Patterns of skill attainment and loss in young children with autism.
The purpose of this study was to extend the literature on the ontogeny of autism spectrum disorder (ASD) by examining early attainment and loss of specific sociocommunicative skills in children with autism (AUT; n = 125), pervasive developmental disorder not otherwise specified (PDD-NOS; n = 42), nonspectrum developmental delays (n = 46), and typical development (n = 31). The ages of skill attainment and loss were obtained from a caregiver interview. The findings indicated that children with AUT, PDD-NOS, and developmental delays diverged from typically developing children in attainment of sociocommunicative skills early in the first year of life. Loss of at least one skill was reported in a majority of children with AUT and PDD-NOS. Significant delays in attainment of skills were also reported in children who lost skills. The wide variation in skill attainment and loss reported across children indicates that symptom onset and regression may be best represented continuously, with at least some early delay and loss present for a great majority of children with ASD.


Mortalin (HSPA9) facilitates BRAF-mutant tumor cell survival by suppressing ANT3-mediated mitochondrial membrane permeability.
Mortalin [also known as heat shock protein family A (HSP70) member 9 (HSPA9) or glucose-regulated protein 75 (GRP75)] is a mitochondrial molecular chaperone that is often up-regulated and mislocalized in tumors with abnormal activation of the kinases MEK and ERK. Here, we found that mortalin depletion was selectively lethal to tumor and immortalized normal cells expressing the mutant kinase B-RafV600E or the chimeric protein ΔRaf-1:ER and that MEK-ERK-sensitive regulation of the peptide-binding domain in mortalin was critical to cell survival or death. Proteomics screening identified adenine nucleotide translocase 3 (ANT3) as a previously unknown mortalin substrate and cell survival/death effector. Mechanistically, increased MEK-ERK signaling activity and mortalin function converged opposingly on the regulation of mitochondrial permeability. Specifically, whereas MEK-ERK activity increased mitochondrial permeability by promoting the interaction between ANT3 and the peptidyl-prolyl isomerase cyclophilin D (CypD), mortalin decreased mitochondrial permeability by inhibiting this interaction. Hence, mortalin depletion increased mitochondrial permeability in MEK-ERK-deregulated cells to an extent that triggered cell death. HSP70 inhibitor derivatives that effectively inhibited mortalin suppressed the proliferation of B-RafV600E tumor cells in culture and in vivo, including their B-Raf inhibitor-resistant progenies. These findings suggest that targeting mortalin has potential as a selective therapeutic strategy in B-Raf-mutant or MEK-ERK-driven tumors.


Nerve growth factor/p75 neurotrophin receptor-mediated sensitization of rat sensory neurons depends on membrane cholesterol.
Nerve growth factor (NGF) is an important mediator in the initiation of the inflammatory response and NGF via activation of the p75 neurotrophin receptor (p75(NTR)) and downstream sphingomyelin signaling leads to significant enhancement of the excitability of small-diameter sensory neurons. Because of the interaction between sphingomyelin and cholesterol in creating membrane liquid-ordered domains known as membrane or lipid rafts, we examined whether neuronal NGF-induced sensitization via p75(NTR) was dependent on the integrity of membrane rafts. Here, we demonstrate that the capacity of NGF to enhance the excitability of sensory neurons may result from the interaction of p75(NTR) with its downstream signaling partner(s) in membrane rafts. Two agents known to disrupt membrane rafts, edelfosine and methyl-β-cyclodextrin (MβCD), block the increase in excitability produced by NGF. In contrast, treatment with MβCD containing saturated amounts of cholesterol does not alter the capacity of NGF to augment excitability. In addition, adding back MβCD with cholesterol restored the NGF-induced sensitization in previously cholesterol-depleted neurons, suggesting that cholesterol and the structural integrity of rafts are key to promoting NGF-mediated sensitization. Using established protocols to isolate detergent-resistant membranes, both p75(NTR) and the neuronal membrane raft marker, flotillin, localize to raft fractions. These results suggest that downstream signaling partners interacting with p75(NTR) in sensory neurons are associated with membrane raft signaling platforms.


Probiotics Upregulate Trefoil Factors and Downregulate Pepsinogen in the Mouse Stomach.
Probiotics are used in the management of some gastrointestinal diseases. However, little is known about their effects on normal gastric epithelial biology. The aim of this study was to explore how the probiotic mixture VSL#3 affects gastric cell lineages in mice with a special focus on protective and aggressive factors. Weight-matching littermate male mice (n = 14) were divided into treated and control pairs. The treated mice received VSL#3 (5 mg/day/mouse) by gastric gavage for 10 days. Control mice received only the vehicle. Food consumption and bodyweight were monitored. All mice were injected intraperitoneally with bromodeoxyuridine (120 mg/Kg bodyweight) two hours before sacrificed to label S-phase cells. Stomach tissues were processed for lectin- and immunohistochemical examination. ImageJ software was used to quantify immunolabeled gastric epithelial cells. Real-time quantitative polymerase chain reaction was used to provide relative changes in expression of gastric cell lineages specific genes. Results revealed that treated mice acquired (i) increased production of mucus, trefoil factor (TFF) 1 and TFF2, (ii) decreased production of pepsinogen, and (iii) increased ghrelin-secreting cells. No significant changes were observed in bodyweight, food consumption, cell proliferation, or parietal cells. Therefore, VSL#3 administration amplifies specific cell types specialized in the protection of the gastric epithelium.


Radiolabeling of Platelets with 99mTc-HYNIC-Duramycin for In Vivo Imaging Studies.
Following the in vivo biodistribution of platelets can contribute to a better understanding of their physiological and pathological roles, and nuclear imaging methods, such as single photon emission tomography (SPECT), provide an excellent method for that. SPECT imaging needs stable labeling of the platelets with a radioisotope. In this study, we report a new method to label platelets with 99mTc, the most frequently used isotope for SPECT in clinical applications. The proposed radiolabeling procedure uses a membrane-binding peptide, duramycin. Our results show that duramycin does not cause significant platelet activation, and radiolabeling can be carried out with a procedure utilizing a simple labeling step followed by a size-exclusion chromatography-based purification step. The in vivo application of the radiolabeled human platelets in mice yielded quantitative biodistribution images of the spleen and liver and no accumulation in the lungs. The performed small-animal SPECT/CT in vivo imaging investigations revealed good in vivo stability of the labeling, which paves the way for further applications of 99mTc-labeled-Duramycin in platelet imaging.


Delirium in a Latin American intensive care unit. A prospective cohort study of mechanically ventilated patients.
To establish the prevalence of delirium in a general intensive care unit and to identify associated factors, clinical expression and the influence on outcomes. This was a prospective cohort study in a medical surgical intensive care unit. The Richmond Agitation-Sedation Scale and Confusion Assessment Method for the Intensive Care Unit were used daily to identify delirium in mechanically ventilated patients. In this series, delirium prevalence was 80% (N = 184 delirious patients out of 230 patients). The number of patients according to delirium psychomotor subtypes was as follows: 11 hyperactive patients (6%), 9 hypoactive patients (5%) and 160 mixed patients (89%). Multiple logistic regression modeling using delirium as the dependent outcome variable (to study the risk factors for delirium) revealed that age > 65 years, history of alcohol consumption, and number of mechanical ventilation days were independent variables associated with the development of delirium. The multiple logistic regression model using hospital mortality as the dependent outcome variable (to study the risk factors for death) showed that severity of illness, according to the Acute Physiology and Chronic Health Evaluation II, mechanical ventilation for more than 7 days, and sedation days were all independent predictors for excess hospital mortality. This Latin American prospective cohort investigation confirmed specific factors important for the development of delirium and the outcome of death among general intensive care unit patients. In both analyses, we found that the duration of mechanical ventilation was a predictor of untoward outcomes.


Fine-Gray subdistribution hazard models to simultaneously estimate the absolute risk of different event types: Cumulative total failure probability may exceed 1.
The Fine-Gray subdistribution hazard model has become the default method to estimate the incidence of outcomes over time in the presence of competing risks. This model is attractive because it directly relates covariates to the cumulative incidence function (CIF) of the event of interest. An alternative is to combine the different cause-specific hazard functions to obtain the different CIFs. A limitation of the subdistribution hazard approach is that the sum of the cause-specific CIFs can exceed 1 (100%) for some covariate patterns. Using data on 9479 patients hospitalized with acute myocardial infarction, we estimated the cumulative incidence of both cardiovascular death and non-cardiovascular death for each patient. We found that when using subdistribution hazard models, approximately 5% of subjects had an estimated risk of 5-year all-cause death (obtained by combining the two cause-specific CIFs obtained from subdistribution hazard models) that exceeded 1. This phenomenon was avoided by using the two cause-specific hazard models. We provide a proof that the sum of predictions exceeds 1 is a fundamental problem with the Fine-Gray subdistribution hazard model. We further explored this issue using simulations based on two different types of data-generating process, one based on subdistribution hazard models and other based on cause-specific hazard models. We conclude that care should be taken when using the Fine-Gray subdistribution hazard model in situations with wide risk distributions or a high cumulative incidence, and if one is interested in the risk of failure from each of the different event types.


Segregation of the myogenic cell lineage in mouse muscle development.
With increasing interest in the idea of therapeutic implantation of normal muscle precursor cells into muscle lacking the protein product of the dystrophin gene, it has become important to obtain enriched populations of myogenic cells from biopsied muscle sources. Myogenic cells for implantation are highly favoured as they are the only cells that will fuse readily with host muscle fibres into which they are implanted, thus carrying the introduced gene into the target fibre with the maximum of efficiency. Second, myogenic cells appear less immunogenic than those of a non-myogenic nature; and third, the use of mononuclear myogenic cells may permit the introduction of multiple copies of a deficient gene into the patient's own cells. From a mixed population of cells obtained by the enzymic disaggregation of neonatal murine muscle we have selected, utilising a modification of the panning technique, for a cell population rich in myogenic cells. Segregation was accomplished using Mab H28, an antibody to the mouse neuronal cell adhesion molecule (N-CAM), derived from mouse/rat hybridoma cells. Following incubation with Mab H28, disaggregated muscle was applied to the surface of a bacteriological grade dish previously coated with anti-rat immunoglobulin. Cells segregated into two populations; those bearing N-CAM, and hence labelled with Mab H28, were adherent to the dish, whereas those not expressing N-CAM remained in suspension. Use of this technique, which involves minimal cell loss, resulted in the segregation of prefusion myogenic cells together with fibroblasts in the 'non-adherent' fraction, whereas cells in the adherent fraction consisted of a highly enriched population of actively dividing myogenic cells.


