Development of a CRISPR/Cas9-mediated gene-editing tool in Streptomyces rimosus.
Clustered regularly interspaced short palindromic repeats, associated proteins (CRISPR/Cas), has been developed into a powerful, targeted genome-editing tool in a wide variety of species. Here, we report an extensive investigation of the type II CRISPR/Cas9 system for targeted gene editing in Streptomyces rimosus. S. rimosus is used in the production of the antibiotic oxytetracycline, and its genome differs greatly from other species of the genus Streptomyces in the conserved chromosome terminal and core regions, which is of major production and scientific research value. The genes zwf2 and devB were chosen as target genes, and were edited separately via single-site mutations, double-site mutations and gene fragment disruptions. The single-site mutation guided by sgRNA-1 or sgRNA-2, respectively, involved GG changing to CA, GC changing to AT, and GG changing to CC. The double-site mutations guided by sgRNA-1 and sgRNA-2 included deletions and/or point mutations. Consistently, all mutations occurred in the gRNA sequence regions. Deletion mutations were characterized by the absence of eight bases, including three bases upstream of the PAM (protospacer adjacent motif) sequence, the PAM sequence itself and two bases downstream of the PAM sequence. A mutant (zwf2-devB-) with a high yield of oxytetracycline was successfully obtained, whose oxytetracycline level was increased by 36.8 % compared to the original strain. These results confirm that CRISPR/Cas9 can successfully serve as a useful targeted genome editing system in S. rimosus.


Affective properties of intra-medial preoptic area injections of testosterone in male rats.
On alternating days, adult male Long-Evans rats implanted with unilateral cannulae in the medial preoptic area (MPOA) received intracerebral injections of testosterone (0.05, 0.1 or 0.2 microg/0.5 microl), or saline immediately prior to confinement for 30 min to one of two compartments of a place preference apparatus. All rats received 8 days of pairings (4 hormone and 4 saline). On day 9, the rats were given a hormone-free 20-min test session during which they had access to all compartments of the apparatus. Intra-MPOA injections of testosterone (0.1 microg) produced a conditioned place preference, while injections of a higher dose (0.2 microg) produced a conditioned place aversion. The rewarding effects of intra-MPOA testosterone may in part mediate the facilatory effects of testosterone on motivational aspects of sexual behavior.


Pituitary adenylate cyclase-activating polypeptide (PACAP) in zebrafish models of nephrotic syndrome.
Pituitary adenylate cyclase-activating polypeptide (PACAP) is an inhibitor of megakaryopoiesis and platelet function. Recently, PACAP deficiency was observed in children with nephrotic syndrome (NS), associated with increased platelet count and aggregability and increased risk of thrombosis. To further study PACAP deficiency in NS, we used transgenic Tg(cd41:EGFP) zebrafish with GFP-labeled thrombocytes. We generated two models for congenital NS, a morpholino injected model targeting nphs1 (nephrin), which is mutated in the Finnish-type congenital NS. The second model was induced by exposure to the nephrotoxic compound adriamycin. Nephrin RNA expression was quantified and zebrafish embryos were live-screened for proteinuria and pericardial edema as evidence of renal impairment. Protein levels of PACAP and its binding-protein ceruloplasmin were measured and GFP-labeled thrombocytes were quantified. We also evaluated the effects of PACAP morpholino injection and the rescue effects of PACAP-38 peptide in both congenital NS models. Nephrin downregulation and pericardial edema were observed in both nephrin morpholino injected and adriamycin exposed congenital NS models. However, PACAP deficiency was demonstrated only in the adriamycin exposed condition. Ceruloplasmin levels and the number of GFP-labeled thrombocytes remained unchanged in both models. PACAP morpholino injections worsened survival rates and the edema phenotype in both congenital NS models while injection with human PACAP-38 could only rescue the adriamycin exposed model. We hereby report, for the first time, PACAP deficiency in a NS zebrafish model as a consequence of adriamycin exposure. However, distinct from the human congenital NS, both zebrafish models retained normal levels of ceruloplasmin and thrombocytes. We further extend the renoprotective effects of the PACAP-38 peptide against adriamycin toxicity in zebrafish.


Effect of oxygen on glucose metabolism: utilization of lactate in Staphylococcus aureus as revealed by in vivo NMR studies.
The ability to successfully adapt to changing host conditions is crucial for full virulence of bacterial pathogens. Staphylococcus aureus has to cope with fluctuating oxygen concentrations during the course of infection. Hence, we studied the effect of oxygen on glucose metabolism in non-growing S. aureus COL-S cells by in vivo(13)C-NMR. Glucose catabolism was probed at different oxygen concentrations in suspensions of cells grown aerobically (direct effects on metabolism) or anaerobically (transcriptional adjustment to oxygen deprivation). In aerobically-grown cells, the rate of glucose consumption diminished progressively with decreasing oxygen concentrations. Additionally, oxygen deprivation resulted in biphasic glucose consumption, with the second phase presenting a higher rate. The fructose-1,6-bisphosphate pool peaked while glucose was still abundant, but the transient maximum varied with the oxygen concentration. As oxygen became limiting mannitol/mannitol-1-phosphate were detected as products of glucose catabolism. Under anoxic conditions, accumulation of mannitol-1-phosphate ceased with the switch to higher glucose consumption rates, which implies the activation of a more efficient means by which NAD(+) can be regenerated. The distribution of end-products deriving from glucose catabolism was dramatically affected by oxygen: acetate increased and lactate decreased with the oxygen concentration; ethanol was formed only anaerobically. Moreover, oxygen promoted the energetically favourable conversion of lactate into acetate, which was particularly noticeable under fully oxygenated conditions. Interestingly, under aerobiosis growing S. aureus cells also converted lactate to acetate, used simultaneously glucose and lactate as substrates for growth, and grew considerably well on lactate-medium. We propose that the efficient lactate catabolism may endow S. aureus with a metabolic advantage in its ecological niche.


Alpha transcranial alternating current stimulation modulates auditory perception.
Studies using transcranial alternating current stimulation (tACS), a type of non-invasive brain stimulation, have demonstrated a relationship between the positive versus negative phase of both alpha and delta/theta oscillations with variable near-threshold auditory perception. These findings have not been directly compared before. Furthermore, as perception was better in the positive versus negative phase of two different frequencies, it is unclear whether changes in polarity (independent of a specific frequency) could also modulate auditory perception. We investigated whether auditory perception depends on the phase of alpha, delta/theta, or polarity alone. We stimulated participants with alpha, delta, and positive and negative direct current (DC) over temporal and central scalp sites while they identified near-threshold tones-in-noise. A Sham condition without tACS served as a control condition. A repeated-measures analysis of variance was used to assess differences in proportions of hits between conditions and polarities. Permutation-based circular-logistic regressions were used to assess the relationship between circular-predictors and single-trial behavioral responses. An exploratory analysis compared the full circular-logistic regression model to the intercept-only model. Overall, there were a greater proportion of hits in the Alpha condition in comparison to Delta, DC, and Sham conditions. We also found an interaction between polarity and stimulation condition; post-hoc analyses revealed a greater proportion of hits in the positive versus negative phase of Alpha tACS. In contrast, no significant differences were found in the Delta, DC, or Sham conditions. The permutation-based circular-logistic regressions did not reveal a statistically significant difference between the obtained RMS of the sine and cosine coefficients and the mean of the surrogate distribution for any of the conditions. However, our exploratory analysis revealed that circular-predictors explained the behavioral data significantly better than an intercept-only model for the Alpha condition, and not the other three conditions. These findings suggest that alpha tACS, and not delta nor polarity alone, modulates auditory perception.


The cohesin complex prevents Myc-induced replication stress.
The cohesin complex is mutated in cancer and in a number of rare syndromes collectively known as Cohesinopathies. In the latter case, cohesin deficiencies have been linked to transcriptional alterations affecting Myc and its target genes. Here, we set out to understand to what extent the role of cohesins in controlling cell cycle is dependent on Myc expression and activity. Inactivation of the cohesin complex by silencing the RAD21 subunit led to cell cycle arrest due to both transcriptional impairment of Myc target genes and alterations of replication forks, which were fewer and preferentially unidirectional. Ectopic activation of Myc in RAD21 depleted cells rescued Myc-dependent transcription and promoted S-phase entry but failed to sustain S-phase progression due to a strong replicative stress response, which was associated to a robust DNA damage response, DNA damage checkpoint activation and synthetic lethality. Thus, the cohesin complex is dispensable for Myc-dependent transcription but essential to prevent Myc-induced replicative stress. This suggests the presence of a feed-forward regulatory loop where cohesins by regulating Myc level control S-phase entry and prevent replicative stress.


Outdoor Inverse Rendering From a Single Image Using Multiview Self-Supervision.
In this paper we show how to perform scene-level inverse rendering to recover shape, reflectance and lighting from a single, uncontrolled image using a fully convolutional neural network. The network takes an RGB image as input, regresses albedo, shadow and normal maps from which we infer least squares optimal spherical harmonic lighting coefficients. Our network is trained using large uncontrolled multiview and timelapse image collections without ground truth. By incorporating a differentiable renderer, our network can learn from self-supervision. Since the problem is ill-posed we introduce additional supervision. Our key insight is to perform offline multiview stereo (MVS) on images containing rich illumination variation. From the MVS pose and depth maps, we can cross project between overlapping views such that Siamese training can be used to ensure consistent estimation of photometric invariants. MVS depth also provides direct coarse supervision for normal map estimation. We believe this is the first attempt to use MVS supervision for learning inverse rendering. In addition, we learn a statistical natural illumination prior. We evaluate performance on inverse rendering, normal map estimation and intrinsic image decomposition benchmarks.


Comparing the Actical and ActiGraph Approach to Measuring Young Children's Physical Activity Levels and Sedentary Time.
Young children's activity and sedentary time were simultaneously measured via the Actical method (i.e., Actical accelerometer and specific cut-points) and the ActiGraph method (i.e., ActiGraph accelerometer and specific cut-points) at both 15-s and 60-s epochs to explore possible differences between these 2 measurement approaches. For 7 consecutive days, participants (n = 23) wore both the Actical and ActiGraph side-by-side on an elastic neoprene belt. Device-specific cut-points were applied. Paired sample t tests were conducted to determine the differences in participants' daily average activity levels and sedentary time (min/h) measured by the 2 devices at 15-s and 60-s time sampling intervals. Bland-Altman plots were used to examine agreement between Actical and ActiGraph accelerometers. Regardless of epoch length, Actical accelerometers reported significantly higher rates of sedentary time (15 s: 42.7 min/h vs 33.5 min/h; 60 s: 39.4 min/h vs 27.1 min/h). ActiGraph accelerometers captured significantly higher rates of moderate-to-vigorous physical activity (15 s: 9.2 min/h vs 2.6 min/h; 60 s: 8.0 min/h vs 1.27 min/h) and total physical activity (15 s: 31.7 min/h vs 22.3 min/h; 60 s: = 39.4 min/h vs 25.2 min/h) in comparison with Actical accelerometers. These results highlight the present accelerometry-related issues with interpretation of datasets derived from different monitors.


