Bacterial Metabolism During Biofilm Growth Investigated by 13C Tracing.
This study investigated the metabolism of Pseudomonas aeruginosa PAO1 during its biofilm development via microscopy imaging, gene expression analysis, and 13C-labeling. First, dynamic labeling was employed to investigate glucose utilization rate in fresh biofilms (thickness 40∼60 micrometer). The labeling turnover time of glucose-6-P indicated biofilm metabolism was substantially slower than planktonic cells. Second, PAO1 was cultured in continuous tubular biofilm reactors or shake flasks. Then 13C-metabolic flux analysis of PAO1 was performed based on the isotopomer patterns of proteinogenic amino acids. The results showed that PAO1 biofilm cells during growth conserved the flux features as their planktonic mode. (1) Glucose could be degraded by two cyclic routes (the TCA cycle and the Entner-Doudoroff-Embden-Meyerhof-Parnas loop) that facilitated NAD(P)H supplies. (2) Anaplerotic pathways (including pyruvate shunt) increased flux plasticity. (3) Biofilm growth phenotype did not require significant intracellular flux rewiring (variations between biofilm and planktonic flux network, normalized by glucose uptake rate as 100%, were less than 20%). (4) Transcription analysis indicated that key catabolic genes in fresh biofilm cells had expression levels comparable to planktonic cells. Finally, PAO1, Shewanella oneidensis (as the comparing group), and their c-di-GMP transconjugants (with different biofilm formation capabilities) were 13C-labeled under biofilm reactors or planktonic conditions. Analysis of amino acid labeling variances from different cultures indicated Shewanella flux network was more flexibly changed than PAO1 during its biofilm formation.


Increased systolic blood pressure in adult rats induced by fetal exposure to maternal low protein diets.
1. Possible associations between maternal nutrition in pregnancy and non-communicable diseases of adulthood were assessed using a rat model. Rats were habituated to diets containing a range of protein levels (18, 12, 9 and 6% by weight), over a 14 day period, before mating. The low protein diets were maintained throughout pregnancy. Lactating mothers and their offspring were transferred to a standard chow diet (20% protein). 2. Pregnant rats demonstrated a graded response to the diets, with those fed 9 and 6% protein tending to consume less energy and gain less weight than 18% protein fed controls. Litter size and newborn death rates were not significantly altered by the low protein diets. 3. Offspring of 12 and 9% protein fed dams were grossly normal, gaining weight at a similar rate to those born to 18% protein fed control rats. Offspring of the 6% protein fed dams were smaller than pups from all other groups, over a 21 week period. 4. At 9 weeks of age, systolic blood pressure was determined in the offspring. All offspring from the three low protein groups were found to have significantly elevated blood pressure (15-22 mmHg) relative to the control group. An inverse relationship between maternal protein intake and the systolic blood pressure of the offspring was observed. Blood pressure remained elevated in the offspring of the 9 and 6% protein fed dams until 21 weeks of age. The observed hypertension was associated with increased pulmonary angiotensin-converting enzyme activity in the low protein groups.(ABSTRACT TRUNCATED AT 250 WORDS)


Accessory heterozygous mutations in cone photoreceptor CNGA3 exacerbate CNG channel-associated retinopathy.
Mutations in CNGA3 and CNGB3, the genes encoding the subunits of the tetrameric cone photoreceptor cyclic nucleotide-gated ion channel, cause achromatopsia, a congenital retinal disorder characterized by loss of cone function. However, a small number of patients carrying the CNGB3/c.1208G>A;p.R403Q mutation present with a variable retinal phenotype ranging from complete and incomplete achromatopsia to moderate cone dysfunction or progressive cone dystrophy. By exploring a large patient cohort and published cases, we identified 16 unrelated individuals who were homozygous or (compound-)heterozygous for the CNGB3/c.1208G>A;p.R403Q mutation. In-depth genetic and clinical analysis revealed a co-occurrence of a mutant CNGA3 allele in a high proportion of these patients (10 of 16), likely contributing to the disease phenotype. To verify these findings, we generated a Cngb3R403Q/R403Q mouse model, which was crossbred with Cnga3-deficient (Cnga3-/-) mice to obtain triallelic Cnga3+/- Cngb3R403Q/R403Q mutants. As in human subjects, there was a striking genotype-phenotype correlation, since the presence of 1 Cnga3-null allele exacerbated the cone dystrophy phenotype in Cngb3R403Q/R403Q mice. These findings strongly suggest a digenic and triallelic inheritance pattern in a subset of patients with achromatopsia/severe cone dystrophy linked to the CNGB3/p.R403Q mutation, with important implications for diagnosis, prognosis, and genetic counseling.


A variant of yellow fluorescent protein with fast and efficient maturation for cell-biological applications.
The green fluorescent protein (GFP) from the jellyfish Aequorea victoria has provided a myriad of applications for biological systems. Over the last several years, mutagenesis studies have improved folding properties of GFP (refs 1,2). However, slow maturation is still a big obstacle to the use of GFP variants for visualization. These problems are exacerbated when GFP variants are expressed at 37 degrees C and/or targeted to certain organelles. Thus, obtaining GFP variants that mature more efficiently is crucial for the development of expanded research applications. Among Aequorea GFP variants, yellow fluorescent proteins (YFPs) are relatively acid-sensitive, and uniquely quenched by chloride ion (Cl-). For YFP to be fully and stably fluorescent, mutations that decrease the sensitivity to both pH and Cl- are desired. Here we describe the development of an improved version of YFP named "Venus". Venus contains a novel mutation, F46L, which at 37 degrees C greatly accelerates oxidation of the chromophore, the rate-limiting step of maturation. As a result of other mutations, F64L/M153T/V163A/S175G, Venus folds well and is relatively tolerant of exposure to acidosis and Cl-. We succeeded in efficiently targeting a neuropeptide Y-Venus fusion protein to the dense-core granules of PC12 cells. Its secretion was readily monitored by measuring release of fluorescence into the medium. The use of Venus as an acceptor allowed early detection of reliable signals of fluorescence resonance energy transfer (FRET) for Ca2+ measurements in brain slices. With the improved speed and efficiency of maturation and the increased resistance to environment, Venus will enable fluorescent labelings that were not possible before.


Binary mixtures of charged colloids: a potential route to synthesize disordered hyperuniform materials.
Disordered hyperuniform materials are a new, exotic class of amorphous matter that exhibits crystal-like behavior, in the sense that volume-fraction fluctuations are suppressed at large length scales, and yet they are isotropic and do not display diffraction Bragg peaks. These materials are endowed with novel photonic, phononic, transport and mechanical properties, which are useful for a wide range of applications. Motivated by the need to fabricate large samples of disordered hyperuniform systems at the nanoscale, we study the small-wavenumber behavior of the spectral density of binary mixtures of charged colloids in suspension. The interaction between the colloids is approximated by a repulsive hard-core Yukawa potential. We find that at dimensionless temperatures below 0.05 and dimensionless inverse screening lengths below 1.0, which are experimentally accessible, the disordered systems become effectively hyperuniform. Moreover, as the temperature and inverse screening length decrease, the level of hyperuniformity increases, as quantified by the "hyperuniformity index". Our results suggest an alternative approach to synthesize large samples of effectively disordered hyperuniform materials at the nanoscale under standard laboratory conditions. In contrast with the usual route to synthesize disordered hyperuniform materials by jamming particles, this approach is free from the burden of applying high pressure to compress the systems.


Postdiagnosis alcohol consumption and breast cancer prognosis in the after breast cancer pooling project.
Alcohol consumption is an established risk factor for incident breast cancer. However, its role in breast cancer prognosis remains unclear. We conducted an investigation of postdiagnosis alcohol consumption with recurrence and mortality among 9,329 breast cancer patients in the After Breast Cancer Pooling Project. Women were diagnosed from 1990 to 2006 with AJCC Stage I-III breast tumors from three prospective US cohorts. Alcohol intake was assessed at cohort entry (mean 2.1 years postdiagnosis) using a food frequency questionnaire. HR and 95% confidence intervals (CI) were estimated using delayed entry Cox proportional hazards models with adjustment for known prognostic factors. After a mean follow-up of 10.3 years, 1,646 recurrences and 1,543 deaths were ascertained. 5,422 women (58%) were considered drinkers (≥0.36 g/day of alcohol, ≥0.25 drinks/week) with a median of 5.3 g/day. Overall, compared with nondrinking, regular alcohol intake (≥6.0 g/day) was not associated with risk of recurrence (HR for 6 to less than 12 g/day, 1.03; 95% CI, 0.86-1.24; HR for 12 to less than 24 g/day, 1.12; 95% CI, 0.93-1.34; HR for ≥24 g/day, 1.04; 95% CI, 0.84-1.31). However, risk varied significantly by menopausal status (P for interaction < 0.05). Postmenopausal women who regularly consumed alcohol (≥6.0 g/day) had increased risk of recurrence (HR, 1.19; 95% CI, 1.01-1.40). Alcohol intake was not associated with mortality. Regular alcohol consumption was not associated with breast cancer recurrence and total mortality overall, yet recurrence risk was only elevated in postmenopausal women. The association between alcohol intake and recurrence may depend on menopausal status at breast cancer diagnosis.


