Persistent, tolerant or subacute infection in Borna disease virus-infected rats.
The rabbit-adapted Borna disease (BD) virus strain V was passaged by intracerebral infection of 1-day-old Wistar rats. Infectivity titres reached 10(8) infectious units per gram of brain 4 weeks after infection. No clinical signs were evident. The persistent infection could be induced with adapted or field strains of BD virus. Strains were identified by neutralization tests. The virulence of the rabbit-adapted BD virus for the rat increased with rat passages. The 5th passage induced clinical symptoms in animals infected at 1 week of age or older. Between 20% and 50% of diseased rats died. Virus-specific antigen was detectable immunohistologically in neurons of rats infected at all ages. Animals inoculated at 1 or 2 months of age, but not the neonatal rats, showed signs of inflammation in the brain. Infected rats produced specific antibodies. In the older groups (infected at ages of 1 or 2 months), and especially in surviving animals, occasionally, neutralizing antibodies with high titres were found. Transfer of primed spleen cells resulted in subacute disease. These findings demonstrate that neonatal rats can acquire a persistent, tolerant infection and that expression of disease is mediated by immunological factors.


Plastic Surgery-Related Hashtag Utilization on Instagram: Implications for Education and Marketing.
Recent data suggest patients are seeking aesthetic surgery to improve their appearance on Instagram and other social media. Despite the rising influence of Instagram in plastic surgery, few academic publications address Instagram, let alone evaluate its utilization in plastic surgery. We set out to answer the following three questions: 1) what plastic surgery-related content is being posted to Instagram; 2) who is posting this content; and 3) what specific hashtags are they using? Our study queried 21 Instagram plastic surgery-related hashtags. Content analysis was used to qualitatively evaluate each of the nine "top" posts associated with each hashtag (189 posts). Duplicate posts and those not relevant to plastic surgery were excluded. A total of 1,789,270 posts utilized the 21 hashtags sampled in this study. Of the top 189 posts for these 21 queried hashtags, 163 posts met inclusion criteria. Plastic surgeons eligible for membership in American Society for Aesthetic Plastic Surgery (ASAPS) accounted for only 17.8% of top posts, whereas noneligible physicians accounted for 26.4%. All nonplastic surgery trained physicians marketed themselves as "cosmetic surgeons." Nine top posts (5.5%) were by nonphysicians, including dentists, spas with no associated physician, and a hair salon. The majority of these posts were self-promotional (67.1%) as opposed to educational (32.9%). Board-certified plastic surgeons were significantly more likely to post educational content to Instagram as compared to nonplastic surgeons (62.1% vs 38.1%, P = 0.02). ASAPS eligible board-certified plastic surgeons are underrepresented amongst physicians posting top plastic surgery-related content to Instagram.


Physician organizing: a convergence of interests.
Economic forces and professional ideals are colliding to create further unrest in the health care industry in the form of organizing physicians into unions. Whereas self-employed or independent contractor physicians are barred from joining together to bargain collectively with third-party payers and HMOs, employed physicians may be able to avoid antitrust problems because they are eligible for protection under the National Labor Relations Act. Consequently, as the number of employed physicians has grown and the frustrations they encounter increase, unions (generally suffering a decrease in membership and political influence) are finding a receptive audience for their message of solidarity. However, will organizing into unions solve or aggravate the physicians' problems?


Ultrasonographic evaluation of renal autografts in normal cats.
The purpose of this study was to determine changes in resistive index (RI) and renal size that occur in normal feline kidney autografts in the immediate post-transplant period. Qualitative changes in renal parenchymal echogenicity and pelvic dilation were also noted, although this was not a major focus of the study. Fourteen domestic short-haired cats underwent bilateral nephrectomies followed by an autograft of the right kidney to either the aorta or external iliac artery. Due to post-operative complications, only nine of these cats completed the study. Ultrasonographic determination of the RI and renal size was made before transplantation and on days 1, 4, 7, 10, and 13 following transplantation. No significant changes in renal RI were identified during the study. Renal size increased significantly, peaking at 63% above baseline on day 7, and stayed elevated at 50% above baseline on day 13. There was no evidence of rejection or other abnormalities found on histologic evaluation of the transplanted kidneys. It was concluded that the RI of normal feline renal autografts does not significantly change in the immediate post-operative period. However, significant renal enlargement, likely due to a combination of post-operative edema and hypertrophy, does occur. This study provides baseline information for comparison with feline allografts in the immediate post-transplant period.


