Feeding and Swallowing Problems in Infants with Spinal Muscular Atrophy Type 1: an Observational Study.
Infantile hereditary proximal spinal muscular atrophy (SMA) type 1 is characterized by onset in the first 6 months of life and severe and progressive muscle weakness. Dysphagia is a common complication but has not been studied in detail. To study feeding and swallowing problems in infants with SMA type 1, and to explore the relation between these problems and functional motor scores. We prospectively included 16 infants with SMA type 1 between September 2016 and October 2018. Eleven infants received palliative care and five infants best supportive care in combination with nusinersen. We compiled and used an observation list with feeding related issues and observed feeding sessions during inpatient and outpatient visits. The Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) was used as a measure of motor function. All infants in the palliative care group (median onset of disease 14 days (range 1-56); median inclusion in the study 52 days (range 16-252) demonstrated symptoms of fatigue during feeding and unsafe swallowing. Symptoms were short nursing sessions (10-15 minutes), and not being able to finish the recommended feeding volumes (72%); increased frequency of feeding sessions (55%); coughing when drinking or eating (91%), and wet breathing during and after feeding (64%).Two out of five infants in the nusinersen group (median onset of disease 38 days (range 21-90); inclusion in the study at 63 days (range 3-218) were clinically pre-symptomatic at the start of treatment. The other three infants showed symptoms of fatigue and unsafe swallowing at inclusion in the study. These symptoms initially decreased after the start of the treatment, but (re)appeared in all five infants between the ages of 8 to 12 months, requiring the start tube of feeding. In the same period motor function scores significantly improved (median increase CHOP INTEND 16 points). Impaired feeding and swallowing remain important complications in infants with SMA type 1 after the start of nusinersen. Improvement of motor function does not imply similar gains in bulbar function.


Variation in paediatric hospital antibiotic guidelines in Europe.
To assess the availability and source of guidelines for common infections in European paediatric hospitals and determine their content and characteristics. Participating hospitals completed an online questionnaire on the availability and characteristics of antibiotic prescribing guidelines and on empirical antibiotic treatment including duration of therapy for 5 common infection syndromes: respiratory tract, urinary tract, skin and soft tissue, osteoarticular and sepsis in neonates and children. 84 hospitals from 19 European countries participated in the survey of which 74 confirmed the existence of guidelines. Complete guidelines (existing guidelines for all requested infection syndromes) were reported by 20% of hospitals and the majority (71%) used a range of different sources. Guidelines most commonly available were those for urinary tract infection (UTI) (74%), neonatal sepsis (71%) and sepsis in children (65%). Penicillin and amoxicillin were the antibiotics most commonly recommended for respiratory tract infections (RTIs) (up to 76%), cephalosporin for UTI (up to 50%) and for skin and soft tissue infection (SSTI) and bone infection (20% and 30%, respectively). Antistaphylococcal penicillins were recommended for SSTIs and bone infections in 43% and 36%, respectively. Recommendations for neonatal sepsis included 20 different antibiotic combinations. Duration of therapy guidelines was mostly available for RTI and UTI (82%). A third of hospitals with guidelines for sepsis provided recommendations for length of therapy. Comprehensive antibiotic guideline recommendations are generally lacking from European paediatric hospitals. We documented multiple antibiotics and combinations for most infections. Considerable improvement in the quality of guidelines and their evidence base is required, linking empirical therapy to resistance rates.


Does High Self-Esteem Cause Better Performance, Interpersonal Success, Happiness, or Healthier Lifestyles?
Self-esteem has become a household word. Teachers, parents, therapists, and others have focused efforts on boosting self-esteem, on the assumption that high self-esteem will cause many positive outcomes and benefits-an assumption that is critically evaluated in this review. Appraisal of the effects of self-esteem is complicated by several factors. Because many people with high self-esteem exaggerate their successes and good traits, we emphasize objective measures of outcomes. High self-esteem is also a heterogeneous category, encompassing people who frankly accept their good qualities along with narcissistic, defensive, and conceited individuals. The modest correlations between self-esteem and school performance do not indicate that high self-esteem leads to good performance. Instead, high self-esteem is partly the result of good school performance. Efforts to boost the self-esteem of pupils have not been shown to improve academic performance and may sometimes be counterproductive. Job performance in adults is sometimes related to self-esteem, although the correlations vary widely, and the direction of causality has not been established. Occupational success may boost self-esteem rather than the reverse. Alternatively, self-esteem may be helpful only in some job contexts. Laboratory studies have generally failed to find that self-esteem causes good task performance, with the important exception that high self-esteem facilitates persistence after failure. People high in self-esteem claim to be more likable and attractive, to have better relationships, and to make better impressions on others than people with low self-esteem, but objective measures disconfirm most of these beliefs. Narcissists are charming at first but tend to alienate others eventually. Self-esteem has not been shown to predict the quality or duration of relationships. High self-esteem makes people more willing to speak up in groups and to criticize the group's approach. Leadership does not stem directly from self-esteem, but self-esteem may have indirect effects. Relative to people with low self-esteem, those with high self-esteem show stronger in-group favoritism, which may increase prejudice and discrimination. Neither high nor low self-esteem is a direct cause of violence. Narcissism leads to increased aggression in retaliation for wounded pride. Low self-esteem may contribute to externalizing behavior and delinquency, although some studies have found that there are no effects or that the effect of self-esteem vanishes when other variables are controlled. The highest and lowest rates of cheating and bullying are found in different subcategories of high self-esteem. Self-esteem has a strong relation to happiness. Although the research has not clearly established causation, we are persuaded that high self-esteem does lead to greater happiness. Low self-esteem is more likely than high to lead to depression under some circumstances. Some studies support the buffer hypothesis, which is that high self-esteem mitigates the effects of stress, but other studies come to the opposite conclusion, indicating that the negative effects of low self-esteem are mainly felt in good times. Still others find that high self-esteem leads to happier outcomes regardless of stress or other circumstances. High self-esteem does not prevent children from smoking, drinking, taking drugs, or engaging in early sex. If anything, high self-esteem fosters experimentation, which may increase early sexual activity or drinking, but in general effects of self-esteem are negligible. One important exception is that high self-esteem reduces the chances of bulimia in females. Overall, the benefits of high self-esteem fall into two categories: enhanced initiative and pleasant feelings. We have not found evidence that boosting self-esteem (by therapeutic interventions or school programs) causes benefits. Our findings do not support continued widespread efforts to boost self-esteem in the hope that it will by itself foster improved outcomes. In view of the heterogeneity of high self-esteem, indiscriminate praise might just as easily promote narcissism, with its less desirable consequences. Instead, we recommend using praise to boost self-esteem as a reward for socially desirable behavior and self-improvement.


Characteristics of physical measurement consent in a population-based survey of older adults.
Collecting physical measurements in population-based health surveys has increased in recent years, yet little is known about the characteristics of those who consent to these measurements. To examine the characteristics of persons who consent to physical measurements across several domains, including one's demographic background, health status, resistance behavior toward the survey interview, and interviewer characteristics. We conducted a secondary data analysis of the 2006 Health and Retirement Study, a nationally-representative panel survey of older adults aged 51 and older. We performed multilevel logistic regressions on a sample of 7457 respondents who were eligible for physical measurements. The primary outcome measure was consent to all physical measurements. Seventy-nine percent (unweighted) of eligible respondents consented to all physical measurements. In weighted multilevel logistic regressions controlling for respondent demographics, current health status, survey resistance indicators, and interviewer characteristics, the propensity to consent was significantly greater among Hispanic respondents matched with bilingual Hispanic interviewers, patients with diabetes, and those who visited a doctor in the past 2 years. The propensity to consent was significantly lower among younger respondents, those who have several Nagi functional limitations and infrequently participate in "mildly vigorous" activities, and those interviewed by black interviewers. Survey resistance indicators, such as number of contact attempts and interviewer observations of resistant behavior in prior wave iterations of the Health and Retirement Study were also negatively associated with physical measurement consent. The propensity to consent was unrelated to prior medical diagnoses, including high blood pressure, cancer (excluding skin), lung disease, heart abnormalities, stroke, and arthritis, and matching of interviewer and respondent on race and gender. Physical measurement consent is not strongly associated with one's health status, though the findings are somewhat mixed. We recommend that physical measurement results be adjusted for characteristics associated with the likelihood of consent, particularly functional limitations, to reduce potential bias. Otherwise, health researchers should exercise caution when generalizing physical measurement results to the population at large, including persons with functional limitations that may affect their participation.


Secrets of the Hospital Underbelly: Patterns of Abundance of Antimicrobial Resistance Genes in Hospital Wastewater Vary by Specific Antimicrobial and Bacterial Family.
Background: Hospital wastewater is a major source of antimicrobial resistance (AMR) outflow into the environment. This study uses metagenomics to study how hospital clinical activity impacts antimicrobial resistance genes (ARGs) abundances in hospital wastewater. Methods: Sewage was collected over a 24-h period from multiple wastewater collection points (CPs) representing different specialties within a tertiary hospital site and simultaneously from community sewage works. High throughput shotgun sequencing was performed using Illumina HiSeq4000. ARG abundances were correlated to hospital antimicrobial usage (AMU), data on clinical activity and resistance prevalence in clinical isolates. Results: Microbiota and ARG composition varied between CPs and overall ARG abundance was higher in hospital wastewater than in community influent. ARG and microbiota compositions were correlated (Procrustes analysis, p=0.014). Total antimicrobial usage was not associated with higher ARG abundance in wastewater. However, there was a small positive association between resistance genes and antimicrobial usage matched to ARG phenotype (IRR 1.11, CI 1.06-1.16, p<0.001). Furthermore, analyzing carbapenem and vancomycin resistance separately indicated that counts of ARGs to these antimicrobials were positively associated with their increased usage [carbapenem rate ratio (RR) 1.91, 95% CI 1.01-3.72, p=0.07, and vancomycin RR 10.25, CI 2.32-49.10, p<0.01]. Overall, ARG abundance within hospital wastewater did not reflect resistance patterns in clinical isolates from concurrent hospital inpatients. However, for clinical isolates of the family Enterococcaceae and Staphylococcaceae, there was a positive relationship with wastewater ARG abundance [odds ratio (OR) 1.62, CI 1.33-2.00, p<0.001, and OR 1.65, CI 1.21-2.30, p=0.006 respectively]. Conclusion: We found that the relationship between hospital wastewater ARGs and antimicrobial usage or clinical isolate resistance varies by specific antimicrobial and bacterial family studied. One explanation, we consider is that relationships observed from multiple departments within a single hospital site will be detectable only for ARGs against parenteral antimicrobials uniquely used in the hospital setting. Our work highlights that using metagenomics to identify the full range of ARGs in hospital wastewater is a useful surveillance tool to monitor hospital ARG carriage and outflow and guide environmental policy on AMR.