The calpactin light chain is tightly linked to the cytoskeletal form of calpactin I: studies using monoclonal antibodies to calpactin subunits.
Calpactins are a family of related Ca++-regulated cytoskeletal proteins. To analyze the expression and cytoskeletal association of calpactins we raised monoclonal antibodies with specificity for the heavy or light chains of calpactin I or to calpactin II. Comparison of the tissue distribution of calpactin I heavy and light chains by Western blots revealed that these subunits are coordinately expressed. Both soluble and cytoskeletal forms of the heavy chain of calpactin I were detected in human fibroblasts whereas only a soluble pool of calpactin II was found. These two forms of the calpactin I heavy chain differed both in their state of association with the light chain and in their rate of turnover. Both the soluble pool of the calpactin I heavy chain and calpactin II turned over three to four times faster than the cytoskeletal pool of heavy and light chains. Immunofluorescence microscopy revealed that the calpactin I light chain was present exclusively in the cytoskeleton whereas the calpactin I heavy chain distribution was more diffuse. No difference in the amount of light chain or the cytoskeletal attachment of phosphorylated calpactin I heavy chain was found in Rous sarcoma virus-transformed chick embryo fibroblasts compared with their normal counterpart. The antibody to the light chain of calpactin I was microinjected into cultured fibroblasts and kidney epithelial cells. In many cases antibody clustering was observed with the concomitant aggregation of the associated calpactin I heavy chain. The distribution of fodrin and calpactin II in injected cells remained unchanged. These results are consistent with the existence of two functionally distinct pools of calpactin I which differ in their association with the cytoskeleton.


Intraarterial delivery of naked plasmid DNA expressing full-length mouse dystrophin in the mdx mouse model of duchenne muscular dystrophy.
Our previous studies have demonstrated that the intraarterial delivery of naked plasmid DNA leads to high levels of foreign gene expression throughout the muscles of the targeted limb. Although the procedure was first developed in rats and then extended to nonhuman primates, the present study has successfully implemented the procedure in normal mice and the mdx mouse model for Duchenne muscular dystrophy. After intraarterial delivery of plasmid DNA expressing the normal, full-length mouse dystrophin from either the cytomegalovirus promoter or a muscle-specific human desmin gene control region, mdx mouse muscle stably expressed dystrophin in 1-5% of the myofibers of the injected hind limb for at least 6 months. This expression generated an antibody response but no apparent cellular response.


Ca2+-dependent phosphoregulation of the plasma membrane Ca2+-ATPase ACA8 modulates stimulus-induced calcium signatures.
Ca2+ signals are transient, hence, upon a stimulus-induced increase in cytosolic Ca2+ concentration, cells have to re-establish resting Ca2+ levels. Ca2+ extrusion is operated by a wealth of transporters, such as Ca2+ pumps and Ca2+/H+ antiporters, which often require a rise in Ca2+ concentration to be activated. Here, we report a regulatory fine-tuning mechanism of the Arabidopsis thaliana plasma membrane-localized Ca2+-ATPase isoform ACA8 that is mediated by calcineurin B-like protein (CBL) and CBL-interacting protein kinase (CIPK) complexes. We show that two CIPKs (CIPK9 and CIPK14) are able to interact with ACA8 in vivo and phosphorylate it in vitro. Transient co-overexpression of ACA8 with CIPK9 and the plasma membrane Ca2+ sensor CBL1 in tobacco leaf cells influences nuclear Ca2+ dynamics, specifically reducing the height of the second peak of the wound-induced Ca2+ transient. Stimulus-induced Ca2+ transients in mature leaves and seedlings of an aca8 T-DNA insertion line exhibit altered dynamics when compared with the wild type. Altogether our results identify ACA8 as a prominent in vivo regulator of cellular Ca2+ dynamics and reveal the existence of a Ca2+-dependent CBL-CIPK-mediated regulatory feedback mechanism, which crucially functions in the termination of Ca2+ signals.


A comparison of outcome for stroke patients in Barbados and South London.
Little is known about the poststroke outcome in Caribbean populations. We investigated differences in the activities of daily living, level of social activities, living circumstances and survival for stroke patients in Barbados and London. Data were collected from the South London Stroke Register and the Barbados Register of Strokes for patients with a first-ever stroke registered between January 2001 and December 2004. The ability to perform activities of daily living was measured by the Barthel Index and level of social activities by the Frenchay Activities Index. Living circumstances were categorised into private household vs. institutional care. Death and dependency, activities of daily living and social activities were assessed at three-months, one- and two-years using logistic regression, adjusted for differences in demographic, socioeconomic and stroke severity characteristics. At three-months, a high level of social activities was more likely for the Barbados Register of Strokes (odds ratio 1.84; 95% confidence interval 1.03-3.29); there were no differences in activities of daily living; and Barbados Register of Strokes patients were less likely to be in institutional care (relative risk ratio 0.38; 95% confidence interval 0.18-0.79). Following adjustment, Barbados Register of Strokes patients had a higher risk of mortality at three-months (relative risk ratio 1.85; 95% confidence interval 1.03-3.30), one-year (relative risk ratio 1.83; 95% confidence interval 1.08-3.09) and two-years (relative risk ratio 1.82; 95% confidence interval 1.08-3.07). This difference was due to early poststroke deaths; for patients alive at four-weeks poststroke, survival thereafter was similar in both settings. In Barbados, there was evidence for a healthy survivor effect, and short-term social activity was greater than that in the South London Stroke Register.


Soul searching and heart throbbing for biological modeling.
Biological models are useful not only because they can simulate biological behaviors, but because they may shed light on the inner workings of complex biological structures and functions as deduced by top-down and/or bottom-up reasoning. Beyond the stylistic appeal of specific implementation methods, a model should be appraised according to its ability to bring out the underlying organizing and operating principles - which are truly the model's heart and soul.


Anti-Golgi Antibody as a Potential Indicator for Rheumatoid Arthritis.
To reveal the relationship between anti-Golgi antibody (AGA) and clinical diseases through retrospective analysis. The clinical data of 584 cases testing positive for AGA in the past 11 years were collected and retrospectively analyzed. AGA pattern accounted for .2% of positive ANA results. In total, 35.0% of diagnosed patients had autoimmune diseases (AID), mainly rheumatoid arthritis (RA). High-titer AGA (≧1:1000) was common in AID. In nondiagnosed patients with clinical symptoms, joint pain/muscle pain was the most common. Positive AGA with high titer was closely related to RA. Joint pain/muscle pain was the most common symptom in patients who tested AGA positive. Therefore, AGA may be a key indicator of RA in the Chinese population.


A new frontier for prescription drug services.
To help payers and patients achieve the full value of their prescription drug benefit, the next frontier of managed pharmacy services will be improving individual health outcomes, raising employee productivity and lowering a plan's overall medical costs.


Accurate integration of single-cell DNA and RNA for analyzing intratumor heterogeneity using MaCroDNA.
Cancers develop and progress as mutations accumulate, and with the advent of single-cell DNA and RNA sequencing, researchers can observe these mutations and their transcriptomic effects and predict proteomic changes with remarkable temporal and spatial precision. However, to connect genomic mutations with their transcriptomic and proteomic consequences, cells with either only DNA data or only RNA data must be mapped to a common domain. For this purpose, we present MaCroDNA, a method that uses maximum weighted bipartite matching of per-gene read counts from single-cell DNA and RNA-seq data. Using ground truth information from colorectal cancer data, we demonstrate the advantage of MaCroDNA over existing methods in accuracy and speed. Exemplifying the utility of single-cell data integration in cancer research, we suggest, based on results derived using MaCroDNA, that genomic mutations of large effect size increasingly contribute to differential expression between cells as Barrett's esophagus progresses to esophageal cancer, reaffirming the findings of the previous studies.


A large case-control study on the predictability of hepatitis B surface antigen levels three years before hepatitis B surface antigen seroclearance.
The kinetics of hepatitis B surface antigen (HBsAg) levels preceding spontaneous HBsAg seroclearance has not been fully investigated. The kinetics of HBsAg and hepatitis B virus (HBV) DNA of 203 treatment-naïve, hepatitis B e antigen (HBeAg)-negative patients with spontaneous HBsAg seroclearance were compared with 203 age- and sex-matched HBeAg-negative controls. Serum samples at 3 years, 2 years, 1 year, and 6 months before HBsAg seroclearance and at the time of HBsAg loss were tested. Median HBsAg levels at these respective time points before HBsAg seroclearance were 23.5, 3.51, 0.524, and 0.146 IU/mL. For all time points, patients with HBsAg seroclearance had significantly lower median HBsAg and HBV DNA levels, compared to those of the controls (all P < 0.001). Median HBsAg and HBV DNA levels declined significantly until HBsAg seroclearance (P < 0.001). Although median HBsAg levels also decreased significantly with time (P = 0.006) in controls, median HBV DNA levels remained similar (P = 0.414). Serum HBsAg levels, followed by HBsAg log reduction, were the best predictors of HBsAg seroclearance, with an area under the receiving operator characteristic (AUROC) of 0.833 (95% confidence interval [CI]: 0.792-0.873) and 0.803 (95% CI: 0.755-0.849), respectively. The optimal cut-off HBsAg level and HBsAg reduction to predict HBsAg seroclearance were <200 IU/mL (sensitivity, 84.2%; specificity, 73.4%) and 0.5 log IU/mL/year (sensitivity, 62.8%; specificity, 88.7%), respectively. For patients with HBsAg levels ≥ 200 IU/mL, an annual 0.5-log reduction was highly predictive of subsequent HBsAg seroclearance (AUROC, 0.867; 95% CI: 0.778-0.956). To conclude, serum HBsAg <200 IU/mL and 0.5-log reduction in HBsAg were predictive of HBsAg seroclearance within 3 years of follow-up. These parameters may serve as good indicators for the consideration of treatment duration and cessation for chronic hepatitis B.