Detection of extensively drug-resistant and hypervirulent Klebsiella pneumoniae ST15, ST147, ST377 and ST442 in Iran.
In this study, we focused on the emergence of extensively drug-resistant (XDR), pandrug-resistant (PDR), and hypervirulent Klebsiella pneumoniae (hvKP) in Iran. During 2018 to 2020 a total of 52 K. pneumoniae isolates were collected from different clinical specimens. The hvKP isolates were identified by PCR amplification of virulence and capsular serotype-specific genes. Hypermucoviscous K. pneumoniae (hmKP) were identified by string test. Carbapenem-resistant hvKP (CR-hvKP), multidrug-resistant hvKP (MDR-hvKP), extensively drug-resistant hvKP (XDR-hvKP), and pandrug-resistant hvKP (PDR-hvKP) were determined by disc diffusion method, Carba-NP test and PCR method. XDR-hvKP isolates were typed by multilocus sequence typing (MLST). Among all K. pneumoniae isolates 14 (26.9%) were identified as hvKP and 78.6% (11/14) of them were hmKP however, none of the classic K. pneumoniae (cKP) isolates were hmKP. The predominant capsular serotype of hvKP was K2 (42.85%) followed by K1 (35.71%). The prevalence of MDR-hvKP, XDR-hvKP and PDR-hvKP isolates were 6 (42.9%), 5 (35.7%) and 1 (7.1%), respectively. ESBL production was found in 85.7% of hvKP isolates and most of them carried bla TEM gene (78.6%) and 6 isolates (42.9%) were CR-hvKP. Among hvKP isolates, 1 (7.1%), 2 (14.3%), 3 (21.4%), 8 (28.6%), and 11 (78.6%) carried bla NDM-6, bla OXA-48, bla CTX-M, bla SHV, and bla TEM genes, respectively. According to MLST analysis, 2, 1, 1, and 1 XDR-hvKP isolates belonged to ST15, ST377, ST442, and ST147, respectively. The occurrence of such isolates is deeply concerning due to the combination of hypervirulence and extensively drug-resistance or pandrug-resistance.


An Arabidopsis brassinosteroid-dependent mutant is blocked in cell elongation.
Cell elongation is a developmental process that is regulated by light and phytohormones and is of critical importance for plant growth. Mutants defective in their response to light and various hormones are often dwarfs. The dwarfed phenotype results because of a failure in normal cell elongation. Little is known, however, about the basis of dwarfism as a common element in these diverse signaling pathways and the nature of the cellular functions responsible for cell elongation. Here, we describe an Arabidopsis mutant, dwarf4 (dwf4), whose phenotype can be rescued with exogenously supplied brassinolide. dwf4 mutants display features of light-regulatory mutants, but the dwarfed phenotype is entirely and specifically brassinosteroid dependent; no other hormone can rescue dwf4 to a wild-type phenotype. Therefore, an intact brassinosteroid system is an absolute requirement for cell elongation.


Ventilation patterns of the songbird lung/air sac system during different behaviors.
Unidirectional, continuous airflow through the avian lung is achieved through an elaborate air sac system with a sequential, posterior to anterior ventilation pattern. This classical model was established through various approaches spanning passively ventilated systems to mass spectrometry analysis of tracer gas flow into various air sacs during spontaneous breathing in restrained ducks. Information on flow patterns in other bird taxa is missing, and these techniques do not permit direct tests of whether the basic flow pattern can change during different behaviors. Here we use thermistors implanted into various locations of the respiratory system to detect small pulses of tracer gas (helium) to reconstruct airflow patterns in quietly breathing and behaving (calling, wing flapping) songbirds (zebra finch and yellow-headed blackbird). The results illustrate that the basic pattern of airflow in these two species is largely consistent with the model. However, two notable differences emerged. First, some tracer gas arrived in the anterior set of air sacs during the inspiration during which it was inhaled, suggesting a more rapid throughput through the lung than previously assumed. Second, differences in ventilation between the two anterior air sacs emerged during calling and wing flapping, indicating that adjustments in the flow pattern occur during dynamic behaviors. It is unclear whether this modulation in ventilation pattern is passive or active. This technique for studying ventilation patterns during dynamic behaviors proves useful for establishing detailed timing of airflow and modulation of ventilation in the avian respiratory system.


Online response-selection and the attentional blink: Multiple-processing channels.
Robust interference often arises when multiple targets (T1 and T2) are discriminated in rapid succession (the attentional blink or AB). The AB has been observed for a wide range of stimuli, and is often thought to reflect a central capacity limitation in working memory consolidation, attentional engagement, and/or online response selection. However, recent evidence challenges the existence of unitary bottleneck during postperceptual processing. Awh et al. (2004) found no AB interference when a digit target preceded a face target, presumably because these stimuli could be processed by means of separable processing channels. Using a modified AB procedure, recent studies have also demonstrated that speeded response selection of T1 leads to an AB effect for T2 identification, supporting the conclusion that response selection induces the same processing limitations that typically gives rise to an AB. The present research tests this hypothesis by examining the effects of response selection on the identification of faces. Although we replicated previous demonstrations that online response selection of a digit disrupts the identification of T2 letters, we found no interference in the identification of T2 faces. However, robust AB interference was once again observed when a speeded response to a T1 face was required, confirming that faces are not simply immune to central interference. These results dispute the existence of a unitary postperceptual capacity limitation that gives rise to the AB.


Laser induced sponge-like Si in Si-rich oxides for photovoltaics.
We show that a sponge-like structure of interconnected Si nanowires embedded in a dielectric matrix can be obtained by laser annealing of silicon rich oxides (SRO). Due to quantum confinement, the large bandgap displayed by these percolated nanostructures can be utilized as a tandem stage in 3rd generation thin-film solar cells. Well passivated by the SiO₂ dielectric matrix, they are expected to overcome the difficulty of carrier separation encountered in the case of isolated crystalline quantum dots. In this study PECVD grown SRO were irradiated by a cw Ar⁺ laser. Raman spectroscopy has been used to assess the crystallinity of the Si nanostructures and thus to optimize the annealing conditions as dwell times and power densities. In addition, Si plasmon imaging in the transmission electron microscope was applied to identify the sponge-like structure of phase-separated silicon.


Cancer incidence among pesticide applicators exposed to captan in the Agricultural Health Study.
Captan is a widely used antifungal pesticide whose potential to cause cancer in humans is uncertain. We evaluated the incidence of cancer among pesticide applicators exposed to captan in the Agricultural Health Study. Detailed information on pesticide exposure and lifestyle factors was obtained from self-administered enrollment questionnaires completed between 1993 and 1997. Of the 48,986 applicators enrolled 4,383 (9%) had applied captan. Median follow-up time was 9.14 years. Poisson regression analysis was used to estimate relative risks (RR) for cancer subtypes by tertiles of captan exposure. We investigated risk for all cancers combined and sites of cancer for which at least 15 cases occurred among captan-exposed applicators. These sites included cancers of the prostate, lung, and colon, blood-related cancers, and colorectal cancers. During follow-up 2,912 incident primary cases of cancer were identified. No association between the highest tertile of captan exposure (>67.375 intensity-weighted days) and development of all cancers (RR = 0.89; 95% CI, 0.71-1.13) or cancer of any specific site was observed. Although our study is limited by low numbers of observed cancer cases and follow-up time of 9.14 years, it does not provide evidence of an increased risk for the development of cancer at the investigated sites.


Avian influenza overview - update on 19 November 2020, EU/EEA and the UK.
Since 16 October 2020, outbreaks ofhighly pathogenic avian influenza (HPAI) viruseshavebeen reported inseveral EU/EEAcountries -Belgium, Denmark, France, Germany, Ireland, the Netherlands, and Swedenas well asin the United Kingdom.As of 19 November,12pm, 302 HPAI A(H5) detections have been reported, with the majority of the detections referring to wild birds (n=281), and a few related to outbreaks in poultry (n=18) and captive birds (n=3). Most of the detections in wild birds were in wild waterbirds,being barnacle goose the most affected species (n=110), followed by greylag goose (n=47), Eurasian wigeon (n=32),mallard (n=14), and common buzzard (n=13).ThreeHPAI virus subtypes were identified, A(H5N8), A(H5N5) and A(H5N1), with A(H5N8) being the most reported subtype (n=284). Phylogenetic analysis indicated that the viruses evolved from a single progenitor virus thatwent through multiple reassortment events. Based on the ongoing autumn migration of wild waterbirds to their wintering areas in Europe, there is a continued risk of further introduction of HPAI A(H5) viruses into Europe. Furthermore, given the expected movements of both migratory, and resident wild birds in Europe during winter, there is a high risk of further spread of HPAI A(H5) viruses within Europe. No genetic markers indicating adaptation to mammals have been identified in the viruses analysed so far,andno human infection due to avian influenza viruses detected in the recent outbreakshas been reported. For that reason,the risk to the general population remains very low.However,following the precautionary principle, people should avoid touching sick or dead birds unprotected to minimise any potential risk.


Transcriptional repression of the GLUT4 and C/EBP genes in 3T3-L1 adipocytes by tumor necrosis factor-alpha.
Fully differentiated 3T3-L1 adipocytes were chronically exposed to 5 nM tumor necrosis factor-alpha (TNF). This resulted in the development of an insulin resistance based on the inability of insulin to stimulate hexose uptake. Western blot analysis for glucose transporter protein in isolated membrane fractions indicated a total depletion of GLUT4 protein (insulin-responsive glucose transporter) in cells chronically treated with TNF. Plasma membrane content of GLUT1 protein (growth-related glucose transporter) was similar in both control and TNF-treated cells; however, the GLUT1 content of the intracellular membrane compartment had decreased markedly after TNF treatment. Continuous exposure to TNF resulted in an 85-90% decrease in the mRNA content for both GLUT4 and 422 (aP2, a lipid binding protein) genes relative to age matched controls, whereas insulin receptor mRNA levels declined by at least 50%. This was preceded by a marked decrease in mRNA accumulation for C/EBP, a transcription factor proposed to control expression of both GLUT4 and 422. The specificity of these observations was demonstrated by the lack of an effect of the chronic TNF treatment on either beta-actin or lipoprotein lipase mRNA content. The decreased content of GLUT4 and C/EBP mRNA was judged to be regulated at least in part at the level of transcription, based on the results of transcription run-on assays. Thus, the lack of response to insulin appeared due to a suppression of GLUT4 expression as well as a decreased intracellular content of GLUT1.