Solution structure of the RNase H domain of the HIV-1 reverse transcriptase in the presence of magnesium.
This paper presents the first solution structure of the RNase H domain of HIV-1 reverse transcriptase (RT) determined by NMR methods. The solution conditions in this study were at physiological pH in the presence of Mg(2+). An investigation of the dependence of the (1)H-(15)N HSQC spectrum of the RNase H domain on [Mg(2+)] indicates that Mg(2+) produces significant, global effects on the amide chemical shifts, implying that divalent metal ion binding is important for stabilizing the structure of the isolated domain in solution. Analysis of amide shift data as a function of MgCl(2) concentration using either a single- or two-site binding model indicated that the latter provided a significantly improved fit, with the K(D) for site A = 2.7-3.2 mM and K(D) for site B approximately 35 mM, calculated on the assumption that site A is already occupied. Resonances of the [U-(13)C,(15)N]RNase H domain, measured at pH 6.8, in 80 mM MgCl(2), were assigned and NOESY data collected in order to determine the structure. Assignment of the NOESY spectra using the ARIA program resulted in a high-resolution structure for residues 6-114 which was similar to the crystal structure of the isolated domain,. The data were insufficient to define a compact structure for the C-terminal residues after 114. Residues I134-L138 located at the C-terminus are highly disordered and give rise to relatively sharp and intense amide resonances, while the amide resonances for the segment from E124 to A132 appear to be largely absent and are presumably subject to significant exchange broadening between different conformational states. Comparisons with crystal structure data for the full reverse transcriptase molecule indicate that the corresponding region is absent in nearly all of the crystal structures determined for the P2(1)2(1)2(1) space group, while these residues adopt an alpha-helix in structures determined for other symmetry groups. This structural heterogeneity indicates that significant conformational variability exists for this segment of the full reverse transcriptase enzyme as well, and the structure of the C-terminal peptide can be selected or deselected, depending on crystallization conditions. This analysis, along with the structural characterization contained herein, challenges the previous paradigm that the dynamic behavior of the isolated RNase H domain differs substantially from the behavior in the intact enzyme. The poor Mg(2+) binding and conformational flexibility of residues located near the active site indicate that substrate binding is a precondition for metal ion binding and for selecting the active site conformation of the RNase H domain.


A combined picture from theory and experiments on water oxidation, oxygen reduction and proton pumping.
In order to illustrate how theory and experiments can be combined, examples are taken from two projects that have been going on for a decade. The goal is to obtain the full mechanistic picture of water oxidation in photosystem II and proton pumping in cytochrome c oxidase. It is argued that for obtaining a complete description of these processes, both experiments and theoretical calculations are needed. It is obvious that there are aspects, which are out of reach for computations, but there are also key aspects that can not be obtained by experiments. This concerns very short-lived species but also, in the case of photosynthesis in particular, structural information that is presently out of reach. The main contributions from theory in the present cases, is for photosynthesis a mechanism for O-O bond formation including new and improved structures for all S-states, and for proton pumping a plausible and simple mechanism for proton gating. The examples also illustrate that sometimes rather qualitative experimental information can be of highest importance.


Absence of genome reduction in diverse, facultative endohyphal bacteria.
Fungi interact closely with bacteria, both on the surfaces of the hyphae and within their living tissues (i.e. endohyphal bacteria, EHB). These EHB can be obligate or facultative symbionts and can mediate diverse phenotypic traits in their hosts. Although EHB have been observed in many lineages of fungi, it remains unclear how widespread and general these associations are, and whether there are unifying ecological and genomic features can be found across EHB strains as a whole. We cultured 11 bacterial strains after they emerged from the hyphae of diverse Ascomycota that were isolated as foliar endophytes of cupressaceous trees, and generated nearly complete genome sequences for all. Unlike the genomes of largely obligate EHB, the genomes of these facultative EHB resembled those of closely related strains isolated from environmental sources. Although all analysed genomes encoded structures that could be used to interact with eukaryotic hosts, pathways previously implicated in maintenance and establishment of EHB symbiosis were not universally present across all strains. Independent isolation of two nearly identical pairs of strains from different classes of fungi, coupled with recent experimental evidence, suggests horizontal transfer of EHB across endophytic hosts. Given the potential for EHB to influence fungal phenotypes, these genomes could shed light on the mechanisms of plant growth promotion or stress mitigation by fungal endophytes during the symbiotic phase, as well as degradation of plant material during the saprotrophic phase. As such, these findings contribute to the illumination of a new dimension of functional biodiversity in fungi.


Evidence for an extrarenal source of inactive renin in rats.
We studied the source of inactive renin in plasma by investigating the changes of active and inactive renin after bilateral nephrectomy in the rat. Active renin rapidly decreased after bilateral nephrectomy, with a half-life of approximately 15 minutes. Inactive renin, on the other hand, was 20.96 +/- 1.63 ng/ml/hr before nephrectomy and gradually increased to reach a peak at 20 hours after nephrectomy (193 +/- 62 ng/ml/hr). The molecular weight of active renin was approximately 40,000 and that of inactive renin was approximately 60,000 on a Sephacryl S-200 column. Inactive renin was separated from active renin by a Cibacron blue column, and the 0 time inactive renin eluted in the same fractions as the inactive renin from 20 hours after nephrectomy. The pH optimum of inactive renin in rat renin substrate was between 5.5 and 7.5, which differs from the optimal value of pepsin or cathepsin D. The increase of inactive renin in nephrectomized rats was not prevented by removal of the salivary glands, uterus, spleen, pancreas, stomach, intestines, adrenal glands, or pituitary. In summary, inactive renin is present in the anephric rat and does not appear to be converted to active renin in the peripheral blood. The source and control of this extrarenal inactive renin are still unclear, but this renin is secreted in the rat within hours after nephrectomy.


The impact of fish and the commercial marine harvest on the ocean iron cycle.
Although iron is the fourth most abundant element in the Earth's crust, bioavailable iron limits marine primary production in about one third of the ocean. This lack of iron availability has implications in climate change because the removal of carbon dioxide from the atmosphere by phytoplankton requires iron. Using literature values for global fish biomass estimates, and elemental composition data we estimate that fish biota store between 0.7-7 × 10(11) g of iron. Additionally, the global fish population recycles through excretion between 0.4-1.5 × 10(12) g of iron per year, which is of a similar magnitude as major recognized sources of iron (e.g. dust, sediments, ice sheet melting). In terms of biological impact this iron could be superior to dust inputs due to the distributed deposition and to the greater solubility of fecal pellets compared to inorganic minerals. To estimate a loss term due to anthropogenic activity the total commercial catch for 1950 to 2010 was obtained from the Food and Agriculture Organization of the United Nations. Marine catch data were separated by taxa. High and low end values for elemental composition were obtained for each taxonomic category from the literature and used to calculate iron per mass of total harvest over time. The marine commercial catch is estimated to have removed 1-6 × 10(9) g of iron in 1950, the lowest values on record. There is an annual increase to 0.7-3 × 10(10) g in 1996, which declines to 0.6-2 × 10(10) g in 2010. While small compared to the total iron terms in the cycle, these could have compounding effects on distribution and concentration patterns globally over time. These storage, recycling, and export terms of biotic iron are not currently included in ocean iron mass balance calculations. These data suggest that fish and anthropogenic activity should be included in global oceanic iron cycles.


The identification of KRAS mutations at codon 12 in plasma DNA is not a prognostic factor in advanced non-small cell lung cancer patients.
Qualitative analysis of circulating DNA in the blood is a promising non-invasive diagnostic and prognostic tool. Our aim was to study the association between the presence of KRAS mutations at codon 12 and several clinical variables in advanced non-small cell lung cancer (NSCLC) patients. We examined 308 stage IIIB and IV NSCLC patients who were treated with cisplatin and docetaxel. Blood samples were collected before chemotherapy, and circulating DNA was extracted from the plasma using commercial adsorption columns. The KRAS mutational status was determined by an RT-PCR method that is based on allelic discrimination. The median age of the patients was 60 years [31-80], 84% were male, 98% had a performance status of 0-1 and 84% of the patients were in stage IV. The histological subtypes were as follows: 30% squamous cell carcinoma (SCC), 51% adenocarcinoma (ADC) and 19% others. Of the 277 response-evaluated patients, 1% achieved a complete response (CR), 26% achieved a partial response (PR), 34% had stable disease (SD) and 39% had progressive disease (PD). Additionally, 27 (8.8%) patients had KRAS mutations; 26 had a KRAS codon 12 TGT mutation, and 1 had a codon 12 GTT mutation. Plasmatic KRAS mutations were found in patients presenting SCC or ADC. Patients with KRAS mutations in plasma DNA had a median progression free survival (PFS) of 5.77 months [3.39-8.14], whereas for patients with wild-type (wt) KRAS, the PFS was 5.43 months [4.65-6.22] (p=0.277). The median overall survival (OS) in KRAS-mutated patients was 9.07 months [4.43-13.70] vs 10.03 months [8.80-11.26] in wt patients (p=0.514). In advanced NSCLC patients, there were no significant differences between patients with or without KRAS mutations in plasma-free DNA with respect to the baseline characteristics, response rates, PFS or OS.