Photocatalytic H2 evolution reaction from aqueous solutions over band structure-controlled (AgIn)xZn2(1-x)S2 solid solution photocatalysts with visible-light response and their surface nanostructures.
(AgIn)(x)Zn(2(1-x))S(2) solid solutions between ZnS photocatalyst with a wide band gap and AgInS(2) with a narrow band gap showed photocatalytic activities for H(2) evolution from aqueous solutions containing sacrificial reagents, SO(3)(2)(-) and S(2)(-), under visible-light irradiation (lambda >or= 420 nm) even without Pt cocatalysts. Loading of the Pt cocatalysts improved the photocatalytic activity. Pt (3 wt %)-loaded (AgIn)(0.22)Zn(1.56)S(2) with a 2.3 eV band gap showed the highest activity for H(2) evolution, and the apparent quantum yield at 420 nm amounted to 20%. H(2) gas evolved at a rate of 3.3 L m(-2) x h(-1) under irradiation using a solar simulator (AM 1.5). The diffuse reflection and the photoluminescence spectra of the solid solutions shifted monotonically to a long wavelength side as the ratio of AgInS(2) to ZnS increased in the solid solutions. The photocatalytic H(2) evolution depended on the compositions as well as the photophysical properties. The dependence of the photophysical and photocatalytic properties upon the composition was mainly due to the change in the band position caused by the contribution of the Ag 4d and In 5s5p orbitals to the valence and conduction bands, respectively. It was found from SEM and TEM observations that the solid solutions partially had nanostep structures on their surfaces. The Pt cocatalysts were selectively photodeposited on the edge of the surface nanosteps. It was suggested that the specific surface nanostructure was effective for the suppression of recombination between photogenerated electrons and holes and for the separation of H(2) evolution sites from oxidation reaction sites.


Maturation of tissue engineered cartilage implanted in injured and osteoarthritic human knees.
The regeneration of damaged organs requires that engineered tissues mature when implanted at sites of injury or disease. We have used new analytic techniques to determine the extent of tissue regeneration after treatment of knee injury patients with a novel cartilage tissue engineering therapy and the effect of pre-existing osteoarthritis on the regeneration process. We treated 23 patients, with a mean age of 35.6 years, presenting with knee articular cartilage defects 1.5 cm2 to 11.25 cm2 (mean, 5.0 cm2) in area. Nine of the patients had X-ray evidence of osteoarthritis. Chondrocytes were isolated from healthy cartilage removed at arthroscopy. The cells were cultured for 14 days, seeded onto esterified hyaluronic acid scaffolds (Hyalograft C), and grown for a further 14 days before implantation. A second-look biopsy was taken from each patient after 6 to 30 months (mean, 16 months). After standard histological analysis, uncut tissue was further analyzed using a newly developed biochemical protocol involving digestion with trypsin and specific, quantitative assays for type II collagen, type I collagen, and proteoglycan, as well as mature and immature collagen crosslinks. Cartilage regeneration was observed as early as 11 months after implantation and in 10 out of 23 patients. Tissue regeneration was found even when implants were placed in joints that had already progressed to osteoarthrosis. Cartilage injuries can be effectively repaired using tissue engineering, and osteoarthritis does not inhibit the regeneration process.


A rapid, polymerase chain reaction-based procedure for identifying mutant restricted ovulator chickens.
Females of the restricted ovulator (RO) strain of White Leghorn chickens fail to lay eggs upon photostimulation and exhibit endogenous hyperlipidemia and atherosclerotic lesions. A mutation in the gene specifying the oocyte vitellogenesis receptor (OVR), a 95-kDa membrane protein that normally mediates the massive uptake of yolk precursors from the serum, is responsible for this abnormal phenotype. Because a single nucleotide substitution (G-->C) is responsible for the defective OVR, a PCR-based procedure, described herein, was developed in order to provide a rapid and accurate method for identifying chickens possessing the mutant allele. Polymerase chain reaction-amplified fragments of apparently identical size (approximately 400 bp) were obtained from genomic DNA using primer pairs specific for either the wild-type or mutant genes. Through cloning and sequencing of the PCR-amplified products, the fragment sizes were determined to be 413 bp each, which included an intron sequence. Polymerase chain reaction-amplified genomic DNA from wild-type (ovr+/ovr+) males, heterozygous carrier (ovr+/ovr-) males, and wild-type (-/ovr+) females all yielded a 413 bp fragment when a primer pair specific for the wild-type gene was used. Because female chickens are heterogametic (ZW), no PCR product was observed in the case of the mutant (-/ovr-) females. When the primer pair specific for the mutant gene was employed, PCR-amplification of genomic DNA from both heterozygous carrier (ovr+/ ovr-) males and mutant (-/ovr-) females, but not wild-type (ovr+/ovr+) males or (-/ovr+) females, also yielded a 413-bp fragment. Employment of the present rapid and accurate procedure would be expected to obviate the need for conventional progeny testing while reducing the time required to identify RO carrier males and mutant females from approximately 1 yr to several days.


A comparative analysis of pre- and post-dialysis albumin as indicators of nutritional and morbi-mortality risks in haemodialysis patients.
Pre-dialysis albumin is likely to be falsely low due to a dilution effect, making its usefulness in assessing protein status questionable. OBJEVTIVES: The purpose of this study was to assess whether post-dialysis albumin would be a better marker of malnutrition and risk of mortality, when compared to pre-dialysis albumin. We evaluated the correlation between pre- and post-dialysis albumin and the following parameters: body mass index (BMI), adequacy of muscle arm circumference (MAC) and tricipital skinfold (TS) to the 50th percentile (P50), C-reactive protein (CRP), phase angle (PA), protein equivalent of nitrogen appearance (PNA), the Kt/V index of dialysis adequacy, and the hydration status (Pearson's correlation coefficient). Agreement in the nutritional status according to pre- and post-dialysis (post-HD) albumin and PA was estimated according to the Kappa (K) coefficient (Bland-Altman). A total of 58 haemodialysis (HD) patients were included in this study (30 female; mean age: 49 years). BMI, PA and CRP had a significant correlation with pre- and post-HD albumin, while MAC and PNA correlated only with post-HD albumin. Agreement in the diagnosis of malnutrition according to PA < 5 and pre- and post-HD albumin < 3.2 g/dL was regular (K = 0.432). When using an albumin cut-off value of 3.7 g/dL for malnutrition (mild malnutrition or risk of malnutrition), the diagnosis was concordant only in the post-HD period (K = 0.544). Post-dialysis albumin levels may be a better marker of protein status and mortality risk in cases of mild malnutrition or risk of malnutrition and in patients with low/medium mortality risk. Pre-dialysis fluid overload may be a confounding factor when evaluating albumin levels.


Interobserver variability of magnetic resonance angiography in the diagnosis of carotid stenosis--effect of observer experience.
Magnetic resonance angiography (MRA) for determining the degree of carotid stenosis prior to carotid endarterectomy is attractive because it does not have the high morbidity associated with conventional intra-arterial angiography. We assessed the interobserver variability in the estimation of the degree of stenosis amongst observers of different experience. In a prospective study, consecutive patients with transient ischaemic attacks and symptomatic tight carotid stenosis shown by Doppler ultrasound underwent conventional intra-arterial angiography and 2-D and 3-D time-of-flight MRA of the carotid bifurcations. The films of the processed MRA images were reviewed blind to other clinical and imaging data by eight observers of different levels of experience and coded for the presence and degree of stenosis. The stenosis on intra-arterial angiography was used as the reference standard. There was considerable variability between observers for estimation of the degree of stenosis on MRA. The observers' accuracy ranged from 41% (student) to 79% (experienced). From these estimations, excluding those of the student, it could be seen that up to 23% of patients who would have had an endarterectomy based on MRA should not have done so according to angiography, and up to 33% of patients who should have had an endarterectomy according to angiography would have inappropriately missed having an endarterectomy based on MRA results. Observer reliability of MRA processed images is not good, even in experienced hands. Using the source images and views of the circle of Willis might improve the accuracy, but a further study is required to assess this.


Emerging trends in the volume and format of outside examinations submitted for secondary interpretation.
The purpose of this article is to describe the trends of secondary interpretations, including the total volume and format of cases. This retrospective study involved all outside neuroradiology examinations submitted for secondary interpretation from November 2006 through December 2010. This practice utilizes consistent criteria and includes all images that cover the brain, neck, and spine. For each month, the total number of outside examinations and their format (i.e., hard-copy film, DICOM CD-ROM, or non-DICOM CD-ROM) were recorded. There was no significant change in the volume of cases (1043 ± 131 cases/month; p = 0.46, two-sided Student t test). There was a significant decrease in the volume of hard-copy films submitted, with the mean number of examinations submitted per month on hard-copy film declining from 297 in 2007 to 57 in 2010 (p < 0.0001, Student t test). This decrease was mirrored by an increase in the mean number of cases submitted on CD-ROM (753 cases/month in 2007 and 1036 cases/month in 2010; p < 0.0001). Although most were submitted in DICOM format, there was almost a doubling of the volume of cases submitted on non-DICOM CD-ROM (mean number of non-DICOM CD-ROMs, nine cases/month in 2007 and 17 cases/month in 2010; p < 0.001). There has been a significant decrease in the number of hard-copy films submitted for secondary interpretation. There has been almost a doubling of the volume of cases submitted in non-DICOM formats, which is unfortunate, given the many advantages of the internationally derived DICOM standard, including ease of archiving, standardized display, efficient review, improved interpretation, and quality of patient care.


The principles of controlled clinical trials of drugs.
The principles of evaluation of new drugs are described and discussed. This evaluation is carried out in three consecutive phases. The first one is performed on young, healthy volunteers. The general response to the drug and signs of toxicity are registered. Preliminary data about absorption, elimination and metabolism are collected. The safe dosage range and preferred route of administration are settled. In the second phase, initial trials on a limited number of patients for specific disease control or prophylaxis are carried out. Patients are included in the trial by random selection and stratification. Studies are strictly controlled. To avoid bias, double-blind examination is used in paired patients, a group of patients or by the crossover design. The problems of planning, design of the study, clinical and statistical evaluation of results are discussed. Two examples of controlled clinical studies are given, concerning the assessment of antirheumatic and antianginal drugs. Finally the principles of the third phase of study are discussed. The methods of evaluation described may be applied for the assessment of entirely new substances as well as for verification of the objective therapeutic value of "old" drugs.


Genetic requirements for RAD51- and RAD54-independent break-induced replication repair of a chromosomal double-strand break.
Broken chromosomes can be repaired by several homologous recombination mechanisms, including gene conversion and break-induced replication (BIR). In Saccharomyces cerevisiae, an HO endonuclease-induced double-strand break (DSB) is normally repaired by gene conversion. Previously, we have shown that in the absence of RAD52, repair is nearly absent and diploid cells lose the broken chromosome; however, in cells lacking RAD51, gene conversion is absent but cells can repair the DSB by BIR. We now report that gene conversion is also abolished when RAD54, RAD55, and RAD57 are deleted but BIR occurs, as with rad51Delta cells. DSB-induced gene conversion is not significantly affected when RAD50, RAD59, TID1 (RDH54), SRS2, or SGS1 is deleted. Various double mutations largely eliminate both gene conversion and BIR, including rad51Delta rad50Delta, rad51Delta rad59Delta, and rad54Delta tid1Delta. These results demonstrate that there is a RAD51- and RAD54-independent BIR pathway that requires RAD59, TID1, RAD50, and presumably MRE11 and XRS2. The similar genetic requirements for BIR and telomere maintenance in the absence of telomerase also suggest that these two processes proceed by similar mechanisms.


