A highly efficient peptide substrate for EGFR activates the kinase by inducing aggregation.
Formation of an asymmetric dimer by the EGFR (epidermal growth factor receptor) kinase domains results in allosteric activation. Since this dimer does not readily form in solution, the EGFR kinase domain phosphorylates most peptide substrates with a relatively low catalytic efficiency. Peptide C is a synthetic peptide substrate of EGFR developed by others that is phosphorylated with a significantly higher catalytic efficiency, and we sought to understand the basis for this. Peptide C was found to increase EGFR kinase activity by promoting formation of the EGFR kinase domain asymmetric dimer. Activation of the kinase domain by Peptide C also enhances phosphorylation of other substrates. Aggregation of the EGFR kinase domain by Peptide C probably underlies activation, and Peptide C precipitates several other proteins. Peptide C was found to form fibrils independent of the presence of EGFR, and these fibrils may facilitate aggregation and activation of the kinase domain. These results establish that a peptide substrate of EGFR may increase catalytic activity by promoting kinase domain dimerization by an aggregation-mediated mechanism.


A Deep Learning-based Method to Extract Lumen and Media-Adventitia in Intravascular Ultrasound Images.
Intravascular ultrasound (IVUS) imaging allows direct visualization of the coronary vessel wall and is suitable for assessing atherosclerosis and the degree of stenosis. Accurate segmentation and lumen and median-adventitia (MA) measurements from IVUS are essential for such a successful clinical evaluation. However, current automated segmentation by commercial software relies on manual corrections, which is time-consuming and user-dependent. We aim to develop a deep learning-based method using an encoder-decoder deep architecture to automatically and accurately extract both lumen and MA border. Inspired by the dual-path design of the state-of-the-art model IVUS-Net, our method named IVUS-U-Net++ achieved an extension of the U-Net++ model. More specifically, a feature pyramid network was added to the U-Net++ model, enabling the utilization of feature maps at different scales. Following the segmentation, the Pearson correlation and Bland-Altman analyses were performed to evaluate the correlations of 12 clinical parameters measured from our segmentation results and the ground truth. A dataset with 1746 IVUS images from 18 patients was used for training and testing. Our segmentation model at the patient level achieved a Jaccard measure (JM) of 0.9080 ± 0.0321 and a Hausdorff distance (HD) of 0.1484 ± 0.1584 mm for the lumen border; it achieved a JM of 0.9199 ± 0.0370 and an HD of 0.1781 ± 0.1906 mm for the MA border. The 12 clinical parameters measured from our segmentation results agreed well with those from the ground truth (all p-values are smaller than .01). Our proposed method shows great promise for its clinical use in IVUS segmentation.


A novel arsenate reductase from the arsenic hyperaccumulating fern Pteris vittata.
Pteris vittata sporophytes hyperaccumulate arsenic to 1% to 2% of their dry weight. Like the sporophyte, the gametophyte was found to reduce arsenate [As(V)] to arsenite [As(III)] and store arsenic as free As(III). Here, we report the isolation of an arsenate reductase gene (PvACR2) from gametophytes that can suppress the arsenate sensitivity and arsenic hyperaccumulation phenotypes of yeast (Saccharomyces cerevisiae) lacking the arsenate reductase gene ScACR2. Recombinant PvACR2 protein has in vitro arsenate reductase activity similar to ScACR2. While PvACR2 and ScACR2 have sequence similarities to the CDC25 protein tyrosine phosphatases, they lack phosphatase activity. In contrast, Arath;CDC25, an Arabidopsis (Arabidopsis thaliana) homolog of PvACR2 was found to have both arsenate reductase and phosphatase activities. To our knowledge, PvACR2 is the first reported plant arsenate reductase that lacks phosphatase activity. CDC25 protein tyrosine phosphatases and arsenate reductases have a conserved HCX5R motif that defines the active site. PvACR2 is unique in that the arginine of this motif, previously shown to be essential for phosphatase and reductase activity, is replaced with a serine. Steady-state levels of PvACR2 expression in gametophytes were found to be similar in the absence and presence of arsenate, while total arsenate reductase activity in P. vittata gametophytes was found to be constitutive and unaffected by arsenate, consistent with other known metal hyperaccumulation mechanisms in plants. The unusual active site of PvACR2 and the arsenate reductase activities of cell-free extracts correlate with the ability of P. vittata to hyperaccumulate arsenite, suggesting that PvACR2 may play an important role in this process.


Association between socioeconomic deprivation and presentation with a ruptured abdominal aortic aneurysm.
Given the ongoing nature of research in the social determinants space and urges to improve United States Preventive Services Task Force screening efforts for abdominal aortic aneurysms (AAAs), this project aims to characterize the association between the level of socioeconomic deprivation, rurality, and ruptured AAA (rAAA) presentation across the United States. We queried the Vascular Quality Initiative registry (2010-2019) for patients with AAAs. The area deprivation index (ADI) is an index from 1 to 100 used to capture socioeconomic status. ADI was grouped into quintiles, with the most deprived regions being quintile 5 and having the highest ADI index. Multivariable logistic regression assessed the association between ADI, rurality, and rAAA presentation overall and before age 65. Of the 82,909 patients included, 11,458 patients (14%) resided in the most socioeconomically deprived regions, and 18,083 patients (22%) lived in rural regions. Overall, 6831 patients (8.2%) experienced an rAAA, with 4696 patients (69%) residing in the three most deprived quintiles. Most patients underwent endovascular repair (n = 67,933; 82%), followed by open repair (n = 14,976; 18%). On multivariable analysis, residence in the most socioeconomically deprived region was associated with a near 1.5-fold increased odds of presenting with an rAAA compared with a residence in the least deprived regions (odds ratio [OR], 1.46; 95% confidence interval [CI], 1.31-1.63; P < .001), whereas urban residence was associated with a decreased odds to present with an rAAA compared with rural residence (OR, 0.84; 95% CI, 0.79-0.89; P < .001). When stratifying the study population by the United States Preventive Services Task Force recommended age for AAA screening (65 years old), 14,147 patients (17%) were under 65. Of those under 65, 1381 patients (9.8%) experienced a rAAA, and 9955 patients (71%) resided in the three most deprived quintiles. Residence in the most socioeconomically deprived region was associated with an increased odds of presenting with an rAAA compared with residence in the least deprived region (OR, 1.31; 95% CI, 1.01-1.69; P = .042). However, there were no significant associations between rural residence and increased rAAA presentation among individuals under 65 (OR, 1.07; 95% CI, 0.93-1.23; P = .36). Among all patients in this study, patients residing in highly socioeconomically deprived or rural regions were more likely to present with an rAAA, but among those under 65, only residence in a socioeconomically deprived area was associated with increased odds of rAAA presentation. Understanding the effects of socioeconomic deprivation on rAAA presentation can identify at-risk populations for early AAA screening before rupture.


Temporal Trends of Psychosociobehavioral Factors Underlying Tobacco Use: A Semi-Automated Exploratory Analysis of Peer-to-Peer Communication in a Health-Related Online Community.
Online communities have been an integral part of tobacco cessation programs. They are rich in content, and offer insights into factors affecting an individual's behavior change efforts. We used word representation techniques to infer implicit meaning embedded in messages exchanged in a health-related online community. Our analysis of peer interactions revealed that individuals factor in safety, glamour, expense, and media projection when choosing a form of nicotine intake. When choosing pharmacotherapy techniques, individuals focus on brands, dosage, and side effects associated with each form (e.g. gums, patches). Our analysis sheds light on factors embedded in peer interactions, which might lead to opinion formation based on peer influence and knowledge dissemination in these social platforms. Such understanding enables design of high-engagement behavior change technologies, through personalization of content delivery by factoring in individual-level beliefs, behavioral state, and community-level influences.


Chromaffin cell xenografts in the rat neocortex can produce antidepressive activity in the forced swimming test.
Adrenal medullary allografts, as well as other monoaminergic tissues, have been demonstrated in our laboratory to increase antidepressive activity when transplanted into the frontal neocortex of rats. Refinement in the optimal parameters for xenograft viability has indicated that isolated bovine chromaffin cells may be an improved source of graft donor tissue. The aim of the present study was to determine whether isolated bovine chromaffin cell grafts to the rat frontal neocortex could provide an alternative source of catecholamines for antidepressant activity. Isolated bovine chromaffin cells, isolated bovine fibroblasts, or an equal volume of vehicle were unilaterally implanted into the right or left frontal cortex or right visual cortex. All rats were assessed before and 6 weeks after transplantation using the forced swimming test, a popular measure of antidepressant activity. Bovine chromaffin cell grafts in either the right or left frontal cortex produced significant increases in antidepressant activity compared to grafts of bovine fibroblasts and sham-operated or nontransplanted rats. In contrast, bovine chromaffin cells transplanted to the visual cortex did not affect antidepressant activity. Bovine fibroblast grafts in the frontal cortex also induced slight increases in antidepressant activity, although significantly less than chromaffin cell grafts. Morphological analysis revealed robust survival of tyrosine hydroxylase-positive chromaffin cells that retained their in situ ultrastructure and occasionally formed synaptic connections with the host parenchyma. These results suggest that xenografted isolated bovine chromaffin cells can provide a viable source of catecholamines for antidepressive activity.


[Estimation of podocyte dysfunction by nephrinuria severity in proteinuric forms of chronic glomerulonephritis].
To evaluate severity of nephrinuria (NU) as a marker of podocyte dysfunction (PD) in patients with proteinuric forms of chronic glomerulonephritis (CGN) and to specify efficacy of this test for assessment of activity and prognosis of CGN. We examined 74 CGN patients: 18 with inactive nephritis (group 1), 18--with subnephrotic proteinuria (group 2), 38--with nephrotic syndrome--NS (group 3). The control group consisted of 10 healthy subjects. Urinary excretion of nephrin was studied with indirect enzyme immunoassay. A response to immunosuppressive treatment (IST) was studied in 23 NS patients depending on a baseline NU level. An NU level was higher in patients with proteinuric forms of CGN (groups 2 and 3) than in inactive disease and in healthy subjects, in NS patients significantly higher than in less severe proteinuria. NU was significantly higher in arterial hypertension, in persistent NS. Remission of NS was achieved within 6 months of treatment in 9 of 11 (82%) patients with a baseline NU level < 17 ng/ml. Eight from 12 (67%) patients with high NU did not respond to IST conducted for 9 months to 2 years. ROC-curve construction showed that NU assessment in NS patients has high informative value in assessment of prognosis and efficacy of treatment in 6 months to come. The NU test in CGN patients is an informative diagnostic test allowing prognosis of a response to IST and assessment of PD severity.