Mean-field models for non-Markovian epidemics on networks.
This paper introduces a novel extension of the edge-based compartmental model to epidemics where the transmission and recovery processes are driven by general independent probability distributions. Edge-based compartmental modelling is just one of many different approaches used to model the spread of an infectious disease on a network; the major result of this paper is the rigorous proof that the edge-based compartmental model and the message passing models are equivalent for general independent transmission and recovery processes. This implies that the new model is exact on the ensemble of configuration model networks of infinite size. For the case of Markovian transmission the message passing model is re-parametrised into a pairwise-like model which is then used to derive many well-known pairwise models for regular networks, or when the infectious period is exponentially distributed or is of a fixed length.


Mapping the environmental coverage of the INDEPTH demographic surveillance system network in rural Africa.
The INDEPTH DSS network was founded in 1998 to provide an international network of field sites for continuous demographic evaluation of populations and their health. Results from the network have been used to derive estimates of mortality, morbidity and health equity. Spatial extrapolation and logical summaries of these findings are dependent on the network covering a representative sample of the environments in a region and their interrelationships being known. Here, we investigate how comprehensive is the coverage of the network of rural DSS sites in Africa in terms of the range of ecological zones found across the continent. We used satellite imagery to define an environmental signature for each INDEPTH DSS site, and then calculate Euclidean distances from these signatures to the environmental signatures of every image pixel across Africa. These distances were then mapped and a gridded population surface used to mask uninhabited areas to illustrate the extent of the environmental coverage of the INDEPTH network. Environmental similarities between DSS sites were also calculated, hierarchically clustered and visualized as a dendrogram to examine between site relationships. Finally, an ecozonation of Africa was used to analyse the per-ecozone environmental similarity of the INDEPTH DSS network. The current INDEPTH DSS network in Africa spans all the major environmental zones, but within these zones the environmental coverage of the network varies. These variations were mapped by ecozone. These maps provide valuable information in determining the confidence with which relationships derived from rural INDEPTH DSS sites can be extended to other areas. The results also indicate suites of sites that form environmentally cohesive groups and from which data can be logically summarized. Finally, the results highlight areas where the location of new INDEPTH DSS sites would increase significantly the environmental coverage of the network.


ModelOMatic: fast and automated model selection between RY, nucleotide, amino acid, and codon substitution models.
Molecular phylogenetics is a powerful tool for inferring both the process and pattern of evolution from genomic sequence data. Statistical approaches, such as maximum likelihood and Bayesian inference, are now established as the preferred methods of inference. The choice of models that a researcher uses for inference is of critical importance, and there are established methods for model selection conditioned on a particular type of data, such as nucleotides, amino acids, or codons. A major limitation of existing model selection approaches is that they can only compare models acting upon a single type of data. Here, we extend model selection to allow comparisons between models describing different types of data by introducing the idea of adapter functions, which project aggregated models onto the originally observed sequence data. These projections are implemented in the program ModelOMatic and used to perform model selection on 3722 families from the PANDIT database, 68 genes from an arthropod phylogenomic data set, and 248 genes from a vertebrate phylogenomic data set. For the PANDIT and arthropod data, we find that amino acid models are selected for the overwhelming majority of alignments; with progressively smaller numbers of alignments selecting codon and nucleotide models, and no families selecting RY-based models. In contrast, nearly all alignments from the vertebrate data set select codon-based models. The sequence divergence, the number of sequences, and the degree of selection acting upon the protein sequences may contribute to explaining this variation in model selection. Our ModelOMatic program is fast, with most families from PANDIT taking fewer than 150 s to complete, and should therefore be easily incorporated into existing phylogenetic pipelines. ModelOMatic is available at https://code.google.com/p/modelomatic/.


Aromatic anchor at an invariant hormone-receptor interface: function of insulin residue B24 with application to protein design.
Crystallographic studies of insulin bound to fragments of the insulin receptor have recently defined the topography of the primary hormone-receptor interface. Here, we have investigated the role of Phe(B24), an invariant aromatic anchor at this interface and site of a human mutation causing diabetes mellitus. An extensive set of B24 substitutions has been constructed and tested for effects on receptor binding. Although aromaticity has long been considered a key requirement at this position, Met(B24) was found to confer essentially native affinity and bioactivity. Molecular modeling suggests that this linear side chain can serve as an alternative hydrophobic anchor at the hormone-receptor interface. These findings motivated further substitution of Phe(B24) by cyclohexanylalanine (Cha), which contains a nonplanar aliphatic ring. Contrary to expectations, [Cha(B24)]insulin likewise exhibited high activity. Furthermore, its resistance to fibrillation and the rapid rate of hexamer disassembly, properties of potential therapeutic advantage, were enhanced. The crystal structure of the Cha(B24) analog, determined as an R6 zinc-stabilized hexamer at a resolution of 1.5 Å, closely resembles that of wild-type insulin. The nonplanar aliphatic ring exhibits two chair conformations with partial occupancies, each recapitulating the role of Phe(B24) at the dimer interface. Together, these studies have defined structural requirements of an anchor residue within the B24-binding pocket of the insulin receptor; similar molecular principles are likely to pertain to insulin-related growth factors. Our results highlight in particular the utility of nonaromatic side chains as probes of the B24 pocket and suggest that the nonstandard Cha side chain may have therapeutic utility.


Cross-strand binding of TFAM to a single mtDNA molecule forms the mitochondrial nucleoid.
Mammalian mitochondrial DNA (mtDNA) is packaged by mitochondrial transcription factor A (TFAM) into mitochondrial nucleoids that are of key importance in controlling the transmission and expression of mtDNA. Nucleoid ultrastructure is poorly defined, and therefore we used a combination of biochemistry, superresolution microscopy, and electron microscopy to show that mitochondrial nucleoids have an irregular ellipsoidal shape and typically contain a single copy of mtDNA. Rotary shadowing electron microscopy revealed that nucleoid formation in vitro is a multistep process initiated by TFAM aggregation and cross-strand binding. Superresolution microscopy of cultivated cells showed that increased mtDNA copy number increases nucleoid numbers without altering their sizes. Electron cryo-tomography visualized nucleoids at high resolution in isolated mammalian mitochondria and confirmed the sizes observed by superresolution microscopy of cell lines. We conclude that the fundamental organizational unit of the mitochondrial nucleoid is a single copy of mtDNA compacted by TFAM, and we suggest a packaging mechanism.


Acute Intake of a Grape and Blueberry Polyphenol-Rich Extract Ameliorates Cognitive Performance in Healthy Young Adults During a Sustained Cognitive Effort.
Despite an increasing level of evidence supporting the individual beneficial effect of polyphenols on cognitive performance, information related to the potential synergistic action of these phytonutrients on cognitive performance during a prolonged cognitive effort is currently lacking. This study investigated the acute and sustained action of a polyphenols-rich extract from grape and blueberry (PEGB), on working memory and attention in healthy students during a prolonged and intensive cognitive effort. In this randomised, cross-over, double blind study, 30 healthy students consumed 600 mg of PEGB or a placebo. Ninety minutes after product intake, cognitive functions were assessed for one hour using a cognitive demand battery including serial subtraction tasks, a rapid visual information processing (RVIP) task and a visual analogical scale. Flow-mediated dilation (FMD) and plasma flavan-3-ols metabolites quantification were also performed. A 2.5-fold increase in serial three subtraction variation net scores was observed following PEGB consumption versus placebo (p < 0.001). A trend towards significance was also observed with RVIP percentage of correct answers (p = 0.058). No treatment effect was observed on FMD. Our findings suggest that consumption of PEGB coupled with a healthy lifestyle may be a safe alternative to acutely improve working memory and attention during a sustained cognitive effort.


Human Salmonella infections linked to contaminated dry dog and cat food, 2006-2008.
Human Salmonella infections associated with dry pet food have not been previously reported. We investigated such an outbreak of Salmonella Schwarzengrund and primarily affecting young children. Two multistate case-control studies were conducted to determine the source and mode of infections among case-patients with the outbreak strain. Study 1 evaluated household exposures to animals and pet foods, and study 2 examined risk factors for transmission among infant case-patients. Environmental investigations were conducted. Seventy-nine case-patients in 21 states were identified; 48% were children aged 2 years or younger. Case-households were significantly more likely than control households to report dog contact (matched odds ratio [mOR]: 3.6) and to have recently purchased manufacturer X brands of dry pet food (mOR: 6.9). Illness among infant case-patients was significantly associated with feeding pets in the kitchen (OR: 4.4). The outbreak strain was isolated from opened bags of dry dog food produced at plant X, fecal specimens from dogs that ate manufacturer X dry dog food, and an environmental sample and unopened bags of dog and cat foods from plant X. More than 23 000 tons of pet foods were recalled. After additional outbreak-linked illnesses were identified during 2008, the company recalled 105 brands of dry pet food and permanently closed plant X. Dry dog and cat foods manufactured at plant X were linked to human illness for a 3-year period. This outbreak highlights the importance of proper handling and storage of pet foods in the home to prevent human illness, especially among young children.


Estimating the cost of new public health legislation.
To develop a new method for estimating the cost to governments of enacting public health legislation. We adopted a central government perspective in estimating costs. The parliamentary cost of legislative acts and regulations in New Zealand was calculated from the proportion of parliamentary time devoted to law-making (i.e. sitting days in the debating chamber), and the cost of associated policy advice from government agencies was calculated from the proportion of documented policy issues related to law-making. The relative costs of acts and regulations were estimated from the number of pages in the legislation. We estimated that, between 1999 and 2010, 26.7% of parliamentary resources and 16.7% of policy advice from government agencies were devoted to generating new laws in New Zealand. The mean cost of an act was 2.6 million United States dollars (US$; 95% uncertainty interval, UI: 1.5 to 4.4 million) and the mean cost of a regulation was US$ 382 000 (95% UI: 22 000 to 665 000). For comparison, the average cost of a bill enacted by the 50 state governments in the United States of America between 2008 and 2009 was US$ 980 000. We were able to estimate the cost of new legislation in New Zealand. Our method for estimating this cost seemed to capture the main government costs involved and appears to be generally applicable to other developed countries. Ideally such costs should be included in economic evaluations of public health interventions that involve new legislation.