Microsecond precision of phase delay in the auditory system of the barn owl.
The auditory system encodes time with sub-millisecond accuracy. To shed new light on the basic mechanism underlying this precise temporal neuronal coding, we analyzed the neurophonic potential, a characteristic multiunit response, in the barn owl's nucleus laminaris. We report here that the relative time measure of phase delay is robust against changes in sound level, with a precision sharper than 20 micros. Absolute measures of delay, such as group delay or signal-front delay, had much greater temporal jitter, for example due to their strong dependence on sound level. Our findings support the hypothesis that phase delay underlies the sub-millisecond precision of the representation of interaural time difference needed for sound localization.


A new intracellular serine protease inhibitor expressed in the rat pituitary gland complexes with granzyme B.
We have cloned a novel serpin (raPIT5a) from a rat pituitary cDNA library which is structurally related to members of the ovalbumin subfamily of serine protease inhibitors. This new cDNA encodes a 374-amino acid protein, designated raPIT5a. raPIT5a was expressed in specific cells in the intermediate and anterior lobes of the pituitary. Recombinant raPIT5a was not secreted suggesting raPIT5a functions to inhibit intracellular proteases. Recombinant raPIT5a formed an SDS-stable complex with human granzyme B, a serine protease which induces apoptosis by activating members of the caspase enzyme family. These data suggest raPIT5a may have a role in regulating granzyme B or related enzymes and apoptosis in the pituitary gland.


Genome-Wide Single Nucleotide Polymorphisms are Robust in Resolving Fine-Scale Population Genetic Structure of the Small Brown Planthopper, Laodelphax striatellus (Fallén) (Hemiptera: Delphacidae).
Deciphering genetic structure and inferring migration routes of insects with high migratory ability have been challenging, due to weak genetic differentiation and limited resolution offered by traditional genotyping methods. Here, we tested the ability of double digest restriction-site associated DNA sequencing (ddRADseq)-based single nucleotide polymorphisms (SNPs) in revealing the population structure relative to 13 microsatellite markers by using four small brown planthopper populations as subjects. Using ddRADseq, we identified 230,000 RAD loci and 5,535 SNP sites, which were present in at least 80% of individuals across the four populations with a minimum sequencing depth of 10. Our results show that this large SNP panel is more powerful than traditional microsatellite markers in revealing fine-scale population structure among the small brown planthopper populations. In contrast to the mixed population structure suggested by microsatellites, discriminant analysis of principal components (DAPC) of the SNP dataset clearly separated the individuals into four geographic populations. Our results also suggest the DAPC analysis is more powerful than the principal component analysis (PCA) in resolving population genetic structure of high migratory taxa, probably due to the advantages of DAPC in using more genetic variation and the discriminant analysis function. Together, these results point to ddRADseq being a promising approach for population genetic and migration studies of small brown planthopper.


Protective effects of L-type fatty acid-binding protein (L-FABP) in proximal tubular cells against glomerular injury in anti-GBM antibody-mediated glomerulonephritis.
In glomerulonephritis (GN), an overload of free fatty acids (FFA) bound to albumin in urinary protein may induce oxidative stress in the proximal tubules. Human liver-type fatty acid-binding protein (hL-FABP) expressed in human proximal tubules, but not rodents, participates in intracellular FFA metabolism and exerts anti-oxidative effects on the progression of tubulointerstitial damage. We examined whether tubular enhancement of this anti-oxidative action modulates the progression of glomerular damage in immune-mediated GN in hL-FABP chromosomal gene transgenic (Tg) mice. Anti-glomerular basement membrane antibody-induced glomerulonephritis (anti-GBM GN) was induced in Tg and wild-type mice (WT). Proteinuria, histopathology, polymorphonuclear (PMN) influx, expression of tubulointerstitial markers for oxidative stress 4-hydroxy-2-Nonenal (HNE) and fibrosis (α-smooth muscle actin), proximal tubular damage (Kim-1), Peroxisome Proliferator-Activated Receptor γ (PPAR γ) and inflammatory cytokines [Monocyte Chemotactic Protein-1, tumor necrosis factor-alpha (TNF-α) and Transforming growth factor beta (TGF-β)] were analyzed. The mice were also treated with an angiotensin type II receptor blocker (ARB). The urinary protein level in Tg mice decreased significantly during the acute phase (~Day 5). Tg mice survived for a significantly longer time than WT mice, with an attenuation of tubulointerstitial damage score and expression of each tubulointerstitial damage marker observed at Day 7. Expression of inflammatory cytokines on Day 7 was higher in WT mice than Tg mice and correlated strongly with PPARγ expression in WT mice, but not in Tg mice. Interestingly, Tg mice showed insufficient PMN influx at 3 and 6 h, with simultaneous elevation of urinary L-FABP and reduction in HNE expression. The two strains of mice showed different types of glomerular damage, with mild mesangial proliferation in Tg mice and severe endothelial swelling with vascular thrombosis in WT mice. The glomerular damage in Tg mice was improved by administration of an ARB. The present experimental model suggests that tubular enhancement of L-FABP may protect mice with anti-GBM GN from progression of both tubulointerstitial and glomerular injury.


Multifaceted support for quality of life in childhood cancer survivors: Questionnaire survey.
Along with improvements in curative treatment for childhood cancer, childhood cancer survivors (CCSs) often face numerous problems such as late complications of cancer treatment, social issues at school, struggles in employment, and financial difficulties. These children have received a wide range of support from the medical, educational, and administrative sectors. However, it was unclear how this multifaceted support contributed to quality of life (QOL) of CCSs in Japan. The subjects were 46 CCSs of 16 years of age or older at the time of the survey, who had been diagnosed and treated for pediatric cancer. A self-administered questionnaire survey was conducted to investigate the in-hospital status during treatment, adjustment when returning to school, and administrative social support. The QOL of CCSs was also evaluated by the Medical Outcome Study 36-Item Short-Form Health Survey. Twenty-four CCSs answered the questions. The respondents who had experienced school-life problems tended to have lower role/social QOL scores (p = 0.046), whereas the CCSs who had experienced administrative counseling tended to have lower physical QOL scores (p = 0.036). The mental QOL scores tended to be higher in respondents who were informed of the exact diagnosis of cancer during hospitalization. The role/social QOL scores tended to be lower in respondents who advanced to their preferred career path. It is essential for three stakeholders-health-care providers, education offices, and public administrative agencies-to collaborate to share long-term psychosocial issues or concerns related to employment or daily living that CCSs may encounter, and to establish a coordinated approach to support CCSs.


Premenopausal breast cancer risk and intake of vegetables, fruits, and related nutrients.
Given the international variations in breast cancer incidence rates and the changes in breast cancer incidence among migrant populations, it has been hypothesized that diet is a factor influencing risk of this disease. Many studies indicate that a diet high in vegetables and fruits may protect against breast cancer. We conducted a case-control study of diet, including the intake of non-food supplements, and premenopausal breast cancer risk. We evaluated in detail usual intake of vegetables and fruits (each measured as the total reported grams consumed for all queried vegetables and fruit), vitamins C and E, folic acid, individual carotenoids, and dietary fiber with its components. Case patients (n=297) were identified through pathology records from hospitals in Erie and Niagara counties in western New York. They consisted of premenopausal women 40 years of age or oder who were diagnosed with breast cancer from November 1986 through April 1991. Control subjects (n=311), frequency-matched to case patients on the basis of age and county of residence, were randomly selected from New York State Department of Motor Vehicles records. In-person interviews included detailed reports of usual diet in the period 2 years before the interview. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). There was a reduction in risk associated with high intake of several nutrients. With the lowest quartile of intake as the referent, adjusted ORs for the highest quartile of intake for specific nutrients were as follows: vitamin C (OR=0.53; 95% CI=0.33-0.86), alpha-tocopheral (OR=0.55; 95% CI=0.34-0.88), folic acid (OR=0.50; 95% CI=0.31-0.82), alpha-carotene (OR=0.67; 95% CI=0.42-1.08) and beta-carotene (OR=0.46; 95% CI=0.28-0.74), lutein + zeaxanthin (OR=0.47; 95% CI=0.28.0-77), and dietary fiber from vegetables and fruits (OR=0.48; 95% CI=0.30-0.78). No association with risk was found for beta-cryptoxanthin, lycopene, or grain fiber. Fruits were weakly associated with a reduction in risk (fourth quartile OR=0.67; 95% CI=0.42-1.09). No association was found between breast cancer risk and intake of vitamins C and E and folic acid taken as supplements. A strong inverse association between total vegetable intake and risk was observed (fourth quartile OR=0.46; 95% CI=0.28-0.74). This inverse association was found to be independent of vitamin C,alpha-tocopherol, folic acid, dietary fiber, and alpha-carotene. Adjusting for beta-carotene or lutein + zeaxanthin somewhat attenuated the inverse association with vegetable intake. In this population, intake of vegetables appears to decrease premenopausal breast cancer risk. This effect may be related, in part, to beta-carotene and lutein + zeaxanthin in vegetables. It appears, however, that, of the nutrients and food components examined, no single dietary factor explains the effect. Evaluated components found together in vegetables may have a synergistic effect on breast cancer risk; alternatively, other unmeasured factors in these foods may also influence risk.


Elevated E-cadherin and alpha/beta-catenin expression after androgen deprivation therapy in prostate adenocarcinoma.
The histological patterns of anti-androgen-treated prostate adenocarcinoma mimic high grade tumors classified according to the widely used Gleason scoring system. However, the biological characteristics of anti-androgen treated carcinoma are largely unknown. E-cadherin, alpha-catenin, and beta-catenin adhesion molecules are down-regulated in pharmacologically untreated high grade prostate carcinoma. In this study, we used immunohistochemical techniques to investigate their expression in twenty acinar adenocarcinomas after anti-androgen therapy in prostatectomy specimens. After adrogen ablation therapy, expression of all these adhesion molecules was higher than that of pretreatment biopsies of the same patient group and high grade matched untreated controls. These results emphasize the inaccuracy of the Gleason score for anti-androgen-treated prostate adenocarcinoma and the more differentiated phenotype of prostate adenocarcinoma after anti-hormonal therapy.


