Analysis of rate of change of IS6110 RFLP patterns of Mycobacterium tuberculosis based on serial patient isolates.
The rate of change of IS6110 restriction fragment length polymorphism (RFLP) patterns of Mycobacterium tuberculosis was determined in serial isolates from 544 patients. In 25 patients (4.6%), the RFLP patterns of the follow-up isolates differed from the initial isolates. Patients with different follow-up strains were less likely to cluster with patients whose strains had indistinguishable RFLP patterns. Changes in RFLP patterns were more common for persons with extrapulmonary disease and for those who had both pulmonary and extrapulmonary isolates. Based on serial isolates spanning for the most part <3 months, the half-life was extrapolated to be 3.2 years (95% confidence interval, 2.1-5.0). The main implication of this study is that the rate of change of IS6110-based RFLP of M. tuberculosis supports the use of IS6110 typing in epidemiologic studies of recent transmission of tuberculosis.


Longitudinal Reliability of the OMERACT Thumb Base Osteoarthritis Magnetic Resonance Imaging Scoring System (TOMS).
To assess the longitudinal reliability of the Outcome Measures in Rheumatology (OMERACT) Thumb base Osteoarthritis Magnetic resonance imaging (MRI) Scoring system (TOMS). Paired MRI of patients with hand osteoarthritis were scored in 2 exercises (6-mo and 2-yr followup) for synovitis, subchondral bone defects (SBD), osteophytes, cartilage assessment, bone marrow lesions (BML), and subluxation. Interreader reliability of delta scores was assessed. Little change occurred. Average-measure intraclass correlation coefficients were good-excellent (≥ 0.71), except synovitis (0.55-0.83) and carpometacarpal-1 osteophytes/cartilage assessment (0.47/0.39). Percentage exact/close agreement was 52-92%/68-100%, except BML in 2 years (28%/64-76%). Smallest detectable change was below the scoring increment, except in SBD and BML. TOMS longitudinal reliability was moderate-good. Limited change hampered assessment.


Expanding allelic and phenotypic spectrum of ZC4H2-related disorder: A novel hypomorphic variant and high prevalence of tethered cord.
ZC4H2 (MIM# 300897) is a nuclear factor involved in various cellular processes including proliferation and differentiation of neural stem cells, ventral spinal patterning and osteogenic and myogenic processes. Pathogenic variants in ZC4H2 have been associated with Wieacker-Wolff syndrome (MIM# 314580), an X-linked neurodevelopmental disorder characterized by arthrogryposis, development delay, hypotonia, feeding difficulties, poor growth, skeletal abnormalities, and dysmorphic features. Zebrafish zc4h2 null mutants recapitulated the human phenotype, showed complete loss of vsx2 expression in brain, and exhibited abnormal swimming and balance problems. Here we report 7 new patients (four males and three females) with ZC4H2-related disorder from six unrelated families. Four of the 6 ZC4H2 variants are novel: three missense variants, designated as c.142T>A (p.Tyr48Asn), c.558G>A (p.Met186Ile) and c.602C>T (p.Pro201Leu), and a nonsense variant, c.618C>A (p.Cys206*). Two variants were previously reported : a nonsense variant c.199C>T (p.Arg67*) and a splice site variant (c.225+5G>A). Five patients were on the severe spectrum of clinical findings, two of whom had early death. The male patient harboring the p.Met186Ile variant and the female patient that carries the p.Pro201Leu variant have a relatively mild phenotype. Of note, 4/7 patients had a tethered cord that required a surgical repair. We also demonstrate and discuss previously under-recognized phenotypic features including sleep apnea, arrhythmia, hypoglycemia, and unexpected early death. To study the effect of the missense variants, we performed microinjection of human ZC4H2 wild-type or variant mRNAs into zc4h2 null mutant zebrafish embryos. The p.Met186Ile mRNA variant was able to partially rescue vsx2 expression while p.Tyr48Asn and p.Pro201Leu mRNA variants were not. However, swimming and balance problems could not be rescued by any of these variants. These results suggest that the p.Met186Ile is a hypomorphic allele. Our work expands the genotypes and phenotypes associated with ZC4H2-related disorder and demonstrates that the zebrafish system is a reliable method to determine the pathogenicity of ZC4H2 variants.


An overview of experiences of Wisconsin dairy farmers who modernized their operations.
Wisconsin dairy producers who modernized their operations between 1994 and 1998 had positive feelings about their expansion experiences, accompanied by increased production and improved profitability and quality of life. The average herd in this survey experienced increased production during the 5-yr period studied. Nearly all producers were satisfied with their expansion experience. The negative effect on milk production normally associated with expansion was minimal for most years and did not exist if all herds were summarized together. Managing labor appeared to be the most daunting challenge facing producers following expansion. Respondents who built all new facilities observed higher production, greater labor efficiency, and satisfaction with measures of profitability and quality of life than respondents who modified facilities or added no new facilities. As herd size increased, milk production, labor efficiency, and satisfaction with herd performance, profitability, and quality of life increased. Producers who built all new facilities spent less time on farm work, more time managing employees, and had less difficulty finding, training, supervising, and keeping farm employees than producers who modified facilities or added new facilities to existing operations. Larger herds were associated with an increased reliance on nonfamily labor. Managing labor appears to be an easier task for managers of larger herds. The most difficult challenges for producers who modernized their operations were with labor management, financing, and loan procurement, construction and cost overruns, and feet and leg health. Difficulties with expansion differed little between expansion types (same type, some new, or all new facilities) or herd sizes.


Image-Guided Thermal Ablation as an Alternative to Surgery for Papillary Thyroid Microcarcinoma: Preliminary Results of an Italian Experience.
To report the results of our preliminary experience in treating patients with papillary thyroid microcarcinoma (PTMC) with image-guided thermal ablation, in particular estimating the feasibility, safety and short-term efficacy. From 2018 patients with cytologically proven PTMC < 10 mm were discussed in a multidisciplinary team and evaluated for feasibility of image-guided thermal ablation. In case of technical feasibility, the three possible alternatives (i.e., image-guided thermal ablation, surgery, and active surveillance) were discussed with patients. Patients who agreed to be treated with image guided thermal ablation underwent radiofrequency (RFA) or laser ablation under local anesthesia and conscious sedation. Treatment feasibility, technical success, technique efficacy, change in thyroid function tests, side effects, minor and major complications, patients satisfaction and pain/discomfort perception during and after treatment, and disease recurrence during follow-up were recorded. A total of 13 patients were evaluated, and 11/13 (84.6%) patients (9 female, 2 male, mean age 49.3 ± 8.7 years) resulted suitable for image-guided thermal ablation. All 11 patients agreed to be treated with image-guided thermal ablation. In addition, 3/11 (27.3%) were treated with laser ablation and 8/11 (72.7%) with RFA. All procedures were completed as preoperatively planned (technical success 100%). Technique efficacy was achieved in all 11/11 (100%) cases. Ablated volume significantly reduced from 0.87 ± 0.67 ml at first follow-up to 0.17 ± 0.36 at last follow-up (p = 0.003). No change in thyroid function tests occurred. No minor or major complications occurred. All patients graded 10 the satisfaction for the treatment, and mean pain after the procedure was reported as 1.4 ± 1.7, and mean pain after the procedure as 1.2 ± 1.1 At a median follow-up of 10.2 months (range 1.5-12 months), no local recurrence or distant metastases were found. Image guided thermal ablations appear to be feasible and safe in the treatment of PTMC. These techniques hold the potential to offer patients a minimally invasive curative alternative to surgical resection or active surveillance. These techniques appear to be largely preferred by patients.


[Auditory asymmetry and tinnitus].
Tinnitus are more frequent when the hearing loss is different, asymmetric for each ear. This means probably an interauricular action through the assistance of efferent nervous fibers.


A mitochondrial disorder with ptosis and exercise intolerance without ophthalmoparesis secondary to m.5865 T > C variant.
We describe a novel mitochondrial variant (m.5865 T > C) in a patient with decreased exercise endurance and juvenile onset slowly progressive bilateral ptosis without ophthamloparesis. The m.5865 T > C variant was seen in 82.9% of mtDNA molecules in skeletal muscle tissue and ~8% of mtDNA molecules in urine epithelium, but was not detected in blood leukocytes. The proband does not demonstrate any additional features often seen in individuals with a mitochondrial disorder (i.e., sensorineural hearing loss, type 2 diabetes, stroke-like episodes, muscle weakness, ophthalmoparesis, cardiomyopathy or cardiac arrhythmias). This case suggests that ptosis and exercise intolerance, without ophthalmoparesis, are the primary clinical features of the m.5865 T > C mtDNA variant.


Cytokine activation through sublethal hemorrhage is protective against early lethal endotoxic challenge.
To determine the immunologic consequences of nonlethal hemorrhage on subsequent exposure to lipopolysaccharide (LPS) and to determine the role of interleukin 1 beta (IL-1) specifically in mediating the response to LPS with and without prior hemorrhage. Prospective, randomized, controlled experimental trial. Male BALB/c mice and transgenic mice deficient in IL-1 converting enzyme. Animals were subjected to hemorrhage (by cardiac puncture), LPS challenge by intraperitoneal injection, or hemorrhage followed 24 hours later by LPS challenge. Mortality was assessed every 4 hours for 96 hours following hemorrhage or LPS exposure. Serum IL-1 levels were determined 24 hours after exposure to hemorrhage and LPS. University of South Florida Core General Surgery Research Facility, Tampa. Mortality and serum IL-1 levels. Hemorrhage alone resulted in complete survival, whereas LPS alone resulted in near-complete (95%) mortality. Hemorrhage, when given 24 hours before LPS challenge, afforded significant protection compared with LPS alone (67% survival vs 5% survival; P < .001). Serum IL-1 levels 24 hours after exposure to LPS were significantly lower in prehemorrhaged mice than in those receiving LPS alone. Transgenic mice incapable of producing biologically active IL-1 were further protected, demonstrating near-complete (95%) survival following hemorrhage and LPS challenge. Cytokine activation through nonlethal hemorrhage attenuates subsequent IL-1 response to early immunologic challenge. Such immune suppression appears to be protective early on and is supported by the near-complete immunity to LPS in animals incapable of producing biologically active IL-1.