Clinical manifestations of VX poisoning following percutaneous exposure in the domestic white pig.
Nerve agents are a class of organophosphorus chemicals that inhibit certain cholinesterase enzymes (ChE). If untreated, percutaneous exposure to nerve agents, such as VX (O-ethyl-S-[2(diisopropylamino)ethyl] methylphosphonothioate) can cause paralysis, apnoea and death. Much of the information concerning the percutaneous absorption and subsequent toxicity of nerve agents has been obtained using various rodent models. However, the most relevant 'skin model' is arguably the pig. Therefore, the purpose of this study was to examine the clinical manifestations of VX intoxication in the domestic white pig following a 2 LD50 (120 microg/kg) percutaneous challenge. There was a consistent onset of signs (where present) in each animal: mastication was followed by miosis, salivation, fasciculations and apnoea. Whilst ChE activity did not correlate with the onset of signs, there was a qualitative relationship in that mastication preceded substantial ChE inhibition, miosis lagged behind the linear decrease in acetylcholinesterase (AChE) activity and fasciculations and apnoea occurred after maximum ChE inhibition had been attained (5-10% of normal). These observations may be of use for the triage of patients exposed to VX. In comparison with similar studies with GD, VX did not affect glucose utilization. However, VX was similar to GD in that it caused a mild hyperkalaemia and hyperphosphataemia, although the significance of this observation was not clear. There was substantial lateral diffusion of the initial droplet of VX over the application site, indicating that, when decontaminating exposed skin, attention should also be directed to areas peripheral to the original site of exposure.


p300/CBP-associated factor drives DEK into interchromatin granule clusters.
DEK is a mammalian protein that has been implicated in the pathogenesis of autoimmune diseases and cancer, including acute myeloid leukemia, melanoma, glioblastoma, hepatocellular carcinoma, and bladder cancer. In addition, DEK appears to participate in multiple cellular processes, including transcriptional repression, mRNA processing, and chromatin remodeling. Sub-nuclear distribution of this protein, with the attendant functional ramifications, has remained a controversial topic. Here we report that DEK undergoes acetylation in vivo at lysine residues within the first 70 N-terminal amino acids. Acetylation of DEK decreases its affinity for DNA elements within the promoter, which is consistent with the involvement of DEK in transcriptional repression. Furthermore, deacetylase inhibition results in accumulation of DEK within interchromatin granule clusters (IGCs), sub-nuclear structures that contain RNA processing factors. Overexpression of P/CAF acetylase drives DEK into IGCs, and addition of a newly developed, synthetic, cell-permeable P/CAF inhibitor blocks this movement. To our knowledge, this is the first reported example of acetylation playing a direct role in relocation of a protein to IGCs, and this may explain how DEK can function in multiple pathways that take place in distinct sub-nuclear compartments. These findings also suggest that DEK-associated malignancies and autoimmune diseases might be amenable to treatment with agents that alter acetylation.


Automated and Computer-Assisted Detection, Classification, and Diagnosis of Diabetic Retinopathy.
Background: The introduction of artificial intelligence (AI) in medicine has raised significant ethical, economic, and scientific controversies. Introduction: Because an explicit goal of AI is to perform processes previously reserved for human clinicians and other health care personnel, there is justified concern about the impact on patient safety, efficacy, equity, and liability. Discussion: Systems for computer-assisted and fully automated detection, triage, and diagnosis of diabetic retinopathy (DR) from retinal images show great variation in design, level of autonomy, and intended use. Moreover, the degree to which these systems have been evaluated and validated is heterogeneous. We use the term DR AI system as a general term for any system that interprets retinal images with at least some degree of autonomy from a human grader. We put forth these standardized descriptors to form a means to categorize systems for computer-assisted and fully automated detection, triage, and diagnosis of DR. The components of the categorization system include level of device autonomy, intended use, level of evidence for diagnostic accuracy, and system design. Conclusion: There is currently minimal empirical basis to assert that certain combinations of autonomy, accuracy, or intended use are better or more appropriate than any other. Therefore, at the current stage of development of this document, we have been descriptive rather than prescriptive, and we treat the different categorizations as independent and organized along multiple axes.


Differential fluorescent staining of human chromosomes with daunomycin and adriamycin--the d-bands.
Human chromosome preparations were treated with a group of anthracycline antibiotics. Well-defined, orange-red fluorescent bands were observed on chromosomes after the slide was stained with daunomycin and adriamycin but not with nogalamycin. The characteristic differential bands appeared to be similar to the banding patterns obtained by the quinacrine techniques. Interaction of these antibiotics with DNA could provide information on the general mechanism of fluorescent banding. Further, these bands (D-bands) appeared to be more stable than the Q-bands and may have some usefulness for routine clinical cytogenetic analysis.


Various non-injectable delivery systems for the treatment of diabetes mellitus.
Diabetes mellitus (diabetes) is suffered by more than 180 million people and is responsible for approximately 2.9 million deaths each year. This mortality rate is expected to increase by 50 % in the next decade. Due to the inconvenience of the traditional treatment of diabetes by subcutaneous administration of insulin injection, various attempts are made in the production, purification, formulation and methods of delivery of insulin. However, despite advances in recent years, these attempts have met with limited success. Various alternative routes such as rectal, ocular, nasal, pulmonary and oral have been exploited. The pulmonary route offers great potential for the delivery of polypeptide drugs due to the large surface area for insulin absorption in the respiratory tract. But due to its low bioavailability, oral route is intensely investigated for the insulin delivery. Microencapsulation, as one of the delivery systems utilising oral route, has shown some potential progress in insulin delivery; though it is at an early stage yet it has proved to be quite encouraging providing new less toxic immunosuppressive agents. Microencapsulation may prove to be an attractive delivery system for controlled release of insulin and beneficial for therapeutic, bio-efficient and bio-effective drug delivery. In this review we discuss the possible alternative routes for insulin delivery (ocular, nasal, pulmonary and oral) and advantages and disadvantages of each. Furthermore we consider the different drug delivery strategies available (aerosols, dry powder inhalers, synthetic beta cells, hydrogels and microcapsules) and their current and potential applications with respect to the different insulin delivery routes.


Inferring the direction of implied motion depends on visual awareness.
Visual awareness of an event, object, or scene is, by essence, an integrated experience, whereby different visual features composing an object (e.g., orientation, color, shape) appear as an unified percept and are processed as a whole. Here, we tested in human observers whether perceptual integration of static motion cues depends on awareness by measuring the capacity to infer the direction of motion implied by a static visible or invisible image under continuous flash suppression. Using measures of directional adaptation, we found that visible but not invisible implied motion adaptors biased the perception of real motion probes. In a control experiment, we found that invisible adaptors implying motion primed the perception of subsequent probes when they were identical (i.e., repetition priming), but not when they only shared the same direction (i.e., direction priming). Furthermore, using a model of visual processing, we argue that repetition priming effects are likely to arise as early as in the primary visual cortex. We conclude that although invisible images implying motion undergo some form of nonconscious processing, visual awareness is necessary to make inferences about motion direction.


Do nurses and cancer patients agree on cancer patients' coping resources, emotional distress and quality of life?
The present study examines differences, associations and agreement in cancer patients' and their nurses' ratings of cancer patients' coping resources, emotional distress and quality of life. The study sample includes 90 individual patient-nurse pairs. The patient and nurse in each pair independently completed the Cancer Behaviour Inventory, the Hospital Anxiety and Depression Scale and the Functional Assessment of Chronic Illness Therapy-Spiritual Well-being. The results indicate a distinct pattern in which nurses overestimate patients' emotional distress and underestimate patients' coping resources and quality of life. A nurse who overestimated a patient's emotional distress and underestimated his/her resources for handling the situation was also likely to underestimate the patient's quality of life. Patient-nurse pairs who demonstrated consistent agreement differed from remaining pairs in that they had a larger percentage of nurses with advanced education and previous responsibility for their patients' care and in that they had higher frequencies of patients who had previously received care at the ward >5 days. Nurses caring for patients with cancer should be aware of the risk of making systematic misjudgements of patients' status. Increased attention to patients' internal resources may improve nurses' ability to make correct assessments and plan for individualized care.


Switching antipsychotic medication to aripiprazole: position paper by a panel of Italian psychiatrists.
Patients with schizophrenia or bipolar disorder treated with antipsychotic medication can frequently experience lack of efficacy and persistent side-effects, so much so that switching from one antipsychotic to another with a different side-effect profile has become a recommended strategy for improving the tolerability and safety of long-term antipsychotic treatment. Aripiprazole is an atypical antipsychotic with proven efficacy in schizophrenia and bipolar I disorder, with a pharmacological profile distinct from other available antipsychotics and a side-effect profile that is different from other agents in the class; these characteristics make it a possible alternative in patients requiring a change in antipsychotic treatment due to lack of efficacy or persistent side-effects. A panel of Italian experts in psychiatry met to discuss the appropriateness of current strategies for the switch to aripiprazole in patients with schizophrenia or bipolar disorder once a clinician has decided to adopt this choice and also to propose alternate strategies where required. The strategies for the switch to aripiprazole presented in this position paper consider various scenarios encountered in clinical practice, highlight the importance of tapering the prior antipsychotic based on its pharmacological characteristics and provide detailed guidance throughout the entire switching process. Literature searches were conducted using the PubMed database and the search strategy (aripiprazole and switching); additional references were added from the reference lists of the papers obtained and also from the authors' knowledge of the topic. Few studies have addressed the indications for antipsychotic switching and the best practical strategies to achieve the desired goal in the clinical practice setting. Studies on antipsychotic switching should clarify why, when and how a switch should be done. The results should standardize the reasons for switching an antipsychotic, assess the optimal time to switch and evaluate the best ways to switch. Both clinical and pharmacological factors should be considered when a patient needs to switch antipsychotics, and specific guidelines for antipsychotic switching that address all these factors are needed.


Novel endoribonucleases as central players in various pathways of eukaryotic RNA metabolism.
For a long time it has been assumed that the decay of RNA in eukaryotes is mainly carried out by exoribonucleases, which is in contrast to bacteria, where endoribonucleases are well documented to initiate RNA degradation. In recent years, several as yet unknown endonucleases have been described, which has changed our view on eukaryotic RNA metabolism. Most importantly, it was shown that the primary eukaryotic 3' --> 5' exonuclease, the exosome complex has the ability to endonucleolytically cleave its physiological RNA substrates, and novel endonucleases involved in both nuclear and cytoplasmic RNA surveillance pathways were discovered concurrently. In addition, endoribonucleases responsible for long-known processing steps in the maturation pathways of various RNA classes were recently identified. Moreover, one of the most intensely studied RNA decay pathways--RNAi--is controlled and stimulated by the action of different endonucleases. Furthermore, endoribonucleolytic cleavages executed by various enzymes are also the hallmark of RNA degradation and processing in plant chloroplasts. Finally, multiple context-specific endoribonucleases control qualitative and/or quantitative changes of selected transcripts under particular conditions in different eukaryotic organisms. The aim of this review is to discuss the impact of all of these discoveries on our current understanding of eukaryotic RNA metabolism.


