E2A expression stimulates Ig hypermutation.
Ig hypermutation is limited to a region of approximately 2 kb downstream of the transcription start sites of the Ig loci. The process requires transcription and the presence of Ig enhancer sequences, and is initiated by the activation-induced cytidine deaminase (AID)-mediated deamination of cytidine bases. It remains unknown why AID causes mutations selectively in the Ig genes and not in most other transcribed loci of B cells. In this study, we report that the inactivation of the E2A gene strongly reduces the rate of Ig L chain mutations in the chicken B cell line DT40 without affecting the levels of surface Ig or AID expression. The defect is complemented by the expression of cDNAs corresponding to either of the two E2A splice variants E12 or E47. The results suggest that E2A-encoded proteins enhance Ig hypermutation by recruitment of AID to the Ig loci.


Unveiling the Role Displayed by Penicillium digitatum PdMut3 Transcription Factor in Pathogen-Fruit Interaction.
Zn2Cys6 transcription factors are unique to fungi and are involved in different regulatory functions. In this study, we have identified the Penicillium digitatumPdMut3 gene, which encodes a putative Zn (II) 2Cys6 DNA-binding protein. Elimination of PdMut3 in Pd1 strain caused increased virulence during citrus infection. The transcription of the PdMut3 gene showed a higher expression rate during fungal growth and less transcription during fruit infection. Furthermore, the deletion of the gene in the wild-type isolate of P. digitatum did not produce any modification of the sensitivity to different fungicides, indicating that the gene is not associated with resistance to fungicides. In contrast, PdMut3 null mutants showed a reduction in growth in minimal media, which was associated with severe alterations in conidiophore development and morphological alterations of the hyphae. Mutants showed greater sensitivity to compounds that interfere with the cell wall and an invasive growth block. Thus, PdMut3 might have an indirect role in fungi virulence through metabolism and peroxisomes development.


Hope against hope: exploring the hopes and challenges of rural female caregivers of persons with advanced cancer.
This paper focuses on the qualitative component of a study evaluating a hope intervention, entitled Living with Hope Program (LWHP), designed to foster hope in female caregivers of family members living with advanced cancer. The purpose of this research is to share, in the form of a story, the experiences of rural female caregivers caring for family members with advanced cancer, focusing on what fosters their hope. Hope is a psychosocial and spiritual resource that has been found to help family caregivers live through difficult transitions and challenges. Twenty-three participants from rural Western Canada completed daily journal entries documenting their hopes and challenges. Cortazzi's (2001) method of narrative analysis was used to analyze the data, which was then transcribed into a narrative entitled 'hope against hope.' The journal entries highlighted: the caregivers' hopes and what fostered their hope; the various challenges of caregiving; self-care strategies, and; their emotional journey. Hope was integrated throughout their entire experience, and 'hope against hope' describes how hope persists even when there is no hope for a cure. This research contributes to the assessment of caregiver interventions that impact hope and quality of life, while illustrating the value of a narrative approach to both research and practice. Journaling may be particularly valuable for rural caregivers who are isolated, and may lack direct professional and peer support. There is an opportunity for health professionals and other providers to foster a relationship of trust with family caregivers, in which their story can be told openly and where practitioners pay closer attention to the psychosocial needs of caregivers.


Lateral organization of membranes and cell shapes.
The relations among membrane structure, mechanical properties, and cell shape have been investigated. The fluid mosaic membrane models used contains several components that move freely in the membrane plane. These components interact with each other and determine properties of the membrane such as curvature and elasticity. A free energy equation is postulated for such a multicomponent membrane and the condition of free energy minimum is used to obtain differential equations relating the distribution of membrane components and the local membrane curvature. The force that moves membrane components along the membrane in a variable curvature field is calculated. A change in the intramembrane interactions can bring about phase separation or particle clustering. This, in turn, may strongly affect the local curvature. The numerical solution of the set of equations for the two dimensional case allows determination of the cell shape and the component distribution along the membrane. The model has been applied to describe certain erythrocytes shape transformations.


Secretion of N-terminal domain of α-dystroglycan in cerebrospinal fluid.
α-Dystroglycan (α-DG) plays crucial roles in maintaining the stability of cells. We demonstrated previously that the N-terminal domain of α-DG (α-DG-N) is secreted by cultured cells into the culture medium. In the present study, to clarify its function in vivo, we generated a monoclonal antibody against α-DG-N and investigated the secretion of α-DG-N in human cerebrospinal fluid (CSF). Interestingly, we found that a considerable amount of α-DG-N was present in CSF. α-DG-N in CSF was a sialylated glycoprotein with both N- and O-linked glycan. These observations suggest that secreted α-DG-N may be transported via CSF and have yet unidentified effects on the nervous system.


Hospital-acquired infections in a tertiary hospital in Iran before and during the COVID-19 pandemic.
Infection prevention protocols are the accepted standard to control nosocomial infections. These protective measures intensified after the coronavirus 2019 (COVID-19) pandemic to reduce the risk of viral transmission. It is the rationale that this practice reduces nosocomial infections. We evaluated the impact of these protective measures on nosocomial infections in our center with more than 20,000 records of annual patient admission. In a retrospective study, we evaluated the incidence of nosocomial infections in Sina hospital for 9 months (April-December 2020) during the COVID-19 period and compared it with the 8 months in the pre-COVID period (April-November 2019). Despite decreasing the number of admissions during the COVID era (hospitalizations showed a reduction of 43.79%), the total hospital nosocomial infections remained unchanged; 4.73% in the pre-COVID period versus 4.78% during the COVID period. During the COVID period the infection percentages increased in the cardiovascular care unit (p-value = 0.002) and intensive care units (p-value = 0.045), and declined in cardiology (p-value = 0.046) and neurology (p-value = 0.019) wards. This study showed that intensifying the infection prevention protocols is important in decreasing the nosocomial infections in some wards (cardiology and neurology). Still, we saw increased nosocomial infection in some wards, e.g., the intensive care unit (ICU) and coronary care unit (CCU). Thus, enhanced infection prevention protocols implemented in hospitals to prevent the spread of a pandemic infection may not always decrease rates of other hospital-acquired infections during a pandemic. Due to limited resources, transfer of staff, and staff shortage due to quarantine measures may prohibit improved prevention procedures from effectively controlling nosocomial infections.


Responses of SHR to combinations of chemical sympathectomy, adrenal demedullation, and training.
The single and combined influences of exercise training, chemical sympathectomy (SYMX), and surgical adrenal demedullation (D) were examined in four separate spontaneously hypertensive rat (SHR) groups. SYMX was accomplished by subcutaneous injections of antinerve growth factor (ANGF) over a 5-day period after birth followed by 20 separate injections of guanethidine sulfate during a 27-day period. Measurements of urine, plasma, or tissue levels of catecholamines indicated that these experimental procedures were effective. The animals were exercise trained (T) for 10 wk or longer at 40-60% of their VO2max capacity, and all T groups exhibited longer run times or higher muscle cytochrome oxidase activity; however, only the SHR + T subgroup had a significantly higher VO2max value than its control (NT). Training lowered resting systolic blood pressure (SBP) in the SHR subgroup but normalization of SBP occurred only with SYMX. Interestingly, only the SYMX + T subgroup with intact adrenal glands also had lower SBP values than the NT. The SHR + T and SYMX + T subgroups but not the SYMX + D + T had less cardiac acceleration after ip injections of atropine than their controls. Heavier heart weights were observed only in the SHR + T subgroup; SYMX was associated with lighter heart weights regardless of whether the rats had been T or D. These collective findings demonstrated again the importance of the sympathetic nervous system to an exercise response, suggesting that an intact adrenal medulla was essential for SHR groups to achieve many of the adaptations associated with training.


Effects of hydroxyl group distribution on the reactivity, stability and optical properties of fullerenols.
We investigate the impact of hydroxyl groups on the properties of C(60)(OH)(n) systems, with n = 1, 2, 3, 4, 8, 10, 16, 18, 24, 32 and 36 by means of first-principles density functional theory calculations. A detailed analysis from the local density of states has shown that adsorbed OH groups can induce dangling bonds in specific carbon atoms around the adsorption site. This increases the tendency to form polyhydroxylated fullerenes (fullerenols). The structural stability is analyzed in terms of the calculated formation enthalpy of each species. Also, a careful examination of the electron density of states for different fullerenols shows the possibility of synthesizing single molecules with tunable optical properties.


Global Overview of Youth Development: Comparison of the 5 Cs and Developmental Assets Across Six Countries.
Positive Youth Development (PYD) frameworks which describe young people's strengths and their relation to thriving and risk outcomes have gained significance among developmental researchers globally. As these models are being increasingly adopted, concerns remain about their generalizability outside of North America. It has been observed that the distribution and salience of assets differ for young people based on their cultural context. To better understand these varying developmental patterns, this paper studies the distribution of developmental assets and 5 Cs (Competence, Confidence, Character, Caring, and Connection) in youth from various countries and contrasting backgrounds. The total sample consisted of 4,175 students (62.5% females) with age ranging from 15 to 25 years (M = 18.95, SD = 2.49). 981 students were from Ghana (52.5% females), 900 students from Kosovo (66.7% females), 425 students from Norway (73.5% females), 247 students from Portugal (42.1% females), 648 students from Slovenia (63.4% females,), and 974 students from Turkey (68.7% females). Before comparisons of the countries, partial scalar invariance was confirmed. Analyses revealed that all countries differed in at least some internal or external developmental assets and at least in one of the 5 Cs. When considering internal assets, participants from Ghana seemed to have higher levels of internal assets together with participants from Norway who have the highest commitment to learning. Slovenian youth reported the highest levels of external assets of support and empowerment. Regarding the 5 Cs, Ghanaian youth reported having the highest confidence and character, and youth from Ghana, Kosovo, and Turkey are more caring and connected to others. The results uncovered unique patterns of PYD for each included country which are discussed through the lens of its political and social context. Through this focus on cross-national PYD patterns, this study advanced knowledge about the experiences of youth from a wide range of backgrounds and put forth suggestions for better policy measures and more culturally relevant interventions for optimal development of youth embedded in different cultures and countries.