Effect of concomitant fasting and cold exposure on sympathoadrenal activity in rats.
Fasting decreases and cold exposure increases sympathetic nervous system activity. The present studies examine the effect of fasting and cold together on sympathoadrenal function. At 4 degrees C animals fasted for 2 days excreted 29% less norepinephrine (NE) than fed animals, averaging 458 +/- 32ng NE/mg creatinine and 646 +/- 68, respectively (P less than 0.005), but 122% more epinephrine (E) 77.9 +/- 11.7 ng E/mg creatinine and 35.1 +/- 6.7, respectively (P less than .01). Fasting for 2 days reduced cardiac NE turnover, a direct measure of sympathetic neuronal activity, 33% in animals at 22 degrees C from 28.2 +/- 3.6 ng NE . heart-1 . h-1 to 18.9 +/- 4.8 (95% confidence intervals) and 25% in animals acutely exposed to 4 degrees C from 60.7 +/- 8.0 to 45.6 +/- 9.5. Similar reductions in urinary NE excretion and cardiac NE turnover were observed in adrenal-demedullated rats. Thus fasting at 4 degrees C lowers sympathetic activity and enhances adrenal medullary secretion. This pattern of decreased sympathetic and increased adrenal medullary activity, previously seen with fasting hypoglycemia, suggests an important role for the adrenal medulla in internal homeostasis at times when the sympathetic nervous system is suppressed.


Creating and Sustaining Care Teams in Primary Care: Perspectives From Innovative Patient-Centered Medical Homes.
To learn from the experiences of innovative primary care practices that have successfully developed care teams. A 2½-day working conference was convened with representatives from 10 innovative primary care practices, content experts, and researchers to discuss experiences of developing care teams. Qualitative data included observation notes, transcripts of conference sessions and interviews, and narrative summaries of innovations. Case summaries of practices and an analysis matrix were created to identify common themes. Ten practices known nationally for innovations in team-based care participated in the conference represented by 1 to 2 practice members. Two domains emerged related to creating effective teams and funding them. Participants emphasized the importance of making practice values explicit and involving everyone in the change process, standardizing routine processes, and mitigating resistance. They also highlighted that team-based care adds comprehensiveness, not necessarily productivity. They, thus, highlighted the need for a long-term financial vision, including resourcefulness and alternate funding. Team-based care is possible and valuable in primary care. It is difficult to develop and sustain, however, and requires dedicated time and resources. The challenges these highly motivated practices described raise the question of feasibility for more average practices in the current funding environment.


Time-order errors and standard-position effects in duration discrimination: An experimental study and an analysis by the sensation-weighting model.
Studies have shown that the discriminability of successive time intervals depends on the presentation order of the standard (St) and the comparison (Co) stimuli. Also, this order affects the point of subjective equality. The first effect is here called the standard-position effect (SPE); the latter is known as the time-order error. In the present study, we investigated how these two effects vary across interval types and standard durations, using Hellström's sensation-weighting model to describe the results and relate them to stimulus comparison mechanisms. In Experiment 1, four modes of interval presentation were used, factorially combining interval type (filled, empty) and sensory modality (auditory, visual). For each mode, two presentation orders (St-Co, Co-St) and two standard durations (100 ms, 1,000 ms) were used; half of the participants received correctness feedback, and half of them did not. The interstimulus interval was 900 ms. The SPEs were negative (i.e., a smaller difference limen for St-Co than for Co-St), except for the filled-auditory and empty-visual 100-ms standards, for which a positive effect was obtained. In Experiment 2, duration discrimination was investigated for filled auditory intervals with four standards between 100 and 1,000 ms, an interstimulus interval of 900 ms, and no feedback. Standard duration interacted with presentation order, here yielding SPEs that were negative for standards of 100 and 1,000 ms, but positive for 215 and 464 ms. Our findings indicate that the SPE can be positive as well as negative, depending on the interval type and standard duration, reflecting the relative weighting of the stimulus information, as is described by the sensation-weighting model.


Synthesis of π-extended B ← N coordinated phenanthroimidazole dimers and their linear and nonlinear optical properties.
Intramolecular B ← N coordinated fluorophores have shown potential applications in optoelectronics and as sensors due to their unique photophysical properties. In this work, we report the synthesis and characterization of π-conjugated boron doped phenanthroimidazole dimers. All the π-conjugated B ← N coordinated phenanthroimidazole dimers exhibited high quantum yields in solution (up to 99%) and moderate quantum yields in the solid state (up to 51%). We investigated the nonlinear optical properties of phenanthroimidazole dimers and found that the measurement of two-photon-absorption cross-section is correlated with the conjugation length.


Treatment effect of Bushen Huayu extract on postmenopausal osteoporosis in vivo.
Bushen Huayu extract (BSHY), a traditional Chinese medicine, has been demonstrated to treat postmenopausal osteoporosis, however, the underlying mechanism remains to be fully elucidated. The aim of the present study was to investigate the therapeutic effect of BSHY and the mechanisms underlying this effect in an in vivo postmenopausal osteoporosis animal model. A total of 1 g BSHY containing 7.12 μg icariin was prepared. Low-dose BSHY (BSHY-L; 11.1 g/kg), medium-dose BSHY (BSHY-M; 22.2 g/kg) and high-dose BSHY (BSHY-H; 44.4 g/kg) was administered to oophorectomized rats using intragastric infusion. Estradiol (E2), interleukin-6 (IL-6) and serum alkaline phosphatase (ALP) levels, as well as bone density, were determined. It was found that the levels of serum ALP in the BSHY-L, BSHY-M and BSHY-H groups (197.75±41.74, 166.63±44.83 and 165.63±44.90 IU/l, respectively) were significantly decreased compared with the model group (299.13±45.79 IU/l; P<0.05), whilst the levels of E2 (16.89±1.71, 17.95±1.40 and 18.34±1.43 pg/ml, respectively) increased compared with the model group (14.54±1.61; P<0.05). In addition, the levels of IL-6 decreased in the BSHY-L, BSHY-M and BSHY-H groups (91.85±14.81, 82.99±15.65 and 80.54±14.61 pg/ml, respectively) compared with the model group (105.93±16.50 pg/ml; P<0.05). Furthermore, it was demonstrated that BSHY increased the bone density in the BSHY-L, BSHY-M and BSHY-H groups (0.20±0.014, 0.22±0.016 and 0.22±0.017 g/cm2, respectively) compared with the model group (0.19±0.011 g/cm2; P<0.05). BSHY was also found to increase the number of osteoblasts in the BSHY-L, BSHY-M and BSHY-H groups (25.38±2.17, 29.25±2.12 and 30.00±2.39, respectively), compared with in the model group (14.75±2.38; P<0.05), and decrease the number of osteoclasts in the BSHY-L, BSHY-M and BSHY-H groups (4.00±1.85, 4.25±1.39 and 5.75±1.49, respectively) compared with 9.50±1.60 observed in the model group (P<0.05). These results suggest that BSHY is a potential therapeutic drug for the treatment of osteoporosis in vivo. Furthermore, these results suggest that the mechanism by which BSHY decreases the serum levels of IL-6 may be by regulating E2.


Studying language change using price equation and Pólya-urn dynamics.
Language change takes place primarily via diffusion of linguistic variants in a population of individuals. Identifying selective pressures on this process is important not only to construe and predict changes, but also to inform theories of evolutionary dynamics of socio-cultural factors. In this paper, we advocate the Price equation from evolutionary biology and the Pólya-urn dynamics from contagion studies as efficient ways to discover selective pressures. Using the Price equation to process the simulation results of a computer model that follows the Pólya-urn dynamics, we analyze theoretically a variety of factors that could affect language change, including variant prestige, transmission error, individual influence and preference, and social structure. Among these factors, variant prestige is identified as the sole selective pressure, whereas others help modulate the degree of diffusion only if variant prestige is involved. This multidisciplinary study discerns the primary and complementary roles of linguistic, individual learning, and socio-cultural factors in language change, and offers insight into empirical studies of language change.


Spatial complexity method for tracking brain development and degeneration using functional near-infrared spectroscopy.
Brain complexity analysis using functional near-infrared spectroscopy (fNIRS) has attracted attention as a biomarker for evaluating brain development and degeneration processes. However, most methods have focused on the temporal scale without capturing the spatial complexity. In this study, we propose a spatial time-delay entropy (STDE) method as the spatial complexity measure based on the time-delay measure between two oxy-hemoglobin (Δ[HbO]) or two deoxy-hemoglobin (Δ[Hb]) oscillations within the 0.01-0.1 Hz frequency band. To do this, we analyze fNIRS signals recorded from infants in their sleeping state, children, adults, and healthy seniors in their resting states. We also evaluate the effects of various noise to STDE calculations and STDE's performance in distinguishing various developmental age groups. Lastly, we compare the results with the normalized global spatial complexity (NGSC) and sample entropy (SampEn) measures. Among these measures, STDEHbO (STDE based on Δ[HbO] oscillations) performs best. The STDE value increases with age throughout childhood (p < 0.001), and then decreases in adults and healthy seniors in the 0.01-0.1 Hz frequency band. This trajectory correlates with cerebrovascular development and degeneration. These findings demonstrate that STDE can be used as a new tool for tracking cerebrovascular development and degeneration across a lifespan based on the fNIRS resting-state measurements.


[Thrombocyte receptors: current views and therapeutic options].
In the action of thrombocytes during stemming of a bleeding after damage to a blood vessel, receptors on the thrombocyte membrane play an important part. Adhesion of platelets takes place via specific binding of receptors; the main binding is that of glycoprotein (Gp) Ib to Von Willebrand factor which is synthetized by endothelial cells. Activation of thrombocytes is stimulated by adhesion and by agonists. Weak agonists, through production of thromboxane A2 and release of agonists from granules cause a self-fortifying process of thrombocyte stimulation; strong agonists (like thrombin) lead also to activation of Gp IIb/IIIa receptors. Aggregation of thrombocytes occurs after activation of Gp IIb/IIIa receptors. During stimulation, a change of shape occurs which enables binding to suitable plasma proteins of which the main one is fibrinogen. Knowledge of thrombocyte receptors enhances the insight into the prognosis and efficacy of certain treatments in diseases in which platelet aggregation is pivotal. Of the six categories of antiplatelet drugs, antagonists of Gp IIb/IIIa receptors are the most potent. In clinical trials good results have been obtained in patients with coronary disease of the intravenously administered form added to acetylsalicylic acid.


