The effect of N-heterocyclic carbene units on the absorption spectra of Fe(II) complexes: a challenge for theory.
The absorption spectra of five Fe(ii) homoleptic and heteroleptic complexes containing strong sigma-donating N-heterocyclic carbene (NHC) and polypyridyl ligands have been theoretically characterized using a tuned range-separation functional. From a benchmark comparison of the obtained results against other functionals and a multiconfigurational reference, it is concluded that none of the methods is completely satisfactory to describe the absorption spectra. As a compromise using 20% exact exchange, the electronic excited states underlying the absorption spectra are analyzed. The low-lying energy band of all the compounds shows predominant metal-to-ligand charge transfer (MLCT) character while the triplet excited states have metal-centered (MC) nature, which becomes more pronounced with increasing the number of NHC-donor groups. Excited MC states with partial charge transfer to the NHC-donor groups are higher in energy than comparable states without these contributions. The presence of the low-lying MC states prevents the formation of long-lived MLCT states.


Effect of a School-Based Water Intervention on Child Body Mass Index and Obesity.
Decreasing the amount of caloric beverages consumed and simultaneously increasing water consumption is important to promoting child health and decreasing the prevalence of childhood obesity. To estimate the impact of water jets (electrically cooled, large clear jugs with a push lever for fast dispensing) on standardized body mass index, overweight, and obesity in elementary school and middle school students. Milk purchases were explored as a potential mechanism for weight outcomes. This quasi-experimental study used a school-level database of cafeteria equipment deliveries between the 2008-2009 and 2012-2013 and included a sample of 1227 New York, New York, public elementary schools and middle schools and the 1,065,562 students within those schools. Installation of water jets in schools. Individual body mass index (BMI) was calculated for all students in the sample using annual student-level height and weight measurements collected as part of New York's FITNESSGRAM initiative. Age- and sex-specific growth charts produced by the Centers for Disease Control and Prevention were used to categorize students as overweight and obese. The hypothesis that water jets would be associated with decreased standardized BMI, overweight, and obesity was tested using a difference-in-difference strategy, comparing outcomes for treated and nontreated students before and after the introduction of a water jet. This study included 1 065 562 students within New York City public elementary schools and middle schools. There was a significant effect of water jets on standardized BMI, such that the adoption of water jets was associated with a 0.025 (95% CI, -0.038 to -0.011) reduction of standardized BMI for boys and a 0.022 (95% CI, -0.035 to -0.008) reduction of standardized BMI for girls (P < .01). There was also a significant effect on being overweight. Water jets were associated with a 0.9 percentage point reduction (95% CI, 0.015-0.003) in the likelihood of being overweight for boys and a 0.6 percentage reduction (95% CI, 0.011-0.000) in the likelihood of being overweight for girls (P < .05). We also found a 12.3 decrease (95% CI, -19.371 to -5.204) in the number of all types of milk half-pints purchased per student per year (P < .01). Results from this study show an association between a relatively low-cost water availability intervention and decreased student weight. Milk purchases were explored as a potential mechanism. Additional research is needed to examine potential mechanisms for decreased student weight, including reduced milk taking, as well as assessing impacts on longer-term outcomes.


Simultaneous PML-IRIS after discontinuation of natalizumab in a patient with MS.
Progressive multifocal leukoencephalopathy (PML) is a severe complication of natalizumab therapy in patients with multiple sclerosis (MS), which is often accompanied by an immune reconstitution inflammatory syndrome (IRIS) after removal of the drug. We describe a patient with MS who presented with simultaneous PML-IRIS 2 months after stopping natalizumab for other reasons. The patient had widespread PML and severe IRIS. He received corticosteroids and displayed a vigorous JC virus-specific cellular immune response. Elevated myoinositol and lipid/creatine peaks measured in PML lesions by proton magnetic resonance spectroscopy ((1)H-MRS) corresponded to episodes of contrast enhancement on MRI scans and persisted after the enhancement subsided. He demonstrated steady clinical improvement, but developed marked residual atrophy in areas affected by PML and inflammation, as well as seizures. New enhancing white matter lesions, occurring after discontinuation of natalizumab, can be the manifestation of PML-IRIS rather than an MS exacerbation. Elevated myoinositol and lipid/creatine peaks appear to be more sensitive markers of inflammation in PML lesions than contrast enhancement. (1)H-MRS may become useful as a biomarker for PML-IRIS by helping clinicians determine the need for corticosteroid administration and anticipate continuing clinical recovery.


PBPK models for the prediction of in vivo performance of oral dosage forms.
Drug absorption from the gastrointestinal (GI) tract is a highly complex process dependent upon numerous factors including the physicochemical properties of the drug, characteristics of the formulation and interplay with the underlying physiological properties of the GI tract. The ability to accurately predict oral drug absorption during drug product development is becoming more relevant given the current challenges facing the pharmaceutical industry. Physiologically-based pharmacokinetic (PBPK) modeling provides an approach that enables the plasma concentration-time profiles to be predicted from preclinical in vitro and in vivo data and can thus provide a valuable resource to support decisions at various stages of the drug development process. Whilst there have been quite a few successes with PBPK models identifying key issues in the development of new drugs in vivo, there are still many aspects that need to be addressed in order to maximize the utility of the PBPK models to predict drug absorption, including improving our understanding of conditions in the lower small intestine and colon, taking the influence of disease on GI physiology into account and further exploring the reasons behind population variability. Importantly, there is also a need to create more appropriate in vitro models for testing dosage form performance and to streamline data input from these into the PBPK models. As part of the Oral Biopharmaceutical Tools (OrBiTo) project, this review provides a summary of the current status of PBPK models available. The current challenges in PBPK set-ups for oral drug absorption including the composition of GI luminal contents, transit and hydrodynamics, permeability and intestinal wall metabolism are discussed in detail. Further, the challenges regarding the appropriate integration of results from in vitro models, such as consideration of appropriate integration/estimation of solubility and the complexity of the in vitro release and precipitation data, are also highlighted as important steps to advancing the application of PBPK models in drug development. It is expected that the "innovative" integration of in vitro data from more appropriate in vitro models and the enhancement of the GI physiology component of PBPK models, arising from the OrBiTo project, will lead to a significant enhancement in the ability of PBPK models to successfully predict oral drug absorption and advance their role in preclinical and clinical development, as well as for regulatory applications.


Prevalence and Density of Demodex folliculorum and Demodex brevis (Acari: Demodicidae) in Erzincan Province.
This study aimed to determine the prevalence and density of Demodex folliculorum and D. brevis in Erzincan Province and the association between Demodex spp. and skin moisture, pH, and temperature. The study included total 300 healthy participants without dermatological ailments and residing in Erzincan Province. Moisture, pH, and temperature of the cheek were measured, and the presence of mite was determined in samples from the cheek, nasolabial, and chin region using the standard superficial skin biopsy technique. The prevalence and density of D. folliculorum and D. brevis were found to be 61.3% (mean 14.3/cm2) and 23.3% (mean 3.2/cm2), respectively, in healthy participants. Infestation by Demodex spp. was greater in the cheek (mean 10.4/cm2), followed by the nasolabial region (mean 7.2/cm2) and chin (mean 6.6/cm2), respectively (p<0.001). The prevalence and density of Demodex spp. were greater in those with dry skin (mean 11.6/cm2), pH of 5.5-7.0 (mean 11.2/cm2), and temperature of 20-23°C (mean 13.1/cm2). Males, with aged >60 years, with lower educational status, and who were single were significantly more infested with Demodex spp. Demodex mites are very prevalent in healthy individuals with different skin moisture, skin pH, skin temperature, and demographic characteristics. This may be taken into consideration when epidemiological and clinical studies are conducted on patients having different dermatological ailments.


Characterization of a novel receptor mutation A-->T at exon 4 in complete androgen insensitivity syndrome and a carrier sibling via bidirectional polymorphism sequence analysis.
The complete androgen insensitivity syndrome (AIS) is a sub-type of X-linked male pseudohermaphroditism resulting from total dysfunction of the androgen receptor. Affected patients are phenotypically female despite a 46,XY genotype; gonadal tissue displays a classic Sertoli cell-only pattern on microscopic examination. We describe the diagnosis and management of a 19(1/2)-year-old patient who presented for primary amenorrhea and absent cervix, identified incidentally during a routine Pap test. Serum total testosterone was elevated (725 ng/dl) and the karyotype was 46,XY. Molecular investigation for specific gene defect(s) causing disruption and functional incapacity of the androgen receptor was undertaken for the proband and her only sibling. From this we discovered a previously unknown hemizygous mutation (A-->T) in exon 4 of the androgen receptor gene, associated with replacement of asparagine (AAT) with tyrosine (TAT) in the resultant androgen receptor protein [N705Y]. Bidirectional, non-isotopic sequence analysis of exon 4 was next undertaken for the proband's sister who was found to be heterozygous for this mutation. Psychological and genetic counseling was provided to both individuals; the patient underwent an outpatient laparoscopic orchiectomy without complication. She continues to receive oral hormone replacement therapy following an oral contraceptive model. In this report, the clinical approach to AIS is outlined from a reproductive endocrinology perspective with special emphasis on psychological counseling and laboratory methods employed to confirm the diagnosis at the molecular level. We also outline other recently described mutations of the androgen receptor gene (Xq11-12) which have been associated with AIS.


Expression of human FALS SOD in motorneurons of Drosophila.
Mutations in human CuZn superoxide dismutase (SOD) have been associated with familial amyotrophic lateral sclerosis (FALS). Although leading to many experimental advances, this finding has not yet led to a clear understanding of the biochemical mechanism by which mutations in SOD promote the degeneration of motorneurons that causes this incurable paralytic disease. To explore the biochemical mechanism of FALS SOD-mediated neuropathogenesis, we used transgenic methodology to target the expression of a human FALS SOD to motorneurons of Drosophila, an organism known for its phenotypic sensitivity to genetic manipulation of SOD. Earlier, we showed that targeted expression of human SOD in motorneurons of Drosophila causes a dramatic extension of adult lifespan (>40%) and rescues most of the phenotypes of SOD-null mutants. Using the same genetic system, we now ask if targeted expression of a mutant allele of human SOD that is associated with FALS causes paralysis and premature death, or is otherwise injurious in Drosophila as it is in humans and transgenic mice. Here we report that high-level expression of a human FALS SOD in motorneurons is not detrimental and does not promote paralysis and premature death when expressed in motorneurons of Drosophila. In sharp contrast, the expression of FALS SOD in Drosophila actually extends lifespan, augments resistance to oxidative stress and partially rescues SOD-null mutants in a manner predicted by our earlier studies on the expression of wildtype human SOD in Drosophila motorneurons.


