Factors Associated with Low Bone Density in Opioid Substitution Therapy Patients: A Systematic Review.
Background: Long-term opioid therapy is a risk factor for low bone mineral density (BMD). However, other factors may also contribute to low BMD. Several studies have examined the variables that might contribute to low BMD in patients receiving opioid replacement therapy (OST). However, to our knowledge, there was no systemic review conducted to address this particular issue. Thus, we reviewed the articles on the factors associated with low BMD in the population of opioid use disorder receiving substitution therapy. Methods: The articles that examined correlates or risk factors of low BMD in OST population were retrieved from OVID, SCOPUS, and PUBMED from inception until July 2020 by two independent investigators. Results: A total of 429 articles from three databases were retrieved initially. After screening based on eligibility criteria, five articles were included in the final analysis. The risk factors or correlates found to be significantly associated with low BMD in the OST population include male gender, low body mass index, low testosterone level, methadone or heroin use, and longer duration of heavy alcohol use. The review limitations include small sample sizes and inconsistent definition of variables. Conclusion: OST patients should be screened for BMD and its associated factors. Guidelines and training of practitioners involving in the OST service should be provided to increase the detection of low BMD in the OST population.


HER2 low expression breast cancer subtyping and their correlation with prognosis and immune landscape based on the histone modification related genes.
Human epidermal growth factor receptor 2 (HER2) plays an important role in diagnosis and treatment of breast cancer (BRCA). The histone modification has been found to be related to the progression of cancer. This study aimed to probe the low HER2 expression BRCA heterogeneity by histone modification genes. The BRCA data and cell lines were collected from The Cancer Genome Atlas database. Weighted gene co-expression network analysis and non-negative matrix factorization clustering were jointly applied to obtain BRCA clusters. The expression of hub histone modification gene was detected using western blot assay. The gene ontology term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed to reveal functional information. The overall survival analysis was performed using survival and survminer packages, and the immune landscape was mainly analyzed using CIBERSORT software. Totally 43 histone modification genes correlated with survival of BRCA patients with HER2 low expression were screened. Based on these 43 histone modification genes, the BRCA samples were classified into cluster1, cluster2 and cluster3. Histone modification gene NFKBIZ exhibited high expression, while RAD51 demonstrated low expression in low HER2 expression BRCA cell. Cluster1 exhibited the best prognosis, while cluster3 had the worse outcomes. Tumor mutational burden (TMB) was remarkably increased in cluster3 group compared to cluster1 and cluster2. Moreover, the relative proportion of 16 immune cell infiltration and 8 immune checkpoint expression were remarkably differential among cluster1, cluster2 and cluster3, and the drug sensitivity exhibited difference among cluster1, cluster2 and cluster3 in BRCA patients with low HER2 expression. This study identified three HER2 low expression BRCA clusters with different characteristics based on histone modification genes. The TMB, immune cell infiltration, immune checkpoints and drug sensitivity were different among the three clusters.


VH and VL Domains of Polyspecific IgM and Monospecific IgG Antibodies Contribute Differentially to Antigen Recognition and Virus Neutralization Functions.
We analysed contributions of variable heavy (FdVH ) and variable light (FdVL ) domains in comparison to scFv (FdVH +FdVL ) of naturally occurring polyspecific bovine IgM with an exceptionally long CDR3H and an induced monospecific bovine herpes virus-1 (BoHV-1) neutralizing IgG1 antibody in the context of to antigen-binding site and antibody function. Various recombinant FdVH , FdVL and scFv were constructed and expressed in Pichia pastoris from the bovine IgM and IgG1 antibody encoding cDNA. The scFv1H12 showed polyspecific antigen binding similar to parent IgM antibody, though subtle differences, for example, higher thyroglobulin recognition. Such differences reflect influence of the constant region on the antigen-binding site configuration. Unlike, variable light domain FdVL 1H12, the variable heavy domain FdVH 1H12 alone recognized multiple antigens that differed from the recognition pattern of scFv1H12 (FdVH +FdVL ) and the parent IgM antibody. Nonetheless, role of FdVL 1H12 in providing structural support to FdVH in antigen recognition is noted, apart from its intrinsic antigen recognition ability. Surface plasmon resonance analysis revealed low to moderate affinity of scFv1H12 to IgG antigen. By contrast, the individual FdVH 073 and FdVL 074, originating from induced BoHV-1 neutralizing IgG1 antibody, recognized target epitope on BoHV-1 weakly when compared to FdVH +FdVL (scFv3-18L). Interestingly, both the FdVH and FdVL domains of induced IgG antibody are required to achieve BoHV-1 neutralization. To conclude, there exist subtle functional differences in the contribution of FdVH and FdVL to antigen-binding site generation of polyspecific IgM and monospecific IgG antibodies relevant to antigen recognition and virus neutralization functions.


Coarse-Grained Many-Body Potentials of Ligand-Stabilized Nanoparticles from Machine-Learned Mean Forces.
Colloidal nanoparticles self-assemble into a variety of superstructures with distinctive optical, structural, and electronic properties. These nanoparticles are usually stabilized by a capping layer of organic ligands to prevent aggregation in the solvent. When the ligands are sufficiently long compared to the dimensions of the nanocrystal cores, the effective coarse-grained forces between pairs of nanoparticles are largely affected by the presence of neighboring particles. In order to efficiently investigate the self-assembly behavior of these complex colloidal systems, we propose a machine-learning approach to construct effective coarse-grained many-body interaction potentials. The multiscale methodology presented in this work constitutes a general bottom-up coarse-graining strategy where the coarse-grained forces acting on coarse-grained sites are extracted from measuring the vectorial mean forces on these sites in reference fine-grained simulations. These effective coarse-grained forces, i.e., gradients of the potential of mean force or of the free-energy surface, are represented by a simple linear model in terms of gradients of structural descriptors, which are scalar functions that are rotationally invariant. In this way, we also directly obtain the free-energy surface of the coarse-grained model as a function of all coarse-grained coordinates. We expect that this simple yet accurate coarse-graining framework for the many-body potential of mean force will enable the characterization, understanding, and prediction of the structure and phase behavior of relevant soft-matter systems by direct simulations. The key advantage of this method is its generality, which allows it to be applicable to a broad range of systems. To demonstrate the generality of our method, we also apply it to a colloid-polymer model system, where coarse-grained many-body interactions are pronounced.


The mechanism of calcium oxalate crystal-induced haemolysis of human erythrocytes.
Calcium oxalate (CaOx) crystals cause membrane damage in human erythrocytes, evident from K+ leakage and haemoglobin release. Whereas the hydrogen acceptor polyvinylpyridine-N-oxide is without effect on CaOx crystal-induced haemolysis, polyanions and negative proteins are strongly inhibitory. This indicates that positive charges are of importance for induction of haemolysis. These positive charges are located on the CaOx crystals. Removal of the negatively charged sialic acid from the cell surface does not affect CaOx crystal-induced haemolysis. CaOx crystals are able to release glucose from negatively charged liposomes, but not from positively charged liposomes. The results are compatible with the view that positive charges on the crystals are of predominant importance in CaOx-induced haemolysis, and that their interactions with negative charges or polarizable structures in the lipid part of the membrane leads to membrane disruption.


Association of the FCN2 Gene Promoter Region Polymorphisms with Very Low Birthweight in Preterm Neonates.
Single nucleotide polymorphisms (SNPs) localised to the promoter region of the FCN2 gene are known to influence the concentration of ficolin-2 in human serum and therefore potentially have clinical associations. We investigated the relationships between SNPs at positions −986 (A > G), −602 (G > A), −64 (A > C) and −4 (A > G) and clinical complications in 501 preterms. Major alleles at positions −986 and −64 and A/A homozygosity for both polymorphisms were less frequent among babies with very low birthweight (VLBW, ≤1500 g) compared with the reference group (OR = 0.24, p = 0.0029; and OR = 0.49, p = 0.024, respectively for A/A genotypes). A lower frequency of G/G homozygosity at position −4 was associated with gestational age <33 weeks and VLBW (OR = 0.38, p = 0.047; and OR = 0.07, p = 0.0034, respectively). The AGAG haplotype was protective for VLBW (OR = 0.6, p = 0.0369), whilst the GGCA haplotype had the opposite effect (OR = 2.95, p = 0.0249). The latter association was independent of gestational age. The AGAG/GGAA diplotype favoured both shorter gestational age and VLBW (OR = 1.82, p = 0.0234 and OR = 1.95, p = 0.0434, respectively). In contrast, AGAG homozygosity was protective for lower body mass (OR = 0.09, p = 0.0155). Our data demonstrate that some FCN2 variants associated with relatively low ficolin-2 increase the risk of VLBW and suggest that ficolin-2 is an important factor for fetal development/intrauterine growth.


The DNA polymerase beta reaction with ultraviolet-irradiated DNA incised by correndonuclease.
Covalently closed circular Col E1 DNA was ultraviolet-irradiated with a dose of 60 J/m2, thus introducing about 3.2 pyrimidine dimers per DNA molecule. Treatment of irradiated Col E1 DNA with Micrococcus luteus correndonuclease resulted, in the vicinity of pyrimidine dimers, in an average of 3.3 incisions per DNA molecule, and converted DNA to the open circular form. Incised Col E1 DNA stimulated no reaction with calf thymus DNA polymerase alpha but was recognized as a template by DNA polymerase beta. The latter enzyme incorporated about 1.6 molecules of dTMP (corresponding to 6 molecules od dNMP) per one correndonuclease incision. The length of the DNA polymerase beta product was comparable to the anticipated length of the DNA region within which the hydrogen bonds were disrupted owing to dimer formation. The enzyme required Mg(2)=nd four dNTPs for reaction and was resistant to N-ethylmaleimide or p-mercuribenzoate. The average numbers of deoxynucleotides incorporated per one DNAase I incision or per one nonspecific break, measured in control samples, were equal, amounting to 0.3 dTMP molecule. This value corresponded to 1.2 dNMP molecule; in our opinion, this reflects contaminating nuclease activity of the system used. The present results testify to the ability of DNA polymerase beta to repair synthesis by the "patch and cut' mechanism.