Anhydrous uric acid: nature and occurrence of a new form of urinary calculi.
A second form of anhydrous uric acid has been found in urinary calculi; it is probably derived as an artifact from uric acid dihydrate during storage. It has been prepared in the laboratory by desiccation of uric acid dihydrate. Mixtures of these two substances sometimes give x-ray powder patterns that resemble that of xanthine on weak photographs, but are distinguishable by their infrared spectra.


A 1-Year Prospective French Nationwide Study of Emergency Hospital Admissions in Children and Adults with Primary Immunodeficiency.
Patients with primary immunodeficiency (PID) are at risk of serious complications. However, data on the incidence and causes of emergency hospital admissions are scarce. The primary objective of the present study was to describe emergency hospital admissions among patients with PID, with a view to identifying "at-risk" patient profiles. We performed a prospective observational 12-month multicenter study in France via the CEREDIH network of regional PID reference centers from November 2010 to October 2011. All patients with PIDs requiring emergency hospital admission were included. A total of 200 admissions concerned 137 patients (73 adults and 64 children, 53% of whom had antibody deficiencies). Thirty admissions were reported for 16 hematopoietic stem cell transplantation recipients. When considering the 170 admissions of non-transplant patients, 149 (85%) were related to acute infections (respiratory tract infections and gastrointestinal tract infections in 72 (36%) and 34 (17%) of cases, respectively). Seventy-seven percent of the admissions occurred during winter or spring (December to May). The in-hospital mortality rate was 8.8% (12 patients); death was related to a severe infection in 11 cases (8%) and Epstein-Barr virus-induced lymphoma in 1 case. Patients with a central venous catheter (n = 19, 13.9%) were significantly more hospitalized for an infection (94.7%) than for a non-infectious reason (5.3%) (p = 0.04). Our data showed that the annual incidence of emergency hospital admission among patients with PID is 3.4%. The leading cause of emergency hospital admission was an acute infection, and having a central venous catheter was associated with a significantly greater risk of admission for an infectious episode.


Planning time for peripheral blood stem cell infusion after high-dose targeted radionuclide therapy using dosimetry.
Myelotoxicity can be ameliorated by peripheral blood stem cell (PBSC) infusion. Continuous irradiation by radioactivity retained in the body after high-dose radioimmunotherapy can damage PBSCs if they are transfused too early. Previously, infusion time was predetermined using the radioactivity concentration in the blood. This study proposes to plan PBSC infusion time based on noninvasive dosimetry that considers damage of PBSCs during PBSC circulation and residence in organs with high radioactivity. The method considers a time-varying distribution of PBSCs and radioactivity in tissues. Five breast cancer patients received (111)In-2IT-BAD-m170 for imaging, and 3 of the 5 received high doses of (90)Y-2IT-BAD-m170 therapy followed by PBSC infusion. (90)Y concentrations in tissues were extrapolated from quantitative imaging of (111)In, and (90)Y blood concentrations were determined from (90)Y in serial blood samples. The radiation dose to PBSCs was determined by time integration of the organ dose rate and PBSC distribution rate. The radiosensitivity of PBSCs was determined by measuring survival of granulocyte-macrophage colony-forming units with (90)Y in cell culture. The mean effective half-life of (90)Y within the imaging period (up to 6 d) was 3.7 d for liver, 2.4 d for spleen, 2.1 d for kidneys, 1.8 d for lungs, and 1.6 d for blood. The survival fractions of PBSCs in patients were determined as functions of the infusion time and the injected dose of (90)Y-2IT-BAD-m170. To achieve 90% PBSC survival rate for a 2.0-GBq injection dose, PBSC dosimetry suggested a time interval of 13 d after radioimmunotherapy for PBSC infusion. In contrast, the simple blood concentration method suggested an interval about 7 d for the same PBSC survival rate. In our clinical practice, an interval of 2 wk has been used and worked well. A noninvasive dosimetry method was developed for optimizing the time interval for PBSC infusion after high-dose radionuclide therapy. Our studies suggested that the PBSC dosimetry method was more effective than the blood concentration method in determining the optimal time to reinfuse PBSCs for radiopharmaceuticals that have much a higher activity concentration in organs than that in the blood.


De Novo Approaches to the Solid-Phase Separation of Titanium(IV) and Scandium(III): Translating Speciation Data to Selective On-Bead Chelation toward Applications in Nuclear Medicine.
The solution chemistry of the hydrolytic, early-transition-metal ions Ti4+ and Sc3+ represents a coordination chemistry challenge with important real-world implications, specifically in the context of 44Ti/44Sc and 45Ti/NatSc radiochemical separations. Unclear speciation of the solid and solution phases and tertiary mixtures of mineral acid, organic chelators, and solid supports are common confounds, necessitating tedious screening of multiple variables. Herein we describe how thermodynamic speciation data in solution informs the design of new solid-phase chelation approaches enabling separations of Ti4+ and Sc3+. The ligands catechol (benzene-1,2-diol) and deferiprone [3-hydroxy-1,2-dimethyl-4(1H)-pyridone] bind Ti4+ at significantly more acidic conditions (2-4 pH units) than Sc3+. Four chelating resins were synthesized using either catechol or deferiprone with two different solid supports. Of these, deferiprone appended to carboxylic acid polymer-functionalized silica (CA-Def) resin exhibited excellent binding affinity for Ti4+ across a wide range of HCl concentrations (1.0-0.001 M), whereas Sc3+ was only retained in dilute acidic conditions (0.01-0.001 M HCl). CA-Def resin produced separation factors of >100 (Ti/Sc) in 0.1-0.4 M HCl, and the corresponding Kd values (>1000) show strong retention of Ti4+. A model 44Ti/44Sc generator was produced, showing 65 ± 3% yield of 44Sc in 200 μL of 0.2 M HCl with a significant 44Ti breakthrough of 0.1%, precluding use in its current form. Attempts, however, removed natSc in loading fractions and a dilute (0.4 M HCl) wash and recovered 80% of the loaded 45Ti activity in 400 μL of 6 M HCl. The previously validated 45Ti chelator TREN-CAM was used for comparative proof-of-concept reactions with the CA-Def eluent (in HCl) and literature-reported hydroxamate-based resin eluents (in citric acid). CA-Def shows improved radiolabeling efficiency with an apparent molar activity (AMA) of 0.177 mCi nmol-1, exceeding the established methods (0.026 mCi nmol-1) and improving the separation and recovery of 45Ti for positron emission tomography imaging applications.


The EVVA Cohort Study: Anal and Cervical Type-Specific Human Papillomavirus Prevalence, Persistence, and Cytologic Findings in Women Living With HIV.
The risk of anal cancer due to high-risk human papillomavirus (HR-HPV) is higher in women living with human immunodeficiency virus (HIV) than in the general population. We present findings of cervical and anal HPV and cytologic tests at baseline in the EVVA cohort study and HPV persistence data 6 months after baseline. Semiannual visits included questionnaires, chart reviews, cervical/anal cytologic and cervical/anal HPV testing for 2 years. Genotyping for 36 HPV genotypes was performed using the Roche Linear Array HPV genotyping test. A total of 151 women living with HIV were recruited. At baseline, 75% had anal HPV, 51% had anal HR-HPV, 50% had cervical HPV, and 29% had cervical HR-HPV. Anal HPV-16 and HPV-51 were more frequent in women born in Canada (31% and 29%, respectively, compared with ≤16% for other women). Most anal HR-HPV types detected at 6 months (57%-93%) were persistent from baseline. Findings of anal cytologic tests were abnormal for 37% of women. Anal HPV is highly prevalent in women living with HIV, and type distribution varies by place of birth. High-resolution anoscopy was indicated in more than one third of results. As anal cancer is potentially preventable, these important findings need to be considered when selecting the best approach for anal cancer screening programs.


COVID-19 infection in patients with sarcoidosis: susceptibility and clinical outcomes.
Patients with sarcoidosis may be at higher risk of coronavirus disease-19 (COVID-19) as over 90% of the patients have pulmonary involvement and many are treated with immunosuppressive agents. This review will summarize the current literature regarding sarcoidosis and COVID-19, with a particular focus on susceptibility, clinical outcomes, management, and approach to vaccination. Data about COVID-19 and sarcoidosis include a number of case series and reports, cohort studies, and registries. Literature is not conclusive whether patients with sarcoidosis have increased susceptibility to COVID-19. Patients with moderate to severe impaired pulmonary function may be at increased risk of adverse outcomes and mortality. Whether immunosuppressive medication increases risk of COVID-19 severity or affects vaccination response is not yet clear. Novel approaches, such as telemedicine and home monitoring programs, are promising to ensure continuity of care for patients with sarcoidosis during the COVID-19 pandemic. Current evidence about the risk and clinical outcomes of COVID-19 infection in patient with sarcoidosis, is mainly extrapolated from other immune-mediated diseases. Hence, further research that focuses on the sarcoidosis population is warranted.


Aromatic aldehydes at the active site of aldehyde oxidoreductase from Desulfovibrio gigas: reactivity and molecular details of the enzyme-substrate and enzyme-product interaction.
Desulfovibrio gigas aldehyde oxidoreductase (DgAOR) is a mononuclear molybdenum-containing enzyme from the xanthine oxidase (XO) family, a group of enzymes capable of catalyzing the oxidative hydroxylation of aldehydes and heterocyclic compounds. The kinetic studies reported in this work showed that DgAOR catalyzes the oxidative hydroxylation of aromatic aldehydes, but not heterocyclic compounds. NMR spectroscopy studies using (13)C-labeled benzaldehyde confirmed that DgAOR catalyzes the conversion of aldehydes to the respective carboxylic acids. Steady-state kinetics in solution showed that high concentrations of the aromatic aldehydes produce substrate inhibition and in the case of 3-phenyl propionaldehyde a suicide substrate behavior. Hydroxyl-substituted aromatic aldehydes present none of these behaviors but the kinetic parameters are largely affected by the position of the OH group. High-resolution crystallographic structures obtained from single crystals of active-DgAOR soaked with benzaldehyde showed that the side chains of Phe425 and Tyr535 are important for the stabilization of the substrate in the active site. On the other hand, the X-ray data of DgAOR soaked with trans-cinnamaldehyde showed a cinnamic acid molecule in the substrate channel. The X-ray data of DgAOR soaked with 3-phenyl propionaldehyde showed clearly how high substrate concentrations inactivate the enzyme by binding covalently at the surface of the enzyme and blocking the substrate channel. The different reactivity of DgAOR versus aldehyde oxidase and XO towards aromatic aldehydes and N-heterocyclic compounds is explained on the basis of the present kinetic and structural data.