Measuring physicians' productivity: a three-year study to evaluate a new remuneration system.
To evaluate a new assessment tool measuring physicians' academic productivity and its use in a performance-based remuneration system. The authors developed an assessment tool based on existing tools to measure productivity. Yearly, from 2008 to 2011, physicians at the University of Western Ontario received a score of up to three points for each of four components (impact, application, scholarly activity, mentorship) in each of four domains (clinical practice, education, research, administration). Scores were weighted by the percentage of time physicians spent on tasks in each domain. Year 1 scores were a baseline. In Years 2 and 3, scores were tied to remuneration. The authors compared scores and associations, accounting for age and academic rank, across the three years. The 37 participating physicians included 11 assistant, 23 associate, and 4 full professors. The mean weighted total baseline score across all four domains was 7.44. Years 2 and 3 scores were highly correlated with Year 1 scores (r = 0.85, Years 1 and 2; r = 0.89, Years 1 and 3). Year 2 mean weighted scores did not differ significantly from Year 1 scores. Assistant professors' scores improved significantly between Years 1 and 2 (+1.08, P < .001). Lower Year 1 scores were correlated with a greater improvement in scores between Years 1 and 2, and age was negatively correlated with score changes between Years 2 and 3. Although the tool may be a robust measurement of physicians' productivity, performance-based remuneration had no effect on physicians' overall performance.


Apoptosis, autophagy and unfolded protein response pathways in Arbovirus replication and pathogenesis.
Arboviruses are pathogens that widely affect the health of people in different communities around the world. Recently, a few successful approaches toward production of effective vaccines against some of these pathogens have been developed, but treatment and prevention of the resulting diseases remain a major health and research concern. The arbovirus infection and replication processes are complex, and many factors are involved in their regulation. Apoptosis, autophagy and the unfolded protein response (UPR) are three mechanisms that are involved in pathogenesis of many viruses. In this review, we focus on the importance of these pathways in the arbovirus replication and infection processes. We provide a brief introduction on how apoptosis, autophagy and the UPR are initiated and regulated, and then discuss the involvement of these pathways in regulation of arbovirus pathogenesis.


District nurses' involvement and attitudes to mental health problems: a three-area cross-sectional study.
The main aims of this study were to obtain information on the extent of staff contact and input with mental health problems and to determine their experience, training and attitudes to such problems. Historical changes and policy shifts have resulted in primary care providers playing an increasing role in the care of mental health problems. Such problems are common within community settings and a major cause of suffering and disability. District nurses in particular are likely to encounter a high level of psychological co-morbidity in their patients. Information is lacking on their involvement, attitudes and specific training for this area of their work. A cross-sectional study was conducted of the staff of district nursing services in three areas, Jersey (Channel Islands), Lewisham and Hertfordshire, using a postal questionnaire. Questionnaires were sent to 331 staff; 66% responded. Community and district nurses estimated a 16% prevalence of mental health problems among their patients, most commonly dementia, depression and anxiety disorders. Staff noted participation in a wide range of psychological care activities, but identified a lack of training for this aspect of their role (three-quarter of nurses had received no such training during the past five years). They reported a willingness to develop their understanding and skills by means of educational programmes. Attitude measures revealed generally optimistic views concerning depression treatment, a rejection of deterministic attitudes about this condition and confidence in the role of district nursing staff in managing such problems. The need for primary care mental health training is widely noted and based upon consistent evidence of the limited detection and treatment of these problems. This study has employed quantitative methods to clarify the extent and nature of district nursing staff involvement in this area of practice and indicates that training needs are acknowledged by community nurses from geographically distinct settings. Staff are interested in developing knowledge and skills pertinent to the psychological problems of their patients and their views reveal a consensus that the most important areas for learning are recognition of mental disorders, anxiety management, crisis intervention and pharmacological treatments for depression.


Comparison of dynamic posteroanterior spinal stiffness to plain film radiographic images of lumbar disk height.
Assessments of spinal stiffness have become more popular in recent years as a noninvasive objective biomechanical means to evaluate the human spine. Studies investigating posteroanterior (PA) forces in spinal stiffness assessment have shown relationships to spinal level, body type, and lumbar extensor muscle activity. Such measures may be important determinants to discriminate between patients with low back pain (LBP) and asymptomatic subjects. To determine the relationships between dynamic PA spinal stiffness and radiographic measures of lower lumbar disk height and disk degeneration. L4 and L5 posterior disk height (PDH), vertebral body height (PVH), anterior disk height (ADH), and vertebral body height (AVH) were obtained from digitized plain film anteroposterior (AP) and lateral radiographs of 18 symptomatic LBP patients presenting to a chiropractic office (8 female patients and 10 male patients, aged 15-69 years, mean 44.3, SD 15.4 years). Disk degeneration (DD) and facet arthrosis (FA) were qualitatively assessed from the films by an independent examiner. Anterior disk height ratios (ADHR = ADH/AVH) and posterior disk height ratios (PDHR = PDH/PVH) were calculated from the disk height measurements and were compared to L4 and L5 posteroanterior spinal stiffness obtained using a previously validated mechanical impedance stiffness assessment procedure. One third of the subjects were found to have radiographic evidence of mild or moderate DD and approximately two thirds of the subjects showed signs of mild or moderate FA. The L4 and L5 anterior disk height and posterior disk height were approximately one half and one fifth of the respective vertebral body heights, and the PA stiffness was greater at L4 than at L5. Male subjects had a greater ADHR than female subjects, but female subjects had a greater L4 and L5 PA stiffness in comparison to male subjects; however, these differences were not statistically significant. Posteroanterior L5 vertebral stiffness was found to be significantly correlated to the L5 PDHR. Computations of spinal input impedance are relatively simple to perform, can provide a noninvasive measure of the dynamic mechanical behavior of the spine, appear to have potential to discriminate pathologic changes to the spine, and warrant further study on a larger sample of normal subjects and patients.


Prospective Trial Evaluating the Surgical Anastomosis at One-Year Colorectal Cancer Surveillance: CT Colonography Versus Optical Colonoscopy and Implications for Patient Care.
The aim of this study was to compare the accuracy of CT colonography versus optical colonoscopy for neoplastic involvement at the surgical anastomosis 1 year after curative-intent colorectal cancer resection. Two hundred one patients (mean age, 58.6 years; 117 men, 84 women) underwent same-day contrast-enhanced CT colonography and colonoscopy approximately 1 year (mean, 12.1 months; median, 11.9 months) after colorectal cancer resection as part of a prospective, multicenter trial. All patients enrolled were without clinical evidence of disease and considered low risk for recurrence (stage I-III). Suspected neoplastic lesions within 5 cm of the colonic anastomosis were recorded at CT colonography, with subsequent colonoscopy performed for the same, with segmental unblinding of colonography findings. Anastomotic region biopsy or polypectomy was performed at the endoscopist's discretion. None of the 201 patients had intraluminal anastomotic cancer recurrence or advanced neoplasia (or metachronous cancers). CT colonography detected extramural perianastomotic recurrence in 2 patients (1.0%); neither was detected at colonoscopy. Only 2 patients (1.0%; 2/201) were called positive at CT colonography for intraluminal anastomotic nondiminutive lesions (7- to 8-mm polyps), which were confirmed at colonoscopy but nonneoplastic at histopathology. At optical colonoscopy, the anastomosis was deemed abnormal and/or biopsied in 10.0% (20/201), yielding only 1 nondiminutive benign neoplasm (7-mm tubular adenoma). The lack of luminal cancer recurrence in our lower-risk cohort precludes assessment of sensitivity for detection, rendering the study underpowered in this regard. Potential cost savings of combined CT/CT colonography over the standard CT/colonoscopy approach were not assessed. Relevant intraluminal anastomotic pathology appears to be very uncommon 1 year after colorectal cancer resection in lower-risk cohorts. Unlike colonoscopy, diagnostic contrast-enhanced CT colonography effectively evaluates both the intra- and extraluminal aspects of the anastomosis. See Video Abstract at http://links.lww.com/DCR/A471.


PROSHIFT: protein chemical shift prediction using artificial neural networks.
The importance of protein chemical shift values for the determination of three-dimensional protein structure has increased in recent years because of the large databases of protein structures with assigned chemical shift data. These databases have allowed the investigation of the quantitative relationship between chemical shift values obtained by liquid state NMR spectroscopy and the three-dimensional structure of proteins. A neural network was trained to predict the (1)H, (13)C, and (15)N of proteins using their three-dimensional structure as well as experimental conditions as input parameters. It achieves root mean square deviations of 0.3 ppm for hydrogen, 1.3 ppm for carbon, and 2.6 ppm for nitrogen chemical shifts. The model reflects important influences of the covalent structure as well as of the conformation not only for backbone atoms (as, e.g., the chemical shift index) but also for side-chain nuclei. For protein models with a RMSD smaller than 5 A a correlation of the RMSD and the r.m.s. deviation between the predicted and the experimental chemical shift is obtained. Thus the method has the potential to not only support the assignment process of proteins but also help with the validation and the refinement of three-dimensional structural proposals. It is freely available for academic users at the PROSHIFT server: www.jens-meiler.de/proshift.html


Effects of Graptopetalum paraguayense consumption on serum lipid profiles and antioxidative status in hypercholesteremic subjects.
Oxidative stress is known to be an important component of cellular damage regarding hypercholesterolemia and its complications. In vitro study had demonstrated that extracts of Graptopetalum paraguayense E. Walther exhibited strong antioxidative activities. This study was aimed at investigating the effect of G. paraguayense consumption on antioxidative status and serum lipid profiles in hypercholesterolemic subjects. Eighteen hypercholesterolemic subjects were instructed to consume 100 g G. paraguayense as a serving of vegetable daily for 8 consecutive weeks. After consumption, there were no changes in waist measurement, body mass index, body fat component, blood pressure, hepatic function (serum alanine aminotransferase activity), renal function (serum creatinine, uric acid) or fasting plasma glucose levels. Daily G. paraguayense consumption significantly increased ascorbic acid and α-tocopherol levels and decreased malondialdehyde level in plasma. Furthermore, daily G. paraguayense consumption significantly increased glutathione levels, glutathione peroxidase and catalase activities in erythrocyte. However, there were no significant changes in serum total cholesterol, triglyceride, low-density lipoprotein cholesterol or high-density lipoprotein cholesterol after G. paraguayense consumption. The present study demonstrated that consumption of G. paraguayense may increase in vivo antioxidant activities and have some protective effects in decreasing oxidative stress in hypercholesterolemic subjects.