An analysis of Part II of the National Board of Medical Examiners Test with regard to questions in emergency medicine.
We conducted a study to determine the number of items and successful response rate to questions specific to emergency medicine on the National Board of Medical Examiners Test, Part II (NBME-II). The 1979 and 1983 NBME-II examinations were reviewed by a subcommittee of the Society of Teachers of Emergency Medicine. Items pertaining directly to the core content knowledge base were selected and classified by core content topic and NBME subspecialty. Overall, 14.7% of the 892 items on the 1983 examination pertained to emergency medicine. The successful response rate was 73.3% for the emergency medicine questions. When looked at by sub-specialty categories, the percentage of items pertaining to emergency medicine varied from 1.3% in obstetrics/gynecology to 27.2% of the items in surgery. On the 1979 examination, 13.8% of the questions pertained to emergency medicine, with a successful response rate of 67.1%. Analysis of the data by core content topic showed that some areas (orientation to emergency medicine, ophthalmologic diseases, environmental emergencies, and behavioral emergencies) had two items or fewer on both examinations. Other topics, such as trauma, showed a consistent pattern of questions on both examinations. Our study emphasizes the difficulty of attempting to test competency in the clinical knowledge base of medicine within the artificiality of knowledge base departmental boundaries.


Big data analytics to improve cardiovascular care: promise and challenges.
The potential for big data analytics to improve cardiovascular quality of care and patient outcomes is tremendous. However, the application of big data in health care is at a nascent stage, and the evidence to date demonstrating that big data analytics will improve care and outcomes is scant. This Review provides an overview of the data sources and methods that comprise big data analytics, and describes eight areas of application of big data analytics to improve cardiovascular care, including predictive modelling for risk and resource use, population management, drug and medical device safety surveillance, disease and treatment heterogeneity, precision medicine and clinical decision support, quality of care and performance measurement, and public health and research applications. We also delineate the important challenges for big data applications in cardiovascular care, including the need for evidence of effectiveness and safety, the methodological issues such as data quality and validation, and the critical importance of clinical integration and proof of clinical utility. If big data analytics are shown to improve quality of care and patient outcomes, and can be successfully implemented in cardiovascular practice, big data will fulfil its potential as an important component of a learning health-care system.


Glomerular-tubular balance for bicarbonate in the dog.
Previous work that apparently showed a functional relationship between GFR and maximum bicarbonate reabsorption was done at a time when the effects on the latter of several factors (PCO2, plasma potassium concentration, and extracellular fluid volume expansion) were not recognized. The present study re-examines this relationship, while controlling these factors. In 14 hydropenic dogs, bicarbonate reabsorption per unt GFR increased linearly with increases in plasma bicarbonate concentration. At any level of plasma bicarbonate concentration,the absolute rate of bicarbonate reabsorption was functionally related to the GFR. In six volume-expanded dogs, bicarbonate reabsorption remained stable at 20-22 mmol/liter GFR as plasma bicarbonate was raised to greater than 40mM. The absolute rate of bicarbonate reabsorption increased with large increases in GFR induced by methylprednisolone and high-protein diet. In a third group of dogs, bicarbonate reabsorption varied directly with increases in GFR, while plasma bicarbonate concentration was held relatively constant above the threshold. We conclude there is a close functional relationship between the absolute rate of bicarbonate reabsorption and GFR in individual dogs.


High-protein diet improves sensitivity to cholecystokinin and shifts the cecal microbiome without altering brain inflammation in diet-induced obesity in rats.
High-protein diet (HPD) curtails obesity and/or fat mass, but it is unknown whether it reverses neuroinflammation or alters glucose levels, CCK sensitivity, and gut microbiome in rats fed a Western diet (WD)-induced obesity (DIO). Male rats fed a WD (high fat and sugar) for 12 wk were switched to a HPD for 6 wk. Body composition, food intake, meal pattern, sensitivity to intraperitoneal CCK-8S, blood glucose, brain signaling, and cecal microbiota were assessed. When compared with a normal diet, WD increased body weight (9.3%) and fat mass (73.4%). CCK-8S (1.8 or 5.2 nmol/kg) did not alter food intake and meal pattern in DIO rats. Switching to a HPD for 6 wk reduced fat mass (15.7%) with a nonsignificantly reduced body weight gain, normalized blood glucose, and decreased feeding after CCK-8S. DIO rats on the WD or switched to a HPD showed comparable microbial diversity. However, in HPD versus WD rats, there was enrichment of 114 operational taxonomic units (OTUs) and depletion of 188 OTUs. Of those, Akkermansia muciniphila (enriched on a HPD), an unclassified Clostridiales, a member of the RF39 order, and a Phascolarctobacterium were significantly associated with fat mass. The WD increased cytokine expression in the hypothalamus and dorsal medulla that was unchanged by switching to HPD. These data indicate that HPD reduces body fat and restores glucose homeostasis and CCK sensitivity, while not modifying brain inflammation. In addition, expansion of cecal Akkermansia muciniphila correlated to fat mass loss may represent a potential peripheral mechanism of HPD beneficial effects.


Endovascular treatment for traumatic scalp arteriovenous fistulas: results with Onyx embolization.
Arteriovenous fistulas of the scalp (S-AVFs) are rare lesions and may occur spontaneously or secondary to trauma. The use of Onyx for the treatment of S-AVFs is not well established at this time. We discuss three cases of traumatic S-AVFs treated successfully with Onyx embolization alone or in association with coils. The database of patients treated at the Baptist Cardiac and Vascular Institute, Miami, Florida, was reviewed. All patients with traumatic S-AVFs treated with Onyx were included. Two men and one woman with progressive enlarging pulsatile mass with bruit or tinnitus had angiographic evidence of S-AVF and were treated. In two patients the S-AVFs were secondary to hair transplantation. They were treated with Onyx-18 embolization as the single treatment modality. One patient with S-AVF resulting from temporomandibular joint arthroscopy was treated with coils and subsequent Onyx-34 embolization. In one patient, transarterial microcatheterization and injection of Onyx-18 was performed. In another patient, the intra-arterial approach was prevented by arterial vessel tortuosity. Therefore, access to the fistula was obtained through direct puncture of a large frontal vein; contrast injection confirmed the positioning of the needle within the draining vein of the AVF and Onyx-18 was then injected while the outflow vein was compressed. In the third patient in this series, coils were deployed to allow safer and more controlled injection of Onyx-34. No procedure related complications were noted. Post-embolization angiography demonstrated successful and complete occlusion of the AVF immediately after treatment. Follow-up revealed complete resolution of the symptoms. Our experience in this small series indicates that endovascular treatment of S-AVFs with Onyx is rapid, safe, and highly effective.


An Incremental Dimensionality Reduction Method for Visualizing Streaming Multidimensional Data.
Dimensionality reduction (DR) methods are commonly used for analyzing and visualizing multidimensional data. However, when data is a live streaming feed, conventional DR methods cannot be directly used because of their computational complexity and inability to preserve the projected data positions at previous time points. In addition, the problem becomes even more challenging when the dynamic data records have a varying number of dimensions as often found in real-world applications. This paper presents an incremental DR solution. We enhance an existing incremental PCA method in several ways to ensure its usability for visualizing streaming multidimensional data. First, we use geometric transformation and animation methods to help preserve a viewer's mental map when visualizing the incremental results. Second, to handle data dimension variants, we use an optimization method to estimate the projected data positions, and also convey the resulting uncertainty in the visualization. We demonstrate the effectiveness of our design with two case studies using real-world datasets.


Cerebral blood flow during plateau waves in a patient with benign intracranial hypertension--case report.
A 50-year-old male presented with benign intracranial hypertension (BIH). He was admitted to our hospital for headache and papilledema. The diagnosis was BIH as continuous monitoring of lumbar cerebrospinal fluid pressure (CSFP) showed high basal pressure with intermittent plateau waves. Ten months after successful ventriculoperitoneal shunting, he presented with headache again due to shunt malfunction. CSFP monitoring showed the same findings as before. Regional cerebral blood flow (rCBF) was measured by positron emission tomography (PET) using the 15O-labeled water autoradiographic method with simultaneous recording of lumbar CSFP. The rCBF values of the cerebral cortex, white matter, thalamus, cerebellar cortex, and pons were evaluated during both the plateau waves and the intervals. In spite of severely reduced cerebral perfusion pressure, rCBF during the plateau waves was not reduced when compared with the rCBF of normal volunteers in all regions. This result might explain why patients with BIH show no impairment of consciousness or focal signs during the plateau waves.


A notch1 ectodomain construct inhibits endothelial notch signaling, tumor growth, and angiogenesis.
Notch signaling is required for vascular development and tumor angiogenesis. Although inhibition of the Notch ligand Delta-like 4 can restrict tumor growth and disrupt neovasculature, the effect of inhibiting Notch receptor function on angiogenesis has yet to be defined. In this study, we generated a soluble form of the Notch1 receptor (Notch1 decoy) and assessed its effect on angiogenesis in vitro and in vivo. Notch1 decoy expression reduced signaling stimulated by the binding of three distinct Notch ligands to Notch1 and inhibited morphogenesis of endothelial cells overexpressing Notch4. Thus, Notch1 decoy functioned as an antagonist of ligand-dependent Notch signaling. In mice, Notch1 decoy also inhibited vascular endothelial growth factor-induced angiogenesis in skin, establishing a role for Notch receptor function in this process. We tested the effects of Notch1 decoy on tumor angiogenesis using two models: mouse mammary Mm5MT cells overexpressing fibroblast growth factor 4 (Mm5MT-FGF4) and NGP human neuroblastoma cells. Exogenously expressed FGF4 induced Notch ligand expression in Mm5MT cells and xenografts. Notch1 decoy expression did not affect tumorigenicity of Mm5MT-FGF4 cells in vitro but restricted Mm5MT-FGF4 xenograft growth in mice while markedly impairing neoangiogenesis. Similarly, Notch1 decoy expression did not affect NGP cells in vitro but disrupted vessels and decreased tumor viability in vivo. These results strongly suggest that Notch receptor signaling is required for tumor neoangiogenesis and provides a new target for tumor therapy.