DM2 intronic expansions: evidence for CCUG accumulation without flanking sequence or effects on ZNF9 mRNA processing or protein expression.
Myotonic dystrophy type 2 (DM2) is caused by a CCTG expansion mutation in intron 1 of the zinc finger protein 9 (ZNF9) gene. The mean expansion size in patients is larger than for DM1 or any previously reported disorder (mean=5000 CCTGs; range=75-11 000), and similar to DM1, repeats containing ribonuclear inclusions accumulate in affected DM2 tissue. Although an RNA gain-of-function mechanism involving DM1 CUG or DM2 CCUG expansion transcripts is now well established, still debated are the potential role that flanking sequences within the DMPK 3'-UTR may have on disease pathogenesis and whether or not decreased expression of DMPK, ZNF9 or neighboring genes at these loci contribute to disease. To address these questions in DM2, we have examined the nucleic acid content of the ribonuclear inclusions and the effects of these large expansions on ZNF9 expression. Using cell lines either haploid or homozygous for the expansion, as well as skeletal muscle biopsy tissue, we demonstrate that pre-mRNAs containing large CCUG expansions are normally spliced and exported from the nucleus, that the expansions do not decrease ZNF9 expression at the mRNA or protein level, and that the ribonuclear inclusions are enriched for the CCUG expansion, but not intronic flanking sequences. These data suggest that the downstream molecular effects of the DM2 mutation are triggered by the accumulation of CCUG repeat tract alone.


Update on measurement of relevant outcomes in rheumatology.
It is now recognized that disease has a multidimensional impact on patients' lives. This impact can be perceived as a spectrum encompassing on one end "hard" disease outcomes such as organ failure and mortality, and on the other end "soft" outcomes such as quality of life or patient satisfaction. This spectrum may be viewed as a framework in measuring both disease impact and response to treatment. In this paper, we review improvements in the methodology of measurement of relevant outcomes and highlight new findings and emerging trends in rheumatology.


Decreased levels of CXC-chemokines in serum of benzene-exposed workers identified by array-based proteomics.
Benzene is an important industrial chemical and environmental contaminant that causes leukemia. To obtain mechanistic insight into benzene's mechanism of action, we examined the impact of benzene on the human serum proteome in a study of exposed healthy shoe-factory workers and unexposed controls. Two sequential studies were performed, each using sera from 10 workers exposed to benzene (overall mean benzene air level >30 ppm) and 10 controls. Serum samples were subjected to anion-exchange fractionation and bound to three types of ProteinChip arrays (Ciphergen Biosystems, Fremont, CA) [hydrophobic (H50), metal affinity (IMAC3-Cu), and cation exchange (WCX2)]. Protein-expression patterns were detected by surface-enhanced laser desorption/ionization (SELDI)-TOF MS. Three proteins (4.1, 7.7, and 9.3 kDa) were consistently down-regulated in exposed compared with control subjects in both studies. All proteins were highly inversely correlated with individual estimates of benzene exposure (r > 0.75). The 7.7- and 9.3-kDa proteins were subsequently identified as platelet factor (PF)4 and connective tissue activating peptide (CTAP)-III. Initial proteomic results for PF4 and CTAP-III were subsequently confirmed in a single experiment using a ProteinChip-array-based immunoassay(Ciphergen Biosystems). The altered expression of the platelet-derived CXC-chemokines (40% and 63% for PF4 and CTAP-III, respectively) could not be explained by changes in absolute platelet counts. Thus, SELDI-TOF analysis of a limited number of exposed and unexposed subjects revealed that lowered expression of PF4 and CTAP-III proteins is a potential biomarker of benzene's early biologic effects and may play a role in the immunosuppressive effects of benzene.


Effects of preparation time on phase of cultured tissues reveal complexity of circadian organization.
The phases of central (SCN) and peripheral circadian oscillators are held in specific relationships under LD cycles but, in the absence of external rhythmic input, may damp or drift out of phase with each other. Rats exposed to prolonged constant light become behaviorally arrhythmic, perhaps as a consequence of dissociation of phases among SCN cells. The authors asked whether individual central and peripheral circadian oscillators were rhythmic in LL-treated arrhythmic rats and, if rhythmic, what were the phase relationships between them. The authors prepared SCN, pineal gland, pituitary, and cornea cultures from transgenic Period1-luciferaserats whose body temperature and locomotor activity were arrhythmic and from several groups of rhythmic rats held in LD, DD, and short-term LL. The authors measured mPer1gene expression by recording light output with sensitive photomultipliers. Most of the cultures from all groups displayed circadian rhythms. This could reflect persistent rhythmicity in vivo prior to culture or, alternatively, rhythmicity that may have been initiated by the culture procedure. To test this, the authors cultured tissues at 2 different times 12 h apart and asked whether phase of the rhythm was related to culture time. The pineal, pituitary, and SCN cultures showed partial or complete dependence of phase on culture time, while peak phases of the cornea cultures were independent of culture time in rhythmic rats and were randomly distributed regardless of culture time in arrhythmic animals. These results suggest that in behaviorally arrhythmic rats, oscillators in the pineal, pituitary, and SCN had been arrhythmic or severely damped in vivo, while the cornea oscillator was free running. The peak phases of the SCN cultures were particularly sensitive to some aspect of the culture procedure since rhythmicity of SCN cultures from robustly rhythmic LD-entrained rats was strongly influenced when the procedure was carried out at any time except the 2nd half of the day.


Costs and benefits of multi-male associations in redfronted lemurs (Eulemur fulvus rufus).
The evolution of group-living has fascinated but also puzzled researchers from the inception of behavioural ecology. We use a simple optimality approach to examine some of the costs and benefits of group-living in redfronted lemurs (Eulemur fulvus rufus). We show that dominant males profit from accepting subordinates within their groups, as the latter significantly decrease the likelihood that the group is taken over by intruders. This benefit is large enough to outweigh the costs of reproductive competition and may constitute the driving force behind the evolution of multi-male associations in this species.


Feasibility in meeting nutrient amounts of the National School Feeding Program and its relationship with the menu cost.
We evaluated the feasibility of the menu adequacy regarding the nutritional constraints established by the National School Feeding Program (PNAE) and its relation to the cost. Each menu accounted for a given food combination within each food group. A diet optimization model comprising each set of foods was designed to obtain food quantities in order to meet the exigences of the PNAE at the lowest cost (menus with 20% and 30% of dietary reference intake for energy, macronutrients, calcium, iron, magnesium, zinc, vitamins A and C, also restrictions for sodium, saturated and trans fats, and added sugar). There was no feasible solution that accommodated all nutrient targets. Limiting components were calcium, sodium, and carbohydrates; but the menus were adequate for the other nutrients. There was a positive correlation between the menu cost and the frequency of meat and fruits, and a negative correlation with the contents of sodium and carbohydrates, and with the frequencies of rice and beans. The probability of obtaining carbohydrate adequacy was close to zero when the meat frequency was higher than one serving per week. In conclusion, it is unlikely to obtain menus that meet all the requirements of the PNAE.


gem-Diamine 1-N-iminosugars and related iminosugars, candidate of therapeutic agents for tumor metastasis.
Cancer metastasis is one of the major challenges in cancer research. Inhibitors of tumor metastasis are rapidly emerging as important new drug candidates for cancer therapy. Tumor metastasis formation occurs via a complex multistage process which involves a crucial step of tumor invasion through the basement membrane. Tumor cell invasion involves attachment of tumor cell to the basement membrane through laminin, degradation of the matrix by proteolytic enzymes from the tumor cell and cell migration through the basement membrane. New drugs aimed at the metabolism of tumor cell surface oligosaccharides and/or catabolism of glycoconjugates of extracellular matrix and basement membrane could inhibit tumor metastasis. In this article, current progress in the control of tumor metastasis by gem-diamine 1-N-iminosugars and related iminosugars (nojirimycin and d-glucaro-delta-lactam), which are potent and specific inhibitors of carbohydrate metabolism and catabolism, has been reviewed. gem-Diamine 1-N-iminosugars related to d-glucuronic acid and l-iduronic acid, nojirimycin and d-glucaro-delta-lactam suppress invasion of B16 melanoma variants and 3LL (lung carcinoma) cells through reconstituted basement membrane, and inhibit pulmonary metastasis of these tumor cells in mice and/or cKDH-8/11 (liver carcinoma) cells in rats. These results suggest that the metabolism of beta-d-glucuronide and alpha-l-iduronide of glycoconjugates and/or the processing of carbohydrates of tumor cell surface may participate in tumor metastasis. That these gem-diamine 1-N-iminosugars and related iminosugars are potent inhibitors of tumor metastasis holds promise of new drug candidates for cancer chemotherapy.


A unique photochromic UV-A sensor protein, Rc-PYP, interacting with the PYP-binding protein.
Photoactive yellow protein (PYP) is one of the typical light sensor proteins. Although its photoreaction has been extensively studied, no downstream partner protein has been identified to date. In this study, the intermolecular interaction dynamics observed between PYP from Rhodobacter capsulatus (Rc-PYP) and a possible downstream protein, PYP-binding protein (PBP), were investigated. It was found that UV light induced a long-lived product (pUV*), which interacts with PBP to form a stable hetero-hexamer (Complex-2). The reaction scheme for this interaction was revealed using transient absorption and transient grating methods. Time-resolved diffusion detection showed that a hetero-trimer (Complex-1) is formed transiently, which produced Complex-2 via a second-order reaction. Any other intermediates, including those from pBL, do not interact with PBP. The reaction scheme and kinetics are determined. Interestingly, long-lived Complex-2 dissociates upon excitation with blue light. These results demonstrate that Rc-PYP is a photochromic and new type of UV sensor to sense the relative intensities of UV-A and blue light.