Educational intervention to improve breast health knowledge among women in Jordan.
Breast cancer is the most common cancer among women in Jordan and on average 70% of the cases present at advanced stages. The aim of this study was to assess the effectiveness of a public educational campaign conducted by the Jordan Breast Cancer Program to improve breast health knowledge among Jordanian women and to relate their knowledge to breast health practices. The campaign was conducted in five governorates in Jordan with a total of 105 public group lectures about breast cancer focusing on early detection. The total number of participants was 2,554 women with a median age of 37 years (range: 15-73 years). Median number of women per lecture was 24 (range: 9-38). Before the lectures, the women answered a structured questionnaire about their knowledge and practices. After the intervention 2,418 of them filled a post-test questionnaire with the same content. Correct answers on the 15 knowledge questions yielded a maximum score of 15. Determinants of breast health practices were identified using multivariable logistic regression analysis. The mean knowledge score increased significantly from 10.9 in the pre-test to 13.5 in the post-test (p<0.001). The percentage with a minimum of 14 correct answers to the 15 questions increased from 18 to 63% (p<0.001). Adequate breast health practices were generally low but increased significantly with increasing age and attendance at a previous lecture on breast cancer. Breast health practices were also higher among married women and housewives, and significantly associated with older age and greater breast health knowledge (p<0.001). Group educational lectures appeared effective for improving breast health knowledge among Jordanian women. However, even with the noticeable level of knowledge at the baseline, there were low breast health practices among the study participants. This necessitates further in-depth research to explore womens experiences and socio-cultural barriers to breast health seeking behaviour in Jordan.


Distinct memory signatures in the hippocampus: intentional States distinguish match and mismatch enhancement signals.
Incoming events that match or mismatch stored representations are thought to influence the ability of the hippocampus to switch between memory encoding and retrieval modes. Electrophysiological work has dissociated match and mismatch signals in the monkey perirhinal cortex, where match signals were selective for matches to goal states, whereas mismatch signals were not modulated by intention (Miller and Desimone, 1994). To investigate whether the theoretically important relational match and mismatch signals in the hippocampus are modulated by goal states, we fully crossed whether a probe stimulus relationally matched or mismatched a previously perceived image or goal state. Subjects performed two working memory tasks in which they either responded "yes" to probes that were identical to the previous sample scene or, after performing a relational manipulation of the scene, responded "yes" only to a probe that was identical to this perceptually novel image. Using functional magnetic resonance imaging, we found evidence for relational match enhancements bilaterally in the hippocampus that were selective for matches between the probe stimulus and goal state, but were not modulated by whether that goal was perceptually novel. Moreover, we found evidence for a complementary hippocampal mismatch enhancement that was triggered by stimuli containing salient perceptual manipulations. Our results provided evidence for parallel memory signatures in the hippocampus: a controlled match signal that can detect matches to internally generated goal states and an automatic mismatch signal that can identify unpredicted perceptual novelty.


Paramyotonia congenita and hyperkalemic periodic paralysis are linked to the adult muscle sodium channel gene.
The hyperkalemic periodic paralyses are a clinically heterogeneous group of autosomal dominant syndromes characterized by episodic paralysis associated with an elevated serum potassium level. Affected individuals in the same family tend to have homogeneous symptom complexes, although phenotypic variation is present among different families. For example, myotonia is absent in some pedigrees, present in others, and, in a third variant, paramyotonia congenita, myotonia coexists with cold-induced paralysis. Electrophysiological studies have demonstrated variant-specific abnormalities in skeletal muscle membrane sodium conductance. We tested the hypothesis that hyperkalemic periodic paralysis (without myotonia) and paramyotonia congenita are tightly linked to the tetrodotoxin-sensitive adult skeletal muscle sodium channel gene on chromosome 17q23-25 in two large pedigrees. The DNA polymorphisms detected in the growth hormone skeletal muscle sodium channel complex (GH1-SCN4A) and by flanking polymorphic markers (D17S74 and D17S40) demonstrated no recombinants between the disease phenotypes and this complex. Phenotypic variation in the hereditary hyperkalemic periodic paralyses may result from allelic heterogeneity at the tetrodotoxin-sensitive adult skeletal muscle sodium channel locus.


Gray matter abnormalities in patients with narcissistic personality disorder.
Despite the relevance of narcissistic personality disorder (NPD) in clinical settings, there is currently no empirical data available regarding the neurobiological correlates of NPD. In the present study, we performed a voxel-based morphometric analysis to provide initial insight into local abnormalities of gray matter (GM) volume. Structural brain images were obtained from patients with NPD (n = 17) and a sample of healthy controls (n = 17) matched regarding age, gender, handedness, and intelligence. Groups were compared with regard to global brain tissue volumes and local abnormalities of GM volume. Regions-of-interest analyses were calculated for the anterior insula. Relative to the control group, NPD patients had smaller GM volume in the left anterior insula. Independent of group, GM volume in the left anterior insula was positively related to self-reported emotional empathy. Complementary whole-brain analyses yielded smaller GM volume in fronto-paralimbic brain regions comprising the rostral and median cingulate cortex as well as dorsolateral and medial parts of the prefrontal cortex. Here we provide the first empirical evidence for structural abnormalities in fronto-paralimbic brain regions of patients with NPD. The results are discussed in the context of NPD patients' restricted ability for emotional empathy.


Low-dose growth hormone inhibits 11 beta-hydroxysteroid dehydrogenase type 1 but has no effect upon fat mass in patients with simple obesity.
GH has potent effects on adipocyte biology, stimulating lipolysis but also promoting preadipocyte proliferation. In addition, GH, acting through IGF-I, inhibits 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1), which converts the inactive glucocorticoid, cortisone (E), to active cortisol (F) in adipose tissue. Although F is an essential requirement for adipocyte differentiation, it also inhibits preadipocyte proliferation. We hypothesized that inhibition of 11 beta-HSD1 activity in adipose tissue by GH may alter fat tissue mass through changes in local F concentrations. We conducted a randomized, double-blind, placebo-controlled study using low-dose GH (Genotropin 0.4 mg/d) for 8 months in 24 patients with obesity. Although GH treatment significantly raised IGF-I, we were unable to demonstrate significant differences in body composition or metabolic profiles between GH- and placebo-treated groups. In addition, there was no alteration in total fat mass over time in the GH-treated group [total fat mass 41.0 +/- 3.0 vs. 41.3 +/- 3.4 kg (8 months), mean +/- SE, P = ns]. However, in comparison with baseline values, systolic blood pressure increased (119 +/- 3 vs. 130 +/- 4 mm Hg, P < 0.05 vs. baseline) and serum F/E ratio decreased (6.1 +/- 0.5 vs. 3.9 +/- 0.5, P < 0.05 vs. baseline) in the GH-treated group only. Furthermore, although the urinary tetrahydrometabolites of F/E ratio fell in the GH-treated group, it rose in the placebo group (mean ratio change, -0.13 +/- 0.05 vs. +0.09 +/- 0.09, GH vs. placebo, P = 0.07). Treatment with low-dose GH in obesity fails to alter fat mass despite a significant elevation in IGF-I and a shift in the global set point of E to F conversion consistent with inhibition of 11 beta-HSD1.


Structure-function relationships in the pulmonary arterial tree.
Knowledge of the relationship between structure and function of the normal pulmonary arterial tree is necessary for understanding normal pulmonary hemodynamics and the functional consequences of the vascular remodeling that accompanies pulmonary vascular diseases. In an effort to provide a means for relating the measurable vascular geometry and vessel mechanics data to the mean pressure-flow relationship and longitudinal pressure profile, we present a mathematical model of the pulmonary arterial tree. The model is based on the observation that the normal pulmonary arterial tree is a bifurcating tree in which the parent-to-daughter diameter ratios at a bifurcation and vessel distensibility are independent of vessel diameter, and although the actual arterial tree is quite heterogeneous, the diameter of each route, through which the blood flows, tapers from the arterial inlet to essentially the same terminal arteriolar diameter. In the model the average route is represented as a tapered tube through which the blood flow decreases with distance from the inlet because of the diversion of flow at the many bifurcations along the route. The taper and flow diversion are expressed in terms of morphometric parameters obtained using various methods for summarizing morphometric data. To help put the model parameter values in perspective, we applied one such method to morphometric data obtained from perfused dog lungs. Model simulations demonstrate the sensitivity of model pressure-flow relationships to variations in the morphometric parameters. Comparisons of simulations with experimental data also raise questions as to the "hemodynamically" appropriate ways to summarize morphometric data.


Uncontrolled Diabetes Mellitus Has No Major Influence on the Platelet Transcriptome.
Diabetes mellitus (DM) has been associated with increased platelet reactivity as well as increased levels of platelet RNAs in plasma. Here, we sought to evaluate whether the platelet transcriptome is altered in the presence of uncontrolled DM. Next-generation sequencing (NGS) was performed on platelet RNA for 5 patients with uncontrolled DM (HbA1c 9.0%) and 5 control patients (HbA1c 5.5%) with otherwise similar clinical characteristics. RNA was isolated from leucocyte-depleted platelet-rich plasma. Libraries of platelet RNAs were created separately for long RNAs after ribosomal depletion and for small RNAs from total RNA, followed by next-generation sequencing. Platelets in both groups demonstrated RNA expression profiles characterized by absence of leukocyte-specific transcripts, high expression of well-known platelet transcripts, and in total 6,343 consistently detectable transcripts. Extensive statistical bioinformatic analysis yielded 12 genes with consistently differential expression at a lenient FDR < 0.1, thereof 8 protein-coding genes and 2 genes with known expression in platelets (MACF1 and ITGB3BP). Three of the four differentially expressed noncoding genes were YRNAs (RNY1, RNY3, and RNY4) which were all downregulated in DM. 23 miRNAs were differentially expressed between the two groups. Of the 13 miRNAs with decreased expression in the diabetic group, 8 belonged to the DLK1-DIO3 gene region on chromosome 14q32.2. In this study, uncontrolled DM had a remote impact on different components of the platelet transcriptome. Increased expression of MACF1, together with supporting predicted mRNA-miRNA interactions as well as reduced expression of RNYs in platelets, may reflect subclinical platelet activation in uncontrolled DM.