Impairment of natural killer functions by interleukin 6 increases lymphoblastoid cell tumorigenicity in athymic mice.
Expression of the human IL-6 gene in EBV-immortalized normal human B lymphocytes following retroviral-mediated transduction rendered these cells highly tumorigenic in athymic mice. The tumors were lymphomas composed of the originally inoculated human lymphoblastoid cells. Co-injection of IL-6 expressing EBV-immortalized cells with IL-6 nonexpressing control cells resulted in increased tumorigenicity of the IL-6 nonexpressing cells. The lymphoblastoid cells expressing IL-6 were indistinguishable from parental cell lines in morphology and in a variety of cell surface characteristics, and did not exhibit growth advantage over parental cell lines in vitro, such that increased tumorigenicity is unlikely to depend upon a direct oncogenic effect of IL-6 on the B cells. Rather, at high concentrations, IL-6 markedly inhibits human lymphoblastoid cell killing by IL-2-activated murine splenocytes in vitro, suggesting that IL-6-related tumorigenicity might depend upon IL-6 inhibiting cytotoxicity at the tumor site. Thus, production of IL-6 by tumor cells that results in natural killer cell dysfunctions illustrates a novel mechanism of tumor cell escape from immune surveillance.


The role of MTJ-1 in cell surface translocation of GRP78, a receptor for alpha 2-macroglobulin-dependent signaling.
MTJ-1 associates with a glucose-regulated protein of Mr approximately 78,000(GRP78) in the endoplasmic reticulum and modulates GRP78 activity as a chaperone. GRP78 also exists on the cell surface membrane, where it is associated with a number of functions. MHC class I Ags on the cell surface are complexed to GRP78. GRP78 also serves as the receptor for alpha2-macroglobulin-dependent signaling and for uptake of certain pathogenic viruses. The means by which GRP78, lacking a transmembrane domain, can fulfill such functions is unclear. In this study we have examined the question of whether MTJ-1, a transmembrane protein, is involved in the translocation of GRP78 to the cell surface. MTJ-1 and GRP78 coimmunoprecipitated from macrophage plasma membrane lysates. Silencing of MTJ-1 gene expression greatly reduced MTJ-1 mRNA and protein levels, but also abolished cell surface localization of GRP78. Consequently, binding of the activated and receptor-recognized form of alpha2-macroglobulin to macrophages was greatly reduced, and activated and receptor-recognized form of alpha2-macroglobulin-induced calcium signaling was abolished in these cells. In conclusion, we show that in addition to assisting the chaperone GRP78 in protein quality control in the endoplasmic reticulum, MTJ-1 is essential for transport of GRP78 to the cell surface, which serves a number of functions in immune regulation and signal transduction.


The neuronal scaffold protein Shank3 mediates signaling and biological function of the receptor tyrosine kinase Ret in epithelial cells.
Shank proteins, initially also described as ProSAP proteins, are scaffolding adaptors that have been previously shown to integrate neurotransmitter receptors into the cortical cytoskeleton at postsynaptic densities. We show here that Shank proteins are also crucial in receptor tyrosine kinase signaling. The PDZ domain-containing Shank3 protein was found to represent a novel interaction partner of the receptor tyrosine kinase Ret, which binds specifically to a PDZ-binding motif present in the Ret9 but not in the Ret51 isoform. Furthermore, we show that Ret9 but not Ret51 induces epithelial cells to form branched tubular structures in three-dimensional cultures in a Shank3-dependent manner. Ret9 but not Ret51 has been previously shown to be required for kidney development. Shank3 protein mediates sustained Erk-MAPK and PI3K signaling, which is crucial for tubule formation, through recruitment of the adaptor protein Grb2. These results demonstrate that the Shank3 adaptor protein can mediate cellular signaling, and provide a molecular mechanism for the biological divergence between the Ret9 and Ret51 isoform.


Occurrence of perfluoroalkyl substances (PFASs) in a large number of wild and farmed aquatic animals collected in the Netherlands.
A range of perfluoroalkyl substances (PFASs) was analysed in marine fish, farmed fish, crustaceans, bivalves and European eel caught in (mostly) Dutch waters, or purchased at Dutch markets (approximately 250 samples, collected between 2012 and 2018). ΣPFAS levels were highest in eels collected from rivers and lakes (average 43.6 ng/g and max 172 ng/g), followed by shrimps collected near the Dutch coast (average 6.7 and max. 33 ng/g ww), and seabass (average 4.5 and max. 9.4 ng/g ww). Most of the farmed fish (e.g. trout, catfish, turbot, salmon, tilapia, pangasius) were among the lowest contaminated samples in this study (averages ranged from 0.06 to 1.5 ng/g ww). Geographically, levels in marine fish from the northern North Sea (e.g. haddock, whiting, herring) were lower than in the central and southern North Sea (e.g. cod and flatfish). Concerning eel, no substantial geographical differences were found (apart from two distinct locations). The contamination pattern was similar in all species, where PFOS mostly dominated the profile, and other long-chain PFASs being frequently detected. Short-chain PFASs were rarely found. PFOS concentrations in eel varied from 3.3 ng/g (close to the North Sea) to 67 ng/g ww in eel caught from Ghent-Terneuzen canal. The majority of detected PFOS levels in eels (93%) and 1 shrimp sample from Eems-Dollard exceeded the EU Environmental Quality Standard (EQS) for surface water of 9.1 μg/kg ww. Other samples (e.g. shrimps, bivalves, flounder), subject to the EQS, did not exceed this level.


CD81 promotes both the degradation of transferrin receptor 2 (TfR2) and the Tfr2-mediated maintenance of hepcidin expression.
Mutations in transferrin receptor 2 (TfR2) cause a rare form of the hereditary hemochromatosis, resulting in iron overload predominantly in the liver. TfR2 is primarily expressed in hepatocytes and is hypothesized to sense iron levels in the blood to positively regulate the expression of hepcidin through activation of the BMP signaling pathway. Hepcidin is a peptide hormone that negatively regulates iron egress from cells and thus limits intestinal iron uptake. In this study, a yeast two-hybrid approach using the cytoplasmic domain of TfR2 identified CD81 as an interacting protein. CD81 is an abundant tetraspanin in the liver. Co-precipitations of CD81 with different TfR2 constructs demonstrated that both the cytoplasmic and ecto-transmembrane domains of TfR2 interact with CD81. Knockdown of CD81 using siRNA significantly increased TfR2 levels by increasing the half-life of TfR2, indicating that CD81 promotes degradation of TfR2. Previous studies showed that CD81 is targeted for degradation by GRAIL, an ubiquitin E3 ligase. Knockdown of GRAIL in Hep3B-TfR2 cells increased TfR2 levels, consistent with inhibition of CD81 ubiquitination. These results suggest that down-regulation of CD81 by GRAIL targets TfR2 for degradation. Surprisingly, knockdown of CD81 decreased hepcidin expression, implying that the TfR2/CD81 complex is involved in the maintenance of hepcidin mRNA. Moreover, knockdown of CD81 did not affect the stimulation of hepcidin expression by BMP6 but increased both the expression of ID1 and SMAD7, direct targets of BMP signaling pathway, and the phosphorylation of ERK1/2, indicating that the CD81 regulates hepcidin expression differently from the BMP and ERK1/2 signaling pathways.


Systematic conservation planning for Antarctic research stations.
The small ice-free areas of Antarctica are essential locations for both biodiversity and scientific research but are subject to considerable and expanding human impacts, resulting primarily from station-based research and support activities, and local tourism. Awareness by operators of the need to conserve natural values in and around station and visitor site footprints exists, but the cumulative nature of impacts often results in reactive rather than proactive management. With human activity spread across many isolated pockets of ice-free ground, the pathway to the greatest reduction of human impacts within this natural reserve is through better management of these areas, which are impacted the most. Using a case study of Australia's Casey Station, we found significant natural values persist within the immediate proximity (<10 m) of long-term station infrastructure, but encroachment by physical disturbance results in ongoing pressures. Active planning to better conserve such values would provide a direct opportunity to enhance protection of Antarctica's environment. Here we introduce an approach to systematic conservation planning, tailored to Antarctic research stations, to help managers improve the conservation of values surrounding their activity locations. Use of this approach provides a potential mechanism to balance the need for scientific access to the continent with international obligations to protect its environment. It may also facilitate the development of subordinate conservation tools, including management plans and natural capital accounting. By proactively minimising and containing their station footprints, national programs can also independently demonstrate their commitment to protecting Antarctica's environment.


Computerized databases: privacy issues in the development of the nursing minimum data set.
Nursing leaders promoting the development and use of computerized databases such as the Nursing Minimum Data Set (NMDS) have not adequately addressed the complex ethical issues involved with computerized information systems. The purpose of this article is to describe the privacy issues involved with the NMDS. Moral considerations and principles guiding resolution of ethical issues concerning violations of patient privacy are discussed. A paradigm case is used to demonstrate the significance of privacy violations in computerized databases. Two security systems currently being considered in other disciplines are included for their relevance to the development of the NMDS. The broader implications concerning the impact of technology on preservation of human dignity and the quality of life are addressed.