Behavioral Interventions in Mild Cognitive Impairment (MCI): Lessons from a Multicomponent Program.
Comparative effectiveness of behavioral interventions to mitigate the impacts of degeneration-based cognitive decline is not well understood. To better address this gap, we summarize the studies from the Healthy Action to Benefit Independence & Thinking (HABIT®) program, developed for persons with mild cognitive impairment (pwMCI) and their partners. HABIT® includes memory compensation training, computerized cognitive training (CCT), yoga, patient and partner support groups, and wellness education. Studies cited include (i) a survey of clinical program completers to establish outcome priorities; (ii) a five-arm, multi-site cluster randomized, comparative effectiveness trial; (iii) and a three-arm ancillary study. PwMCI quality of life (QoL) was considered a high-priority outcome. Across datasets, findings suggest that quality of life was most affected in groups where wellness education was included and CCT withheld. Wellness education also had greater impact on mood than CCT. Yoga had a greater impact on memory-dependent functional status than support groups. Yoga was associated with better functional status and improved caregiver burden relative to wellness education. CCT had the greatest impact on cognition compared to yoga. Taken together, comparisons of groups of program components suggest that knowledge-based interventions like wellness education benefit patient well-being (e.g., QoL and mood). Skill-based interventions like yoga and memory compensation training aid the maintenance of functional status. Notably, better adherence produced better outcomes. Future personalized intervention approaches for pwMCI may include different combinations of behavioral strategies selected to optimize outcomes prioritized by patient values and preferences.


An outbreak of pneumonia and meningitis caused by a previously undescribed gram-negative bacterium in a hot spring spa.
An outbreak of infection caused by a previously undescribed Gram-negative bacterium affected people attending a hot (37 degrees C) spring spa in France in 1987. Thirty-five case of pneumonia and two cases of meningitis occurred. None of these patients died. Attack rates were significantly higher for patients above 70 years old and for male patients. An epidemiological comparison of the 26 hospitalized cases with 52 matched controls suggests that spa treatment early on the first day (OR = 4.8) and attendance at the vapour baths (OR = 10.7) were significant risk factors for acquiring the infection. Person-to-person spread was not thought to have occurred. The same bacterium was isolated from the hot spring water. All strains studied shows a single rRNA gene restriction pattern. Epidemiological data indicated that the thermal water was the source of infection. This outbreak stresses the need for increased surveillance of infections in people attending hot spring spas.


[Present and future of cell therapy in burns].
Severe burned patients need definitive and efficient wound coverage. Outcome of massive burns has been improved by using cultured epithelial autografts (CEA). Despite fragility, percentages of success take, cost of treatment and long-term tendency to contracture, this surgical technique has been developed in few burn centres. First improvements were to combine CEA and dermis-like substitute. Cultured skin substitutes provide earlier skin closure and satisfying functional result. These methods have been used successfully in massive burns. Second improvement was to allow skin regeneration by using epidermal stem cells. Stem cells have capacity to differentiate into keratinocytes, to promote wound repair and to regenerate skin appendages. Human mesenchymal stem cells contribute to wound healing and were evaluated in cutaneous radiation syndrome. Skin regeneration and tissue engineering methods remain a complex challenge and offer the possibility of new treatment for injured and burned patients.


Novel Viruses That Lyse Plant and Human Strains of Kosakonia cowanii.
Kosakonia cowanii (syn. Enterobacter cowanii) is a highly competitive bacterium that lives with plant, insect, fish, bird, and human organisms. It is pathogenic on some plants and an opportunistic pathogen of human. Nine novel viruses that lyse plant pathogenic strains and/or human strains of K. cowanii were isolated, sequenced, and characterized. Kc166A is a novel kayfunavirus, Kc261 is a novel bonnellvirus, and Kc318 is a new cronosvirus (all Autographiviridae). Kc237 is a new sortsnevirus, but Kc166B and Kc283 are members of new genera within Podoviridae. Kc304 is a new winklervirus, and Kc263 and Kc305 are new myoviruses. The viruses differ in host specificity, plaque phenotype, and lysis kinetics. Some of them should be suitable also as pathogen control agents.


Analysis and management of gene and allelic diversity in subdivided populations using the software program METAPOP.
METAPOP (http://webs.uvigo.es/anpefi/metapop/) is a desktop application that provides an analysis of gene and allelic diversity in subdivided populations from molecular genotype or coancestry data as well as a tool for the management of genetic diversity in conservation programs. A partition of gene and allelic diversity is made within and between subpopulations, in order to assess the contribution of each subpopulation to global diversity for descriptive population genetics or conservation purposes. In the context of management of subdivided populations in in situ conservation programs, the software also determines the optimal contributions (i.e., number of offspring) of each individual, the number of migrants, and the particular subpopulations involved in the exchange of individuals in order to maintain the largest level of gene diversity in the whole population with a desired control in the rate of inbreeding. The partition of gene and allelic diversity within and between subpopulations is illustrated with microsatellite and SNP data from human populations.


Predicting self-harm in an ethnically diverse sample of lesbian, gay and bisexual people in the United Kingdom.
Poor mental health is prevalent in lesbian, gay and bisexual (LGB) people due in part to social stigma. The social, psychological and clinical risk factors for self-harm among LGB people are unclear, which limits our ability to predict when and how this will occur and, crucially, how to prevent it. Drawing on the cognitive-behavioral approach in clinical psychology, this study identifies the predictors of self-harm in LGB people in the United Kingdom. Women, lesbians, those with lower income and younger people were more likely to engage in self-harm. Self-harmers exhibited much more discrimination, LGB victimization and, thus, internalized homophobia and depressive symptomatology than non-self-harmers. The structural equation model showed direct effects of age and gender, and indirect effects of income and sexual orientation, on self-harm, through the mediating variables of discrimination, LGB victimization and internalized homophobia. Consistent with the cognitive-behavioral model, the results indicate that exposure to situational stressors can increase the risk of developing a self-hatred and depressive psychological self-schema, resulting in greater risk of self-harm as a maladaptive coping strategy. An integrative clinical intervention for enhancing psychological wellbeing in LGB people is proposed to mitigate the risk of self-harm in this population.


Inhibition of plasminogen activation by lipoprotein(a): critical domains in apolipoprotein(a) and mechanism of inhibition on fibrin and degraded fibrin surfaces.
Similarity between the apolipoprotein(a) (apo(a)) moiety of lipoprotein(a) (Lp(a)) and plasminogen suggests a potentially important link between atherosclerosis and thrombosis. Lp(a) may interfere with tissue plasminogen activator (tPA)-mediated plasminogen activation in fibrinolysis, thereby generating a hypercoagulable state in vivo. A fluorescence-based system was employed to study the effect of apo(a) on plasminogen activation in the presence of native fibrin and degraded fibrin cofactors and in the absence of positive feedback reactions catalyzed by plasmin. Human Lp(a) and a physiologically relevant, 17-kringle recombinant apo(a) species exhibited strong inhibition with both cofactors. A variant lacking the protease domain also exhibited strong inhibition, indicating that the apo(a)-plasminogen binding interaction mediated by the apo(a) protease domain does not ultimately inhibit plasminogen activation. A variant in which the strong lysine-binding site in kringle IV type 10 had been abolished exhibited substantially reduced inhibition whereas another lacking the kringle V domain showed no inhibition. Amino-terminal truncation mutants of apo(a) also revealed that additional sequences within kringle IV types 1-4 are required for maximal inhibition. To investigate the inhibition mechanism, the concentrations of plasminogen, cofactor, and a 12-kringle recombinant apo(a) species were systematically varied. Kinetics for both cofactors conformed to a single, equilibrium template model in which apo(a) can interact with all three fibrinolytic components and predicts the formation of ternary (cofactor, tPA, and plasminogen) and quaternary (cofactor, tPA, plasminogen, and apo(a)) catalytic complexes. The latter complex exhibits a reduced turnover number, thereby accounting for inhibition of plasminogen activation in the presence of apo(a)/Lp(a).


Coral-Eating Sea Stars Acanthaster planci in Hawaii.
An aggregation of 2 x 10(4) Acanthaster planci was observed from September 1969 to November 1970. The sea stars within the aggregation were very uniform in size, and their reproduction was seasonal. Their average diameter and weight also varied seasonally in a manner that suggests a correlation between average size and breeding condition. The aggregation remained compactly situated in a band a few to tens of meters wide and about 2 kilometers long, parallel to the shore. The band did not move appreciably during the observation period. The sea stars were feeding selectively on a coral which was a minor component of the total coral cover. The coral in the area was predominantly alive, and the proportion of dead coral did not increase appreciably during our period of observation.


Lateral hypothalamic stimulation gates nucleus gigantocellularis-induced aversion via a reward-independent process.
A monophasic pulse-pair stimulation technique was used behaviorally to infer neurophysiological interaction between 'reward' sites in the lateral hypothalamus (LH) and pain-implicated nucleus reticularis gigantocellularis (NGC). Rats lever-pressed for 3 s escapes from an otherwise continuous train of 0.1 ms NGC pulses delivered every 40 ms. When pulses to the LH were interdigitated with those to NGC, inter-response latencies were significantly longer. This occurred whether LH pulses were also interrupted by each lever-press (experiment 1) or not (experiment 2). Further, the same intensities of LH stimulation which inhibited escape supported high rates of lever-pressing for 3 s LH trains during inescapable NGC stimulation even though these LH trains were not of sufficient intensity to support 'rewarding' lever-pressing in the absence of NGC stimulation. This finding indicates that escape-inhibition in the first two experiments was not due to interfering motor effects of LH stimulation but most probably due to LH amelioration of NGC-induced aversion. Indeed, when aversion was ameliorated by morphine, lever-pressing for sub-reward-threshold LH stimulation during inescapable NGC stimulation decreased although classical self-stimulation did not. In the escape experiments, inhibition was greatest when each NGC pulse was preceded by an LH pulse at an interval of 0.1 or 10 ms. During inescapable NGC stimulation, rates of lever-pressing for LH trains were greatest when LH pulses preceded NGC pulses again at intervals of 0.1 or 10 ms. This congruence of the temporal bimodal profiles in the response functions of these two different behavioral experiments strongly suggests that the same integrative mechanism underlies both LH inhibition of NGC escape and lever-pressing for LH trains during inescapable stimulation of NGC. Since gastric loading did not alter lever-pressing for sub-reward-threshold LH trains during inescapable NGC stimulation but did inhibit classical self-stimulation, it was concluded that the inferred common integrative mechanism mediates a supraspinal gating of aversion which is independent of the LH self-stimulation reward process.