Structural basis of DNA recognition by PCG2 reveals a novel DNA binding mode for winged helix-turn-helix domains.
The MBP1 family proteins are the DNA binding subunits of MBF cell-cycle transcription factor complexes and contain an N terminal winged helix-turn-helix (wHTH) DNA binding domain (DBD). Although the DNA binding mechanism of MBP1 from Saccharomyces cerevisiae has been extensively studied, the structural framework and the DNA binding mode of other MBP1 family proteins remains to be disclosed. Here, we determined the crystal structure of the DBD of PCG2, the Magnaporthe oryzae orthologue of MBP1, bound to MCB-DNA. The structure revealed that the wing, the 20-loop, helix A and helix B in PCG2-DBD are important elements for DNA binding. Unlike previously characterized wHTH proteins, PCG2-DBD utilizes the wing and helix-B to bind the minor groove and the major groove of the MCB-DNA whilst the 20-loop and helix A interact non-specifically with DNA. Notably, two glutamines Q89 and Q82 within the wing were found to recognize the MCB core CGCG sequence through making hydrogen bond interactions. Further in vitro assays confirmed essential roles of Q89 and Q82 in the DNA binding. These data together indicate that the MBP1 homologue PCG2 employs an unusual mode of binding to target DNA and demonstrate the versatility of wHTH domains.


Middleborns disadvantaged? Testing birth-order effects on fitness in pre-industrial Finns.
Parental investment is a limited resource for which offspring compete in order to increase their own survival and reproductive success. However, parents might be selected to influence the outcome of sibling competition through differential investment. While evidence for this is widespread in egg-laying species, whether or not this may also be the case in viviparous species is more difficult to determine. We use pre-industrial Finns as our model system and an equal investment model as our null hypothesis, which predicts that (all else being equal) middleborns should be disadvantaged through competition. We found no overall evidence to suggest that middleborns in a family are disadvantaged in terms of their survival, age at first reproduction or lifetime reproductive success. However, when considering birth-order only among same-sexed siblings, first-, middle- and lastborn sons significantly differed in the number of offspring they were able to rear to adulthood, although there was no similar effect among females. Middleborn sons appeared to produce significantly less offspring than first- or lastborn sons, but they did not significantly differ from lastborn sons in the number of offspring reared to adulthood. Our results thus show that taking sex differences into account is important when modelling birth-order effects. We found clear evidence of firstborn sons being advantaged over other sons in the family, and over firstborn daughters. Therefore, our results suggest that parents invest differentially in their offspring in order to both preferentially favour particular offspring or reduce offspring inequalities arising from sibling competition.


Nanostructural anisotropy underlies anisotropic electrical bistability.
Regular arrays of nanorods having asymmetric cross-sections are fabricated by a combination of electrodeposition and glancing-angle deposition (GLAD). When these nanorods are embedded in a polymer matrix, they give rise to composite materials in which the structural anisotropy at the nanoscale translates into functional anisotropy in the form of direction-dependent electrical bistability. The degree of this directional bistability depends on and can be controlled by the spacing between the nearby nanorods.


Measuring antimicrobial use on dairy farms: A method comparison cohort study.
Antimicrobial use on UK dairy farms is measured for surveillance purposes, with veterinary sales data as a proxy for use. Two other methods of recording use have been used commonly on-farm: medicine waste bins and farm medicine records. However, none of these methods has been validated to measure antimicrobial use. The objective of this research was to assess agreement between the 3 most common methods for measuring on-farm antimicrobial use with a predetermined reference method on UK dairy farms. Antimicrobial use was measured prospectively on 26 UK dairy farms using medicine waste bins into which participants placed all discarded medicine packaging for a 12-mo period. At the end of 12 mo, farm medicine records and veterinary sales data were obtained retrospectively for participating farms. The reference method used was based on pre- and poststudy inventories combined with veterinary sales data. We investigated the systematic difference between the mean on-farm antimicrobial use measured by each of the 3 methods and a reference method, using one-way repeated-measures ANOVA models. Reliability and clinical relevance of the agreement between each pair of methods was quantified using the concordance correlation coefficient (CCC) and the Bland-Altman method, respectively. When compared with the reference method, veterinary sales data had excellent reliability for injectable antimicrobials and intramammary antimicrobials [95% confidence interval (CI) of CCC > 0.90] and moderate to excellent reliability for other antimicrobials (95% CI of CCC: 0.68-0.97). Medicine waste bins had good to excellent reliability for injectable (95% CI of CCC: 0.84-0.99), and intramammary products (95% CI of CCC: 0.78-0.94) and no agreement for other forms of antimicrobial. Farm medicine records did not agree for any form of antimicrobial when compared with the reference method. The use of veterinary sales data as a proxy for on-farm antimicrobial use in the UK represented excellent statistical reliability and offered clinically good agreement with the reference method when used to measure injectable antimicrobials. This study applies to the UK context and included a relatively small number of farms. However, these results have research and policy implications, both nationally and internationally, and are essential in accurately quantifying agricultural antimicrobial use to inform both animal and human health.


Characterization of the Xp21-23 region in the wood lemming, a region involved in XY sex reversal.
The wood lemming (Myopus schisticolor) harbors two types of X chromosome, a normal X and a variant X, designated X*. The X* chromosome contains a mutation that causes XY sex reversal. We have previously demonstrated that the Xp21-23 region is deleted from X* and is associated with XY sex reversal. To further analyze the deleted region, we have constructed and characterized seven X chromosome- and region-specific recombinant DNA libraries. Further, we have screened mouse fetal gonad cDNA libraries with the microdissected Xp21-23 DNA as a probe in an attempt to identify homologous and expressed sequences from the deletion. Fourteen positive clones were isolated, and sequence analyses showed that ten of these contained identical sequences homologous to mouse gamma-satellite sequences. One of the remaining four was perfectly homologous to the mouse gene Ccth (chaperonin containing t-complex polypeptide 1, eta subunit). Southern blot indicated that the Ccth cDNA was located on the X chromosome, not deleted from the X* but closely linked to the deletion region. Although the role of the Ccth containing region in sex determination of the wood lemming requires additional studies, the isolation of the mouse Ccth gene by the deletion Xp21-23 probe could be important since this gene is mainly expressed in testis.


New model to explain tooth wear with implications for microwear formation and diet reconstruction.
Paleoanthropologists and vertebrate paleontologists have for decades debated the etiology of tooth wear and its implications for understanding the diets of human ancestors and other extinct mammals. The debate has recently taken a twist, calling into question the efficacy of dental microwear to reveal diet. Some argue that endogenous abrasives in plants (opal phytoliths) are too soft to abrade enamel, and that tooth wear is caused principally by exogenous quartz grit on food. If so, variation in microwear among fossil species may relate more to habitat than diet. This has important implications for paleobiologists because microwear is a common proxy for diets of fossil species. Here we reexamine the notion that particles softer than enamel (e.g., silica phytoliths) do not wear teeth. We scored human enamel using a microfabrication instrument fitted with soft particles (aluminum and brass spheres) and an atomic force microscope (AFM) fitted with silica particles under fixed normal loads, sliding speeds, and spans. Resulting damage was measured by AFM, and morphology and composition of debris were determined by scanning electron microscopy with energy-dispersive X-ray spectroscopy. Enamel chips removed from the surface demonstrate that softer particles produce wear under conditions mimicking chewing. Previous models posited that such particles rub enamel and create ridges alongside indentations without tissue removal. We propose that although these models hold for deformable metal surfaces, enamel works differently. Hydroxyapatite crystallites are "glued" together by proteins, and tissue removal requires only that contact pressure be sufficient to break the bonds holding enamel together.


SARS-CoV-2 Rebound With and Without Use of COVID-19 Oral Antivirals.
Early treatment with a first-line therapy (nirmatrelvir/ritonavir [Paxlovid] or remdesivir) or second-line therapy (molnupiravir) prevents hospitalization and death among patients with mild-to-moderate COVID-19 who are at risk for severe disease and is recommended by the National Institutes of Health COVID-19 Treatment Guidelines. On May 25, 2023, the Food and Drug Administration approved nirmatrelvir/ritonavir for treatment of adults at high risk for severe disease. Although antiviral therapies are widely available, they are underutilized, possibly because of reports of SARS-CoV-2 rebound after treatment. To enhance current understanding of rebound, CDC reviewed SARS-CoV-2 rebound studies published during February 1, 2020- November 29, 2023. Overall, seven of 23 studies that met inclusion criteria, one randomized trial and six observational studies, compared rebound for persons who received antiviral treatment with that for persons who did not receive antiviral treatment. In four studies, including the randomized trial, no statistically significant difference in rebound rates was identified among persons receiving treatment and those not receiving treatment. Depending on the definition used, the prevalence of rebound varied. No hospitalizations or deaths were reported among outpatients who experienced rebound, because COVID-19 signs and symptoms were mild. Persons receiving antiviral treatment might be at higher risk for rebound compared with persons not receiving treatment because of host factors or treatment-induced viral suppression early in the course of illness. The potential for rebound should not deter clinicians from prescribing lifesaving antiviral treatments when indicated to prevent morbidity and mortality from COVID-19.


Substituent effects on the nonradical reactivity of 4-dehydropyridinium cation.
Recent studies have shown that the reactivity of the 4-dehydropyridinium cation significantly differs from the reactivities of its isomers toward tetrahydrofuran. While only hydrogen atom abstraction was observed for the 2- and 3-dehydropyridinium cations, nonradical reactions were observed for the 4-isomer. In order to learn more about these reactions, the gas-phase reactivities of the 4-dehydropyridinium cation and several of its derivatives toward tetrahydrofuran were investigated in a Fourier transform ion electron resonance mass spectrometer. Both radical and nonradical reactions were observed for most of these positively charged radicals. The major parameter determining whether nonradical reactions occur was found to be the electron affinity of the radicals--only those with relatively high electron affinities underwent nonradical reactions. The reactivities of the monoradicals are also affected by hydrogen bonding and steric effects.