A new method for the second-stage auricular projection of the Nagata method: ultra-delicate split-thickness skin graft in continuity with full-thickness skin.
Staged auricular reconstruction remains mainstream among the various techniques of microtia reconstruction using autogenous costal cartilage. The initial stage involves fabrication and implantation of the cartilage framework, followed by projection of the reconstructed auricle in the second stage. During the projection stage, the line of incision is usually made close to the helical rim, from the superoanterior margin of the helical rim to the region of the lobule. Generally, a fascial flap is raised and covered over a cartilage block to project the auricle, and a skin graft is inset over the raw surface of the newly created postauricular sulcus. The authors developed a new refinement for the second-stage auricular projection, whereby the skin cover for the raw surface over the posterior aspect of the auricle and the postauricular sulcus is an ultra-delicate split-thickness skin graft raised in continuity with the full-thickness skin over the anterior aspect of the auricle. Incorporation of this new technique has minimized the visibility of suture lines and improved the appearance of the superior otobasion. In addition, the dimension of the skin cover required can be designed with greater precision. Postoperative outcomes using this new technique for auricular projection have been more than satisfactory. More favorable results that carry less surgical stigma can now be achieved in auricular reconstruction using this new modification of Nagata's two-stage method.


Carbohydrate mouth rinsing has no effect on power output during cycling in a glycogen-reduced state.
The effect of mouth rinsing with a carbohydrate (CHO) solution on exercise performance is inconclusive with no benefits observed in the fed state. This study examined the effect of CHO mouth rinse or CHO ingestion on performance in 9 moderately trained male cyclists. Four trials were undertaken, separated by 7 days, in a randomized, counterbalanced design. Each trial included a 90-min glycogen-reducing exercise protocol, immediately followed by a low CHO meal and subsequent overnight fast; the following morning a 1-h cycling time trial was conducted. The trials included 15 % CHO mouth rinse (CHOR), 7.5 % CHO ingestion (CHOI), placebo mouth rinse and placebo ingestion. Solutions were provided after every 12.5 % of completed exercise: 1.5 mL · kg(-1) and 0.33 mL · kg(-1) body mass during ingestion and rinse trials, respectively. During rinse trials participants swirled the solution for 8 s before expectorating. Blood samples were taken at regular intervals before and during exercise. Performance time was not different between trials (P = 0.21) but the 4.5-5.2 % difference between CHOI and other trials showed moderate practical significance (Cohen's d 0.57-0.65). Power output was higher in CHOI relative to other trials (P < 0.01). There were no differences between CHOR and placebo groups for any performance variables. Plasma glucose, insulin and lactate concentrations were higher in CHOI relative to other groups (P < 0.05). In a fasted and glycogen-reduced state ingestion of a CHO solution during high-intensity exercise enhanced performance through stimulation of insulin-mediated glucose uptake. The CHO mouth rinsing had neither ergogenic effects nor changes in endocrine or metabolic responses relative to placebo.


Scar or recurrent rectal cancer. Positron emission tomography is more helpful for diagnosis than immunoscintigraphy.
We used positron emission tomography and fludeoxyglucose F 18 to assess metabolic activity of a pelvic mass in 18 patients who had suspected recurrent rectal cancer. Computed tomography could not differentiate tumor from scar. All patients presenting increased uptake of fludeoxyglucose F 18 by the mass were proved by histologic studies to suffer from recurrent tumor. Six of seven patients with low fludeoxyglucose uptake had nonmalignant lesions. Using immunoscintigraphy in 14 patients with elevated carcinoembryonic antigen levels, only four of ten recurrences could be identified by increased antibody accumulation in the mass. On the other hand, two of four benign lesions were interpreted as being recurrent tumor because of high uptake. Therefore, only positron emission tomography seems to be a useful diagnostic tool in the differentiation of recurrent rectal cancer and scar by providing information about the metabolic activity of a mass.


Comparison of RNA- or LNA-hybrid oligonucleotides in template-switching reactions for high-speed sequencing library preparation.
Analyzing the RNA pool or transcription start sites requires effective means to convert RNA into cDNA libraries for digital expression counting. With current high-speed sequencers, it is necessary to flank the cDNAs with specific adapters. Adding template-switching oligonucleotides to reverse transcription reactions is the most commonly used approach when working with very small quantities of RNA even from single cells. Here we compared the performance of DNA-RNA, DNA-LNA and DNA oligonucleotides in template-switching during nanoCAGE library preparation. Test libraries from rat muscle and HeLa cell RNA were prepared in technical triplicates and sequenced for comparison of the gene coverage and distribution of the reads within transcripts. The DNA-RNA oligonucleotide showed the highest specificity for capped 5' ends of mRNA, whereas the DNA-LNA provided similar gene coverage with more reads falling within exons. While confirming the cap-specific preference of DNA-RNA oligonucleotides in template-switching reactions, our data indicate that DNA-LNA hybrid oligonucleotides could potentially find other applications in random RNA sequencing.


[Reproductive effects of occupational exposure to mercury on female workers in China: a meta-analysis].
To analyze and evaluate the reproductive effects of occupational exposure to mercury among female workers and to identify relative sensitive indicators. Documents on the relations of occupational exposure to mercury and reproductive effects on female workers were collected through computer and manually that were published in Chinese language during 1989-2006. After strict selection, homogeneity test and integrated analysis for the abstracted data of the eligible studies were conducted using Review Manager Statistic Software. Combined RR value was used as the index for total effect on each project for Meta-analysis. In total, 14 original research papers were included (totally 2148 subjects and 2044 controls). When comparing to the controls, the occupational exposure to mercury was significantly associated with longer menstrual period (RR = 1.82, 95% CI: 1.45-2.30), menstrual cycle delay (RR = 2.03, 95% CI: 1.74-2.37) and the changes of menstrual blood volume (RR = 2.06, 95% CI: 1.47-2.09), dysmenorrhea (RR = 2.14, 95% CI: 1.54-2.99), pregnancy-induced hypertension (RR = 2.17, 95% CI: 1.32-3.57), stillbirths (RR = 2.54, 95% CI: 1.41-4.56) and low birth weight (RR = 3.39, 95% CI: 1.38-8.33)/birth defect (RR = 2.67, 95% CI: 1.55-4.60) of their offspring (P < 0.05). Occupational exposure to mercury could cause dysfunction of the menstrual period, menstrual cycle, menstrual blood volume, as well as dysmenorrhea for female workers being exposed to mercury and inducing adverse reproductive outcomes, including pregnancy-induced hypertension, stillbirth, low birth weight and birth defects of their offspring.


Disability and the post-2015 development agenda.
The article considers the extent to which disability has been recognized and included in two main documents produced to date as part of the United Nations Post-2015 Development agenda process. This is the process that is defining the Sustainable Development Goals (SDGs), which will succeed the UN Millennium Development Goals (MDGs) after the latter reach their target date in 2015. The two documents examined in the article are the Outcome Document (July 2014) of the Open Working Group (OWG) on SDGs and the Report (August 2014) of the Intergovernmental Committee of Experts on Sustainable Development Financing (ICESDF). The OWG consisted of 30 seats shared by 70 UN Member States and was in charge of proposing goals and targets for the SDGs. The ICESDF worked in parallel to the OWG and its report proposed options on an effective financing strategy. The article emphasizes the importance of including persons with disabilities in the Post-2015 Agenda, especially in view of the latter's overarching focus on eradicating poverty. The inclusion of persons with disabilities is being recognized in the Post-2015 Agenda discussions as central to achieving sustainable development. Disability has been explicitly mentioned in the OWG and ICESDF documents. Although the results so far have been very good, more work still needs to be done to ensure that these explicit references are maintained in the final version of the SDGs, which will be adopted in September 2015. Furthermore, the new framework needs to have a stronger human rights foundation on which to ground these references and future indicators. Light for the World is an international confederation of national development non-governmental organizations (NGOs) aiming at an inclusive society, where the rights of persons with disabilities are realized without discrimination. Through a rights-based approach, Light for the World supports 175 programs in 25 countries in the areas of prevention of blindness, rehabilitation, inclusive education, awareness raising and advocacy, both at EU and UN level. Light for the World has been advocating for the inclusion of persons with disabilities in the Post-2015 Agenda, working closely with the International Disability and Development Consortium (IDDC), of which it is a member, and the International Disability Alliance (IDA). Implications for Rehabilitation The new Post-2015 development agenda is a fundamental opportunity to ensure that persons with disabilities are fully included in future development efforts. Inclusive development, as enshrined in the UNCRPD, has clear implications for the disability community and for policy makers. Advocacy from the disability community is critical to help keep the inclusion of persons with disabilities high on the agenda of the Post-2015 process.


The Prevalence of Autism Spectrum Disorders in Adult Psychiatric Inpatients: A Systematic Review.
Whilst the prevalence of autism spectrum disorders in adults within the community setting is well-established, less is known about the prevalence among adults based within a psychiatric inpatient setting. To conduct a systematic literature review pertaining to the prevalence of autism spectrum disorders among the adult psychiatric inpatient population. Eligibility criteria included: (a) investigation of the prevalence of autism spectrum disorders (b) adult psychiatric inpatient study population (c) published in English language. Electronic databases accessed included PubMed, Medline, CINAHL, PsycINFO and EMBASE. Additionally, the ancestry method was utilised for the references of eligible papers, as well as grey literature searches and consultation with experts in the field. From the search, 4 studies were identified which satisfied the inclusion criteria, conducted in a variety of inpatient psychiatric settings, including secure forensic and intellectual disability units and a state psychiatric hospital. There were significant differences in methodological approaches, including the screening tests, diagnostic instruments and diagnostic criteria utilised. Autism spectrum disorder prevalence estimates varied considerably, from 2.4-9.9%. From the limited research data currently available, it appears that the prevalence of autism spectrum disorders is increased in inpatient psychiatric settings relative to the general population. There is a need for further high quality research in this patient group, to add to this limited evidence base, as well as in developing effective strategies to identify patients with a high likelihood of autism spectrum disorders within this setting.