[Infection of the mollusc Littorina saxatilis with parthenites of trematodes and their impact on a shell form: analysis of populations inhabiting the littoral coast of the White Sea].
12 rocky shore populations of Littorina saxatilis from three islands of Chupa Inlet (Kandalaksha Bay, White Sea) were examined for infection with trematodes. Morphometric characters (6 indexes of the shell and aperture shape) of molluscs were investigated for all these populations. Exposed and sheltered sites were considered at every island and high and low littoral samples were fulfilled at every site. Seven species of trematodes, Podocotyle atomon, Cryptocotyle lingua, Renicola sp., Himasthla sp., Microphallus piriformes, M. pygmaeus, M. pseudopygmaeus, were found. Uneven distribution of trematodes was confirmed by log-linear analysis. Sheltered populations of L. saxatilis have the greater infection prevalence than exposed ones. This is due to the heavy infection with M. piriformes and M. pygmaeus. The prevalences by these trematodes are up to 52.97% and 27.16% respectively in sheltered populations of the host. The prevalence of M. piriformes tend to be higher at the upper shore level of sheltered sites. In a contrast, the prevalence of M. pygmaeus is significantly higher at the low part of such sites. Factor analysis shows a significant association of the indices of L. saxatilis shell shape with three factors. The first one is associated with the "elongation" of a shell and reveals L. saxatilis from the exposed rocky shore to be more elongated than the molluscs from sheltered sites. The second one is connected with the "aperture shape" index. There is an association of this factor with the shore level position of samples. The third factor reflects the affect of trematodes on the shell shape. The molluscs infected with M. piriformes show "elongated" shell shape and relatively smaller aperture. Shall peculiarities of the hosts infected with M. piriformes and M. pygmaeus are somewhat different. The results of the factor analysis is justified by the series of analysis of variances on the values of shell indices (MANOVA) according to the factors "exposure", "shore level" and "infection".


Expression analysis of Arabidopsis thaliana small secreted protein genes.
Small proteins secreted to the extracellular matrix in plants regulate many physiological activities, including pathogen response, material transport, and morphogenesis, but the functions of most small secreted proteins have not been elucidated except for some well-known small secreted proteins. To predict the functions and physiological roles of unidentified small secreted proteins, information on their expression patterns is valuable. Here, we report expression analysis of Arabidopsis thaliana small secreted protein (ATSP) genes that encode proteins possessing a signal peptide at N-terminal, and protein sizes were less than 100 amino acid residues. By promoter:reporter experiments, we examined the expression of 122 ATSPs, including 47 unannotated ATSPs that do not have any discernable motifs, in tissues and at the cellular level in Arabidopsis seedlings, and floral organs. As a result, 79 ATSP genes were expressed in various regions of the seedlings, and 37 ATSP genes were specifically expressed.


[The developmental characteristics of the larvae of malarial mosquitoes in salt water].
In terms of water salinity, the following developmental ranges were established for the larvae of 5 mosquito species: 1.5% in Anopheles sacharovi, 1.0% in An. atroparvus, 1.8% in An. stephensi, 1.2% in An. superpictus, and 1.0% in An. pulcherrimus. Salinity was demonstrated to affect the survival of larvae to the greatest extent and the duration of their development and weight to a much lesser one.


Structural basis for the restoration of TCR recognition of an MHC allelic variant by peptide secondary anchor substitution.
Major histocompatibility complex (MHC) class I variants H-2K(b) and H-2K(bm8) differ primarily in the B pocket of the peptide-binding groove, which serves to sequester the P2 secondary anchor residue. This polymorphism determines resistance to lethal herpes simplex virus (HSV-1) infection by modulating T cell responses to the immunodominant glycoprotein B(498-505) epitope, HSV8. We studied the molecular basis of these effects and confirmed that T cell receptors raised against K(b)-HSV8 cannot recognize H-2K(bm8)-HSV8. However, substitution of Ser(P2) to Glu(P2) (peptide H2E) reversed T cell receptor (TCR) recognition; H-2K(bm8)-H2E was recognized whereas H-2K(b)-H2E was not. Insight into the structural basis of this discrimination was obtained by determining the crystal structures of all four MHC class I molecules in complex with bound peptide (pMHCs). Surprisingly, we find no concerted pMHC surface differences that can explain the differential TCR recognition. However, a correlation is apparent between the recognition data and the underlying peptide-binding groove chemistry of the B pocket, revealing that secondary anchor residues can profoundly affect TCR engagement through mechanisms distinct from the alteration of the resting state conformation of the pMHC surface.


Contribution of the two genes encoding histone variant h3.3 to viability and fertility in mice.
Histones package DNA and regulate epigenetic states. For the latter, probably the most important histone is H3. Mammals have three near-identical H3 isoforms: canonical H3.1 and H3.2, and the replication-independent variant H3.3. This variant can accumulate in slowly dividing somatic cells, replacing canonical H3. Some replication-independent histones, through their ability to incorporate outside S-phase, are functionally important in the very slowly dividing mammalian germ line. Much remains to be learned of H3.3 functions in germ cell development. Histone H3.3 presents a unique genetic paradigm in that two conventional intron-containing genes encode the identical protein. Here, we present a comprehensive analysis of the developmental effects of null mutations in each of these genes. H3f3a mutants were viable to adulthood. Females were fertile, while males were subfertile with dysmorphic spermatozoa. H3f3b mutants were growth-deficient, dying at birth. H3f3b heterozygotes were also growth-deficient, with males being sterile because of arrest of round spermatids. This sterility was not accompanied by abnormalities in sex chromosome inactivation in meiosis I. Conditional ablation of H3f3b at the beginning of folliculogenesis resulted in zygote cleavage failure, establishing H3f3b as a maternal-effect gene, and revealing a requirement for H3.3 in the first mitosis. Simultaneous ablation of H3f3a and H3f3b in folliculogenesis resulted in early primary oocyte death, demonstrating a crucial role for H3.3 in oogenesis. These findings reveal a heavy reliance on H3.3 for growth, gametogenesis, and fertilization, identifying developmental processes that are particularly susceptible to H3.3 deficiency. They also reveal partial redundancy in function of H3f3a and H3f3b, with the latter gene being generally the most important.


[Efficacy and safety of mildronate in emergency medical care].
Detailed clinical data about patients who used emergency services during 2011 are presented. The main attention is focused on the state of patients with acute and chronic brain ischemia before and after treatment with mildronate. Mean age of patients with ischemic stroke and chronic brain ischemia was 63.4 and 57.7 years, respectively. Mildronate was injected slowly intravenously in one dose 1000 mg (10 ml of 10% solution). The results obtained in the study allow to recommend mildronate for such patients and provide the useful information to physicians and medical attendants about current methods of diagnosis and treatment of patients with acute and chronic brain ischemia in out- and inpatient health services.


Use of Articaine in loco-regional anesthesia for day care surgical procedures.
The popularity of day case surgical procedures has increased immensely over the last few years. Though various techniques are available for carrying out day-case anesthesia, preference for a technique depends upon the type of procedure, patient profile, associated co-morbidities, available infrastructure and back-up facilities, monitoring devices and comfort of the attending anesthesiologist with the technique. Day-case spinal anesthesia for ambulatory surgery has gained a wider acceptance and numerous drugs are available for use in loco-regional anesthesia. Articaine is one such amide local anesthetic drug which is increasingly being used in day care surgeries. Properties of articaine such as faster onset, shorter elimination time and rapid recovery from sensory and motor blockade make it a very useful agent in local and regional anesthesia for day care surgical procedures. This article aims to review these properties of articaine so as to evaluate how useful articaine can be for ambulatory surgical procedures.


Ultraviolet radiation and skin cancer risk in offshore workers.
Excess skin cancer mortality and incidence have been reported among both land-based and offshore petroleum workers. The association between skin cancer and ultraviolet radiation (UVR) exposure has not been examined in these workers, although they have long off-duty periods and high average income that may allow travelling to sunny destinations. In addition, they have access to solariums free of charge on many accommodation platforms. To prospectively examine risk of incident cutaneous melanoma (CM) and non-melanoma skin cancer (NMSC), according to sun-tanning habits with adjustment for aromatic hydrocarbon exposure. A cohort of men employed offshore from 1965 to 1999 was linked through the Cancer Registry of Norway 1999-2012. Cox regression adapted to a stratified case-cohort design was used to estimate hazard ratios with 95% confidence intervals. The cohort included 24917 men. During 13.5 years of follow-up, 112 CMs and 70 NMSCs occurred. A positive dose-response relationship was seen between sunburn frequency and risk of CM (Ptrend < 0.05) and NMSC (Ptrend < 0.01). Solarium use both before and after age 20 was related to increased risk of NMSC. Sunscreen use was associated with increased risk of NMSC (Ptrend < 0.001). UVR exposure seems to be a significant contributor to the elevated risk of skin cancer observed in North Sea offshore workers. The positive association between solarium use and NMSC risk adds to the growing body of literature on artificial UV devices as carcinogenic.


Human wild-type alpha-synuclein impairs neurogenesis.
Neurodegenerative diseases classified as synucleinopathies are characterized by alpha-synuclein inclusions. In these disorders, alpha-synuclein accumulates within glial or neuronal cells in the brain including regions of adult neurogenesis. We hypothesized a pathophysiological role for alpha-synuclein in newly generated cells of the adult brain and in this study examined regions of neurogenesis in adult mice overexpressing human wild-type alpha-synuclein under the control of the platelet-derived growth factor promoter. The number of proliferating cells and the fate of newly generated cells were analyzed in the olfactory bulb system and in the hippocampal dentate gyrus. There were no effects on proliferation detectable; however, significantly less neurogenesis and fewer neurons were observed in the olfactory bulb as well as in the hippocampus of adult human alpha-synuclein mice compared to control littermates. This effect was almost exclusively due to diminished survival of neuronal precursors in the target regions of neurogenesis. Our data imply that the finely tuned equilibrium of neuronal cell birth and death in neurogenic regions may be altered in human alpha-synuclein-overexpressing mice. We hypothesize that reduced adult neurogenesis in the olfactory bulb may contribute to olfactory deficits in neurodegenerative disorders associated with alpha-synuclein inclusions.