Sequence analysis and transformation by the catabolic 3-dehydroquinase (QUTE) gene from Aspergillus nidulans.
The induction of catabolic 3-dehydroquinase by quinic acid in Aspergillus nidulans has been shown to involve transcriptional control and yields a single major 0.8 kb mRNA. The nucleotide sequence of the catabolic 3-dehydroquinase QUTE gene has been determined and contains a single uninterrupted open reading frame of 462 bases encoding a 16,505 Da protein of 153 residues. Comparison with the corresponding QA2 gene of Neurospora crassa reveals the absence of 75 nucleotides encoding 25 amino acids from the centre of the QUTE gene of A. nidulans and the presence of 21 additional nucleotides at its 3' end. There is no nucleotide or amino acid homology between these two elements. A 16 bp inverted repeat (5' GGCAGAGCGTTCTGCC) shows similarity to such repeats found in other fungal promoters. The functional integrity of the QUTE gene was demonstrated by the transformation of a qutE mutant strain which regains growth on quinic acid as sole carbon source. Four of the twelve transformed strains examined contained vector sequences integrated at the qutE locus, and these strains all exhibited normal regulation of 3-dehydroquinase even when 16 copies of the QUTE gene were present.


Sliding of water droplets on smooth hydrophobic silane coatings with regular triangle hydrophilic regions.
The effect of the triangular pinning region on the sliding of water droplets on the smooth hydrophobic surface was investigated. Smooth hydrophobic silane coatings with various regular triangle hydrophilic regions were prepared using photolithography and octadecyltrimethoxysilane (ODS). The hydrophilic area in the surfaces was aligned hexagonally with a constant area fraction. Thereby water contact angles of the coatings were almost equivalent. The water droplet sliding velocity increased continuously with increasing pattern size. Anisotropic sliding velocity was observed on the surface, suggesting different pinning effects. The sliding motion of water droplets on the gradient surface with changing hydrophilic region size deflects against the downward direction. The deflection length depends on the direction of triangle hydrophilic regions and the initial sliding position. These results demonstrate that control of the sliding velocity while sustaining the static contact angle is feasible by designing the shape and alignment of chemical heterogeneity.


Hormone pulsatility discrimination via coarse and short time sampling.
Pulsatile hormonal secretion is a ubiquitous finding in endocrinology. However, typical protocols employed to generate data sets suitable for "pulsatility analysis" have required 60-300 samples, rendering such studies largely research methodologies, due primarily to considerable assay expense. One successful mathematical strategy in calibrating changes in pulsatility modalities is approximate entropy (ApEn), a quantification of sequential irregularity. Given the degree of differences between ApEn values in pathophysiological subjects vs. healthy controls reported in several recent studies, we queried to what extent coarser (less frequent) and shorter duration time sampling would still retain significant ApEn differences between clinically distinct cohorts. Accordingly, we reanalyzed data from two studies of 24-h profiles of healthy vs. tumoral hormone secretion: 1) growth hormone comparisons of normal subjects vs. acromegalics, originally sampled every 5 min; and 2) ACTH and cortisol comparisons of normal subjects vs. Cushing's disease patients, originally sampled every 10 min. By multiple statistical analyses, we consistently and highly significantly (P < 0.0001) established that serum concentration patterns in tumor patients are more irregular than those of controls, with high sensitivity and specificity, even at very coarse (e.g., 60 min) sampling regimens and over relatively short (2-4 h) time intervals. The consistency of these findings suggests a broadly based utility of such shorter and/or coarser sampling methodologies. Substantial reduction in sampling requirements holds the potential to move analysis of pulsatile hormone release from a primarily research tool to a clinically applicable protocol, in appropriate diagnostic and therapeutic contexts.