Relationship of residual feed intake and protein efficiency in lactating cows fed high- or low-protein diets.
Our objectives were to determine the repeatability of residual feed intake (RFI) across dietary protein levels and to determine the association between RFI and protein efficiency in lactating cows. Holstein cows (n = 166; 92 primiparous, 74 multiparous) with initial milk yield 41.3 ± 9.8 kg/d were fed diets with high or low protein in peak lactation. Experiments were conducted as crossovers with 2 treatment periods of 28 to 35 d. Production of 69 of the 166 cows (42 primiparous, 27 multiparous) was also measured in late lactation. Low-protein diets were 14% crude protein (CP) in peak lactation and 13% CP in late lactation and were formulated to contain adequate rumen-degradable protein to maintain rumen function. High-protein diets were 18% CP in peak lactation and 16% CP in late lactation and contained extra expeller soybean meal to increase absorbed protein. Cows were milked twice daily; DMI and milk yield were recorded daily. Milk composition was measured over 4 consecutive milkings weekly, and body weight (BW) was measured 3 times weekly. Fixed effects of diet, parity, and treatment period, interaction of parity and diet, and random effects of experiment and cow nested within experiment were included in the model to compare intake and production performance between cows fed different levels of CP. The RFI value was calculated for each cow on each treatment based on the actual intake, milk energy output, metabolic BW, and body energy (calculated from BW change and body condition score over the treatment period) change. Ranking of cows for RFI was moderately repeatable across dietary protein in peak lactation (r = 0.59) but less repeatable in late lactation (r = 0.41). Negative correlation was observed between RFI and protein efficiency values (dietary protein captured in milk) for cows in both peak lactation (r = -0.42) and late lactation (r = -0.24), which suggested that cows with higher energy efficiency had greater protein efficiency. In conclusion, RFI was repeatable across dietary protein levels within lactation stage, and cows with lower RFI values utilized protein more efficiently.


Safety and Efficacy of Nemonoxacin vs Levofloxacin in Patients With Community-Acquired Pneumonia: A Systematic Review and Meta-Analysis of Randomized Control Trials.
Community-acquired pneumonia is a leading cause of morbidity and mortality throughout the world, which incurs significant healthcare costs. The aim of his meta-analysis is to assess the clinical efficacy and safety of a novel non-fluorinated quinolone, nemonoxacin, compared with levofloxacin in treating community-acquired pneumonia (CAP). A recursive literature search was conducted using PubMed, Google Scholar, and Scopus up to August 2022. All randomized clinical trials comparing nemonoxacin to levofloxacin for community-acquired pneumonia were included. The patients selected for this study had mild to moderate CAP. Each individual received treatment with either nemonoxacin (500 mg or 750 mg) or levofloxacin (500 mg) for a duration of 3-10 days. Four randomized control trials with a total of 1955 patients were included. Nemonoxacin and levofloxacin were found to have similar clinical cure rates in the treatment of CAP. There were no significant differences reported in the treatment-emergent adverse events between the two drugs (RR=0.95, 95% CI: 0.86, 1.08, I2=0%). However, the most frequent symptoms exhibited were gastrointestinal system-related. Both the dosages (500 mg and 750 mg) of nemonoxacin were found to have similar efficacy as that of levofloxacin. Our meta-analysis indicates that nemonoxacin is a well-tolerated and effective antibiotic therapy for the treatment of community-acquired pneumonia (CAP), with clinical success rates comparable to those of levofloxacin. Furthermore, the adverse effects associated with nemonoxacin are generally mild. Therefore, both the 500 mg and 750 mg dosages of nemonoxacin can be recommended as appropriate antibiotic therapy regimens for the treatment of CAP.


Oncocytic carcinoma of the male breast.
Primary oncocytic carcinoma of the breast was diagnosed in a 76-year-old man. The histologic and electron microscopic features are characteristic of oncocytic neoplasms that occur at other sites, such as salivary glands and endocrine organs. The pathologic features and the presence of estrogen receptors biochemically are distinct from apocrine carcinoma. The patient is alive 7 years after modified radical mastectomy without additional chemotherapy or radiotherapy.


The natural history of osteoporosis.
Osteoporosis remains a formidable challenge to medicine. A greater understanding of the variables that influence bone mineralization will allow the development of strategies to determine those at risk of developing osteoporosis. Advances in the management of this disease will probably come from prevention and selective screening.


Effects of feeding frequency and exogenous somatotropin on lipolysis, hormone profiles, and milk production in dairy cows.
Effects of feeding frequency and exogenous bovine somatotropin on lactational performance and hormone profiles were examined with 12 multiparous Holstein cows. At 45 d postpartum, cows were assigned to one of two feeding systems. Concentrates were offered in two equal portions at 0800 and 1600 h or in 12 equal portions at 2-h intervals. Chopped alfalfa hay (2.6 kg/d) and barley silage (ad libitum) were fed at 0900 and 1500 h. At 136 d postpartum, cows within each feeding frequency were assigned in a single crossover design to injection of 30 mg of bST/d or solubilization vehicle. Feeding frequency did not influence any of the parameters measured nor did bST interact with feeding frequency. Somatotropin injection increased daily milk yield of cows by 4.4 kg and concentrations of fat and lactose in milk. Protein concentration and fatty acid composition of milk were not influenced by bST injection. Average plasma somatotropin concentrations were elevated threefold, peak concentrations were increased sevenfold, and concentrations at 48 h postinjection were 1.5 times control values. Plasma insulin concentrations were decreased by bST treatment. Results indicate that responses to short-term bST injection are not influenced by feeding frequency.


Cardiac mitochondria exhibit dynamic functional clustering.
Multi-oscillatory behavior of mitochondrial inner membrane potential ΔΨ m in self-organized cardiac mitochondrial networks can be triggered by metabolic or oxidative stress. Spatio-temporal analyses of cardiac mitochondrial networks have shown that mitochondria are heterogeneously organized in synchronously oscillating clusters in which the mean cluster frequency and size are inversely correlated, thus suggesting a modulation of cluster frequency through local inter-mitochondrial coupling. In this study, we propose a method to examine the mitochondrial network's topology through quantification of its dynamic local clustering coefficients. Individual mitochondrial ΔΨ m oscillation signals were identified for each cardiac myocyte and cross-correlated with all network mitochondria using previously described methods (Kurz et al., 2010a). Time-varying inter-mitochondrial connectivity, defined for mitochondria in the whole network whose signals are at least 90% correlated at any given time point, allowed considering functional local clustering coefficients. It is shown that mitochondrial clustering in isolated cardiac myocytes changes dynamically and is significantly higher than for random mitochondrial networks that are constructed using the Erdös-Rényi model based on the same sets of vertices. The network's time-averaged clustering coefficient for cardiac myocytes was found to be 0.500 ± 0.051 (N = 9) vs. 0.061 ± 0.020 for random networks, respectively. Our results demonstrate that cardiac mitochondria constitute a network with dynamically connected constituents whose topological organization is prone to clustering. Cluster partitioning in networks of coupled oscillators has been observed in scale-free and chaotic systems and is therefore in good agreement with previous models of cardiac mitochondrial networks.


Participatory methods effective for ergonomic workplace improvement.
Recent experiences in using participatory methods for ergonomic workplace improvement are reviewed to know how these methods can be effective in different settings. The review covered participatory programmes for managers and workers in small enterprises, home workers, construction workers and farmers in Asian countries. To meet diversifying ergonomic needs, participatory steps reviewed are found to usually follow a good-practice approach easily adjustable according to local needs. These steps are found to usually focus on low-cost improvements. They can thus lead to concrete results particularly by addressing multiple technical areas together. Typical areas include materials handling, workstation design, physical environment and work organization. Further, the review confirms that the participatory methods are always modified according to each local situation. This is done by developing a group-work toolkit comprising action checklists and illustrated manuals and by building a support network of trained trainers. It is suggested that participatory methods taking a good-practice approach by multi-area low-cost improvements through the group use of locally adjusted toolkits are effective for improving small-scale workplaces including those in developing countries.


Usefulness of insulin-like growth factor II mRNA-binding protein 3 (IMP3) as a new marker for the diagnosis of esophageal adenocarcinoma in challenging cases.
Insulin-like growth factor II mRNA-binding protein 3 (IMP3) is an oncofetal protein with vital function during human embryogenesis in terms of cellular growth and migration. Although it has minimum and undetectable expression in human adult tissues, it is highly expressed in various types of cancer. Few studies have recommend application of IMP3 expression to diagnose challenging cases of esophageal adenocarcinoma. This survey was aimed to evaluate the benefit of IMP3 expression detection in the diagnosis of esophageal adenocarcinoma and high-grade dysplasia by using immunohistochemistry (IHC). An immunohistochemistry study of IMP3 oncofetal protein was performed on paraffin-embedded blocks of 76 cases, including Barrett's esophagus, esophageal squamous epithelium, Barrett's esophagus with low-grade dysplasia, Barrett's esophagus with high-grade dysplasia, moderately differentiated esophageal adenocarcinoma, and poorly differentiated esophageal adenocarcinoma. Two pathologists reevaluated the diagnosis and evaluated the positivity and intensity of the IHC staining as well. Insulin-like growth factor II mRNA-binding protein 3 expression was intensely positive in all cases of esophageal adenocarcinoma and Barrett's esophagus with HGD. Only mild positivity in 30% of Barrett's esophagus with LGD was seen. However, Barrett's esophagus and esophageal squamous epithelium had, in fact, no IMP3 expression. The percentage and intensity of IP3 IHC staining showed a significant difference between high-grade dysplasia and adenocarcinoma versus Barrett's esophagus with low-grade dysplasia, Barrett's esophagus, and esophageal squamous epithelium. Therefore, IMP3 oncofetal protein could be a very useful marker for the diagnosis of high-grade dysplasia and adenocarcinoma. However, to test the validation, a larger number samples is required.