Adaptations of the Marsupial Newborn: Birth as an Extreme Environment.
At birth a mammalian neonate enters an extreme environment compared to the intrauterine environment in which it has grown. This transition may be particularly extreme in marsupials because they are born at an exceedingly altricial state, after an exceptionally short gestation. Their stage of development must be considered embryonic by almost any criteria. Yet at this very early stage of development marsupials must travel to the teat, attach and suckle, and have basic functioning of all major physiological systems. In this article, we review the adaptations of the marsupial neonate for survival at an embryonic state, showing that the neonate exhibits a mosaic of accelerations and delays of various tissues and organs as well as several special adaptations to produce the functioning newborn. We then discuss the development of the craniofacial region, the body axis and limbs in order to detail some of the major changes to development leading to this uniquely configured neonate. We show that marsupial development arises out of a variety of heterochronies (changes in relative timing of events) and heterotopies (changes in location of specific developmental events) at the genetic, cellular and organ level. We argue that these data support hypotheses that many of the specific patterns seen in marsupial development arise from the basic constraint of embryonic energetic and tissue resources. Finally ideas on the evolutionary context of the marsupial developmental strategy are briefly reviewed. Anat Rec, 2019. © 2018 Wiley Periodicals, Inc. Anat Rec, 303:235-249, 2020. © 2018 American Association for Anatomy.


A method of introducing lipid-conjugated antigens into the surface of schistosomula.
Introduction of synthetic antigens into the surface of schistosomula of Schistosoma mansoni was achieved by brief incubation of the worms with liposomes carrying the lipid-bound antigens in their bilayers. Three-hour-old schistosomula were surface-labeled with lipid-conjugated dinitrophenyl (DNP) groups by using liposomes made of egg lecithin-N-dinitrophenil-epsilon-aminocaproyl-phosphatidylethanolamine (5:1). The DNP groups incorporated in this way could be detected for more than 21 hours in vitro by using rabbit anti-DNP antibodies stained with fluorescein isothiocyanate-conjugated goat anti-rabbit IgG. Immunofluorescence microscopy showed the lipid antigen to be uniformly distributed over the entire surface of the worms. Electron microscope studies, performed with purified rabbit anti-DNP antibodies followed by ferritin-conjugated goat anti-rabbit IgG, showed that the DNP groups were evenly and densely distributed over the entire outer membrane of the schistosomula, including spines. The distance between the ferritin molecules and the parasite's surface was 24 +/- 5 nm, indicating that the lipid antigen had been incorporated into the outer membrane of the schistosomula.


[Acute fibrinous and organizing pneumonia].
The histologic pattern of Acute Fibrinous and Organizing Pneumonia (AFOP), described by Beasley in 2002, is characterized by the existence of intra alveolar fibrin in the form of fibrin "balls" and diffuse organizing pneumonia. Presenting symptoms of this interstitial pulmonary disease can be acute or subacute. However, it differs from the well -recognized histologic patterns of acute pulmonary lesion - Diffuse Alveolar Damage (DAD), Organizing Pneumonia (OP) and Eosinophilic Pneumonia (EP). The authors carry out a review of the literature concerning this topic and describe the clinical case of a 44 -year -old patient with unusual imaging features and outcome.


Characterization of transiently and constitutively expressed progesterone receptors: evidence for two functional states.
Activated steroid receptors induce chromatin remodeling events in the promoters of some target genes. We previously reported that transiently expressed progesterone receptor (PR) cannot activate mouse mammary tumor virus (MMTV) promoter when it adopts the form of ordered chromatin. However, when expressed continuously, the PR acquires this ability. In this study we explored whether this gain of function occurs through alterations in nucleoprotein structure at the MMTV promoter or through changes in receptor status. We observed no major structural differences at the MMTV promoter in the presence of constitutively expressed PR and found its mechanism of activation to be very similar to that of the glucocorticoid receptor (GR). However, a systematic comparison of the functional behavior of the transiently and constitutively expressed PR elucidated significant differences. The transiently expressed PR is activated in the absence of ligand by cAMP and by components in FBS and has significantly increased sensitivity to progestins. In contrast, the constitutively expressed PR is refractory to activation by cAMP and serum and has normal sensitivity to its ligand. In addition, while the PR is localized to the nucleus in both cases, a significant fraction of the transiently expressed PR is tightly bound to the nucleus even in the absence of ligand, while the majority of constitutively expressed PR is not. These results strongly suggest that the PR undergoes processing in the cell subsequent to its initial expression and that this processing is important for various aspects of its function, including its ability to productively interact with target genes that require chromatin remodeling for activation.


Acute kidney injury after cardiac surgery.
Patients undergoing cardiac surgery are at high risk to develop cardiac surgery-associated acute kidney injury (CS-AKI) postoperatively. CS-AKI is associated with an increased risk for persistent renal dysfunction, morbidity and mortality. This review summarizes the epidemiology and pathophysiology of CS-AKI, as well as current treatment and prevention strategies. As AKI is a syndrome with complex pathophysiology, no causative treatment strategies exist. Recent advances in the field of AKI biomarkers offer new perspectives on the issue and the implementation of biomarker-guided preventive strategies may reduce rates of CS-AKI. Finally, nephroprotective treatments and angiotensin II as a novel vasopressor may offer new opportunities for high-risk patients undergoing cardiac surgery. Based on the described novel approaches for early detection, prevention and management of CS-AKI, a precision-medicine approach should be implemented in order to prevent the development of AKI in patients undergoing cardiac surgery.


Inactivation of human thrombin in the presence of human alpha1-proteinase inhibitor.
Both the clotting and esterase activities of thrombin are inhibited by alpha1-proteinase inhibitor (alpha1-antitrypsin). The inhibition is a time-and temperature-dependent reaction which is proportional to the molar ratio of thrombin to inhibitor. Both the active-site serine residue of thrombin and the reactive-site lysine residue of alpha1-proteinase inhibitor are involved. alpha1-Proteinase inhibitor forms a 1:1 complex with thrombin that is comparable with the complex formed with trypsin and other proteinases. Incubation of the inhibitor with excess of thrombin, however, results in inactivation of nearly all the enzyme, even though only as much complex is formed as alpha1-proteinase inhibitor present. A portion of the remaining thrombin apparently aggregates. These results suggest that the mechanism for inhibition of thrombin may not be exactly the same as for trypsin, which is inhibited only to the extent to which complex is formed.


Identification of mitochondrial carriers in Saccharomyces cerevisiae by transport assay of reconstituted recombinant proteins.
The inner membranes of mitochondria contain a family of carrier proteins that are responsible for the transport in and out of the mitochondrial matrix of substrates, products, co-factors and biosynthetic precursors that are essential for the function and activities of the organelle. This family of proteins is characterized by containing three tandem homologous sequence repeats of approximately 100 amino acids, each folded into two transmembrane alpha-helices linked by an extensive polar loop. Each repeat contains a characteristic conserved sequence. These features have been used to determine the extent of the family in genome sequences. The genome of Saccharomyces cerevisiae contains 34 members of the family. The identity of five of them was known before the determination of the genome sequence, but the functions of the remaining family members were not. This review describes how the functions of 15 of these previously unknown transport proteins have been determined by a strategy that consists of expressing the genes in Escherichia coli or Saccharomyces cerevisiae, reconstituting the gene products into liposomes and establishing their functions by transport assay. Genetic and biochemical evidence as well as phylogenetic considerations have guided the choice of substrates that were tested in the transport assays. The physiological roles of these carriers have been verified by genetic experiments. Various pieces of evidence point to the functions of six additional members of the family, but these proposals await confirmation by transport assay. The sequences of many of the newly identified yeast carriers have been used to characterize orthologs in other species, and in man five diseases are presently known to be caused by defects in specific mitochondrial carrier genes. The roles of eight yeast mitochondrial carriers remain to be established.


IBUPROFEN-INDUCED ASEPTIC MENINGITIS: A CASE REPORT.
To report a case of a male adolescent with the diagnosis of ibuprofen-induced meningitis. We discuss themain causes of drug-induced aseptic meningitis (DIAM) and highlight the importance of early recognition of DIAM, sothat the offending drug can be withdrawn, and recurrences prevented. Only few DIAM cases have been reported in pediatric age. A healthy 15-year-old boy presented to the emergency department with headache, nausea, dizziness, fever, conjunctival hyperemia and blurred vision 30 minutes after ibuprofen-intake. During his stay, he developed emesis and neck stiffness. Cerebrospinal fluid analysis excluded infectious causes, and DIAM was considered. He totally recovered after drug withdrawal. DIAM is a rare entity, that should be considered in the differential diagnosis of an aseptic meningitis. The major causative agents are nonsteroidal anti-inflammatory drugs, particularly ibuprofen. Suspicion is made by the chronologic link between drug intake and the beginning of symptoms, but infectious causes should always be ruled out.


Application of cell-derived exosomes in the hematological malignancies therapy.
Exosomes are small membrane vesicles of endocytic origin that are produced by both tumor and normal cells and can be found in physiological fluids like plasma and cell culture supernatants. They include cytokines, growth factors, proteins, lipids, RNAs, and metabolites and are important intercellular communication controllers in several disorders. According to a vast amount of research, exosomes could support or inhibit tumor start and diffusion in a variety of solid and hematological malignancies by paracrine signaling. Exosomes are crucial therapeutic agents for a variety of illnesses, such as cancer and autoimmune diseases. This review discusses the most current and encouraging findings from in vitro and experimental in vivo research, as well as the scant number of ongoing clinical trials, with a focus on the impact of exosomes in the treatment of malignancies. Exosomes have great promise as carriers of medications, antagonists, genes, and other therapeutic materials that can be incorporated into their core in a variety of ways. Exosomes can also alter the metabolism of cancer cells, alter the activity of immunologic effectors, and alter non-coding RNAs, all of which can alter the tumor microenvironment and turn it from a pro-tumor to an anti-tumor milieu. This subject is covered in the current review, which also looks at how exosomes contribute to the onset and progression of hematological malignancies, as well as their importance in diagnosing and treating these conditions.