[Supersorbicid in comprehensive treatment of acute pyoinflammatory processes in maxillofacial region].
Antibiotic-containing Supersorbicid was used for drainage during treatment of 56 patients with abscesses and phlegmon of maxillo-facial region. Clinical-laboratory and bacteriological assessment showed that in local application of antibiotic-containing Supersorbicid in the complex treatment of abscesses and phlegmon of maxillo-facial region liquidation of local and common signs of inflammation was faser and corbent accumulated microbes and their toxins and the wound cleaning from necrotic mass was faser that resulted in acceleration of wound healing by secondary adhesion. The results showed that leucocyte intoxication index was significantly decreased in the studied patients and the content of infectious agents was decreased too in patients in comparison with control subjects.


[Use of the monkey pox virus for evaluating the intensity of the immunity against smallpox in experiments on M. rhesus].
Monkeypox virus causing in M, rhesus upon aerogenic infection a disease similar to human varioloid was used to evaluate the intensity of immunity against smallpox in immunized M. rhesus monkeys. Postvaccination immunity was solid in all the animals vaccinated intradermally or orally. In 2 out of 14 monkeys immunized orally, however, the immunity was partially overcome. Neutralizing antibody titers in these two monkeys were 1:5 and 1:25, respectively. This agreed with the observations made in Pakistan indicating the possibility that some humans having serum neutralizing antibody titers up to 1:32 could contract smallpox and develop the disease.


The intra- and inter-observer reliability of the physical examination methods used to assess patients with patellofemoral joint instability.
An accurate physical examination of patients with patellar instability is an important aspect of the diagnosis and treatment. While previous studies have assessed the diagnostic accuracy of such physical examination tests, little has been undertaken to assess the inter- and intra-tester reliability of such techniques. The purpose of this study was to determine the inter- and intra-tester reliability of the physical examination tests used for patients with patellar instability. Five patients (10 knees) with bilateral recurrent patellar instability were assessed by five members of the International Patellofemoral Study Group. Each surgeon assessed each patient twice using 18 reported physical examination tests. The inter- and intra-observer reliability was assessed using weighted Kappa statistics with 95% confidence intervals. The findings of the study suggested that there were very poor inter-observer reliability for the majority of the physical tests, with only the assessments of patellofemoral crepitus, foot arch position and the J-sign presenting with fair to moderate agreement respectively. The intra-observer reliability indicated largely moderate to substantial agreement between the first and second tests performed by each assessor, with the greatest agreement seen for the assessment of tibial torsion, popliteal angle and the Bassett's sign. For the common physical examination tests used in the management of patients with patellar instability inter-observer reliability is poor, while intra-observer reliability is moderate. Standardization of physical exam assessments and further study of these results among different clinicians and more divergent patient groups is indicated.


TAR Syndrome-associated Rbm8a deficiency causes hematopoietic defects and attenuates Wnt/PCP signaling.
Defects in blood development frequently occur among syndromic congenital anomalies. Thrombocytopenia-Absent Radius (TAR) Syndrome is a rare congenital condition with reduced platelets (hypomegakaryocytic thrombocytopenia) and forelimb anomalies, concurrent with more variable heart and kidney defects. TAR syndrome associates with hypomorphic gene function for RBM8A/Y14 that encodes a component of the exon junction complex involved in mRNA splicing, transport, and nonsense-mediated decay. How perturbing a general mRNA-processing factor causes the selective TAR Syndrome phenotypes remains unknown. Here, we connect zebrafish rbm8a perturbation to early hematopoietic defects via attenuated non-canonical Wnt/Planar Cell Polarity (PCP) signaling that controls developmental cell arrangements. In hypomorphic rbm8a zebrafish, we observe a significant reduction of cd41-positive thrombocytes. rbm8a-mutant zebrafish embryos accumulate mRNAs with individual retained introns, a hallmark of defective nonsense-mediated decay; affected mRNAs include transcripts for non-canonical Wnt/PCP pathway components. We establish that rbm8a-mutant embryos show convergent extension defects and that reduced rbm8a function interacts with perturbations in non-canonical Wnt/PCP pathway genes wnt5b, wnt11f2, fzd7a, and vangl2. Using live-imaging, we found reduced rbm8a function impairs the architecture of the lateral plate mesoderm (LPM) that forms hematopoietic, cardiovascular, kidney, and forelimb skeleton progenitors as affected in TAR Syndrome. Both mutants for rbm8a and for the PCP gene vangl2 feature impaired expression of early hematopoietic/endothelial genes including runx1 and the megakaryocyte regulator gfi1aa. Together, our data propose aberrant LPM patterning and hematopoietic defects as possible consequence of attenuated non-canonical Wnt/PCP signaling upon reduced rbm8a function. These results link TAR Syndrome to a potential LPM origin and developmental mechanism.


Seroprevalence of parvovirus B19 infection in daycare educators.
This study was undertaken to provide first-time estimates for the seroprevalence of parvovirus B19 infection among daycare educators in Montréal, Canada, and to identify factors associated with seropositivity. A cross-sectional design was used. Directors and educators from 81 daycare centres (DCCs) were surveyed about DCC and personal characteristics respectively, and serum samples from 477 female educators were tested for parvovirus B19 IgG antibodies. The seroprevalence of parvovirus B19 was 70%. Parvovirus B19 seropositivity was significantly associated with age and with working experience in DCCs, but the latter association was restricted to educators aged less than 40 years. In conclusion, working as a daycare educator appears to be associated with increased risk of acquiring parvovirus B19 infection, but this finding will require further investigation. Because of the large proportion of educators susceptible to acquiring parvovirus B19 infection, our findings also highlight the need for preventive measures.


The meaning of living with malodorous exuding ulcers.
This study illuminates the meaning of living with malodorous, exuding ulcers. Difficulties for patients with chronic ulcers and the ulcers' impact on patients' daily life are described in the literature. Suffering and consolation are also addressed in the literature as important issues in nursing care. The first author interviewed seven women and two men, aged 41-95, with various diagnoses. We interpreted the transcribed interviews using a phenomenological hermeneutic method. Two processes were identified: 'being struck down'- themes: feeling dirty, being trapped, losing confidence, losing hope, becoming frustrated and protecting oneself; and 'finding consolation'- themes: experiencing kinship, encountering genuineness and gaining control. The meaning of living with malodorous and exuding ulcers can be understood as being trapped in a debilitating process that slowly strikes one down. There is a longing for purity and wholeness and for one's life to improve. When people with malodorous, exuding ulcers encounter genuineness and feel loved, regarded and respected as fully human despite their ulcers, they feel purified. The contaminated body no longer contaminates their self-image and self-esteem and they feel restored and fully human again. Only when they feel fully human can they regain control and see life beyond their ulcers. Although nurses cannot make ulcers or smell disappear, they can contribute significantly to improve the patients' life. Finding consolation makes patients feel purified despite their contaminated body. This study points to the importance of seeing the human being beyond the ulcer and considering not only the body but the whole person.


The Interface Theory of Perception.
Perception is a product of evolution. Our perceptual systems, like our limbs and livers, have been shaped by natural selection. The effects of selection on perception can be studied using evolutionary games and genetic algorithms. To this end, we define and classify perceptual strategies and allow them to compete in evolutionary games in a variety of worlds with a variety of fitness functions. We find that veridical perceptions--strategies tuned to the true structure of the world--are routinely dominated by nonveridical strategies tuned to fitness. Veridical perceptions escape extinction only if fitness varies monotonically with truth. Thus, a perceptual strategy favored by selection is best thought of not as a window on truth but as akin to a windows interface of a PC. Just as the color and shape of an icon for a text file do not entail that the text file itself has a color or shape, so also our perceptions of space-time and objects do not entail (by the Invention of Space-Time Theorem) that objective reality has the structure of space-time and objects. An interface serves to guide useful actions, not to resemble truth. Indeed, an interface hides the truth; for someone editing a paper or photo, seeing transistors and firmware is an irrelevant hindrance. For the perceptions of H. sapiens, space-time is the desktop and physical objects are the icons. Our perceptions of space-time and objects have been shaped by natural selection to hide the truth and guide adaptive behaviors. Perception is an adaptive interface.


Fatigue resistance of monolithic and multilayer zirconia crowns using veneer layering or CAD-on technique.
This study aims to evaluate the fatigue resistance of monolithic zirconia (Yz) and multilayer ceramic structures using the CAD-on technique in different thicknesses. Fifty (N=50) standardized single crowns preparations were made in fiberglass-reinforced epoxy resin (NEMA grade G10), digitalized, and restorations were machined in CAD-CAM, composing 5 groups (n= 10): Control: 1.5 mm (milled zirconia framework + manual layered porcelain); Yz monolithic 1.5 mm; Yz monolithic 1.0 mm; CAD-on 1.5 mm; and CAD-on 1.0 mm (milled zirconia framework 0.5 mm thickness bonded by a low fuse ceramic to a milled lithium disilicate layer of 1.0 mm or 0.5 mm, respectively). The G10 bases were conditioned with 10% hydrofluoric acid; the crowns were air abraded with 110 μm alumina particles; and then luted onto each other with self-adhesive resin cement. A cyclic fatigue test was performed (initial load: 400N for 10,000 cycles, frequency of 20 Hz, step size of 200N) until failure, and the data was submitted to a survival statistical analysis. No failures were observed at Yz monolithic 1.5 mm. High and similar performance was observed for Cad-On groups and Yz monolithic 1.0 mm. The control group depicted the worst behavior. The Weibull modulus of CAD-on 1.5 mm was higher than the control while being similar to the other conditions. Both the monolithic systems and the CAD-on technique showed high and similar fatigue fracture behavior and survival rates, which were also higher than the control bilayer system. Both systems reduced the occurrence of delamination failures, making them suitable for clinical use.