beta-Amyloid(1-42) binds to alpha7 nicotinic acetylcholine receptor with high affinity. Implications for Alzheimer's disease pathology.
Alzheimer's disease pathology is characterized by the presence of neuritic plaques and the loss of cholinergic neurons in the brain. The underlying mechanisms leading to these events are unclear, but the 42-amino acid beta-amyloid peptide (Abeta(1-42)) is involved. Immunohistochemical studies on human sporadic Alzheimer's disease brains demonstrate that Abeta(1-42) and a neuronal pentameric cation channel, the alpha7 nicotinic acetylcholine receptor (alpha7nAChR), are both present in neuritic plaques and co-localize in individual cortical neurons. Using human brain tissues and cells that overexpress either alpha7nAChR or amyloid precursor protein as the starting material, Abeta(1-42) and alpha7nAChR can be co-immunoprecipitated by the respective specific antibodies, suggesting that they are tightly associated. The formation of the alpha7nAChR.Abeta(1-42) complex can be efficiently suppressed by Abeta(12-28), implying that this Abeta sequence region contains the binding epitope. Receptor binding experiments show that Abeta(1-42) and alpha7nAChR bind with high affinity, and this interaction can be inhibited by alpha7nAChR ligands. Human neuroblastoma cells overexpressing alpha7nAChR are readily killed by Abeta(1-42), whereas alpha7nAChR agonists such as nicotine and epibatidine offered protection. Because Abeta(1-42) inhibits alpha7nAChR-dependent calcium activation and acetylcholine release, two processes critically involved in memory and cognitive functions, and the distribution of alpha7nAChR correlates with neuritic plaques in Alzheimer's disease brains, we propose that interaction of the alpha7nAChR and Abeta(1-42) is a pivotal mechanism involved in the pathophysiology of Alzheimer's disease.


Estrogens, progestins, menopause and neurodegeneration: basic and clinical studies.
Two classes of ovarian steroids, estrogens and progestins, are potent in protecting neurons against acute toxic events as well as chronic neurodegeneration. Herein we review the evidence for neuroprotection by both classes of steroids, provide plausible mechanisms for these potent neuroprotective activities and indicate the need for further clinical trials of both estrogens and progestins in protection against acute and chronic conditions that cause neuronal death. Estrogens at concentrations ranging from physiological to pharmacological are neuroprotective in a variety of in vitro and in vivo models of cerebral ischemia and brain trauma as well as in reducing key neuropathologies of Alzheimer's disease. While the mechanisms of this potent neuroprotection are currently unresolved, a mitochondrial mechanism is involved. Progestins have been recently shown to activate many of the signaling pathways used by estrogens to neuroprotect, and progestins have been shown to protect against neuronal loss in vitro and in vivo in a variety of models of acute insult. Collectively, results of these animal and tissue culture models suggest that the loss of both estrogens and progestins at the menopause makes the brain more vulnerable to acute insults and chronic neurodegenerative diseases. Further clinical assessment of appropriate regimens of estrogens, progestins and their combination are supported by these data.


Relationship between depression and chronic periodontitis.
Periodontitis is a chronic, multifactorial, polymicrobial disease causing inflammation in the supporting structures of the teeth. There is a plethora of nonoral risk factors which can be quoted to aid in the development of chronic periodontitis. According to WHO, depression is a common mental disorder that presents with depressed mood, loss of interest or pleasure, feelings of guilt, disturbed sleep or appetite, low energy and poor concentration. Depression is associated with negligent oral health care and another mechanism proposed disturbance in the hypothalamic-pituitary axis system and hypothalamic-pituitary-thyroid system, which can affect the periodontal status by affecting the immune system. The aim of this study was to assess the association between periodontal clinical parameters and depression rating. The study design is a case-control study with 35 patients each in case and control group. The periodontal parameters taken for measurement were probing depth and clinical attachment loss. Depression was calculated using Beck's depression scale. The statistical analysis was performed by means of SPSS software (SPSS Inc., Chicago, IL, USA; version 17.0 under windows 2000). Student's t-test was used to determine the relationship between the clinical periodontal parameters and depression. Self-reported scoring of depression by using Beck's depression inventory has shown that periodontal patients had a significantly higher total depression score than normal controls. This study reveals that there is a direct correlation between the severity of periodontal disease and the severity of depression in patients.


Purification, characterisation and identification of acidocin LCHV, an antimicrobial peptide produced by Lactobacillus acidophilus n.v. Er 317/402 strain Narine.
In the last two decades, antimicrobial peptides (AMPs) have been gaining attention as antimicrobial alternatives to chemical food preservatives and commonly used antibiotics. Lactobacillus acidophilus n.v. Er 317/402 strain Narine produces a small AMP with a molecular weight of 1.1kDa, designated acidocin LCHV. In this study, the AMP was extremely heat stable (90min at 130 degrees C), was active over a wide pH range and was found to be sensitive to proteolytic enzymes (trypsin, pepsin and proteinase K). Acidocin LCHV has a broad spectrum of activity both against Gram-positive and Gram-negative pathogens, including several that are classified as Especially Dangerous Infections by the World Health Organization as well as meticillin-resistant Staphylococcus aureus (MRSA) and Clostridium difficile. Matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF/MS) was used to determine the molecular mass and sequence of the purified peptide. Complete killing with immediate impact on cells was observed within a very short period of time (10min).


Transmission and evolutionary dynamics of human coronavirus OC43 strains in coastal Kenya investigated by partial spike sequence analysis, 2015-16.
Human coronavirus OC43 (HCoV-OC43) is a major contributor to seasonal outbreaks of acute respiratory illness (ARI). The origins of locally circulating HCoV-OC43 strains and characteristics of their genetic diversity are unknown for most settings despite significance to effective HCoV control strategies. Between December 2015 and June 2016, we undertook ARI surveillance in coastal Kenya in nine outpatients and one inpatient health facility (HF). Ninety-two patient samples tested HCoV-OC43 positive and forty (43.5%) were successfully sequenced in spike (S) gene region (2,864 long, ∼70%). Phylogenetic analysis confirmed co-circulation of two distinct HCoV-OC43 clades that closely clustered with genotype G (n = 34, 85%) and genotype H (n = 6, 15%) reference strains. Local viruses within the same clade displayed low genetic diversity yielding identical sequences in multiple HF. Furthermore, the newly sequenced Kenyan viruses showed close phylogenetic relationship to other contemporaneous sampled strains (2015-16) including those originating from distant places (e.g. USA and China). Using a genetic similarity threshold of 99.1 per cent at nucleotide level, the HCoV-OC43 strains sampled globally between 1967 and 2019 fell into nine sequence clusters. Notably, some of these clusters appeared to have become extinct, or occurred only sporadically in a few geographical areas while others persisted globally for multiple years. In conclusion, we found that HCoV-OC43 strains spread rapidly both locally and across the globe with limited genetic evolution in the spike gene. Full-genome sequences that are spatio-temporally representative are required to advance understanding of the transmission pathways of this important human respiratory pathogen.


Expression of somatostatin receptor subtypes in human pituitary adenomas -- immunohistochemical studies.
The highly variable expression of SSTR subtypes in pituitary adenomas (PA) may partially explain why the subgroup of somatotropinomas or other adenomas do not respond to the therapeutic action of currently used long-acting somatostatin analogues like octreotide or lanreotide. Our study summarizes the data on expression of all somatostatin receptor subtypes (SSTR 1-5), extended for 2A and 2B SSTR isoforms, revealed by means of immunohistochemistry in dependence to different hormonal phenotype of the tumour. The pattern of SSTR immunostaining (estimated according to the percentage frequency of appearance) was in acromegaly: SSTR 5 > SSTR 1 > SSTR 2A = SSTR 3 > SSTR 2B, in prolactinomas: SSTR 2B = SSTR 3 = SSTR 5 > SSTR 1 = SSTR 2A, in gonadotropinomas: SSTR 3 > SSTR 2B > SSTR 1 = SSTR 2A > SSTR 5, in corticotropinomas: SSTR 2A > SSTR 1 = SSTR 3 > SSTR 5 > SSTR 2B. In PA immunonegative for pituitary hormones, we noticed only a weak staining of all receptor subtypes including SSTR 4. In plurihormonal adenomas with positive GH phenotype the staining pattern was: SSTR 5 > SSTR 1 = SSTR 2B and in plurihormonal PA with negative GH phenotype: SSTR 1 = SSTR 5 > SSTR 2A = SSTR 2B = SSTR 3. In plurihormonal adenoma with ACTH immunopositivity, the staining pattern was: SSTR = SSTR 2A = SSTR 3 = SSTR 5. SSTR 1 and SSTR 5 were the most frequent subtypes of somatostatin receptor in plurihormonal adenomas without ACTH expression. Human PA represents a group of tumours with a much more differentiated appearance of somatostatin receptor subtypes. It is very important to determine the SSTR profile individually for each tumour to make an appropriate decision as to therapeutic strategy choice. Apart from applying SSTR 2 and SSTR 5-preferring octreotide and lanreotide - newly synthesized multiligand analogues, such as SOM 230, KE 108, or other SST selective analogues, may represent a further useful approach for the treatment, especially in cases other than somatotropinoma or thyrotropinoma.


Inverse Identification of Single-Crystal Plasticity Parameters of HCP Zinc from Nanoindentation Curves and Residual Topographies.
This paper investigates the orientation-dependent characteristics of pure zinc under localized loading using nanoindentation experiments and crystal plasticity finite element (CPFEM) simulations. Nanoindentation experiments on different grain orientations exhibited distinct load-depth responses. Atomic force microscopy revealed two-fold unsymmetrical material pile-up patterns. Obtaining crystal plasticity model parameters usually requires time-consuming micromechanical tests. Inverse analysis using experimental and simulated loading-unloading nanoindentation curves of individual grains is commonly used, however the solution to the inverse identification problem is not necessarily unique. In this study, an approach is presented allowing the identification of CPFEM constitutive parameters from nanoindentation curves and residual topographies. The proposed approach combines the response surface methodology together with a genetic algorithm to determine an optimal set of parameters. The CPFEM simulations corroborate with measured nanoindentation curves and residual profiles and reveal the evolution of deformation activity underneath the indenter.