In-vitro activity of ofloxacin, levofloxacin and D-ofloxacin against staphylococci.
The in-vitro activity of levofloxacin was compared with ofloxacin and D-ofloxacin against 130 isolates of Staphylococcus aureaus and 117 isolates of coagulase-negative staphylococci, using the agar dilution method. In general, levofloxacin was equally active or up to fourfold more active than ofloxacin against all staphylococci, including 61 methicillin-resistant S. aureus. In contrast, D-ofloxacin showed little activity against all isolates tested.


[An evaluation of health learning during a visit to the Museum of Life].
Museums offer visitors both play and interactive activities that allow for learning. Yet it is challenging to understand learning in this context. How does it actually influence the learning process? This article stems from research on how a visit to a science museum may contribute to shaping the health concepts held by young people. The results identify the context of the museum as an environment favorable to meaningful learning and how meanings are grasped from the content explored during activities. Another important aspect of learning for these young people was the exploration of topics like the history of health, the relation between health and environment, science as a human product, and the role of the scientist within society.


A Step toward Healthy Newborn: An Assessment of 2 Years' Admission Pattern and Treatment Outcomes of Neonates Admitted in Special Newborn Care Units of Gujarat.
Facility Based Newborn Care (FBNC) is a key strategy to improve child survival, especially in newborn care where neonatal mortality rate (NMR) is stagnant in declining. Gujarat has achieved considerable amount of reduction in child deaths, but neonatal health requires attention. The study was aimed to assess the admission pattern of Special Newborn Care Units (SNCUs) which supports decision-making. A cross-sectional descriptive analysis was done from secondary data of the SNCU reports on the aspects of admission patterns, morbidity, and mortality pattern. The reports had been analyzed on various critical variables. In 2015-2016, Gujarat has operationalized forty SNCUs by saturating each district with at least one SNCU. The study found near proportions of (53%) inborn - (47%) outborn admission and 44% admission of female. Out of 69,662 admissions, 67% were discharged, 16% died, 10% leaving against medical advice, and 7% referred to higher centers. Major reasons for admission were respiratory distress syndrome (RDS) (22%) and infection (21%). Similar pattern in mortality found as final diagnosis of deaths was RDS (23%) and infection (21%). The proportion of neonatal deaths in outborn was high compared to inborn. Strengthening of FBNC is essential to address neonatal mortality. NMR is of prime focus because the health interventions needed to tackle NMR differ from those needed for infant mortality rate and under-five mortality rate. This accentuates the need for focused attention on facility- and community-based child health interventions along with quality maternal health services and robust referral mechanisms to all delivery points.


Skin protection in the healthcare setting.
Professions of the healthcare setting are at high risk for occupational skin diseases. Irritant and allergic contact dermatitis of the hands frequently occurs, whereas contact urticaria and hospital-acquired infections are less common. Wet work and irritant exposure are frequent due to hand hygiene which is indispensable with regard to prevention of crossinfections. In the healthcare setting, protection gloves are frequently used alternating with protection creams. Since the use of occlusive protection gloves has adversary effects on the skin barrier, use times have to be limited. Furthermore, a 3-step concept consisting of skin protection before work, cleaning and skin care after work is one of the generally recommended measures to prevent occupational contact dermatitis. Recently, educational programmes for skin protection as measure of primary, secondary and tertiary prevention of occupational skin diseases have been effectively introduced in the healthcare setting. The effectiveness of skin care programmes is based on 3 factors: the effectiveness of the products used, the frequency of the application and, finally, the effectiveness of the education (reduction of exposure to skin-damaging substances). For the identification of contact allergens in healthcare workers with hand dermatitis, supplementary work-specific series as well as substances used at work should be patch-tested in addition to the standard series.


Lower Levels of Education Are Associated with Cognitive Impairment in the Old Order Amish.
Lower education has been reported to be associated with dementia. However, many studies have been done in settings where 12 years of formal education is the standard. Formal schooling in the Old Order Amish communities (OOA) ends at 8th grade which, along with their genetic homogeneity, makes it an interesting population to study the effect of education on cognitive impairment. The objective of this study was to examine the association of education with cognitive function in individuals from the OOA. We hypothesized that small differences in educational attainment at lower levels of formal education were associated with risk for cognitive impairment. Data of 2,426 individuals from the OOA aged 54-99 were analyzed. The Modified Mini-Mental State Examination (3MS-R) was used to classify participants as CI or normal. Individuals were classified into three education categories: <8, 8, and >8 years of education. To measure the association of education with cognitive status, a logistic regression model was performed adding age and sex as covariates. Our results showed that individuals who attained lowest levels of education (<8 and 8) had a higher probability of becoming cognitvely impaired compared with people attending >8 years (OR = 2.96 and 1.85). Even within a setting of low levels of formal education, small differences in educational attainment can still be associated with the risk of cognitive impairment. Given the homogeneity of the OOA, these results are less likely to be biased by differences in socioeconomic backgrounds.


Time and temperature sensitivity of the Hybrid III neck.
The Hybrid III (HIII) dummy is one of the most widely used anthropomorphic test devices (ATDs) in the world, and researchers have found a variety of uses for it outside of its original purpose as an automotive crash test dummy. These expanded roles have introduced situations outside the dummy's original design parameters, where a number of tests must be run in relatively rapid succession or where it may not be possible to control the temperature of the test environment. This study has 2 aims. The first is to determine how the duration of the time interval between tests affects the axial compression performance of the HIII neck. The second is to quantify the effect of temperature on the neck's compressive stiffness through a range of temperatures relevant to indoor or outdoor testing. To characterize the effects of different test conditions, a series of high-rate axial compressive tests was run on a 50th percentile male HIII neck component in a materials testing machine. Between-test recovery intervals were varied from 2 h to 1 min, and temperature conditions of 0, 12.5, 25, and 37.5 °C were tested. Though the duration of the recovery interval had little impact on the recorded force (less than 1%), the component did exhibit considerable strain creep over the course of the test. Temperature had a strong influence on the compressive stiffness of the component. Compared to the stiffness at 25 °C (near room temperature), the stiffness of the neck at 37.5 °C fell by 15%; at 0 °C, the stiffness more than doubled. This study demonstrates that though the duration of the recovery interval between tests has a small influence on neck stiffness, temperature effects should not be overlooked because they influence neck compressive stiffness considerably. The relationship between recorded force and temperature is well represented by exponential decay models. These findings highlight the importance of monitoring and controlling for temperature effects during all HIII testing.


Colonoscopy: Advanced and Emerging Techniques-A Review of Colonoscopic Approaches to Colorectal Conditions.
A complete colonoscopy is key in the diagnostic and therapeutic approaches to a variety of colorectal diseases. Major challenges are incomplete polyp removal and missed polyps, particularly in the setting of a difficult colonoscopy. There are a variety of both well-established and newer techniques that have been developed to optimize polyp detection, perform complete polypectomy, and endoscopically treat various complications and conditions such as strictures and perforations. The objective of this article is to familiarize the colorectal surgeon with techniques utilized by advanced endoscopists.


Evidence-Based Assessment of Developmental Disorders.
Developmental disorders are diverse, common, and impairing; still, many clinicians lack comprehensive training in their assessment. This review presents thorough guidelines for the evaluation and diagnosis of common communication, sleeping, feeding, and elimination disorders that often onset in the early developmental period and that are commonly encountered in clinical practice. Thorough guidance on the evidence-based assessment of developmental disorders is critical, as they are prevalent, impairing, and commonly comorbid with other psychiatric disorders of childhood. This review is the first of its kind-providing critically needed, step-by-step guidance on the existing evidence-based methodologies and assessment tools available for diagnosis. This review also makes clear the dire need for further development and validation of relevant screening and diagnostic measure and calls for specific attention to the development of specific screening and diagnostic assessment measures for feeding disorders and elimination disorders in particular. Clinicians and researchers alike may find this article useful in guiding diagnostic, treatment, and research procedures.


Machine learning enhanced Hankel dynamic-mode decomposition.
While the acquisition of time series has become more straightforward, developing dynamical models from time series is still a challenging and evolving problem domain. Within the last several years, to address this problem, there has been a merging of machine learning tools with what is called the dynamic-mode decomposition (DMD). This general approach has been shown to be an especially promising avenue for accurate model development. Building on this prior body of work, we develop a deep learning DMD based method, which makes use of the fundamental insight of Takens' embedding theorem to build an adaptive learning scheme that better approximates higher dimensional and chaotic dynamics. We call this method the Deep Learning Hankel DMD. We likewise explore how our method learns mappings, which tend, after successful training, to significantly change the mutual information between dimensions in the dynamics. This appears to be a key feature in enhancing DMD overall, and it should help provide further insight into developing other deep learning methods for time series analysis and model generation.


Current concepts in the diagnosis and management of metabolic complications of HIV infection and its therapy.
Changes in fat distribution, dyslipidemia, disordered glucose metabolism, and lactic acidosis have emerged as significant challenges to the treatment of human immunodeficiency virus (HIV) infection. Over the past decade, numerous investigations have been conducted to better define these conditions, identify risk factors associated with their development, and test potential therapeutic interventions. The lack of standardized diagnostic criteria, as well as disparate study populations and research methods, have led to conflicting data regarding the diagnosis and treatment of metabolic and body shape disorders associated with HIV infection. On the basis of a review of the medical literature published and/or data presented before April 2006, we have prepared a guide to assist the clinician in the detection and management of these complications.