Association Between the Prevalence of Frailty and Doubly Labeled Water-Calibrated Energy Intake Among Community-Dwelling Older Adults.
Appropriate energy intake (EI) is essential to prevent frailty. Because self-reported EI is inaccurate and has systematic errors, adequate biomarker calibration is required. This study examined the association between doubly labeled water (DLW)-calibrated EI and the prevalence of frailty among community-dwelling older adults. A cross-sectional study was performed using baseline data of 7,022 older adults aged ≥65 years in the Kyoto-Kameoka Study. EI was evaluated using a validated food frequency questionnaire (FFQ), and calibrated EI was obtained from a previously established equation using the DLW method. Physical and comprehensive frailty were defined by the Fried phenotype (FP) model and the Kihon Checklist (KCL), respectively. We used multivariable-adjusted restricted cubic spline logistic regression analysis. The prevalence of physical frailty was 14.8% and 13.6% in women and men, respectively. The spline models showed significant reverse J-shaped or U-shaped relationships between the prevalence of physical or comprehensive frailty against the DLW-calibrated EI, respectively. The lowest prevalence of both types of frailty was found at 1,900-2,000 kcal/d in women and 2,400-2,500 kcal/d in men, which corresponded to approximately 40 kcal/d/kg IBW (ideal body weight = 22 × height2) with DLW-calibrated EI. Uncalibrated EI underestimated approximately 20% compared with calibrated EI; underestimated EI were attenuated by calibration approach. This study suggests that low EI has a greater detrimental effect compared with excessive EI, particularly on physical frailty. Using biomarkers to calibrate EI holds promise for providing accurate energy requirements to establish guidelines used in public health and clinical nutrition.


A paradigm for the control of upright standing in paraplegic patients.
The objective of this paper is to present a new paradigm in control strategy for unsupported paraplegic standing, based on closed-loop control of paraplegics' lower extremities. The main advantage of our approach is taking into account voluntary motions of the upper-part of the body by controlling Center of Mass (CoM) position. The validity of our approach is tested, in computer simulations, using human CoM trajectories estimated from experimental data and by applying perturbations in simulation during quiet standing in order to simulate voluntary upper body movements. From the results presented in this study it can be seen that controller is able to track desired CoM position with sufficient precision and to maintain stability even in the presence of simulated movements of the upper body.


Prevailing familial, social and cultural obstacles in keeping tobacco-free homes in urban areas of Bangladesh: A mixed-method study.
Millions of children and others across the world are being dangerously exposed to tobacco smoke and toxins in their own homes. Whilst there is limited interest in laws and interventions controlling tobacco use in public places in Bangladesh, no attention has been given to preventing tobacco-use inside homes. This study explores the familial and socio-cultural factors that provide obstacles for ensuring tobacco-free homes in Bangladesh. A mixed-method design was adopted and from among the 1,436 tobacco users identified in a population of 11,853, 400 (tobacco users) were selected for cross-sectional survey. This survey involved a probability proportional sampling procedure, and 24 In-Depth Interviews. Multivariate logistic regression was performed to explore the association of familial and socio-cultural factors with tobacco-use at home adjusted by other demographic characteristics. Thematic content analysis was done on the qualitative data, and then inferences were drawn out collectively. This study revealed that the prevalence of tobacco-use in the home was 25.7% in urban residential areas in Bangladesh. Multivariate logistic regression analysis identified that familial and socio-cultural factors were significantly associated with tobacco-use at home: marital status (OR 3.23, 95% CI: 1.37-6.61), education (OR 2.14, 95% CI: 1.15-3.99), smoking habits of older family members (OR 1.81 95% CI: 0.91-2.89), tobacco being offered as hospitality and for entertainment (OR 1.85, 95% CI: .94-2.95) and lack of religiosity practice (OR 2.39, 95% CI: 1.27-4.54). Qualitative findings indicated that social customs, lack of religious practice, tobacco-use of older family members, and lack of family guidance were key obstacles for enabling tobacco-free homes in urban areas. Use of tobacco at home is continuing as part of established familial and socio-cultural traditions. If tobacco-use at home is not addressed seriously by the authorities then the emerging threat of second-hand smoke exposure and harmful consequences of tobacco- use will be exacerbated.


Involvement of cathepsins in the invasion, metastasis and proliferation of cancer cells.
Tumor cell invasion and metastasis are associated with the proteolytic activity of various types of proteinases. Among them, cathepsins, which are lysosomal proteinases, have received more attention recently. Since elevated expressions of cathepsins and diminished levels of their inhibitors have been observed in several human cancers, including breast, gastric and prostate cancer, especially in aggressive cancer cells, cathepsins have been suggested to be biological markers of malignant tumors and have proved useful for prognosis of the disease. Furthermore, cathepsins have various roles in cancer progression. Cathepsin D has a mitogenic activity independent of its proteolytic activity and it attenuates the anti-tumor immune response of decaying chemokines to inhibit the function of dendritic cells. Cathepsins B and L have been shown to play an important role in matrix degradation and cell invasion. The administration of their inhibitors prevents the invasion and metastasis of cancer cells. These results indicate that cancer cells orchestrate various cathepsins to progress malignant diseases. Cathepsins may be a potential target for cancer therapy.