Crack front dynamics across a single heterogeneity.
We study the spatiotemporal dynamics of a crack front propagating at the interface between a rigid substrate and an elastomer. We first characterize the kinematics of the front when the substrate is homogeneous and find that the equation of motion is intrinsically nonlinear. We then pattern the substrate with a single defect. Steady profiles of the front are well described by a standard linear theory with nonlocal elasticity, except for large slopes of the front. In contrast, this theory seems to fail in dynamical situations, i.e., when the front relaxes to its steady shape, or when the front pinches off after detachment from a defect. More generally, these results may impact the current understanding of crack fronts in heterogeneous media.


Increased expression of cellular retinol-binding protein 1 in laryngeal squamous cell carcinoma.
To investigate the genomic alterations in larynx carcinomas (LaCa) tissues and its prognostics values in predicting survival. To analyse the aberrations in the genome of LaCa patients, we used array comparative genomic hybridization in 19 human laryngeal tumour samples. DNA samples were also subjected to detect human papillomavirus (HPV) sequences by polymerase chain reaction (PCR). Copy number gain was confirmed by real-time PCR. The cellular retinol-binding protein 1 (CRBP-1) gene expression was also confirmed by immunohistochemistry assay on LaCa tissues. To identify prognostic feature, CRBP-1 gene gain was correlated to patient survival. The most common gains were detected for CRBP-1 and EGFR genes, while DNA lost in RAF-1 gene. Immunohistochemistry assay was revealed strong expression of CRBP1 protein in those cases with CRBP-1 gene gain. The CRBP-1 gene gain and its expression correlated significantly with survival (P = 0.003). Cox regression analysis indicated that CRBP-1 expression level was a factor of survival (P = 0.008). HPV sequences were detected in 42% of the samples, and did not show any relationship with specific gene alterations. Our data shows that CRBP-1 gene gain can be determined by immunohistochemistry on routinely processed tissue specimens, and could support as a potential novel marker for long-term survival in laryngeal squamous cell carcinoma.


Turbulent Micropolar SPH Fluids with Foam.
In this paper we introduce a novel micropolar material model for the simulation of turbulent inviscid fluids. The governing equations are solved by using the concept of Smoothed Particle Hydrodynamics (SPH). As already investigated in previous works, SPH fluid simulations suffer from numerical diffusion which leads to a lower vorticity, a loss in turbulent details and finally in less realistic results. To solve this problem we propose a micropolar fluid model. The micropolar fluid model is a generalization of the classical Navier-Stokes equations, which are typically used in computer graphics to simulate fluids. In contrast to the classical Navier-Stokes model, micropolar fluids have a microstructure and therefore consider the rotational motion of fluid particles. In addition to the linear velocity field these fluids also have a field of microrotation which represents existing vortices and provides a source for new ones. However, classical micropolar materials are viscous and the translational and the rotational motion are coupled in a dissipative way. Since our goal is to simulate turbulent fluids, we introduce a novel modified micropolar material for inviscid fluids with a non-dissipative coupling. Our model can generate realistic turbulences, is linear and angular momentum conserving, can be easily integrated in existing SPH simulation methods and its computational overhead is negligible. Another important visual feature of turbulent liquids is foam. Therefore, we present a post-processing method which considers microrotation in the foam particle generation. It works completely automatic and requires only one user-defined parameter to control the amount of foam.


Incidence and mechanisms of infiltration of sarcomas in the shoulder.
The intraarticular infiltration of sarcomas around the shoulder was analyzed. Of 58 sarcomas located around the shoulder, which were treated between 1993 and 1998, 15 osteosarcomas, 12 chondrosarcomas, and one Ewing's sarcoma that abutted the shoulder were selected. Radiologic images of 28 tumors were analyzed and compared with pathologic examinations. In 17 of 28 sarcomas (15 in the proximal humerus and two in the scapula), joint infiltration was suspected radiologically because of the existence of a tumor mass probably inside the joint or disruption of the joint surface and protrusion of the tumor. Seven of 17 tumors with radiologically positive and zero of 11 tumors with radiologically negative findings showed histologically positive findings for tumor inside the joint. Four of 11 osteosarcomas and three of four chondrosarcomas of the proximal humerus showed histologic findings of joint infiltration. Pericapsular extension was seen in two patients, direct articular spread with a pathologic fracture was seen in two patients, direct articular spread was seen in one patient, direct articular spread with pericapsular extension was seen in one patient, and pericapsular extension with a pathologic fracture was seen in one patient. The current study showed that pericapsular or direct articular infiltration into the glenohumeral joint is a phenomenon in sarcoma around the shoulder. Exact assessment of tumor existence inside the joint can be difficult in osteosarcoma and chondrosarcoma, so abnormal radiologic findings should be regarded as proof of existence of tumor, and extraarticular wide resection should be planned.


The effect of male circumcision on sexuality.
To prospectively study, using a questionnaire, the sexuality of men circumcised as adults compared to uncircumcised men, and to compare their sex lives before and after circumcision. The study included 373 sexually active men, of whom 255 were circumcised and 118 were not. Of the 255 circumcised men, 138 had been sexually active before circumcision, and all were circumcised at >20 years of age. As the Brief Male Sexual Function Inventory does not specifically address the quality of sex life, questions were added to compare sexual and masturbatory pleasure before and after circumcision. There were no significant differences in sexual drive, erection, ejaculation, and ejaculation latency time between circumcised and uncircumcised men. Masturbatory pleasure decreased after circumcision in 48% of the respondents, while 8% reported increased pleasure. Masturbatory difficulty increased after circumcision in 63% of the respondents but was easier in 37%. About 6% answered that their sex lives improved, while 20% reported a worse sex life after circumcision. There was a decrease in masturbatory pleasure and sexual enjoyment after circumcision, indicating that adult circumcision adversely affects sexual function in many men, possibly because of complications of the surgery and a loss of nerve endings.


Keratin promoter based gene manipulation in the murine conducting airway.
Systems capable of targeting genetic manipulations to keratin-positive airway basal cells are more poorly developed than systems targeting other airway epithelial cell populations and this has likely hindered development of animal models of diseases such as lung squamous cell carcinoma. Although keratin promoter driven-Cre recombinase constructs are potentially useful for targeting these cells, these constructs have substantially higher activity in the skin and oral epithelium than in the airways. We developed a method for delivering RU486, the conditional activator of Cre recombinase progesterone receptor (CrePR) fusion proteins to the lung and then examined the activity of three keratin-driven CrePR constructs in the conducting airways. We also developed a technique for survival bronchioalveolar lavage on non-ventilated animals to examine the effects of the acetone/oil vehicle required to deliver RU486 to the lung. K5CrePR1 and K14CrePR1 constructs differ only in the keratin promoter used to target CrePR1 expression while K5Cre*PR contains a truncated progesterone receptor designed to reduce RU486-independent Cre activity. While all three constructs demonstrate RU486-inducible Cre activity in the conducting airways, both construct activity and tightness of regulation vary considerably. K5Cre*PR is the most tightly regulated Cre driver making it ideal for targeting somatic mutations to the airway epithelia while K5CrePR1 and K14CrePR1 may be better suited to studying diseases of the conducting airways where gene targeting of keratin expressing cells and their derivatives is desired.


A Double-Blind, Randomized Controlled 12-Week Follow-Up Trial to Evaluate the Efficacy and Safety of Polycan in Combination with Glucosamine for the Treatment of Knee Osteoarthritis.
The aim of the present study was to examine the efficacy and safety of Polycan, a β-glucan produced from the black yeast Aureobasidium pullulans SM-2001, in combination with glucosamine in reducing knee osteoarthritis-associated symptoms. This was a double-blind, randomized controlled trial of a formulated product composed of 16.7 mg of Polycan and 250 mg of glucosamine (Group A), 16.7 mg of Polycan and 500 mg of glucosamine (Group B), or 500 mg of glucosamine (control group) per capsule, administered as three capsules once per day over a period of 12 weeks, conducted with 100 osteoarthritis patients, aged 35-80 years. The primary outcome measure was osteoarthritis symptoms assessed by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire. The secondary outcome measures included rescue medication use (according to data from a patient-reported diary) and other safety indices (body weight, blood pressure, hematological, and biochemistry markers). Compared with the control group, Group B demonstrated a statistically significant reduction in the total WOMAC score after 12 weeks of treatment (p < 0.05). There was a significant reduction in the frequency of rescue medication used in Groups A and B compared with the control group (p < 0.05). There were no significant changes in hematology and biochemistry parameters or health indices between the active and the control group. Among patients with mild or moderate osteoarthritis, a daily oral dose of Polycan (50 mg) in combination with glucosamine (750 mg or 1500 mg; Group A or B, respectively) resulted in a better treatment outcome than treatment with glucosamine (1500 mg) alone.


Ultrasound-Guided Miniscalpel-Needle Release versus Dry Needling for Chronic Neck Pain: A Randomized Controlled Trial.
Objective. To compare ultrasound-guided miniscalpel-needle (UG-MSN) release versus ultrasound-guided dry needling (UG-DN) for chronic neck pain. Methods. A total of 169 patients with chronic neck pain were randomized to receive either UG-MSN release or UG-DN. Before treatment and at 3 and 6 months posttreatment, pain was measured using a 10-point visual analogue scale (VAS). Neck function was examined using the neck disability index. Health-related quality of life was examined using the physical component score (PCS) and mental component score (MCS) of the SF-36 health status scale. Results. Patients in the UG-MSN release had greater improvement on the VAS (by 2 points at 3 months and 0.9 points at 6 months) versus in the UG-DN arm; (both P < 0.0001). Patients receiving UG-MSN release also showed significantly lower scores on the adjusted neck disability index, as well as significantly lower PCS. No severe complications were observed. Conclusion. UG-MSN release was superior to UG-DN in reducing pain intensity and neck disability in patients with chronic neck pain and was not associated with severe complications. The procedural aspects in the two arms were identical; however, we did not verify the blinding success. As such, the results need to be interpreted with caution.