Understanding innovators' experiences of barriers and facilitators in implementation and diffusion of healthcare service innovations: a qualitative study.
Healthcare service innovations are considered to play a pivotal role in improving organisational efficiency and responding effectively to healthcare needs. Nevertheless, healthcare organisations encounter major difficulties in sustaining and diffusing innovations, especially those which concern the organisation and delivery of healthcare services. The purpose of the present study was to explore how healthcare innovators of process-based initiatives perceived and made sense of factors that either facilitated or obstructed the innovation implementation and diffusion. A qualitative study was designed. Fifteen primary and secondary healthcare organisations in the UK, which had received health service awards for successfully generating and implementing service innovations, were studied. In-depth, semi structured interviews were conducted with the organisational representatives who conceived and led the development process. The data were recorded, transcribed and thematically analysed. Four main themes were identified in the analysis of the data: the role of evidence, the function of inter-organisational partnerships, the influence of human-based resources, and the impact of contextual factors. "Hard" evidence operated as a proof of effectiveness, a means of dissemination and a pre-requisite for the initiation of innovation. Inter-organisational partnerships and people-based resources, such as champions, were considered an integral part of the process of developing, establishing and diffusing the innovations. Finally, contextual influences, both intra-organisational and extra-organisational were seen as critical in either impeding or facilitating innovators' efforts. A range of factors of different combinations and co-occurrence were pointed out by the innovators as they were reflecting on their experiences of implementing, stabilising and diffusing novel service initiatives. Even though the innovations studied were of various contents and originated from diverse organisational contexts, innovators' accounts converged to the significant role of the evidential base of success, the inter-personal and inter-organisational networks, and the inner and outer context. The innovators, operating themselves as important champions and being often willing to lead constructive efforts of implementation to different contexts, can contribute to the promulgation and spread of the novelties significantly.


Superior and basal segment lung cancers in the lower lobe have different lymph node metastatic pathways and prognosis.
Although the lower lobe is a large entity that occupies half of the hemithorax, all tumors located within the lower lobe have been treated uniformly regardless of tumor location. The aim of this study was to reveal differences in the metastatic pathway to the mediastinum and in prognosis of N2 disease between lung cancers originating from superior and basal segment of the lower lobe. Data on 139 patients who underwent pulmonary resection with systematic nodal dissection for pN2 non-small cell lung cancer (NSCLC) originating from the lower lobe between 1980 and 2001 were retrospectively reviewed. Those lower lobe N2 tumors were divided into two groups by origin: 51 were superior segment, and 88 were basal segment. The superior segment group showed a significantly higher incidence of superior mediastinal metastasis than the basal segment group (64% vs 36%, p = 0.0012). When superior mediastinal metastasis existed, the basal segment group showed a significantly higher incidence of synchronous subcarinal metastasis than the superior segment group (81% vs 39%, p = 0.0006). Pneumonectomy was required significantly more often in the superior segment group than in the basal segment group (45% vs 17%, p = 0.0003). The basal segment origin tumors with only subcarinal metastasis showed significantly better prognosis than other lower lobe N2 tumors (5-year survival, 43% vs 18%; p = 0.0155). Basal segment tumor metastasizes to the superior mediastinum mostly through the subcarinal node, whereas superior segment tumors often metastasize directly to the superior mediastinum without concomitant metastasis to the subcarinal node. Superior mediastinal dissection will be mandatory for accurate staging of superior segment tumors even when the subcarinal node is negative on frozen section. As for the prognosis among lower lobe N2 tumors, only in cases with basal segment tumor without superior mediastinal metastasis may long-term survival be expected.


Parvulin 14 and Parvulin 17 Bind to HBx and cccDNA and Upregulate Hepatitis B Virus Replication from cccDNA to Virion in an HBx-Dependent Manner.
The parvulin 14 (Par14) and parvulin 17 (Par17) proteins, which are both encoded by the PIN4 gene, play roles in protein folding, chromatin remodeling, DNA binding, ribosome biogenesis, and cell cycle progression. However, the effects of Par14 and Par17 on viral replication have never been explored. In this study, we found that, in the presence of HBx, either Par14 or Par17 could upregulate hepatitis B virus (HBV) replication, whereas in the absence of HBx, neither Par14 nor Par17 had any effect on replication. Overexpression of Par14/Par17 markedly increased the formation of covalently closed circular DNA (cccDNA), synthesis of HBV RNA and DNA, and virion secretion. Conversely, PIN4 knockdown significantly decreased HBV replication in HBV-transfected and -infected cells. Coimmunoprecipitation revealed that Par14/Par17 engaged in direct physical interactions with HBx in the cytoplasm, nucleus, and mitochondria, possibly mediated through substrate-binding residues on Par14/Par17 (E46/D74 and E71/D99, respectively) and conserved 19R20P-28R29P motifs on HBx. Furthermore, these interactions enhanced HBx stability, promoted HBx translocation to the nuclear and mitochondrial fractions, and increased HBV replication. Chromatin immunoprecipitation assays revealed that, in the presence of HBx, Par14/Par17 were efficiently recruited to cccDNA and promoted transcriptional activation via specific DNA-binding residues (S19/44). In contrast, in the absence of HBx, Par14/Par17 bound cccDNA only at the basal level and did not promote transcriptional activation. Taken together, our results demonstrate that Par14 and Par17 upregulate HBV RNA transcription and DNA synthesis, thereby increasing the HBV cccDNA level, through formation of the cccDNA-Par14/17-HBx complex.IMPORTANCE The HBx protein plays an essential regulatory role in HBV replication. We found that substrate-binding residues on the human parvulin peptidylprolyl cis/trans isomerase proteins Par14 and Par17 bound to conserved arginine-proline (RP) motifs on HBx in the cytoplasm, nucleus, and mitochondria. The HBx-Par14/Par17 interaction stabilized HBx; promoted its translocation to the nucleus and mitochondria; and stimulated multiple steps of HBV replication, including cccDNA formation, HBV RNA and DNA synthesis, and virion secretion. In addition, in the presence of HBx, the Par14 and Par17 proteins bound to cccDNA and promoted its transcriptional activation. Our results suggest that inhibition or knockdown of Par14 and Par17 may represent a novel therapeutic option against HBV infection.


The clinical and pathological significance of increased expression of the cannabinoid receptors CB-1R and CB-2R in patients with papillary thyroid carcinomas compared to benign thyroid lesions.
Papillary thyroid carcinoma is the most common malignancy of the endocrine system. Most papillary thyroid carcinoma patients enjoy excellent outcomes. However, in patients with biologically aggressive features, additional prognostic and predictive data may aid disease management. Dysregulation of the endocannabinoid system including the cannabinoid receptors 1 and 2 (CB-1R and CB-2R) during carcinogenesis has been extensively studied over the last few decades. The aim of this study was to evaluate immunohistochemically the expression levels of both receptors in patients with papillary thyroid carcinoma and benign diseases, and to compare these rates and the histopathologically and clinically prognostic features. The pathological materials and clinical data of 100 patients with papillary thyroid carcinoma and 40 with benign diseases were retrospectively re-evaluated. All tissues were immunohistochemically stained for CB-1R and CB-2R. The expression levels of CB-1R and CB-2R in papillary thyroid carcinomas, and benign lesions were recorded and compared with the pathological and clinical features. The expression levels of both receptors were significantly higher in papillary thyroid carcinoma patients than in those with benign conditions (P = 0.001). CB-1R expression correlated with both extrathyroidal extension (P = 0.022) and capsular invasion (P = 0.001). CB-2R expression was associated with the risk group of the American Thyroid Association stratification system (P = 0.004). Our study suggests that increased cannabinoid receptor expression contributes to thyroid carcinogenesis. The CB-2R expression level could provide additional information aiding risk management. Furthermore, the CB-1R and CB-2R antibodies might increase the accuracy of papillary thyroid carcinoma diagnosis when combined with the papillary thyroid carcinoma biomarkers assayed after fine-needle aspiration of neoplastic cells.


Prologue: 2013 Annual Meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA).
The 2013 Annual Meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) was held in July 2013 in Toronto, Canada, and attended by rheumatologists, dermatologists, and representatives of biopharmaceutical companies and patient groups. We introduce the articles that summarize the meeting: A summary of a GRAPPA-organized Fellows Symposium adjacent to the 2013 European Academy of Dermatology and Venereology meeting in Istanbul; at the GRAPPA meeting proper, proceedings of a trainee symposium, where rheumatology fellows and dermatology residents presented their research; a summary of experiences and perspectives of psoriasis and psoriatic arthritis (PsA) research of 8 patient research partners with PsA who were invited to participate as delegates. Other presentations and discussions included an interactive session on composite measures of disease severity and response, including voting by GRAPPA members; a 3 part update of basic/translational/clinical science, including new bone formation, enthesitis pathophysiology, and comorbidity monitoring; a 3 part dermatology update on psoriasis outcome measures, the Brigham Scalp Nail Inverse Palmoplantar Psoriasis Composite Index, and large-scale databases; a short summary of the ongoing GRAPPA effort to update treatment guidelines for PsA; updates on several GRAPPA educational and rheumatology-related projects; and a discussion of clinical criteria to identify inflammatory arthritis, enthesitis, dactylitis, and spondylitis as distinguished from non-inflammatory conditions.


Quality of life after the initial treatments of non-small cell lung cancer: a persistent predictor for patients' survival.
Health-related quality of life (HRQoL) before treatment may predict survival of patients with non-small-cell lung cancer (NSCLC). We investigated the predictive role of HRQoL after the initial treatments, on the survival of these patients. A prospective multi-center study conducted in northeastern France. The SF-36 and European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire Core-30 (QLQ C-30) were mailed to patients 3 months after the end of the diagnostic process. High scores for functioning dimensions on both questionnaires indicated better QoL, and low scores for symptom dimensions on the QLQ C-30 indicated few symptoms. Cox regression modeling was used to identify predictive factors of survival. In total, 230 (63.5%) patients responded to the SF-36 and QLQ C-30. Before completing the questionnaires, almost 60% of patients had undergone some chemotherapy, about 10% underwent radio/chemotherapy or both and more than 30% underwent surgery or surgery plus chemo/radiotherapy. On SF-36, the highest mean score was for social functioning dimension (55.5 ± 28), and the lowest was for the physical role dimension (17.9 ± 32.2). On QLQ C-30, for the functioning dimensions, the highest mean score was for cognitive functioning (74.6 ± 25.9) and the lowest was for role functioning (47.2 ± 34.1). For symptom dimensions, the lowest score was for diarrhoea (11.5 ± 24.2) and the highest was for fatigue (59.7 ± 27.7). On multivariate analysis, high bodily pain, social functioning and general health scores (SF-36) were associated with a lower risk of death (hazard ratio 0.580; 95% confidence interval [0.400-0.840], p = 0.004; HR 0.652 [0.455-0.935], p < 0.02; HR 0.625 [0.437-0.895] respectively). Better general QoL on QLQ C-30 was related to lower risk of death (HR 0.689 [0.501-0.946], p = 0.02). Adding to previous knowledge about factors that may influence patients QoL, this study shows a persisting relationship between better perceived health in HRQoL after the initial treatment of NSCLC and better survival.