Management of retrograde type A IMH with acute arch tear/type B dissection.
The incidence of intramural hematomas (IMH) in acute dissection (AD) patients varies between 6% and 30% in the literature, most frequently involving only the descending aorta (58%) than the arch or ascending aorta (42%). In this setting, IMH that initiate in the descending aorta, but extend into the arch or ascending aorta have been described, and referred to as a retrograde type A IMH. In these patients the risk of neurological or cardiac complications are high, and therefore an open surgical or hybrid approach has been proposed as the most appropriate. Nevertheless, the endovascular management of such lesions in surgically unfit patients for open surgery have been offered with acceptable outcomes, although the risk of landing in an unsuitable proximal landing zone is evident. In conclusion, retro-TAIMH is an acute aortic syndrome and should be managed as such. The recommended treatment strategy is open surgery for treating ascending or arch involvement, and TEVAR/medical, based on a complication-specific approach, for those with only descending localization. In those patients in whom retro-TAIMH is associated with an acute B dissection presenting with a proximal entry tear located into the descending aorta, a TEVAR represents an option treatment.


Randomized, controlled evaluation of short- and long-term benefits of heart failure disease management within a diverse provider network: the SPAN-CHF trial.
Several trials support the usefulness of disease management (DM) for improving clinical outcomes in heart failure (HF). Most of these studies are limited by small sample size; absence of concurrent, randomized controls; limited follow-up; restriction to urban academic centers; and low baseline use of effective medications. We performed a prospective, randomized assessment of the effectiveness of HF DM delivered for 90 days across a diverse provider network in a heterogeneous population of 200 patients with high baseline use of approved HF pharmacotherapy. During a 90-day follow-up, patients randomized to DM experienced fewer hospitalizations for HF [primary end point, 0.55+/-0.15 per patient-year alive versus 1.14+/-0.22 per patient-year alive in control subjects; relative risk (RR), 0.48, P=0.027]. Intervention patients experienced reductions in hospital days related to a primary diagnosis of HF (4.3+/-0.4 versus 7.8+/-0.6 days hospitalized per patient-year; RR, 0.54; P<0.001), cardiovascular hospitalizations (0.81+/-0.19 versus 1.43+/-0.24 per patient-year alive; RR, 0.57; P=0.043), and days in hospital per patient-year alive for cardiovascular cause (RR, 0.64; P<0.001). Intervention patients showed a trend toward reduced all-cause hospitalizations and total hospital days. On long-term (mean, 283 days) follow-up, there was substantial attrition of the 3-month gain in outcomes, with sustained significant reduction only in days in hospital for cardiac cause. In a population with high background use of standard HF therapy, a DM intervention, uniformly delivered across varied clinical sites, produced significant short-term improvement in HF-related clinical outcomes. Longer-term benefit likely requires more active chronic intervention, even among patients who appear clinically stable.


Making sustainable water and sanitation in the Peruvian Andes: an intervention model.
Sustainability of water supplies in remote rural communities is problematic and resource consuming. CARE has a long history of working hand in hand with remote rural communities and devising programs tailored to their needs. We present here an intervention that integrates development of water supplies and sanitation, with operation and maintenance skills development and training of health promoters that can educate from within the community that ensures the sustainability of drinking water supply systems in rural communities. The training used is innovative in that it uses a series of video-workshops which are found to be particularly useful in communities with high illiteracy rates.


Female employment and fertility in Peninsular Malaysia: the maternal role incompatibility hypothesis reconsidered.
Multivariate analysis of the 1974 Malaysian Fertility and Family Survey tests the hypothesis that an inverse relationship between women's work and fertility occurs only when there are serious conflicts between working and caring for children. The results are only partly consistent with the hypothesis and suggest that normative conflicts between working and mothering affect the employment-fertility relationship in Malaysia more than spacio-temporal conflicts do. The lack of consistent evidence for the hypothesis, as well as some conceptual problems, lead us to propose an alternative framework for understanding variation in the employment-fertility relationship, both in Malaysia and elsewhere. This framework incorporates ideas from the role incompatibility hypothesis but views the employment-fertility relationship as dependent not just on role conflicts but more generally on the structure of the household's socioeconomic opportunities.


Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL.
Zanubrutinib is a potent and highly selective inhibitor of Bruton tyrosine kinase (BTK). In this first-in-human, open-label, multicenter, phase 1 study, patients in part 1 (3 + 3 dose escalation) had relapsed/refractory B-cell malignancies and received zanubrutinib 40, 80, 160, or 320 mg once daily or 160 mg twice daily. Part 2 (expansion) consisted of disease-specific cohorts, including treatment-naive or relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The primary end points were safety and tolerability, and definition of the maximum tolerated dose (part 1). Additional end points included pharmacokinetics/pharmacodynamics and preliminary efficacy. Reported herein are results from 144 patients enrolled in the dose-finding and CLL/SLL cohorts. No dose-limiting toxicities occurred in dose escalation. Median BTK occupancy in peripheral blood mononuclear cells was >95% at all doses. Sustained complete (>95%) BTK occupancy in lymph node biopsy specimens was more frequent with 160 mg twice daily than 320 mg once daily (89% vs 50%; P = .0342). Consequently, 160 mg twice daily was selected for further investigation. With median follow-up of 13.7 months (range, 0.4-30.5 months), 89 CLL/SLL patients (94.7%) remain on study. Most toxicities were grade 1/2; neutropenia was the only grade 3/4 toxicity observed in >2 patients. One patient experienced a grade 3 subcutaneous hemorrhage. Among 78 efficacy-evaluable CLL/SLL patients, the overall response rate was 96.2% (95% confidence interval, 89.2-99.2). Estimated progression-free survival at 12 months was 100%. Zanubrutinib demonstrated encouraging activity in CLL/SLL patients, with a low incidence of major toxicities. This trial was registered at www.clinicaltrials.gov as #NCT02343120.


Transcriptional metabolic inflexibility in skeletal muscle among individuals with increasing insulin resistance.
Disturbances in skeletal muscle lipid metabolism may play an important role in development of insulin resistance (IR). The aim was to investigate transcriptional control of skeletal muscle fatty acid (FA) metabolism in individuals with the metabolic syndrome (MetS) with varying degrees of insulin sensitivity (S(I)). 122 individuals with MetS (NCEP-ATP III criteria) at age 35-70 years, BMI 27-38 kg/m(2) were studied (subgroup EU-LIPGENE study). Individuals were divided into quartiles of S(I) measured during a frequently sampled insulin modified intravenous glucose tolerance test. Skeletal muscle normalized mRNA expression levels of genes important in skeletal muscle FA handling were analyzed with quantitative real-time PCR. The expression of sterol regulatory element binding protein 1c (SREBP1c), acetyl-CoA carboxylase 2 (ACC2), diacylglycerol acyltransferase (DGAT1), and nuclear respiration factor (NRF) was higher in the lowest two quartiles of S(I) (<50th) compared with the highest two quartiles of S(I) (>50th). Interestingly, peroxisome proliferator-activated receptor coactivator 1α (PGC1α), peroxisome proliferator-activated receptor α (PPARα), and muscle carnitine palmitoyl transferase 1b (mCPT1), important for oxidative metabolism, showed a complex mRNA expression profile; levels were lower in both the most "insulin sensitive" (IS) as well as the most "IR" individuals. Lipoprotein lipase (LPL) mRNA was reduced in the lowest quartile of S(I). Enhanced gene expression of SREBP1c and ACC2 in the IR state suggests a tendency towards FA storage rather than oxidation. From the lower expression of PGC1α, PPARα, and mCPT1 in both the most "IS" as well as the most "IR" individuals, it may be speculated that "IS" subjects do not need to upregulate these genes to have a normal FA oxidation, whereas the most "IR" individuals are inflexible in upregulating these genes.


TEMPO-functionalized zinc phthalocyanine: synthesis, magnetic properties, and its utility for electrochemical sensing of ascorbic acid.
Zinc(ii) phthalocyanine (TEMPO-ZnPc), peripherally functionalized with 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) radicals is synthesized and its magneto structural and electrochemical behaviors are investigated. TEMPO-ZnPc shows multi-electron ring based reduction reactions and a TEMPO based oxidation reaction. Spectroelectrochemical measurements support these peak assignments. TEMPO-ZnPc is tested as a homogeneous and heterogeneous ascorbic acid (AA) sensor. Disappearance of TEMPO-ZnPc based reduction processes and the observation of new waves at around 0 and 1.20 V with respect to increasing AA concentration indicate the interaction of TEMPO-ZnPc with AA and usability of the complex as an electrochemical AA sensor. For practical usage as heterogeneous electrocatalysts for AA sensing, a glassy carbon electrode (GCE) is coated with TEMPO-ZnPc (GCE/TEMPO-ZnPc) and this modified electrode is tested as a heterogeneous AA sensor. The redox peak of GCE/TEMPO-ZnPc at 0.81 V decreases the peak current while a new wave is observed at 0.65 V during the titration of the electrolyte with AA. GCE/TEMPO-ZnPc sense AA with 1.75 × 10(-6) mol dm(-3) LOD with a sensitivity of 1.89 × 10(3) A cm mol(-1).


A model for post-occlusive reactive hyperemia as measured with laser-Doppler perfusion monitoring.
To facilitate the quantitative analysis of post-occlusive reactive hyperaemia (PORH), measured with laser-Doppler perfusion monitoring (LDPM) on extremities, we present a flow model for the dynamics of the perfusion of the tissue during PORH, based on three parameters: two time constants (tau1 and tau2) and the ratio of the maximum flux and the resting flux. With these three constants quantitative comparisons between experiments will be possible and, therefore, we propose to adopt this approach as future standard. For this reason, we also developed a computer program to perform the fit of the model to measured data.