Comparison of Postoperative Pain Following One-Visit and Two-Visit Vital Pulpectomy in Primary Teeth: A Single-Blind Randomized Clinical Trial.
The aim of this study was to compare post-operative pain following one-visit pulpectomy and placing stainless steel crown (SSC), with two-visit treatment (performing pulpectomy at the first visit followed by placing SSC at the next visit one week later) in vital pulp of primary molars with carious involvement. In this randomized clinical trial, 100 children aged 6-12 years with a carious primary molar tooth in need of pulpectomy were randomly divided into two groups of 50 each. In one-visit group, pulpectomy and placement of SSC were carried out at the same appointment. In two-visit group, pulpectomy of root canals was carried out at the first visit and placement of SSC was performed at the second visit one week after the first appointment. Post-operative pain was recorded using visual analogue scale (VAS) during one week after each treatment visit. No significant difference was found in the mean age and gender distribution between the two groups (P˃0.05 for both comparisons). Findings revealed that in the two-visit (pulpectomy) group during first three days and 4-7 days after the first treatment appointment, pain felt by the children was significantly lower than that felt by the one-visit group at the same time period (P˂0.0001 for both comparisons). Moreover, children in two-visit (pulpectomy) group consumed significantly lower amount of analgesics than those in the one-visit group (P<0.0001). No significant difference was found between pain felt by children during the first three days following one-visit pulpectomy and placement of SSC at the same appointment. Therefore, one-visit treatment of vital primary tooth is recommended.


Treatment of relapsed undifferentiated acute myeloid leukemia (AML-M0) with Ayurvedic therapy.
A 16-year-old boy was detected with acute myeloid leukemia (AML - M0) with bone marrow pathology showing 85% blasts in February 07, 1997. He received two cycles of induction chemotherapy (3+7 protocol) with daunomycin and cytosar, following which he achieved incomplete remission with bone marrow aspirate showing 14% blasts. Subsequently, the patient received two cycles of high-dose cytosine arabinoside Ara-C and achieved remission. However, his disease relapsed on August 29, 1997. Peripheral blood smear showed 6% blast cells and bone marrow showed 40% blast cells. The patient refused further chemotherapy and/or bone marrow transplant and volunteered for Ayurvedic therapy (AYT) advocated by the author from September 09, 1997. Bone marrow studies done after six months of AYT indicated that the disease was in remission. The AYT was continued for five years and stopped. Thereafter, the patient received intermittent maintenance AYT for three months in the next two years. At present, the patient is normal and healthy and has completed 12 years of disease-free survival with AYT.


Review of Simulation Training in Interventional Radiology.
Simulation training has evolved and is now able to offer numerous training opportunities to supplement the practice of and overcome some of the shortcomings of the traditional Master-Apprentice model currently used in medical training. Simulation training provides new opportunities to practice skills used in clinical procedures, crisis management scenarios, and everyday clinical practice in a risk-free environment. Procedural and nonprocedural skills used in interventional radiology can be taught with the use of simulation devices and technologies. This review will inform the reader of which clinical skills can be trained with simulation, the types of commercially available simulators and their educational validity, and the assessment tools used to evaluate simulation training.


Lithium-induced hyperpolarization of the human rectum in vivo.
The transmucosal potential difference across the rectal mucosa was measured in 30 healthy subjects and in 13 psychiatric patients on lithium treatment for manic-depressive psychosis. It was significantly greater in the lithium-treated patients. A highly significant correlation was found between the potential difference and the serum lithium, and in all eight patients in whom it was measured before and one week after starting lithium treatment a rising potential difference was found. This phenomenon may possibly be explained in terms of resistance of the rectal mucosa to vasopressin.


Asymptotic description of pulsed ultrawideband electromagnetic beam field propagation in dispersive, attenuative media.
The asymptotic description of the coupled spatial and temporal evolution of a pulsed ultrawideband electromagnetic beam field as it propagates through a dispersive, attenuative material that occupies the half-space z > or = z(0) is obtained from the angular spectrum of plane waves representation. This angular-spectrum representation expresses the wave field as a superposition of both homogeneous and inhomogeneous plane waves. The paraxial approximation of the spatial part of this representation for nontruncated beam fields results in a description that explicitly displays the temporal evolution of the pulsed-beam field through a single-contour integral that is of the same form as that obtained for a pulsed plane-wave field propagating in the positive z direction in a lossy, dispersive medium. The accuracy of this paraxial approximation is shown to improve as the material's attenuation increases.


Survival, stress resistance, and alterations in protein expression in the marine vibrio sp. strain S14 during starvation for different individual nutrients.
The response of the marine Vibrio sp. strain S14 to starvation for carbon, nitrogen, or phosphorus and to simultaneous depletion of all these nutrients (multiple-nutrient starvation) was examined with respect to survival, stress resistance, quantitative and qualitative alterations in protein and RNA synthesis, and the induction of the stringent control. Of the conditions tested, carbon starvation and multiple-nutrient starvation both promoted long-term starvation resistance and a rapid induction of the stringent control, as deduced from the kinetics of RNA synthesis. Carbon- and multiple-nutrient-starved cells were also found to become increasingly resistant to heat, UV, near-UV, and CdCl2 stress. Nitrogen- and phosphorus-starved cells demonstrated a poor ability to survive in the presence of carbon and did not develop a marked resistance to the stresses examined. The carbon, nitrogen, and phosphorus starvation stimulons consisted of about 20 proteins each, while simultaneous starvation for all the nutrients elicited an increased synthesis of 42 polypeptides. Nine common proteins were found to be induced regardless of the starvation condition used and were tentatively termed general starvation proteins. It was also demonstrated that the total number of proteins induced in response to multiple-nutrient starvation was not a predictable sum of the different individual starvation stimulons. Multiple-nutrient starvation induced 14 proteins which were not detected at increased levels of expression in response to individual starvation conditions. Furthermore, four out of five phosphorus starvation-specific polypeptides were not induced during simultaneous starvation for phosphorus, nitrogen, and carbon. The results are discussed in light of the physiological alterations previously described for Vibrio sp. strain S14 cells starved for carbon, nitrogen, and phosphorus simultaneously.


Recognition and treatment of osteosarcoma in the military health care system.
Forty-two patients with high-grade intramedullary osteosarcoma treated at Walter Reed Army Medical Center between 1985 and 1995 were reviewed to determine what effects military "managed health care" had on diagnosis, treatment, and outcome. Five-year survival was 61% overall (SE +/- 9.9%), despite local disease control obtained in 95% of patients. There was a statistically significant difference between active duty members and dependents in time to diagnosis (p = 0.008), yet there was no significant difference in survival between the two groups. Five-year survival in our patient population was slightly lower than 5-year survival reported in some large civilian medical centers despite good local disease control and intensive multiagent chemotherapy. Delays in diagnosis and military status had no apparent effect on survival, although limb salvage was not possible in nearly 40% of patients because of tumor size, disease extent, and involvement of neurovascular structures.


Growing season moisture drives interannual variation in woody productivity of a temperate deciduous forest.
The climate sensitivity of forest ecosystem woody productivity (ANPPstem ) influences carbon cycle responses to climate change. For the first time, we combined long-term annual growth and forest census data of a diverse temperate broadleaf deciduous forest, seeking to resolve whether ANPPstem is primarily moisture- or energy-limited and whether climate sensitivity has changed in recent decades characterised by more mesic conditions and elevated CO2 . We analysed tree-ring chronologies across 109 yr of monthly climatic variation (1901-2009) for 14 species representing 97% of ANPPstem in a 25.6 ha plot in northern Virginia, USA. Radial growth of most species and ecosystem-level ANPPstem responded positively to cool, moist growing season conditions, but the same conditions in the previous May-July were associated with reduced growth. In recent decades (1980-2009), responses were more variable and, on average, weaker. Our results indicated that woody productivity is primarily limited by current growing season moisture, as opposed to temperature or sunlight, but additional complexity in climate sensitivity may reflect the use of stored carbohydrate reserves. Overall, while such forests currently display limited moisture sensitivity, their woody productivity is likely to decline under projected hotter and potentially drier growing season conditions.


Aminoglycoside-resistant enterococci.
Thirty-four recent clinical isolates of Streptococcus faecalis were tested for sensitivity to amoxycillin, benzylpenicillin, streptomycin, kanamycin, gentamicin, tobramycin, and amikacin. Amoxycillin was two- to four-fold more active than benzylpenicillin and all strains were inhibited by low concentrations of the penicillins. The aminoglycosides were less active against the enterococci than were the penicillins and a significant number of strains were insensitive or relatively insensitive to one or more of the aminoglycosides. Thus, eight (23%) strains showed a high level of resistance to streptomycin and kanamycin (MIC greater 5000 microng/ml) but were sensitive to gentamicin, tobramycin, and amikacin. In addition, two strains of Strep. faecalis, isolated at different hospitals from patients who had received topical gentamicin therapy, were relatively resistant to gentamicin (MIC250 to 500 microng/ml) and were less sensitive also to the other aminoglycosides. Bactericidal synergy was demonstrated by amoxycillin/aminoglycoside combinations against the enterococci, provided that the test strain of Strep. faecalis was sensitive to the aminoglycoside in the combination. An exception to this was the combination of amoxycillin plus amikacin which was not synergistic against kanamycin-resistant strains of Strep. faecalis although these organisms were sensitive to amikacin in the growth inhibition tests. The gentamicin-resistant strains showed variable responses to amoxycillin/aminoglycoside combinations in tests for bactericidal synergy and were generally less sensitive than typical strains of Strep. faecalis.


Endothelial Heterogeneity in Development and Wound Healing.
The vasculature is comprised of endothelial cells that are heterogeneous in nature. From tissue resident progenitors to mature differentiated endothelial cells, the diversity of these populations allows for the formation, maintenance, and regeneration of the vascular system in development and disease, particularly during situations of wound healing. Additionally, the de-differentiation and plasticity of different endothelial cells, especially their capacity to undergo endothelial to mesenchymal transition, has also garnered significant interest due to its implication in disease progression, with emphasis on scarring and fibrosis. In this review, we will pinpoint the seminal discoveries defining the phenotype and mechanisms of endothelial heterogeneity in development and disease, with a specific focus only on wound healing.