Childhood cancer among Alaska Natives.
The primary purpose of this study was to examine the occurrence of cancer in Alaska Native (AN) children (under age 20). Although several studies have compared differences in cancer incidence between white and black children, few have examined cancer among Alaska Natives/American Indians. We know of no published article describing cancer incidence in AN children. We compared our findings with those of American Indian children of New Mexico and of Alaska white children. Data on mortality, survival, and prevalence are also included. Alaska Native is the term used collectively for the inhabitants whose ancestors occupied the area before European contact of what is now the state of Alaska. Alaska Natives include Eskimo, Indian, and Aleut groups. Although the 3 major groups differ in culture, language, and probably genetics, there are similarities in numerous social and economic indicators. The Northern Eskimo of Alaska (Inupiat) are related to Canadian and Greenland Inuit. Indians in Alaska include Athabaskan (in the interior of the state), who share commonalities with Canadian Athabaskan as well as with Navajo and Apache in the southwestern United States. Tlingit, Haida, and Tsimshian groups reside primarily in the southeast panhandle of the state. The panhandle Indian groups are similar to those of British Columbia. Data on cancer incidence are from the Alaska Native Tumor Registry, 1969-1996. We studied children under age 20 to make our results comparable to national data as presented in the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) Pediatric Monograph. Population data for AN are based on census data and Indian Health Service intercensal estimates. Data for US whites and New Mexico Indians are from the National Cancer Institute's SEER program. Calculations were made using SEERStat software. Data for Alaska whites are for the years 1996-2000. (The Alaska Cancer Registry has collected data for all Alaskans only since 1996). Odds ratios (ORs) of rates with 95% confidence intervals (CIs) were calculated. The rate among all AN children (both sexes) for all cancers combined is similar to that of US whites (OR: 1.0; 95% CI: 0.8-1.1). Examination of childhood cancer rates by ethnicity, however, reveal that rates are significantly lower for Indian (OR: 0.6; 95% CI: 0.4-0.8) but not significantly different for Eskimo or Aleut children. For most International Classification of Childhood Cancers groups, incidence rates for AN children are also similar to those of US whites. However, AN children are at significantly higher risk for hepatic tumors (OR: 13.1; 95% CI: 7.9-20.5), particularly hepatocellular carcinoma (OR: 43.8; 95% CI:24.4-75.1) and retinoblastoma (OR: 2.8; 95% CI: 1.3-5.3). By ethnic group, rates for hepatocellular carcinoma are significantly high only for Eskimo. Rates for all AN children are lower for neuroblastoma (OR: 0.1; 95% CI: 0.1-0.6) and lymphoma (OR: 0.5; 95% CI: 0.3-0.9), particularly Hodgkin's disease (OR: 0.2; 95% CI: 0.0-0.5). On the basis of 5 years of data, rates for Alaska white children do not seem to differ from those of US white children. Because of our findings of differences between AN and US whites, we reviewed data of other relevant populations, specifically American Indian data from the New Mexico SEER registry. Using SEER data and SEER software, we calculated rates for New Mexican American Indians (NMAI) and compared them with US white rates. Rates for all cancers combined among NMAI are significantly lower than for US white (OR: 0.8). However, similar to AN children, the rate among NMAI for retinoblastoma is higher compared with US whites (OR: 2.5; 95% CI:1.4-4.5). Similar to AN, NMAI also seem to be at low risk for neuroblastoma (OR: 0.2; 95% CI: 0.1-0.7), lymphoma as a group (OR: 0.1; 95% CI: 0.0-0.3), and, specifically, Hodgkin's disease (OR: 0.1; 95% CI: 0.0-0.4). Rates among NMAI children are low for central nervous system tumors (OR: 0.5; 95% CI: 0.3-0.7). The average annual age-adjusted cancer mortality rate among AN children is lower but not significantly lower than that of US white children (28.6 vs 37.3 per million). Comparison of AN rates for all cancers combined are similar to those of US and Alaska white children but seem higher than those of NMAI. Differences between AN and US whites exist for select International Classification of Childhood Cancers groups. The most striking rate differences are found in hepatic tumors, largely because of elevated rates of hepatitis B-associated hepatocellular carcinoma. All children in our study with hepatocellular carcinoma were hepatitis B antigen positive. A statewide hepatitis B virus immunization program was begun in late 1982. Although 16 children who were born before 1983 developed hepatocellular carcinoma, no children who were born in the 20 years since hepatitis B immunization was instituted among infants have received a diagnosis of hepatocellular carcinoma, a significant difference. Comparing AN and US white childhood cancer rates after removing hepatocellular carcinoma cases from both populations results in an OR of 0.8 (95% CI: 0.7-1.0). Thus, if no increase in other childhood cancers occurs in the coming generations, then rates for childhood cancer may soon be significantly lower than those in US white children. Rates are low for all lymphomas, largely because of very low rates of Hodgkin's disease. Rates are also low for neuroblastoma. It is reassuring that rates for AN children are not in excess and do not seem to be increasing. There is concern among the population regarding environmental exposure, including ionizing radiation. Our data do not show excess childhood leukemia or thyroid cancers, malignancies for which radiation is known to increase risk.


Responses to central oxotremorine and scopolamine support the cholinergic control of male mating behavior in hamsters.
The responses of hamsters to intracranial injections of the cholinergic agonist oxotremorine (OXO) implicate cholinergic mechanisms in the medial preoptic area (MPOA) in the control of male mating behavior. To extend these observations, we ran three studies of responses to cholinergic drugs delivered singly or in combination to the vicinity of the MPOA. The first tested responses to OXO, confirming its ability to reduce the postejaculatory interval. The second complemented the first by examining responses to MPOA microinjections of the cholinergic antagonist scopolamine (SCO). These caused several changes revolving around intromission. These included increases in intromission frequency and ejaculation latency. They also included a change in the patterning of intromissions, marked by continuous strings without the usual separation by dismounts. The final study resembled the others in examining the effects of MPOA injections of OXO and SCO but focused on the ability of each drug to antagonize responses to the other. Most of the responses to OXO and SCO individually replicated earlier findings, though the measures examined here also permitted the description of effects on some noncopulatory sexual behaviors, specifically the male's inspection of the female. However, the most interesting results may be those suggesting asymmetry in the responses to the addition of the second drug: Whereas responses to OXO tended to be antagonized by SCO, OXO was less effective at counteracting responses to SCO. Though the explanation of this asymmetry is not completely clear, it is consistent with previous suggestions of differences in the affinities of these drugs for subtypes of muscarinic receptors. Therefore, it suggests that the cholinergic synapses and circuits controlling distinct elements of male behavior could differ in their dependence on these receptors.


Assessment of the implementation of DOTS strategy in two chest facilities in Alexandria, Egypt.
We conducted a cohort analysis of all patients with tuberculosis (TB) attending 2 chest facilities in Alexandria, Egypt for the year 2003. A pre-coded checklist was used for auditing medical records. Conformity to the DOTS drug regimen during the continuation phase of therapy, conformity to the recommended schedule of sputum smear microscopy, and quality of registration of medical records were the 3 variables that significantly predicted treatment success. About half the patients received poor quality care. Strict adherence to standardized DOTS strategy is essential to bring TB under control. The overall quality index devised in this study may be used to assess and improve overall quality of antituberculosis care.


Cellular internalization of cytolethal distending toxin: a new end to a known pathway.
The cytolethal distending toxins (CDTs) are unique in their ability to induce DNA damage, activate checkpoint responses and cause cell cycle arrest or apoptosis in intoxicated cells. However, little is known about their cellular internalization pathway. We demonstrate that binding of the Haemophilus ducreyi CDT (HdCDT) on the plasma membrane of sensitive cells was abolished by cholesterol extraction with methyl-beta-cyclodextrin. The toxin was internalized via the Golgi complex, and retrogradely transported to the endoplasmic reticulum (ER), as assessed by N-linked glycosylation. Further translocation from the ER did not require the ER-associated degradation (ERAD) pathway, and was Derlin-1 independent. The genotoxic activity of HdCDT was dependent on its internalization and its DNase activity, as induction of DNA double-stranded breaks was prevented in Brefeldin A-treated cells and in cells exposed to a catalytically inactive toxin. Our data contribute to a better understanding of the CDT mode of action and highlight two important aspects of the biology of this bacterial toxin family: (i) HdCDT translocation from the ER to the nucleus does not involve the classical pathways followed by other retrogradely transported toxins and (ii) toxin internalization is crucial for execution of its genotoxic activity.


Development of synovial membrane in the temporomandibular joint of the human fetus.
The development of the synovial membrane was analyzed in serial sections of 21 temporomandibular joints of human fetuses at 9 to 13 weeks of gestation. Sections of two fetuses at 12 weeks of development were used to perform immunohistochemical expression of the markers CD68 and Hsp27 on the synovial lining. Macrophage-like type A and fibroblast-like type B cells, which express CD68 and Hsp27, respectively, were observed at the twelfth week of development. Our results suggest that the development of the synovial membrane is related to the vascularization of the joint and the formation of the articular cavities.


Criteria for substituting amalgam with composite resins.
In recent years patients' aesthetic requirements have increased as knowledge of new materials and techniques has spread. Enamel etching and composite filling materials have enabled dentists to meet high functional and aesthetic standards in the placing of anterior and, latterly, posterior restorations. There has been a dramatic growth in the use of posterior composites and the aim of this paper is to provide the practising dentist with guidelines for the use of these materials.


Knowledge-based function optimization using fuzzy cultural algorithms with evolutionary programming.
In this paper, the advantages of a fuzzy representation in problem solving and search is investigated using the framework of Cultural algorithms (CAs). Since all natural languages contain a fuzzy component, the natural question is "Does this fuzzy representation facilitate the problem-solving process, within these systems". In order to investigate this question we use the CA framework of Reynolds (1996), CAs are a computational model of cultural evolution derived from and used to express basic anthropological models of culture and its development. A mathematical model of a full fuzzy CA is developed there. In it, the problem solving knowledge is represented using a fuzzy framework. Several theoretical results concerning its properties are presented. The model is then applied to the solution of a set of 12 difficult, benchmark problems in nonlinear real-valued function optimization. The performance of the full fuzzy model is compared with 8 other fuzzy and crisp architectures. The results suggest that a fuzzy approach can produce a statistically significant improvement in search efficiency over nonfuzzy versions for the entire set of functions, the then investigate the class of performance functions for which the full fuzzy system exhibits the greatest improvements over nonfuzzy systems. In general, these are functions which require some preliminary investigation in order to embark on an effective search.


Sorting of calcium signals at the junctions of endoplasmic reticulum and mitochondria.
Calcium signal transmission between endoplasmic reticulum (ER) and mitochondria is supported by a local [Ca(2+)] control that operates between IP(3)receptor Ca(2+)release channels (IP(3)R) and mitochondrial Ca(2+)uptake sites, and displays functional similarities to synaptic transmission. Activation of IP(3)R by IP(3)is known to evoke quantal Ca(2+)mobilization that is associated with incremental elevations of mitochondrial matrix [Ca(2+)] ([Ca(2+)](m)). Here we report that activation of IP(3)R by adenophostin-A (AP) yields non-quantal Ca(2+)mobilization in mast cells. We also show that the AP-induced continuous Ca(2+)release causes relatively small [Ca(2+)](m)responses, in particular, the sustained phase of Ca(2+)release is not sensed by the mitochondria. Inhibition of ER Ca(2+)pumps by thapsigargin slightly increases IP(3)-induced [Ca(2+)](m)responses, but augments AP-induced [Ca(2+)](m)responses in a large extent. In adherent permeabilized cells exposed to elevated [Ca(2+)], ER Ca(2+)uptake fails to affect global cytosolic [Ca(2+)], but attenuates [Ca(2+)](m)responses. Moreover, almost every mitochondrion exhibits a region very close to ER Ca(2+)pumps visualized by BODIPY-FL-thapsigargin or SERCA antibody. Thus, at the ER-mitochondrial junctions, localized ER Ca(2+)uptake provides a mechanism to attenuate the mitochondrial response during continuous Ca(2+)release through the IP(3)R or during gradual Ca(2+)influx to the junction between ER and mitochondria.


