. The aim of this systematic review was to compare the outcomes after laparoscopic inguinal repair using new lightweight or traditional heavyweight mesh in published randomised controlled trials. Medline, Embase, trial registries, conference proceedings, and reference lists were searched for controlled trials of heavyweight versus lightweight mesh for laparoscopic repair of inguinal hernias. The primary outcomes were recurrence and chronic pain. Secondary outcomes were visual analogue pain score at 7 days postoperatively, seroma formation, and time to return to work. Risk differences were calculated for categorical outcomes and standardised mean differences for continuous outcomes. Eight trials were included in the analysis of 1,667 hernias in 1,592 patients. Mean study follow-up was between 2 and 60 months. There was no effect on recurrence [pooled analysis risk difference 0.00 (95% CI -0.01 to 0.01), p = 0.86] or chronic pain [pooled analysis risk difference -0.02 (95% CI -0.04 to 0.00); p = 0.1]. Lightweight and heavyweight mesh repair had similar outcomes with regard to postoperative pain, seroma development, and time to return to work. Both mesh options appear to result in similar long- and short-term postoperative outcomes. Further long-term analysis may guide surgeon selection of mesh weight for laparoscopic inguinal hernia repair.


Essential genes of a minimal bacterium.
Mycoplasma genitalium has the smallest genome of any organism that can be grown in pure culture. It has a minimal metabolism and little genomic redundancy. Consequently, its genome is expected to be a close approximation to the minimal set of genes needed to sustain bacterial life. Using global transposon mutagenesis, we isolated and characterized gene disruption mutants for 100 different nonessential protein-coding genes. None of the 43 RNA-coding genes were disrupted. Herein, we identify 382 of the 482 M. genitalium protein-coding genes as essential, plus five sets of disrupted genes that encode proteins with potentially redundant essential functions, such as phosphate transport. Genes encoding proteins of unknown function constitute 28% of the essential protein-coding genes set. Disruption of some genes accelerated M. genitalium growth.


Split the Charge Difference in Two! A Rule of Thumb for Adding Proper Amounts of Ions in MD Simulations.
Despite the relevance of properly setting ionic concentrations in Molecular Dynamics (MD) simulations, methods or practical rules to set ionic strength are scarce and rarely documented. Based on a recently proposed thermodynamics method we provide an accurate rule of thumb to define the electrolytic content in simulation boxes. Extending the use of good practices in setting up MD systems is promptly needed to ensure reproducibility and consistency in molecular simulations.


Effect of aromatase inhibition on functional gene modules in estrogen receptor-positive breast cancer and their relationship with antiproliferative response.
To investigate potential associations between gene modules representing key biologic processes and response to aromatase inhibitors (AI) in estrogen receptor-positive (ER(+)) breast cancer. Paired gene expression and Ki67 protein expression were available from 69 postmenopausal women with ER(+) early breast cancer, at baseline and 2 weeks post-anastrozole treatment, in the presurgical setting. Functional gene modules (n = 26) were retrieved from published studies and their module scores were computed before and after elimination of proliferation-associated genes (PAG). Ki67 and module scores were assessed at baseline and 2 weeks post-anastrozole. Unsupervised clustering was used to assess associations between modules and Ki67. Proliferation-based modules were highly correlated with Ki67 expression both pretreatment and on-treatment. At baseline with and without PAGs, Ki67 expression was significantly inversely correlated with ERG, ESR1.2, SET, and PIK3CA modules. Modules measuring estrogen signaling strongly predicted antiproliferative response to therapy with and without PAGs. Baseline expression of insulin-like growth factor-1 (IGF-I) module predicted a poor change in Ki67-implicating genes within the module as involved in de novo resistance to AIs. High expression of Immune.2.STAT1 module pretreatment predicted poor antiproliferative response to therapy. A significant association between estrogen-regulated genes modules (ESR1, ESR1-2, SET, and ERG) was evident post AI. Multiple processes and pathways are affected by AI treatment in ER(+) breast cancer. Modules closely associated with ESR1 expression were predictive of good antiproliferative response to AIs, but modules representing immune activity and IGF-I/MAPK were predictive of poor Ki67 response, supporting their therapeutic targeting in combination with AIs.


Fluorinated copolymer nanoparticles for multimodal imaging applications.
Nanomaterials have emerged as valuable tools in biomedical imaging techniques. Here, the synthesis and characterization of a novel fluorinated nanoparticle with potential applications as an MRI contrast agent is reported. Particles were synthesized using a free radical polymerization technique. Secondary ion mass spectrometry analysis showed that the particles' surface contained fluorinated groups and nitrogen-containing groups. Solid-state NMR spectroscopy suggested the presence of two distinct fluorine resonances, which conforms to the structure of the fluorinated monomer. Ongoing studies aim to evaluate the performance of the nanoparticles as MRI contrast agents both in vitro and in vivo.


The relationship between adolescents' pain catastrophizing and attention bias to pain faces is moderated by attention control.
This study considered the attentional functioning of adolescents with varying levels of pain catastrophizing. Specifically, we investigated the relationship between pain catastrophizing and attention bias to pain facial expressions. Furthermore, drawing on dual process models in the context of pain, we investigated the moderating role of attention control on this relationship. Adolescents (N = 73; age, 16-18 years) performed a dot-probe task in which facial expressions of pain and neutral expressions were presented for 100 milliseconds and 1250 milliseconds. Participants also completed self-report pain catastrophizing and attention control measures. We found that although there was no main effect of pain catastrophizing on attention bias towards pain faces, attention control did significantly moderate this relationship. Further analysis revealed that lower levels of attention control were significantly associated with increasing attentional vigilance towards pain faces only within high catastrophizing adolescents. In addition, we found that poorer attention control was related to increased attention bias for pain faces (regardless of pain catastrophizing level) when these faces were presented for relatively longer durations (ie, 1250 milliseconds) but not for short durations (ie, 100 milliseconds). This study supports a dual process model of attentional processes in pain, thus replicating previous findings within the psychopathology literature but extending them to the study of pain. Theoretical and clinical implications of our findings are discussed.