Herpes simplex virus type 1 DNA replication is specifically required for high-frequency homologous recombination between repeated sequences.
Using an assay for recombination that measures deletion of a beta-galactosidase gene positioned between two directly repeated 350-bp sequences in plasmids transiently maintained in COS cells, we have found that replication from a simian virus 40 origin produces a high frequency of nonhomologous recombination. In contrast, plasmids replicating from a herpesvirus origin (oris) in COS cells superinfected with herpes simplex virus type 1 (HSV-1) show high levels of homologous recombination between the repeats and an enhanced recombinogenicity of the HSV-1 a sequence that is not seen during simian virus 40 replication. When the same assay was used to study recombination between 120- to 150-bp repeats in uninfected Vero cells, the level of recombination was extremely low or undetectable (< 0.03%), consistent with the fact that these repeats are smaller than the minimal efficient processing sequence for homologous recombination in mammalian cells. Recombination between these short repeats was easily measurable (0.5 to 0.8%) following HSV-1 infection, suggesting that there is an alteration of the recombination machinery. The frequency of recombination between repeats of the Uc-DR1 region, previously identified as the only segment of the HSV-1 a sequence indispensable for enhanced a-sequence recombination, was not significantly higher than that measured for other short sequences.


Occupational gender composition and mild to severe depression in a Swedish cohort: The impact of psychosocial work factors.
The aim of the present study was to investigate associations between occupational gender composition, psychosocial work factors and mild to severe depression in Swedish women and men with various educational backgrounds. The study included 5560 participants from two waves of the Swedish Longitudinal Occupational Survey of Health, an approximately representative sample of the Swedish working population. Odds ratios (OR) and 95% confidence intervals of mild to severe depression in 2014 were estimated for five strata of occupational gender composition with >20-40%, >40-60%, >60-80% and >80-100% women, using 0-20% women as the reference. Analyses were stratified by gender and education. Job strain, organisational injustice, poor social support and effort-reward imbalance in 2012 were added in separate models, and changes in OR of mild to severe depression for strata of occupational gender composition were evaluated. Among women, the odds of mild to severe depression did not vary by occupational gender composition. Among men with low to intermediate education, the odds were higher in the stratum with >80-100% women, and among men with high education, the odds were higher in strata with >20-40% and >60-80% women. Psychosocial work factors affected the odds ratios of mild to severe depression, but most of the variation remained unexplained. Odds of mild to severe depression appeared to vary by occupational gender composition among Swedish men but not women. This variation seemed only to a small extent to be explained by psychosocial work factors.


Hydroxybutyrate near-patient testing to evaluate a new end-point for intravenous insulin therapy in the treatment of diabetic ketoacidosis in children.
The aim of this study was to assess the clinical application of a near-patient testing (NPT) device for capillary blood hydroxybutyrate (HOB) measurement in evaluating a new end-point for intravenous insulin therapy in the treatment of diabetic ketoacidosis (DKA) in children. Children fulfilling the criteria for DKA were treated according to an integrated care pathway (ICP) with fluid replacement and insulin infusion. We measured capillary HOB hourly by NPT (Abbott Optium meter, analytical range 0-6.0 mmol/L), venous blood gases 4 hourly, and venous HOB 4 hourly by laboratory enzymatic method and tested all urine passed for ketones. Two possible ICP end-points were compared: A, pH > 7.3 followed by two successive NPT HOB measurements <1 mmol/L, and B, pH > 7.3 and urine ketone free (our current end-point). In 35 patient episodes, the ICP was completed (28 to negative ketonuria) without significant variation. Before treatment, median (range) laboratory HOB was 9.5 mmol/L (4.6-15.70 mmol/L), pH 7.18 (6.98-7.38), and standard bicarbonate 11.5 mmol/L (4.3-18.6 mmol/L). ICP end-point A was reached after 17 h (4-39 h), whereas end-point B was not reached until 28 h (14-64 h) after starting treatment. The median lag was 11 h (1-36 h). For 59 paired venous samples (excluding samples with laboratory HOB >6 mmol/L), the relation between NPT (y) and laboratory (x) HOB was y = 0.92x - 0.05, r(2)= 0.94, mean bias -0.25 mmol/L. (i) Serial measurement of NPT HOB allows evaluation of a new, simple, earlier end-point for intravenous insulin therapy. (ii) Agreement between NPT and laboratory HOB was clinically acceptable for HOB levels within the meter's analytical range.


Correspondence between Simulator and On-Road Drive Performance: Implications for Assessment of Driving Safety.
Forty-two younger (Mean age = 35) and 37 older drivers (Mean age = 77) completed four similar simulated drives. In addition, 32 younger and 30 older drivers completed a standard on-road drive in an instrumented vehicle. Performance in the simulated drives was evaluated using both electronic drive data and video-review of errors. Safety errors during the on-road drive were evaluated by a certified driving instructor blind to simulator performance, using state Department of Transportation criteria. We examined the degree of convergence in performance across the two platforms on various driving tasks including lane change, lane keeping, speed control, stopping, turns, and overall performance. Differences based on age group indicated a pattern of strong relative validity for simulator measures. However, relative rank-order in specific metrics of performance suggested a pattern of moderate relative validity. The findings have implications for the use of simulators in assessments of driving safety as well as its use in training and/or rehabilitation settings.


Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention.
The signal transducers and activators of transcription (STAT)factors function as downstream effectors of cytokine and growth factor receptor signaling. Compared with normal cells and tissues, constitutively activated STATs have been detected in a wide variety of human cancer cell lines and primary tumors. STATs are activated by tyrosine phosphorylation, which is normally a transient and tightly regulated process. In tumor cells, constitutive activation of STATs is linked to persistent activity of tyrosine kinases, including Src, epidermal growth factor receptor, Janus kinases, Bcr-Abl, and many others. Such oncogenic tyrosine kinases are often activated as a consequence of permanent ligand/receptor engagement in autocrine or paracrine cytokine and growth factor signaling or represent autonomous constitutively active enzymes as a result of genetic alterations found in tumor but not normal cells. Persistent signaling of specific STATs, in particular Stat3 and Stat5, has been demonstrated to directly contribute to oncogenesis by stimulating cell proliferation and preventing apoptosis. STATs participate in oncogenesis through up-regulation of genes encoding apoptosis inhibitors and cell cycle regulators such as Bcl-x(L), Mcl-1, cyclins D1/D2, and c-Myc. Inhibition of constitutively active STAT signaling pathways has been shown repeatedly to inhibit tumor cell growth in vitro and in vivo and provides a novel means for therapeutic intervention in human cancer. In this review, we will: (a) explain the mechanisms of STAT activation in normal and malignant signaling; (b) summarize recent evidence for the critical role of constitutively activated Stat3 and Stat5 in oncogenesis; (c) identify candidate STAT target genes implicated in tumor progression; and (d) discuss molecular and pharmacological strategies to interfere with STAT signaling for potential therapeutic intervention in human cancer.


Malignant lymphoma, diffuse mixed small and large cell. A clinicopathologic study of 47 cases.
The clinical and pathologic features of 47 cases of malignant lymphoma, diffuse mixed small and large cell (diffuse mixed lymphoma) are described. Diffuse mixed lymphomas contained approximately equal numbers of small and large cells (30-70%) and comprised 6% of all non-Hodgkin's lymphomas. They occurred in middle-aged and elderly patients (median age = 63 years), showed a female predominance, and were clinically advanced at presentation. The majority of patients exhibited prominent extranodal disease, which frequently involved multiple unrelated sites and usually occurred in conjunction with nodal disease. A notable morphologic spectrum of lymphoma was seen within this series, including 20 cases of mixed small cleaved and large cell (with cleaved and noncleaved nuclei), eight cases of mixed small lymphocytic and large cell (transformed prolymphocytes and blast-like cells), and 12 cases of mixed small cell and large cell, "immunoblastic" lymphoma (with plasmacytoid, clear cell or hyperconvoluted features). There was no significant difference in response to treatment and survival between those cases with less than 50% large cells and those with greater than 50% large cells. The poorest treatment response appeared to be in patients with mixed small cell and large cell, "immunoblastic" lymphomas. Patients with diffuse mixed lymphoma appeared to show a favorable response to cyclphosphamide, Adriamycin, vincristine, and prednisone (CHOP) and an unfavorable response to other treatment modalities.


Quantifying and reducing spurious alignments for the analysis of ultra-short ancient DNA sequences.
The study of ancient DNA is hampered by degradation, resulting in short DNA fragments. Advances in laboratory methods have made it possible to retrieve short DNA fragments, thereby improving access to DNA preserved in highly degraded, ancient material. However, such material contains large amounts of microbial contamination in addition to DNA fragments from the ancient organism. The resulting mixture of sequences constitutes a challenge for computational analysis, since microbial sequences are hard to distinguish from the ancient sequences of interest, especially when they are short. Here, we develop a method to quantify spurious alignments based on the presence or absence of rare variants. We find that spurious alignments are enriched for mismatches and insertion/deletion differences and lack substitution patterns typical of ancient DNA. The impact of spurious alignments can be reduced by filtering on these features and by imposing a sample-specific minimum length cutoff. We apply this approach to sequences from four ~ 430,000-year-old Sima de los Huesos hominin remains, which contain particularly short DNA fragments, and increase the amount of usable sequence data by 17-150%. This allows us to place a third specimen from the site on the Neandertal lineage. Our method maximizes the sequence data amenable to genetic analysis from highly degraded ancient material and avoids pitfalls that are associated with the analysis of ultra-short DNA sequences.


[Mental health care in Austria: history--developments--perspectives].
The reform of psychiatric services in Austria started during the second half of the seventies of the 20th century. During the early phase the reform focussed on dehospitalization and principles of community psychiatry. About 60% of psychiatric hospital beds were closed and the size of psychiatric hospitals was reduced. One of the psychiatric hospitals was closed and psychiatric departments were opened as part of district general hospitals. During this time the number of psychiatric hospital admissions increased markedly and a large proportion of mentally ill are treated as inpatients in non-psychiatric wards. Only about a fifth of self-employed psychiatrists working in their own office have a contract with health insurances. In Austria, the number of psychotherapists is much higher than the number of psychiatrist. A variety of different types of community services provide social and vocational rehabilitation, focussing on consultation, housing, daily structure and employment. Psychiatric services are nowadays fragmented into a number of sub-disciplines such as psychosomatics or child and adolescent psychiatry. This fragmentation and the missing coordination of psychiatric services hamper the enhancements of psychiatric care. This complicates the development of integrated services, i.e. the structured and planned cooperation of the different types of services. Since there are no binding rules for the organisation and planning in entire Austria, financing and organisation of services is fragmented. For establishing an integrated health care, coordination and cooperation between providers, sponsors of health care as well as policy makers are essential.