Impact of the SARS-CoV-2 pandemic on pancreatic cancer: diagnosis and short-term survival.
The COVID-19 pandemic has delayed medical consultation, possibly leading to the diagnosis of gastrointestinal cancer. The aim of the study was to analyze the impact of SARS-Cov-2 pandemic on new diagnosis and short-term survival of patients with pancreatic cancer (PC). All consecutive patients who had a suspected diagnosis of pancreatic lesion before (from March to September 2019) and during COVID 19 pandemic (from March to September 2020). Demographics, clinical and treatment were collected and compared. Short-term survival was assessed. A total of 25 patients (n=13 men) with diagnosis of adenocarcinoma of the pancreas and a median age of 70 years (IQR 62-74) were included. An increase was observed in the number of patients with newly diagnosed PC (n= 12 [19.1%] versus n=13 [20.9%]; P= 0.603). The subgroup analysis revealed a tendency toward a longer diagnosis (11 versus 12 days; P= 0.219) and treatment (28 versus 44; P= 0.375) delay for patients with PC during COVID-19 pandemic. A significant increase was observed for number of cases of advanced stage III and IV (n=4 [30.8%] versus n=7 [53.8%]; P= 0.006). Palliative treatment was the most frequent approach during COVID-19 period. During 1-year follow-up, 6 (50%) and 7 (61.5%) deaths were observed among patients diagnosed before and after COVID-19 (P= 0.449), respectively. The COVID-19 pandemic has led to delays in diagnosis and treatment in PC, which translates into an advanced staging and a worse prognosis. These data should stimulate health care provider to facilitate procedures for detection pancreatic cancer.


VEGF alleviates lower limb ischemia in diabetic mice by altering muscle fiber types.
Lower limb ischemia caused by diabetic foot (DF) is one of the most serious complications of diabetes. The therapeutic role of VEGF in DF is well documented. However, the mechanism for action of VEGF is still not clear. The present study aimed to explore the effects of VEGF-mediated skeletal muscle fiber type switch in angiogenesis and the treatment of DF. C57BL/6 mice housed in cages equipped with a voluntary running wheel were used to access VEGF protein level and citrate synthase activity (by ELISA) as well as muscle fiber type changes (by immunofluorescence) in the gastrocnemius muscle. C57BL/6 mice were fed on a high-fat diet for 6 weeks and then injected with streptozocin to induce diabetic lower limb ischemia model. Control adenovirus (Ad-GFP) or Ad-VEGF-GFP were then injected into the left gastrocnemius of the ischemic diabetic mice. Blood flow perfusion was examined by laser Doppler imaging at 1, 3, 7 and 14 days after adenovirus transduction. On day 14, all mice were anesthetized and sacrificed. VEGF expression levels, citrate synthase activity and muscle fiber type changes in the gastrocnemius muscle were assayed by ELISA and immunofluorescence analysis of myosin heavy chain IIa (MHCIIa) expression, respectively. Transwell assays were performed to determine whether VEGF-treated C2C12 myotubes played a role on tubule formation and migration of HUVECs. It was found that VEGF levels and citrate synthase activity were upregulated after voluntary exercise, along with the increased frequency of oxidized muscle fibers. Notably, adenovirus-mediated VEGF overexpression in the muscle also increased the frequency of oxidized (MHCIIa-positive) muscle fibers, enhanced citrate synthase activity and ameliorated lower limb ischemia in diabetic mice. VEGF treatment enhanced the phosphorylation of PI3K, Akt and AMPK (assayed by western blotting), as well as glucose consumption and metabolism (assayed by western blotting and glucose uptake assay), in the C2C12 myotubes. Interestingly, VEGF-treated C2C12 myotubes promoted the migration and tubule formation of HUVEC cells. The present findings suggest that skeletal muscle fiber conversion might be a potential approach for VEGF-mediated angiogenesis and disease treatment, which may provide new options for the prevention and treatment of DF.


Diversity, host specificity and biogeography in the Cladocorynidae (Hydrozoa, Capitata), with description of a new genus.
The hydrozoan family Cladocorynidae inhabits tropical to temperate waters and comprises the two genera Pteroclava and Cladocoryne. Pteroclava lives in association with some octocorals and hydrozoans, whereas Cladocoryne is more generalist in terms of substrate choice. This work provides a thorough morpho-molecular reassessment of the Cladocorynidae by presenting the first well-supported phylogeny of the family based on the analyses of three mitochondrial and four nuclear markers. Notably, the two nominal genera were confirmed to be monophyletic and both morphological and genetic data led to the formal description of a new genus exclusively associated with octocorals, Pseudozanclea gen. nov. Maggioni & Montano. Accordingly, the diagnosis of the family was updated. The ancestral state reconstruction of selected characters revealed that the symbiosis with octocorals likely appeared in the most recent common ancestor of Pteroclava and Pseudozanclea. Additionally, the presence of euryteles aggregation in the polyp stage and the exumbrellar nematocyst pouches with euryteles represent synapomorphies of all cladocorynid taxa and probably emerged in their most recent common ancestor. The analysis of several Pteroclava krempfi colonies from Indo-Pacific and Caribbean localities associated with several host octocorals revealed a high intra-specific genetic variability. Single- and multi-locus species delimitations resulted in three to five species hypotheses, but the statistical analysis of morphometric data showed only limited distinction among the clades of P. krempfi. However, P. krempfi clades showed differences in both host specificity, mostly at the octocoral family level, and geographic distribution, with one clade found exclusively in the Caribbean Sea and the others found in the Indo-Pacific.


Dispositional contempt: A first look at the contemptuous person.
Contempt is a powerful emotion. Marriages fail (Gottman, 1994), coworkers are shamed (Melwani & Barsade, 2011), terrorism is tended toward (Tausch et al., 2011). Despite its importance, contempt has not been investigated at the level of personality. The present research examines how our contemptuous reactions can be conceptualized and measured as a stable individual-difference variable with a range of theoretically predicted correlates. First, we introduce a measure of dispositional contempt, the tendency to look down on, distance, and derogate others who violate our standards. We then unpack the dynamics of dispositional contempt. Across 6 studies using self-report and emotion elicitation in student and MTurk samples (Ns = 165 to 1,368), we examined its (a) nomological network, (b) personality and behavioral correlates, and (c) implications for relationship functioning. Dispositional contempt was distinguished from tendencies toward related emotions and was most associated with dispositional envy, anger, and hubristic pride. Somewhat paradoxically, dispositional contempt was related to being cold and "superior," with associations found with narcissism, other-oriented perfectionism, and various antisocial tendencies (e.g., Disagreeableness, Machiavellianism, racism), but it was also related to being self-deprecating and emotionally fragile, with associations found with low self-esteem, insecure attachment, and feeling that others impose perfectionistic standards on oneself. Dispositional contempt predicted contemptuous reactions to eliciting film clips, particularly when targets showed low competence/power. Finally, perceiving one's romantic partner as dispositionally contemptuous was associated with lower commitment and satisfaction. Taken together, results give a first look at the contemptuous person and provide a new organizing framework for understanding contempt. (PsycINFO Database Record


Current management of refractory ascites in patients with cirrhosis.
Liver cirrhosis is a health problem worldwide, and ascites is its principal symptom. Refractory ascites is intractable and occurs in 5%-10% of all patients with ascites due to cirrhosis. Refractory ascites leads to a poor quality of life and high mortality rate. Ascites develops as a result of portal hypertension, which leads to water-sodium retention and renal failure. Various therapeutic measures can be used for refractory ascites, including large-volume paracentesis, transjugular intrahepatic portosystemic shunt, vasoconstrictive drugs, and an automated low-flow ascites pump system. However, ascites generally can be resolved only by liver transplantation. Because not all patients can undergo liver transplantation, traditional approaches are still used to treat refractory ascites. The choice of treatment modality for refractory ascites depends, among other factors, on the condition of the patient.


MYOSIN SUBSTRUCTURE: ISOLATION OF A HELICAL SUBUNIT FROM HEAVY MEROMYOSIN.
A highly alpha-helical subunit has been isolated from the heavy-mero-myosin portion of myosin. This molecule has a helix content of about 73 percent and an amino acid composition similar to that of light meromyosin. The presence of this subunit supports the current view that the myosin molecule consists of a long helical rod with a globular region at one end.


A molecular basis for the selective recognition of 2-hydroxy-dATP and 8-oxo-dGTP by human MTH1.
MTH1 hydrolyzes oxidized purine nucleoside triphosphates such as 8-oxo-dGTP, 8-oxo-dATP, 2-hydroxy-dATP, and 2-hydroxy rATP to monophosphates, and thus avoids errors caused by their misincorporation during DNA replication or transcription, which may result in carcinogenesis or neurodegeneration. This substrate specificity for oxidized purine nucleoside triphosphates was investigated by mutation analyses based on the sequence comparison with the Escherichia coli homolog, MutT, which hydrolyzes only 8-oxo-dGTP and 8-oxo-rGTP but not oxidized forms of dATP or ATP. Neither a replacement of the phosphohydrolase module of MTH1 with that of MutT nor deletions of the C-terminal region of MTH1, which is unique for MTH1, altered the substrate specificity of MTH1. In contrast, the substitution of residues at position Trp-117 and Asp-119 of MTH1, which showed apparent chemical shift perturbations with 8-oxo-dGDP in NMR analyses but are not conserved in MutT, affected the substrate specificity. Trp-117 is essential for MTH1 to recognize both 8-oxo-dGTP and 2-hydroxy-dATP, whereas Asp-119 is only essential for recognizing 2-hydroxy-dATP, thus suggesting that origins of the substrate-binding pockets for MTH1 and MutT are different.


Peptide-induced conformational changes in class I heavy chains alter major histocompatibility complex recognition.
Small peptides, derived from endogenous proteins bind within the antigen binding groove created by the beta-pleated sheets and alpha helices of the alpha 1 and alpha 2 domains of the class I molecule of the major histocompatibility complex (MHC). However, the precise role of peptide in class I MHC conformation remains unclear. Here, we have shown that, in at least some instances, changes induced in the MHC molecule by the binding of distinct peptides can be identified as specific alterations in serological epitopes expressed on the class I protein. The nature of specific peptides expressed by class I-bearing cells may, therefore, have a dramatic influence on T cell development, self-tolerance, and alloreactivity.