Thiocolchicine-podophyllotoxin conjugates: dynamic libraries based on disulfide exchange reaction.
A dynamic combinatorial library of thiocolchicine-podophyllotoxin derivatives based on the disulfide bond exchange reaction is described. The influence of a biological target on the composition of the reaction mixture has been demonstrated. Use of high-resolution ESI mass spectrometry to evaluate the composition of the mixture shows promise for the design of new large libraries. The biological evaluation demonstrates that formation of a divalent compound affords a new chemical entity whose biological activity is not merely the sum of the single ligands activities, thus reflecting a different interaction with the biological target.


Antiepileptic drug treatment in pregnancy: changes in drug disposition and their clinical implications.
Pregnancy is a state where pharmacokinetic changes are more pronounced and more rapid than during any other period of life. The consequences of such changes can be far reaching, not least in the management of epilepsy where the risks with uncontrolled seizures during pregnancy need to be balanced against potential teratogenic effects of antiepileptic drugs (AEDs). This article aims to review the literature on gestational effects on the pharmacokinetics of older and newer generation AEDs and discuss the implications for the treatment of epilepsy in women during pregnancy. Pregnancy can affect the pharmacokinetics of AEDs at any level from absorption, distribution, metabolism, to elimination. The effect varies depending on the type of AED. The most pronounced decline in serum concentrations is seen for AEDs that are eliminated by glucuronidation (UGT), in particular lamotrigine where the effect may be profound. Serum concentrations of AEDs that are cleared mainly through the kidneys, for example, levetiracetam, can also decline significantly. Some AEDs, such as carbamazepine seem to be affected only marginally by pregnancy. Data on pharmacokinetics during pregnancy are lacking completely for some of the newer generation AEDs: pregabalin, lacosamide, retigabine, and eslicarbazepine acetate. Where data are available, the effects of pregnancy on serum concentrations seem to vary considerably individually and are thus difficult to predict. Although large-scale systematic studies of the clinical relevance of the pharmacokinetic alterations are lacking, prospective and retrospective case series have reported an association between declining serum concentrations and deterioration in seizures control. The usefulness of routine monitoring of AED serum concentrations in pregnancy and of dose adjustments based on falling levels, are discussed in this review. We suggest that monitoring could be important, in particular when women have been titrated to the lowest effective AED dose and serum concentration before pregnancy, and when that individual optimal concentration can be used as reference.


Treatment outcomes and risk factors for an unsuccessful outcome among patients with highly drug-resistant tuberculosis in Ukraine.
To describe demographics, clinical features, and treatment outcomes of patients with highly drug-resistant tuberculosis (TB) in Ukraine, and to evaluate risk factors for an unsuccessful outcome. Data from patients with multi-, pre-extensively, or extensively drug-resistant TB were collected prospectively from TB dispensaries in 15 out 24 Ukrainian oblasts (regions) from 2020 to 2021. Treatment outcomes were evaluated using WHO definitions. Risk factors for an unsuccessful outcome were identified using a multivariable logistic regression model. Among 1748 patients, the overall proportion of successful outcomes was 58% (95% confidence interval [95%CI] 56-60) (n=1015/1748), ranging from 65% (95%CI 62-69) (n=531/814) for multidrug-resistant TB to 54% (95%CI 49-58) (n=301/563) for pre-extensively drug-resistant TB and 49% (95%CI 44-55) (n=183/371) for extensively drug-resistant TB. Results were similar across oblasts, with few exceptions. The strongest risk factors for an unsuccessful outcome were extensively drug-resistant TB (adjusted OR [aOR] 3.23; 95%CI 1.88-5.53), total serum protein below 62 g/L in adults and below 57 g/L for children and adolescents (aOR 2.79; 95%CI 1.93-4.04), psychiatric illness (aOR 2.79; 95%CI 1.46, 5.33), age at TB diagnosis > 65 years (aOR 2.50; 95%CI 1.42-4.42), and alcohol misuse (aOR 2.48; 95%CI 1.89-3.26). The overall proportion of successful outcomes among Ukrainians treated for highly drug-resistant TB was 58%, notably better compared with previous years, but still low for extensively drug-resistant TB. Risk factors for unsuccessful outcomes highlight that addressing socioeconomic factors in TB management is crucial. Efforts in maintaining TB dispensaries during and following the ongoing war are highly warranted.


[Home health care in supplementary care: a device for a productive restructuring].
This study discusses the role the Brazilian Home Health Care Program (Programa de Atenção Domiciliar - PAD) plays in supplementary care using the example of a Group Care provider headquartered in Rio de Janeiro. The purpose of the study was to understand how home health care is produced by verifying the interaction between the medical team, beneficiaries and family members considering that the service in this care model is delivered in the micro-political scenery of the process, in the client's own home. The assessment of this program must consider: infrastructure and logistics, beneficiary eligibility criteria, the care-network formed in support of the PAD and above all the work process. Especially the latter is a strong indicator, in the present case characterized by an eminently multi-professional team operating in networks with integrated therapeutic projects. For the professionals, Home Health Care has the meaning of an innovative and highly valuable approach to care delivery. The article concludes considering the PAD an important device for a fruitful restructuring of supplementary care through different ways of care delivery.


Immunohistochemical measurement of estrogen receptors in breast cancer tissue samples.
A new estrogen receptor immunocytochemical assay (ER-ICA) which uses monoclonal antibodies to the estrogen receptor protein was applied to 97 breast cancer tissues. The results were correlated to those obtained by conventional dextran coated charcoal assays. The presence or absence of nuclear staining was significantly associated with positive or negative estrogen receptor status by dextran-coated charcoal (P less than 0.001). Furthermore ER-ICA results showed a high degree of correlation with a light microscopic grading. The relationship between ER-ICA results and response to endocrine therapies in patients with advanced disease was assessed in 20 patients. Six of 11 (55%) ER-ICA positive patients responded, whereas 8 of 9 (89%) ER-ICA negative patients failed.


A probabilistic latent semantic analysis model for coclustering the mouse brain atlas.
The mammalian brain contains cells of a large variety of types. The phenotypic properties of cells of different types are largely the results of distinct gene expression patterns. Therefore, it is of critical importance to characterize the gene expression patterns in the mammalian brain. The Allen Developing Mouse Brain Atlas provides spatiotemporal in situ hybridization gene expression data across multiple stages of mouse brain development. It provides a framework to explore spatiotemporal regulation of gene expression during development. We employ a graph approximation formulation to cocluster the genes and the brain voxels simultaneously for each time point. We show that this formulation can be expressed as a probabilistic latent semantic analysis (PLSA) model, thereby allowing us to use the expectation-maximization algorithm for PLSA to estimate the coclustering parameters. To provide a quantitative comparison with prior methods, we evaluate the coclustering method on a set of standard synthetic data sets. Results indicate that our method consistently outperforms prior methods. We apply our method to cocluster the Allen Developing Mouse Brain Atlas data. Results indicate that our clustering of voxels is more consistent with classical neuroanatomy than those of prior methods. Our analysis also yields sets of genes that are co-expressed in a subset of the brain voxels.


Persistent infection of mouse fibroblasts (L cells) with Chlamydia psittaci: evidence for a cryptic chlamydial form.
When monolayers of mouse fibroblasts (L cells) were infected with enough Chlamydia psittaci (strain 6BC) to destroy most of the host cells, 1 in every 10(5) to 10(6) originally infected cells gave rise to a colony of L cells persistently infected with strain 6BC. In these populations, the density of L cells and 6BC fluctuated periodically and reciprocally as periods of host cell increase were followed by periods of parasite multiplication. Successive cycles of L-cell and 6BC reproduction were sustained indefinitely by periodic transfer to fresh medium. Isolation of L cells and 6BC from persistent infections provided no evidence that there had been any selection of variants better suited for coexistence. Persistently infected populations consisting mainly of inclusion-free L cells yielded only persistently infected clones, grew more slowly, and cloned less efficiently. They were also almost completely resistant to superinfection with high multiplicities of either 6BC or the lymphogranuloma venereum strain 440L of Chlamydia trachomatis. These properties of persistently infected L cells may be accounted for by assuming that all of the individuals in these populations are cryptically infected with 6BC and that cryptic infection slows the growth of the host cell and makes it immune to infection with exogenous chlamydiae. According to this hypothesis, the fluctuations in host and parasite density occur because some factor periodically sets off the conversion of cryptic chlamydial forms into reticulate bodies that multiply and differentiate into infectious elementary bodies in a conventional chlamydial developmental cycle.


Electrochemical and Structural Study of the Buried Tryptophan in Azurin: Effects of Hydration and Polarity on the Redox Potential of W48.
Tryptophan serves as an important redox-active amino acid in mediating electron transfer and mitigating oxidative damage in proteins. We previously showed a difference in electrochemical potentials for two tryptophan residues in azurin with distinct hydrogen-bonding environments. Here, we test whether reducing the side chain bulk at position Phe110 to Leu, Ser, or Ala impacts the electrochemical potentials (E°) for tryptophan at position 48. X-ray diffraction confirmed the influx of crystallographically resolved water molecules for both the F110A and F110L tyrosine free azurin mutants. The local environments of W48 in all azurin mutants were further evaluated by UV resonance Raman (UVRR) spectroscopy to probe the impact of mutations on hydrogen bonding and polarity. A correlation between the frequency of the ω17 mode─considered a vibrational marker for hydrogen bonding─and E° is proposed. However, the trend is opposite to the expectation from a previous study on small molecules. Density functional theory calculations suggest that the ω17 mode reflects hydrogen bonding as well as local polarity. Further, the UVRR data reveal different intensity/frequency shifts of the ω9/ω10 vibrational modes that characterize the local H-bonding environments of tryptophan. The cumulative data support that the presence of water increases E° and reveal properties of the protein microenvironment surrounding tryptophan.