Transcription factors IIE and IIH and ATP hydrolysis direct promoter clearance by RNA polymerase II.
Using a defined RNA polymerase II (pol II) transcription system, we have investigated the roles of basal factors at discrete stages during the transcription cycle (e.g., initiation, promoter clearance, and transcript elongation). Abortive initiation assays revealed that TATA-binding protein, transcription factors TFIIB and TFIIF, and pol II were necessary and sufficient to form functional initiation complexes on both linear and supercoiled templates. By contrast, TFIIE, TFIIH, and ATP hydrolysis were additionally required during promoter clearance from linear templates, while negative supercoiling obviated the need for these auxiliary factors. Furthermore, TFIIE, TFIIH, and supercoiling were not required during elongation. Our results suggest a role for TFIIH-associated helicase activity or supercoiling during promoter clearance rather than open complex formation. These results establish abortive initiation as a useful assay for studying functional initiation complex formation in defined eukaryotic transcription systems and provide a framework for investigating regulation at different stages of the eukaryotic transcription cycle.


Time-course study of the protection induced by an interferon-inducible DNA vaccine against viral haemorrhagic septicaemia in rainbow trout.
The highly effective DNA vaccines against diseases caused by fish rhabdoviruses in farmed fish consist of a DNA plasmid vector encoding the viral glycoprotein under the control of a constitutive cytomegalovirus promoter (CMV). Among others, attempts to improve efficacy and safety of these DNA vaccines have focused on regulatory elements of plasmid vectors, which play a major role in controlling expression levels of vaccine antigens. Depending on the context, use of a fish-derived promoter with minimal activity in mammalian cells could be preferable. Another aspect related to the CMV promoter is that constitutive expression of the vaccine antigen may lead to rapid elimination of antigen expressing cells in the fish and thereby potentially reduce the long-term effects of the vaccine. In this study, we compared DNA vaccines with the interferon-inducible Mx promoter from rainbow trout and the CMV promoter, respectively. Plasmid constructs encoding the enhanced green fluorescent protein (EGFP) were used for the in vitro analysis, whereas DNA vaccines encoding the glycoprotein (G) of the viral haemorrhagic septicaemia virus (VHSV) were applied for the in vivo examination. The in vitro analysis showed that while the DNA vaccine with the CMV promoter constitutively drove the expression of EGFP in both fish and human cell lines, the DNA vaccine with the Mx promoter inducibly enhanced the expression of EGFP in the fish cell line. To address the impact on protection, a time-course model was followed as suggested by Kurath et al. (2006), where vaccinated fish were challenged with VHSV at 2, 8 and 78 weeks post-vaccination (wpv). The DNA vaccine with the CMV promoter protected at all times, while vaccination with the DNA vaccine containing the Mx promoter only protected the fish at 8 wpv. However, following induction with Poly (I:C) one week before the challenge, high protection was also evident at 2 wpv. In conclusion, the results revealed a more fish host dependent activity of the trout Mx promoter compared to the traditionally used cross species-active CMV promoter, but improvements will be needed for its application in DNA vaccines to ensure long term protection.


Estimation and prediction system for multi-state disease process: application to analysis of organized screening regime.
The disease progression of cancer and non-malignant chronic disease often involve a multi-state transition. However, estimation of parameters and prediction regarding the multi-state disease process are complex. This study aimed to develop an estimation and prediction system with a computer-assisted software using SAS/SCL as a platform to predict the risk of any outcome arising from the underlying multi-state process with or without the incorporation of individual characteristics. The computer-aided system is first constructed following the theoretical framework of stochastic process. The functions provided in this software include model specification, formulation of likelihood function, parameter estimation, model validation and model prediction. An example of breast cancer screening for a high-risk group in Taiwan was used to demonstrate the usefulness of this software. The natural history of breast cancer of a three-state disease process has been demonstrated. Two suspected risk factors, late age at first full-term pregnancy and obesity, were considered by the form of the proportional hazard model. Formulation of intensity matrix, likelihood function, assignment of initial values, and parameter constraint and estimation were successfully demonstrated in model specification. Model validation suggested a good fit of the constructed model. The application of model prediction enables one to project the effectiveness of organized screening by different inter-screening intervals from a policy level or from an individual basis. A computer-aided estimation and prediction system for multi-state disease process was developed and demonstrated. This system can be applied to data with the property of multi-state transitions in association with events or disease.


Correlation of Alzheimer Disease Neuropathologic Staging with Amyloid and Tau Scintigraphic Imaging Biomarkers.
PET neuroimaging of amyloid-β (Aβ) provides an in vivo biomarker for pathologic changes associated with Alzheimer disease (AD). Aβ-targeted agents have been approved by the Food and Drug Administration, with additional agents, most notably targeting tau, currently under clinical investigation and one approved in May 2020. These agents, along with nonscintigraphic biomarkers from blood and cerebrospinal fluid, have provided an opportunity to investigate the pathogenesis, prodromal changes, and time course of the disease in living individuals. The current understanding is that the neuropathologic changes of the AD continuum begin up to 25 y before the onset of clinical symptomatology. The opportunities afforded by in vivo biomarkers of AD, whether by serum, cerebrospinal fluid examination or PET, have transformed the design of AD therapeutic trials by shifting focus to the preclinical stages of disease. Future disease-modifying therapies, should they be forthcoming, will rely heavily on the use of approved biomarkers or biomarkers currently under investigation to confirm the presence of target pathology. Understanding the progressive neuropathologic changes that occur in AD-and how scintigraphic findings relate to these changes-will help the interpreting physician to fully appreciate the implications of the scintigraphic findings and provide a basis to interpret the examinations. The recently adopted National Institute on Aging-Alzheimer Association guidelines define postmortem AD neuropathologic changes as a composite score based on 3 elements. These elements are the extent of involvement (spread) by cerebral Aβ based on the progression model defined by the Thal Aβ phases, the extent of involvement (spread) by neurofibrillary tangles (composed of hyperphosphorylated tau proteins) based on the progression model defined by Braak, and the Consortium to Establish a Registry for Alzheimer's Disease score, which describes the density of neuritic plaques based on certain key locations in the neocortex. This paper will review the 3 elements that define the National Institute on Aging-Alzheimer's Association scoring system and discusses current evidence on how these elements relate to findings based on Aβ and tau PET scintigraphy.