Patient Satisfaction and Treatments Offered to Swedish Patients with Suspected Pediatric Acute-Onset Neuropsychiatric Syndrome and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections.
Objectives: Pediatric acute-onset neuropsychiatric syndrome (PANS) and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) are subtypes of Obsessive-Compulsive Disorder (OCD) with suggested autoimmune etiology. Immunomodulatory treatments have been introduced as treatment options. A recent systematic review concluded that the evidence for all treatment options for PANS and PANDAS is inconclusive. However, case reports and clinical experience suggest that antibiotics and immunomodulatory treatment may be helpful. Treatment may also affect the patients' satisfaction with health care services offered. This study aims to describe the treatments given to a cohort of Swedish patients with suspected PANS and PANDAS, the patient rated treatment effects, and to establish if any specific treatment predicts higher patient satisfaction. Methods: Fifty-three patients (m = 33, f = 20, median age = 14, age range = 4-36) with suspected PANS or PANDAS were enrolled and assessed for PANS and PANDAS caseness, treatments given, treatment effects, global improvement, and patient satisfaction. Cases with confirmed and suspected PANS or PANDAS were compared regarding the frequency of treatments given and treatment effect. A linear regression model was used to see if treatments given or global improvement predicted patient satisfaction. Results: Twenty-four participants fulfilled criteria for PANS or PANDAS and 29 did not. The most common treatments given were antibiotics (88%), nonsteroidal anti-inflammatory drugs (67%), cognitive behavioral therapy (53%), and selective serotonin reuptake inhibitors (42%). There were no major differences between confirmed and suspected cases regarding what treatments they had received or their effect. Patient satisfaction was predicted by overall clinical improvement at the time of assessment. Antibiotics and intravenous immunoglobulin (IVIG) were rated as the most successful treatments by participants and were associated with higher patient satisfaction. Conclusions: It was more common that patients had received antibiotics than common psychiatric treatments for their psychiatric symptoms. Antibiotics and IVIG were experienced as effective treatments by the patients. Patient satisfaction was on average moderately low, and higher patient satisfaction was associated with global clinical improvement.


Sepsis-Associated Mortality, Resource Use, and Healthcare Costs: A Propensity-Matched Cohort Study.
To examine long-term mortality, resource utilization, and healthcare costs in sepsis patients compared to hospitalized nonsepsis controls. Propensity-matched population-based cohort study using administrative data. Ontario, Canada. We identified a cohort of adults (≥ 18) admitted to hospitals in Ontario between April 1, 2012, and March 31, 2016, with follow-up to March 31, 2017. Sepsis patients were flagged using a validated International Classification of Diseases, 10th Revision-coded algorithm (Sepsis-2 definition), including cases with organ dysfunction (severe sepsis) and without (nonsevere). Remaining hospitalized patients were potential controls. Cases and controls were matched 1:1 on propensity score, age, sex, admission type, and admission date. None. Differences in mortality, rehospitalization, hospital length of stay, and healthcare costs were estimated, adjusting for remaining confounders using Cox regression and generalized estimating equations. Of 270,669 sepsis cases, 196,922 (73%) were successfully matched: 64,204 had severe and 132,718 nonsevere sepsis (infection without organ dysfunction). Over follow-up (median 2.0 yr), severe sepsis patients had higher mortality rates than controls (hazard ratio, 1.66; 95% CI, 1.63-1.68). Both severe and nonsevere sepsis patients had higher rehospitalization rates than controls (hazard ratio, 1.53; 95% CI, 1.50-1.55 and hazard ratio, 1.41; 95% CI, 1.40-1.43, respectively). Incremental costs (Canadian dollar 2018) in sepsis cases versus controls at 1-year were: $29,238 (95% CI, $28,568-$29,913) for severe and $9,475 (95% CI, $9,150-$9,727) for nonsevere sepsis. Severe sepsis was associated with substantially higher long-term risk of death, rehospitalization, and healthcare costs, highlighting the need for effective postdischarge care for sepsis survivors.


Transparently reporting adverse effects of traditional Chinese medicine interventions in randomized controlled trials.
Although all Chinese materia medica (CMM) come from nature, CMM interventions have both therapeutic effects and adverse effects (AEs). Normally, AEs in randomized controlled trial (RCT) with traditional Chinese medicine (TCM) could be divided into five types as follows: 1) AEs under proper TCM principles and guidelines, such as the toxicity (acute and chronic) and allergy; 2) AEs due to improper usage without following TCM principles, involving without following the TCM therapeutic principles, over-dosage, improper processing and preparation methods, improper formula strategy, etc; 3) AEs due to contamination in CMM, such as heavy metal and pesticides contaminations in Chinese herbal medicine interventions, and intentional or unintentional contamination with drug(s); 4) AEs due to replacement of CMMs; 5) AEs due to drug-herb interaction. AEs of TCM should be treated properly. Overestimation or underestimation about AEs of TCM intervention will bring a wrong message to patients and health care providers. In order to give readers a more comprehensive understanding about the safety issue of study intervention, Consolidated Standards of Reporting Trials (CONSORT) for TCM should involve the background information on side effects of each CMM constituents and/or the study intervention, specific outcome assessment on AEs, the details of reported AEs and the interpretation of the AEs occurrence in a structural RCT report.


Evaluation of a novel Serious Game based assessment tool for patients with Alzheimer's disease.
Despite growing interest in developing ecological assessment of difficulties in patients with Alzheimer's disease new methods assessing the cognitive difficulties related to functional activities are missing. To complete current evaluation, the use of Serious Games can be a promising approach as it offers the possibility to recreate a virtual environment with daily living activities and a precise and complete cognitive evaluation. The aim of the present study was to evaluate the usability and the screening potential of a new ecological tool for assessment of cognitive functions in patients with Alzheimer's disease. Eighteen patients with Alzheimer's disease and twenty healthy controls participated to the study. They were asked to complete six daily living virtual tasks assessing several cognitive functions: three navigation tasks, one shopping task, one cooking task and one table preparation task following a one-day scenario. Usability of the game was evaluated through a questionnaire and through the analysis of the computer interactions for the two groups. Furthermore, the performances in terms of time to achieve the task and percentage of completion on the several tasks were recorded. Results indicate that both groups subjectively found the game user friendly and they were objectively able to play the game without computer interactions difficulties. Comparison of the performances between the two groups indicated a significant difference in terms of percentage of achievement of the several tasks and in terms of time they needed to achieve the several tasks. This study suggests that this new Serious Game based assessment tool is a user-friendly and ecological method to evaluate the cognitive abilities related to the difficulties patients can encounter in daily living activities and can be used as a screening tool as it allowed to distinguish Alzheimer's patient's performance from healthy controls.


Automated extraction of typing information for bacterial pathogens from whole genome sequence data: Neisseria meningitidis as an exemplar.
Whole genome sequence (WGS) data are increasingly used to characterise bacterial pathogens. These data provide detailed information on the genotypes and likely phenotypes of aetiological agents, enabling the relationships of samples from potential disease outbreaks to be established precisely. However, the generation of increasing quantities of sequence data does not, in itself, resolve the problems that many microbiological typing methods have addressed over the last 100 years or so; indeed, providing large volumes of unstructured data can confuse rather than resolve these issues. Here we review the nascent field of storage of WGS data for clinical application and show how curated sequence-based typing schemes on websites have generated an infrastructure that can exploit WGS for bacterial typing efficiently. We review the tools that have been implemented within the PubMLST website to extract clinically useful, strain-characterisation information that can be provided to physicians and public health professionals in a timely, concise and understandable way. These data can be used to inform medical decisions such as how to treat a patient, whether to instigate public health action, and what action might be appropriate. The information is compatible both with previous sequence-based typing data and also with data obtained in the absence of WGS, providing a flexible infrastructure for WGS-based clinical microbiology.


Clinical and socio demographic aspects of congestive heart failure patients at Kenyatta National Hospital, Nairobi.
To analyse the underlying aetiology, precipitating factors and certain socio-demographic determinants in patients admitted to Kenyatta National Hospital, Nairobi in congestive heart failure. Cross sectional descriptive study. All patients aged thirteen years and above of either sex consecutively admitted with clinical diagnosis of congestive heart failure. Kenyatta National Hospital (KNH), a national referral hospital. PATIENT EVALUATION: Detailed history including socio-demographic characteristics and physical examination was done. Patients underwent haematological and biochemistry tests followed by a chest x-ray, ECG and 2D Echo-doppler examination. Blood culture sensitivity was done when clinically indicated. Ninety one patients were studied, 44 males and 47 females. Almost 32% had rheumatic heart disease, 25.2% had cardiomyopathy, 17.6% hypertensive heart disease, 13.2% had pericardial disease while 2.2% had ischaemic heart disease. Three quarters of patients with hypertensive heart disease were above the age of 50 years, while 79% of patients with rheumatic heart disease were below the age of 30 years. Factors associated with patient deterioration leading to admission with congestive heart failure (CHF) included inadequate therapy (27.4%), arrhythmia (20.9%), respiratory infections (17.6%), anaemia (13.2%) and infective endocardiatis. Sixty two per cent of patients investigated were in New York Heart Association (NYHA) functional classification class IV, 31.9% in class III and 5.5% in class II. Congestive heart failure constitutes 3.3% of all medical admissions at KNH. Rheumatic heart disease is the commonest cause of congestive heart failure in our set-up while inadequate therapy, arrhythmias and respiratory infections are the three major causes of decompensation in our patients with cardiac disease.


Key targets of hormonal treatment of prostate cancer. Part 2: the androgen receptor and 5alpha-reductase.
The inhibition of 5alpha-reductase (5AR) blocks the synthesis of the most powerful intracellular androgen, dihydrotestosterone (DHT). The prostate has two 5AR isoenzymes (5AR1 and 5AR2) that change in expression and cellular location during the development of prostate cancer and tumour progression. The objective of this review is to provide an understanding of the pharmacological properties and the potential clinical benefits of 5AR inhibition. We searched Pubmed for data obtained from pharmacological, preclinical and clinical studies. 5AR1 expression increases with increasing aggressiveness and extension of malignant prostatic disease. Conversely, 5AR2 expression decreases from benign prostatic tissue to localized prostate cancer. The efficacy of 5AR2 monotherapy with finasteride alone or in combination with an androgen receptor antagonist on more final outcome measures seems to be limited. Combining an androgen receptor antagonist with a 5AR inhibitor in patients with asymptomatic, locally advanced or recurrent prostate cancer might be a reasonable first therapeutic hormonal approach. As plasma testosterone levels are maintained, beneficial effects on quality of life, potency and sexual function are expected. From studies on the dual 5AR inhibitor dutasteride, the drug produces a biochemical response in some men who progressed under androgen-deprivation therapy, and is generally well tolerated. Achieving more potent suppression of intracellular DHT synthesis by 5AR inhibition is expected to provide clinical benefit to patients. Previous studies have shown that 5AR inhibition, by dutasteride in particular, halts/delays the progression of disease, and might even cause regression of disease in patients with advanced prostate cancer.