Evidence-based systemic antibiotic prescription in periodontal and dental implant procedures: A mini-review.
To evaluate and summarize the available scientific evidence regarding antibiotic prescription protocols in periodontal and dental implant procedures. A bibliographic search was conducted in PubMed, ScienceDirect, Scielo, Cochrane Library, EBSCOhost and Google Scholar up to February 2023. Manual and electronic searches were conducted, including publications in English. Medical Subject Headings (MeSH), free text terms and Boolean operators were used. Antibiotic prescription protocols have been restricted due to antimicrobial resistance. While for certain clinical circumstances there are guidelines with clear and unanimous criteria for appropriate antibiotic use, for other conditions evidence showed an insufficiency of available literature and the persistence of crucial issues where no consensus has been reached. This mini-review summarizes the most up-to-date recommendations regarding the prescription of antibiotics in periodontal and dental implant procedures in order to guide evidence-based decision-making.


Spectral karyotyping of sarcomas and fibroblasts derived from Ink4a/Arf-deficient mice reveals chromosomal instability in vitro.
The Ink4a/Arf locus is functionally linked to the Rb and p53 pathways through the action of its two gene products. Mouse models null for this locus show rapid onset of cancer with a preponderance of lymphomas and sarcomas. We report on a study of cell lines derived from sarcomas arising in Ink4a/Arf null mice. The cytogenetics of these lines was monitored over the course of serial passage. Results indicate that early passage cells are relatively normal. However, after multiple passages chromosomal instability becomes apparent as evidenced by increasing tetraploidy and aneuploidy, and the concomitant loss of clonality. To further evaluate the effect of Ink4a/Arf-deficiency on chromosomal stability in vitro, we isolated Ink4a/Arf deficient primary murine embryonic fibroblasts (MEFs), serially passaged them, and analyzed their chromosomal stability by spectral karyotyping (a 24-color chromosome paint-FISH technique). We found that chromosomal instability in Ink4a/Arf deficient MEFs developed with the same timing as seen in cell lines derived from Ink4a/Arf deficient sarcomas. Thus, chromosomal instability seen in Ink4a/Arf deficient tumors in vitro may be unrelated to the original phenotype of the tumor in vivo. Therefore, interpretation of cytogenetic data from cell lines derived from Ink4a/Arf deficient tumors should be done on early passage cells.


LEA-135 expression: its association with a lower risk of recurrence and increased overall survival of patients with lymph node-positive primary invasive breast cancer.
A retrospective study was undertaken to determine and compare the prognostic significance of LEA-135 protein expression by immunohistochemistry with other prognostic pathological parameters, with respect to recurrence and overall survival. This study was conducted in freshly-frozen tissue sections from a cohort of 367 patients having primary invasive breast cancer, with axillary lymph node metastasis. The association of LEA-135 expression was compared with estrogen and progesterone receptor status, segmentectomy or radical mastectomy and hormonal therapy or chemotherapy in terms of recurrence or disease-free survival. Pathologic parameters including tumor size, histological tumor type and histological grade, as well as age of patients at the time of initial diagnosis, and the treatments, together with a median follow-up of 8.8 years were contemplated for the study. Among these parameters, tumor size and histological grade were individually and significantly associated with an increased probability of recurrence (log rank p<0.001 in both cases) and short survival (log ranks p<0.001 and p=0.002, respectively), whereas age was only significantly associated with an increased probability of recurrence (log rank p=0.002) by univariate analysis. By multivariate analysis, both tumor size and histological grade remained statistically significant for recurrence (log rank p<0.001 and p=0.013, respectively) and overall survival (log ranks p<0.001 and p=0.016, respectively). Among the prognostic biomarkers, both ER and PR expression were associated with a decreased rate of recurrence (log ranks p<0.001 and p=0.008, respectively) and overall survival (log ranks p<0.001 and p=0.002, respectively) by univariate analysis. By multivariate analysis, only the ER expression remained significantly associated with a decreased recurrence and increased overall survival (log ranks p=0.023 and p=0.002, respectively). Patients with high (>50% positive cells) or moderate (5-50% positive cells) number of LEA-135-positive cells had a lower probability (46%) of recurrence at 10 years after surgery compared to 76% in LEA-135-negative patients (log rank p<0.001) by univariate analysis. Moreover, the probability of overall survival was higher in patients with high or moderate expression of LEA-135 (46% and 47%, respectively) compared to LEA-135-negative patients (24%) by univariate analysis (log rank p=0.009). By multivariate analysis, the association remained statistically significant for recurrence (log rank p<0.001) and survival (log rank p=0.002). However, there was no significant association between LEA-135 and any of the pathological parameters, age, hormone receptor status, the mode of surgery or the form of therapy (chemo- and/or hormonal) received by this cohort of patients. The results show that an improved prognosis was directly associated with the density of LEA-135-positive cancer cells, while loss of LEA-135 expression was associated with an aggressive phenotype of cancer cells during breast cancer progression. Thus, LEA-135 expression can be implicated as a significant and independent biomarker to identify and distinguish high- from low-risk patients with lymph node-positive invasive breast cancer for an aggressive treatment. Moreover, according to the present results, LEA-135 expression appears to be associated with the tumor cells that have retained certain normal biological characteristics, leading to their lack of aggressiveness and hence a better prognosis.


Attitudes and perceptions of affected women towards endocrine endometriosis therapy: an international survey based on free-word association networks.
What are the attitudes and perceptions towards endocrine endometriosis therapy? Among the study population, endocrine endometriosis therapies are associated with negative mental images and emotions and there seems to be a pre-therapeutic information deficit on the part of physicians. Endocrine therapies, as the current standard of conservative endometriosis treatment, have good efficacy and improve symptoms and quality of life in most patients. Nevertheless, clinical practice repeatedly shows rejection on the part of patients, which may result in reduced compliance and discontinuation of therapy. Cross-sectional study among endometriosis patients using a multilingual questionnaire distributed via the most popular social media channels between November 2020 and February 2021. A total of 3348 women participated in the study. Based on a pilot phase, an international, multilingual online survey was conducted among women affected by endometriosis. The questionnaire included free-word associations and questions about personal medical history, source of information, and demographic data. Mental representations were detected based on modules of the co-occurrence network of associations. Six modules with different dominant emotional labels emerged from the confluence of associations to endocrine endometriosis therapy mentioned by participants. Five modules reflected negative mental associations, with the most frequently mentioned words being 'side effects', 'pain', 'ineffective', 'depression', and 'uncertainty'. Of the 12 most frequently selected emotions, only 'optimistic' was positive. Side effects affecting mental health are the most important reason for deciding against endocrine therapy in our survey population. Twenty-seven percent of respondents reported knowing little about endocrine therapies for endometriosis. Social media are the most frequently used sources of information and were rated as the most useful. By translating the questionnaire, questions might have been understood differently depending on the language. By using social media channels for distribution, digitally literate patients were targeted. The survey population might not be representative as patients who are critical/unhappy with therapy are more likely to seek advice from peer groups. The findings of this study replicate the findings of a recent survey in three European countries. Given the prevalence of endometriosis and the few emerging pharmaceutical alternatives, these data point to a growing need for further research and development of non-hormonal drugs for treating endometriosis. Most endometriosis patients are young and digitally literate, and much information is obtained from alternative sources, such as social media. Careful education before starting therapy should be taken seriously, and patients' concerns should be addressed individually by health care providers. This could help reduce misunderstanding and misinformation and improve treatment adherence and satisfaction. There is no funding or conflict of interest to declare. The trial is not registered at any trial registry.


Problem of image superresolution with a negative-refractive-index slab.
By means of the angular spectrum representation of wave fields, a discussion is given on the propagation and restoration of the wave-front structure in a slab of a left-handed medium (or negative-index medium) whose surface impedance matches that of vacuum, namely, one whose effective optical parameters are n = epsilon = mu = -1. This restoration was previously discussed [Phys. Rev. Lett. 85, 3866 (2000)] in regard to whether it may yield superresolved images. The divergence of the wave field in the slab, and its equivalence with that of the inverse diffraction propagator in free space, is addressed. Further, the existence of absorption, its regularization of this divergence, and the trade-off of a resulting limited superresolution are analyzed in detail in terms of its effect on the evanescent components of the wave field and hence on the transfer function width.


Accurate marker-free alignment with simultaneous geometry determination and reconstruction of tilt series in electron tomography.
An image alignment method for electron tomography is presented which is based on cross-correlation techniques and which includes a simultaneous refinement of the tilt geometry. A coarsely aligned tilt series is iteratively refined with a procedure consisting of two steps for each cycle: area matching and subsequent geometry correction. The first step, area matching, brings into register equivalent specimen regions in all images of the tilt series. It determines four parameters of a linear two-dimensional transformation, not just translation and rotation as is done during the preceding coarse alignment with conventional methods. The refinement procedure also differs from earlier methods in that the alignment references are now computed from already aligned images by reprojection of a backprojected volume. The second step, geometry correction, refines the initially inaccurate estimates of the geometrical parameters, including the direction of the tilt axis, a tilt angle offset, and the inclination of the specimen with respect to the support film or specimen holder. The correction values serve as an indicator for the progress of the refinement. For each new iteration, the correction values are used to compute an updated set of geometry parameters by a least squares fit. Model calculations show that it is essential to refine the geometrical parameters as well as the accurate alignment of the images to obtain a faithful map of the original structure.


Concentrations of some metabolites in the breath of healthy children aged 7-18 years measured using selected ion flow tube mass spectrometry (SIFT-MS).
Using selected ion flow tube mass spectrometry (SIFT-MS), measurements have been made of the levels of several metabolites in the exhaled breath of 200 healthy school children. Thus, concentration distributions of each metabolite have been obtained for the first time in the paediatric age range. The median values (in parentheses) of the concentrations in parts per billion, ppb, were ammonia (628), acetone (297), methanol (193), ethanol (187), isoprene (37), propanol (16), acetaldehyde (23) and pentanol (15). Hydrogen cyanide was not present in the breath above the detection limit of 2 ppb in the majority of subjects. The water vapour level (humidity) of the breath samples was routinely measured as a check on the sample integrity. Such data are essential if SIFT-MS breath analyses are to be used as a clinical tool to aid diagnosis and/or as a monitor of disease in children. The levels of metabolites usually followed a log-normal distribution and the levels of some compounds were similar to those obtained previously in adults. Lower values were found in the levels of acetone, ammonia, methanol and isoprene. There were no major variations in relation to gender. Some metabolites showed significant variation in relation to age and body mass index. To our knowledge, these are the first measurements of exhaled mouth breath pentanol levels. The median ammonia levels in mouth-exhaled breath of these children decreased with age, whereas in older adults, ammonia has been shown to increase with age. Breath acetone levels were significantly increased for those who had not eaten for more than 6 h prior to providing the breath sample, although dietary control was not a mandatory aspect of the protocol.