Altered CD4+ T cell immunity in nurses occupationally exposed to viral pathogens.
Pathogen exposure, including but not limited to herpesviruses, moulds the shape of the immune system, both at a basal state and in response to immune challenge. However, little is known about the impact of high exposure to other viruses on baseline immune signatures and how the immune system copes with repetitive exposures to maintain a balanced functionality. Here we investigated baseline immune signatures, including detailed T cell phenotyping, antigen-specific CD4+ and CD8+ T cell responses and cytokine profile in paediatric (PED) nurses, who have high occupational exposure to viral pathogens including varicella zoster virus (VZV) and respiratory viruses, and in neonatal intensive care unit (NICU) nurses, as a control group with infrequent occupational exposure. Our results show a lower CD4+ T cell response to two VZV proteins (IE62 and gE) and to tetanus toxoid (TT) in PED nurses who are cytomegalovirus (CMV)-seronegative, compared to CMV-seronegative NICU nurses, and that the decline might be more pronounced the more sustained the exposure. This decline might be due to an attrition of VZV- and TT-specific T cells as a result of the continuous pressure on the CD4+ T cell compartment. Moreover, our data suggest that the distinct T cell phenotypes known to be associated with CMV-seropositivity might be less prominent in PED nurses compared to NICU nurses, implying a plausible attenuating effect of occupational exposure on CMV-associated immunosenescence. Overall, this pilot study reveals an impact of occupational exposure to viral pathogens on CD4+ T cell immunity and supports further investigation in a larger cohort.


Ivermectin treatment of bancroftian filariasis in Recife, Brazil.
To determine the effectiveness of single oral dosages of ivermectin ranging between 20 and 200 micrograms/kg and to make detailed observations of both the kinetics of parasite killing and the adverse reactions induced by treatment, the present double-blind study on ivermectin treatment of lymphatic filariasis caused by Wuchereria bancrofti was undertaken with 43 microfilaremic patients in Recife, Brazil. Follow-up at one year indicated equivalent efficacy for the 20-, 100-, and 200-micrograms/kg drug dosages in reducing microfilaremia to geometric means of 13-25% of pretreatment levels. Adverse clinical reactions (predominantly fever, headache, weakness, and myalgia) occurred to some degree in almost all patients but generally lasted only 24-48 hr and were easily managed symptomatically. Adverse reactions were significantly milder in those receiving the lowest (20 micrograms/kg) ivermectin dose, and they were significantly correlated with individuals' pretreatment microfilaremia levels in all groups. Posttreatment eosinophilia was a regular feature of the response to treatment, with the magnitude and kinetics also proportional to pretreatment microfilarial levels. Transient pulmonary function abnormalities (16 of 42, 38%), liver enzyme elevations (10 of 43, 23%), and hematuria (9 of 42, 22%) developed posttreatment, but all cleared without significant complications. The results indicate that W. bancrofti from Brazil is similar to strains of the parasites studied elsewhere in susceptibility to ivermectin, that the drug's systemic adverse reactions are essentially those resulting from parasite clearance, and that the intensity of these reactions can be significantly reduced by using the low (20 micrograms/kg) dose of ivermectin. This detailed dose-finding study provides information necessary for developing optimal regimens to treat bancroftian filariasis with ivermectin either alone or in combination with other medications.


Clonal analysis of a human antibody response. II. Sequences of the VH genes of human IgM, IgG, and IgA to rabies virus reveal preferential utilization of VHIII segments and somatic hypermutation.
The construction of mAb-producing cell lines has been instrumental in dissecting the fine specificities and genetic makeup of murine antibodies to exogenous and self Ag. The analysis of the genetic composition of human antibody responses has been hampered by the difficulty in generating human mAb of predetermined class and specificity. Using B lymphocytes from three healthy subjects vaccinated with inactivated rabies virus vaccine, we generated nine human mAb binding to rabies virus and analyzed the genes encoding their VH regions. Six mAb (five IgG1 and one IgA1) were monoreactive and displayed high affinities for rabies virus Ag. The remaining three mAb (IgM) were polyreactive and displayed lower affinities for rabies virus Ag. Seven mAb (3 IgG1, the IgA1, and the three IgM) utilized VH gene segments of the VHIII family. The remaining two IgG1 mAb utilized gene segments of the VHI and VHIV families. Of the seven expressed VHIII family genes, three were similar to the germline VH26c gene, two to the germline 22-2B gene, one to the germline H11 gene, and one to the germline 8-1B gene. The expressed VHI and VHIV genes displayed sequences similar to those of the germline hv1263 and V71-4 genes, respectively. The VH genes of all but one mAb (mAb55) resembled those that are predominantly expressed by C mu + clones in human fetal liver libraries. When compared with known germline sequences, the VH genes of the rabies virus-binding mAb displayed variable numbers of nucleotide differences. That such differences resulted from a process of somatic hypermutation was formally demonstrated (by analyzing DNA from polymorphonuclear neutrophil of the same subject whose B lymphocytes were used for the mAb generation) in the case of the VH gene of the high affinity (anti-rabies virus glycoprotein) IgG1 mAb57 that has been shown to efficiently neutralize the virus in vitro and in vivo. The distribution, mainly within the complementarity determining regions, and the high replacement-to-silent ratio of the mutations, were consistent with the hypothesis that the mAb57-producing cell clone underwent a process of Ag-driven affinity maturation through clonal selection. The D gene segments of the rabies virus-selected mAb were heterogeneous and, in most cases, flanked by significant N segment additions. The JH segment utilization was unbalanced and reminiscent of those of the adult and fetus. Four mAb utilized JH4, two JH6, two JH3, and one JH5; no mAb utilized JH1 or JH2 genes.(ABSTRACT TRUNCATED AT 400 WORDS)


Use of helium-oxygen mixture (Heliox®) in the treatment of obstructive lower airway disease in a pediatric emergency department.
To determine whether the use of salbutamol, in a helium-oxygen mixture (80:20), can modify outcome and risk of hospitalization of pediatric patients. A controlled cohort study including patients aged 2 months to 12 years with diagnoses of asthmatic crisis or viral bronchiolitis. Intensity was characterized from moderate to severe, as measured by clinical score (pulmonary index, PI) for obstructive disease. Scores > 8 were considered eligible. The Heliox® group was composed of 20 patients and the Oxygen group of 40 patients. Patients received sequentially, at 20-min intervals, until six nebulization cycles were completed (2-h period): salbutamol 0.15 mg/kg/dose (maximum 5 mg). The nebulized drug was driven either by Heliox® mixture (80:20) or 100% oxygen. Patients diagnosed with acute asthmatic crisis received, additionally, prednisolone (2 mg/kg) orally. Eleven patients in the Heliox® group still required treatment at 6 h, against 38 patients in the group receiving oxygen-driven nebulization (p = 0.034). At 12 h, 7 patients in the Heliox® group remained under observation, against 27 in the Oxygen group. Differences regarding the need for supplemental oxygen were observed only at 6 h of treatment (p = 0.02). Heliox® (80:20), for salbutamol administration, is effective in the treatment of pediatric obstructive disease that responds to bronchodilator therapy. Compared to usual aerosol delivery technique, Heliox®-driven salbutamol nebulization is associated with shorter stay in the observation room after 6 h of treatment.