Raised plasma concentrations of atrial natriuretic peptide are independent of left atrial dimensions in patients with chronic atrial fibrillation.
The aim of the present study was to determine whether left atrial size--a likely indicator of atrial stretching--correlates with the plasma concentration of atrial natriuretic peptide and whether this relation is different in patients in sinus rhythm and in those with atrial fibrillation. Arterial plasma concentrations of immunoreactive atrial natriuretic peptide (ir-ANP), adrenaline, noradrenaline, aldosterone, and vasopressin were measured in 13 patients in sinus rhythm without apparent heart failure and in 13 patients in atrial fibrillation. The two groups were matched for left atrial diameter and the ratio of the left atrial diameter to the diameter of the aortic root (assessed by echocardiography). There were no significant differences in age, heart rate, blood pressure, or left ventricular end diastolic diameter between the two groups. Left atrial diameters varied from 33 to 60 mm. The mean (SD) plasma concentration of ir-ANP was significantly higher (35 (21) pmol/l) in the patients with atrial fibrillation than in those in sinus rhythm (12 (11) pmol/l). The concentration of plasma aldosterone was also higher in patients with atrial fibrillation (831 (366) v 523 (211) pmol/l). Concentrations of adrenaline, noradrenaline, and vasopressin were similar in both groups. None of the hormone concentrations correlated with left atrial dimensions. These results indicate that plasma concentrations of ir-ANP and aldosterone are highly sensitive indicators of changes in haemodynamic function during atrial fibrillation. They also underscore the difficulties of correlating echocardiographic assessment of patients with plasma concentrations of a vasoactive hormone.


Engineering cell heterogeneity into organs-on-a-chip.
Organ-on-a-chip development is an application that will benefit from advances in cell heterogeneity characterization because these culture models are intended to mimic in vivo microenvironments, which are complex and dynamic. Due in no small part to advances in microfluidic single cell analysis methods, cell-to-cell variability is an increasingly understood feature of physiological tissues, with cell types from as common as 1 out of every 2 cells to as rare as 1 out of every 100 000 cells having important roles in the biochemical and biological makeup of tissues and organs. Variability between neighboring cells can be transient or maintained, and ordered or stochastic. This review covers three areas of well-studied cell heterogeneity that are informative for organ-on-a-chip development efforts: tumors, the lung, and the intestine. Then we look at how recent single cell analysis strategies have enabled better understanding of heterogeneity within in vitro and in vivo tissues. Finally, we provide a few work-arounds for adapting current on-chip culture methods to better mimic physiological cell heterogeneity including accounting for crucial rare cell types and events.


Psychosocial sequelae of violent victimization in a national youth sample.
In a national telephone sample of youths aged 10-16 years, over one third reported having been the victims of an assault. Victimized respondents displayed significantly more psychological and behavioral symptomatology than did nonvictimized respondents (more symptomatology related to posttraumatic stress disorder, more sadness, and more school difficulties), even after controlling for some other possible sources of distress. Sexual assault was associated with particularly high levels of symptomatology. However, victims of other forms of assault--nonfamily assaults involving weapons or physical injury (aggravated assaults), assaults by parents, violence to genitals, and attempted kidnappings--also evidenced levels of distress that were not statistically lower than those suffered by victims of sexual assault. The findings suggest that substantial mental health morbidity in the general child and adolescent population is associated with victimization.


Reducing bias in telephone survey estimates of the prevalence of drug use: a randomized trial of telephone audio-CASI.
To assess the impact of telephone audio computer-assisted self-interviewing (T-ACASI) on reporting of alcohol use, alcohol problems and illicit drug use in telephone surveys of the general population. Prior research suggests that illicit drug use is underreported in traditional, interviewer-administered, telephone surveys. Randomized experiment embedded in telephone survey of probability samples of populations of USA and Baltimore, MD. Survey respondents were randomly assigned to be interviewed either by human telephone interviewers or by T-ACASI after household screening, recruitment, and informed consent procedures were completed. Respondents were interviewed by telephone in their homes. Probability samples of 1543 English-speaking adults ages 18-45 residing in telephone-accessible households in USA and 744 similarly defined adults residing in Baltimore, MD, USA. Nine questions on alcohol, marijuana, cocaine, and injection drug use adapted from 1994 NHSDA and four CAGE questions on alcohol problems. Crude odds ratios and odds ratios controlling for demographic factors calculated to test for differences between responses obtained by T-ACASI and human interviewers. T-ACASI had mixed effects on reporting of alcohol use, but it did increase reporting of one of four CAGE alcohol problems: feeling guilty about drinking (23.0% in T-ACASI vs. 17.6% in T-IAQ, OR = 1.4, P < 0.01). T-ACASI also obtained significantly more frequent reporting of marijuana, cocaine, and injection drug use. The impact of T-ACASI was most pronounced for reporting of recent use of 'harder' drugs. Thus T-ACASI respondents were more likely to report marijuana use in the past month (10.0% vs. 5.7%, crude OR = 1.9, P < 0.001), cocaine use in the past month (2.1% vs. 0.7%, crude 3.2, P < 0.001) and injection drug use in the past five years (1.6% vs. 0.3%, crude OR = 4.8, P < 0.01). Telephone survey respondents were more likely to report illicit drug use and one alcohol problem when interviewed by T-ACASI rather than by human telephone interviews.


Obesity and cardiovascular disease risk factors among the indigenous and immigrant Pakistani population: a systematic review.
The aim of this study was to systematically describe the gender and ethnic differences regarding the prevalence of general/central obesity and cardiovascular disease (CVD) risk factors such as diabetes mellitus type 2, hypertension, and hypercholesterolemia among the indigenous and immigrant Pakistani communities. The search engine used was PubMed, supplemented with regional data from the Medical Institutes of Pakistan. The focus was on the adult Pakistani population (18 years and older). We found only 7 studies among the immigrant Pakistani community and 24 studies among the indigenous Pakistani community. The studies had limitations such as low participation rates and use of self-reported data. There is a higher prevalence of central obesity among women (42.2%) than among men (14.7%) (National Health Survey of Pakistan). Certain ethnicities such as Muhajir and Baluchis showed a higher prevalence of cardiovascular risk factors when compared to other ethnicities in the indigenous Pakistani population. The results also indicate that the prevalence of obesity is 10-20% higher among the immigrant Pakistanis than in the indigenous Pakistanis. The relatively high prevalence of obesity and associated CVD risk factors (especially in women) among both indigenous and immigrant Pakistani populations require the attention of the healthcare professionals and policy makers, both inside and outside Pakistan.


Development of temporally refined land-use regression models predicting daily household-level air pollution in a panel study of lung function among asthmatic children.
Regulatory monitoring data and land-use regression (LUR) models have been widely used for estimating individual exposure to ambient air pollution in epidemiologic studies. However, LUR models lack fine-scale temporal resolution for predicting acute exposure and regulatory monitoring provides daily concentrations, but fails to capture spatial variability within urban areas. This study coupled LUR models with continuous regulatory monitoring to predict daily ambient nitrogen dioxide (NO(2)) and particulate matter (PM(2.5)) at 50 homes in Windsor, Ontario. We compared predicted versus measured daily outdoor concentrations for 5 days in winter and 5 days in summer at each home. We also examined the implications of using modeled versus measured daily pollutant concentrations to predict daily lung function among asthmatic children living in those homes. Mixed effect analysis suggested that temporally refined LUR models explained a greater proportion of the spatial and temporal variance in daily household-level outdoor NO(2) measurements compared with daily concentrations based on regulatory monitoring. Temporally refined LUR models captured 40% (summer) and 10% (winter) more of the spatial variance compared with regulatory monitoring data. Ambient PM(2.5) showed little spatial variation; therefore, daily PM(2.5) models were similar to regulatory monitoring data in the proportion of variance explained. Furthermore, effect estimates for forced expiratory volume in 1 s (FEV(1)) and peak expiratory flow (PEF) based on modeled pollutant concentrations were consistent with effects based on household-level measurements for NO(2) and PM(2.5). These results suggest that LUR modeling can be combined with continuous regulatory monitoring data to predict daily household-level exposure to ambient air pollution. Temporally refined LUR models provided a modest improvement in estimating daily household-level NO(2) compared with regulatory monitoring data alone, suggesting that this approach could potentially improve exposure estimation for spatially heterogeneous pollutants. These findings have important implications for epidemiologic studies - in particular, for research focused on short-term exposure and health effects.


Comparative clinical characteristics and outcomes of patients with community acquired bacteremia caused by Escherichia coli, Burkholderia pseudomallei and Staphylococcus aureus: A prospective observational study (Ubon-sepsis).
Community acquired bacteremia (CAB) is a common cause of sepsis in low and middle-income countries (LMICs). However, knowledge about factors associated with outcomes of CAB in LMICs is limited. A prospective observational study (Ubon-sepsis) of adults admitted to a referral hospital with community-acquired infection in Northeastern Thailand was conducted between March 1, 2013 and February 1, 2017. In the present analysis, patients with a blood culture collected within 24 hours of admission that was positive for one of the three most common pathogens were studied. Clinical features, management, and outcomes of patients with each cause of CAB were compared. Of 3,806 patients presenting with community-acquired sepsis, 155, 131 and 37 patients had a blood culture positive for Escherichia coli, Burkholderia pseudomallei and Staphylococcus aureus, respectively. Of these 323 CAB patients, 284 (89%) were transferred from other hospitals. 28-day mortality was highest in patients with B. pseudomallei bactaeremia (66%), followed by those with S. aureus bacteraemia (43%) and E. coli (19%) bacteraemia. In the multivariable Cox proportional hazards model adjusted for age, sex, transfer from another hospital, empirical antibiotics prior to or during the transfer, and presence of organ dysfunction on admission, B. pseudomallei (aHR 3.78; 95%CI 2.31-6.21) and S. aureus (aHR 2.72; 95%CI 1.40-5.28) bacteraemias were associated with higher mortality compared to E. coli bacteraemia. Receiving empirical antibiotics recommended for CAB caused by the etiologic organism prior to or during transfer was associated with survival (aHR 0.58; 95%CI 0.38-0.88). Mortality of patients with CAB caused by B. pseudomallei was higher than those caused by S. aureus and E. coli, even after adjusting for presence of organ dysfunction on admission and effectiveness of empirical antibiotics received. Improving algorithms or rapid diagnostic tests to guide early empirical antibiotic may be key to improving CAB outcomes in LMICs.