The impact of cone beam computed tomography on the choice of endodontic diagnosis.
To determine whether the outcome of cone beam computed tomography (CBCT) examinations performed in accordance with the European Commission guidelines in a clinical setting has an impact on choosing diagnoses in endodontics. A prospective observational study was conducted. Fifty-three consecutive patients (81 teeth) from two different endodontic specialist clinics in Sweden were followed. After performing a thorough clinical examination (based on the history, clinical findings, and diagnostic tests such as intra-oral radiography), the examiner wrote down a preliminary diagnosis before CBCT examination. After the CBCT examination, a new diagnosis was made by the same examiner. Both the pre- and the post-CBCT examination diagnoses were plotted according to patients and teeth. The CBCT examinations were performed using similar equipment and protocols that were standardized amongst the clinics. The diagnoses were changed for at least one tooth in 22 patients (41%); overall, the diagnoses were changed for 28 teeth (35%). CBCT has a substantial impact on diagnostic thinking in endodontics when used in accordance with the European Commission guidelines.


Structural elucidation and functional characterization of the Hyaloperonospora arabidopsidis effector protein ATR13.
The oomycete Hyaloperonospora arabidopsidis (Hpa) is the causal agent of downy mildew on the model plant Arabidopsis thaliana and has been adapted as a model system to investigate pathogen virulence strategies and plant disease resistance mechanisms. Recognition of Hpa infection occurs when plant resistance proteins (R-genes) detect the presence or activity of pathogen-derived protein effectors delivered to the plant host. This study examines the Hpa effector ATR13 Emco5 and its recognition by RPP13-Nd, the cognate R-gene that triggers programmed cell death (HR) in the presence of recognized ATR13 variants. Herein, we use NMR to solve the backbone structure of ATR13 Emco5, revealing both a helical domain and a disordered internal loop. Additionally, we use site-directed and random mutagenesis to identify several amino acid residues involved in the recognition response conferred by RPP13-Nd. Using our structure as a scaffold, we map these residues to one of two surface-exposed patches of residues under diversifying selection. Exploring possible roles of the disordered region within the ATR13 structure, we perform domain swapping experiments and identify a peptide sequence involved in nucleolar localization. We conclude that ATR13 is a highly dynamic protein with no clear structural homologues that contains two surface-exposed patches of polymorphism, only one of which is involved in RPP13-Nd recognition specificity.


Protein Biomarkers for Breast Cancer Risk Are Specifically Correlated with Local Steroid Hormones in Nipple Aspirate Fluid.
The local endocrine environment of the breast may have stronger relations to breast cancer risk than systemic hormones. Nipple aspiration fluid (NAF) provides a window into this milieu. We hypothesized that the correlations between proteins and steroid hormones in NAF are stronger, and specific relationships may reveal links to breast cancer risk. NAF and blood samples were obtained simultaneously from 54 healthy women and from the contralateral unaffected breast of 60 breast cancer patients. The abundance of five proteins, superoxide dismutase (SOD1), C-reactive protein (CRP), chitinase-3-like protein 1 (YKL40), cathepsin D (CatD), and basic fibroblast growth factor (bFGF) in NAF was measured using ELISA. The NAF and serum concentrations of estradiol, estrone, progesterone, androstenedione, testosterone, and dehydroepiandrostrerone (DHEA) were measured using ELISA or RIA. The correlations between proteins and hormones revealed that NAF proteins correlated with each other: SOD1 with CRP (R = 0.276, P = 0.033) and CatD (R = 0.340, P = 0.0036), and bFGF with CRP (R = 0.343, P = 0.0021). NAF proteins displayed significant correlations with NAF steroids, but not with serum steroids: SOD1 with DHEA (R = 0.333, P = 0.019), YKL40 with testosterone (R = 0.389, P = 0.0012), and bFGF negatively correlated with testosterone (R = -0.339, P = 0.015). The regulation of YKL40 and bFGF by testosterone was confirmed in breast cancer cell lines. In summary, NAF proteins were more strongly related to local hormone levels than to systematic hormone levels. Some proteins were specifically correlated with different NAF steroids, suggesting that these steroids may contribute to breast cancer risk through different mechanisms.


Students perceive healthcare as a valuable learning environment when accepted as a part of the workplace community.
The healthcare system is complex and the education of medical and nursing students is not always a priority within it. However, education offered at the point of care provides students with opportunities to apply knowledge, and to develop the necessary skills and attitudes needed to practice their future profession. The major objective of this study was to identify students' views of generic aspects of the healthcare environment that influences their progress towards professional competence. We collected free text answers of 75 medical students and 23 nursing students who had completed an extensive questionnaire concerning their learning in clinical wards. In order to obtain richer data and a deeper understanding, we also interviewed a purposive sample of students. Qualitative content analysis was conducted. We identified three themes: (1) How management, planning and organising for learning enabled content and learning activities to relate to the syllabus and workplace, and how this management influenced space and resources for supervision and learning; (2) Workplace culture elucidated how hierarchies and communication affected student learning and influenced their professional development and (3) Learning a profession illustrated the importance of supervisors' approaches to students, their enthusiasm and ability to build relationships, and their feedback to students on performance. From a student perspective, a valuable learning environment is characterised as one where management, planning and organising are aligned and support learning. Students experience a professional growth when the community of practice accepts them, and competent and enthusiastic supervisors give them opportunities to interact with patients and to develop their own responsibilities.


An investigation into the population abundance distribution of mRNAs, proteins, and metabolites in biological systems.
Distribution analysis is one of the most basic forms of statistical analysis. Thanks to improved analytical methods, accurate and extensive quantitative measurements can now be made of the mRNA, protein and metabolite from biological systems. Here, we report a large-scale analysis of the population abundance distributions of the transcriptomes, proteomes and metabolomes from varied biological systems. We compared the observed empirical distributions with a number of distributions: power law, lognormal, loglogistic, loggamma, right Pareto-lognormal (PLN) and double PLN (dPLN). The best-fit for mRNA, protein and metabolite population abundance distributions was found to be the dPLN. This distribution behaves like a lognormal distribution around the centre, and like a power law distribution in the tails. To better understand the cause of this observed distribution, we explored a simple stochastic model based on geometric Brownian motion. The distribution indicates that multiplicative effects are causally dominant in biological systems. We speculate that these effects arise from chemical reactions: the central-limit theorem then explains the central lognormal, and a number of possible mechanisms could explain the long tails: positive feedback, network topology, etc. Many of the components in the central lognormal parts of the empirical distributions are unidentified and/or have unknown function. This indicates that much more biology awaits discovery.


Sadistic homosexual pedophilia: treatment with cyproterone acetate: a single case study.
This single case study demonstrates the effects of antiandrogen treatment on a subject with a very serious sexual deviation and a poor prognosis. It assesses the effects of cyproterone acetate (CPA) on an individual with a serious chronic organic brain syndrome combined with sadistic homosexual pedophilia. Furthermore, this individual had failed to respond to a behavioural treatment program and long-term milieu therapy. Finally, this case study is the first report of CPA differentially affecting penile responses to deviant and non-deviant stimuli.


Cochlear immunoglobulin in the C3H/lpr mouse model for autoimmune hearing loss.
Immunoglobulin staining was conducted in cochlear tissue from the C3H/lpr autoimmune strain mouse to better understand the local immune processes underlying autoimmune inner ear disease. This mouse is a model for spontaneous systemic lupus erythematosus with coincident elevated cochlear thresholds. Cochleas were examined from C3H/lpr mice at 2 months of age, before disease onset, and at 8 months of age, when systemic disease and hearing loss are manifested. Sections of these cochleas, along with cochlear sections from age-matched C3H/HeJ nonautoimmune controls, were immunocytochemically stained for IgG and IgM to identify areas of abnormal immunoglobulin activity. IgM immunoreactivity was similar in control and autoimmune cochlear tissue and did not appear to vary with disease progression. Staining was limited to the inside of capillaries in the stria vascularis and other areas within the cochlea. Similar staining patterns were seen in control animals stained for IgG. However, C3H/lpr mice with autoimmune disease showed extensive IgG immunoreactivity spreading out from the stria vascularis capillaries into the extracapillary spaces. This increased permeability suggested that breakdown of the blood labyrinth barrier was coincident with systemic autoimmune disease.


Morphological Analysis of Bone Deformities of the Distal Femur in Toy Poodles with Medial Patellar Luxation.
The aim of this study was to evaluate the bone deformities of the distal femur of Toy Poodles with medial patellar luxation (MPL) using computed tomography. Computed tomography data from 37 stifles of Toy Poodles (16 normal, 10 grade 2 MPL and 11 grade 4 MPL) were analysed. For trochlear morphology, sulcus angle, medial or lateral trochlear inclination and trochlear angle were compared. For condylar morphology, distance between the apex of the medial or lateral trochlear ridge and the most caudal point of the medial or lateral femoral condyle (MC or LC), the length of the cranial/middle (anterior) part (MC(a) or LC(a')) and caudal (posterior) part (MC(p) or LC(p')) of distal femur and medial or lateral condyle width (MCW or LCW) were measured, and the ratios of medial-to-lateral condyles and anterior-posterior parts were compared. Sulcus angle was significantly higher, and medial trochlear inclination was significantly lower in grade 4 MPL group than other groups. Lateral trochlear inclination was not significantly different among 3 groups. Trochlear angles at proximal trochlear groove were significantly lower in grade 4 MPL group than other groups. MC/LC, MC(a)/LC(a'), MC(a)/MC(p), and LC(a')/LC(p') were significantly lower in grade 4 MPL group than other groups; however, there were no significant differences in MC(p)/LC(p') and MCW/LCW among three groups. Hypoplasia of the cranial and middle rather than caudal compartment of the distal femur was the primary morphological abnormality in Toy Poodles with grade 4 MPL.