Dynamics of life expectancy and life span equality.
As people live longer, ages at death are becoming more similar. This dual advance over the last two centuries, a central aim of public health policies, is a major achievement of modern civilization. Some recent exceptions to the joint rise of life expectancy and life span equality, however, make it difficult to determine the underlying causes of this relationship. Here, we develop a unifying framework to study life expectancy and life span equality over time, relying on concepts about the pace and shape of aging. We study the dynamic relationship between life expectancy and life span equality with reliable data from the Human Mortality Database for 49 countries and regions with emphasis on the long time series from Sweden. Our results demonstrate that both changes in life expectancy and life span equality are weighted totals of rates of progress in reducing mortality. This finding holds for three different measures of the variability of life spans. The weights evolve over time and indicate the ages at which reductions in mortality increase life expectancy and life span equality: the more progress at the youngest ages, the tighter the relationship. The link between life expectancy and life span equality is especially strong when life expectancy is less than 70 y. In recent decades, life expectancy and life span equality have occasionally moved in opposite directions due to larger improvements in mortality at older ages or a slowdown in declines in midlife mortality. Saving lives at ages below life expectancy is the key to increasing both life expectancy and life span equality.


Structural basis of the unfolded protein response.
The unfolded protein response (UPR) is a network of intracellular signaling pathways that maintain the protein-folding capacity of the endoplasmic reticulum (ER) in eukaryotic cells. Dedicated molecular sensors embedded in the ER membrane detect incompletely folded or unfolded proteins in the ER lumen and activate a transcriptional program that increases the abundance of the ER according to need. In metazoans the UPR additionally regulates translation and thus relieves unfolded protein load by globally reducing protein synthesis. If homeostasis in the ER cannot be reestablished, the metazoan UPR switches from the prosurvival to the apoptotic mode. The UPR involves a complex, coordinated action of many genes that is controlled by one ER-embedded sensor, Ire1, in yeasts, and three sensors, Ire1, PERK, and ATF6, in higher eukaryotes, including human. We discuss the emerging molecular understanding of the UPR and focus on the structural biology of Ire1 and PERK, the two recently crystallized UPR sensors.


Renal pseudoaneurysm: an overview.
Renal pseudoaneurysm is a rare vascular lesion that arises when an arterial injury within the kidney leads to contained hemorrhage. The associated hematoma forms outside the arterial wall and is typically surrounded by a layer of fibrous inflammatory tissue and blood clot. These lesions are unstable and their rupture can lead to life-threatening hemorrhage. Renal pseudoaneurysm has been reported to occur in various clinical scenarios, including after renal trauma, surgery and percutaneous procedures, as well as inflammatory and neoplastic processes within the kidney. Endovascular selective angioembolization is the mainstay of treatment, although surgery might be indicated when hemostasis and repair of the arterial wall defect are required. Percutaneous ultrasound-guided embolization is an additional option for patients with unfavorable vascular anatomy, or who cannot tolerate or have contraindications to the use of intravenous contrast agents. Some evidence suggests that these lesions can regress without intervention, although observation alone is not recommended as a management strategy in the vast majority of patients owing to the high risk of rupture. Evaluation and management of patients with renal pseudoaneurysm must take into account each individual's circumstances, due to the difficulty of accurately predicting the probability of spontaneous resolution or rupture.


Probability density estimation with tunable kernels using orthogonal forward regression.
A generalized or tunable-kernel model is proposed for probability density function estimation based on an orthogonal forward regression procedure. Each stage of the density estimation process determines a tunable kernel, namely, its center vector and diagonal covariance matrix, by minimizing a leave-one-out test criterion. The kernel mixing weights of the constructed sparse density estimate are finally updated using the multiplicative nonnegative quadratic programming algorithm to ensure the nonnegative and unity constraints, and this weight-updating process additionally has the desired ability to further reduce the model size. The proposed tunable-kernel model has advantages, in terms of model generalization capability and model sparsity, over the standard fixed-kernel model that restricts kernel centers to the training data points and employs a single common kernel variance for every kernel. On the other hand, it does not optimize all the model parameters together and thus avoids the problems of high-dimensional ill-conditioned nonlinear optimization associated with the conventional finite mixture model. Several examples are included to demonstrate the ability of the proposed novel tunable-kernel model to effectively construct a very compact density estimate accurately.


Impact of COVID-19 on drowning patterns in the Great Lakes region of North America.
The COVID-19 pandemic significantly altered personal and group behaviors that may directly or indirectly affect other public health issues. This paper examines if and how COVID-19 indirectly influenced beach safety and drownings within the Great Lakes region using daily drowning data from 2020 in comparison to historical trends in drownings pre-COVID. Results suggest that the number of beach drownings in the Great Lakes region was significantly greater compared to the pre-COVID period of 2010-2019. Statistically significant increases in drownings were observed in Lake Michigan (+14), Lake Ontario (+11) and Lake Huron (+4), while no change and a slight decrease was observed in Lake Superior and Lake Erie respectively. Drownings were lower than the historical average early in the pandemic but began to increase as stay-at-home orders were lifted through June and July. It is argued that the increase in drowning is due to a combination of reduced local lifeguard resources, cancelled swimming lessons, large beach crowds, warm weather, high-water levels and self-isolation fatigue. Whether in the Great Lakes region or elsewhere around the world, beach safety cannot be sacrificed in a future public health emergency by budget cuts or by reducing the focus of lifeguards with enforcement of social distancing.


Urethrectomy following cystectomy for bladder cancer in men: practice patterns and impact on survival.
The benefit of urethrectomy in patients with bladder cancer who are undergoing cystectomy is controversial. We describe the frequency of urethrectomy by bladder cancer stage and identify clinical characteristics that predict urethrectomy. We also investigated whether urethrectomy offers any additional independent survival benefit. A total of 2,401 men who underwent radical cystoprostatectomy between 1991 and 2002 were identified in the Surveillance, Epidemiology and End Results-Medicare database. A multivariate logistic regression model was used to analyze factors driving urethrectomy. We then analyzed the records of 195 men who underwent urethrectomy to find predictors of that procedure as salvage for urethral recurrence vs concurrently with cystoprostatectomy or as a staged procedure. Using multivariate Cox regression analysis we analyzed whether urethrectomy had an independent effect on disease specific survival. The only significant predictor of urethrectomy was stage. Patients at a teaching hospital were more likely to undergo salvage urethrectomy for recurrence vs immediate urethrectomy compared to those at urban nonteaching hospitals. Patient age, race, number of comorbidities and tumor stage were significant independent predictors of survival. Survival in men who underwent urethrectomy concurrently with cystoprostatectomy was higher than in those who did not undergo urethrectomy but not statistically significant (HR = 0.775, 95% CI 0.592-1.014, p = 0.0632). Disease stage is related to urethrectomy performance. Age, race, stage and comorbidities were independent predictors of overall survival in patients with bladder cancer undergoing cystectomy. Urethrectomy did not confer a significant independent survival benefit.