Developmental Sensitivity in Schistosoma mansoni to Puromycin To Establish Drug Selection of Transgenic Schistosomes.
Schistosomiasis is considered the most important disease caused by helminth parasites, in terms of morbidity and mortality. Tools to facilitate gain- and loss-of-function approaches can be expected to precipitate the discovery of novel interventions, and drug selection of transgenic schistosomes would facilitate the establishment of stable lines of engineered parasites. Sensitivity of developmental stages of schistosomes to the aminonucleoside antibiotic puromycin was investigated. For the schistosomulum and sporocyst stages, viability was quantified by fluorescence microscopy following dual staining with fluorescein diacetate and propidium iodine. By 6 days in culture, the 50% lethal concentration (LC50) for schistosomula was 19 μg/ml whereas the sporocysts were 45-fold more resilient. Puromycin potently inhibited the development of in vitro-laid eggs (LC50, 68 ng/ml) but was less effective against liver eggs (LC50, 387 μg/ml). Toxicity for adult stages was evaluated using the xCELLigence-based, real-time motility assay (xWORM), which revealed LC50s after 48 h of 4.9 and 17.3 μg/ml for male and female schistosomes, respectively. Also, schistosomula transduced with pseudotyped retrovirus encoding the puromycin resistance marker were partially rescued when cultured in the presence of the antibiotic. Together, these findings will facilitate selection on puromycin of transgenic schistosomes and the enrichment of cultures of transgenic eggs and sporocysts to facilitate the establishment of schistosome transgenic lines. Streamlining schistosome transgenesis with drug selection will open new avenues to understand parasite biology and hopefully lead to new interventions for this neglected tropical disease.


Prevalence and Correlates of HIV Disclosure Among Children and Adolescents in Low- and Middle-Income Countries: A Systematic Review.
Disclosure of HIV status among children and adolescents living with HIV has both beneficial and challenging aspects. To address existing knowledge gaps and update the literature on childhood disclosure, we conducted a systematic review on caregivers' perceptions and practices of HIV disclosure in low- and middle-income countries (LMICs). Standard databases were searched for studies conducted in LMICs, published in English between 2004 and 2015. Excluded articles were reviews or case reports, and those not reporting childhood disclosure. Data regarding prevalence, correlates and impact of disclosure, were presented as frequencies. Two authors independently screened 982 articles. After applying eligibility criteria, 22 articles representing 12 countries and 2,843 children were reviewed. The proportion of fully disclosed children ranged from 1.7% to 41.0%. Up to 49.5% children were provided "deflected" information (use of a non-HIV-related reason for explaining illness and health care visits). Factors associated with full disclosure included antiretroviral treatment initiation and caregivers' felt need for maintaining optimal adherence. Barriers to disclosure included fear of negative psychological reactions and inadvertent disclosure to others. Caregivers perceived a strong need for active participation from health care providers to aid the process of disclosure. Full disclosure of HIV status was not common among children and adolescents in LMICs, while the practice of deflected disclosure was prominent. Caregivers perceived the need for support from health care providers during the disclosure process. Evidence-based guidelines incorporating the developmental status of the child, locally prevalent cultures, and caregiver perceptions are prerequisite to enhancing disclosure in these settings.


Cellular and physiological mechanisms of new-onset diabetes mellitus after solid organ transplantation.
New-onset diabetes after transplantation is recognized as one of the metabolic consequences which may increase the risk of morbidity and mortality after solid organ transplantation. The pathophysiology of new-onset diabetes after transplantation has not been clearly defined and may resemble that of Type 2 diabetes, characterized by predominantly insulin resistance or defective insulin secretion, or both. This review aims to summarize the current state of knowledge regarding the prevalence, consequences, pathogenesis, and management of new-onset diabetes after transplantation, with a major focus on the possible mechanisms involved in the pathogenesis of the disorder. The aetiology of new-onset diabetes after transplantation is multifactorial, with diabetogenic immunosuppressive drugs playing a major role. Multiple cellular and physiologic mechanisms are involved in the process. Selection of an appropriate maintenance immunosuppressive regimen should involve balancing the risk of patient and graft survival vs. the potential for new-onset diabetes after transplantation.


Sustaining a healthy work force in the 21st century--a model for collaborating through reciprocation.
Occupational health nurses are positioned to restore and maintain worker health, well-being, and safety, thereby increasing productivity. A model of practice is needed that provides a comprehensive worker-environment perspective. A model that incorporates reciprocation and collaboration increases workers' engagement in their own health action plan. It empowers workers and provides a broader multidimensional perspective on factors affecting or influencing their health. The Reciprocation Model has been designed using the nursing process; it incorporates reciprocation and collaboration to assist occupational health nurses improve or maintain worker health and safety, as well as achieve corporate goals of reducing on-the-job lost time and increasing productivity.


Are SSRIs safe for pregnant and breastfeeding women?
To summarize the literature on use of the selective serotonin reuptake inhibitor (SSRI) class of antidepressants for pregnant and breastfeeding women. MEDLINE was searched over the past 9 years. An examination of the literature over the last 8 years was included in this review. Primary studies consist of prospective investigations and case studies. Evidence for the safety of SSRIs is limited, but some good studies describe the effects of untreated depression. All studies report that infants are exposed to SSRIs; the drugs can be measured in their plasma and urine. Some evidence shows an increase in minor perinatal complications among infants exposed to SSRIs late in gestation or while nursing. No studies, however, have found an increase in major fetal malformations or pregnancy-related complications. The only investigation of long-term neurodevelopmental outcomes found no negative outcomes among infants exposed to SSRIs during pregnancy. Data are scarce, and readers are cautioned to take into consideration the limitations of the studies reviewed before making definite treatment decisions. Major fetal malformations and exposure to SSRIs during pregnancy and lactation do not appear to be associated. Some minor perinatal complications have been reported. Data on the long-term developmental outcomes of children exposed to SSRIs in utero and during breastfeeding are limited.


Variational Nested Dropout.
Nested dropout is a variant of dropout operation that is able to order network parameters or features based on the pre-defined importance during training. It has been explored for: I. Constructing nested nets Cui et al. 2020, Cui et al. 2021: the nested nets are neural networks whose architectures can be adjusted instantly during testing time, e.g., based on computational constraints. The nested dropout implicitly ranks the network parameters, generating a set of sub-networks such that any smaller sub-network forms the basis of a larger one. II. Learning ordered representation Rippel et al. 2014: the nested dropout applied to the latent representation of a generative model (e.g., auto-encoder) ranks the features, enforcing explicit order of the dense representation over dimensions. However, the dropout rate is fixed as a hyper-parameter during the whole training process. For nested nets, when network parameters are removed, the performance decays in a human-specified trajectory rather than in a trajectory learned from data. For generative models, the importance of features is specified as a constant vector, restraining the flexibility of representation learning. To address the problem, we focus on the probabilistic counterpart of the nested dropout. We propose a variational nested dropout (VND) operation that draws samples of multi-dimensional ordered masks at a low cost, providing useful gradients to the parameters of nested dropout. Based on this approach, we design a Bayesian nested neural network that learns the order knowledge of the parameter distributions. We further exploit the VND under different generative models for learning ordered latent distributions. In experiments, we show that the proposed approach outperforms the nested network in terms of accuracy, calibration, and out-of-domain detection in classification tasks. It also outperforms the related generative models on data generation tasks.


Deep learning approach towards accurate state of charge estimation for lithium-ion batteries using self-supervised transformer model.
Accurate state of charge (SOC) estimation of lithium-ion (Li-ion) batteries is crucial in prolonging cell lifespan and ensuring its safe operation for electric vehicle applications. In this article, we propose the deep learning-based transformer model trained with self-supervised learning (SSL) for end-to-end SOC estimation without the requirements of feature engineering or adaptive filtering. We demonstrate that with the SSL framework, the proposed deep learning transformer model achieves the lowest root-mean-square-error (RMSE) of 0.90% and a mean-absolute-error (MAE) of 0.44% at constant ambient temperature, and RMSE of 1.19% and a MAE of 0.7% at varying ambient temperature. With SSL, the proposed model can be trained with as few as 5 epochs using only 20% of the total training data and still achieves less than 1.9% RMSE on the test data. Finally, we also demonstrate that the learning weights during the SSL training can be transferred to a new Li-ion cell with different chemistry and still achieve on-par performance compared to the models trained from scratch on the new cell.


The Critical Role of Word Reading as a Predictor of Response to Intervention.
This study examines the initial word reading performance of fourth-grade struggling readers and the extent to which differing levels of word reading performance at pretest influenced their response to reading interventions. A large group of students with significant reading comprehension difficulties (N = 481) were classified into three clusters of word reading proficiency based on their pretest performance: (a) very low, (b) low, and (c) near adequate. We examined their performance on several academic, language, and executive functioning measures at the beginning of the year and their reading comprehension performance at the beginning of year and after 1 year of reading intervention to examine how each cluster responded to instruction. Results from a discriminant function analysis indicated that performance on five pretest variables were meaningful predictors of word reading proficiency cluster membership: phonological processing, writing fluency, math calculation, math fluency, and reading efficiency and comprehension. Results also demonstrated that word reading proficiency at pretest was related to response to intervention on reading comprehension measures. Students in the very low word reading proficiency cluster showed minimal response to intervention whereas the near-adequate word reading cluster demonstrated greatest response to intervention. These results suggest word reading is a critical predictor of response to intervention for students with significant comprehension problems in the upper elementary grades and that students with the most substantial word reading problems may require more intensive and specialized treatments than students with greater word reading performance to show meaningful progress in reading.


Histology of the Ovary of the Laying Hen (Gallus domesticus).
The laying hen (Gallus domesticus) is a robust animal model for epithelial ovarian cancer. The use of animal models is critical in identifying early disease markers and developing and testing chemotherapies. We describe the microscopic characteristics of the normally functioning laying hen ovary and proximal oviduct to establish baselines from which lesions associated with ovarian cancer can be more readily identified. Ovaries and oviducts were collected from 18-month-old laying hens (n = 18) and fixed in 10% neutral buffered formalin. Hematoxylin- and eosin-stained sections were examined by light microscopy. Both post-ovulatory follicular regression and atresia of small follicles produce remnant clusters of vacuolated cells with no histological evidence that scar tissue persists. Infiltrates of heterophils are associated with atresia of small follicles, a relationship not previously documented in laying hen ovaries. Because these tissues can be mistaken for cancerous lesions, we present a detailed histological description of remnant Wolffian tissues in the laying hen ovary. Immunohistochemical staining for pancytokeratin produced a positive response in ovarian surface epithelium and staining for vimentin produced a positive response in granulosa cells of follicles. Epithelial cells lining glands of the remnant epoöphoron had a positive response to both pancytokeratin and vimentin, a result also observed in women.