Minding metals: tailoring multifunctional chelating agents for neurodegenerative disease.
Neurodegenerative diseases like Alzheimer's and Parkinson's disease are associated with elevated levels of iron, copper, and zinc and consequentially high levels of oxidative stress. Given the multifactorial nature of these diseases, it is becoming evident that the next generation of therapies must have multiple functions to combat multiple mechanisms of disease progression. Metal-chelating agents provide one such function as an intervention for ameliorating metal-associated damage in degenerative diseases. Targeting chelators to adjust localized metal imbalances in the brain, however, presents significant challenges. In this perspective, we focus on some noteworthy advances in the area of multifunctional metal chelators as potential therapeutic agents for neurodegenerative diseases. In addition to metal chelating ability, these agents also contain features designed to improve their uptake across the blood-brain barrier, increase their selectivity for metals in damage-prone environments, increase antioxidant capabilities, lower Abeta peptide aggregation, or inhibit disease-associated enzymes such as monoamine oxidase and acetylcholinesterase.


Validation of the French 3-year prognostic score using the Canadian Cystic Fibrosis registry.
Studies of large CF populations using registry data are important to identify people at high risk for death. Nkam et al. published a prognostic score developed on French CF registry data to predict death or lung transplantation (LT) over a 3-year period in the adult CF population. The goal of our study was to validate the proposed tool using the Canadian CF registry. Using data between 2011 and 2014, a total of 2043 adult CF patients were included. We found that the French prognostic score was a good predictor of death or LT in the Canadian CF population (OR for each unit increase: 3.12, 95% CI: 2.74-3.55; p value < 0.001). The proposed prognostic score accurately categorizes patients when applied to an external dataset. This score provides an important tool for early identification of patients at high risk for death or LT, in whom specific therapeutic intervention can be proposed.


Opinion of the Scientific Committee on health, environmental and emerging risks on the safety of titanium dioxide in toys.
The Opinion of the Scientific Committee on Health, Environmental and Emerging Risks advises the European Commission on whether the uses of titanium dioxide in toys and toy materials can be considered to be safe in light of the identified exposure, and the classification of titanium dioxide as carcinogenic category 2 after inhalation. Four toy products including casting kits, chalk, powder paints and white colour pencils containing various amounts of TiO2 as colouring agent were evaluated for inhalation risks. For the oral route, childrens' lip gloss/lipstick, finger paint and white colour pencils were evaluated. When it can be demonstrated with high certainty that no ultrafine fraction is present in pigmentary TiO2 preparations used in toys and toy materials, safe use with no or negligible risk for all products considered is indicated based on the exposure estimations of this Opinion. However, if an ultrafine fraction is assumed to be present, safe use is not indicated, except for white colour pencils.


Do physicians discuss genetic testing with family-history-positive breast cancer patients?
Genetic testing for carriers of known germ-cell mutations involved in hereditary breast cancer in families should start with affected family members, in order to avoid ambiguous test results in unaffected members. A survey was conducted (May to August 1997) of physicians involved in the follow-up care of family-history-positive breast cancer patients diagnosed in 1994 and 1995, identified in the Connecticut Tumor Registry. Only 14 (18%) of 76 responding physicians reported having received an advertisement about commercially available tests for genes involved in inherited breast cancer, and only 12 (16%) reported discussing genetic testing with a patient included in this study. None of the 74 patients involved were known (by the responding physicians) to have been tested. However, further surveys are needed because awareness of the availability of genetic tests may be growing.


Monte Carlo simulation of physicochemical processes of liquid water radiolysis. The effects of dissolved oxygen and OH scavenger.
The paper describes developments of the physicochemical part of a computer code system that estimates DNA strand break induction on plasmid pBR322 DNA. In order to test the reliability of the model, we evaluated the dielectric function and the time-dependent yield of chemical species in the presence of OH radical scavenger or dissolved oxygen. Results agree with measurements on the radiolysis of liquid water. When a hybrid model of a liquid inelastic cross-section and a vapour elastic cross-section is used, energy deposition by vibrational excitations is estimated to be approximately 11% of total energy deposition.


[Age-related trends in spatio-temporal structure of simple graphic movements performed in a cyclic manner at a maximal tempo. Part I. Tempo increase is accounted for by a reduction in the number of submovements in a movement cycle].
Right-handed human subjects of 4 different ages (5-6, 8-9, 11-12 yo. and adult subjects) performed simple graphical movements in a cyclic manner with maximal possible tempo. The movements differed with respect to their coordination and serial complexity and were performed by each hand while holding the stylus either by the fingers or the fist. It was found that cycle duration considerably decreased with age from the age of 5 to adulthood and the amount of the age-related gain in the performance rate depended on which hand (right vs. left) and/or grip (fingers vs. fist) was used to perform a movement. The rate of successive submovements neither changed substantially with age nor showed any lateral asymmetry however it did depend on the movement being performed and the grip being used. The results show that the age-related trend in the cyclic movements can almost entirely be accounted for by a reduction in the number of submovements in a cycle. The results are discussed in the view of the hypothesis that considers submovements to be the building blocks of a graphical movement.


Development of an instrument to assess the quality of acupuncture: results from a Delphi process.
Quality acupuncture influences the outcomes of clinical research, and issues associated with effective administration of acupuncture in randomized controlled trials need to be addressed when appraising studies. The study objective was to achieve consensus on domains and items for inclusion in a rating scale to assess quality acupuncture administered in clinical research. An active group of Australian acupuncture researchers initially identified a pool of items assessing quality. The Delphi consensus process was then used to select and reduce the number of items, and an additional expert panel of 42 researchers were invited to participate. Participants initially ranked items along a five-point scale for the first Delphi round, and indicated an agree or disagree response during the second round. For an item to be retained into the second round, an item had to attain greater than 80% agreement that the item described a dimension of quality acupuncture and related study design. Thirty-two (32) experts agreed to participate in the study. After two rounds of the Delphi process, consensus was reached on 14 domains and 26 items relating to quality acupuncture. Domains, items, and minimum standards related to study design; rationale of the intervention; criteria relating to needling stimulation either manual or electrostimulation; duration and frequency of treatment; and practitioner training. Items for inclusion in an instrument to assess quality acupuncture in clinical research were identified. Further development of the instrument including relative weighting of items and reliability testing is under way.


Purification of native and recombinant double-stranded RNA-specific adenosine deaminases.
ADAR1 and ADAR2 are members of a family of enzymes that catalyze the conversion of adenosine to inosine in double-stranded RNA. Unlike the other types of RNA editing that involve multiprotein editing complexes, the site-specific deamination of an adenosine to inosine is catalyzed by single enzymes. ADAR1 and ADAR2 have been purified and the genes cloned from various sources. Each gene encodes multiple splice variants. As it is crucial to have an adequate supply of pure protein to investigate this type of RNA editing, we describe in this article methods for both the purification and the overexpression of either full-length or partial ADAR1 and ADAR2 isoforms.


A molecular clock for malaria parasites.
The evolutionary origins of new lineages of pathogens are fundamental to understanding emerging diseases. Phylogenetic reconstruction based on DNA sequences has revealed the sister taxa of human pathogens, but the timing of host-switching events, including the human malaria pathogen Plasmodium falciparum, remains controversial. Here, we establish a rate for cytochrome b evolution in avian malaria parasites relative to its rate in birds. We found that the parasite cytochrome b gene evolves about 60% as rapidly as that of host cytochrome b, corresponding to approximately 1.2% sequence divergence per million years. This calibration puts the origin of P. falciparum at 2.5 million years ago (Ma), the initial radiation of mammalian Plasmodium at 12.8 Ma, and the contemporary global diversity of the Haemosporida across terrestrial vertebrates at 16.2 Ma.


Pure laparoscopic posterior sectionectomy for liver metastasis resulting from choroidal malignant melanoma: a case report.
Liver metastases resulting from primary choroidal malignant melanomas occur frequently and have a poor prognosis. As a result of advancements in multidisciplinary approaches, life expectancy can be increased when R0 resection is possible. Herein we report the surgical outcomes of pure laparoscopic posterior sectionectomy (PLPS) in a patient with a solitary liver metastasis resulting from choroidal malignant melanoma. The subject was a 46-year-old Japanese man who had received radiotherapy for primary right choroidal malignant melanoma 2 years before presenting at our hospital; he subsequently underwent ophthalmectomy as a result of the relapse. During follow-up, CT revealed a metastatic lesion in the liver S7, and interventional treatments were performed sequentially. The lesion still showed a tendency to enlarge, so we performed PLPS. On postoperative day 7, the patient was discharged from the hospital, and he started to receive adjuvant chemotherapy 2 weeks after PLPS. Although PLPS is deemed to be difficult for lesions in the upper part or posterior segment of the liver, we performed this modality safely.


Neuromuscular taping treatment of diabetic foot: a concept analysis.
The definition of neuromuscular taping (NMT) has yet to be clearly analysed as a possible treatment for diabetic foot. Case studies, theoretical analysis and results of existing research may lead to varying perceptions on the definition of NMT and its possible effects on diabetic foot. This article aims to analyse the definition of the NMT concept and furthermore as a basis for future research development on diabetic foot. The procedure for reference source search include the principal data bases using "neuromuscular taping" and "diabetic foot" keywords for the period of 2010-2019. The concept analysis uses an 8-step approach with the Walker and Avant's method. NMT is a decompression application of an elastic tape on the skin on the diabetic foot that has the effect of reducing the inflammatory response, improving vascularity and neuromusculoskel-etal function. It aims to improve neuromusculoskeletal and lymphatic system functioning due to the presence of wrinkles, indicating dila-tion, with local effects on the sensorimotor and proprioceptive senses in conditions of care, rehabilitation and injury. Analysis of the NMT concept on diabetic foot obtained attributes of elastic tape, skin, pain, edema, injury, sensorimotor, circulation, drainage, relaxation, local, proprioceptive, motion func-tion, strength, contraction, stabilisation, reflex, rehabilitation, care, musculoskeletal, nerve, muscles, tendons, fascia, joints, lymphatic, longitudinal, wrinkles. There were four groups of attributes, namely inflammatory response, vascularity, neuromusculoskeletal function and musculoskeletal system. NMT application benefits for diabetic foot can be attributed to improving walking function, leg position, decreasing pain response, improving body function index, improving leg muscle strength and motor function, increasing range of movement (ROM), maintaining stability of leg joint function, preventing injury, increas-ing strength and improving position of ankle joints, reducing stiffness, reducing edema and helping wound healing processes.