[Review of patients with musculoskeletal injury treated during winter months in a highland hospital].
The authors examined the incidence of musculoskeletal injuries according to their type and location in the period of winter at a highland hospital, which also functions as a regional hospital for a few winter sport resorts. . In the sample there were 1644 patients (696 women, 948 men) treated for primary musculoskeletal injuries from 1.1. to 31.3.2008. This was a retrospective study; the data were collected from medical reports. It included: age, sex, mechanism of injury, diagnosis and whether the patient had to be hospitalised or not. Age of the patients ranged from 1 to 95 years with an average of 29 years (31 for women and 28 for men). Younger age groups dominated among men. After 70 years of age there was a prevalence of women. Fractures were the most common cause of injury (653, 39.7%), followed by injuries to the joints' ligamentary apparatus by mechanism of distortion (379, 23.1%). Next in incidence were soft tissue injuries caused by contusion (325, 19.7%) and open wounds (241, 14.7%). The least common were luxated joints (43, 2.6%) and closed injury to muscles and tendons (3, 0.1%). The most frequent site of injury was the hand (404, 24.6%), while the least frequent place was the thigh (17, 1.0%). In conclusion the study confirmed that other than the age, gender and the season, the geographic location also influences the spectrum of musculoskeletal injuries. The study also showed that the most common type of injuries was that of the upper extremity. The study did not confirm the expected prevalence of fractures among women. The prevalence of men was probably because of the prevalence of winter sport activities as a leading cause of injury (mostly skiing and snowboarding).


Mendelian breeding units versus standard sampling strategies: Mitochondrial DNA variation in southwest Sardinia.
We report a sampling strategy based on Mendelian Breeding Units (MBUs), representing an interbreeding group of individuals sharing a common gene pool. The identification of MBUs is crucial for case-control experimental design in association studies. The aim of this work was to evaluate the possible existence of bias in terms of genetic variability and haplogroup frequencies in the MBU sample, due to severe sample selection. In order to reach this goal, the MBU sampling strategy was compared to a standard selection of individuals according to their surname and place of birth. We analysed mitochondrial DNA variation (first hypervariable segment and coding region) in unrelated healthy subjects from two different areas of Sardinia: the area around the town of Cabras and the western Campidano area. No statistically significant differences were observed when the two sampling methods were compared, indicating that the stringent sample selection needed to establish a MBU does not alter original genetic variability and haplogroup distribution. Therefore, the MBU sampling strategy can be considered a useful tool in association studies of complex traits.


The Abuse Intervention Model: A Pragmatic Approach to Intervention for Elder Mistreatment.
Ten percent of older adults experience elder mistreatment, and it is much more common in older adults with dementia. It is associated with higher rates of psychological distress, hospitalization, and death and, in the United States, costs billions of dollars each year. Although elder mistreatment is relatively common and costly, it is estimated that fewer than 10% of instances of elder mistreatment are reported. Given these data, there is a great need for research on interventions to mitigate elder mistreatment and for a practical model or framework to use in approaching such interventions. Although many theories have been proposed, adapted, and applied to understand elder mistreatment, there has not been a simple, coherent framework of known risk factors of the victim, perpetrator, and environment that applies to all types of abuse. This article presents a new model to examine the multidimensional and complex relationships between risk factors. Theories of elder mistreatment, research on risk factors for elder mistreatment, and 10 years of experience of faculty and staff at an Elder Abuse Forensics Center who have investigated more than 1,000 cases of elder mistreatment inform this model. It is hoped that this model, the Abuse Intervention Model, will be used to study and intervene in elder mistreatment.


Spironolactone directly inhibits proliferation of cultured human facial sebocytes and acts antagonistically to testosterone and 5 alpha-dihydrotestosterone in vitro.
Spironolactone produces antiacne effects and has recently been shown to inhibit 5 alpha-dihydrotestosterone (5 alpha-DHT) receptors in human sebaceous glands. We applied spironolactone alone and combined with testosterone and 5 alpha-DHT to investigate its effects on the proliferation of human sebocyte cultures derived from facial skin. Secondary human facial sebocytes in 96-well culture plates were treated for 10 d by a single or combined application of testosterone (10(-8)-10(-5) M), 5 alpha-DHT (10(-8)-10(-5) M), and spironolactone (10(-12)-10(-7) M) in serum-free basal medium. Cell proliferation was assessed in six wells using a fluorometric assay. Testosterone and 5 alpha-DHT significantly stimulated sebocyte proliferation in a dose-dependent manner, the effect being strongest with 5 alpha-DHT. Spironolactone, on the other hand, caused a dose-dependent inhibition (25% and 50% at 10(-9) and 10(-7) M, respectively). Combined treatment of human facial sebocytes with spironolactone and testosterone or 5 alpha-DHT resulted in a lower proliferation than with androgens alone. The fact that spironolactone directly and dose dependently inhibits the proliferation of cultured human facial sebocytes and acts antagonistically to testosterone and 5 alpha-DHT at the cellular level is indicative of a receptor-mediated effect.


SPATIAL DENSITY DEPENDENCE SCALES UP BUT DOES NOT PRODUCE TEMPORAL DENSITY DEPENDENCE IN A REEF FISH.
Field experiments provide rigorous tests of ecological hypotheses but are typically of short duration and use small spatial replicates. We assessed empirically whether the results of experiments testing for density dependence applied at larger spatial domains and explained temporal population dynamics. We studied a small coral reef fish, the goldspot goby (Gnatholepis thompsoni), in the Bahamas. We assessed the effects of interactions with conspecifics and with an ecologically similar species, the bridled goby (Coryphopterus glaucofraenum). Two density manipulations on small reef patches revealed that goldspot goby mortality over one month increased as conspecifics became crowded. On five large natural reefs, we correlated the initial year-class density of both species (annual larval settlement) with the subsequent decline of goldspot goby year-classes for five years. Mortality was correlated with conspecific density among reefs for all years, but not among years for all reefs. Thus, spatial density dependence in mortality scaled up qualitatively from small patches to entire reefs but was not associated with temporal density dependence. Our results support the conclusion that field experiments may be extrapolated to larger spatial domains with care, but that using small spatial comparisons to predict temporal responses is difficult without knowing the underlying biological mechanisms.