Na-H Exchanger Isoform-2 (NHE2) Mediates Butyrate-dependent Na+ Absorption in Dextran Sulfate Sodium (DSS)-induced Colitis.
Diarrhea associated with ulcerative colitis (UC) occurs primarily as a result of reduced Na(+) absorption. Although colonic Na(+) absorption is mediated by both epithelial Na(+) channels (ENaC) and Na-H exchangers (NHE), inhibition of NHE-mediated Na(+) absorption is the primary cause of diarrhea in UC. As there are conflicting observations reported on NHE expression in human UC, the present study was initiated to identify whether NHE isoforms (NHE2 and NHE3) expression is altered and how Na(+) absorption is regulated in DSS-induced inflammation in rat colon, a model that has been used to study UC. Western blot analyses indicate that neither NHE2 nor NHE3 expression is altered in apical membranes of inflamed colon. Na(+) fluxes measured in vitro under voltage clamp conditions in controls demonstrate that both HCO3 (-)-dependent and butyrate-dependent Na(+) absorption are inhibited by S3226 (NHE3-inhibitor), but not by HOE694 (NHE2-inhibitor) in normal animals. In contrast, in DSS-induced inflammation, butyrate-, but not HCO3 (-)-dependent Na(+) absorption is present and is inhibited by HOE694, but not by S3226. These observations indicate that in normal colon NHE3 mediates both HCO3 (-)-dependent and butyrate-dependent Na(+) absorption, whereas DSS-induced inflammation activates NHE2, which mediates butyrate-dependent (but not HCO3 (-)-dependent) Na(+) absorption. In in vivo loop studies HCO3 (-)-Ringer and butyrate-Ringer exhibit similar rates of water absorption in normal rats, whereas in DSS-induced inflammation luminal butyrate-Ringer reversed water secretion observed with HCO3 (-)-Ringer to fluid absorption. Lumen butyrate-Ringer incubation activated NHE3-mediated Na(+) absorption in DSS-induced colitis. These observations suggest that the butyrate activation of NHE2 would be a potential target to control UC-associated diarrhea.


The association of exposure to suicide-related Internet content and emergency department visits in children: A population-based time series analysis.
Suicide-related emergency department (ED) visits by children are increasing in tandem with suicide-related Internet content. Following the announcement of Amanda Todd's suicide, her YouTube video received widespread views, providing an opportunity to explore this association. Our research question was: Among Ontario children age 11-17 years, was the release of Amanda Todd's YouTube video following her death announcement in October 2012 associated with an increase in average monthly ED visit rates for suicide-related diagnoses? We performed an interrupted time series analysis from April 2002 to December 2013, with the primary outcome as a composite of the average monthly rate of initial ED visits for suicidal ideation, intentional self-poisoning, and intentional self-harm. Secondary outcomes were average monthly rates of intensive care unit (ICU) admission and death resulting from the index visit. There was a statistically significant increase in the monthly ED visit rate for the composite outcome (p = 0.02) and death or ICU admission (p = 0.006) from April 2002 to December 2013. There was no significant change in ED visit rate for the composite outcome before and after the announcement of Amanda Todd's death, overall (119.8 versus 219.2 respectively, p = 0.5), among females (167.4 versus 316.8 respectively, p = 0.47) or among males (74.7 versus 116.9 respectively, p = 0.33). Ontario ED visits for suicide-related diagnoses in 11-17 year olds increased from 2002 to 2013. However, the increase from October 2012 to December 2013 could not be attributed to a highly publicized adolescent suicide. Our findings suggest that suicide-related Internet content is not associated with the increase in ED visits for suicidal behaviour.


Valve implants compared to other surgical methods.
The results of eighty-seven inner ear valve implant procedures for Meniere's disease are compared to those of 181 other surgical procedures performed during the same period, and 339 cases reported in our previous series. Indications are that all procedures give comparable results, although it is suggested that in isolated cases the inner ear valve implant can improve hearing by much greater margins than can be achieved using alternative surgical methods. In spite of this advantage, however, there is a possibility that the approach to the endolymphatic duct used in the implant procedure may jeopardize the inner ear function, and thus it should still be used with caution.


Parental Scaffolding during Book-Sharing Predicts Child General Intelligence.
While much variance in general intelligence or g is genetic, a substantial environmental component suggests a possible role for parent-child interaction. In particular, previous evidence suggests the importance of parental scaffolding, or provision of cognitive structure to shape child behaviour. A role for scaffolding is consistent with the proposal that, in adult cognition, a critical aspect of g is decomposition of complex problems into a structure of simpler parts. Building on previous work, we recruited 162 parents attending Children's Centres with a child aged 2-4 years, and examined parental scaffolding during a book-sharing activity. Scaffolding was measured as the first principal component of a variety of parental behaviours, including sensitivity, focusing attention, extending comprehension, and promoting child participation. Child g was measured as the first principal component of a broad cognitive battery, including language, attention, working memory, and executive function. Importantly, we assessed contributions of the parent's own intelligence, education, and family income. Though these variables were all associated with both child g and parental scaffolding, scaffolding remained predictive of child g even once the influence of these variables was removed. In contrast to the correlation with cognitive proficiency, scaffolding did not predict child pro-social behaviour. We suggest that parental scaffolding supports the child's development of a broad skill of attentional structuring, promoting the across-the-board cognitive proficiency that is reflected in g.


Linear humidity response of carbon dot-modified molybdenum disulfide.
Molybdenum disulfide (MoS2)-based humidity sensors suffer from low sensitivity and long response time. Herein, this problem has been effectively solved by modifying MoS2 nanosheets using carbon dots (CDs) with abundant functional groups via a convenient and facile hydrothermal method. The mechanism for the enhanced humidity response of CD-modified MoS2 has been proposed through the characterization of physical and chemical properties of the as-prepared composites. The introduction of CDs is expected to enhance the adsorption of water molecules by increasing the specific surface area and surface active sites of the MoS2 nanosheets. Moreover, a three-dimensional conductive network is jointly established by the chemisorbed water molecules, CDs, and MoS2 nanosheets, which ensures continuous transmission of charges in a low humidity environment. As a result, the response performance and the repeatability have been significantly improved in CD-MoS2-based humidity sensors. The response curve shows an excellent linear property in the range of 15-80% RH. This study demonstrates the potential applications of CD-modified two-dimensional nanomaterials with their improved performance towards humidity sensing.


Optogenetic regulation of transcription.
Optogenetics has become widely recognized for its success in real-time control of brain neurons by utilizing non-mammalian photosensitive proteins to open or close membrane channels. Here we review a less well known type of optogenetic constructs that employs photosensitive proteins to transduce the signal to regulate gene transcription, and its possible use in medicine. One of the problems with existing gene therapies is that they could remain active indefinitely while not allowing regulated transgene production on demand. Optogenetic regulation of transcription (ORT) could potentially be used to regulate the production of a biological drug in situ, by repeatedly applying light to the tissue, and inducing expression of therapeutic transgenes when needed. Red and near infrared wavelengths, which are capable of penetration into tissues, have potential for therapeutic applications. Existing ORT systems are reviewed herein with these considerations in mind.


Sorting mouse jejunal epithelial cells with CD24 yields a population with characteristics of intestinal stem cells.
Intestinal stem cells (ISCs) have been studied for more than three decades; however, their isolation has remained a challenge. We hypothesized that, just as for stem cells of other tissues, one or more membrane markers would allow positive selection of ISCs by antibody-based sorting. To explore this hypothesis, microarray data of putative ISC fractions generated by side population sorting and laser capture microdissection were subjected to bioinformatic analysis to identify common membrane antigens. The microarray comparison suggested CD24 as a candidate surface marker, and immunohistochemistry showed expression of CD24 in epithelial cells of crypt bases. Flow cytometry of jejunal epithelial preparations revealed a CD24(+) CD45(-) fraction comprising ∼1% of the cells. Analysis with epithelial cell adhesion molecule and CD31 confirmed that the cell preparations were epithelial and without endothelial contamination. Cycling cells identified by prior injection with 5-ethynyl-2'-deoxyuridine were found predominantly in the CD24(lo) subfraction. Transcript analysis by real-time RT-PCR showed this subfraction to be enriched in the ISC markers leucine-rich-repeat-containing G-protein-coupled receptor 5 (40-fold) and Bmi1 (5-fold), but also enriched in lysozyme (10-fold). Flow cytometry with anti-lysozyme antibodies demonstrated that Paneth cells comprise ∼30% of the CD24(lo) subfraction. Additional flow analyses with leucine-rich-repeat-containing G-protein-coupled receptor 5-enhanced green fluorescent protein (EGFP) epithelium demonstrated colocalization of EGFP(hi) and CD24(lo). In contrast, CD24 cells were negative for the quiescent ISC marker doublecortin and CaM kinase-like-1. Culture of CD24(lo) cells in Matrigel generated organoid structures, which included all four epithelial lineages, thus giving functional evidence for the presence of ISCs. We conclude that the CD24(lo) fraction of jejunal epithelium is highly enriched with cycling ISCs. This isolation method should be useful to many investigators in the field to advance both the basic understanding of ISC biology and the therapeutic applications of ISCs.


Contraceptive practice, unwanted pregnancies and induced abortion in Southwest Nigeria.
Despite widespread awareness of and access to modern contraception, high rates of unwanted pregnancies and abortions still persist in many parts of the world, even where abortion is legally restricted. This article explores perspectives on contraception and abortion, contraceptive decision-making within relationships, and the management of unplanned pregnancies. It presents findings from an exploratory qualitative study based on 17 in-depth interviews and 6 focus group discussions conducted in 2 locations in Nigeria in 2006. The results suggest that couples do not practice contraception consistently because of perceived side effects and partner objections. Abortion is usually resorted to because pregnancy was unwanted due to incomplete educational attainment, economic hardship, immaturity, close pregnancy interval, and social stigma. Males usually have greater influence in contraceptive-decision making than females. Though induced abortion is negatively viewed in the community, it is still common, and women usually patronise quacks to obtain such services. An abortion experience can change future views and decisions towards contraception. Family planning interventions should include access to and availability of adequate family planning information. Educational campaigns should target males since they play an important role in contraceptive decision-making.