Improved chromatic dispersion monitoring using single RF monitoring tone.
We demonstrate an improved chromatic dispersion monitoring technique using a single RF monitoring tone. Compared to conventional techniques using a single RF monitoring tone, our proposed technique is able to monitor the sign of the residual dispersion and doubles the monitoring range. Our proposed technique utilizes the RF fading caused by chromatic dispersion and a two-detector dispersion monitor setup, where a dispersion offset is inserted before one of the detectors. The observed monitoring error is less than +/-35 ps/nm over a 1300 ps/nm monitoring range. A small power penalty less than 0.5 dB is observed due to the addition of the RF monitoring tone. Our technique is more than twice as accurate as the conventional technique.


The effects of advertisement location and familiarity on selective attention.
This study comprised two experiments to examine the distracting effects of advertisement familiarity, location, and onset on the performance of a selective attention task. In Exp. 1, familiar advertisements presented in peripheral vision disrupted selective attention when the attention task was more demanding, suggesting that the distracting effect of advertisements is a product of task demands and advertisement familiarity and location. In Exp. 2, the onset of the advertisement shortly before, or after, the attention task captured attention and disrupted attentional performance. The onset of the advertisement before the attention task reduced target response time without an increase in errors and therefore facilitated performance. Despite being instructed to ignore the advertisements, the participants were able to recall a substantial proportion of the familiar advertisements. Implications for the presentation of advertisements during human-computer interaction were discussed.


Rationalizing the Decavanadate(V) and Oxidovanadium(IV) Binding to G-Actin and the Competition with Decaniobate(V) and ATP.
The experimental data collected over the past 15 years on the interaction of decavanadate(V) (V10O286-; V10), a polyoxometalate (POM) with promising anticancer and antibacterial action, with G-actin, were rationalized by using several computational approaches (docking, density functional theory (DFT), and molecular dynamics (MD)). Moreover, a comparison with the isostructural and more stable decaniobate(V) (Nb10O286-; Nb10) was carried out. Four binding sites were identified, named α, β, γ, and δ, the site α being the catalytic nucleotide site located in the cleft of the enzyme at the interface of the subdomains II and IV. It was observed that the site α is preferred by V10, whereas Nb10 is more stable at the site β; this indicates that, differently from other proteins, G-actin could contemporaneously bind the two POMs, whose action would be synergistic. Both decavanadate and decaniobate induce conformational rearrangements in G-actin, larger for V10 than Nb10. Moreover, the binding mode of oxidovanadium(IV) ion, VIVO2+, formed upon the reduction of decavanadate(V) by the -SH groups of accessible cysteine residues, is also found in the catalytic site α with (His161, Asp154) coordination; this adduct overlaps significantly with the region where ATP is bound, accounting for the competition between V10 and its reduction product VIVO2+ with ATP, as previously observed by EPR spectroscopy. Finally, the competition with ATP was rationalized: since decavanadate prefers the nucleotide site α, Ca2+-ATP displaces V10 from this site, while the competition is less important for Nb10 because this POM shows a higher affinity for β than for site α. A relevant consequence of this paper is that other metallodrug-protein systems, in the absence or presence of eventual inhibitors and/or competition with molecules of the organism, could be studied with the same approach, suggesting important elements for an explanation of the biological data and a rational drug design.


Pheromonal influences on sociosexual behavior in postmenopausal women.
To determine whether a putative human sex-attractant pheromone increases specific sociosexual behaviors of postmenopausal women, we tested a chemically synthesized formula derived from research with underarm secretions from heterosexually active, fertile women that was recently tested on young women. Participants (n = 44, mean age = 57 years) were postmenopausal women who volunteered for a double-blind placebo-controlled study designed, to test an odorless pheromone, added to your preferred fragrance, to learn if it might increase the romance in your life. During the experimental 6-week period, a significantly greater proportion of participants using the pheromone formula (40.9%) than placebo (13.6%) recorded an increase over their own weekly average baseline frequency of petting, kissing, and affection (p = .02). More pheromone (68.2%) than placebo (40.9%) users experienced an increase in at least one of the four intimate sociosexual behaviors (p = .04). Sexual motivation frequency, as expressed in masturbation, was not increased in pheromone users. These results suggest that the pheromone formulation worn with perfume for a period of 6 weeks has sex-attractant effects for postmenopausal women.


Multicentre surveillance of the prevalence and molecular epidemiology of macrolide resistance among pharyngeal isolates of group A streptococci in the USA.
Rates of macrolide resistance in group A streptococci (GAS) were reported to be low in the US in the 1990s. However, we documented an unexpectedly high rate of macrolide resistance among GAS in Pittsburgh, PA, in 2001 and 2002. In an effort to define the current prevalence of macrolide-resistant GAS in the US, a multicentre surveillance project was initiated. Between October 2002 and May 2003, 50 pharyngeal GAS isolates per month were requested from each of the nine participating sites representing a wide geographical distribution. Standard susceptibility testing was performed and the macrolide resistance phenotype was assessed using double-disc diffusion testing. Monthly and annual rates of macrolide resistance were calculated for each site. An adjusted overall rate of macrolide resistance was determined to account for differences in the numbers of GAS isolates sent from each centre. Overall, 171 of the 2797 collected isolates of GAS (6.1%) were resistant to erythromycin. The adjusted overall resistance rate was 5.2%. Rates of macrolide resistance varied by site (range 3.0-8.7%) and also by month (<2% to >10%). The M phenotype of macrolide resistance accounted for >60% of all macrolide-resistant isolates recovered in this study. These data suggest an increasing prevalence and broad geographical distribution of macrolide-resistant GAS in the US, indicating the need for ongoing local and national longitudinal surveillance to define the extent of this problem.


Population Pharmacokinetics and Safety of Ceftolozane-Tazobactam in Adult Cystic Fibrosis Patients Admitted with Acute Pulmonary Exacerbation.
Ceftolozane-tazobactam has potent activity against Pseudomonas aeruginosa, a pathogen associated with cystic fibrosis (CF) acute pulmonary exacerbations (APE). Due to the rapid elimination of many antibiotics, CF patients frequently have altered pharmacokinetics. In this multicenter, open-label study, we described the population pharmacokinetics and safety of ceftolozane-tazobactam at 3 g every 8 h (q8h) in 20 adult CF patients admitted with APE. Population pharmacokinetics were determined using the nonparametric adaptive grid program in Pmetrics for R. A 5,000-patient Monte Carlo simulation was performed to determine the probability of target attainment (PTA) for the ceftolozane component at 1.5 g and 3 g of ceftolozane-tazobactam q8h across a range of MICs using a primary threshold exposure of 60% free time above the MIC (fT>MIC). In these 20 adult CF patients, ceftolozane and tazobactam concentration data were best described by 2-compartment models, and ceftolozane clearance (CL) was significantly correlated with creatinine clearance (r = 0.71, P < 0.001). These data suggest that ceftolozane and tazobactam clearance estimates in CF patients are similar to those in adults without CF (ceftolozane CF CL, 4.76 ± 1.13 liter/h; tazobactam CF CL, 20.51 ± 4.41 liter/h). However, estimates of the volume of the central compartment (Vc) were lower than those for adults without CF (ceftolozane CF Vc, 7.51 ± 2.05 liters; tazobactam CF Vc, 7.85 ± 2.66 liters). Using a threshold of 60% fT>MIC, ceftolozane-tazobactam regimens of 1.5 g and 3 g q8h should achieve PTAs of ≥90% at MICs up to 4 and 8 μg/ml, respectively. Ceftolozane-tazobactam at 3 g q8h was well tolerated. These observations support additional studies of ceftolozane-tazobactam for Pseudomonas aeruginosa APE in CF patients. (This study has been registered at ClinicalTrials.gov under identifier NCT02421120.).


Birth and weaning traits in crossbred cattle from Hereford, Angus, Norwegian Red, Swedish Red and White, Wagyu, and Friesian sires.
The objective of this study was to characterize breeds representing diverse biological types for birth and weaning traits in crossbred cattle (Bos taurus). Gestation length, calving difficulty, percentage of unassisted calving, percentage of perinatal survival, percentage of survival from birth to weaning, birth weight, weaning weight, BW at 205 d, and ADG was measured in 1,370 calves born and 1,285 calves weaned. Calves were obtained by mating Hereford, Angus, and MARC III (1/4 Hereford, 1/4 Angus, 1/4 Pinzgauer, and 1/4 Red Poll) mature cows to Hereford or Angus (British breeds), Norwegian Red, Swedish Red and White, Wagyu, and Friesian sires. Calves were born during the spring of 1997 and 1998. Sire breed was significant for gestation length, birth weight, BW at 205 d, and ADG (P < 0.001). Offspring from Swedish Red and White and Friesian had the shortest gestation length (282 d), whereas offspring from Wagyu sires had the longest gestation length (286 d). Progeny from British breeds were the heaviest at birth (40.5 kg) and at 205 d (237 kg), and grew faster (0.97 kg/d) than offspring from other breeds. Offspring from Wagyu sires were the lightest at birth (36.3 kg) and at 205 d (214 kg), and had the slowest growth (0.91 kg/d). Dam breed was significant for gestation length (P < 0.001), birth weight (P = 0.009), BW at 205 d, and ADG (P < 0.001). Offspring from Hereford cows had the longest gestation length (284 d), whereas offspring from Angus cows had the shortest (282 d). Offspring from MARC III cows were the heaviest at birth (39.4 kg) when compared with offspring from Hereford (38.2 kg) and Angus (38.6 kg) cows. Progeny from Angus cows were the heaviest at 205 d (235 kg) and grew faster (0.96 kg/d), whereas offspring from Hereford cows were the lightest at 205 d (219 kg) and were the slowest in growth (0.88 kg/d). Sex was significant for gestation length (P = 0.026), birth weight, BW at 205 d, and ADG (P < 0.001). Male calves had a longer gestation length (284 d) when compared with female calves (283 d). Males were heavier than females at birth and at 205 d, and grew faster. Sire breed effects can be optimized by selection and use of appropriate crossbreeding systems.