Cytomegalovirus and immune senescence: culprit or innocent bystander?
Immune senescence may be defined as the age-related reduction and dysregulation of immune function, and has been associated with increased incidence and severity of infectious diseases and with poor efficacy of prophylactic vaccines in the elderly. Several studies have demonstrated that persistent infections with Herpes viruses in general and Cytomegalovirus (CMV) in particular have a profound influence on subset distribution, phenotype and potentially also on the function of T cells in ageing individuals. The association of CMV-seropositivity and accumulation of CMV-specific CD8+ T cells with decreased survival in longitudinal studies of very elderly has fostered the hypothesis that CMV-infection may be an important causative factor for the development of immune senescence. Here, we have critically summarized the current body of evidence supporting this hypothesis, highlight some controversial issues about its relevance and mechanisms and propose areas of future research to demonstrate unequivocally whether and how persistent infections might compromise the ageing immune system.


Differential preservation of endogenous human and microbial DNA in dental calculus and dentin.
Dental calculus (calcified dental plaque) is prevalent in archaeological skeletal collections and is a rich source of oral microbiome and host-derived ancient biomolecules. Recently, it has been proposed that dental calculus may provide a more robust environment for DNA preservation than other skeletal remains, but this has not been systematically tested. In this study, shotgun-sequenced data from paired dental calculus and dentin samples from 48 globally distributed individuals are compared using a metagenomic approach. Overall, we find DNA from dental calculus is consistently more abundant and less contaminated than DNA from dentin. The majority of DNA in dental calculus is microbial and originates from the oral microbiome; however, a small but consistent proportion of DNA (mean 0.08 ± 0.08%, range 0.007-0.47%) derives from the host genome. Host DNA content within dentin is variable (mean 13.70 ± 18.62%, range 0.003-70.14%), and for a subset of dentin samples (15.21%), oral bacteria contribute > 20% of total DNA. Human DNA in dental calculus is highly fragmented, and is consistently shorter than both microbial DNA in dental calculus and human DNA in paired dentin samples. Finally, we find that microbial DNA fragmentation patterns are associated with guanine-cytosine (GC) content, but not aspects of cellular structure.


Role of primate flocculus during rapid behavioral modification of vestibuloocular reflex. I. Purkinje cell activity during visually guided horizontal smooth-pursuit eye movements and passive head rotation.
1. Extracellular recordings were obtained from 124 Purkinje cells (P-cells) in the flocculus of alert monkeys. P-cell simple spike-firing rate was analyzed quantitatively during various combinations of smooth-pursuit eye movement and passive head rotation. 2. During sinusoidal smooth eye movements, 80% of the P-cells displayed increased firing rate during ipsilateral and 20% during contralateral eye movement. Over the frequency range 0.3--1.4 Hz, firing-rate modulation was proportional to and in phase with maximum eye velocity. During the steady state of triangle-wave tracking, firing rate increased monotonically as a function of eye velocity. Since firing rate was uncorrelated with retinal-error velocity, one component of P-cell firing rate was related to eye velocity. 3. During the transient phase of triangle-wave tracking, when an instantaneous change in the direction of target movement caused a large retinal-error velocity, 40% of the P-cells were related only to eye velocity. Sixty percent of the P-cells displayed an overshoot or undershoot in firing rate, indicating a relationship to either retinal-error velocity or eye acceleration as well as to eye velocity. 4. During the vestibuloocular reflex (VOR), evoked by head rotation in the dark, P-cell firing rate was only weakly modulated. In contrast, when the monkey suppressed the VOR by fixating a target that rotated with him, P-cell rate was deeply modulated. Since the modulation was proportional to and in phase with maximum head velocity, another component of P-cell firing rate was related to head velocity. 5. Of 36 P-cells tested, 35 displayed firing-rate modulation during both suppression of the VOR and smooth-pursuit eye movement. P-cells that reached peak firing rate during ipsilateral head rotation also reached peak firing rate during ipsilateral smooth eye rotation. Average population sensitivitites to head velocity and eye velocity were equal. In three conditions in which eye and head velocity were elicited simultaneously, P-cell firing rate could be predicted by the linear, vector addition of the separate eye and head velocity components of firing rate. Therefore, the relatively weak modulation of P-cell firing rate during the VOR in the dark can be accounted for by the cancellation of equal but opposite head and eye velocity components. 6. The connections of flocculus P-cells to interneurons in the brain stem VOR pathways have been established in other mammals. In the context of those connections, P-cell firing patterns were appropriate to facilitate the eye movements the monkey was required to make. We conclude that the flocculus is important for sustaining any smooth eye movements that are different from those evoked by head rotation in the dark. The eye velocity component may represent an efference copy signal that sustains ongoing eye velocity during smooth pursuit.


Cumulative exposure to cell-free HIV in breast milk, rather than feeding pattern per se, identifies postnatally infected infants.
We quantified the relationship between human immunodeficiency virus (HIV) RNA shedding in breast milk, cumulative RNA exposure, and postnatal transmission, relating timing of infection in the infant to estimated total volume of milk exposure. Nested case-control study of 36 infants of HIV-infected mothers. Case patients were infants who acquired HIV infection through breastfeeding from age 6 through 28 weeks, and control subjects were uninfected infants matched on age at obtainment of a breast milk sample. Mothers and infants received peripartum single-dose nevirapine prophylaxis. Feeding data were collected daily; breast milk samples were collected and infant anthropometry was performed at 6 weeks and monthly thereafter. Volume of milk ingested was estimated using infant weight and feeding pattern. Before HIV acquisition in case patients, feeding pattern (exclusive breastfeeding; median duration, 65 vs 70 days; P = .6) and daily milk intake (mean volume, 638 vs 637 mL; P = .97) did not differ significantly between case patients and control subjects. Case mothers were more likely to shed virus (64% vs 9% always, 22% vs 20.5% intermittently, 14% vs 70.5% never shed; overall, P < .001). Case patients ingested ~15 times more HIV-1 RNA particles than did control subjects (196.5 vs 13 × 10⁶ copies; P < .001). Allowing for maternal antenatal CD4 cell count and plasma HIV-1 load, child sex and duration of mixed breastfeeding, the association between HIV RNA exposure and infection remained statistically significant (P < .001). Postnatal acquisition of HIV-1 is more strongly associated with cumulative exposure to cell-free particles in breast milk than with feeding mode. Reducing breast milk viral load through antiretroviral therapy to mother or child can further decrease postnatal transmission in exclusively breastfed infants.