Axitinib effectively inhibits BCR-ABL1(T315I) with a distinct binding conformation.
The BCR-ABL1 fusion gene is a driver oncogene in chronic myeloid leukaemia and 30-50% of cases of adult acute lymphoblastic leukaemia. Introduction of ABL1 kinase inhibitors (for example, imatinib) has markedly improved patient survival, but acquired drug resistance remains a challenge. Point mutations in the ABL1 kinase domain weaken inhibitor binding and represent the most common clinical resistance mechanism. The BCR-ABL1 kinase domain gatekeeper mutation Thr315Ile (T315I) confers resistance to all approved ABL1 inhibitors except ponatinib, which has toxicity limitations. Here we combine comprehensive drug sensitivity and resistance profiling of patient cells ex vivo with structural analysis to establish the VEGFR tyrosine kinase inhibitor axitinib as a selective and effective inhibitor for T315I-mutant BCR-ABL1-driven leukaemia. Axitinib potently inhibited BCR-ABL1(T315I), at both biochemical and cellular levels, by binding to the active form of ABL1(T315I) in a mutation-selective binding mode. These findings suggest that the T315I mutation shifts the conformational equilibrium of the kinase in favour of an active (DFG-in) A-loop conformation, which has more optimal binding interactions with axitinib. Treatment of a T315I chronic myeloid leukaemia patient with axitinib resulted in a rapid reduction of T315I-positive cells from bone marrow. Taken together, our findings demonstrate an unexpected opportunity to repurpose axitinib, an anti-angiogenic drug approved for renal cancer, as an inhibitor for ABL1 gatekeeper mutant drug-resistant leukaemia patients. This study shows that wild-type proteins do not always sample the conformations available to disease-relevant mutant proteins and that comprehensive drug testing of patient-derived cells can identify unpredictable, clinically significant drug-repositioning opportunities.


Physician supply, treatment, and amputation rates for peripheral arterial disease.
To test whether the availability of vascular surgeons and interventional radiologists in a region affects revascularization and amputation rates for patients with peripheral arterial disease (PAD). We identified all patients with PAD in the Medicare claims database in 1994 and tracked their claims through 1999. We aggregated risk-adjusted data on the 143,202 patients who survived through 1999 by Hospital Referral Region and merged this data with information on local physician supply and other regional characteristics. Instrumental variables analysis was used to account for unobserved illness severity. Main outcome measures were risk-adjusted rates of lower extremity bypass surgery, angioplasty, and amputation by region. Increasing vascular surgeon supply in a region by approximately one standard deviation (.30/10,000 Medicare beneficiaries) is associated with a 0.9 percentage point increase in bypass surgery rates and a 1.6 percentage point reduction in amputation rates. We find weaker evidence that greater availability of interventional radiologists increases angioplasty rates and reduces amputation rates. Factors reflecting regional attractiveness, such as the rating of a region based on climate, recreation, crime, and other attributes, were strong independent predictors of the number of vascular surgeons and interventional radiologists in an area. Availability of specialists affects outcomes for PAD patients. Regional variability in specialists who treat PAD is influenced by factors other than regional medical needs. Policies aimed at increasing the supply of vascular surgeons and interventional radiologists and their provision of bypass surgery in underserved areas may help to reduce regional disparities in amputation.


Informing about mammographic screening: Ethical challenges and suggested solutions.
Providing high quality and user oriented information about mammographic screening is no easy task, as screening has been subject to heated professional and public debates. Although the information has to be developed and provided in context for each screening program, the basic challenges are very much the same for all programs. Accordingly, the objective of this article is to analyze key ethical challenges in informing about mammographic screening, and based on these, to suggest some guiding principles for practical solutions. A literature review identifies five crucial issues with respect to informing women about mammographic screening. By analyzing and addressing these issues, five guiding principles are suggested: the content and the form of information should be developed through open and transparent processes with strong stakeholder involvement. Facts should be presented in a balanced way and uncertainties should be acknowledged, e.g., by presenting outcomes in ranges. Information should be layered without attempts to frame information. Attending mammographic screening should be as easy as not attending. Although apparently trivial, the suggested principles can be useful for elaborating specific information material about mammographic screening in a field of great ethical controversy.


Identification of target genes of the homeotic gene Antennapedia by enhancer detection.
Localized expression of the homeotic gene Antennapedia (Antp) in Drosophila melanogaster is required for normal development of the thoracic segments. When the Antp gene is expressed ectopically in the larval primordium of the antenna, the antennal imaginal disc, the developmental fate of the disc is switched and the adult antenna is transformed to a mesothoracic leg. We screened approximately 550 different fly strains carrying single copies of an enhancer-detector transposon to identify regulatory elements and corresponding genes that are either activated or repressed in antennal discs in response to this transformation. Several regulatory elements that are either direct or indirect targets of Antp were found. One transposant that expresses the reporter gene (lacZ) in the antennal disc, but not in the leg disc, was studied in more detail. The enhancer detector in this strain is located near a similarly regulated gene at the spalt (sal) locus, which encodes a homeotic function involved in embryonic head and tail development. The expression of this newly discovered gene, spalt major (salm) is strongly repressed in gain-of-function mutants that express Antp in the antennal disc. Recessive loss-of-function mutations (Antp-) have the opposite developmental effect; they cause the differentiation of antennal structures in the second leg disc. Accordingly, salm is derepressed in clones of homozygous Antp- cells. Therefore, we conclude that Antp negatively regulates salm. The time course of the interaction and reporter gene fusion experiments suggests (but does not prove) a direct interaction between Antp and cis-regulatory elements of salm. Our analysis of several enhancer-detector strains suggests that the basic patterning information in the antennal and leg imaginal discs is very similar.


Intestinal water absorption through aquaporin 1 expressed in the apical membrane of mucosal epithelial cells in seawater-adapted Japanese eel.
To elucidate the mechanisms associated with water absorption in the intestine, we compared drinking and intestinal water absorption in freshwater- and seawater-adapted Japanese eels, and investigated a possible involvement of aquaporin (AQP) in the absorption of water in the intestine. Seawater eels ingested more water than freshwater eels, the drinking rate being 0.02 ml kg(-1) h(-1) in fresh water and 0.82 ml kg(-1) h(-1) in sea water. In intestinal sacs prepared from freshwater and seawater eels, water absorption increased in time- and hydrostatic pressure-dependent manners. The water absorption rates were greater in seawater sacs than in freshwater sacs, and also greater in the posterior intestine than in the anterior. In view of the enhanced water permeability in the intestine of seawater eel, we cloned two cDNAs encoding AQP from the seawater eel intestine, and identified two eel homologues (S-AQP and L-AQP) of mammalian AQP1. S-AQP and L-AQP possessed the same amino acid sequence, except that one amino acid was lacking in S-AQP and two amino acids were substituted. Eel AQP1 was expressed predominantly in the intestine, and the expression levels were higher in seawater eel than in freshwater eel. Immunocytochemical studies revealed intense AQP1 immunoreaction in the apical surface of columnar epithelial cells in seawater eel, in which the immunoreaction was stronger in the posterior intestine than in the anterior. In contrast, the immunoreaction was faint in the freshwater eel intestine. Preferential localization of AQP1 in the apical membrane of epithelial cells in the posterior intestine of seawater eel indicates that this region of the intestine is responsible for water absorption, and that AQP1 may act as a water entry site in the epithelial cells.


Machine learning predicts mortality based on analysis of ventilation parameters of critically ill patients: multi-centre validation.
Mechanical Ventilation (MV) is a complex and central treatment process in the care of critically ill patients. It influences acid-base balance and can also cause prognostically relevant biotrauma by generating forces and liberating reactive oxygen species, negatively affecting outcomes. In this work we evaluate the use of a Recurrent Neural Network (RNN) modelling to predict outcomes of mechanically ventilated patients, using standard mechanical ventilation parameters. We performed our analysis on VENTILA dataset, an observational, prospective, international, multi-centre study, performed to investigate the effect of baseline characteristics and management changes over time on the all-cause mortality rate in mechanically ventilated patients in ICU. Our cohort includes 12,596 adult patients older than 18, associated with 12,755 distinct admissions in ICUs across 37 countries and receiving invasive and non-invasive mechanical ventilation. We carry out four different analysis. Initially we select typical mechanical ventilation parameters and evaluate the machine learning model on both, the overall cohort and a subgroup of patients admitted with respiratory disorders. Furthermore, we carry out sensitivity analysis to evaluate whether inclusion of variables related to the function of other organs, improve the predictive performance of the model for both the overall cohort as well as the subgroup of patients with respiratory disorders. Predictive performance of RNN-based model was higher with Area Under the Receiver Operating Characteristic (ROC) Curve (AUC) of 0.72 (± 0.01) and Average Precision (AP) of 0.57 (± 0.01) in comparison to RF and LR for the overall patient dataset. Higher predictive performance was recorded in the subgroup of patients admitted with respiratory disorders with AUC of 0.75 (± 0.02) and AP of 0.65 (± 0.03). Inclusion of function of other organs further improved the performance to AUC of 0.79 (± 0.01) and AP 0.68 (± 0.02) for the overall patient dataset and AUC of 0.79 (± 0.01) and AP 0.72 (± 0.02) for the subgroup with respiratory disorders. The RNN-based model demonstrated better performance than RF and LR in patients in mechanical ventilation and its subgroup admitted with respiratory disorders. Clinical studies are needed to evaluate whether it impacts decision-making and patient outcomes. NCT02731898 ( https://clinicaltrials.gov/ct2/show/NCT02731898 ), prospectively registered on April 8, 2016.