Links of gut microbiota composition with alcohol dependence syndrome and alcoholic liver disease.
Alcohol abuse has deleterious effects on human health by disrupting the functions of many organs and systems. Gut microbiota has been implicated in the pathogenesis of alcohol-related liver diseases, with its composition manifesting expressed dysbiosis in patients suffering from alcoholic dependence. Due to its inherent plasticity, gut microbiota is an important target for prevention and treatment of these diseases. Identification of the impact of alcohol abuse with associated psychiatric symptoms on the gut community structure is confounded by the liver dysfunction. In order to differentiate the effects of these two factors, we conducted a comparative "shotgun" metagenomic survey of 99 patients with the alcohol dependence syndrome represented by two cohorts-with and without liver cirrhosis. The taxonomic and functional composition of the gut microbiota was subjected to a multifactor analysis including comparison with the external control group. Alcoholic dependence and liver cirrhosis were associated with profound shifts in gut community structures and metabolic potential across the patients. The specific effects on species-level community composition were remarkably different between cohorts with and without liver cirrhosis. In both cases, the commensal microbiota was found to be depleted. Alcoholic dependence was inversely associated with the levels of butyrate-producing species from the Clostridiales order, while the cirrhosis-with multiple members of the Bacteroidales order. The opportunist pathogens linked to alcoholic dependence included pro-inflammatory Enterobacteriaceae, while the hallmarks of cirrhosis included an increase of oral microbes in the gut and more frequent occurrence of abnormal community structures. Interestingly, each of the two factors was associated with the expressed enrichment in many Bifidobacterium and Lactobacillus-but the exact set of the species was different between alcoholic dependence and liver cirrhosis. At the level of functional potential, the patients showed different patterns of increase in functions related to alcohol metabolism and virulence factors, as well as pathways related to inflammation. Multiple shifts in the community structure and metabolic potential suggest strong negative influence of alcohol dependence and associated liver dysfunction on gut microbiota. The identified differences in patterns of impact between these two factors are important for planning of personalized treatment and prevention of these pathologies via microbiota modulation. Particularly, the expansion of Bifidobacterium and Lactobacillus suggests that probiotic interventions for patients with alcohol-related disorders using representatives of the same taxa should be considered with caution. Taxonomic and functional analysis shows an increased propensity of the gut microbiota to synthesis of the toxic acetaldehyde, suggesting higher risk of colorectal cancer and other pathologies in alcoholics.


Multilocus sequence typing of Streptococcus pyogenes representing most known emm types and distinctions among subpopulation genetic structures.
A long-term goal is to characterize the full range of genetic diversity within Streptococcus pyogenes as it exists in the world today. Since the emm locus is subject to strong diversifying selection, emm type was used as a guide for identifying a genetically diverse set of strains. This report contains a description of multilocus sequence typing based on seven housekeeping loci for 495 isolates representing 158 emm types, yielding 238 unique combinations of sequence type and emm type. A genotypic marker for tissue site preference (emm pattern) revealed that only 17% of the emm types displayed the marker representing strong preference for infection at the throat and that 39% of emm types had the marker for skin tropism, whereas 41% of emm types harbored the marker for no obvious tissue site preference. As a group, the emm types bearing the emm pattern marker indicative of no obvious tissue site preference were far less likely to have two distinct emm types associated with the same sequence type than either of the two subpopulations having markers for strong tissue tropisms (P < 0.002). In addition, all genetic diversification events clearly ascribed to a recombinational mechanism involved strains of only two of the emm pattern-defined subpopulations, those representing skin specialists and generalists. The findings suggest that the population genetic structure differs for the tissue-defined subpopulations of S. pyogenes. The observed differences may partly reflect differential host immune selection pressures.


Psychometric Properties of the Spence Children's Anxiety Scale: Parent Report in Children with Autism Spectrum Disorder.
Although anxiety is frequently reported in children with autism spectrum disorder (ASD), existing anxiety scales are often psychometrically inappropriate for this population. This study examined the internal structure, reliability, convergent and discriminant validity of the Spence Children's Anxiety Scale-Parent Report (SCAS-P; Spence 1999) in 238 school-aged children with ASD. While confirmatory factor analysis did not support the original six-correlated-factor structure, structural support as well as acceptable internal consistency and convergent validity was found for Generalized Anxiety, Separation Anxiety, Panic, and Agoraphobia subscales. Use of the SCAS-P in its original form for assessment in children with ASD was not supported. However, four subscales showed viability, and may benefit re-analyses of existing SCAS-P data and future scale adaptations for research and clinical purposes.


Worldwide genetic relationships among Francisella tularensis isolates determined by multiple-locus variable-number tandem repeat analysis.
The intracellular bacterium Francisella tularensis is the causative agent of tularemia and poses a serious threat as an agent of bioterrorism. We have developed a highly effective molecular subtyping system from 25 variable-number tandem repeat (VNTR) loci. In our study, multiple-locus VNTR analysis (MLVA) was used to analyze genetic relationships and potential population structure within a global collection of 192 F. tularensis isolates, including representatives from each of the four subspecies. The VNTR loci displayed between 2 and 31 alleles with Nei's diversity values between 0.05 and 0.95. Neighbor-joining cluster analysis of VNTR data revealed 120 genotypes among the 192 F. tularensis isolates, including accurate subspecies identification. F. tularensis subsp. tularensis (type A) isolates showed great diversity at VNTR loci, while F. tularensis subsp. holarctica (type B) isolates showed much lower levels despite a much broader geographical prevalence. The resolution of two distinct clades within F. tularensis subsp. tularensis (designated A.I and A.II) revealed a previously unrecognized genetic division within this highly virulent subspecies. F. tularensis subsp. holarctica appears to have recently spread globally across continents from a single origin, while F. tularensis subsp. tularensis has a long and complex evolutionary history almost exclusively in North America. The sole non-North American type A isolates (Slovakian) were closely related to the SCHU S4 strain. Significant linkage disequilibrium was detected among VNTR loci of F. tularensis consistent with a clonal population structure. Overall, this work greatly augments the study of tularemia ecology and epidemiology, while providing a framework for future forensic analysis of F. tularensis isolates.


Relative changes in the function of muscle ribosomes and mitochondria during the early phase of steroid-induced catabolism.
1. Five glucocorticoids, when administered daily to rats for 5-7 days at a dosage of 5mg/kg, were in the following order of effectiveness with respect to their ability to decrease the weight gain of whole animals and the vastus lateralis, vastus medialis and gluteus medius muscles: corticosterone<prednisolone<triamcinolone <betamethasone<dexamethasone<triamcinolone acetonide. 2. The low catabolic potencies of corticosterone and prednisolone were reflected in the high doses (20mg/kg) required to decrease significantly the incorporating activity in vitro of ribosomes isolated from the muscles 6h later. However, triamcinolone was as effective as triamcinolone acetonide in causing a significant effect at 0.05mg/kg, although it had a far lower catabolic potency than the acetonide. 3. The relationship between decrease in ribosomal activity in vitro and weight loss was better understood by considering the duration of the effect after single doses of steroids. Ribosomes returned to normal function between 6 and 12h after the administration of corticosterone (20mg/kg), but still had decreased activity 12h after a similar dose of prednisolone. Normal ribosomal function was renewed between 12 and 18h after the administration of triamcinolone and betamethasone at 5mg/kg, but decreased activity persisted for more than 48h after similar doses of dexamethasone or triamcinolone acetonide. 4. There was no difference in the rate of incorporation of amino acids into nascent protein on polyribosomes from muscle of control animals and animals treated 6h previously with triamcinolone acetonide or dexamethasone. 5. The rate of weight gain of the heart was not affected by any of the steroids tested and heart ribosomes maintained normal activity although concentrations of steroids in this organ 5min after administration were 2-3 times that in skeletal muscle. 6. Mitochondria, isolated from the muscle of animals that had received triamcinolone acetonide (20mg/kg) 12h previously, were shown, by using a Coulter counter, to be enlarged. Nevertheless oxidation was only slightly uncoupled 12h after drug administration and they had normal function 6h later. Similar results with respect to mitochondrial function were obtained after the administration of dexamethasone (20mg/kg) and betamethasone (20mg/kg). 7. From these results it is concluded that the mitochondria are not functionally involved in the early phase of steroid-induced muscle catabolism. The observed decrease in the incorporating ability of muscle ribosomes in vitro appears to be much more closely linked to the initial catabolic event.


Experimental observation of coincidence fractional Fourier transform with a partially coherent beam.
The coincidence Fractional Fourier transform (FRT) is implemented with a partially coherent light source experimentally. The visibility and quality of the coincidence FRT pattern of an object are investigated theoretically. The FRT pattern of an object is obtained by measuring the coincidence counting rate between the detected signals passing through two different optical paths. The experimental results are analyzed and found to be consistent with the theoretical results.


Regulation of ribosomal protein mRNA content and translation in growth-stimulated mouse fibroblasts.
When resting (G0) mouse 3T6 fibroblasts are serum stimulated to reenter the cell cycle, the rates of synthesis of rRNA and ribosomal proteins increase, resulting in an increase in ribosome content beginning about 6 h after stimulation. In this study, we monitored the content, metabolism, and translation of ribosomal protein mRNA (rp mRNA) in resting, exponentially growing, and serum-stimulated 3T6 cells. Cloned cDNAs for seven rp mRNAs were used in DNA-excess filter hybridization studies to assay rp mRNA. We found that about 85% of rp mRNA is polyadenylated under all growth conditions. The rate of labeling of rp mRNA relative to total polyadenylated mRNA changed very little after stimulation. The half-life of rp mRNA was about 11 h in resting cells and about 8 h in exponentially growing cells, values which are similar to the half-lives of total mRNA in resting and growing cells (about 9 h). The content of rp mRNA relative to total mRNA was about the same in resting and growing 3T6 cells. Furthermore, the total amount of rp mRNA did not begin to increase until about 6 h after stimulation. Since an increase in rp mRNA content did not appear to be responsible for the increase in ribosomal protein synthesis, we determined the efficiency of translation of rp mRNA under different conditions. We found that about 85% of pulse-labeled rp mRNA was associated with polysomes in exponentially growing cells. In resting cells, however, only about half was associated with polysomes, and about 30% was found in the monosomal fraction. The distribution shifted to that found in growing cells within 3 h after serum stimulation. Similar results were obtained when cells were labeled for 10.5 h. About 70% of total polyadenylated mRNA was in the polysome fraction in all growth states regardless of labeling time, indicating that the shift in mRNA distribution was species specific. These results indicate that the content and metabolism of rp mRNA do not change significantly after growth stimulation. The rate of ribosomal protein synthesis appears to be controlled during the resting-growing transition by an alteration of the efficiency of translation of rp mRNA, possibly at the level of protein synthesis initiation.