Noonan syndrome: comparing mutation-positive with mutation-negative dutch patients.
Noonan syndrome (NS) is an autosomal dominant disorder characterized by facial dysmorphisms, short stature and congenital heart defects. The disorder is genetically heterogeneous and shows clinical overlap with other RASopathies. These syndromes are caused by mutations in a variety of genes leading to dysregulation of the RAS-MAPK pathway: PTPN11, KRAS, SOS1, RAF1, CBL, SHOC2, NRAS, BRAF, MAP2K1, MAP2K2, HRAS, NF1 and SPRED1. In this study, we conduct a genotype-phenotype analysis of 33 patients with a clinical diagnosis of NS without a PTPN11 mutation. Mutation analysis of the genes involved in RASopathies was performed, except for NF1 and SPRED1. In 14 (42%) NS patients, a mutation was found, 7 (21%) had a mutation in SOS1, 3 (9%) in RAF1 and 1 (3%) in KRAS, MAP2K2, BRAF and SHOC2 each. The phenotype of these mutation-positive cases corresponded to that described in the literature. In the cases with a BRAF and MAP2K2 mutation, the diagnosis cardio-facio-cutaneous syndrome was made. The patient with the SHOC2 mutation had features compatible with 'Noonan-like syndrome with loose anagen hair'. Three major clinical features of NS - a typical face, short stature and a pulmonary valve stenosis - were less frequently present in the group without a mutation. Missense mutations in genes encoding proteins of the RAS-MAPK pathway cause NS. The 3 major clinical features of NS were less frequently present in the mutation-negative patients, which stresses the importance of the syndrome-specific symptoms of the face, heart and short stature in NS. However, all mutation-negative cases met the NS criteria, indicating that the involvement of novel genes is to be expected.


Screening for Structural Hemoglobin Variants in Bahia, Brazil.
Brazil was the country that received the largest number of Africans during the time of colonization, and Bahia was the Brazilian state that received the largest number of slaves from Africa. The purpose of this study was to evaluate the coverage of the newborn screening program for sickle cell disease in the Recôncavo Baiano region of the state of Bahia, and to show the frequency of the subjects with hemoglobin variants in the 2006-2009 period. Blood samples from neonates in twelve cities in the Recôncavo Baiano region were analyzed by High Performance Liquid Chromatography. A total of 16,402 children were born in this period, 14,773 of which underwent newborn screening. In this period 1416 children were born carrying hemoglobin variants HbS and HbC. Forty-seven patients--20 HbSS genotype and 27 HbSC genotype--were diagnosed in eleven of the twelve cities surveyed. The proportion of children born with sickle cell disease in the Recôncavo Baiano region was 1/314, which was higher than the 1/650 rate for the state of Bahia. The data presented in this study confirm the high frequency of sickle cell disease in Recôncavo Baiano, demonstrating the need to create a referral center for the care of patients with sickle cell diseases in the region.


Molecular Surveillance Identifies Multiple Transmissions of Typhoid in West Africa.
The burden of typhoid in sub-Saharan African (SSA) countries has been difficult to estimate, in part, due to suboptimal laboratory diagnostics. However, surveillance blood cultures at two sites in Nigeria have identified typhoid associated with Salmonella enterica serovar Typhi (S. Typhi) as an important cause of bacteremia in children. A total of 128 S. Typhi isolates from these studies in Nigeria were whole-genome sequenced, and the resulting data was used to place these Nigerian isolates into a worldwide context based on their phylogeny and carriage of molecular determinants of antibiotic resistance. Several distinct S. Typhi genotypes were identified in Nigeria that were related to other clusters of S. Typhi isolates from north, west and central regions of Africa. The rapidly expanding S. Typhi clade 4.3.1 (H58) previously associated with multiple antimicrobial resistances in Asia and in east, central and southern Africa, was not detected in this study. However, antimicrobial resistance was common amongst the Nigerian isolates and was associated with several plasmids, including the IncHI1 plasmid commonly associated with S. Typhi. These data indicate that typhoid in Nigeria was established through multiple independent introductions into the country, with evidence of regional spread. MDR typhoid appears to be evolving independently of the haplotype H58 found in other typhoid endemic countries. This study highlights an urgent need for routine surveillance to monitor the epidemiology of typhoid and evolution of antimicrobial resistance within the bacterial population as a means to facilitate public health interventions to reduce the substantial morbidity and mortality of typhoid.


Ego-Dissolution and Psychedelics: Validation of the Ego-Dissolution Inventory (EDI).
The experience of a compromised sense of "self", termed ego-dissolution, is a key feature of the psychedelic experience. This study aimed to validate the Ego-Dissolution Inventory (EDI), a new 8-item self-report scale designed to measure ego-dissolution. Additionally, we aimed to investigate the specificity of the relationship between psychedelics and ego-dissolution. Sixteen items relating to altered ego-consciousness were included in an internet questionnaire; eight relating to the experience of ego-dissolution (comprising the EDI), and eight relating to the antithetical experience of increased self-assuredness, termed ego-inflation. Items were rated using a visual analog scale. Participants answered the questionnaire for experiences with classical psychedelic drugs, cocaine and/or alcohol. They also answered the seven questions from the Mystical Experiences Questionnaire (MEQ) relating to the experience of unity with one's surroundings. Six hundred and ninety-one participants completed the questionnaire, providing data for 1828 drug experiences (1043 psychedelics, 377 cocaine, 408 alcohol). Exploratory factor analysis demonstrated that the eight EDI items loaded exclusively onto a single common factor, which was orthogonal to a second factor comprised of the items relating to ego-inflation (rho = -0.110), demonstrating discriminant validity. The EDI correlated strongly with the MEQ-derived measure of unitive experience (rho = 0.735), demonstrating convergent validity. EDI internal consistency was excellent (Cronbach's alpha 0.93). Three analyses confirmed the specificity of ego-dissolution for experiences occasioned by psychedelic drugs. Firstly, EDI score correlated with drug-dose for psychedelic drugs (rho = 0.371), but not for cocaine (rho = 0.115) or alcohol (rho = -0.055). Secondly, the linear regression line relating the subjective intensity of the experience to ego-dissolution was significantly steeper for psychedelics (unstandardized regression coefficient = 0.701) compared with cocaine (0.135) or alcohol (0.144). Ego-inflation, by contrast, was specifically associated with cocaine experiences. Finally, a binary Support Vector Machine classifier identified experiences occasioned by psychedelic drugs vs. cocaine or alcohol with over 85% accuracy using ratings of ego-dissolution and ego-inflation alone. Our results demonstrate the psychometric structure, internal consistency and construct validity of the EDI. Moreover, we demonstrate the close relationship between ego-dissolution and the psychedelic experience. The EDI will facilitate the study of the neuronal correlates of ego-dissolution, which is relevant for psychedelic-assisted psychotherapy and our understanding of psychosis.