The Fat-to-Lean Mass Ratio Is Associated with Hyperinsulinemia in Healthy Mexican Adolescents.
Objective: To evaluate whether the Fat-to-Lean Mass (FyM) ratio is associated to hyperinsulinemia in healthy adolescents.Methods: Apparently healthy adolescents aged 10 to 15 years that according to sex, age, and percentiles of body fat percent, were included and allocated into the groups with elevated (body fat percent ≥85 percentile) and normal total body fat (body fat percent <85 percentile). The FyM ratio was calculated as total lean mass (kg)/total body fat (kg) and hyperinsulinemia was defined by fasting insulin levels ≥20 µUI/mL.Results: A total of 1,299 adolescents, 665 (51.9%) girls and 634 (48.1%) boys, were enrolled and allocated into the groups with high (n = 439) and normal (n = 860) body fat. The FyM index remained significantly associated with hyperinsulinemia (OR 5.58; 95%CI: 1.54-28.10) after logistic regression analysis adjusted by sex, age, body-weight, body mass index, and waist circumference.Conclusion: The FyM index is highly associated to the presence of hyperinsulinemia in adolescents, emerging as a useful tool from anthropometric measurements for identify insulin abnormalities.


2D/3D-Display Auto-Adjustment Switch System.
Recently, 2-D/3-D switchable displays have become the mainstream in 3-D display technologies, and people can now watch 3-D movies with a naked 2-D/3-D switchable display at home. However, some studies have indicated that people might encounter visual fatigue after enjoying a 3-D film in the theater. Although 2-D/3-D switchable technologies have been widely developed, 3-D display technologies are still lacking in ergonomic and human-care factors such as reducing visual fatigue. This study proposes a novel 2-D/3-D display autoadjustment switch system to provide biofeedback functions to reduce users' visual fatigue. In addition, the relationship between the blink rate and the visual fatigue state while watching 3-D films was investigated and quantified. In this study, liquid crystal barrier technology was used to develop a 2-D/3-D switchable display, and a wearable EOG acquisition device was also designed to monitor electro-oculography signals to estimate the blink rate. Here, the 2-D/3-D display autoadjustment criterion of the proposed system was designed according to the change in the visual fatigue state as estimated from the blink rate. Finally, the experimental results show that the proposed system could effectively reduce users' visual fatigue while watching 3-D films.


Effect of long- and short-term antidiuretic hormone availability on internephron heterogeneity in the adult rat.
We have previously shown that certain aspects of internephron heterogeneity are reduced or absent in Brattleboro rats with hereditary diabetes insipidus (DI) lacking ADH and can be restored by long-term ADH administration started before complete kidney maturation. In the present study, the effects of long- and short-term availability of ADH in adulthood were studied in Brattleboro DI rats. Single nephron glomerular filtration rate (SNGFR), glomerular volume (GV), and proximal tubular length (PTL) were measured in superficial and juxtamedullary nephrons using the ferrocyanide and microdissection techniques. ADH administration for 6 wk in adult DI rats (group A) restored normal nephron heterogeneity of SNGFR, GV, and PTL by increasing the filtration and size of deep nephrons. Acute changes in ADH availability induced either by 1-h ADH infusion in DI rats (group C) or by ADH discontinuation for 2 days in treated DI rats (group D) did not significantly change the anatomical parameters and only moderately affected SNGFR compared with the preexisting states (groups B and A, respectively). These results suggest that the influence of ADH on internephron heterogeneity is initiated by an increase in deep nephron SNGFR. Based on recent findings concerning the effects of ADH on the medullary (M) part of the thick ascending limbs (TAL), we suggest that the increase in deep nephron SNGFR after ADH may be due to a change in the tubuloglomerular feedback signal at the macula densa resulting from ADH-induced stimulation of the solute reabsorption in the MTAL. Superficial nephrons would be less sensitive to this change due to their long cortical TAL, which removes the macula densa further from the MTAL and provides additional sites for solute reabsorption.


A REVIEW ON EMERGING PATHOGENESIS OF COVID-19 AND POINTS OF CONCERN FOR RESEARCH COMMUNITIES IN NIGERIA.
COVID-19 remains an emerging pandemic that continuously poses an alarming threat and challenge to economic, social and well-being of the people throughout the world. It also remains an evolving disease which complete pathogenesis that translates into clinical features is only just emerging by each second of the day. There have been observations about the emerging trends of the disease in Nigeria like in any other country in the world where there is outbreak. This study examined from evidence-based literature the emerging pathogenesis of COVID-19 and important points of concern of the disease in Nigeria. The paper reviewed published articles in PubMed and Google Scholar using search terms 'COVID-19" and "SARS-CoV-2", as well as searched for general COVID-19 information on internet. The result summarized literature on emerging pathogenesis of COVID-19 and important points of concern as well as research questions as to the peculiar trends of the disease in Nigeria. Pathogenesis of COVID-19 remains an emerging knowledge and there are many important research questions that need to be scientifically answered for a successful containment of COVID-19 in Nigeria. It is recommended that all members of intellectual research communities should join the fight against COVID-19 pandemic.


Direct correlation of collagen matrix deformation with focal adhesion dynamics in living corneal fibroblasts.
The purpose of this study was to develop and apply a new model for investigating how the organization and movement of cell-matrix adhesion sites correlate with force generation by corneal fibroblasts on a fibrillar collagen extracellular matrix. Primary cultures of rabbit corneal fibroblasts were transfected using a vector encoding GFP-zyxin to allow visualization of adhesion sites. Cells were plated at low density on top of 100 micro m thick fibrillar collagen lattices embedded with 2 micro m diameter red fluorescent beads. Time-lapse imaging was performed at one minute intervals for up to 3 hours. At each time interval, GFP-zyxin, bead and DIC images were acquired in rapid succession using filter wheels. Cells were treated with cytochalasin D and/or Triton X-100 at the end of each experiment. The movements of adhesions and nearby matrix landmarks were measured and correlated from the time-lapse digital images, and the size, intensity and orientation of the adhesions were quantified. GFP-zyxin was detected in adhesions of transfected corneal fibroblasts as confirmed using vinculin counterstaining. Time-lapse imaging revealed extensions and retractions of cell processes and displacements of the fiduciary beads that were similar to control cells. Extending processes exhibited the most complex behavior, with new adhesions continuously forming at the leading edge while existing adhesions moved backward in a retrograde fashion. This process generated tractional forces as indicated by pulling in of the extracellular matrix in front of the cell. Interestingly, during extension, adhesions along the ventral surface of the cell body generally moved toward those at the tip, resulting in contractile-like shortening and matrix compression at the base of lamellipodia. Overall, a high correlation was found between both the magnitude (R=0.87, P<0.001) and direction (R=0.98, P<0.001) of the adhesions and nearby matrix displacements. Cytochalasin D induced rapid and reversible disassembly of adhesions, cell elongation and matrix relaxation, including decompression at the base of the lamellipodia. This new experimental model allows direct, dynamic assessment of cell-matrix interactions on a fibrillar collagen matrix. Our results are consistent with the previously described 'frontal towing' model of cell motility and demonstrate for the first time that this mechanism is employed by cells interacting with a fibrillar extracellular matrix.


Abnormal rich club organization and functional brain dynamics in schizophrenia.
The human brain forms a large-scale structural network of regions and interregional pathways. Recent studies have reported the existence of a selective set of highly central and interconnected hub regions that may play a crucial role in the brain's integrative processes, together forming a central backbone for global brain communication. Abnormal brain connectivity may have a key role in the pathophysiology of schizophrenia. To examine the structure of the rich club in schizophrenia and its role in global functional brain dynamics. Structural diffusion tensor imaging and resting-state functional magnetic resonance imaging were performed in patients with schizophrenia and matched healthy controls. Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, the Netherlands. Forty-eight patients and 45 healthy controls participated in the study. An independent replication data set of 41 patients and 51 healthy controls was included to replicate and validate significant findings. MAIN OUTCOME(S) AND MEASURES: Measures of rich club organization, connectivity density of rich club connections and connections linking peripheral regions to brain hubs, measures of global brain network efficiency, and measures of coupling between brain structure and functional dynamics. Rich club organization between high-degree hub nodes was significantly affected in patients, together with a reduced density of rich club connections predominantly comprising the white matter pathways that link the midline frontal, parietal, and insular hub regions. This reduction in rich club density was found to be associated with lower levels of global communication capacity, a relationship that was absent for other white matter pathways. In addition, patients had an increase in the strength of structural connectivity-functional connectivity coupling. Our findings provide novel biological evidence that schizophrenia is characterized by a selective disruption of brain connectivity among central hub regions of the brain, potentially leading to reduced communication capacity and altered functional brain dynamics.


Clarithromycin As an Alternative and Prophylactic Agent in a Hematopoietic Stem Cell Transplantation Patient.
BACKGROUND Nocardia infections have rarely been reported in hematopoietic stem cell transplantation (HSCT) patients, who usually receive the prophylactic use of sulfamethoxazole/trimethoprim (ST) against Pneumocystis jiroveci. However, the ST prophylaxis, sensitive to Nocardia species, sometimes induces renal toxicities. Therefore, alternative prophylactic or therapeutic drugs are required for nocardiosis in HSCT patients. CASE REPORT A 34-year-old Japanese man with acute mixed phenotypic leukemia with t(9; 22) received allogenic peripheral blood HSCT from a haplo-identical sibling donor. He developed graft versus host disease (GVHD) with grade II, and was treated with prednisolone and cyclosporine A with concurrent ciprofloxacin, fluconazole, valacyclovir, and ST. However, the prophylactic ST was ceased because of its renal toxicity. He developed a pulmonary nodular lesion with elevated ß-D-glucan and Aspergillus galactomannan antigen. Repeated blood and sputum culture isolated no pathogens. Voriconazole treatment administered once improved these lesions and laboratory findings. One month later, he presented with right pleuritic chest pain and multiple ring-enhancing cavitation lesions along the ribs. A needle biopsy demonstrated Nocardia elegans, which is an extremely rare infection induced by Nocardia species, in the cavitation lesions, shown by 16S rRNA gene sequencing. He was started on doripenem and liposomal amphotericin B, and a subsequent treatment kept him free from Nocardia elegans infection, without any adverse effects, while continuing the cyclosporine A and prednisolone treatment for chronic GVHD. CONCLUSIONS Clarithromycin has fewer adverse effects than ST. This case suggests that clarithromycin is an appropriate alternative and prophylactic therapy for patients with nocardiosis and ST toxicities.