Comamonas denitrificans sp. nov., an efficient denitrifying bacterium isolated from activated sludge.
To find a biomarker for denitrification in activated sludge, five denitrifying strains isolated from three wastewater treatment plants were studied. These strains were selected from among 1,500 isolates for their excellent denitrifying properties. They denitrify quickly and have no lag phase when switching from aerobic to anoxic conditions. All strains have the cd1-type of nitrite reductase. The strains are Gram-negative rods and they all grow as filamentous chains when cultivated in liquid solution. The strains differ in colony morphology when grown on nutrient agar. Almost full-length 16S rDNA sequences were determined and phylogenetic analysis revealed that these strains are positioned among members of the genus Comamonas in the beta-subclass of the Proteobacteria. Signature nucleotides and bootstrap percentages were also analysed to verify this position. Strains 110, 123T, 2.99g, 5.38g and P17 were < or = 96.7% similar to known strains, but > or = 99.7% similar to each other, as judged from their 16S rDNA sequences, and grouped tightly together in the phylogenetic tree. Sequence motifs in the 16S rRNA gene were also found, suggesting the monophyletic origin of these strains. Nevertheless, some strains differed from the others, for example strain 110 branches early from the other strains and 5.38g is phenotypically more inert. Therefore, it is proposed that strains 110, 123T, 2.99g and P17 are classified into a new species, Comamonas denitrificans sp. nov., while the taxonomic status of strain 5.38g will have to await the outcome of further studies. The type strain of Comamonas denitrificans is 123T (ATCC 700936T).


Lactate and amino acid catabolism in the cheese-ripening yeast Yarrowia lipolytica.
The consumption of lactate and amino acids is very important for microbial development and/or aroma production during cheese ripening. A strain of Yarrowia lipolytica isolated from cheese was grown in a liquid medium containing lactate in the presence of a low (0.1x) or high (2x) concentration of amino acids. Our results show that there was a dramatic increase in the growth of Y. lipolytica in the medium containing a high amino acid concentration, but there was limited lactate consumption. Conversely, lactate was efficiently consumed in the medium containing a low concentration of amino acids after amino acid depletion was complete. These data suggest that the amino acids are used by Y. lipolytica as a main energy source, whereas lactate is consumed following amino acid depletion. Amino acid degradation was accompanied by ammonia production corresponding to a dramatic increase in the pH. The effect of adding amino acids to a Y. lipolytica culture grown on lactate was also investigated. Real-time quantitative PCR analyses were performed with specific primers for five genes involved in amino acid transport and catabolism, including an amino acid transporter gene (GAP1) and four aminotransferase genes (ARO8, ARO9, BAT1, and BAT2). The expression of three genes involved in lactate transport and catabolism was also studied. These genes included a lactate transporter gene (JEN1) and two lactate dehydrogenase genes (CYB2-1 and CYB2-2). Our data showed that GAP1, BAT2, BAT1, and ARO8 were maximally expressed after 15 to 30 min following addition of amino acids (BAT2 was the most highly expressed gene), while the maximum expression of JEN1, CYB2-1, and CYB2-2 was delayed (>or=60 min).


A comparison of educational interventions. Multimedia textbook, standard lecture, and printed textbook.
To compare the instructional effectiveness and efficiency of a pediatric multimedia textbook (MMTB) with that of a standard lecture and of a printed textbook in a prospective, interinstitutional study. Randomized, prospective cohort. An urban and a rural medical school affiliated with tertiary care hospitals. Third- and fourth-year medical students from June 1992 to June 1993. INTERVENTIONS/OUTCOME MEASURES: Students were randomized to one of four treatment groups: (1) computer-aided instruction with MMTBs (n = 39), (2) traditional lecture (n = 39), (3) printed textbook (n = 39), or (4) a control group (n = 62). Only the control group was pretested. Following their randomized instruction, all groups were tested via a 26-question multiple-choice test. Statistical analysis was accomplished by analysis of variance of mean post-test scores. The amount of time that students spent with each educational intervention was recorded. Three hundred two students were eligible for the study, 267 entered the study, and 179 completed the study. The instructional effectiveness of the MMTB was greater than that of the lecture (P < .05), and it was the same as that of the printed textbook. All instructional methods were more effective than the control group (P < .05). The instructional efficiency of the MMTB was equal to that of the lecture and of the printed textbook. The subjective response to the MMTB instruction was positive. The MMTBs constitute an educationally sound alternative instructional method and have a promising future in medical education.


Dengue infections in the Philippines: clinical and virological findings in 517 hospitalized patients.
From May 1983 to January 1984, 517 patients with laboratory confirmed dengue were studied at a hospital in Manila. Secondary dengue infections were diagnosed in 78% of these cases. Peak admission (28%) occurred towards the end of the rainy season in November. Most patients (78%) were less than 15 years old but only 3 were infants. Although some type of hemorrhagic finding occurred in 460 cases (89%), only 110 were classified as dengue hemorrhagic fever and the remainder as dengue fever with hemorrhagic manifestations. The clinical course was usually mild. Gastrointestinal bleeding was present in 65 cases, but only 2 patients developed shock. No fatalities occurred. Dengue 2 was the predominant serotype with 53 isolates, followed by dengue 1 with 48 isolates, dengue 3 with 39 isolates, and dengue 4 with only 8 isolates. Dengue 2 was the only serotype with more isolates from sera with a homologous HI antibody titer greater than 1:20 (57%) than from sera with a homologous HI titer less than or equal to 1:20 (43%). In contrast, most of the dengue 1 isolates (63%) were from sera with a homologous HI antibody titer less than 1:10, and this serotype was strongly associated with primary infections. This study shows that dengue infections remain an important cause of pediatric hospitalization in the Philippines; however, the occurrence of life-threatening dengue hemorrhagic fever as has been described in several other large urban areas of Southeast Asia appears to be rare.


A bacterial acyl aminoacyl peptidase couples flexibility and stability as a result of cold adaptation.
Life in cold environments requires an overall increase in the flexibility of macromolecular and supramolecular structures to allow biological processes to take place at low temperature. Conformational flexibility supports high catalytic rates of enzymes in the cold but in several cases is also a cause of instability. The three-dimensional structure of the psychrophilic acyl aminoacyl peptidase from Sporosarcina psychrophila (SpAAP) reported in this paper highlights adaptive molecular changes resulting in a fine-tuned trade-off between flexibility and stability. In its functional form SpAAP is a dimer, and an increase in flexibility is achieved through loosening of intersubunit hydrophobic interactions. The release of subunits from the quaternary structure is hindered by an 'arm exchange' mechanism, in which a tiny structural element at the N terminus of one subunit inserts into the other subunit. Mutants lacking the 'arm' are monomeric, inactive and highly prone to aggregation. Another feature of SpAAP cold adaptation is the enlargement of the tunnel connecting the exterior of the protein with the active site. Such a wide channel might compensate for the reduced molecular motions occurring in the cold and allow easy and direct access of substrates to the catalytic site, rendering transient movements between domains unnecessary. Thus, cold-adapted SpAAP has developed a molecular strategy unique within this group of proteins: it is able to enhance the flexibility of each functional unit while still preserving sufficient stability. Structural data are available in the Protein Data Bank under the accession number 5L8S.


In vitro efficacy of new antiprotozoals against Philasterides dicentrarchi (Ciliophora, Scuticociliatida).
Philasterides dicentrarchi is a histiophagous ciliate that causes severe losses in turbot and sea bass farming. This study investigated the in vitro efficacy against P. dicentrarchi of 85 newly synthesized compounds and 12 commercial compounds, of which 2 are fluoroquinolones (norfloxacine and lomefloxacine) with known antibacterial activity. Seventeen of the newly synthesized compounds (2 naphthyridines, 2 pyridothienodiazines and 13 pyridothienotriazines) and the fluoroquinolone norfloxacin showed good activity. The most promising compound was the pyridothienotriazine 12k, with activity similar to that of the salicylanilides niclosamide and oxiclozanide (MLC 0.8 mg l(-1) in PBS, 1.5 mg l(-1) in seawater; MLC = minimum 24 h lethal concentration).


[The proportion of suicides committed by patients with a mental health disorder for which treatment costs are now no longer reimbursed by health insurance].
Suffering from a psychiatric disorder is a well-known risk factor for suicide and suicidal behavior. Treatment of psychiatric disorders can reduce the risk of suicidal behavior and suicide. In the Netherlands, however, since 2012 the treatment costs of some psychiatric disorders have no longer been covered by health insurance.
 AIM: To find out what proportion of suicides were committed by patients with a psychiatric disorder for which treatment costs are no longer covered by health insurance since the rules changed in 2012.
 METHOD: We studied the files of 314 patients who were known to one of the large mental health hospitals in the Netherlands and who had committed suicide between 1 January 1999 and January 2012. We were able to determine the various psychiatric disorders from which the patients were suffering at the time they died.
 RESULTS: About 6% of the patients who committed suicide between 1999 and 2012 suffered from a psychiatric disorder for which treatment costs are now no longer covered by health insurance.
 CONCLUSION: Given the results of this study, the increased rates of suicide in the Netherlands and the importance of scientific research into the characteristics of suicide, we recommend that patients with suicidal behavior are not excluded from adequate treatment in the event they may or may not have met the criteria for a DSM-IV classification.


Infection structures from rust urediospores: effect of RNA and protein synthesis inhibitors.
Urediospores of Puccinia graminis tritici, floated on buffer, produce infection structures when subjected briefly to 30 degrees C soon after germination. Inhibitors of RNA synthesis interfere with the difierentiation of infection structures if present during this heat treatment. Inhibitors of protein synthesis prevent differentiation if present following heat treatment. Apparently infection structure formation is accompanied by synthesis of RNA, and the completion of infection structure development requires protein synthesis.


Risky Alcohol Use: The Impact on Health Service Use.
To examine health services use on the basis of alcohol consumption. A cross-sectional study was carried out on patients visiting the Primary Health Care (PHC) settings in Catalonia during 2011 and 2012; these patients had a history of alcohol consumption. Information about outpatient visits in the PHC setting, hospitalizations, specialists' visits and emergency room visits for the year 2013 was obtained from 2 databases (the Information System for the Development of Research in PHC and the Catalan Health Surveillance System). Risky drinkers were defined as those who consumed more than 280 g per week for men or more than 170 g per week for women, or any amount of alcohol while being involved in a high risk work activity, or taking medication that significantly interferes with alcohol or when being pregnant. Binge drinkers (> 60 g in men or > 50 g in women in a short amount of time more than once a month) were also considered risky drinkers. A total of 606,948 patients reported consuming alcohol (of which 10.5% were risky drinkers). Risky drinkers were more likely to be admitted to hospitals or emergency departments (range of ORs 1.08-1.18) compared to light drinkers. Male risky drinkers used fewer PHC services than male light drinkers (OR 0.89, 95% CI 0.87-0.92). In general, risky alcohol users used services more and had longer hospital stays. When stratifying by socioeconomic level of the residential area, we found that risky drinking failed significance, while current or past cigarette smoking was associated with higher healthcare use. Risky drinkers use more expensive services, such as hospitals and emergency rooms, but not PHC services, which may suggest that prevention strategies and alcohol interventions should also be implemented in those settings.