Safety of a Novel Calcium/Potassium Saltof (-)-Hydroxycitric Acid (HCA-SX): II.Developmental Toxicity Study in Rats.
ABSTRACT (-)-Hydroxycitric acid (HCA), active constituent (10%-30%) of the dried fruit rind of Garcinia cambogia, is commonly used as a dietary supplement for weight management. The objective of the present study was to evaluate the teratogenic potential of a novel calcium/potassium salt of HCA (HCA-SX) in Sprague-Dawley rats. Due to its potential to affect fat synthesis and reduce food intake, processes that are often crucial in normal fetal development, this teratology study was undertaken as part of a multigeneration reproductive investigation. The animals in this study were selected randomly after weaning from each F(2b) litter of the F(1) generation from the two-generation reproductive toxicity study. To start the teratology study, Sprague-Dawley rat pups ( approximately 30/sex/group) from the F(2b) generation were allowed to grow up to 10 to 12 weeks of age before mating. The rats in the treatment group were exposed directly to HCA-SX through feed, while prior to their weaning, they had indirect exposure to the test material during lactation. The dietary exposure levels were the same as those employed for the two-generation reproductive toxicity study, viz. 1000, 3000, or 10,000 ppm. Following mating at maturity, the pregnant rats were observed daily for clinical signs of adverse effects, and body weight and feed consumption were recorded. On day 20 of gestation, animals were subjected to a necropsy and cesarean section to examine the uterus, ovaries, and fetuses for assessment of different parameters of pregnancy and embryo-fetal defects. Despite a slight (13%) lowering of maternal body weight gain during gestation period in the group receiving 10,000 ppm HCA-SX, no evidence of maternal toxicity, adverse effects on the parameters evaluated for the gravid uteri, external abnormalities in the fetuses, soft tissue abnormalities in the fetuses, or skeletal abnormalities in the fetuses were noted. Based on the results of this developmental toxicity study, conducted in continuation of a two-generation reproductive toxicity study, HCA-SX was not found to be teratogenic in the Sprague-Dawley rat at the dietary exposure levels of 1000, 3000, and 10,000 ppm, equivalent to the dose levels of 103, 352, or 1240 mg/kg/day, respectively.


Rapid perturbation of free-energy landscapes: from in vitro to in vivo.
Biological systems are often studied under the most "physiological" conditions possible. However, purposeful perturbation of biological systems can provide much information about their dynamics, robustness, and function. Such perturbations are particularly easy to apply at the interface of molecular biophysics and cellular biology, at which complex and highly regulated networks emerge from the behavior of individual biomolecules. Due to the size of diffusion coefficients and the length scale of biomolecules, the fastest timescales at this interface extend to below a microsecond. Thus perturbations must be induced and detected rapidly. We focus on examples of proteins and RNAs interacting with themselves (folding) or one another (binding, signaling). Beginning with general principles that have been learned from simple models and perturbation experiments in vitro, we progress to more complex environments that mimic aspects of the living cell, and finally rapid perturbation experiments in living cells. On the experimental side we highlight in particular two classes of rapid perturbation methods (nanoseconds to seconds) that have been traditionally employed in biophysical chemistry, but that will become increasingly important in cell biology and in vivo: fast relaxation techniques and phase-sensitive modulation techniques. These techniques are now increasingly married with imaging to produce a spatiotemporal map of biomolecular stability, dynamics and, in the near future, interaction networks inside cells. Many important chemical processes occur on biologically fast timescales, and yet have important ramifications for slower biological networks.


Deep intramedullary infection in tibial lengthening over an intramedullary nail.
Tibial lengthening over an intramedullary (IM) device is associated with a risk of deep intramedullary infection; there is so far no guideline for decision making between early removal and delayed removal of the nail. Tibial lengthening over an intramedullary nail/Rush pin was performed in 118 limb segments (63 patients) from 2004 to 2008 in our institution. Fifty five patients had bilateral tibial lengthening. Ninety nine of the 118 segments went on to healing without infection, while 13 segments developed superficial infection and 6 segments developed deep infection. Among 6 patients with deep infection, 4 patients underwent early removal of the nail when deep infection signs and symptoms occurred and 2 patients underwent delayed removal of the nail at 11 months. The 6 segments with deep infection differed significantly with respect t to the callus pattern (p < 0.05) and density (p = 0.0001) from those without infection and with superficial infection. In this small sugroup, removal of the nail was delayed in two patients as there was visible callus bridging at more than one cortex, and deep infection subsided after local drainage.


Burch colposuspension versus fascial sling to reduce urinary stress incontinence.
Many surgical procedures are available for women with urinary stress incontinence, yet few randomized clinical trials have been conducted to provide a basis for treatment recommendations. We performed a multicenter, randomized clinical trial comparing two procedures--the pubovaginal sling, using autologous rectus fascia, and the Burch colposuspension--among women with stress incontinence. Women were eligible for the study if they had predominant symptoms associated with the condition, a positive stress test, and urethral hypermobility. The primary outcomes were success in terms of overall urinary-incontinence measures, which required a negative pad test, no urinary incontinence (as recorded in a 3-day diary), a negative cough and Valsalva stress test, no self-reported symptoms, and no retreatment for the condition, and success in terms of measures of stress incontinence specifically, which required only the latter three criteria. We also assessed postoperative urge incontinence, voiding dysfunction, and adverse events. A total of 655 women were randomly assigned to study groups: 326 to undergo the sling procedure and 329 to undergo the Burch procedure; 520 women (79%) completed the outcome assessment. At 24 months, success rates were higher for women who underwent the sling procedure than for those who underwent the Burch procedure, for both the overall category of success (47% vs. 38%, P=0.01) and the category specific to stress incontinence (66% vs. 49%, P<0.001). However, more women who underwent the sling procedure had urinary tract infections, difficulty voiding, and postoperative urge incontinence. The autologous fascial sling results in a higher rate of successful treatment of stress incontinence but also greater morbidity than the Burch colposuspension. (ClinicalTrials.gov number, NCT00064662 [ClinicalTrials.gov] .).


An ensemble model of QSAR tools for regulatory risk assessment.
Quantitative structure activity relationships (QSARs) are theoretical models that relate a quantitative measure of chemical structure to a physical property or a biological effect. QSAR predictions can be used for chemical risk assessment for protection of human and environmental health, which makes them interesting to regulators, especially in the absence of experimental data. For compatibility with regulatory use, QSAR models should be transparent, reproducible and optimized to minimize the number of false negatives. In silico QSAR tools are gaining wide acceptance as a faster alternative to otherwise time-consuming clinical and animal testing methods. However, different QSAR tools often make conflicting predictions for a given chemical and may also vary in their predictive performance across different chemical datasets. In a regulatory context, conflicting predictions raise interpretation, validation and adequacy concerns. To address these concerns, ensemble learning techniques in the machine learning paradigm can be used to integrate predictions from multiple tools. By leveraging various underlying QSAR algorithms and training datasets, the resulting consensus prediction should yield better overall predictive ability. We present a novel ensemble QSAR model using Bayesian classification. The model allows for varying a cut-off parameter that allows for a selection in the desirable trade-off between model sensitivity and specificity. The predictive performance of the ensemble model is compared with four in silico tools (Toxtree, Lazar, OECD Toolbox, and Danish QSAR) to predict carcinogenicity for a dataset of air toxins (332 chemicals) and a subset of the gold carcinogenic potency database (480 chemicals). Leave-one-out cross validation results show that the ensemble model achieves the best trade-off between sensitivity and specificity (accuracy: 83.8 % and 80.4 %, and balanced accuracy: 80.6 % and 80.8 %) and highest inter-rater agreement [kappa (κ): 0.63 and 0.62] for both the datasets. The ROC curves demonstrate the utility of the cut-off feature in the predictive ability of the ensemble model. This feature provides an additional control to the regulators in grading a chemical based on the severity of the toxic endpoint under study.


Scalable graphene coatings for enhanced condensation heat transfer.
Water vapor condensation is commonly observed in nature and routinely used as an effective means of transferring heat with dropwise condensation on nonwetting surfaces exhibiting heat transfer improvement compared to filmwise condensation on wetting surfaces. However, state-of-the-art techniques to promote dropwise condensation rely on functional hydrophobic coatings that either have challenges with chemical stability or are so thick that any potential heat transfer improvement is negated due to the added thermal resistance of the coating. In this work, we show the effectiveness of ultrathin scalable chemical vapor deposited (CVD) graphene coatings to promote dropwise condensation while offering robust chemical stability and maintaining low thermal resistance. Heat transfer enhancements of 4× were demonstrated compared to filmwise condensation, and the robustness of these CVD coatings was superior to typical hydrophobic monolayer coatings. Our results indicate that graphene is a promising surface coating to promote dropwise condensation of water in industrial conditions with the potential for scalable application via CVD.


Anti-protein C antibodies and acquired protein C resistance in SLE: novel markers for thromboembolic events and disease activity?
Risk factors for thromboembolism in SLE are poorly understood. We hypothesized a possible role for protein C, based on its dual activity in inflammation and haemostasis and on the evidence of an association between acquired activated protein C (APC) resistance (APCR) and high-avidity anti-protein C antibodies (anti-PC) with a severe thrombotic phenotype in venous thrombosis APS patients. In a cross-sectional study of 156 SLE patients, the presence and avidity of IgG anti-PC was established by in house-ELISA, and APCR to exogenous recombinant human APC (rhAPC) and Protac (which activates endogenous protein C) was assessed by thrombin generation-based assays. Associations with aPL profile, thrombotic history and disease activity (BILAG and SLEDAI-2K) were also established. Anti-PC were detected in 54.5% of patients and APCR in 59%. Anti-PC positivity was associated with APCR to both rhAPC (P <0.0001) and Protac (P =0.0001). High-avidity anti-PC, detected in 26.3% of SLE patients, were associated with APCR in patients with thrombosis only (P <0.05), and with the development of thrombosis over time (range: 0-52 years; P =0.014). High-avidity anti-PC levels correlated with SLEDAI-2K (P =0.033) and total BILAG (P =0.019); SLEDAI-2K correlated inversely with APCR to Protac (P =0.004). Anti-PC occur in patients with SLE, independently of aPL profile, and are associated with APCR. High-avidity anti-PC are associated with thrombosis and with active disease and might prove a novel marker to monitor the risk of thrombosis and disease progression in SLE.