Risks to birds traded for African traditional medicine: a quantitative assessment.
Few regional or continent-wide assessments of bird use for traditional medicine have been attempted anywhere in the world. Africa has the highest known diversity of bird species used for this purpose. This study assesses the vulnerability of 354 bird species used for traditional medicine in 25 African countries, from 205 genera, 70 families, and 25 orders. The orders most represented were Passeriformes (107 species), Falconiformes (45 species), and Coraciiformes (24 species), and the families Accipitridae (37 species), Ardeidae (15 species), and Bucerotidae (12 species). The Barn owl (Tyto alba) was the most widely sold species (seven countries). The similarity of avifaunal orders traded is high (analogous to "morphospecies", and using Sørensen's index), which suggests opportunities for a common understanding of cultural factors driving demand. The highest similarity was between bird orders sold in markets of Benin vs. Burkina Faso (90%), but even bird orders sold in two geographically separated countries (Benin vs. South Africa and Nigeria vs. South Africa) were 87% and 81% similar, respectively. Rabinowitz's "7 forms of rarity" model, used to group species according to commonness or rarity, indicated that 24% of traded bird species are very common, locally abundant in several habitats, and occur over a large geographical area, but 10% are rare, occur in low numbers in specific habitats, and over a small geographical area. The order with the highest proportion of rare species was the Musophagiformes. An analysis of species mass (as a proxy for size) indicated that large and/or conspicuous species tend to be targeted by harvesters for the traditional medicine trade. Furthermore, based on cluster analyses for species groups of similar risk, vultures, hornbills, and other large avifauna, such as bustards, are most threatened by selective harvesting and should be prioritised for conservation action.


Food parenting measurement issues: working group consensus report.
Childhood obesity is a growing problem. As more researchers become involved in the study of parenting influences on childhood obesity, there appears to be a lack of agreement regarding the most important parenting constructs of interest, definitions of those constructs, and measurement of those constructs in a consistent manner across studies. This article aims to summarize findings from a working group that convened specifically to discuss measurement issues related to parental influences on childhood obesity. Six subgroups were formed to address key measurement issues. The conceptualization subgroup proposed to define and distinguish constructs of general parenting styles, feeding styles, and food parenting practices with the goal of understanding interrelating levels of parental influence on child eating behaviors. The observational subgroup identified the need to map constructs for use in coding direct observations and create observational measures that can capture the bidirectional effects of parent-child interactions. The self-regulation subgroup proposed an operational definition of child self-regulation of energy intake and suggested future measures of self-regulation across different stages of development. The translational/community involvement subgroup proposed the involvement of community in the development of surveys so that measures adequately reflect cultural understanding and practices of the community. The qualitative methods subgroup proposed qualitative methods as a way to better understand the breadth of food parenting practices and motivations for the use of such practices. The longitudinal subgroup stressed the importance of food parenting measures sensitive to change for use in longitudinal studies. In the creation of new measures, it is important to consider cultural sensitivity and context-specific food parenting domains. Moderating variables such as child temperament and child food preferences should be considered in models.


The embryonic transcription cofactor LBH is a direct target of the Wnt signaling pathway in epithelial development and in aggressive basal subtype breast cancers.
Limb-bud and heart (LBH) is a novel key transcriptional regulator of vertebrate development. However, the molecular mechanisms upstream of LBH and its role in adult development are unknown. Here we show that in epithelial development, LBH expression is tightly controlled by Wnt signaling. LBH is transcriptionally induced by the canonical Wnt pathway, as evident by the presence of conserved functional T-cell factor (TCF)/lymphoid enhancer-binding factor (LEF) binding sites in the LBH locus and rapid beta-catenin-dependent upregulation of endogenous LBH by Wnt3a. In contrast, LBH induction by Wnt/beta-catenin signaling is inhibited by Wnt7a, which in limb development signals through a noncanonical pathway involving Lmx1b. Furthermore, we show that LBH is aberrantly overexpressed in mammary tumors of mouse mammary tumor virus (MMTV)-Wnt1-transgenic mice and in aggressive basal subtype human breast cancers that display Wnt/beta-catenin hyperactivation. Deregulation of LBH in human basal breast cancer appears to be Wnt/beta-catenin dependent, as DKK1 and Wnt7a inhibit LBH expression in breast tumor cells. Overexpression studies indicate that LBH suppresses mammary epithelial cell differentiation, an effect that could contribute to Wnt-induced tumorigenesis. Taken together, our findings link LBH for the first time to the Wnt signaling pathway in both development and cancer and highlight LBH as a potential new marker for therapeutically challenging basal-like breast cancers.


Prevalence of chronic insomnia in adult patients and its correlation with medical comorbidities.
Insomnia is one of the common but neglected conditions seen in family practice with long term and serious effects on health of a patient. Family physicians have the responsibility of diagnosing and adequately treating this. This study was done to find the prevalence of chronic insomnia in adult patients visiting a family medicine outpatient department (OPD) in a hospital and to assess the risk factors and co morbidities associated with it. A cross-sectional study was done in the family medicine OPD at St. Philomena's Hospital, Bengaluru. All adult patients attending the OPD from September 1 to October 30, 2015 were enrolled in the study after obtaining written consent. Athens Insomnia Scale was used to diagnose insomnia and information regarding medical co morbidities was collected. Data was analyzed for the prevalence of insomnia and its association with co morbidities. Chronic insomnia was seen in 33% of the adult population sampled. Increasing age and diabetes were significantly associated with insomnia, while other socioeconomic factors and co morbidities were not significantly associated. Twenty-seven percent of patients who had insomnia did not perceive the condition, which was statistically significant. Insomnia is a common sleep disorder which is many times missed by a primary care physician until/unless asked for. Since there is a higher incidence with increasing age and co morbidities such as diabetes, all patients, especially middle-aged and diabetics, should be screened for insomnia by the primary care physician with a self assessed questionnaire and counseled.