[Age-related macular degeneration].
The review provides an update on the pathogenesis and new treatment modalities for neovascular age-related macular degeneration (AMD). The impact of polymorphism in particular genes, including complement factor H (CFH), age-related maculopathy susceptibility 2 (ARMS2/LOC387715), and serine peptidase (HTRA1), on AMD development is discussed. Clinical presentations of different forms of exudative AMD, that is classic, occult, or more often mixed choroidal neovascularization, retinal angiomatous proliferation, and choroidal polypoidal vasculopathy, are described. Particular attention is paid to the results of recent clinical trials and safety issues around the therapy.


Electrophysiological analysis of synaptic transmission in Drosophila.
Synaptic transmission is dynamic, plastic, and highly regulated. Drosophila is an advantageous model system for genetic and molecular studies of presynaptic and postsynaptic mechanisms and plasticity. Electrical recordings of synaptic responses represent a wide-spread approach to study neuronal signaling and synaptic transmission. We discuss experimental techniques that allow monitoring synaptic transmission in Drosophila neuromuscular and central systems. Recordings of synaptic potentials or currents at the larval neuromuscular junction (NMJ) are most common and provide numerous technical advantages due to robustness of the preparation, large and identifiable muscles, and synaptic boutons which can be readily visualized. In particular, focal macropatch recordings combined with the analysis of neurosecretory quanta enable rigorous quantification of the magnitude and kinetics of transmitter release. Patch-clamp recordings of synaptic transmission from the embryonic NMJ enable overcoming the problem of lethality in mutant lines. Recordings from the adult NMJ proved instrumental in the studies of temperature-sensitive paralytic mutants. Genetic studies of behavioral learning in Drosophila compel an investigation of synaptic transmission in the central nervous system (CNS), including primary cultured neurons and an intact brain. Cholinergic and GABAergic synaptic transmission has been recorded from the Drosophila CNS both in vitro and in vivo. In vivo patch-clamp recordings of synaptic transmission from the neurons in the olfactory pathway is a very powerful approach, which has a potential to elucidate how synaptic transmission is associated with behavioral learning. WIREs Dev Biol 2017, 6:e277. doi: 10.1002/wdev.277 For further resources related to this article, please visit the WIREs website.


Hepatitis B virus: pathogenesis and prevention of primary cancer of the liver.
The currently available data indicate that persistent infection of the liver with hepatitis B virus (HBV) is involved in the etiology and pathogenesis of nearly all primary hepatocellular carcinomas in humans. Immunization of high risk populations with the hepatitis B vaccine and prevention of mother-to-child transmission of HBV with hepatitis B immunoglobulin should prevent the development of chronic hepatitis B infection and, therefore, should also prevent the development of hepatocellular carcinoma. How HBV "causes" cancer of the liver is unknown. Research on the role of HBV in hepatocarcinogenesis may provide information on how HBV and other viruses induce cancer and may lead to the discovery of other virus-cancer relationships in humans.


Metallothionein I+II expression as an early sign of chronic relapsing experimental autoimmune encephalomyelitis in rats.
Metallothioneins (MTs) are small, cysteine-rich proteins which have been implicated in various forms of stress providing cytoprotective action against oxidative injury, DNA damage and apoptosis. Owing to their high affinity for physiological metals, such as zinc and copper MTs are also critical components of regulatory proteins involved in cell growth and multiplication, as well as in the maintenance of immune homeostasis. To elucidate the role of MTs in the pathomechanisms of autoimmune CNS disorders we estimated the expression of MT I+II proteins and the content of free Zn ions in the brain, spinal cord and in the liver early in the course of chronic relapsing experimental autoimmune encephalomyelitis (CR-EAE) pathogenesis, i.e. before the onset of any clinical symptoms. Disease was induced in the genetically susceptible Dark Agouti (DA) rats by subcutaneous injection of bovine brain homogenate in CFA. Control animals were treated with CFA alone. The data, obtained by immuno-histochemistry and in situ fluorescent labeling of free zinc ions, have shown that in the presymptomatic phase of CR-EAE (on the seventh postimmunization day) MTs I+II were markedly upregulated in the cells that form blood-brain and blood-cerebrospinal fluid barriers, as well as in the cerebellar parenchyma and hippocampal dentate gyri. Furthermore, we found that the liver also becomes a site of extensive MTs I+II synthesis shortly after immunization. Simultaneously, tissue content of free zinc ions increased at the sites of MTs induction, reflecting their antioxidative activity. The data, described in this paper point to regulatory and neuroprotective role of MTs in the pathogenesis of CR-EAE.


Applications of ultrasound to the synthesis of nanostructured materials.
Recent advances in nanostructured materials have been led by the development of new synthetic methods that provide control over size, morphology, and nano/microstructure. The utilization of high intensity ultrasound offers a facile, versatile synthetic tool for nanostructured materials that are often unavailable by conventional methods. The primary physical phenomena associated with ultrasound that are relevant to materials synthesis are cavitation and nebulization. Acoustic cavitation (the formation, growth, and implosive collapse of bubbles in a liquid) creates extreme conditions inside the collapsing bubble and serves as the origin of most sonochemical phenomena in liquids or liquid-solid slurries. Nebulization (the creation of mist from ultrasound passing through a liquid and impinging on a liquid-gas interface) is the basis for ultrasonic spray pyrolysis (USP) with subsequent reactions occurring in the heated droplets of the mist. In both cases, we have examples of phase-separated attoliter microreactors: for sonochemistry, it is a hot gas inside bubbles isolated from one another in a liquid, while for USP it is hot droplets isolated from one another in a gas. Cavitation-induced sonochemistry provides a unique interaction between energy and matter, with hot spots inside the bubbles of approximately 5000 K, pressures of approximately 1000 bar, heating and cooling rates of >10(10) K s(-1); these extraordinary conditions permit access to a range of chemical reaction space normally not accessible, which allows for the synthesis of a wide variety of unusual nanostructured materials. Complementary to cavitational chemistry, the microdroplet reactors created by USP facilitate the formation of a wide range of nanocomposites. In this review, we summarize the fundamental principles of both synthetic methods and recent development in the applications of ultrasound in nanostructured materials synthesis.


Tailored ethylenediamine-functionalized graphene oxide membrane on kaolin hollow fibers for pectin concentration.
Pectin is a valuable product that can be extracted from waste fruit peels. Here we propose the use of graphene oxide (GO)-based membranes for pectin concentration. The synthesized GO was functionalized with ethylenediamine (EDA) to molecularly design the GO framework. Kaolin hollow fibers with asymmetric pore distribution were used as a porous substrate for GO/EDA deposition. A GO/EDA layer with a thickness of 2.86 ± 0.24 μm was assembled on the substrate by the simple vacuum-assisted deposition method. After GO/EDA depositions, the water permeance of the pristine kaolin hollow fibers reduced from 8.46 ± 0.17 to 0.52 ± 0.03 L h-1·m-2·kPa-1. A pectin aqueous extract from orange peels was filtered at cross-flow mode through the prepared membranes and the steady-state fluxes through pristine and GO/EDA-coated hollow fibers were 56 ± 2 and 20 ± 3 L h-1 m-2, respectively. The GO/EDA-coated membrane presented greater pectin selectivity than the pristine hollow fiber. The GO/EDA-coated hollow fiber concentrated the galacturonic acid, phenolic, and methoxyl contents in 19.5, 17.4, and 29.2 %, respectively. Thus, filtration through the GO/EDA-based membrane is a suitable alternative for pectin concentration.


Regulation of food intake and body weight in rats by the synthetic heme analogue cobalt protoporphyrin.
Cobalt protoporphyrin (CoPP) in single subcutaneous doses produces prolonged weight loss in adult and aged male rats. The altered body weight level in treated animals is actively defended against starvation or overfeeding over prolonged time periods (greater than 50-100 days). The actions of CoPP on appetite and body weight regulation are biphasic, comprising an initial period of hypophagia, probably mediated centrally, until a particular body weight level is attained. Resumption of normal calorie intake follows, although lowered body weight levels are sustained, suggesting an additional action of the compound on peripheral substrate metabolism. Controlled decrements in body weight can be produced by repetitive low-dose CoPP treatment (e.g., 1 mumol/kg body wt weekly); low-dose regimens do not elicit altered hormonal homeostasis or aberrations in heme/cytochrome P-450 regulation that have been observed following larger doses (25-50 mumol/kg body wt) of the compound. CoPP may be a valuable probe with which to explore the role of heme-related molecules in the regulation of appetite and body weight.


Effects of seawater acidification on gene expression: resolving broader-scale trends in sea urchins.
Sea urchins are ecologically and economically important calcifying organisms threatened by acidification of the global ocean caused by anthropogenic CO2 emissions. Propelled by the sequencing of the purple sea urchin (Strongylocentrotus purpuratus) genome, profiling changes in gene expression during exposure to high pCO2 seawater has emerged as a powerful and increasingly common method to infer the response of urchins to ocean change. However, analyses of gene expression are sensitive to experimental methodology, and comparisons between studies of genes regulated by ocean acidification are most often made in the context of major caveats. Here we perform meta-analyses as a means of minimizing experimental discrepancies and resolving broader-scale trends regarding the effects of ocean acidification on gene expression in urchins. Analyses across eight studies and four urchin species largely support prevailing hypotheses about the impact of ocean acidification on marine calcifiers. The predominant expression pattern involved the down-regulation of genes within energy-producing pathways, a clear indication of metabolic depression. Genes with functions in ion transport were significantly over-represented and are most plausibly contributing to intracellular pH regulation. Expression profiles provided extensive evidence for an impact on biomineralization, epitomized by the down-regulation of seven spicule matrix proteins. In contrast, expression profiles provided limited evidence for CO2-mediated developmental delay or induction of a cellular stress response. Congruence between studies of gene expression and the ocean acidification literature in general validates the accuracy of gene expression in predicting the consequences of ocean change and justifies its continued use in future studies.