New insights into the performance of human whole-exome capture platforms.
Whole exome sequencing (WES) is increasingly used in research and diagnostics. WES users expect coverage of the entire coding region of known genes as well as sufficient read depth for the covered regions. It is, however, unknown which recent WES platform is most suitable to meet these expectations. We present insights into the performance of the most recent standard exome enrichment platforms from Agilent, NimbleGen and Illumina applied to six different DNA samples by two sequencing vendors per platform. Our results suggest that both Agilent and NimbleGen overall perform better than Illumina and that the high enrichment performance of Agilent is stable among samples and between vendors, whereas NimbleGen is only able to achieve vendor- and sample-specific best exome coverage. Moreover, the recent Agilent platform overall captures more coding exons with sufficient read depth than NimbleGen and Illumina. Due to considerable gaps in effective exome coverage, however, the three platforms cannot capture all known coding exons alone or in combination, requiring improvement. Our data emphasize the importance of evaluation of updated platform versions and suggest that enrichment-free whole genome sequencing can overcome the limitations of WES in sufficiently covering coding exons, especially GC-rich regions, and in characterizing structural variants.


Interplay between competitive and cooperative interactions in a three-player pathogen system.
In ecological systems, heterogeneous interactions between pathogens take place simultaneously. This occurs, for instance, when two pathogens cooperate, while at the same time, multiple strains of these pathogens co-circulate and compete. Notable examples include the cooperation of human immunodeficiency virus with antibiotic-resistant and susceptible strains of tuberculosis or some respiratory infections with Streptococcus pneumoniae strains. Models focusing on competition or cooperation separately fail to describe how these concurrent interactions shape the epidemiology of such diseases. We studied this problem considering two cooperating pathogens, where one pathogen is further structured in two strains. The spreading follows a susceptible-infected-susceptible process and the strains differ in transmissibility and extent of cooperation with the other pathogen. We combined a mean-field stability analysis with stochastic simulations on networks considering both well-mixed and structured populations. We observed the emergence of a complex phase diagram, where the conditions for the less transmissible, but more cooperative strain to dominate are non-trivial, e.g. non-monotonic boundaries and bistability. Coupled with community structure, the presence of the cooperative pathogen enables the coexistence between strains by breaking the spatial symmetry and dynamically creating different ecological niches. These results shed light on ecological mechanisms that may impact the epidemiology of diseases of public health concern.


The Role of Robotic Path Assistance and Weight Support in Facilitating 3D Movements in Individuals With Poststroke Hemiparesis.
Background. High-intensity repetitive training is challenging to provide poststroke. Robotic approaches can facilitate such training by unweighting the limb and/or by improving trajectory control, but the extent to which these types of assistance are necessary is not known. Objective. The purpose of this study was to examine the extent to which robotic path assistance and/or weight support facilitate repetitive 3D movements in high functioning and low functioning subjects with poststroke arm motor impairment relative to healthy controls. Methods. Seven healthy controls and 18 subjects with chronic poststroke right-sided hemiparesis performed 300 repetitions of a 3D circle-drawing task using a 3D Cable-driven Arm Exoskeleton (CAREX) robot. Subjects performed 100 repetitions each with path assistance alone, weight support alone, and path assistance plus weight support in a random order over a single session. Kinematic data from the task were used to compute the normalized error and speed as well as the speed-error relationship. Results. Low functioning stroke subjects (Fugl-Meyer Scale score = 16.6 ± 6.5) showed the lowest error with path assistance plus weight support, whereas high functioning stroke subjects (Fugl-Meyer Scale score = 59.6 ± 6.8) moved faster with path assistance alone. When both speed and error were considered together, low functioning subjects significantly reduced their error and increased their speed but showed no difference across the robotic conditions. Conclusions. Robotic assistance can facilitate repetitive task performance in individuals with severe arm motor impairment, but path assistance provides little advantage over weight support alone. Future studies focusing on antigravity arm movement control are warranted poststroke.


UK phenomics platform for developing and validating electronic health record phenotypes: CALIBER.
Electronic health records (EHRs) are a rich source of information on human diseases, but the information is variably structured, fragmented, curated using different coding systems, and collected for purposes other than medical research. We describe an approach for developing, validating, and sharing reproducible phenotypes from national structured EHR in the United Kingdom with applications for translational research. We implemented a rule-based phenotyping framework, with up to 6 approaches of validation. We applied our framework to a sample of 15 million individuals in a national EHR data source (population-based primary care, all ages) linked to hospitalization and death records in England. Data comprised continuous measurements (for example, blood pressure; medication information; coded diagnoses, symptoms, procedures, and referrals), recorded using 5 controlled clinical terminologies: (1) read (primary care, subset of SNOMED-CT [Systematized Nomenclature of Medicine Clinical Terms]), (2) International Classification of Diseases-Ninth Revision and Tenth Revision (secondary care diagnoses and cause of mortality), (3) Office of Population Censuses and Surveys Classification of Surgical Operations and Procedures, Fourth Revision (hospital surgical procedures), and (4) DM+D prescription codes. Using the CALIBER phenotyping framework, we created algorithms for 51 diseases, syndromes, biomarkers, and lifestyle risk factors and provide up to 6 validation approaches. The EHR phenotypes are curated in the open-access CALIBER Portal (https://www.caliberresearch.org/portal) and have been used by 40 national and international research groups in 60 peer-reviewed publications. We describe a UK EHR phenomics approach within the CALIBER EHR data platform with initial evidence of validity and use, as an important step toward international use of UK EHR data for health research.


The mitochondrial protein hFis1 regulates mitochondrial fission in mammalian cells through an interaction with the dynamin-like protein DLP1.
The yeast protein Fis1p has been shown to participate in mitochondrial fission mediated by the dynamin-related protein Dnm1p. In mammalian cells, the dynamin-like protein DLP1/Drp1 functions as a mitochondrial fission protein, but the mechanisms by which DLP1/Drp1 and the mitochondrial membrane interact during the fission process are undefined. In this study, we have tested the role of a mammalian homologue of Fis1p, hFis1, and provided new and mechanistic information about the control of mitochondrial fission in mammalian cells. Through differential tagging and deletion experiments, we demonstrate that the intact C-terminal structure of hFis1 is essential for mitochondrial localization, whereas the N-terminal region of hFis1 is necessary for mitochondrial fission. Remarkably, an increased level of cellular hFis1 strongly promotes mitochondrial fission, resulting in an accumulation of fragmented mitochondria. Conversely, cell microinjection of hFis1 antibodies or treatment with hFis1 antisense oligonucleotides induces an elongated and collapsed mitochondrial morphology. Further, fluorescence resonance energy transfer and coimmunoprecipitation studies demonstrate that hFis1 interacts with DLP1. These results suggest that hFis1 participates in mitochondrial fission through an interaction that recruits DLP1 from the cytosol. We propose that hFis1 is a limiting factor in mitochondrial fission and that the number of hFis1 molecules on the mitochondrial surface determines fission frequency.


Flow estimation solely from image data through persistent homology analysis.
Topological data analysis is an emerging concept of data analysis for characterizing shapes. A state-of-the-art tool in topological data analysis is persistent homology, which is expected to summarize quantified topological and geometric features. Although persistent homology is useful for revealing the topological and geometric information, it is difficult to interpret the parameters of persistent homology themselves and difficult to directly relate the parameters to physical properties. In this study, we focus on connectivity and apertures of flow channels detected from persistent homology analysis. We propose a method to estimate permeability in fracture networks from parameters of persistent homology. Synthetic 3D fracture network patterns and their direct flow simulations are used for the validation. The results suggest that the persistent homology can estimate fluid flow in fracture network based on the image data. This method can easily derive the flow phenomena based on the information of the structure.


Novel strategies for Alzheimer's disease treatment: An overview of anti-amyloid beta monoclonal antibodies.
Alzheimer's disease (AD) is a multifactorial, progressive neurodegenerative disorder with a poor prognosis, and thus, novel therapies for AD are certainly needed in a growing population of elderly patients or asymptomatic individuals, who are at risk for AD, worldwide. It has been established that some AD biomarkers such as amyloid-beta load in the brain, precede the onset of the disease, by approximately 20 years. Therefore, the therapy to prevent or effectively treat AD has to be initiated before the emergence of symptoms. A goal of this review is to present the results of recent clinical trials on monoclonal antibodies against amyloid beta, used for the treatment of AD and also to address some of the current challenges and emerging strategies to prevent AD. In recent trials, a monoclonal antibody, i.e. solanezumab has shown some beneficial cognitive effects among mild AD patients. Ongoing studies with gantenerumab and crenezumab will examine when exactly the AD treatment, aimed at modifying the disease course has to be started. This review was based on Medline database search for trials on passive anti-AD immunotherapy, for which the main timeframe was set from 2012 to 2015.


Stat3 regulates desmoglein 3 transcription in epithelial keratinocytes.
Pemphigus vulgaris (PV) is an epithelial blistering disease caused by autoantibodies to the desmosomal cadherin desmoglein 3 (DSG3). Glucocorticoids improve disease within days by increasing DSG3 gene transcription, although the mechanism for this observation remains unknown. Here, we show that DSG3 transcription in keratinocytes is regulated by Stat3. Treatment of primary human keratinocytes (PHKs) with hydrocortisone or rapamycin, but not the p38 MAPK inhibitor SB202190, significantly increases DSG3 mRNA and protein expression and correspondingly reduces phospho-S727 Stat3. Stat3 inhibition or shRNA-knockdown also significantly increases DSG3 mRNA and protein levels. Hydrocortisone- or rapamycin-treated PHKs demonstrate increased number and length of desmosomes by electron microscopy and are resistant to PV IgG-induced loss of cell adhesion, whereas constitutive activation of Stat3 in PHKs abrogates DSG3 upregulation and inhibits hydrocortisone and rapamycin's therapeutic effects. Topical hydrocortisone, rapamycin, or Stat3 inhibitor XVIII prevents autoantibody-induced blistering in the PV passive transfer mouse model, correlating with increased epidermal DSG3 expression and decreased phospho-S727 Stat3. Our data indicate that glucocorticoids and rapamycin upregulate DSG3 transcription through inhibition of Stat3. These studies explain how glucocorticoids rapidly improve pemphigus and may also offer novel insights into the physiologic and pathophysiologic regulation of desmosomal cadherin expression in normal epidermis and epithelial carcinomas.