Cryo-EM structure of antibacterial efflux transporter QacA from Staphylococcus aureus reveals a novel extracellular loop with allosteric role.
Efflux of antibacterial compounds is a major mechanism for developing antimicrobial resistance. In the Gram-positive pathogen Staphylococcus aureus, QacA, a 14 transmembrane helix containing major facilitator superfamily antiporter, mediates proton-coupled efflux of mono and divalent cationic antibacterial compounds. In this study, we report the cryo-EM structure of QacA, with a single mutation D411N that improves homogeneity and retains efflux activity against divalent cationic compounds like dequalinium and chlorhexidine. The structure of substrate-free QacA, complexed to two single-domain camelid antibodies, was elucidated to a resolution of 3.6 Å. The structure displays an outward-open conformation with an extracellular helical hairpin loop (EL7) between transmembrane helices 13 and 14, which is conserved in a subset of DHA2 transporters. Removal of the EL7 hairpin loop or disrupting the interface formed between EL7 and EL1 compromises efflux activity. Chimeric constructs of QacA with a helical hairpin and EL1 grafted from other DHA2 members, LfrA and SmvA, restore activity in the EL7 deleted QacA revealing the allosteric and vital role of EL7 hairpin in antibacterial efflux in QacA and related members.


Prevalence Estimates of Arthritis and Activity-Limiting Pain Among Family Caregivers to Older Adults.
Little is known about the prevalence of physical pain among family caregivers to older adults. We used national survey data to assess the relative prevalence of caregivers' arthritis and activity-limiting bothersome pain by caregiver and care recipient characteristics to identify which caregivers may be at a higher risk for physical pain. We analyzed data collected from 1,930 caregivers who participated in the National Study on Caregiving (2017). We utilized modified Poisson models to estimate adjusted associations of caregiver and care recipient characteristics with the relative prevalence of arthritis and bothersome pain. 40% of caregivers had a lifetime diagnosis of arthritis. 75% of caregivers with arthritis reported bothersome pain, nearly 30% of whom endorsed bothersome pain that limited their activities on most or every day of the previous month (i.e., activity-limiting bothersome pain). Regardless of whether they had arthritis, 51% of the sample reported bothersome pain in the previous month, 24% of whom indicated activity-limiting bothersome pain. Caregivers who were older or more highly educated had a higher prevalence of arthritis. Black caregivers had a lower prevalence of arthritis and activity-limiting bothersome pain compared to White caregivers. Caregivers with physical difficulty providing care had higher prevalence of arthritis and activity-limiting bothersome pain than caregivers without physical difficulty providing care. Arthritis and activity-limiting bothersome pain are highly prevalent among caregivers. Given increased prevalence of pain among certain caregivers, it may be efficient to target these groups for pain management interventions.


Endocrine Insights into the Pathophysiology of Autism Spectrum Disorder.
Autism spectrum disorder (ASD) is a class of neurodevelopmental disorders that affects males more frequently than females. Numerous genetic and environmental risk factors have been suggested to contribute to the development of ASD. However, no one factor can adequately explain either the frequency of the disorder or the male bias in its prevalence. Gonadal, thyroid, and glucocorticoid hormones all contribute to normal development of the brain, hence perturbations in either their patterns of secretion or their actions may constitute risk factors for ASD. Environmental factors may contribute to ASD etiology by influencing the development of neuroendocrine and neuroimmune systems during early life. Emerging evidence suggests that the placenta may be particularly important as a mediator of the actions of environmental and endocrine risk factors on the developing brain, with the male being particularly sensitive to these effects. Understanding how various risk factors integrate to influence neural development may facilitate a clearer understanding of the etiology of ASD.


Immediate unidirectional epigenetic reprogramming of NORs occurs independently of rDNA rearrangements in synthetic and natural forms of a polyploid species Brassica napus.
The dynamics of genome modification that occurred from the initial hybridization event to the stabilization of allopolyploid species remains largely unexplored. Here, we studied inheritance and expression of rDNA loci in the initial generations of Brassica napus allotetraploids (2n = 38, AACC) resynthesized from Brassica oleracea (2n = 18, CC) and B. rapa (2n = 20, AA) and compared the patterns to natural forms. Starting already from F1 generation, there was a strong uniparental silencing of B. oleracea genes. The epigenetic reprogramming was accompanied with immediate condensation of C-genome nucleolar organizer region (NOR) and progressive transgeneration hypermethylation of polymerase I promoters, mainly at CG sites. No such changes were observed in the A-genome NORs. Locus loss and gains affecting mainly non-NOR loci after the first allotetraploid meiosis did not influence established functional status of NORs. Collectively, epigenetic and genetic modifications in synthetic lines resemble events that accompanied formation of natural allopolyploid species.


Human immunodeficiency virus type 1 vpr gene induces phenotypic effects similar to those of the DNA alkylating agent, nitrogen mustard.
The product of the human immunodeficiency virus type 1 (HIV-1) vpr gene induces cell cycle arrest in the G2 phase of the cell cycle and is characterized by an accumulation of the hyperphosphorylated form of cdc2 kinase. This phenotype is similar to the effect of DNA-damaging agents, which can also cause cells to arrest at G2. We previously reported that Vpr mimicked some of the effects of a DNA alkylating agent known as nitrogen mustard (HN2). Here we extend these earlier observations by further comparing the activation state of cdc2 kinase, the kinetics of G2 arrest, and the ability to reverse the arrest with chemical compounds known as methylxanthines. Infection of cells synchronized in the G1 phase of the cell cycle with a pseudotyped HIV-1 resulted in arrest at G2 within 12 h postinfection, before the first mitosis. Similar to that induced by HN2, Vpr-induced arrest led to a decrease in cdc2 kinase activity. Vpr-mediated G2 arrest was alleviated by methylxanthines at concentrations similar to those needed to reverse the G2 arrest induced by HN2, and cells proceeded apparently normally through at least one complete cell cycle. These results are consistent with the hypothesis that Vpr induces G2 arrest through pathways that are similar to those utilized by DNA-damaging agents.


[Primary health care policy in Brazil: notes on Federal regulation and funding].
This article analyzes the Federal implementation of primary health care policy in Brazil from 2003 to 2008, considering the government functions of health planning, regulation, financing, and health services delivery. The methodology included literature and document review, interviews with key policy actors, budget analysis, and health database analysis. The analysis showed a reduction in direct Federal health services delivery and weaknesses in Federal planning. Federal performance mainly involved regulation, based on norms linked to financial mechanisms. As for funding, the results showed a slight increase in the share for primary care in the Federal budget, adjustments, and creation of new incentives, some aimed at equity. Although some progress occurred, a remaining challenge is to reconfigure the Federal regulatory model and ensure a greater supply of resources for primary health care in Brazil.


[The optimal protein quantity in infant nutrition].
Nowadays, the trend of recommendations to prepare infant formulas with only 2 per cent or less of protein does not correspond with the optimal protein demand and protein utilization in infants. Such formulas often prompt mothers to add carbohydrates to the protein half-strength milks in order to satisfy the infant's hunger. This often leads to the unwanted effect to obesity. There is no evidence to prove that infants above the age of 1 month should not receive 2.2 or 2.3% of protein in their formulas. This quantity is fully utilized by the infants; it has no disadvantages and is safe. Hence, the recommendations should not be based on the minimum daily requirements but on the optimal utilization, whereby the tendency to obesity can also be reduced.


Positron emission tomography: radioisotope and radiopharmaceutical production.
A Centre for Positron Emission Tomography (PET) has been operational within the Department of Nuclear Medicine at the Austin & Repatriation Medical Centre (A&RMC) in Melbourne for seven years. PET is a non-invasive imaging technique based on the use of biologically relevant compounds labelled with short-lived positron-emitting radionuclides such as carbon-11, nitrogen-13, oxygen-15 and fluorine-18. The basic facility consists of a medical cyclotron (10 MeV proton & 5 MeV deuteron), six lead-shielded hotcells with associated radiochemistry facilities, radiopharmacy and a whole body PET scanner. A strong radiolabelling development program, including the production of 15O-oxygen, 15O-carbon monoxide, 15O-carbon dioxide, 15O-water, 13N-ammonia, 18F-FDG, 18F-FMISO, 11C-SCH23390 and 11C-flumazenil has been pursued to support an ambitious clinical and research program in neurology, oncology, cardiology and psychiatry.


Explanatory models of mental illness among family caregivers of persons in psychiatric rehabilitation services: A pilot study.
Understanding the explanatory models of family caregivers is particularly important in interdependent contexts like India, where they often play a significant role in the help-seeking behaviours, treatment decision-making and long-term care of those diagnosed with mental illness. This study was planned to explore the diversity of explanatory models among family caregivers at a centre for recovery-oriented rehabilitation services in South India. The sample for this study included 60 family caregivers of patients referred to Psychiatric Rehabilitation Services within a tertiary-care hospital for mental health and neurosciences. Bart's Explanatory Model Inventory, including a semi-structured interview and a checklist, assessed the family caregivers' explanatory model of distress on five domains: identity, cause, timeline, consequences and control/cure/treatment. The results indicated the coexistence of multiple causal explanatory models including psychosocial, supernatural, situational and behavioural contributors. While 36.7% of the caregivers displayed two explanatory models, 33.3% of the caregivers held three explanatory models and 16.6% of the caregivers endorsed four explanatory models. Caregivers shared their concerns about varied consequences of mental illness but less than half of them were aware of the name of the psychiatric disorder. While they accessed various forms of treatments and adjunctive supports such as prayer, medication was the most frequently used treatment method. The findings have implications for collaborative goal setting in recovery-oriented services for persons with mental illness and their families.


Ectodermal patterning in vertebrate embryos.
Recent molecular insights on how the ectodermal layer is patterned in vertebrates are reviewed. Studies on the induction of the central nervous system (CNS) by Spemann's Organizer led to the isolation of noggin and chordin. These secretory proteins function by binding to, and inhibiting, ventral BMPs, in particular BMP-4. Neural induction can be considered as the dorsalization of ectoderm, in which low levels of BMP-signaling result in CNS formation. At high levels of BMP signaling the ectoderm adopts a ventral fate and skin is formed. In Xenopus the forming neural plate already has extensive dorsal-ventral (D-V) patterning, and neural induction and D-V patterning may share common molecular mechanisms. At later stages sonic hedgehog (shh) plays a principal role in D-V patterning, particularly in the neural tube of the amniote embryo. A great many transcription factor markers are available and mouse knockouts provide evidence of their involvement in the regional specification of the neural tube. Recent evidence indicating that differentiation of posterior CNS is promoted by FGF, Wnt-3a, and retinoic acid is reviewed from the point of view of the classical experiments of Nieuwkoop that defined an activation and a transformation step during neural induction.