Suppression of bcl-2 gene by RNA interference increases chemosensitivity to cisplatin in nasopharyngeal carcinoma cell line CNE1.
To explore the effect of suppressing BCL-2 expression using RNA interference (RNAi) technique in nasopharyngeal carcinoma cell line CNE1. CNE1 cell lines stably expressing shRNAs targeted bcl-2 and GL3 gene were established and gene expression inhibition was assessed by Western blotting analysis. The effect of suppressing bcl-2 by RNAi on cell growth was studied, the apoptosis induction and the sensitization of CNE1 cells to cisplatin were quantified by MTT assays and flow cytometry. The results showed that: stable transfection of CNE1 cells with vectors expressing shRNAs against bcl-2 decreased the expression of BCL-2 protein; suppression of BCL-2 expression did not affect cell proliferation but could increase the chemosensitivity to cisplatin in CNE1 cells. This will help physicians to make some clinical trials of gene therapy on nasopharyngeal carcinoma by RNAi.


[Transcranial Doppler sonography and hemodynamics].
13 patients without cerebral or cerebrovascular diseases were investigated by transcranial Doppler sonography during Swan-Ganz catheterisation for cardiologic purposes. Massive increases of mean arterial pressure, heart rate and cardiac index were observed during exercise; flow velocities in the middle cerebral artery increased only to the same extent as the endexpiratory carbon dioxide rose. However, the pulsatility index increased significantly (p less than 0.01) although a decrease should have been expected due to carbon dioxide accumulation. These results are indicative of a functioning autoregulation independent of carbon dioxide; they are relevant for interpretation of TCD results in patients with disturbed autoregulation.


Blood-brain barrier resealing in neuromyelitis optica occurs independently of astrocyte regeneration.
Approximately 80% of neuromyelitis optica spectrum disorder (NMOSD) patients harbor serum anti-aquaporin-4 autoantibodies targeting astrocytes in the CNS. Crucial for NMOSD lesion initiation is disruption of the blood-brain barrier (BBB), which allows the entrance of Abs and serum complement into the CNS and which is a target for new NMOSD therapies. Astrocytes have important functions in BBB maintenance; however, the influence of their loss and the role of immune cell infiltration on BBB permeability in NMOSD have not yet been investigated. Using an experimental model of targeted NMOSD lesions in rats, we demonstrate that astrocyte destruction coincides with a transient disruption of the BBB and a selective loss of occludin from tight junctions. It is noteworthy that BBB integrity is reestablished before astrocytes repopulate. Rather than persistent astrocyte loss, polymorphonuclear leukocytes (PMNs) are the main mediators of BBB disruption, and their depletion preserves BBB integrity and prevents astrocyte loss. Inhibition of PMN chemoattraction, activation, and proteolytic function reduces lesion size. In summary, our data support a crucial role for PMNs in BBB disruption and NMOSD lesion development, rendering their recruitment and activation promising therapeutic targets.


Nonparametric tests of association of multiple genes with human disease.
The genetic basis of many common human diseases is expected to be highly heterogeneous, with multiple causative loci and multiple alleles at some of the causative loci. Analyzing the association of disease with one genetic marker at a time can have weak power, because of relatively small genetic effects and the need to correct for multiple testing. Testing the simultaneous effects of multiple markers by multivariate statistics might improve power, but they too will not be very powerful when there are many markers, because of the many degrees of freedom. To overcome some of the limitations of current statistical methods for case-control studies of candidate genes, we develop a new class of nonparametric statistics that can simultaneously test the association of multiple markers with disease, with only a single degree of freedom. Our approach, which is based on U-statistics, first measures a score over all markers for pairs of subjects and then compares the averages of these scores between cases and controls. Genetic scoring for a pair of subjects is measured by a "kernel" function, which we allow to be fairly general. However, we provide guidelines on how to choose a kernel for different types of genetic effects. Our global statistic has the advantage of having only one degree of freedom and achieves its greatest power advantage when the contrasts of average genotype scores between cases and controls are in the same direction across multiple markers. Simulations illustrate that our proposed methods have the anticipated type I-error rate and that they can be more powerful than standard methods. Application of our methods to a study of candidate genes for prostate cancer illustrates their potential merits, and offers guidelines for interpretation.


The primary empty sella an endocrine study on 12 cases.
Twelve patients (10 women and 2 men) with a primary empty sella turcica were studied. Endocrine function tests were performed as follows: growth hormone (GH) was measured after insulin-induced-hypoglycaemia, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) after LH-releasing hormone, thyrotrophin (TSH) and prolactin after thyrotrophin-releasing hormone; pituitary reserve of adrenocorticotrophin (ACTH) was determined by measurement of plasma cortisol after lysine-vasopressin and 11 deoxycortisol after metyrapone. Five of the patients (group A) had no endocrine disturbance. Seven patients (group B) had a hypothalamo-pituitary disorder. Two of them had panhypopituitarism which appeared in one case after meningoencephalitis and in the other after a severe cranial trauma. In two cases an amenorrhoea-galactorrhoea syndrome with increased prolactin level (68 and 230 ng/ml) led to a diagnosis of a prolactin producing adenoma, which was confirmed by surgery. Finally three cases of amenorrhoeagalactorrhoea, with normal prolactin level, and/or diabetes insipidus remained unexplained. However, no causal relationship could be demonstrated between the pituitary disturbance and the "empty sella". Primary empty sella turcica is therefore a neuroanatomical and neuroradiological entity with no endocrine implication. A pituitary disorder might suggest a microadenoma or an incidentally associated disease.


Lightning strike: a rare cause of bilateral ossicular disruption.
Otologic injury associated with fatal and nonfatal lightning strikes has been sporadically reported in the literature. The most common acoustic insult is a conductive hearing loss secondary to rupture of the tympanic membrane. Although conjecture has been made of the theoretic possibility of ossicular injury from lightning strike, to our knowledge, none has been demonstrated intraoperatively or postmortem. We report the first documented case of ossicular disruption in a lightning-strike victim.


Patterns of local and tourist use of an emergency department.
Illness patterns of local and tourist patients in an emergency department of a medium-sized Ontario city with a single hospital were compared. Frequencies of specific and broad categories of ailments and rates of admission to the hospital were similar in the two groups. However, non-Canadian tourists were admitted to hospital at a much lower rate than Canadian tourists. Rates of visits to the emergency department within certain age categories were remarkably similar, as were rates within the sexes. It is concluded that, in view of the striking similarity in the illness pattern of a group of patients not professionally referred to the hospital and that of local patients, who have potential contact with a more extensive medical network, public attitudes, rather than availability of health professionals, determine the pattern of illness observed in an emergency department.


Evasion of predators contributes to the maintenance of male eyes in sexually dimorphic Euphilomedes ostracods (Crustacea).
Sexual dimorphisms have long drawn the attention of evolutionary biologists. However, we still have much to learn about the evolutionary, genetic, and developmental drivers of sexual dimorphisms. Here, we introduce ostracods of the genus Euphilomedes (Myodocopida, Ostracoda, and Crustacea) as a promising new system in which to investigate why and how sexual dimorphisms evolve. First, we ask whether male-skewed selective pressure from pelagic predators may help explain a dramatic sexual dimorphism in which male Euphilomedes have compound eyes, but females do not. Manipulative experiments demonstrate that blindfolding reduces the survival rate of male Euphilomedes when they are exposed to predatory fish. Blindfolding of the female rudimentary eyes (rudiments) does not, however, similarly influence the survival rate of brooding females. Further, numerical estimates of sighting distances, based on reasonable extrapolations from Euphilomedes's eye morphology, suggest that the eyes of male Euphilomedes are useful for detecting objects roughly the size of certain pelagic predators, but not conspecifics. We conclude that eyes do not mediate direct interactions between male and female Euphilomedes, but that differences in predation pressure-perhaps associated with different reproductive behaviors-contribute to maintaining the sexually dimorphic eyes of these ostracods. Second, through transcriptome sequencing, we examined potential gene regulatory networks that could underlie sexual dimorphism in Euphilomedes' eyes. From the transcriptome of juvenile male Euphilomedes' eyes, we identified phototransduction genes and components of eye-related developmental networks that are well characterized in Drosophila and other species. The presence of suites of eye regulatory genes in our Euphilomedes juvenile male transcriptome will allow us, in future studies, to test how ostracods regulate the development of their sexually dimorphic eyes.


Vesicle pool heterogeneity at hippocampal glutamate and GABA synapses.
Glutamate and GABA are the major fast excitatory and inhibitory neurotransmitters, respectively, in the CNS. Although glutamate and GABA have clearly distinct postsynaptic actions, we are just beginning to appreciate that presynaptic differences between glutamatergic and GABAergic neurons may contribute to distinct functions of these transmitter systems. We therefore probed possible differences between the functional synaptic vesicle populations of glutamatergic and GABAergic neurons. We examined superecliptic synaptopHluorin (SpH) fluorescence during 20 Hz electrical stimulation in transfected hippocampal neurons and identified the phenotype of SpH-fluorescent synapses with post hoc immunostaining. With 200 stimuli (10 s), individual glutamate synapses displayed considerably more variability in peak SpH fluorescence than GABA synapses, without a strong difference in the mean SpH fluorescence increase. This spatial heterogeneity could not be accounted for by differences in endocytosis, which was nearly constant over these short time periods across glutamate and GABA synapses. Instead, variability in vesicle exocytosis correlated with variability in total vesicle staining and in measures of the total recycling pool size. Differences were also evident using FM1-43 [N-(3-triethylammoniumpropyl)-4-(4-(dibutylamino)styryl) pyridinium dibromide] uptake. These data support the idea that the population of glutamate synapses exhibits more heterogeneity in release properties than the population of GABA synapses, possibly correlated with glutamatergic synaptic malleability.