Long fiber Bragg grating sensor interrogation using discrete-time microwave photonic filtering techniques.
A novel technique for interrogating photonic sensors based on long fiber Bragg gratings (FBGs) is presented and experimentally demonstrated, dedicated to detect the presence and the precise location of several spot events. The principle of operation is based on a technique used to analyze microwave photonics (MWP) filters. The long FBGs are used as quasi-distributed sensors. Several hot-spots can be detected along the FBG with a spatial accuracy under 0.5 mm using a modulator and a photo-detector (PD) with a modest bandwidth of less than 1 GHz. The proposed interrogation system is intrinsically robust against environmental changes.


Mapping of the IDDM locus Idd3 to a 0.35-cM interval containing the interleukin-2 gene.
Currently, 16 loci that contribute to the development of IDDM in the NOD mouse have been mapped by linkage analysis. To fine map these loci, we used congenic mapping. Using this approach, we localized the Idd3 locus to a 0.35-cM interval on chromosome 3 containing the Il2 gene. Segregation analysis of the known variations within this interval indicated that only one variant, a serine-to-proline substitution at position 6 of the mature interleukin-2 (IL-2) protein, consistently segregates with IDDM in crosses between NOD and a series of nondiabetic mouse strains. These data, taken together with the immunomodulatory role of IL-2, provide circumstantial evidence in support of the hypothesis that Idd3 is an allelic variation of the Il2 gene, or a variant in strong linkage disequilibrium.


Original antigenic sin: A comprehensive review.
The concept of "original antigenic sin" was first proposed by Thomas Francis, Jr. in 1960. This phenomenon has the potential to rewrite what we understand about how the immune system responds to infections and its mechanistic implications on how vaccines should be designed. Antigenic sin has been demonstrated to occur in several infectious diseases in both animals and humans, including human influenza infection and dengue fever. The basis of "original antigenic sin" requires immunological memory, and our immune system ability to autocorrect. In the context of viral infections, it is expected that if we are exposed to a native strain of a pathogen, we should be able to mount a secondary immune response on subsequent exposure to the same pathogen. "Original antigenic sin" will not contradict this well-established immunological process, as long as the subsequent infectious antigen is identical to the original one. But "original antigenic sin" implies that when the epitope varies slightly, then the immune system relies on memory of the earlier infection, rather than mount another primary or secondary response to the new epitope which would allow faster and stronger responses. The result is that the immunological response may be inadequate against the new strain, because the immune system does not adapt and instead relies on its memory to mount a response. In the case of vaccines, if we only immunize to a single strain or epitope, and if that strain/epitope changes over time, then the immune system is unable to mount an accurate secondary response. In addition, depending of the first viral exposure the secondary immune response can result in an antibody-dependent enhancement of the disease or at the opposite, it could induce anergy. Both of them triggering loss of pathogen control and inducing aberrant clinical consequences.


Syphilis outbreak among Hispanic immigrants in Decatur, Alabama: association with commercial sex.
Despite national progress in syphilis control, increases in rates have recently occurred, and syphilis is still an endemic problem in the southern United States. An outbreak of infectious syphilis among Hispanics was identified in Decatur, Alabama. An investigation was initiated to describe the outbreak and to assist with prevention activities. We reviewed case interview records and syphilis surveillance data. The Morgan County Health Department (MCHD) performed voluntary door-to-door syphilis screening in neighborhoods where a large number of cases had been identified. During screening activities, sociodemographic and behavioral data were collected. From June 2000 to February 2001, 49 cases of syphilis were reported; 26 (53%) were primary or secondary, 17 (35%) were early latent, and 6 (12%) late latent. Of the early syphilis cases, 70% were male and half were Hispanic; 93% of cases were linked to commercial sex and 70% of female cases reported crack cocaine use. During the screening, 172 individuals completed a questionnaire; 70% of participants were male, 83% were Hispanic, 17% of Hispanic participants spoke English, 21% reported sex with a commercial sex worker, and 8 (5%) had positive syphilis serology. Among men, factors associated with commercial sex were not having a regular partner (odds ratio [OR], 3.9; confidence interval [CI], 1.1-14.3), not living with a family member in the United States (OR, 4.5; CI, 1.6-12.8), and having visited their country of origin since arrival to the United States (OR, 9.2; CI, 2.3-36.5). Factors contributing to this outbreak were crack cocaine use and increased prostitution in close proximity to the Hispanic community. At present, there are an increasing number of Hispanic immigrants in the United States, the majority of whom do not speak English. To prevent similar outbreaks in the future, public health officials need to be aware of the health and health education needs of these populations.


Association between testicular dysgenesis syndrome (TDS) and testicular neoplasia: evidence from 20 adult patients with signs of maldevelopment of the testis.
Based on a well established association between testicular cancer and undescended testis and more recent publications on epidemiological links between these disorders and male infertility, we proposed the existence of a testicular dysgenesis syndrome (TDS). In most cases TDS presents with impaired spermatogenesis, only in rare cases the full range of its signs, including genital malformations and testicular cancer can be seen in one patient. In order to further corroborate our hypothesis about the presence of testicular dysgenesis in patients with testicular abnormalities, we decided to re-analyse recent testicular biopsies derived from patients with infertility, hypospadias and undescended testis. We searched for histological signs of testicular dysgenesis: microliths, Sertoli-cell-only tubules, immature seminiferous tubules with undifferentiated Sertoli cells, and tubules containing carcinoma in situ (CIS) cells. We identified 20 patients who fulfilled the histological criteria for testicular dysgenesis, 9 of whom were diagnosed with uni- or bilateral testicular germ cell neoplasia, and the remaining ones with subfertility. The presence of CIS was detected in 5 patients (3 of them with overt contralateral germ cell tumours). In all but one of the CIS cases, at least one additional sign of testicular dysgenesis was detected. Clinical records of all patients were subsequently analysed. The majority of cases had oligozoospermia or azoospermia. Their reproductive hormone profiles correlated with the results of semen sampling and testicular histology. In conclusion, our study of 20 patients with various reproductive abnormalities provided evidence that TDS is a real clinical entity. We speculate that most of these abnormalities are caused by adverse environmental effects rather than specific gene mutations.


Water safety in healthcare facilities. The Vieste Charter.
The Study Group on Hospital Hygiene of the Italian Society of Hygiene, Preventive Medicine and Public Health (GISIO-SItI) and the Local Health Authority of Foggia, Apulia, Italy, after the National Convention "Safe water in healthcare facilities" held in Vieste-Pugnochiuso on 27-28 May 2016, present the "Vieste Charter", drawn up in collaboration with experts from the National Institute of Health and the Ministry of Health. This paper considers the risk factors that may affect the water safety in healthcare facilities and reports the current regulatory frameworks governing the management of installations and the quality of the water. The Authors promote a careful analysis of the risks that characterize the health facilities, for the control of which specific actions are recommended in various areas, including water safety plans; approval of treatments; healthcare facilities responsibility, installation and maintenance of facilities; multidisciplinary approach; education and research; regional and national coordination; communication.


Effect of Natural Cycle Endometrial Preparation for Frozen-Thawed Embryo Transfer in Patients with Advanced Endometriosis.
BACKGROUND The aim of this study was to investigate the effect of natural cycle (NC) endometrial preparation for frozen-thawed embryo transfer (FET) in women with advanced endometriosis. MATERIAL AND METHODS This retrospective study included 179 patients with stage III-IV endometriosis who underwent 233 FET cycles at a tertiary care academic reproductive medical center between March 2011 and August 2013 (group A). The control group included 258 patients with tubal factor infertility who underwent 300 FET cycles (group B). Both groups were prepared for FET using a NC protocol. Rates of implantation, clinical pregnancy, live birth, ongoing pregnancy, miscarriage, and pregnancy complication were recorded. RESULTS The implantation rate (A: 36.0%, B: 30.4%, P=0.06), the pregnancy rate (A: 50.2%, B: 45.3%, P=0.263), and the live birth rate (A: 39.91%, B: 39.0%, P=0.428) were similar between the stage III-IV endometriosis and tubal factor infertility groups. No differences were observed in ongoing rates of pregnancy, miscarriage, and pregnancy complications, independent of endometriosis severity. No congenital birth defects were found. When high-quality embryos are transferred, pregnancy results were not affected by active endometriosis. Although severe endometriosis did not affect birth rate, higher frequencies of premature delivery (mean gestational age A: 37 weeks, B: 38.3 weeks, P=0.044) and low birth weight were observed (<2500 g A: 26.4%, B: 16.6%, P=0.047). CONCLUSIONS There was no difference in pregnancy outcomes between patients with endometriosis and those with tubal infertility. Pregnancy outcomes in patients with endometriosis were not affected by endometriosis severity. Pregnancy outcomes were not affected by active endometrial cyst.


Prevalence and nature of connexin 26 mutations in children with non-syndromic deafness.
To determine (1) the prevalence and nature of connexin 26 mutations in a cohort of Australian children with non-syndromic hearing loss, and (2) the carrier frequency of the common connexin 26 mutation (35delG) in the general population. A cohort, case-finding study. Mutation analysis was performed on DNA extracted from white blood cells, buccal cells, or Guthrie blood spots. A hearing loss investigation clinic and a deafness centre in two Australian capital cities, 1 January 1998 to 31 October 2000. (1) 243 children (age range, 4 weeks to 16 years; median, 4 years), attending hearing loss clinics in Sydney and Melbourne; (2) 1000 blood samples obtained from anonymous Guthrie card blood spots collected in 1984 [corrected] by the Victorian Clinical Genetics Service as part of the newborn screening program. (1) The prevalence and types of connexin 26 mutations in a cohort of children with prelingual deafness; (2) the carrier frequency of the common connexin 26 mutation, 35delG, in the general population. Connexin 26 mutations were identified and characterised in 52 (21%) of the 243 children; 14 different mutations, including four previously unreported mutations (135S, C53R, T123N and R127C), were identified. The common 35delG mutation was found in 56 of the 104 alleles (ie, 86 of the connexin 26 alleles in which a mutation was positively identified). The mutations V371 and M34T were also relatively common. The carrier frequency of connexin 26 mutations and of the common 35delG connexin 26 mutation in the Victorian population was estimated to be 1 in 54 and 1 in 100, respectively. Mutations in the connexin 26 gene (especially the 35delG mutation) are a common cause of prelingual hearing loss in Australia.