Hemiepiphyseodesis for Juvenile and Adolescent Tibia Vara Utilizing Percutaneous Transphyseal Screws.
In juvenile and adolescent tibia vara patients with sufficient growth remaining, implant-controlled hemiepiphyseodesis, or guided growth, can be used to correct deformity. Recent reports have described hardware failure of certain hemiepiphyseodesis implants in overweight patients with tibia vara. We describe our experience using transphyseal screws to correct deformity in this patient population. A retrospective chart and radiograph review was conducted on all juvenile and adolescent tibia vara patients who underwent lateral proximal tibial hemiepiphyseodesis using a single transphyseal screw. Charts were queried for preoperative and postoperative mechanical axis deviation, medial proximal tibial angle, lateral distal femoral angle, and postoperative complications or need for further surgery. In total, 14 affected limbs in 9 patients (6 males) who underwent lateral proximal tibial transphyseal screw hemiepiphyseodesis were considered. Average chronologic age at implantation was 10.4 years and average body mass index was 31.7 kg/m. At average 23-month follow-up, the average mechanical axis deviation improved from 46 to 0 mm (P<0.001), and the average medial proximal tibial angle improved from 81 to 92 degrees (P<0.001). No limbs underwent further surgery to correct residual deformity. There were no complications or instances of implant failure associated with the transphyseal screws. Hemiepiphyseodesis using transphyseal screws is an effective technique to correct deformity in juvenile and adolescent tibia vara patients with sufficient growth remaining. This method can be used safely with few complications and with minimal risk of mechanical failure, even in overweight patients. Level IV-therapeutic.


Exploring Multiple Measures of Pregnancy Preferences and Their Relationship with Postpartum Contraceptive Uptake Using Longitudinal Data from PMA Ethiopia.
There are significant gaps in our understanding of how the experience of an unintended pregnancy affects subsequent contraceptive behavior. Our objective was to explore how three measures of pregnancy preferences-measuring timing-based intentions, emotional orientation, and planning status-were related to the uptake of postpartum family planning within one year after birth. Additionally, we tested whether the relationship between each measure and postpartum family planning uptake differs by parity, a key determinant of fertility preference. Adjusted hazards regression results show that the timing-based measure, specifically having a mistimed pregnancy, and the emotional response measure, specifically being unhappy, were associated with contraceptive uptake in the extended postpartum period, while those related to pregnancy planning, as measured by an adapted London Measure of Unplanned Pregnancy, were not. This effect differed by parity; high parity women were consistently the least likely to use contraception in the postpartum period, but the effect of experiencing an unwanted pregnancy or having a mixed reaction to a pregnancy was significantly stronger among high parity compared to low parity women. Greater attention to the entirety of women's responses to unanticipated pregnancies is needed to fully understand the influence of unintended pregnancy on health behaviors and outcomes for women and their children.


Multinucleated podocytes as a clue to diagnosis of juvenile nephropathic cystinosis.
BACKGROUND : Cystinosis is a rare autosomal recessive lysosomal disorder that mainly affects the kidney and eye. Early treatment with cysteamine significantly improves the prognosis. However, early diagnosis of cystinosis, especially the juvenile nephropathic form, remains challenging because typical symptoms only become apparent in adulthood. We herein describe a 13-year-old girl who presented with proteinuria only but was diagnosed with juvenile nephropathic cystinosis based on multinucleated podocytes in her kidney biopsy specimen. We also studied the nephropathology of another case to determine the features of the multinucleated podocytes. CASE DIAGNOSIS: A previously healthy 13-year-old girl presented to our hospital because proteinuria had been detected in her school urine screening. She had been noted to have proteinuria on her school urine screening when she was 11 years of age but there was no consultation with her physician at that time. She was asymptomatic and had no other abnormalities on examination other than a relatively high urinary β-2 microglobulin level. Her kidney biopsy showed 15 multinucleated podocytes in 34 glomeruli, and the mean number of nuclei per multinucleated podocyte was 4.4. Ophthalmological examination showed cystine crystals in her cornea. Her white blood cell cystine level was high, and she was diagnosed with juvenile nephropathic cystinosis. She started oral cysteamine treatment and showed almost no progression of the disease after 2 years. In another patient with juvenile nephropathic cystinosis, there were 25 multinucleated podocytes in 63 glomeruli, and the mean number of nuclei per multinucleated podocyte was 2.9. CONCLUSION: Early diagnosis is crucial to improve the prognosis of patients with cystinosis. This report emphasizes the importance of recognizing the unique pathological feature of multinucleated podocytes as an essential clue to the diagnosis of cystinosis.


The sequential tissue distribution of duck Tembusu virus in adult ducks.
In 2010, a novel Tembusu virus (TMUV) that caused a severe decrease in the egg production of ducks was isolated in southeast China. Given the novelty of this duck pathogen, little information is available regarding its pathogenesis. Here, we systematically investigated the replication kinetics of TMUV PTD2010 in adult male and female ducks. We found that PTD2010 was detectable in most of the parenchymatous organs as well as the oviduct and intestinal tract from days 1 to 7 after inoculation. Viral titers were maintained at high levels for at least 9 days in the spleen, kidney, bursa of Fabricius, brain, and ovary. No virus was detected in any of these organs or tissues at 18 days after inoculation. PTD2010, thus, causes systemic infections in male and female ducks; its replication kinetics show similar patterns in most organs, with the exception of the ovaries and testes.


Analysis of maxillary arch expansion in growing patients treated with early Class III protocol versus RME.
To evaluate and compare the maxillary arch expansion obtained in growing patients treated with Class III early treatment protocol (the modified SEC III protocol), or rapid maxillary expansion (RME). This retrospective observational study included patients in the mixed dentition with maxillary constriction and/ or dental crowding. The first group consisted of 30 patients (11 males and 19 females, mean age 9.4 ±1.7 years) with dentoskeletal Class III malocclusion treated with the modified SEC III protocol. The second group of 30 patients (14 males and 16 females, mean age 9.3 ±1.5 years) with Class I or II malocclusion was treated with a Hyrax-type expander applied to bands on the first upper molars. For each subject, initial (T0) and post expansion (T1) digital dental casts were collected. The intermolar and intercanine widths, the arch lengths at both cusp and gingival levels, the anteroposterior length and the palatal depth were measured at T0 and T1. At T1 there were statistically significant differences for 3-3 occlusal (OC) (P < 0.009), arch-length OC (P <0.030), anteroposterior arch-length (AP) (P <0.003), Depth (P <0.030) and Ap (P <0.000). No statistically significant T0-T1 changes were found between the modified SEC III and Hyrax groups except for Depth (P <0.011) with a mean difference of 2.3 mm between the two groups. Both bonded and banded expanders, used in the modified SEC III protocol and RME treatment respectively, produced similar changes in the upper arch. The different initial dentoskeletal malocclusions of the two sample groups were not relevant to the post-expansion arch changes.


U3 sequences from HTLV-I and -II LTRs confer pX protein response to a murine leukemia virus LTR.
Human T-cell leukemia virus (HTLV) types I and II are unusual among replication-competent retroviruses in that they contain a fourth gene (chi) necessary for replication. The chi gene product, p chi, transcriptionally transactivates the viral long repeat (LTR), and is thus a positive regulator. To investigate p chi transactivation, sequences from the U3 regions of the LTRs of HTLV-I and -II were inserted into the Moloney murine leukemia virus (M-MuLV) LTR by recombinant DNA techniques. Transient expression assays of the chimeric LTRs indicated that the HTLV sequences conferred to the M-MuLV LTR responsiveness to HTLV p chi protein. M-MuLV enhancers were not required for function of the chimeric LTRs. Infectious recombinant M-MuLVs containing chimeric LTRs were also generated. These viruses showed higher infectivity when assayed in mouse cells expressing HTLV-II p chi protein compared to normal mouse cells. Thus the HTLV sequences were able to confer p chi responsiveness to infectious M-MuLV. The generation of a virus dependent on a transactivating protein for its replication has implications for the evolution of the human T-cell leukemia viruses.


Lessons learned from the investigational device exemption review of Children's Oncology Group trial AAML1031.
The U.S. Food and Drug Administration is now exerting its regulatory authority over the use of molecular diagnostics and related assays for medical decision making in clinical trials, by performing pre-Investigational Device Exemption reviews in all phases of clinical trials. In this review, we assess the analytical performance of the assay for the diagnostic, and consider how that performance affects the diagnostic and the patient and their risks and benefits from treatment. We also discuss the process involved in the first review of a new Children's Oncology Group phase III trial in acute myelogenous leukemia. The lessons learned and recommendations for how to prepare for and incorporate this new level of regulatory review into the protocol development process are presented.


Relationships and parenthood in couples after assisted reproduction and in spontaneous primiparous couples: a prospective long-term follow-up study.
The aim of this study was to analyse relationships and parenthood in primiparous IVF couples and spontaneous primiparous couples. In total, 110 consecutive IVF couples were studied. The control group was matched for women's age and selected out of the total spontaneous pregnant population in the study area. Questionnaires and semi-structured telephone interviews were used to gain information about sociodemographic data, couples' relationships, and the children's health, temperament and behaviour. Obstetrical variables concerning the course and outcome of pregnancy and delivery as well as the health status of the new-borns were obtained from standardized antenatal care and delivery files. There were no differences concerning gestational age, mode of delivery or neonatal health between the two groups. The IVF couples were more stable over time-from pregnancy until the child was 1 year old-in their relationship, while the control group experienced a decrease in marital satisfaction. The children in the IVF group were assessed by their parents as being more regular/habitual, sensitive and manageable than the control children. The differences present between the groups were in favour of the IVF families, and the effects of the infertility crisis were not notable when the children were 1 year old.