Molecular Design Principles for Near-Infrared Absorbing and Emitting Indolizine Dyes.
Desirable components for dye-sensitzed solar cell (DSC) sensitizers and fluorescent imaging dyes include strong donating building blocks coupled with well-balanced acceptor functionalities for absorption beyond the visible range. We have evaluated the effects of increasing acceptor strengths and incorporation of dye morphology controlling groups on molar absorptivity and absorption breadth with indolizine donor-based dyes. Indolizine-based D-A and D-π-A sensitizers incorporating bis-rhodanine, tricyanofuran (TCF), and cyanoacrylic acid functionalities were analyzed for performance in DSC devices. The TCF derivatives were also evaluated as near-infrared (NIR)-emissive materials with the AH25 emissions extending past 1000 nm.


[Hemangiopericytoma of the rectal mesentery].
The authors present a case of hemangiopericytoma of the rectal mesentery, this is an uncommon type of vascular tumor, exceptional in this localization. We analyze the difficulty of a preoperative diagnosis, the lack of specificity of the clinical signs and the importance of the radical resection linked to the biological aggressiveness and the frequency of local recurrences and distant metastases.


The meaning that people with severe mental illnesses ascribe to e-health in encounters with healthcare professionals - A repeat interview study.
This study sought to explore the meaning that people with severe mental illnesses attribute to e-health solutions regarding user involvement and encounters with healthcare professionals. A qualitative design with a social phenomenological approach was applied, and data were collected via repeat interviews. Using a purposive sampling strategy, eight people with severe mental illness were interviewed two times between August 2021 to May 2022, at three different treatment sites in southern Denmark. To be included, participants needed to be 18-65 years of age, diagnosed with severe mental illness (schizophrenia, bipolar disorder, or depression), and using an e-health solution in collaboration with a health professional. The interviews lasted between 20 and 70 min and were audio recorded and then transcribed. The data were analysed with Braun and Clarke's 6-step thematic analysis. Participants experienced the use of an e-health solution as helpful for structuring their everyday lives, and e-health used together with healthcare professionals was considered to have a positive impact on the collaboration. The participants experienced feeling involved and in control when e-health solutions were used, which engaged them in their treatment. Furthermore, the participants found it important to have had some in-person meetings with healthcare professionals to build trust before the e-health solutions could be implemented successfully. E-health solutions used in collaboration with a trusted healthcare professional whom the participants had met in person tended to affect treatment engagement positively.


Granzyme B promotes cytotoxic lymphocyte transmigration via basement membrane remodeling.
Granzyme B (GzmB) is a protease with a well-characterized intracellular role in targeted destruction of compromised cells by cytotoxic lymphocytes. However, GzmB also cleaves extracellular matrix components, suggesting that it influences the interplay between cytotoxic lymphocytes and their environment. Here, we show that GzmB-null effector T cells and natural killer (NK) cells exhibited a cell-autonomous homing deficit in mouse models of inflammation and Ectromelia virus infection. Intravital imaging of effector T cells in inflamed cremaster muscle venules revealed that GzmB-null cells adhered normally to the vessel wall and could extend lamellipodia through it but did not cross it efficiently. In vitro migration assays showed that active GzmB was released from migrating cytotoxic lymphocytes and enabled chemokine-driven movement through basement membranes. Finally, proteomic analysis demonstrated that GzmB cleaved basement membrane constituents. Our results highlight an important role for GzmB in expediting cytotoxic lymphocyte diapedesis via basement membrane remodeling.


[Systematic approach to family nursing: thoughtful considerations].
This study is part of the theoretical referential of doctorate in development thesis based on Bertalanffy, Vasconcellos and Capra's ideas. It searches from the systemic approach to comprehend the family as a inter-relations system among the members, an irreducible open unit to the continuous flow of entrance and exit of energy, a dynamic unit in which the whole and the parts are influenced mutually. It aims the development of a professional reflection for the Care of Nursing for the family not as context, but the familiar one. Its genesis is related to the many concerns that have surfaced from professional activities which have met answers in the new paradigmatic approach of the post-modern science of the complexity, instability, intersubjectiveness for the think/act of Nursing in the interdisciplinary development of their careful actions of joint way: the unit family.


Distinguishing bipolar major depression from unipolar major depression with the screening assessment of depression-polarity (SAD-P).
Patients with bipolar I or II major depression are often misdiagnosed with unipolar major depression. The goal of this study was to develop and validate a brief instrument to screen for bipolar disorder in patients actively ill with major depression. The sample consisted of subjects who enrolled in the National Institute of Mental Health-Collaborative Program on the Psychobiology of Depression-Clinical Studies from 1978 to 1981 during an episode of major depression and included 91 subjects with bipolar I major depression, 52 with bipolar II major depression, and 338 with unipolar major depression diagnosed according to Research Diagnostic Criteria. Most of the subjects were inpatients at the time of enrollment, and subjects were prospectively followed for up to 20 years. In order to create, test, and cross-validate the screening instrument, a split-sample data analytic procedure was performed. This procedure yielded 3 groups of subjects: the bipolar I index sample, the bipolar I cross-validation sample, and the bipolar II cross-validation sample. Each group included subjects with bipolar major depression and subjects with unipolar major depression. Within the bipolar I index sample, subjects with bipolar I major depression at study intake were compared with subjects with unipolar major depression at study intake on a pool of 59 sociodemographic and clinical candidate variables. The 3 variables showing the greatest disparity between bipolar I subjects and unipolar subjects were selected for the screen, the Screening Assessment of Depression-Polarity (SAD-P). The operating characteristics of the SAD-P were then examined within the bipolar I index sample, bipolar I cross-validation sample, and bipolar II cross-validation sample. The items selected for the screening instrument were (1) presence of delusions during the current episode of major depression, (2) number of prior episodes of major depression, and (3) family history of major depression or mania. The screen identified bipolar major depression with a sensitivity of 0.82 in the bipolar I index sample, 0.72 in the bipolar I cross-validation sample, and 0.58 in the bipolar II cross-validation sample. With regard to misclassifying subjects with unipolar major depression, the screen provided a positive predictive value of 0.36 in the bipolar I index sample, 0.29 in the bipolar I cross-validation sample, and 0.27 in the bipolar II cross-validation sample. We suggest using the 3-item SAD-P as a preliminary screen for bipolar disorder in patients who present with an active episode of major depression.


Vast underestimation of Madagascar's biodiversity evidenced by an integrative amphibian inventory.
Amphibians are in decline worldwide. However, their patterns of diversity, especially in the tropics, are not well understood, mainly because of incomplete information on taxonomy and distribution. We assess morphological, bioacoustic, and genetic variation of Madagascar's amphibians, one of the first near-complete taxon samplings from a biodiversity hotspot. Based on DNA sequences of 2,850 specimens sampled from over 170 localities, our analyses reveal an extreme proportion of amphibian diversity, projecting an almost 2-fold increase in species numbers from the currently described 244 species to a minimum of 373 and up to 465. This diversity is widespread geographically and across most major phylogenetic lineages except in a few previously well-studied genera, and is not restricted to morphologically cryptic clades. We classify the genealogical lineages in confirmed and unconfirmed candidate species or deeply divergent conspecific lineages based on concordance of genetic divergences with other characters. This integrative approach may be widely applicable to improve estimates of organismal diversity. Our results suggest that in Madagascar the spatial pattern of amphibian richness and endemism must be revisited, and current habitat destruction may be affecting more species than previously thought, in amphibians as well as in other animal groups. This case study suggests that worldwide tropical amphibian diversity is probably underestimated at an unprecedented level and stresses the need for integrated taxonomic surveys as a basis for prioritizing conservation efforts within biodiversity hotspots.


Avelumab in patients with previously treated metastatic Merkel cell carcinoma (JAVELIN Merkel 200): updated overall survival data after >5 years of follow-up.
Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer that has a poor prognosis in patients with advanced disease. Avelumab [anti-programmed death-ligand 1 (PD-L1)] became the first approved treatment for patients with metastatic MCC (mMCC), based on efficacy and safety data observed in the JAVELIN Merkel 200 trial. We report long-term overall survival (OS) data after >5 years of follow-up from the cohort of patients with mMCC whose disease had progressed after one or more prior lines of chemotherapy. In Part A of the single-arm, open-label, phase II JAVELIN Merkel 200 trial, patients with mMCC that had progressed following one or more prior lines of chemotherapy received avelumab 10 mg/kg by intravenous infusion every 2 weeks until confirmed disease progression, unacceptable toxicity, or withdrawal. In this analysis, long-term OS was analyzed. In total, 88 patients were treated with avelumab. At data cut-off (25 September 2020), median follow-up was 65.1 months (range 60.8-74.1 months). One patient (1.1%) remained on treatment, and an additional patient (1.1%) had reinitiated avelumab after previously discontinuing treatment. Median OS was 12.6 months [95% confidence interval (CI) 7.5-17.1 months], with a 5-year OS rate of 26% (95% CI 17% to 36%). In patients with PD-L1+ versus PD-L1- tumors, median OS was 12.9 months (95% CI 8.7-29.6 months) versus 7.3 months (95% CI 3.4-14.0 months), and the 5-year OS rate was 28% (95% CI 17% to 40%) versus 19% (95% CI 5% to 40%), respectively (HR 0.67; 95% CI 0.36-1.25). Avelumab monotherapy resulted in meaningful long-term OS in patients with mMCC whose disease had progressed following chemotherapy. These results further support the role of avelumab as a standard of care for patients with mMCC.


[Thermographic assessment of Raynaud's phenomenon in childhood mixed connective tissue disease].
To assess Raynaud's phenomenon objectively, thermographic estimation of hands and fingers was performed before and after the disease- and Raynaud's phenomenon-directed therapy in 3 children with mixed connective tissue disease. All the cases were positive in Raynaud's phenomenon, and the surface temperature of their hands and fingers were decreased even before cold challenge. After the cold provocation test at 4 degrees C for 10 sec., the temperature of all or some of the fingers were rapidly decreased, and the recovery of surface temperature of these fingers were markedly delayed. Even after methylprednisolone pulse therapy the pattern of the finger temperature were essentially unchanged, suggesting that steroids are not effective in the treatment of Raynaud's phenomenon. The long-term administration of vitamin-E, oral prostaglandin E1, and/or serotonin-receptor inhibitor were also proved to be not beneficial in improving Raynaud's phenomenon. Thus, thermography is useful in diagnosing Raynaud's phenomenon objectively, in determining the efficacy of anti-Raynaud drugs, and in estimating long-term course of the phenomenon.