Theoretical analysis of spatial nonhomogeneous patterns of entomopathogenic fungi growth on insect pest.
This paper presents the study of the dynamics of intrahost (insect pests)-pathogen [entomopathogenic fungi (EPF)] interactions. The interaction between the resources from the insect pest and the mycelia of EPF is represented by the Holling and Powell type II functional responses. Because the EPF's growth is related to the instability of the steady state solution of our system, particular attention is given to the stability analysis of this steady state. Initially, the stability of the steady state is investigated without taking into account diffusion and by considering the behavior of the system around its equilibrium states. In addition, considering small perturbation of the stable singular point due to nonlinear diffusion, the conditions for Turing instability occurrence are deduced. It is observed that the absence of the regeneration feature of insect resources prevents the occurrence of such phenomena. The long time evolution of our system enables us to observe both spot and stripe patterns. Moreover, when the diffusion of mycelia is slightly modulated by a weak periodic perturbation, the Floquet theory and numerical simulations allow us to derive the conditions in which diffusion driven instabilities can occur. The relevance of the obtained results is further discussed in the perspective of biological insect pest control.


Animal health constraints to livestock exports from the Horn of Africa.
The Horn of Africa (Djibouti, Ethiopia, Somalia, Eritrea) is home to the largest population of livestock in Africa and is the historic centre of the livestock trade to the Middle East and northern Africa. The recent resumption of livestock exports from the region has resulted in the handling of over one million head of cattle, sheep, goats and camels at one quarantine facility during a single year. Several of the importing countries for which the facility operates have differing hygiene requirements for the same diseases. Most of the animals handled in the facility come from pastoralist areas, which lack state Veterinary Services. The pathological conditions encountered during one year of monitoring were recorded and the impacts of some of the endemic diseases are discussed, together with particular import-limiting hygiene requirements on this trade.


Reductive Cleavage Method for Quantitation of Monolignols and Low-Abundance Monolignol Conjugates.
As interest in biomass utilization has grown, the manipulation of lignin biosynthesis has received significant attention, such that recent work has demanded more robust lignin analytical methods. As the derivatization followed by reductive cleavage (DFRC) method is particularly effective for structurally characterizing natively acylated lignins, we used an array of synthetic β-ether γ-acylated model compounds to determine theoretical yields for all monolignol conjugates currently known to exist in lignin, and we synthesized a new set of deuterated analogs as internal standards for quantification using GC-MS/MS. Yields of the saturated ester conjugates ranged from 40 to 90 %, and NMR analysis revealed the presence of residual unsaturated conjugates in yields of 20 to 35 %. In contrast to traditional selected-ion-monitoring, we demonstrated the superior sensitivity and accuracy of multiple-reaction-monitoring detection methods, and further highlighted the inadequacy of traditional standards relative to isotopically labeled analogs.


Reward-related dorsal striatal activity differences between former and current cocaine dependent individuals during an interactive competitive game.
Cocaine addiction is characterized by impulsivity, impaired social relationships, and abnormal mesocorticolimbic reward processing, but their interrelationships relative to stages of cocaine addiction are unclear. We assessed blood-oxygenation-level dependent (BOLD) signal in ventral and dorsal striatum during functional magnetic resonance imaging (fMRI) in current (CCD; n = 30) and former (FCD; n = 28) cocaine dependent subjects as well as healthy control (HC; n = 31) subjects while playing an interactive competitive Domino game involving risk-taking and reward/punishment processing. Out-of-scanner impulsivity-related measures were also collected. Although both FCD and CCD subjects scored significantly higher on impulsivity-related measures than did HC subjects, only FCD subjects had differences in striatal activation, specifically showing hypoactivation during their response to gains versus losses in right dorsal caudate, a brain region linked to habituation, cocaine craving and addiction maintenance. Right caudate activity in FCD subjects also correlated negatively with impulsivity-related measures of self-reported compulsivity and sensitivity to reward. These findings suggest that remitted cocaine dependence is associated with striatal dysfunction during social reward processing in a manner linked to compulsivity and reward sensitivity measures. Future research should investigate the extent to which such differences might reflect underlying vulnerabilities linked to cocaine-using propensities (e.g., relapses).


Analysis of nanoparticle-protein coronas formed in vitro between nanosized welding particles and nasal lavage proteins.
Welding fumes include agglomerated particles built up of primary nanoparticles. Particles inhaled through the nose will to some extent be deposited in the protein-rich nasal mucosa, and a protein corona will be formed around the particles. The aim was to identify the protein corona formed between nasal lavage proteins and four types of particles with different parameters. Two of the particles were formed and collected during welding and two were manufactured iron oxides. When nasal lavage proteins were added to the particles, differences were observed in the sizes of the aggregates that were formed. Measurements showed that the amount of protein bound to particles correlated with the relative size increase of the aggregates, suggesting that the surface area was associated with the binding capacity. However, differences in aggregate sizes were detected when nasal proteins were added to UFWF and Fe2O3 particles (having similar agglomerated size) suggesting that yet parameters other than size determine the binding. Relative quantitative mass spectrometric and gel-based analyses showed differences in the protein content of the coronas. High-affinity proteins were further assessed for network interactions. Additional experiments showed that the inhibitory function of secretory leukocyte peptidase inhibitor, a highly abundant nasal protein, was influenced by particle binding suggesting that an understanding of protein function following particle binding is necessary to properly evaluate pathophysiological events. Our results underscore the importance of including particles collected from real working environments when studying the toxic effects of particles because these effects might be mediated by the protein corona.


Contrast media-induced nephropathy: case report and review of the literature focusing on pathogenesis.
Contrast media administration during diagnostic and invasive procedures in high risk patients for nephrotoxicity is a common problem in clinical practice. The mechanisms involved in renal function impairment after contrast media administration are not precisely known but are intensively investigated, and new data have emerged in the literature lately. We present the case of a 72-year old male patient with diabetic nephropathy to whom a new generation iso-osmolar contrast medium (iodixanol) was administered during intravenous pyelography. Due to the contrast agent administration, the patient developed irreversible acute renal failure and became dialysis-dependent. This case suggests that even new generation contrast media (including iodixanol) may be severely nephrotoxic, when administered to high risk patients. Additionally we review the complex mechanisms involved in pathogenesis of contrast media nephrotoxicity.


Inertial control as novel technique for in vitro gait simulations.
In vitro gait simulations are a preferential platform to study new intervention techniques or surgical procedures as they allow studying the isolated effect of surgical interventions. Commonly, simulations are performed by applying pre-defined setpoints for the kinetics and kinematics on all degrees of freedom (DOFs) of the cadaveric specimen. This however limits the applicability of the experiment to simulations for which pre-defined kinematics and kinetics can be measured in vivo. In this study we introduce inertial control as a new methodology for gait simulations that omits the need for pre-defined setpoints for the externally applied vertical ground reaction force (vGRF) and therefore allows the effect of interventions to be reflected upon it. Gait simulations of stance (1 s) were performed in 10 cadaveric specimens under three clinically relevant conditions: native ankle, total ankle prosthesis (TAP) and total ankle prosthesis plus triple arthrodesis (TAP+TA). In the native ankle, simulated vGRF was compared against the vGRF measured in vivo in 15 healthy volunteers and high correlations were found (R(2)=0.956, slope of regression line S=1.004). In TAP and TAP+TA, vGRF changed, therefore confirming the sensitivity of the method to kinematic constrains imposed with surgery. Inertial control can replicate in vivo kinetic conditions and allows investigating the isolated effect of surgical interventions on kinematic as well as kinetics.


Further observations on cerebral or retinal ischemia in patients with right-left intracardiac shunts.
Between October 1983 and November 1986, 20 patients suspected of having a paradoxical cerebral or retinal embolism were identified. Cerebral infarction was the most common presentation. Six patients had a patent foramen ovale demonstrated by cardiac catheterization or surgery. Three patients had a newly discovered atrial septal defect, and one had an atrial septal defect that had previously been treated surgically. Results of the cardiac physical examination, chest roentgenography, and electrocardiography were unremarkable in 12 patients. Eighteen patients had a right-to-left shunt demonstrated by contrast echocardiography. Nine of these patients underwent cardiac catheterization; seven had abnormal catheterization study results: four had a patent foramen ovale and three had an atrial septal defect. Sixteen patients received medical therapy only while four underwent surgery. All patients survived the initial insult. There were no deaths or ischemic recurrences on follow-up ranging from one month to three years. We believe that contrast echocardiography can provide important diagnostic information, even in situations in which cardiac involvement is not suspected. Additional studies are needed before the optimal treatment of presumptive paradoxical cerebral embolism can be determined.


Correlation between clinical and cognitive aspects and nutritional indicators of elderly patients with new-onset epilepsy.
Nutritional indicators were correlated with cognitive and clinical aspects of 25 elderly patients with new-onset epilepsy (EPWE). The nutritional indicators of the EPWE were compared with those of a similar control group at a significance level of p < 0.05. There was lower cognitive performance, greater risk of malnutrition and muscle tissue depletion, and higher waist circumference (WC) in the EPWE. Longer epilepsy duration was correlated with loss of muscle mass (Pearson's correlation: 0.433; p = 0.044). Performance in the verbal fluency test, in the clock-drawing test, and in the immediate memory test was negatively associated with body fat. Better performance in the image recognition test was negatively associated with the indicators of muscle reserve. There was lower cognitive performance, higher risk of malnutrition, and high abdominal obesity in EPWE. Cognitive performance was related to adiposity. Cognitive impairment and longer disease duration are related to increased nutritional risk.