[Update on new antithrombotic treatments].
Update on new antithrombotic treatments Antithrombotic treatments are frequently prescribed in different clinical situations. Classical anticoagulants have some disadvantages. New anticoagulants have emerged recently. Fondaparinux is now prescribed for both prophylaxis and treatment of venous thromboembolism. Two drugs are particularly interesting: rivaroxaban and dabigatran. Concerning the new antiplatelet agents, many molecules such as prasugrel, ticagrelor, cangrelor, SCH530348 or terutroban have appeared recently. They are directed either to the P2Y12 receptor or to other original targets. Studies have shown an increased bleeding risk for some of them as well as unexpected side effects. In the next future, these new molecules could allow a more individualised prescription of antithrombotic agents.


Modulating the gut microbiota by probiotics, prebiotics, postbiotics, and fecal microbiota transplantation: An emerging trend in cancer patient care.
Treatment resistance, together with acute and late adverse effects, represents critical issues in the management of cancer patients. Promising results from preclinical and clinical research underline the emerging trend of a microbiome-based approach in oncology. Favorable bacterial species and higher gut diversity are associated with increased treatment efficacy, mainly in chemo- and immunotherapy. On the other hand, alterations in the composition and activity of gut microbial communities are linked to intestinal dysbiosis and contribute to high treatment-induced toxicity. In this Review, we provide an overview of studies concerning gut microbiota modulation in patients with solid and hematologic malignancies with a focus on probiotics, prebiotics, postbiotics, and fecal microbiota transplantation. Targeting the gut microbiome might bring clinical benefits and improve patient outcomes. However, a deeper understanding of mechanisms and large clinical trials concerning microbiome and immunological profiling is warranted to identify safe and effective ways to incorporate microbiota-based interventions in routine clinical practice.


Mobility of Phosphine-Susceptible and -Resistant Rhyzopertha dominica (Coleoptera: Bostrichidae) and Tribolium castaneum (Coleoptera: Tenebrionidae) After Exposure to Controlled Release Materials With Existing and Novel Active Ingredients.
There is interest in developing controlled release materials (CRMs) with novel modes of action to improve resistance management. Long-lasting insecticide-incorporated netting (LLIN) with deltamethrin has been effectively used against stored-product pests. Here, we evaluated the efficacy of different CRMs (LLIN or packaging) with each of four active ingredients (AI) (deltamethrin, permethrin, indoxacarb, and dinotefuran) and compared them to control CRMs in reducing movement and increasing mortality of phosphine-susceptible and -resistant Rhyzopertha dominica and Tribolium castaneum. Adults were exposed for 0.5, 2, or 60 min, and movement was assessed immediately or after 24, or 168 h using video-tracking and Ethovision software. We recorded total distance and velocity traveled by adults. Finally, we tested higher rates of each AI on surrogate netting material (e.g., standardized-sized cheesecloth) and varied exposure time to obtain median lethal time (LT50) for each compound and susceptibility. Exposure to LLIN with deltamethrin significantly reduced the movement of both species compared to the other CRMs regardless of their susceptibility to phosphine. Deltamethrin was the most effective AI for both species, while dinotefuran and indoxacarb were the least effective for R. dominica and T. castaneum adults, respectively. Most AIs resulted in appreciable and approximately equivalent mortality at higher concentrations among phosphine-susceptible and -resistant strains. Our results demonstrate that CRMs can be an additional approach to combat phosphine-resistant populations of stored product insects around food facilities. Other compounds such as permethrin, dinotefuran, and indoxacarb are also effective against phosphine-resistant populations of these key stored product insects except indoxacarb for T. castaneum.


[The methodological bases of topographic neuropathomorphology].
This paper describes the major features of topographic and anatomical studies of CNS structures, CSF circulation system, extracerebral structures and vertebral column. These methods include brain fixation, which is able to prevent post mortem brain deformation due to decalcification (even for block-preparations like "brain-skull base" or "posterior cerebral fossa-cervical spine"). The author also presents the following methods: spatial reconstruction of the brain and skull base subtracted from the series of slices of different thickness and various planes of transection; biopsy investigation of cerebral midline structures and CSF system in relation with skull base and convex structures; staged microdissection of tumors; filling of arterial and venous systems. All these modalities were used in examining the topographical features of craniopharyngiomas, hypophyseal adenomas, parasagittal and sagittal meningiomas, pineal tumors, VIII cranial nerve neurinomas, arachnoid cysts and in developing surgical approaches to the tumors of the third ventricle, skull base and foramen magna.


Interkingdom fusion between human (HeLa) cells and tobacco hybrid (GGLL) protoplasts.
The fusion of human HeLa cells with tobacco protoplasts has been accomplished with the use of polyethylene glycol. The sequence from heterocellular adherence to heterokaryon formation has been followed with light microscopy and confirmed by autoradiographs of heterokaryons containing unlabeled tobacco nuclei and tritium-labeled HeLa nuclei. The HeLa nucleus retained its integrity in the tobacco cytoplasm up to 6 days after fusion.


Do geography and ethnicity play a role in juvenile Spondyloarthritis? A multi-center binational retrospective study.
Observations among Israeli pediatric rheumatologists reveal that pediatric Juvenile Spondyloarthritis (JSpA) may present differently compared to patients from the United States (US). This study is aimed to compare the demographic and clinical variables of Israeli and US JSpA patients upon presentation. We performed a retrospective, cross-sectional, multicenter comparison of JSpA patients among 3 large Israeli pediatric rheumatology centers and a large US pediatric rheumatology center. Patients with diagnosis of Juvenile Ankylosing Spondylitis (JAS) and/or Enthesitis-related Arthritis (ERA) were included. The demographic, clinical and radiologic features were compared. Overall 87 patients were included (39 Israeli, 48 US patients). Upon presentation, inflammatory back pain, sacroiliac joint tenderness and abnormal modified Schober test, were significantly more prevalent among Israeli patients (59% vs. 35.4, 48.7% vs. 16.7, and 41.2% vs. 21.5%, respectively, all p < 0.05), whereas peripheral arthritis and enthesitis were significantly more prevalent among US patients (43.6% vs. 91.7 and 7.7% vs. 39.6% in Israeli patients vs. US patients, p < 0.05). In addition, 96.7% of the Israeli patients versus 29.7% of the US patients demonstrated sacroiliitis on MRI (p < 0.001, N = 67). Less than one-third of the Israeli patients (32%) were HLA-B27 positive vs. 66.7% of US patients (p = 0.007). Israeli children with JSpA presented almost exclusively with axial disease compared to US patients who were more likely to present with peripheral symptoms. HLA B27 prevalence was significantly lower in the Israeli cohort compared to the US cohort. Further studies are needed to unravel the genetic and possibly environmental factors associated with these findings.


RNA Polymerase I Inhibition with CX-5461 as a Novel Therapeutic Strategy to Target MYC in Multiple Myeloma.
Dysregulation of MYC is frequently implicated in both early and late myeloma progression events, yet its therapeutic targeting has remained a challenge. Among key MYC downstream targets is ribosomal biogenesis, enabling increases in protein translational capacity necessary to support the growth and self-renewal programmes of malignant cells. We therefore explored the selective targeting of ribosomal biogenesis with the small molecule RNA polymerase (pol) I inhibitor CX-5461 in myeloma. CX-5461 induced significant growth inhibition in wild-type (WT) and mutant TP53 myeloma cell lines and primary samples, in association with increases in downstream markers of apoptosis. Moreover, Pol I inhibition overcame adhesion-mediated drug resistance and resistance to conventional and novel agents. To probe the TP53-independent mechanisms of CX-5461, gene expression profiling was performed on isogenic TP53 WT and knockout cell lines and revealed reduction of MYC downstream targets. Mechanistic studies confirmed that CX-5461 rapidly suppressed both MYC protein and MYC mRNA levels. The latter was associated with an increased binding of the RNA-induced silencing complex (RISC) subunits TARBP2 and AGO2, the ribosomal protein RPL5, and MYC mRNA, resulting in increased MYC transcript degradation. Collectively, these studies provide a rationale for the clinical translation of CX-5461 as a novel therapeutic approach to target MYC in myeloma.


A tunable diode laser absorption spectrometer for formaldehyde atmospheric measurements validated by simulation chamber instrumentation.
A tunable diode laser absorption spectrometer (TDLAS) for formaldehyde atmospheric measurements has been set up and validated through comparison experiments with a Fourier transform infrared spectrometer (FT-IR) in a simulation chamber. Formaldehyde was generated in situ in the chamber from reaction of ethene with ozone. Three HCHO ro-vibrational line intensities (at 2909.71, 2912.09 and 2914.46 cm(-1)) possibly used by TDLAS were calibrated by FT-IR spectra simultaneously recorded in the 1600-3200 cm(-1) domain during ethene ozonolysis, enabling the on-line deduction of the varying concentration for HCHO in formation. The experimental line intensities values inferred confirmed the calculated ones from the updated HITRAN database. In addition, the feasibility of stratospheric in situ HCHO measurements using the 2912.09 cm(-1) line was demonstrated. The TDLAS performances were also assessed, leading to a 2sigma detection limit of 88 ppt in volume mixing ratio with a response time of 60 sec at 30 Torr and 294 K for 112 m optical path. As part of this work, the room-temperature rate constant of this reaction and the HCHO formation yield were found to be in excellent agreement with the compiled literature data.