Practice patterns and guideline adherence of medical oncologists in managing patients with early breast cancer.
Studies of adherence to breast cancer guidelines have often focused on primary therapies, but concordance with other guideline recommendations has not been examined as extensively. This study assesses the knowledge and practice patterns of medical oncologists in the United States to inform education and quality improvement initiatives that can improve breast cancer care. A survey containing case vignettes and related questions was developed to examine oncologists' clinical decision-making in evaluating and treating women with early breast cancer. The instrument was distributed to a random sample of 742 oncologists in the United States and yielded 205 responses (27.6% response rate). Responses from 184 practicing medical oncologists were analyzed relative to the 2007 NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. Most oncologists made guideline-consistent choices in clarifying indeterminate human epidermal growth factor 2 (HER2) status (85%), initial treatment for early breast cancer (95%), and postsurgical management of locally advanced breast cancer (82%). Guideline-discordant choices were seen in the lack of clip placement before neoadjuvant chemotherapy (36%), unnecessary use of PET scanning for initial assessment (34%), inappropriate assessment of menopausal status (33%), inappropriate use of tumor markers (22%), and use of chest imaging (16%) during posttherapeutic surveillance. Oncologists often make guideline-consistent choices, but discordant clinical decisions may occur in important aspects of care for early breast cancer. Broadening the diffusion and adoption of guideline recommendations is an important mechanism for addressing these gaps and may substantially improve the quality of breast cancer care.


Effect of haemolysis and repeated freeze-thawing cycles on wild boar serum antibody testing by ELISA.
Monitoring wildlife diseases is needed to identify changes in disease occurrence. Wildlife blood samples are valuable for this purpose but are often gathered haemolysed. To maximise information, sera often go through repeated analysis and freeze-thaw cycles. Herein, we used samples of clean and haemolysed Eurasian wild boar (Sus scrofa) serum stored at -20°C and thawed up to five times to study the effects of both treatments on the outcome of a commercial ELISA test for the detection of antibodies against Suid Herpesvirus 1 (ADV). The estimated prevalence of antibodies against ADV was 50-53% for clean and haemolysed sera. Hence, haemolysis did not reduce the mean observed serum antibody prevalence. However, 10 samples changed their classification after repeated freeze-thawing. This included 3 (15%) of the clean sera and 7 (41%) of the haemolysed sera. We recommend (1) establishing more restrictive cut-off values when testing wildlife sera, (2) recording serum quality prior to sample banking, (3) recording the number of freezing-thawing cycles and (4) store sera in various aliquots to reduce repeated usage. For instance, sera with more than 3 freeze-thaw cycles and a haemolysis of over 3 on a scale of 4 should better be discarded for serum antibody monitoring. Even clean (almost not haemolysed) sera should not go through more than 5 freeze-thaw cycles.


Plasticity-induced symmetry relationships between adjacent self-organizing topographic maps.
In many species, adjacent topographic maps in sensory neocortex are found to be oriented as roughly mirror-image copies of one another. Here we use a computational model to show for the first time that, in principle, adjacent cortical topographic maps that are mirror-image symmetric along two dimensions can arise from activity-dependent changes if the distribution radius of afferents sufficiently exceeds that of horizontal intracortical interactions. We also find that infrequently, other types of intermap symmetry and previously unexpected map relationships (such as interlocking rotation, in which two adjacent maps become intertwined) can occur. These results support the hypothesis that activity-dependent synaptic changes play a more important role in forming the orientations of adjacent cortical maps than is currently recognized.


Angiographic assessment of peritoneovenous shunt malfunction.
On 12 patients with reaccumulation of ascitic fluid after peritoneovenous (LeVeen) shunt insertion, shuntograms were performed by direct percutaneous puncture of the venous limb of the shunt. Shunt function was evaluated by pressure determination and injection of sterile iodinated contrast material. The shuntogram correctly predicted the cause of shunt malfunction in ten of 12 patients. Two failures were attributable to central venous hypertension. The addition of pressure measurements has been shown to correlate with central venous pressure at the time of surgery and hopefully will eliminate the inability of the procedure to diagnose shunt malfunction secondary to venous hypertension. There have been no episodes of pulmonary embolization is a safe and effective method for assessing peritoneovenous shunt malfunction. The information gained from this procedure is valuable to the surgeon who plans an operation to correct shunt malfunction.


Association of pre-transplant statin use with delayed graft function in kidney transplant recipients.
Administration of HMG-CoA reductase inhibitors (statins), prior to ischemia or prior to reperfusion has been shown to decrease ischemia-reperfusion renal injury in animal studies. It is unknown whether this protective effect is applicable to renal transplantation in humans. The aim of this study was to determine the relationship between prior statin use in renal transplant recipients and the subsequent risk of delayed graft function. All patients who underwent deceased or living donor renal transplantation at the Princess Alexandra Hospital between 1 July 2008 and 1 August 2010 were included in this retrospective, observational cohort study. Graft function was classified as immediate graft function (IGF), dialysis-requiring (D-DGF) and non-dialysis-requiring (ND-DGF) delayed graft function. The independent predictors of graft function were evaluated by multivariable logistic regression, adjusting for donor characteristics, recipient characteristics, HLA mismatch and ischaemic times. Overall, of the 266 renal transplant recipients, 21% exhibited D-DGF, 39% had ND-DGF and 40% had IGF. Statin use prior to renal transplantation was not significantly associated with the risk of D-DGF (adjusted odds ratio [OR] 1.05, 95% CI 0.96 - 1.15, P = 0.28). This finding was not altered when D-DGF and ND-DGF were pooled together (OR 0.98; 95% CI 0.89-1.06, p = 0.56). The present study did not show a significant, independent association between prior statin use in kidney transplant recipients and the occurrence of delayed graft function.


Two species of Rhabdochona (Nematoda: Rhabdochonidae) from the cyprinid fish Luciobarbus kersin (Heckel) in northern Iraq, including R. (Globochona) kurdistanensis sp. n.
A new nematode species, Rhabdochona (Globochona) kurdistanensis sp. n. (Rhabdochonidae), is decribed based on specimens collected from the intestine of the barbel Luciobarbus kersin (Heckel) (Cyprinidae) in the Greater Zab (type locality) and the Lesser Zab Rivers, Tigris River basin, Kurdistan Region, northern Iraq. It is mainly characterized by a prostom with 8 anterior teeth, the presence of basal prostomal teeth, bifurcated deirids, length ratio of the muscular and glandular portions of oesophagus (1:14.4-17.8), conspicuously short left spicule (180-204 microm), arrangement of genital papillae, nonfilamented eggs, and by having cuticular ornamentations on the tail tip (2 lateral denticular outgrowths in female and numerous fine spines in male). Description of a gravid female of Rhabdochona (Rhabdochona) sp. with 14 anterior prostomal teeth and filamented eggs, recorded from L. kersin of the Greater Zab River, is also provided. R. kurdistanensis sp. n. is the fifth valid species of Rhabdochona Railliet, 1916 and the only representative of the subgenus Globochona Moravec, 1972 recorded from Iraq.


Fire-eater's pneumonia after aspiration of liquid paraffin.
Fire-eater's pneumonia is a distinct type of chemical pneumonitis that results from aspiration of different types of hydrocarbons. This article describes a case of fire-eater's pneumonia due to accidental aspiration of liquid paraffin. The adolescent patient became febrile the day after the accident. The diagnosis of fire-eater's pneumonia was delayed because aspiration history was not divulged by the patient from the beginning. The most prominent chest X-ray finding was multiple pneumatoceles. He responded well to antibiotics and corticosteroids. Two months after the accident, the lesions had almost completely resolved and only minor scarring was evident. Diagnosis of fire-eater's pneumonia can be difficult, especially if key aspects of related history are not divulged by the patient. Corticosteroid therapy was thought to be beneficial in the rapid recovery of the present case together with broad spectrum antibiotics.


The emergence of a superorganism through intergroup competition.
Surveys of insect societies have revealed four key, recurring organizational trends: (i) The most elaborated cooperation occurs in groups of relatives. (ii) Cooperation is typically more elaborate in species with large colony sizes than in species with small colony sizes, the latter exhibiting greater internal reproductive conflict and lesser morphological and behavioral specialization. (iii) Within a species, per capita brood output typically declines as colony size increases. (iv). The ecological factors of resource patchiness and intergroup competition are associated with the most elaborated cooperation. Predictions of all four patterns emerge elegantly from a game-theoretic model in which within-group tug-of-wars are nested within a between-group tug-of-war. In this individual selection model, individuals are faced with the problem of how to partition their energy between investment in intercolony competition versus investment in intracolony competition, i.e., internal tugs-of-war over shares of the resources gained through intergroup competition. An individual's evolutionarily stable investment in between-group competition (i.e., within-group cooperation) versus within-group competition is shown to increase as within-group relatedness increases, to decrease as group size increases (for a fixed number of competing groups), to increase as the number of competing groups in a patch increases, and to decrease as between-group relatedness increases. Moreover, if increasing patch richness increases both the number of individuals within a group and the number of competing groups, greater overall cooperation within larger groups will be observed. The model presents a simple way of determining quantitatively how intergroup conflict will propel a society forward along a "superorganism continuum."