13-year clinical assessment of 10 amalgam alloys.
The first commercial high-copper amalgam was developed in the mid-1960's. In 1975, a study to evaluate in vivo/in vitro performance of nine of these new alloys was initiated at Indiana University. These nine high-copper amalgams plus a traditional amalgam were tested for four laboratory properties and their gamma-2 content, and were clinically assessed for fracture at the margins. Originally, 60 restorations of each material were placed in patients and then recalled at six, 12, and 24 months. Recently, 13 years post-operatively, approximately one-third of the original patients were located. These patients were given a clinical exam, and photographs were taken of their restorations. From these recall data, the mean loss of all restorations at 13 years was 11.3%. The alloys Cupralloy, Tytin, and Dispersalloy had the lowest loss rates. The evaluation of the fracture at the margins (ridit means) indicates that there are five groups of alloys with some overlap between groups. The alloys Cupralloy, Indiloy, Dispersalloy, and Phasealloy exhibited the least fracture at the margins. The gamma-2-containing alloys--Optaloy II, Micro II, Velvalloy, and Aristaloy CR--showed the greatest rate of fracture at the margins. A correlation matrix of the ridit means at different years, the loss of restorations at 13 years, and the mechanical properties indicate that the early (one- and two-year) fracture at the margins predicts the 13-year results. Mechanical properties, however, do not predict the clinical performance of the materials at 13 years.


[Cathepsin L-like activity in hemolymph of females crammed with Boophilus microplus].
The cysteine-proteinase activity present in the hemolymph of females crammed with Boophilus microplus at the second oviposition was proved. The enzyme assay was performed using the synthetic N-carbobenzoxi-phenilalanyl-arginil-4-metoxibetan++ +-naphthylamide substrate, and hydrolysis in both raw ovarim extract and hemolymph were observed. The activity was 100% inhibited by trans-epoxisuscinyl-L-leucidamide (4-guadinine) butane, an specific inhibitor for cysteine-proteinase. Polyacrylamide and gelatin-gel electrophoresis showed the existence of only one active band in both samples tested with the same electrophoretic sliding (approximately 38 kDa).


Phospholipid composition of several clinically relevant Corynebacterium species as determined by mass spectrometry: an unusual fatty acyl moiety is present in inositol-containing phospholipids of Corynebacterium urealyticum.
A comparative study on phospholipids of Corynebacterium amycolatum, Corynebacterium jeikeium and Corynebacterium urealyticum was carried out using fast-atom bombardment (FAB) and electrospray ionization (ESI) mass spectrometry. Data obtained indicate the presence of acylphosphatidylglycerol (APG), diphosphatidylglycerol, phosphatidylglycerol (PG), phosphatidylinositol (PI) and triacylphosphatidylinositol dimannosides (Ac(3)PIM(2)) in these bacteria. In general, octadecenoyl and hexadecanoyl fatty acyl moieties predominated in phospholipids of C. amycolatum, whereas high levels of hexadecenoyl were found in C. jeikeium and C. urealyticum. Mass spectra from purified APG and PG indicated that the sn-1 position of the glycerol was occupied by octadecenoyl in the three species studied. Notably, several major molecular species of PI and Ac(3)PIM(2) from C. urealyticum contained significant amounts of a moiety identified as 10-methyleneoctadecanoyl, located at the sn-1 position of these molecules. On the other hand, multiantibiotic resistant and susceptible strains of C. amycolatum differed in several minor phospholipid fatty acids of 19 carbon atoms, identified as 10-methyloctadecenoic, 10-methyloctadecanoic (tuberculostearic acid) and 10-methyleneoctadecanoic. The results demonstrate an overall similarity among the phospholipids of the different species studied but also significant differences related to the acyl chains of the glycerol moiety of these compounds, notably the high levels of an unusual fatty acyl moiety in inositol-containing phospholipids of C. urealyticum.


Predicting progression of Alzheimer's disease.
Clinicians need to predict prognosis of Alzheimer's disease (AD), and researchers need models of progression to develop biomarkers and clinical trials designs. We tested a calculated initial progression rate to see whether it predicted performance on cognition, function and behavior over time, and to see whether it predicted survival. We used standardized approaches to assess baseline characteristics and to estimate disease duration, and calculated the initial (pre-progression) rate in 597 AD patients followed for up to 15 years. We designated slow, intermediate and rapidly progressing groups. Using mixed effects regression analysis, we examined the predictive value of a pre-progression group for longitudinal performance on standardized measures. We used Cox survival analysis to compare survival time by progression group. Patients in the slow and intermediate groups maintained better performance on the cognitive (ADAScog and VSAT), global (CDR-SB) and complex activities of daily living measures (IADL) (P values < 0.001 slow versus fast; P values < 0.003 to 0.03 intermediate versus fast). Interaction terms indicated that slopes of ADAScog and PSMS change for the slow group were smaller than for the fast group, and that rates of change on the ADAScog were also slower for the intermediate group, but that CDR-SB rates increased in this group relative to the fast group. Slow progressors survived longer than fast progressors (P = 0.024). A simple, calculated progression rate at the initial visit gives reliable information regarding performance over time on cognition, global performance and activities of daily living. The slowest progression group also survives longer. This baseline measure should be considered in the design of long duration Alzheimer's disease clinical trials.


Mechanics of the anterior interval of the knee using open dynamic MRI.
The anterior interval of the knee has been defined as the space between the infrapatellar fat pad and patellar tendon anteriorly, and the anterior border of the tibia and the transverse meniscal ligament posteriorly. Investigation of the normal kinematics of this region is necessary as we begin to appreciate the significant impact that pathologic processes of the anterior interval have on the knee. Non-weight bearing and weight bearing dynamic MRIs of 20 healthy knees were evaluated at 30 degrees intervals from 0 degrees to 120 degrees flexion. The angle subtended by the patellar tendon and the anterior tibia was measured at each interval of flexion by three independent observers. The amount of angular change over each interval of flexion was also evaluated and the differences between the relative weight bearing conditions were statistically evaluated. The angle formed by the anterior tibia and the patellar tendon decreases with knee flexion (45.2 degrees (SD 10.1 degrees ) at full extension vs. 1.2 degrees (SD 2.1 degrees ) at full flexion). The average patellar tendon-tibial angle excursion was significantly reduced with full-weight bearing, 43.1 degrees (SD 11.2 degrees ) from 0 degrees to 120 degrees of flexion, compared to non-weight bearing, 30.9 degrees (SD 6.1 degrees ) over the same range of motion (P<0.001). Full-weight bearing decreased the angle excursion by 28% compared to non-weight bearing. The observed changes in the anterior interval are influenced by multiple factors including load, knee architecture, tendon elasticity and tibio-femoral and patello-femoral kinematics. The impact of load on the mechanics of the anterior interval is most pronounced between 0 degrees and 30 degrees of flexion.


Characterization of novel cathepsin K mutations in the pro and mature polypeptide regions causing pycnodysostosis.
Cathepsin K, a lysosomal cysteine protease critical for bone remodeling by osteoclasts, was recently identified as the deficient enzyme causing pycnodysostosis, an autosomal recessive osteosclerotic skeletal dysplasia. To investigate the nature of molecular lesions causing this disease, mutations in the cathepsin K gene from eight families were determined, identifying seven novel mutations (K52X, G79E, Q190X, Y212C, A277E, A277V, and R312G). Expression of the first pro region missense mutation in a cysteine protease, G79E, in Pichia pastoris resulted in an unstable precursor protein, consistent with misfolding of the proenzyme. Expression of five mature region missense defects revealed that G146R, A277E, A277V, and R312G precursors were unstable, and no mature proteins or protease activity were detected. The Y212C precursor was activated to its mature form in a manner similar to that of the wild-type cathepsin K. The mature Y212C enzyme retained its dipeptide substrate specificity and gelatinolytic activity, but it had markedly decreased activity toward type I collagen and a cathepsin K-specific tripeptide substrate, indicating that it was unable to bind collagen triple helix. These studies demonstrated the molecular heterogeneity of mutations causing pycnodysostosis, indicated that pro region conformation directs proper folding of the proenzyme, and suggested that the cathepsin K active site contains a critical collagen-binding domain.


[Towards understanding human ecology in nursing practice: a concept analysis].
Human ecology is an umbrella concept encompassing several social, physical, and cultural elements existing in the individual's external environment. The pragmatic utility method was used to analyze the "human ecology" concept in order to ascertain the conceptual fit with nursing epistemology and to promote its use by nurses in clinical practice. Relevant articles for the review were retrieved from the MEDLINE, CINAHL, PsycINFO, and CSA databases using the terms "human ecology," "environment," "nursing," and "ecology." Data analysis revealed that human ecology is perceived as a theoretical perspective designating a complex, multilayered, and multidimensional system, one that comprises individuals and their reciprocal interactions with their global environments and the subsequent impact of these interactions upon their health. Human ecology preconditions include the individuals, their environments, and their transactions. Attributes of this concept encompass the characteristics of an open system (e.g., interdependence, reciprocal).


Cells of origin of medullary projections in central gray of rat mesencephalon.
1. Seventy-four neurons in the central gray of the mesencephalon were antidromically activated by electrical stimulation of the gigantocellular and magnocellular nuclei region of the ipsilateral medullary reticular formation in urethan-anesthetized female rats. An additional eight cells were located contralaterally. With control of the lordosis reflex (facilitated from central gray) in mind, each cell was characterized by the properties of its antidromic response and by its response to pressure stimulation of the hindquarters of the hindquarters of the animal. 2. The antidromically activated spikes had constant latencies between 1.0 and 25.5 ms, with a mean of 10.7 +/- 0.7 ms. 3. Cells of origin of the descending projections were located in all parts of the central gray and adjacent mesencephalic reticular field except within the inner ring of the central gray that surrounds the cerebral aqueduct. A particularly dense group of cells was noted in the ventrolateral aspect of the central gray. Fewer were found in the dorsal central gray over the cerebral aqueduct. 4. These cells had very low rates of spontaneous discharge or none at all. No specific changes in activity could be elicited by lordosis-relevant somatosensory stimuli. Therefore, these cells appear not to be involved in stimulus-bound reflexive control of lordosis behavior. Instead, they may be engaged in mediating influences descending from hypothalamus, known to control lordosis (see Ref. 48). In turn, they could modulate activity in reflex arcs completed at lower levels of the neuraxis.