Individual nutritional intervention for prevention of readmission among geriatric patients-a randomized controlled pilot trial.
Approximately 20% of older people are readmitted to the hospital within 30 days of discharge. Even a short hospital stay decreases the ability to cope with the activities of daily living. The aims of this study were to (1) assess the feasibility of recruitment, (2) assess the acceptability of the intervention, and (3) investigate if an individual nutritional intervention could reduce the readmission rate of geriatric patients within 30 days of being discharged to their own homes. The unblinded, randomized, controlled pilot trial includes geriatric patients discharged to their own homes. Forty patients were recruited from a medical ward and randomized to standard treatment (n = 19) or individualized nutritional intervention (n = 21). The intervention was dietary counseling and a nutrition plan before discharge, combined with two home visits performed by an educated nutritionist over a period of 4 weeks. Outcomes were readmission (primary), mortality, protein and energy intake, body weight, activity of daily living, handgrip strength, number of chair stands, and quality of life. Intention-to-treat analysis, per-protocol analysis, and post hoc analysis of readmissions were carried out. Recruitment was feasible, and there was high compliance to the intervention. There was no difference in readmission between the intervention group and control group 30 days after discharge (29% vs 11%). The individual nutritional intervention had a positive impact on achieving 75% of energy requirements at 30 days for the intervention group compared to the control group (93% vs 47%, p = 0.01). No other differences were found between the groups. The individual nutritional intervention did not prevent readmission among geriatric patients in this trial. Recruitment procedures functioned well, and the intervention was well accepted by the patients. ClinicalTrial.gov, NCT03519139 . Retrospectively registered on 8 May 2018.


Bibliometric analysis of nutrition and dietetics research activity in Arab countries using ISI Web of Science database.
Reducing nutrition-related health problems in Arab countries requires an understanding of the performance of Arab countries in the field of nutrition and dietetics research. Assessment of research activity from a particular country or region could be achieved through bibliometric analysis. This study was carried out to investigate research activity in "nutrition and dietetics" in Arab countries. Original and review articles published from Arab countries in "nutrition and dietetics" Web of Science category up until 2012 were retrieved and analyzed using the ISI Web of Science database. The total number of documents published in "nutrition and dietetics" category from Arab countries was 2062. This constitutes 1% of worldwide research activity in the field. Annual research productivity showed a significant increase after 2005. Approximately 60% of published documents originated from three Arab countries, particularly Egypt, Kingdom of Saudi Arabia, and Tunisia. However, Kuwait has the highest research productivity per million inhabitants. Main research areas of published documents were in "Food Science/Technology" and "Chemistry" which constituted 75% of published documents compared with 25% for worldwide documents in nutrition and dietetics. A total of 329 (15.96%) nutrition - related diabetes or obesity or cancer documents were published from Arab countries compared with 21% for worldwide published documents. Interest in nutrition and dietetics research is relatively recent in Arab countries. Focus of nutrition research is mainly toward food technology and chemistry with lesser activity toward nutrition-related health research. International cooperation in nutrition research will definitely help Arab researchers in implementing nutrition research that will lead to better national policies regarding nutrition.


Reovirus core protein mu2 determines the filamentous morphology of viral inclusion bodies by interacting with and stabilizing microtubules.
Cells infected with mammalian reoviruses often contain large perinuclear inclusion bodies, or "factories," where viral replication and assembly are thought to occur. Here, we report a viral strain difference in the morphology of these inclusions: filamentous inclusions formed in cells infected with reovirus type 1 Lang (T1L), whereas globular inclusions formed in cells infected with our laboratory's isolate of reovirus type 3 Dearing (T3D). Examination by immunofluorescence microscopy revealed the filamentous inclusions to be colinear with microtubules (MTs). The filamentous distribution was dependent on an intact MT network, as depolymerization of MTs early after infection caused globular inclusions to form. The inclusion phenotypes of T1L x T3D reassortant viruses identified the viral M1 genome segment as the primary genetic determinant of the strain difference in inclusion morphology. Filamentous inclusions were seen with 21 of 22 other reovirus strains, including an isolate of T3D obtained from another laboratory. When the mu2 proteins derived from T1L and the other laboratory's T3D isolate were expressed after transfection of their cloned M1 genes, they associated with filamentous structures that colocalized with MTs, whereas the mu2 protein derived from our laboratory's T3D isolate did not. MTs were stabilized in cells infected with the viruses that induced filamentous inclusions and after transfection with the M1 genes derived from those viruses. Evidence for MT stabilization included bundling and hyperacetylation of alpha-tubulin, changes characteristically seen when MT-associated proteins (MAPs) are overexpressed. Sequencing of the M1 segments from the different T1L and T3D isolates revealed that a single-amino-acid difference at position 208 correlated with the inclusion morphology. Two mutant forms of mu2 with the changes Pro-208 to Ser in a background of T1L mu2 and Ser-208 to Pro in a background of T3D mu2 had MT association phenotypes opposite to those of the respective wild-type proteins. We conclude that the mu2 protein of most reovirus strains is a viral MAP and that it plays a key role in the formation and structural organization of reovirus inclusion bodies.


PARAMOUNT: Descriptive subgroup analyses of final overall survival for the phase III study of maintenance pemetrexed versus placebo following induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer.
The PARAMOUNT phase III trial demonstrated that pemetrexed continuation maintenance significantly reduced the risk of disease progression (hazard ratio = 0.62) and death (hazard ratio = 0.78) versus placebo in patients with advanced nonsquamous non-small-cell lung cancer. To further understand the survival data, descriptive subgroup analyses were undertaken. Nine hundred thirty-nine patients received induction therapy (four 21-day cycles pemetrexed 500 mg/m and cisplatin 75 mg/m), after which 539 nonprogressing patients with an Eastern Cooperative Oncology Group performance status (PS) of 0/1 were randomized (2:1) to maintenance pemetrexed (500 mg/m) cycles or placebo until disease progression. Baseline characteristics of patients surviving for longer periods were comparable to patients surviving shorter periods, suggesting overall survival (OS) benefit for all subgroups of patients on maintenance therapy. An examination of type and severity of induction adverse events also found no association with survival duration. Response to induction (tumor response versus stable disease) was not determinate of pemetrexed maintenance OS outcome as assessed by waterfall plot and scattergrams and by the distribution of patients among various OS intervals. The length of the interval before beginning maintenance therapy (<7 days versus ≥7/≤30 days) also did not impact the survival results. PS, a known prognostic factor, was the only baseline characteristic associated with improved OS; however, both PS 0 and PS 1 patients exhibited a survival benefit from pemetrexed maintenance. In PARAMOUNT, the OS benefit was seen across all subgroups. Other than PS, no baseline or clinical parameter clearly identified a subgroup more likely to benefit. Maintenance treatment decisions should be made on an individual basis.


Evolution, emotions, and emotional disorders.
Emotions research is now routinely grounded in evolution, but explicit evolutionary analyses of emotions remain rare. This article considers the implications of natural selection for several classic questions about emotions and emotional disorders. Emotions are special modes of operation shaped by natural selection. They adjust multiple response parameters in ways that have increased fitness in adaptively challenging situations that recurred over the course of evolution. They are valenced because selection shapes special processes for situations that have influenced fitness in the past. In situations that decrease fitness, negative emotions are useful and positive emotions are harmful. Selection has partially differentiated subtypes of emotions from generic precursor states to deal with specialized situations. This has resulted in untidy emotions that blur into each other on dozens of dimensions, rendering the quest for simple categorically distinct emotions futile. Selection has shaped flexible mechanisms that control the expression of emotions on the basis of an individual's appraisal of the meaning of events for his or her ability to reach personal goals. The prevalence of emotional disorders can be attributed to several evolutionary factors.


Artificial neural nets for K-complex detection.
An explorative study was initiated to determine whether artificial neural nets (ANNs) can be used to detect K-complexes in EEGs (electroencephalograms). K-complexes are relatively large waves with a duration of between 500 and 1500 ms often seen during sleep stage 2. Sleep spindles (bursts of rhythmic activity with a frequency of 12 to 16 Hz) are almost always observed in the neighborhood of K-complexes. The data and methods used to analyze K-complex are described. In all cases, a multilayer backpropagation ANN was used. The number of input nodes and hidden layers varied. Two different strategies were used to prepare the input to the ANN, and results for both are presented. The results indicate that the neural net approaches used are not adequate for the detection of K-complexes.


Basic Psychological Needs, Physical Self-Concept, and Physical Activity Among Adolescents: Autonomy in Focus.
The contribution of this research lies in its dual approach to the question of physical activity (PA) among adolescents, combining objective measurement of PA by teenagers and a comparison of psychological satisfaction through physical activities involving differing degrees of autonomy (i.e., organized or unstructured). Using the conceptual framework of Self-Determination Theory, the analysis also examines the relationship between levels of PA among adolescents and physical self-concept and satisfaction of basic psychological needs during exercise. The study surveyed 129 first-year higher secondary education students from schools in the city of A Coruña. Satisfaction of basic psychological needs during organized and unstructured physical activities was measured using the Basic Psychological Needs in Exercise Scale. PA levels were assessed based on step count per day for a week as measured by an accelerometer. The results show that the daily step average recorded by students (7,400) is below the minimum recommended levels of PA for this age group, that students are more active on weekdays than at the weekend, and that there is no significant difference in PA levels between male and female subjects (T = 0.23, p < 0.05, d = 0.04). Findings from the comparative analysis of the three basic psychological needs show greater satisfaction of the need for autonomy during unstructured activities (T = 6.15, p < 0.001, d = 0.68), and greater satisfaction of the need for competence during organized activities (T = -2.50, p < 0.05, d = 0.27). No variation in terms of sex was found in relation to satisfaction of the need for autonomy or relatedness from unstructured activities; however, girls showed notably lower satisfaction than boys in relation to the need for competence (T = -2.62, p < 0.01, d = 0.49). Self-esteem was found to play an important mediating role and observed to be strongly related to sex (T = -5.16, p < 0.001, d = 0.90). Organized PA was found to provide greater need satisfaction among boys than girls across all categories. The study showed no relationship between psychological variables and objectively measured PA (Pillai's trace: F = 0.86, p > 0.05, η2 = 0.08, observed power = 0.66). Basic psychological needs show significant positive interrelation between them and a significant positive relationship between them and physical self-concept, as expected based on previous literature.