Racial disparities in tissue plasminogen activator treatment rate for stroke: a population-based study.
Some prior studies have shown that racial disparities exist in intravenous tissue plasminogen activator (tPA) use for acute ischemic stroke. We sought to determine whether race was associated with tPA treatment for stroke in a predominantly black urban population. Systematic chart abstraction was performed on consecutive hospitalized patients with ischemic stroke from all 7 acute care hospitals in the District of Columbia from February 1, 2008, to January 31, 2009. Of 1044 patients with ischemic stroke, 74% were black, 19% non-Hispanic white, and 5% received intravenous tPA. Blacks were one third less likely than whites to receive intravenous tPA (3% versus 10%, P<0.001). However, blacks were also less likely than whites to present within 3 hours of symptom onset (13% versus 21%, P=0.004) and also less likely to be tPA-eligible (5% versus 13%, P<0.001). Of those who presented within 3 hours, blacks were almost half as likely to be treated with intravenous tPA than whites (27% versus 46%, P=0.023). The treatment rate for tPA-eligible patients was similar for blacks and whites (70% versus 76%, P=0.62). In this predominantly black urban population hospitalized for acute ischemic stroke, blacks were significantly less likely to be treated with intravenous tPA due to contraindications to treatment, delayed presentation, and stroke severity. Effective interventions designed to increase treatment in this population need to focus on culturally relevant education programs designed to address barriers specific to this population.


Willingness to share personal health record data for care improvement and public health: a survey of experienced personal health record users.
Data stored in personally controlled health records (PCHRs) may hold value for clinicians and public health entities, if patients and their families will share them. We sought to characterize consumer willingness and unwillingness (reticence) to share PCHR data across health topics, and with different stakeholders, to advance understanding of this issue. Cross-sectional 2009 Web survey of repeat PCHR users who were patients over 18 years old or parents of patients, to assess willingness to share their PCHR data with an-out-of-hospital provider to support care, and the state/local public health authority to support monitoring; the odds of reticence to share PCHR information about ten exemplary health topics were estimated using a repeated measures approach. Of 261 respondents (56% response rate), more reported they would share all information with the state/local public health authority (63.3%) than with an out-of-hospital provider (54.1%) (OR 1.5, 95% CI 1.1, 1.9; p = .005); few would not share any information with these parties (respectively, 7.9% and 5.2%). For public health sharing, reticence was higher for most topics compared to contagious illness (ORs 4.9 to 1.4, all p-values < .05), and reflected concern about anonymity (47.2%), government insensitivity (41.5%), discrimination (24%). For provider sharing, reticence was higher for all topics compared to contagious illness (ORs 6.3 to 1.5, all p-values < .05), and reflected concern for relevance (52%), disclosure to insurance (47.6%) and/or family (20.5%). Pediatric patients and their families are often willing to share electronic health information to support health improvement, but remain cautious. Robust trust models for PCHR sharing are needed.


Early signs of colonic inflammation, intestinal dysfunction, and olfactory impairments in the rotenone-induced mouse model of Parkinson's disease.
The factors that trigger the pathophysiology of Parkinson's disease (PD) are unknown. However, it is suggested that environmental factors, such as exposure to pesticides, play an important role, in addition to genetic predisposition and aging. Early signs of PD can appear in the gastrointestinal (GI) tract and in the olfactory system, preceding the onset of motor impairments by many years. The present study assessed the effects of oral rotenone administration (30 mg/kg) in inducing GI and olfactory dysfunctions associated with PD in mice. Here we show that rotenone transiently increased myeloperoxidase activity within 24 h of administration. Leucocyte infiltration in the colon, associated with histological damage and disrupted GI motility, were observed following treatment with rotenone for 7 days. Moreover, 7 days of treatment with rotenone disrupted olfactory discrimination in mice without affecting social recognition ability. The presence of specific deficits in olfactory function occurred with a concomitant decrease in tyrosine hydroxylase-positive neurons and an increase in serotonin (5-hydroxytryptamine) turnover in the olfactory bulb. These findings suggest that in Swiss mice, exposure to rotenone induces GI and olfactory dysfunction involving immunological and neurotransmitter alterations, similar to early signs of PD. This provides further evidence for the involvement of the gut-brain axis in PD.


Harmonic nanocrystals for biolabeling: a survey of optical properties and biocompatibility.
Nonlinear optical nanocrystals have been recently introduced as a promising alternative to fluorescent probes for multiphoton microscopy. We present for the first time a complete survey of the properties of five nanomaterials (KNbO(3), LiNbO(3), BaTiO(3), KTP, and ZnO), describing their preparation and stabilization and providing quantitative estimations of their nonlinear optical response. In the light of their prospective use as biological and clinical markers, we assess their biocompatibility on human healthy and cancerous cell lines. Finally, we demonstrate the great potential for cell imaging of these inherently nonlinear probes in terms of optical contrast, wavelength flexibility, and signal photostability.


Incorporating single-side sparing in models for predicting parotid dose sparing in head and neck IMRT.
Sparing of single-side parotid gland is a common practice in head-and-neck (HN) intensity modulated radiation therapy (IMRT) planning. It is a special case of dose sparing tradeoff between different organs-at-risk. The authors describe an improved mathematical model for predicting achievable dose sparing in parotid glands in HN IMRT planning that incorporates single-side sparing considerations based on patient anatomy and learning from prior plan data. Among 68 HN cases analyzed retrospectively, 35 cases had physician prescribed single-side parotid sparing preferences. The single-side sparing model was trained with cases which had single-side sparing preferences, while the standard model was trained with the remainder of cases. A receiver operating characteristics (ROC) analysis was performed to determine the best criterion that separates the two case groups using the physician's single-side sparing prescription as ground truth. The final predictive model (combined model) takes into account the single-side sparing by switching between the standard and single-side sparing models according to the single-side sparing criterion. The models were tested with 20 additional cases. The significance of the improvement of prediction accuracy by the combined model over the standard model was evaluated using the Wilcoxon rank-sum test. Using the ROC analysis, the best single-side sparing criterion is (1) the predicted median dose of one parotid is higher than 24 Gy; and (2) that of the other is higher than 7 Gy. This criterion gives a true positive rate of 0.82 and a false positive rate of 0.19, respectively. For the bilateral sparing cases, the combined and the standard models performed equally well, with the median of the prediction errors for parotid median dose being 0.34 Gy by both models (p = 0.81). For the single-side sparing cases, the standard model overestimates the median dose by 7.8 Gy on average, while the predictions by the combined model differ from actual values by only 2.2 Gy (p = 0.005). Similarly, the sum of residues between the modeled and the actual plan DVHs is the same for the bilateral sparing cases by both models (p = 0.67), while the standard model predicts significantly higher DVHs than the combined model for the single-side sparing cases (p = 0.01). The combined model for predicting parotid sparing that takes into account single-side sparing improves the prediction accuracy over the previous model.


The effects of symptomatic seroma on lymphedema symptoms following breast cancer treatment.
It has been speculated that symptomatic seroma, or seroma requiring needle aspiration, is one of the risk factors for lymphedema symptoms following breast cancer treatment. These symptoms exert tremendous impact on patients' quality of life and include arm swelling, chest/breast swelling, heaviness, tightness, firmness, pain, numbness, stiffness, or impaired limb mobility. Our aim was to explore if symptomatic seroma affects lymphedema symptoms following breast cancer treatment. Data were collected from 130 patients using a Demographic and Medical Information interview tool, Lymphedema and Breast Cancer Questionnaire, and review of medical record. Arm swelling was verified by Sequential Circumferential Arm Measurements and Bioelectrical Impedance Spectroscopy. Data analysis included descriptive statistics, Chi-squared tests, regression, exploratory factor analysis and exploratory structural equation modeling. Thirty-five patients (27%) developed symptomatic seroma. Locations of seroma included axilla, breast, and upper chest. Significantly, more women with seroma experienced more lymphedema symptoms. A well-fit exploratory structural equation model [X2(79) = 92.15, p = 0.148; CFI = 0.97; TLI = 0.96] revealed a significant unique effect of seroma on lymphedema symptoms of arm swelling, chest/breast swelling, tenderness, and blistering (beta = 0.48, p < 0.01). Patients who developed symptomatic seroma had 7.78 and 10.64 times the odds of developing arm swelling and chest/breast swelling versus those who did not, respectively (p < 0.001). Symptomatic seroma is associated with increased risk of developing lymphedema symptoms following breast cancer treatment. Patients who develop symptomatic seroma should be considered at higher risk for lymphedema symptoms and receive lymphedema risk reduction interventions.


Physical and hormonal evaluation of transsexual patients during hormonal therapy.
The optimal hormonal therapy for transsexual patients is not known. The physical and hormonal characteristics of 38 noncastrate male-to-female transsexuals and 14 noncastrate female-to-male transsexuals have been measured before and/or during therapy with various forms and dosages of hormonal therapy. All patients were hormonally and physically normal prior to therapy. Ethinyl estradiol was superior to conjugated estrogen in suppression of testosterone and gonadotropins but equal in effecting breast growth. The changes in physical and hormonal characteristics were the same for 0.1 mg/d and 0.5 mg/d of ethinyl estradiol. The female-to-male transsexuals were well managed with a dose of intramuscular testosterone cypionate of 400 mg/month, usually given 200 mg every two weeks. The maximal clitoral length reached was usually 4 cm. Higher doses of testosterone did not further increase clitoral length or suppression of gonadotropins; lower doses did not suppress the gonadotropins. Based on the information found in this study, we recommend 0.1 mg/d of ethinyl estradiol for the noncastrate male-to-female transsexual and 200 mg of intramuscular testosterone cypionate every two weeks for the noncastrate female-to-male transsexual.


An approach for identifying brainstem dopaminergic pathways using resting state functional MRI.
Here, we present an approach for identifying brainstem dopaminergic pathways using resting state functional MRI. In a group of healthy individuals, we searched for significant functional connectivity between dopamine-rich midbrain areas (substantia nigra; ventral tegmental area) and a striatal region (caudate) that was modulated by both a pharmacological challenge (the administration of the dopaminergic agonist bromocriptine) and a dopamine-sensitive cognitive trait (an individual's working memory capacity). A significant inverted-U shaped connectivity pattern was found in a subset of midbrain-striatal connections, demonstrating that resting state fMRI data is sufficiently powerful to identify brainstem neuromodulatory brain networks.