The relative extensibility of cell surfaces.
Observations have been made on the response, in vitro, of cultured and freshly dissociated cells to mechanical deformation. Large numbers of individual cells were studied by means of a special culture chamber bounded by two parallel glass coverslips whose spacing could be reduced from 140 to 2 microns in steps of roughly 0.5 micron. The degree of deformation required for herniation of the cell surface was measured. These measurements lead to the definition of a statistical index characteristic of the extensibility of cell surfaces. This index has been shown to be distinctive for several types of cells; to alter with certain stages of embryonic development; and to be stable with respect to the culturing of cells and certain alterations in the method of cell culture.


Nitric oxide and apoptosis induced in Peyer's patches by attenuated strains of Salmonella enterica serovar Enteritidis.
Nitric oxide (NO) is a toxic molecule of the immune system which contributes to the control of microbial pathogens. Additional functions of NO in innate and adaptive immunity have recently been described; these functions include the modulation of the cytokine response of lymphocytes and the regulation of immune cell apoptosis. In addition to direct microbicidal actions, NO has immunoregulatory effects relevant to the control of infections. In turn, infected macrophages and macrophage-regulating lymphocytes may undergo apoptosis during infection by Salmonella spp. In this work we investigated the ability of attenuated strains of Salmonella enterica serovar Enteritidis with different protective capacities to induce intestinal inducible nitric oxide synthase (iNOS) and apoptosis in Peyer's patches (PP) in mice. Results showed that the intestinal iNOS activity correlated with increased apoptosis in PP. Furthermore, the ability to induce intestinal NO production and apoptosis within the first few hours after immunization seemed to correlate with the protective capacity of mutant E/1/3 of S. enterica serovar Enteritidis. It was found that nonprotective mutant C/2/2, which was unable to induce intestinal NO production, also failed to induce apoptosis in PP. Moreover, aminoguanidine treatment at the time of immunization resulted in inhibition of the NO production and apoptosis induced by protective mutant E/1/3 and completely abolished protection against challenge. These results suggest that the induction of iNOS in the intestinal mucosa by attenuated mutant E/1/3 of S. enterica serovar Enteritidis at the time of immunization is necessary to generate a protective immune response.


Opposing transcriptional outputs of Hedgehog signaling and engrailed control compartmental cell sorting at the Drosophila A/P boundary.
The wing imaginal disc is subdivided into two nonintermingling sets of cells, the anterior (A) and posterior (P) compartments. Anterior cells require reception of the Hedgehog (Hh) signal to segregate from P cells. We provide evidence that Hh signaling controls A/P cell segregation not by directly modifying structural components but by a Cubitus interruptus (Ci)-mediated transcriptional response. A shift in the balance between repressor and activator forms of Ci toward the activator form is necessary and sufficient to define "A-type" cell sorting behavior. Moreover, we show that Engrailed (En), in the absence of Ci, is sufficient to specify "P-type" sorting. We propose that the opposing transcriptional activities of Ci and En control cell segregation at the A/P boundary by regulating a single cell adhesion molecule.


Spatial and temporal variations of persistent organic pollutants impacted by episodic sediment resuspension in southern Lake Michigan.
The impacts of large-scale, episodic sediment resuspension on the cycling of polychlorinated biphenyl congeners (PCBs) were examined using a spatially coordinated air and water sampling strategy conducted in southern Lake Michigan in the late winters of 1998, 1999, and 2000. We found no significant temporal changes in gas phase, dissolved phase, or suspended sediment PCB concentrations despite large-scale seasonal storms occurring before and after sampling campaigns. Only gas phase and suspended sediment PCBs varied spatially. Higher total suspended material (TSM) concentrations and fraction organic carbon (foc ) were measured at sampling stations located in the near-shore region of southern Lake Michigan than at open-water sampling stations. Gas phase concentrations (ΣPCBg) were higher in the west (0.436 ± 0.200 ng/m3, n = 11) and south (0.408 ± 0.286 ng/m3, n = 5) than the east (0.214 ± 0.082 ng/m3, n = 10) and central (0.253 ± 0.145 ng/m3, n = 8) regions of southern Lake Michigan. Dissolved phase concentrations (ΣPCBd) averaged 0.18 ± 0.024 ng/L (n = 52); suspended sediment concentrations (ΣPCBs) accounted for between 4% and 72% (23 ± 4%, n = 52) of the total ΣPCB concentrations (ΣPCBT = ΣPCBd + ΣPCBs). Despite no consistent temporal variations in both dissolved phase or suspended sediment ΣPCB concentrations, there were temporal and spatial variations in the distribution shift between phases that can be linked to sediment resuspension, not a state of equilibrium. Specifically, our analysis suggests sediment resuspension results in preferential sorption of heavier, more chlorinated PCB congeners.


Recurrent episodes of falls and amnestic confusional states as diagnostic challenge in the elderly.
New-onset paroxysmal events in patients over 60 years of age are often diagnostically challenging owing to atypical presentation. Recurrent falls and transient states of confusion are especially common in the elderly population, yet their causes often remain undiagnosed due to concomitant cognitive deficits and motor impairments. We present an elderly patient with newly occurring 'blackouts' without obvious triggers and transient states of confusion for which he was amnestic. All neurological exams including brain MRI scan and routine electroencephalography (EEG) were normal. Long-term ECG monitoring using an event recorder captured an asystole during a habitual episode, leading to the diagnosis of syncope and pacemaker implantation. A subsequent video EEG monitoring performed due to ongoing unexplained confusional states revealed both bradycardia and long-lasting confusional states to be caused by unrecognised temporal lobe seizures. Ictal video EEG monitoring may play a crucial role in establishing a diagnosis of atypical temporal lobe seizures in the elderly.


Externalizing behaviors among adopted children: A longitudinal comparison of preadoptive childhood sexual abuse and other forms of maltreatment.
Previous research has established that child sexual abuse (CSA) and other forms of child maltreatment can have lasting and profound implications for survivors in terms of externalizing symptomatology. Few studies, however, have examined long-term consequences of CSA and maltreatment among adopted children. Guided by a polyvictimization framework, the present study investigated: (a) rates of co-occurrence of pre-adoptive CSA and maltreatment among adopted children, and (b) the relative impact of pre-adoptive CSA and maltreatment on externalizing behaviors at 14 years post-adoption. Analyses were based on four waves of data from the California Long-Range Adoption Study (CLAS) (n = 522); outcomes were measured using an adapted version of the Behavioral Problems Index (BPI). The diverse sample (36% non-White) was evenly divided by gender (50% female/male) and included a large number of children adopted from foster care (42.1%). Results indicated that 24.3% (n = 127) of children experienced at least one form of maltreatment; of those children, nearly half (46.5%; n = 59) experienced multiple abuse types (e.g., neglect, sexual, physical). Among cases of CSA (7.7%; n = 40), the vast majority (92.5%; n = 37) occurred with other forms of maltreatment. Hierarchical linear mixed models indicated that pre-adoptive CSA was associated with nearly a full unit increase in BPI scores (.92; p<.01). Neglect was associated with nearly a half unit increase in BPI (.48; p<.05). Gender was also significant; girls had lower BPI scores than boys (-0.57; p< .001). Implications for future research and practice are discussed.


The pipeline system for Octave and Matlab (PSOM): a lightweight scripting framework and execution engine for scientific workflows.
The analysis of neuroimaging databases typically involves a large number of inter-connected steps called a pipeline. The pipeline system for Octave and Matlab (PSOM) is a flexible framework for the implementation of pipelines in the form of Octave or Matlab scripts. PSOM does not introduce new language constructs to specify the steps and structure of the workflow. All steps of analysis are instead described by a regular Matlab data structure, documenting their associated command and options, as well as their input, output, and cleaned-up files. The PSOM execution engine provides a number of automated services: (1) it executes jobs in parallel on a local computing facility as long as the dependencies between jobs allow for it and sufficient resources are available; (2) it generates a comprehensive record of the pipeline stages and the history of execution, which is detailed enough to fully reproduce the analysis; (3) if an analysis is started multiple times, it executes only the parts of the pipeline that need to be reprocessed. PSOM is distributed under an open-source MIT license and can be used without restriction for academic or commercial projects. The package has no external dependencies besides Matlab or Octave, is straightforward to install and supports of variety of operating systems (Linux, Windows, Mac). We ran several benchmark experiments on a public database including 200 subjects, using a pipeline for the preprocessing of functional magnetic resonance images (fMRI). The benchmark results showed that PSOM is a powerful solution for the analysis of large databases using local or distributed computing resources.


The self as healer: reflections from a nurse's journey.
Complementary and alternative medicine is rapidly making its way into the mainstream through the addition of a variety of therapies in existing settings. Yet, in national surveys, the public seems interested not only in alternative therapies, but also in a more holistic form of healthcare. Nurses have a critical role to play in creating such a healthcare system. Recovering their own identity as healers is a first step in that direction. This article explores the topic of the self as healer through four key questions: what is healing, who or what is the locus of healing, how can nurses facilitate healing, and how does one become a healer?


Predictive Validity of an Empirical Approach for Selecting Promising Message Topics: A Randomized-Controlled Study.
Several message topic selection approaches propose that messages based on beliefs pretested and found to be more strongly associated with intentions will be more effective in changing population intentions and behaviors when used in a campaign. This study aimed to validate the underlying causal assumption of these approaches which rely on cross-sectional belief-intention associations. We experimentally tested whether messages addressing promising themes as identified by the above criterion were more persuasive than messages addressing less promising themes. Contrary to expectations, all messages increased intentions. Interestingly, mediation analyses showed that while messages deemed promising affected intentions through changes in targeted promising beliefs, messages deemed less promising also achieved persuasion by influencing nontargeted promising beliefs. Implications for message topic selection are discussed.