Ovarian Reserve after Chemotherapy in Breast Cancer: A Systematic Review and Meta-Analysis.
Background: Worldwide, breast cancer (BC) is the most common malignancy in the female population. In recent years, its diagnosis in young women has increased, together with a growing desire to become pregnant later in life. Although there is evidence about the detrimental effect of chemotherapy (CT) on the menses cycle, a practical tool to measure ovarian reserve is still missing. Recently, anti-Mullerian hormone (AMH) has been considered a good surrogate for ovarian reserve. The main objective of this paper is to evaluate the effect of CT on AMH value. A systematic review and meta-analysis were conducted on the PubMed and Scopus electronic databases on articles retrieved from inception until February 2021. Trials evaluating ovarian reserves before and after CT in BC were included. We excluded case reports, case-series with fewer than ten patients, reviews (narrative or systematic), communications and perspectives. Studies in languages other than English or with polycystic ovarian syndrome (PCOS) patients were also excluded. AMH reduction was the main endpoint. Egger's and Begg's tests were used to assess the risk of publication bias. Eighteen trials were included from the 833 examined. A statistically significant decline in serum AMH concentration was found after CT, persisting even after years, with an overall reduction of -1.97 (95% CI: -3.12, -0.82). No significant differences in ovarian reserve loss were found in the BRCA1/2 mutation carriers compared to wild-type patients. Although this study has some limitations, including publication bias, failure to stratify the results by some important factors and low to medium quality of the studies included, this metanalysis demonstrates that the level of AMH markedly falls after CT in BC patients, corresponding to a reduction in ovarian reserve. These findings should be routinely discussed during oncofertility counseling and used to guide fertility preservation choices in young women before starting treatment.


Mexican American intergenerational caregiving model.
This study employed grounded theory to formulate a conceptual model of intergenerational caregiving among Mexican American families. The sample consisted of 10 Mexican American caregivers of various generations older than 21 who provided at least one intermittent service (without pay at least once a month) to an elder, related through consanguinal or acquired kinship ties. The inductively generated theory of role acceptance is composed of four phases: (a) introduction--early caregiving experiences, (b) role reconciliation, (c) role imprint, and (d) providing or projecting care. This model can be used to study varied generations of Mexican American caregivers. It also provides a framework for comparison with other groups of caregivers. The results can help in designing nursing interventions to support caregivers based on understanding the issues, to create and design systems that address the varying and ever-changing needs of informal caregivers, and to assist in the formulation of policy that supports Mexican American caregivers.


The Quorum Sensing System of Yersinia enterocolitica 8081 Regulates Swimming Motility, Host Cell Attachment, and Virulence Plasmid Maintenance.
Although Yersinia enterocolitica genomes are highly heterogeneous, they contain a conserved N-acylhomoserine lactone-dependent (AHL) quorum sensing (QS) system consisting of the luxR and luxI orthologs yenR and yenI respectively. Certain hypervirulent strains also contain a putative orphan luxR gene, ycoR, that is not linked to an AHL synthase. To explore the contribution of yenR/yenI/ycoR to QS-dependent phenotypes in Yersinia enterocolitica strain 8081, single and multiple mutants were constructed. AHL profiling identified N-(3-oxohexanoyl) homoserine lactone, N-hexanoylhomoserine lactone, and N-(3-oxoseptanoyl) homoserine lactone as the most abundant. The AHL profiles of the yenR, ycoR and yenR/ycoR mutants were similar to the parent suggesting that the two LuxR homologues do not regulate AHL production while the yenI mutants were AHL-negative. A role for QS in swimming motility and cell attachment was demonstrated. Down-regulation of the virulence plasmid partition gene, spyA, in yenI and yenI/yenR/ycoR mutants is consistent with the greater loss of the Y. enterocolitica pYVe virulence plasmid in the yenI mutant during serial passage at 37 °C but not at 22 °C. A role for QS-regulated spyA in virulence plasmid maintenance is suggested.


Urinary marker of oral pregnenolone administration.
Pregnenolone (PREG) can potentially be abused by athletes to maintain an equilibration of the steroidal environment after sex steroids administrations. Five men volunteers orally ingested 50 mg PREG to determine optimal urinary markers for detection of this steroid. Our findings show that ingestion of PREG has no significant effects on the testosterone/epitestosterone (T/E) and testosterone/luteinizing hormone (T/LH) ratios, whereas variable changes on the carbon isotopic values of three T metabolites: androsterone, etiocholanolone, 5beta-androstane-3alpha,17beta-diol (5beta-androstanediol) together with 16(5alpha)-androsten-3alpha-ol (androstenol) and 5beta-pregnane-3alpha,20alpha-diol (pregnanediol) have been observed. The difference between the carbon isotopic values (delta13C-values) of androstenol and pregnanediol is potentially the most reliable marker of exogenous PREG administration in males. For all subjects, the differences differ by 3.0 per thousand or more over a period of about 10 h and for both of them the detection window for positivity is extended over 40 h.


Toxicity of tigecycline on the freshwater microalga Scenedesmus obliquus: Photosynthetic and transcriptional responses.
Tigecycline (TGC) is a new tetracycline antibiotic medication against multidrug-resistant bacteria. However, the toxicity of TGC to microalgae remains largely unknown. In this study, the toxicity of TGC on Scenedesmus obliquus was examined, focusing on changes in algal growth, photosynthetic activity, and transcriptome. According to an acute toxicity test, the IC10 and IC50 values were 0.72 mg/L and 4.15 mg/L, respectively. Analyses of photosynthetic efficiency and related parameters, such as light absorption, energy capture, and electron transport, identified a 35% perturbation in the IC50 group, while the IC10 group remained largely unaffected. Transcriptomic analysis showed that in the IC10 and IC50 treatment groups, there were 874 differentially expressed genes (DEGs) (220 upregulated and 654 downregulated) and 4289 DEGs (2660 upregulated and 1629 downregulated), respectively. Gene Ontology enrichment analysis showed that TGC treatment markedly affected photosynthesis, electron transport, and chloroplast functions. In the IC50 group, a clear upregulation of genes related to photosynthesis and chloroplast functions was observed, which could be an adaptive stress response. In the IC10 group, significant downregulation of DEGs involved in ribosomal pathways and peptide biosynthesis processes was observed. Kyoto Encyclopedia of Gene and Genomes enrichment analysis showed that treatment with TGC also disrupted energy production, protein synthesis, and metabolic processes in S. obliquus. Significant downregulation of key proteins related to Photosystem II was observed under the IC10 TGC treatment. Conversely, IC50 TGC treatment resulted in substantial upregulation across a broad array of photosystem-related proteins from both Photosystems II and I. IC10 and IC50 TGC treatments differentially influenced proteins involved in the photosynthetic electron transport process. This study emphasizes the potential risks of TGC pollution to microalgae, which contributes to a better understanding of the effects of antibiotic contamination in aquatic ecosystems.


Short-chain fatty acid-supplemented total parenteral nutrition enhances functional adaptation to intestinal resection in rats.
Intestinal adaptation is a complex physiological process that is not completely understood. Total parenteral nutrition (TPN) induces intestinal atrophy that is prevented by the systemic administration of short-chain fatty acids (SCFAs) as measured by morphological indices (i.e., mucosal weight and mucosal DNA, RNA, and protein concentration). The aim of this study was to examine the effect of SCFA-supplemented TPN on functional markers of intestinal adaptation. Forty-eight male Sprague-Dawley rats underwent an 80% jejunoileal resection and jugular catheterization. Rats received standard TPN or an isoenergetic, isonitrogenous TPN supplemented with SCFA (TPN + SCFA). Animals were further randomized to receive nutrient solutions for 3 or 7 days. Ileal uptakes of D-glucose were higher (P < 0.05) in both TPN + SCFA groups. Expression of glucose transporter (GLUT)2 messenger RNA (mRNA) was higher (P < 0.007) in the TPN + SCFA group at day 3. Expression of sodium-dependent glucose transporter 1 tended to be higher in both TPN + SCFA groups (P = 0.1). Na+,K+-adenosine triphosphatase mRNA was significantly more abundant in the TPN groups. GLUT5 and sucrase-isomaltase mRNA abundance did not differ between groups. Intravenous SCFAs facilitate intestinal adaptation after resection by increasing basolateral intestinal nutrient transport. The addition of SCFAs to current TPN formulations may be warranted to improve functional characteristics of the gastrointestinal tract.


PET-CT image registration in the chest using free-form deformations.
We have implemented and validated an algorithm for three-dimensional positron emission tomography transmission-to-computed tomography registration in the chest, using mutual information as a similarity criterion. Inherent differences in the two imaging protocols produce significant nonrigid motion between the two acquisitions. A rigid body deformation combined with localized cubic B-splines is used to capture this motion. The deformation is defined on a regular grid and is parameterized by potentially several thousand coefficients. Together with a spline-based continuous representation of images and Parzen histogram estimates, our deformation model allows closed-form expressions for the criterion and its gradient. A limited-memory quasi-Newton optimization algorithm is used in a hierarchical multiresolution framework to automatically align the images. To characterize the performance of the method, 27 scans from patients involved in routine lung cancer staging were used in a validation study. The registrations were assessed visually by two expert observers in specific anatomic locations using a split window validation technique. The visually reported errors are in the 0- to 6-mm range and the average computation time is 100 min on a moderate-performance workstation.


Complication avoidance and management in ambulatory spine surgery.
The positive safety profile and potential cost savings associated with ambulatory spine surgery have resulted in an increasing number of spine procedures being performed on an outpatient basis. As indications become more inclusive and the variety and volume of ambulatory procedures grow, the incidence of complications may rise. Limiting adverse events in the outpatient setting starts with patient selection. Surgeons should be aware of the potential complications and associated risk factors for common ambulatory spine procedures and employ strategies to limit and appropriately manage them. Protocols which include patient education, multimodal anesthesia and analgesia, standardized post-operative monitoring, and safe discharge planning are also essential for maximizing safety in the ambulatory setting.