Evaluation of Mg[B(HFIP)4]2-Based Electrolyte Solutions for Rechargeable Mg Batteries.
One of the greatest challenges toward rechargeable magnesium batteries is the development of noncorrosive electrolyte solutions with high anodic stability that can support reversible Mg deposition/dissolution. In the last few years, magnesium electrolyte solutions based on Cl-free fluorinated alkoxyborates were investigated for Mg batteries due to their high anodic stability and ionic conductivity and the possibility of reversible deposition/dissolution in ethereal solvents. Here, the electrochemical performance of Mg[B(hexafluoroisopropanol)4]2/dimethoxyethane (Mg[B(HFIP)4]2/DME) solutions was examined. These electrolyte solutions require a special "conditioning" pretreatment that removes undesirable active moieties. Such a process was developed and explored, and basic scientific issues related to the mechanism by which it affects Mg deposition/dissolution were addressed. The chemical changes that occur during the conditioning process were examined. Mg[B(HFIP)4]2/DME solutions were found to enable reversible Mg deposition, albeit with a relatively low Coulombic efficiency of 95% during the first cycles. Prolonged deposition/dissolution cycling tests demonstrate a stable behavior of magnesium electrodes. Overall, this system presents a reasonable electrolyte solution and can serve as a basis for future efforts to develop chlorine-free alternatives for secondary magnesium batteries. It is clear that such a conditioning process is mandatory, as it removes reactive contaminants that lead to unavoidable passivation and deactivation of Mg electrodes from the solution.


A Southeastern Cancer Study Group phase I/II trial with vaccinia melanoma oncolysates.
Vaccinia melanoma oncolysates (VMO) were tested in a Southeastern Cancer Study Group (SECSG) Phase I/II trial. Forty-eight patients with high-risk Stage I or pathologic Stage II disease were placed on study at six different dose levels and two different treatment regimens. Patients were monitored for toxicity to the VMO after each injection. Patients' sera were tested for anti-human melanoma reactivity with the Staphylococcus Protein A (SpA) assay. Toxicity was minimal at all doses tested. In only 2 of 19 patients on delayed treatment did reactivity develop in the SpA assay by 6 months. However, 13 of 23 patients on immediate treatment showed reactivity, including 8 of 8 at the two highest doses. Since the VMO appears to be safe at all of the doses tested, and because of the immunogenicity of the VMO at the higher doses as demonstrated by the SpA assay, the 2-mg dose level, for immediate treatment, was chosen for use in future trials.


Propranolol inhibits the compensatory increase in androgen secretion after unilateral orchidectomy in rats.
Adrenergic antagonists were administered to rats by intratesticular injection at the time of unilateral orchidectomy and 5 h before autopsy, 24 h after surgery. Injections of the beta-receptor antagonist DL-propranolol (0.5 or 1.0 mg/injection) significantly inhibited the increase in the concentration of androgens in testicular vein plasma or interstitial fluid that occurred in unilaterally orchidectomized animals injected with vehicle. DL-Propranolol injections in animals with both testes did not reduce testicular or peripheral androgen concentrations or their increase after hCG administration. Injections of the less potent isomer (+)-propranolol or the alpha-receptor antagonist phentolamine did not inhibit the response to unilateral orchidectomy. It is concluded that the compensatory increase in androgen secretion induced by unilateral orchidectomy is, at least in part, the result of beta-adrenergic stimulation of steroidogenesis.


Bacterial arthritis in the adult.
A brief review of bacterial arthritis as seen at the Mayo Clinic in the years 1958 through 1973 has been presented with a selected literature review. Once considered a disease of children and adolescents, this disease now is seen more often in adults, especially in those who are elderly, are chronically ill, or are receiving medications that lower the host resistance in invading bacteria. The diagnosis must be made early, with rapid isolation and identification of the organism. Proper antibacterial drugs should be selected on the basis of in vitro susceptibility tests. The joint should be either aspirated or decompressed by closed suction-irrigation. In instances in which diagnosis is late and joint destruction occurs, joint débridement will be necessary.


Delay activity of specific prefrontal interneuron subtypes modulates memory-guided behavior.
Memory-guided behavior requires maintenance of task-relevant information without sensory input, but the underlying circuit mechanism remains unclear. Calcium imaging in mice performing a delayed Go or No-Go task revealed robust delay activity in dorsomedial prefrontal cortex, with different pyramidal neurons signaling Go and No-Go action plans. Inhibiting pyramidal neurons by optogenetically activating somatostatin- or parvalbumin-positive interneurons, even transiently during the delay, impaired task performance, primarily by increasing inappropriate Go responses. In contrast, activating vasoactive intestinal peptide (VIP)-positive interneurons enhanced behavioral performance and neuronal action plan representation. Furthermore, while endogenous activity of somatostatin and parvalbumin neurons was strongly biased toward Go trials, VIP neurons were similarly active in Go and No-Go trials. Somatostatin or VIP neuron activation also impaired or enhanced performance, respectively, in a delayed two-alternative forced-choice task. Thus, dorsomedial prefrontal cortex is a crucial component of the short-term memory network, and activation of its VIP neurons improves memory retention.


Nurses' perspective of conducting family conversation.
Nurses are in a prime position to manage to support families that have a family member living in a residential home for older people. Nurses' attitudes about meeting patients' family members vary. Studies describe that some nurses consider family members as a burden. But some nurses consider family members a resource and think it is important to establish good relationships with them. The aim of this study was to describe how registered nurses (RNs) experienced to participate in and conduct the intervention Family Health Conversations (FamHCs) with families in residential homes for older people. The intervention FamHC was accomplished at three residential homes for older people. FamHC is a family systems nursing (FSN) intervention developed to support families facing the ill health of someone in the family. One RN from each residential home conducted the conversations. The RNs wrote diary notes directly after each conversation. The RNs were also interviewed 1 month after they had each conducted four FamHCs. The diary notes and the interviews were analysed separately by qualitative content analysis, and the findings were then summarized in one theme and further discussed together. The main findings were that the RNs experience the conversations as a valuable professional tool involving the whole family. The RNs grasped that silence can be a valuable tool and had learned to attentively listen to what the families were saying without interrupting, allowing them and the families to reflect upon what the family members said. The findings show that the FamHC can be helpful for RNs in their work, helping them to perceive and understand the needs and desires of the families.


A COMPARISON OF THE SPECIFICITY OF INHIBITION BY PHOSPHONATE ESTERS OF THE FIRST COMPONENT OF COMPLEMENT AND THE ANTIGEN-INDUCED RELEASE OF HISTAMINE FROM GUINEA PIG LUNG.
The ability of a number p-nitrophenylethyl alkyl, phenyl alkyl, chloroalkyl, and aminoalkyl phosphonates to inhibit the activated first component (C'1a) of guinea pig complement, and the antigen-induced release of histamine from sliced, perfused guinea pig lung has been compared. C'1a in its reactivity with these phosphonates is distinctly more similar to trypsin than to any of the other enzymes studied previously. It is suggested that both trypsin and C'1a possess an anionic group in the active center of the respective enzyme, but the distance between the anionic and esteratic site in C'1a might be less than in trypsin. The pattern of inhibition of histamine relase by the alkyl, phenyl alkyl, and chloroalkyl phosphonates is similar to the inhibition of C'1a by these compounds, although distinct differences are apparent. The aminoalkyl phosphonates are distinctly less active inhibitors of histamine release than the corresponding alkyl phosphonates, whereas the reverse is true of the inhibition of C'1a. On the basis of these differences, it is tentatively concluded that the organophosphorus-inhibitable enzymes in the guinea pig systems studied here are similar but not identical.


The regulatory ancestral network of surgical meshes.
All surgical meshes entering the U.S. market have been cleared for clinical use by the 510(k) process of the Food and Drug Administration (FDA), in which devices simply require proof of "substantial equivalence" to predicate devices, without the need for clinical trials. However, recalled meshes associated with adverse effects may, indirectly, continue to serve as predicates for new devices raising concerns over the safety of the 510(k) route. Here we assess the potential magnitude of this problem by determining the ancestral network of equivalence claims linking recently cleared surgical meshes. Using the FDA website we identified all surgical meshes cleared by the 510(k) route between January 2013 and December 2015 along with all listed predicates for these devices. Using a network approach, we trace the ancestry of predicates across multiple generations of equivalence claims and identify those meshes connected to devices that have since recalled from the market along with the reason for their recall. We find that the 77 surgical meshes cleared between 2013 and 2015 are based on 771 interconnected predicate claims of equivalence from 400 other devices. The vast majority of these devices (97%) are descended from only six surgical meshes that were present on the market prior to 1976. One of these ancestral meshes alone, provided the basis of 183 subsequent devices. Furthermore, we show that 16% of recently cleared devices are connected through equivalence claims to the 3 predicate meshes that have been recalled for design and material related flaws causing serious adverse events. Taken together, our results show that surgical meshes are connected through a tangled web of equivalency claims and many meshes recently cleared by the FDA have connections through chains of equivalency to devices which have been recalled from the market due to concerns over clinical safety. These findings raise concerns over the efficacy of the 510(k) route in ensuring patient safety.


Inhibition of FGFR Signaling Partially Rescues Hypophosphatemic Rickets in HMWFGF2 Tg Male Mice.
Transgenic mice harboring high molecular weight fibroblast growth factor (FGF)2 isoforms (HMWTg) in osteoblast lineage cells phenocopy human X-linked hypophosphatemic rickets (XLH) and Hyp murine model of XLH demonstrating increased FGF23/FGF receptor signaling and hypophosphatemic rickets. Because HMWFGF2 was upregulated in bones of Hyp mice and abnormal FGF receptor (FGFR) signaling is important in XLH, HMWTg mice were used to examine the effect of the FGFR inhibitor NVP-BGJ398, now in clinical trials for cancer therapy, on hypophosphatemic rickets. Short-term treatment with NVP-BGJ398 rescued abnormal FGFR signaling and hypophosphatemia in HMWTg. Long-term treatment with NVP-BGJ398 normalized tail, tibia, and femur length. Four weeks NVP-BGJ398 treatment significantly increased total body bone mineral density (BMD) and bone mineral content (BMC) in HMWTg mice; however, at 8 weeks, total body BMD and BMC was indistinguishable among groups. Micro-computed tomography revealed decreased vertebral bone volume, trabecular number, and increased trabecular spacing, whereas femur trabecular tissue density was increased; however, NVP-BGJ398 rescued defective cortical bone mineralization, increased thickness, reduced porosity, and increased endosteal perimeter and cortical tissue density in HMWTg. NVP-BGJ398 improved femur cancellous bone, cortical bone structure, growth plate, and double labeling in cortical bone and also increased femur trabeculae double labeled surface, mineral apposition rate, bone formation rate, and osteoclast number and surface in HMWTg. The decreased NPT2a protein that is important for renal phosphate excretion was rescued by NVP-BGJ398 treatment. We conclude that NVP-BGJ398 partially rescued hypophosphatemic rickets in HMWTg. However, long-term treatment with NVP-BGJ398 further increased serum FGF23 that could exacerbate the mineralization defect.