Dynamic integrated analysis of DNA methylation and gene expression profiles in in vivo and in vitro fertilized mouse post-implantation extraembryonic and placental tissues.
How does in vitro fertilization (IVF) alter promoter DNA methylation patterns and its subsequent effects on gene expression profiles during placentation in mice? IVF-induced alterations in promoter DNA methylation might have functional consequences in a number of biological processes and functions during IVF placentation, including actin cytoskeleton organization, hematopoiesis, vasculogenesis, energy metabolism and nutrient transport. During post-implantation embryonic development, both embryonic and extraembryonic tissues undergo de novo DNA methylation, thereby establishing a global DNA methylation pattern, and influencing gene expression profiles. Embryonic and placental tissues of IVF conceptuses can have aberrant morphology and functions, resulting in adverse pregnancy outcomes such as pregnancy loss, low birthweight, and long-term health effects. To date, the IVF-induced global profiling of DNA methylation alterations, and their functional consequences on aberrant gene expression profiles in IVF placentas have not been systematically studied. Institute for Cancer Research mice (6 week-old females and 8-9 week-old males) were used to generate in vivo fertilization (IVO) and IVF blastocysts. After either IVO and development (IVO group as control) or in vitro fertilization and culture (IVF group), blastocysts were collected and transferred to pseudo-pregnant recipient mice. Extraembryonic (ectoplacental cone and extraembryonic ectoderm) and placental tissues from both groups were sampled at embryonic day (E) 7.5 (IVO, n = 822; IVF, n = 795) and E10.5 (IVO, n = 324; IVF, n = 278), respectively. The collected extraembryonic (E7.5) and placental tissues (E10.5) were then used for high-throughput RNA sequencing (RNA-seq) and methylated DNA immunoprecipitation sequencing (MeDIP-seq). The main dysfunctions indicated by bioinformatic analyses were further validated using molecular detection, and morphometric and phenotypic analyses. Dynamic functional profiling of high-throughput data, together with molecular detection, and morphometric and phenotypic analyses, showed that differentially expressed genes dysregulated by DNA methylation were functionally involved in: (i) actin cytoskeleton disorganization in IVF extraembryonic tissues, which may impair allantois or chorion formation, and chorioallantoic fusion; (ii) disturbed hematopoiesis and vasculogenesis, which may lead to abnormal placenta labyrinth formation and thereby impairing nutrition transport in IVF placentas; (iii) dysregulated energy and amino acid metabolism, which may cause placental dysfunctions, leading to delayed embryonic development or even lethality; (iv) disrupted genetic information processing, which can further influence gene transcriptional and translational processes. Findings in mouse placental tissues may not be fully representative of human placentas. Further studies are necessary to confirm these findings and determine their clinical significance. Our study is the first to provide the genome-wide analysis of gene expression dysregulation caused by DNA methylation during IVF placentation. Systematic understanding of the molecular mechanisms implicated in IVF placentation can be useful for the improvement of existing assisted conception systems to prevent these IVF-associated safety concerns. This work was supported by grants from the National Natural Science Foundation of China (No. 31472092), and the National High-Tech R&D Program (Nos. 2011|AA100303, 2013AA102506). There was no conflict of interest.


Isolation and primary culture of murine alveolar type II cells.
Previous attempts to culture mouse alveolar type II (ATII) cells have been hampered by limited purity and cell recovery. We have now obtained culturable ATII cells from female C57BL/6 mice at a purity of 92% +/- 3 (mean +/- SD; n = 20), with viabilities of 96% +/- 2 and total yields of 5.1 +/- 0.7 X 10(6) cells per mouse. Crude lung cell suspensions were prepared by intratracheal instillation of Dispase and agarose followed by mechanical disaggregation of the lungs. Crude cell suspensions were purified by negative selection using a biotinylated-antibody, streptavidin-coated biomagnetic particle system. Cell purities were determined by Pap staining and confirmed ultrastructurally. Purified ATII cells were cultured on fibronectin-coated chamber slides and maintained for up to 5 days in DMEM with 10% fetal bovine serum. Cultures exhibited minimal contamination by Clara cells, mesenchymal cells, or endothelial cells, and the epithelial nature of the cultures was confirmed by positive cytokeratin staining in at least 97% of the cells through day 5. Day 3 cultures demonstrated osmium tetroxide/tannic acid-stained granules consistent with lamellar bodies in 76% +/- 3.6 of the cells. The cultures displayed features distinct from those previously described for adult rat ATII cells, including irregularly-shaped cells and the formation of numerous cytoplasmic projections in direct contact with other cells. These studies indicate that excellent yields of highly purified, culturable ATII cells can be obtained from genetically defined mice. These techniques may provide powerful new models for the study of parenchymal lung disease in vitro.


The Effects of Childhood Adversity and Self-Regulation on the Well-Being of Adults with Delinquency Histories: A Mediation Model.
Most youth with delinquency histories experience childhood adversity leaving them vulnerable to poor adult well-being. Previous research indicates that self-regulation difficulties could explain how childhood adversity affects adult well-being. Yet, very few studies target adult self-regulation intervention. Therefore, this study examined the intervening effects of emerging adult self-regulation on the association between childhood adversity and adult well-being. Using data from the first four waves of the Add Health Study, the researchers conducted structural equation modeling for mediation with bootstrapping. The researchers tested the mediation effects of emerging adult self-regulation on the association between childhood adversity (child maltreatment and violent victimization) and later adult well-being (mental health problems, alcohol and drug use, criminal behaviors) among people with delinquency histories and/or arrest prior to age 18 (N = 1,792). Several significant direct effects and one partial mediation effect were found. For example, child maltreatment significantly predicted adult mental health problems and criminal behaviors. Self-regulation (via the dissatisfaction with life and self subscale) mediated the association between child maltreatment and adult mental health problems. Findings highlight the need for social workers to focus on prevention services and trauma-informed treatment for people with delinquency histories. In addition, evidence-based practice requires self-regulation interventions for adults with histories of childhood adversity and delinquency to focus on their emotional and cognitive functioning as well as self-esteem. Implementing self-regulation interventions during emerging adulthood can be useful to mitigate later adult mental health problems among people with histories of childhood adversity and delinquency.


Platinum derivatives: a multidisciplinary approach.
Cancer is one of the most difficult diseases to be treated. The particularities regarding the tumors' occurrence mechanism, their evolution under chemotherapy, disease-free interval, but also the increasing number of patients make cancer an intensively studied health domain. Although introduced in therapy since the early 80s, platinum derivatives play an essential role in anticancer therapy. Their use in therapy resulted in improving the patient quality of life and prolonging disease-free interval, which makes them still a benchmark for other anticancer compounds. However, adverse reactions and allergic reactions are a major impediment in therapy with platinum derivatives. This paper summarizes data about platinum derivatives through a multidisciplinary approach, starting from a chemical point of view and on to their mechanism of action, mechanism of cellular resistance, predictive factors for the outcome of chemotherapy such as micro RNAs (miRNAs), tumor suppressor protein p53, and the excision repair cross-complementing 1 protein (ERCC1).


Pituitary intermediate lobe in dog: two cell types and high bioactive adrenocorticotropin content.
The pituitary intermediate lobe of most species is cytologically monotonous, but that of the dog is composed of two immunocytochemically distinct cell types. The predominant A cells are typical pars intermedia cells: they stain immunocytochemically for alpha-melanotropin and, more weakly, for adrenocorticotropin and beta-lipotropin. The B cells are like the corticotrophs of the anterior lobe: they stain intensely for adrenocorticotropin and beta-lipotropin but not for alpha-melanotropin. The B cells may account for the high concentration of bioactive adrenocorticotropin measured in the canine pars intermedia, and may explain why in dogs adenomas causing Cushing's disease through hypersecretion of adrenocorticotropin can arise from the intermediate as well as the anterior pituitary lobe.


[Manufacture of upholstered furniture and work-related upper limb musculoskeletal disorders: an industrial sector prevention project].
In cooperation with the IRCCS Fondazione Maugeri and the IRCCS Fondazione Ospedale Maggiore Policlinico - EPM-CEMOC, of Milan, the Local Health Unit in Bari, Italy carried out a research project, sponsored partly by the Italian Ministry of Health, on upper limb work-related musculoskeletal disorders (UL-WMSDs) in a specific manufacturing sector, the upholstered furniture industry. This "sofa district" is widely represented with approximately 14,000 workers and 500 factories over a wide geographic area of southern Italy. Advanced technology in the manufacturing process is combined with workers performing intensive arm-hand tasks. The aim of the study included: a) assessment of exposure to repetitive strain and movements of the upper limb in a representative sample of the factories using the OCRA method, b) analysis of the annual prevalence and incidence rates, c) definition of possible improvement via ergonomic solutions in the various factories. Via a network of occupational physicians a total of more than 6000 subjects were examined over a 5-year period. Case-definition was assessed through standardized procedures. A detailed description of the manufacturing process of the upholstered furniture industry and of the characteristics of the working population is provided Exposed groups at risk were:filling preparation workers, leather-cutting operators, sewing and upholstery-assembly workers. Data collected in private companies of different size in this extensive industrial "sofa area" emphasize the importance of prevention through adequate ergonomic solutions and the need to improve training programmes covering the whole area.


Sensation seeking and error processing.
Sensation seeking is defined by a strong need for varied, novel, complex, and intense stimulation, and a willingness to take risks for such experience. Several theories propose that the insensitivity to negative consequences incurred by risks is one of the hallmarks of sensation-seeking behaviors. In this study, we investigated the time course of error processing in sensation seeking by recording event-related potentials (ERPs) while high and low sensation seekers performed an Eriksen flanker task. Whereas there were no group differences in ERPs to correct trials, sensation seeking was associated with a blunted error-related negativity (ERN), which was female-specific. Further, different subdimensions of sensation seeking were related to ERN amplitude differently. These findings indicate that the relationship between sensation seeking and error processing is sex-specific.