Automatically you become a polygamist': 'culture' and 'norms' as resources for normalization and managing accountability in talk about responses to infertility.
In the developing world, infertility is a serious problem. It leads to both psychological and social hardship, in part because childless marriages often result in divorce, men taking another wife or extramarital relationships. Such responses have been attributed to cultural norms that mandate procreation. However, there are theoretical, methodological and moral issues with treating cultural norms as behavioural determinants. They have been insufficiently acknowledged in health research. Therefore, I demonstrate an alternative discursive approach, which examines how people actively mobilize ;culture' or ;norms' in interactions, and the interpersonal functions thereby fulfilled (e.g. blaming or justifying). Analysis is presented of interviews on (responses to) infertility in Malawi. I show how respondents construct polygamy and extramarital affairs as culturally and normatively required, ;automatic' and normal solutions for fertility problems and play down people's accountability for these practices. These accounts and constructions appear to facilitate engagement in affairs and polygamy when people face fertility problems, which seems problematic from a health and gender perspective. Thus, detailed analysis of how people use ;culture' and ;norms' in situ is important because it provides insights into its potentially undesirable consequences. Moreover, such analysis provides a starting point for culturally and gender sensitive interventions, since it highlights people's agency, and creates a space to re-construct and change practices.


A comparison of efficacy between cognitive behavioral therapy (CBT) and CBT combined with medication in adults with attention-deficit/hyperactivity disorder (ADHD).
The study aimed to explore whether cognitive behavioral therapy (CBT) combined with medication is superior to CBT alone in core symptoms, emotional symptoms, self-esteem as well as social and cognitive functions of adult attention-deficit/hyperactivity disorder (ADHD) patients. Samples from a previous RCT study and outpatient participants were all included. A total of 124 patients received 12 weeks of manualized CBT sessions, either with (n = 57) or without (n = 67) medication. Efficacy variables were evaluated at baseline and each week. Mixed linear models (MLM) were used to compare differences between the two groups in all of the above domains. Within-group comparisons showed that both groups had robust improvements in core ADHD symptoms, emotional symptoms and social functional outcomes. The CBT + M group presented more domains of improvement in executive functions than the CBT group. However, comparisons between groups didn't indicate the superiority of CBT + M in core symptoms, emotional symptoms and self-esteem. Instead, the CBT group showed a greater improvement in the physical domain of the WHOQOL-BREF than the CBT + M group. This study further indicated that CBT is an effective treatment for adults with ADHD. A combination of CBT and medication presented broader improvements in executive functions, but not in clinical symptoms, than CBT alone.


Overexpression of cyclin E messenger ribonucleic acid in nasopharyngeal carcinoma correlates with poor prognosis.
S-phase kinase-associated protein 2 is required for the degradation of p27 protein, which is a negative regulator of cyclin E/cyclin-dependent kinase 2 complex. The present study examined the expression of cyclin E, S-phase kinase-associated protein 2 and p27 protein in nasopharyngeal carcinoma. Tissue from 35 cases of nasopharyngeal carcinoma and 10 normal nasopharyngeal tissue samples underwent reverse polymerase chain reaction to detect messenger ribonucleic acid. Immunohistochemical analysis was performed on 29 nasopharyngeal tissue samples in order to detect protein expression. Messenger ribonucleic acid expression in the nasopharyngeal carcinoma tissue samples analysed indicated a 1.75-fold change in the amount of S-phase kinase-associated protein 2, a 0.34-fold change in the amount of cyclin E and a 0.31-fold change in the amount of p27 protein, compared with positive controls. High levels of cyclin E significantly correlated with late-stage nasopharyngeal carcinoma (p = 0.009) and a poor overall survival (p = 0.010). Immunohistochemical analysis indicated positive expression of S-phase kinase-associated protein 2 in 16/29 nasopharyngeal tissue samples (55 per cent), of cyclin E in 13/29 samples (45 per cent) and of p27 protein in 17/29 (59 per cent) samples. Overexpression of cyclin E messenger ribonucleic acid showed an adverse prognostic significance, correlating with an advanced stage of nasopharyngeal carcinoma and a low overall survival rate.


Insights into Eukaryotic Translation Initiation from Mass Spectrometry of Macromolecular Protein Assemblies.
Translation initiation in eukaryotes requires the interplay of at least 10 initiation factors that interact at the different steps of this phase of gene expression. The interactions of initiation factors and related proteins are in general controlled by phosphorylation, which serves as a regulatory switch to turn protein translation on or off. The structures of initiation factors and a complete description of their post-translational modification (PTM) status are therefore required in order to fully understand these processes. In recent years, mass spectrometry has contributed considerably to provide this information and nowadays is proving to be indispensable when studying dynamic heterogeneous protein complexes such as the eukaryotic initiation factors. Herein, we highlight mass spectrometric approaches commonly applied to identify interacting subunits and their PTMs and the structural techniques that allow the architecture of protein complexes to be assessed. We present recent structural investigations of initiation factors and their interactions with other factors and with ribosomes and we assess the models generated. These models allow us to locate PTMs within initiation factor complexes and to highlight possible roles for phosphorylation sites in regulating interaction interfaces.


Correlation of the absorbed dose to the blood and DNA damage in leukocytes after internal ex-vivo irradiation of blood samples with Ra-224.
Irradiation with α-particles creates densely packed damage tracks along particle trajectories in exposed cells, including complex DNA damage and closely spaced double-strand breaks (DSBs) in hit nuclei. Here, we investigated the correlation of the absorbed dose to the blood and the number of α-induced DNA damage tracks elicited in human blood leukocytes after ex-vivo in-solution exposure with Ra-224. The aim was to compare the data to previously published data on Ra-223 and to investigate differences in DNA damage induction between the two radium isotopes. Blood samples from three healthy volunteers were exposed ex-vivo to six different concentrations of Ra-224 dichloride. Absorbed doses to the blood were calculated assuming local energy deposition of all α- and β-particles of the Ra-224 decay chain, ranging from 0 to 127 mGy. γ-H2AX + 53BP1 DNA damage co-staining and analysis was performed on ethanol-fixed leukocytes isolated from the irradiated blood samples. For damage quantification, α-induced DNA damage tracks and small γ-H2AX + 53BP1 DSB foci were enumerated in the exposed leukocytes. This revealed a linear relationship between the frequency of α-induced γ-H2AX damage tracks and the absorbed dose to the blood, while the frequency of small γ-H2AX + 53BP1 DSB foci indicative of β-irradiation was similar to baseline values. Our data provide a first estimation of the DNA damage induced by Ra-224 in peripheral blood mononuclear cells. A comparison with our previously published Ra-223 data suggests that there is no difference in the induction of radiation-induced DNA damage between the two radium isotopes due to their similar decay properties.


A Subset of Cerebrospinal Fluid Proteins from a Multi-Analyte Panel Associated with Brain Atrophy, Disease Classification and Prediction in Alzheimer's Disease.
In this exploratory neuroimaging-proteomic study, we aimed to identify CSF proteins associated with AD and test their prognostic ability for disease classification and MCI to AD conversion prediction. Our study sample consisted of 295 subjects with CSF multi-analyte panel data and MRI at baseline downloaded from ADNI. Firstly, we tested the statistical effects of CSF proteins (n = 83) to measures of brain atrophy, CSF biomarkers, ApoE genotype and cognitive decline. We found that several proteins (primarily CgA and FABP) were related to either brain atrophy or CSF biomarkers. In relation to ApoE genotype, a unique biochemical profile characterised by low CSF levels of Apo E was evident in ε4 carriers compared to ε3 carriers. In an exploratory analysis, 3/83 proteins (SGOT, MCP-1, IL6r) were also found to be mildly associated with cognitive decline in MCI subjects over a 4-year period. Future studies are warranted to establish the validity of these proteins as prognostic factors for cognitive decline. For disease classification, a subset of proteins (n = 24) combined with MRI measurements and CSF biomarkers achieved an accuracy of 95.1% (Sensitivity 87.7%; Specificity 94.3%; AUC 0.95) and accurately detected 94.1% of MCI subjects progressing to AD at 12 months. The subset of proteins included FABP, CgA, MMP-2, and PPP as strong predictors in the model. Our findings suggest that the marker of panel of proteins identified here may be important candidates for improving the earlier detection of AD. Further targeted proteomic and longitudinal studies would be required to validate these findings with more generalisability.


One-step RNA pathogen detection with reverse transcriptase activity of a mutated thermostable Thermus aquaticus DNA polymerase.
We describe the cloning and characterization of a mutated thermostable DNA polymerase from Thermus aquaticus (Taq) that exhibits an increased reverse transcriptase activity and is therefore designated for one-step PCR pathogen detection using established real-time detection methods. We demonstrate that this Taq polymerase mutant (Taq M1) has similar PCR sensitivity and nuclease activity as the respective Taq wild-type DNA polymerase. In addition, and in marked contrast to the wild-type, Taq M1 exhibits a significantly increased reverse transcriptase activity especially at high temperatures (>60 degrees C). RNA generally hosts highly stable secondary structure motifs, such as hairpins and G-quadruplexes, which complicate, or in the worst case obviate, reverse transcription (RT). Thus, RT at high temperatures is desired to weaken or melt secondary structure motifs. To demonstrate the ability of Taq M1 for RNA detection of pathogens, we performed TaqMan probe-based diagnostics of Dobrava viruses by one-step RT-PCR. We found similar detection sensitivities compared to commercially available RT-PCR systems without further optimization of reaction parameters, thus making this enzyme highly suitable for any PCR probe-based RNA detection method.


Clubhouse model of psychiatric rehabilitation: how is recovery reflected in documentation?
Recovery-oriented models of psychiatric rehabilitation, such as the Clubhouse model, are an important addendum to the clinical treatment modalities that assist people with chronic and severe mental illness. Several studies have described the subjective experiences of personal recovery of individuals in the clubhouse context, but limited research has been undertaken on how clubhouses have operationalized recovery in practice. The research question addressed in this paper is: How are recovery-oriented practices reflected in the documentation of a clubhouse? The documents examined included representative samples of key documents produced or utilized by a clubhouse, including public health-promotion materials and policy and membership documents. Data were subjected to content analysis, supported by the Recovery Promotion Fidelity Scale. The recovery categories identified in the documents included collaboration (27.7%), acceptance and participation (25.3%), quality improvement (18.0%), consumer and staff development (14.5%), and self-determination (14.5%). These categories show how the clubhouse constructs and represents personal recovery through its documentation. The findings are important in light of the role that documentation can play in influencing communication, relationships, and behaviour within organizations. The findings can also be used to inform future research related to recovery-oriented practices in clubhouse settings.