Interrogating Host Antiviral Environments Driven by Nuclear DNA Sensing: A Multiomic Perspective.
Nuclear DNA sensors are critical components of the mammalian innate immune system, recognizing the presence of pathogens and initiating immune signaling. These proteins act in the nuclei of infected cells by binding to foreign DNA, such as the viral genomes of nuclear-replicating DNA viruses herpes simplex virus type 1 (HSV-1) and human cytomegalovirus (HCMV). Upon binding to pathogenic DNA, the nuclear DNA sensors were shown to initiate antiviral cytokines, as well as to suppress viral gene expression. These host defense responses involve complex signaling processes that, through protein-protein interactions (PPIs) and post-translational modifications (PTMs), drive extensive remodeling of the cellular transcriptome, proteome, and secretome to generate an antiviral environment. As such, a holistic understanding of these changes is required to understand the mechanisms through which nuclear DNA sensors act. The advent of omics techniques has revolutionized the speed and scale at which biological research is conducted and has been used to make great strides in uncovering the molecular underpinnings of DNA sensing. Here, we review the contribution of proteomics approaches to characterizing nuclear DNA sensors via the discovery of functional PPIs and PTMs, as well as proteome and secretome changes that define a host antiviral environment. We also highlight the value of and future need for integrative multiomic efforts to gain a systems-level understanding of DNA sensors and their influence on epigenetic and transcriptomic alterations during infection.


Ageing of skeletal muscle extracellular matrix and mitochondria: finding a potential link.
Aim: To discuss the progress of extracellular matrix (ECM) characteristics, mitochondrial homeostasis, and their potential crosstalk in the pathogenesis of sarcopenia, a geriatric syndrome characterized by a generalized and progressive reduction in muscle mass, strength, and physical performance.Methods: This review focuses on the anatomy and physiology of skeletal muscle, alterations of ECM and mitochondria during ageing, and the role of the interplay between ECM and mitochondria in the pathogenesis of sarcopenia.Results: Emerging evidence points to a clear interplay between mitochondria and ECM in various tissues and organs. Under the ageing process, the ECM undergoes changes in composition and physical properties that may mediate mitochondrial changes via the systematic metabolism, ROS, SPARC pathway, and AMPK/PGC-1α signalling, which in turn exacerbate muscle degeneration. However, the precise effects of such crosstalk on the pathobiology of ageing, particularly in skeletal muscle, have not yet been fully understood.Conclusion: The changes in skeletal muscle ECM and mitochondria are partially responsible for the worsened muscle function during the ageing process. A deeper understanding of their alterations and interactions in sarcopenic patients can help prevent sarcopenia and improve its prognoses.


Rates and predictors of developing a manic or hypomanic episode 1 to 2 years following a first hospitalization for major depression with psychotic features.
Although the presence of psychosis during major depression has been identified as a predictor of later developing mania or hypomania, to our knowledge there have been no studies examining rates and predictors of developing a manic or hypomanic episode in patients who were admitted for their first psychiatric hospitalization for major depressive disorder with psychosis (MDDP). Patients admitted for their first psychiatric hospitalization, with a Diagnostic and Statistical Manual of Mental Disorders (fourth edition) diagnosis of MDDP, were recruited from three sites (N = 157) and evaluated prospectively for up to 2 years to identify new symptoms of mania or hypomania. Family history was assessed using the Family History-Research Diagnostic Criteria Interview. Clinical and demographic factors associated with developing a manic or hypomanic episode were identified using stepwise logistic regression. Thirteen percent (n = 21) of patients with MDDP developed mania or hypomania within the follow-up period. Family history of affective disorders and age at onset of MDDP were not predictive of switch. MDDP patients who were treated with antidepressants were four times less likely to develop mania or hypomania than those who were not treated with antidepressants, after controlling for site differences. Our findings suggest that within the first 1 to 2 years following first hospitalization for MDDP, a subset of patients will develop mania or hypomania. Additionally, our data suggest that antidepressant exposure does not increase the risk of, and may be protective against, developing a manic or hypomanic episode in patients hospitalized for MDDP.


Enhanced excitability of cortical neurons in low-divalent solutions is primarily mediated by altered voltage-dependence of voltage-gated sodium channels.
Increasing extracellular [Ca2+] ([Ca2+]o) strongly decreases intrinsic excitability in neurons but the mechanism is unclear. By one hypothesis, [Ca2+]o screens surface charge, reducing voltage-gated sodium channel (VGSC) activation and by another [Ca2+]o activates Calcium-sensing receptor (CaSR) closing the sodium-leak channel (NALCN). Here we report that neocortical neurons from CaSR-deficient (Casr-/-) mice had more negative resting potentials and did not fire spontaneously in reduced divalent-containing solution (T0.2) in contrast with wild-type (WT). However, after setting membrane potential to -70 mV, T0.2 application similarly depolarized and increased action potential firing in Casr-/- and WT neurons. Enhanced activation of VGSCs was the dominant contributor to the depolarization and increase in excitability by T0.2 and occurred due to hyperpolarizing shifts in VGSC window currents. CaSR deletion depolarized VGSC window currents but did not affect NALCN activation. Regulation of VGSC gating by external divalents is the key mechanism mediating divalent-dependent changes in neocortical neuron excitability.


Identifying 'at risk' women and the impact of maternal obesity on National Health Service maternity services.
Obesity is a public health concern worldwide, arising from multifaceted and complex causes that relate to individual choice and lifestyle, and the influences of wider society. In addition to a long-standing focus on both childhood and adult obesity, there has been more recent concern relating to maternal obesity. This review explores the published evidence relating to maternal obesity incidence and associated inequalities, the impact of obesity on maternity services, and associated guidelines. Epidemiological data comprising three national maternal obesity datasets within the UK have identified a significant increase in maternal obesity in recent years, and reflect broad socio-demographic inequalities particularly deprivation, ethnicity and unemployment. Obese pregnancies present increased risk of complications that require more resource intensive antenatal and perinatal care, such as caesarean deliveries, gestational diabetes, haemorrhage, infections and congenital anomalies. Healthcare professionals also face difficulties when managing the care of women in pregnancy as obesity is an emotive and stigmatising topic. There is a lack of good-quality evidence for effective interventions to tackle maternal obesity. Recently published national guidelines for the clinical management and weight management of maternal obesity offer advice for professionals, but acknowledge the limitations of the evidence base. The consequence of these difficulties is an absence of support services available for women. Further evaluative research is thus required to assess the effectiveness of interventions with women before, during and after pregnancy. Qualitative work with women will also be needed to help inform the development of more sensitive risk communication and women-centred services.


Menstrual abnormalities and polycystic ovary syndrome in women taking valproate for bipolar mood disorder.
Valproate treatment has been associated with high rates of menstrual abnormalities, hyperandrogenism, and polycystic ovaries in women with epilepsy. This pilot study investigated whether valproate treatment had the same associations in women with bipolar disorder. One hundred forty outpatient women with a DSM-IV diagnosis of bipolar disorder (aged 15-45 years) were surveyed on their medical, psychiatric, and reproductive health history. Thirty-two women met entry criteria for the study and were divided into 2 groups: (1) those currently receiving valproate (valproate, N = 17) and (2) those who were not currently taking valproate (nonvalproate, N = 15). These 2 groups were compared with a normal (never diagnosed with a psychiatric disorder) control group of 22 women. Women in the valproate group with current menstrual problems (N = 7) underwent further assessment for the presence of polycystic ovaries and hyperandrogenism. The age at onset of menses, mean length of menstrual cycle, and mean length of menses were not significantly different between the groups. Significantly more women reported menstrual abnormalities in the valproate group (47%) than women not receiving valproate (13%) and controls (0%). Forty-one percent of women with bipolar disorder taking valproate had polycystic ovary syndrome. These results suggest high rates of menstrual disturbances and polycystic ovary syndrome in women with bipolar disorder currently receiving valproate.


Blood partitioning and whole-blood-based maternal transfer assessment of chlorinated paraffins in mother-infant pairs from South China.
As a new group of persistent organic pollutants of concern, chlorinated paraffins (CPs) have been widely detected in the environment and biota, but their occurrence, partitioning, and transfer in humans have been not well documented. In this study, 32 pairs of maternal blood, cord blood, and placenta samples were collected from pregnant women in South China, and the blood was further separated into plasma and red blood cells (RBCs) for blood partitioning study. Short- and medium-chain CPs (SCCPs and MCCPs, respectively) were detected in all the five human biological matrices, suggesting prevalent exposure and maternal transfer of CPs in the pregnant women. Discrepant congener group profiles of CPs were observed in different human biological matrices. Significant differences in the plasma-RBC partitioning of CPs in the maternal and cord bloods were identified (p < 0.001). CP partitioning to plasma was stronger than that to RBCs in maternal blood, but the converse was true for cord blood. Mass fractions in plasma (Fp) for SCCPs (mean, 0.78) and MCCPs (0.74) in maternal blood were significantly higher than the values in cord blood. Transplacental transfer efficiencies (TTEs) were evaluated based on the whole blood concentrations of CPs in the maternal and cord bloods, and the TTEs ranged from 0.50 to 0.69 (first to third quartiles) for SCCPs and MCCPs, indicating that the placenta can partially restrict maternal transfer. The extent of CP retention in the placenta was assessed by the concentration ratio (RPM) of matched placenta and maternal blood, and interestingly, a U-shaped trend for placental retention (RPM) with increasing chain length was observed for individual congener groups. Significant relationships of the CP concentrations among the maternal blood, cord blood, and placenta were observed (p < 0.001). To our knowledge, this is the first study to report the plasma-RBC partitioning of CPs in human maternal and cord bloods, as well as the first study to evaluate TTEs based on whole blood concentrations. Our study confirmed that whole blood is the preferred matrix for accurately assessing human internal exposure and transplacental transfer of CPs.


Corrosion of iron by iodide-oxidizing bacteria isolated from brine in an iodine production facility.
Elemental iodine is produced in Japan from underground brine (fossil salt water). Carbon steel pipes in an iodine production facility at Chiba, Japan, for brine conveyance were found to corrode more rapidly than those in other facilities. The corroding activity of iodide-containing brine from the facility was examined by immersing carbon steel coupons in "native" and "filter-sterilized" brine samples. The dissolution of iron from the coupons immersed in native brine was threefold to fourfold higher than that in the filter-sterilized brine. Denaturing gradient gel electrophoresis analyses revealed that iodide-oxidizing bacteria (IOBs) were predominant in the coupon-containing native brine samples. IOBs were also detected in a corrosion deposit on the inner surface of a corroded pipe. These results strongly suggested the involvement of IOBs in the corrosion of the carbon steel pipes. Of the six bacterial strains isolated from a brine sample, four were capable of oxidizing iodide ion (I(-)) into molecular iodine (I(2)), and these strains were further phylogenetically classified into two groups. The iron-corroding activity of each of the isolates from the two groups was examined. Both strains corroded iron in the presence of potassium iodide in a concentration-dependent manner. This is the first report providing direct evidence that IOBs are involved in iron corrosion. Further, possible mechanisms by which IOBs corrode iron are discussed.