Translation of an integral membrane protein in distal dendrites of hippocampal neurons.
Maintenance of synaptic plasticity requires protein translation. Because changes in synaptic strength are regulated at the level of individual synapses, a mechanism is required for newly translated proteins to specifically and persistently modify only a subset of synapses. Evidence suggests this may be accomplished through local translation of proteins at or near synapses in response to plasticity-inducing patterns of activity. A number of proteins important for synaptic function are integral membrane proteins, which require a specialized group of organelles, proteins and enzymatic activities for proper synthesis. Dendrites appear to contain machinery necessary for the proper production of these proteins, and mRNAs for integral membrane proteins have been found localized to dendrites. Experiments are described that investigate the local translation of membrane proteins in the dendrites of cultured rat hippocampal neurons, using fluorescence recovery after photobleaching. Neurons were transfected with cDNAs encoding a fluorescently labeled transmembrane protein, TGN-38. Under conditions where the transport of this reporter construct was inhibited, the appearance of newly synthesized protein was observed via fluorescent microscopy. The dendritic translation of this protein required activation of glutamate receptors. The results demonstrate a functional capacity for activity-dependent synthesis of integral membrane proteins for distal dendrites in hippocampal neurons.


Vaccines based on structure-based design provide protection against infectious diseases.
Vaccines elicit immune responses, provide protection against microorganisms and are considered as one of the most successful medical interventions against infectious diseases. Vaccines can be produced using attenuated virus or bacteria, recombinant proteins, bacterial polysaccharides, carbohydrates or plasmid DNA. Conventional vaccines rely on the induction of immune responses against antigenic proteins to be effective. The genetic diversity of microorganisms, coupled with the high degree of sequence variability in antigenic proteins, presents a challenge to developing broadly effective conventional vaccines. The observation that whole protein antigens are not necessarily essential for inducing immunity has led to the emergence of a new branch of vaccine design termed 'structural vaccinology'. Structure-based vaccines are designed on the rationale that protective epitopes should be sufficient to induce immune responses and provide protection against pathogens. Recent studies demonstrated that designing structure-based vaccine candidates with multiple epitopes induce a higher immune response. As yet there are no commercial vaccines available based on structure-based design and most of the structure-based vaccine candidates are in the preclinical stages of development. This review focuses on recent advances in structure-based vaccine candidates and their application in providing protection against infectious diseases.


Real-space visualization of remnant Mott gap and magnon excitations.
We demonstrate the ability to visualize real-space dynamics of charge gap and magnon excitations in the Mott phase of the single-band Hubbard model and the remnants of these excitations with hole or electron doping. At short times, the character of magnetic and charge excitations is maintained even for large doping away from the Mott and antiferromagnetic phases. Doping influences both the real-space patterns and long timescales of these excitations with a clear carrier asymmetry attributable to particle-hole symmetry breaking in the underlying model. Further, a rapidly oscillating charge-density-wave-like pattern weakens, but persists as a visible demonstration of a subleading instability at half-filling which remains upon doping. The results offer an approach to analyzing the behavior of systems where momentum space is either inaccessible or poorly defined.


Long-term cognitive trajectories and heterogeneity in patients with schizophrenia and their unaffected siblings.
This study aimed to assess the heterogeneity and stability of cognition in patients with a non-affective psychotic disorder and their unaffected siblings. In addition, we aimed to predict the cognitive subtypes of siblings by their probands. Assessments were conducted at baseline, 3 and 6 years in 1119 patients, 1059 siblings and 586 controls from the Genetic Risk and Outcome of Psychosis (GROUP) study. Group-based trajectory modeling was applied to identify trajectories and clustered multinomial logistic regression analysis was used for prediction modeling. A composite score of eight neurocognitive tests was used to measure cognitive performance. Five stable cognitive trajectories ranging from severely altered to high cognitive performance were identified in patients. Likewise, four stable trajectories ranging from moderately altered to high performance were found in siblings. Siblings had a higher risk of cognitive alteration when patients' alteration was mild (OR = 2.21), moderate (OR = 5.70), and severe (OR = 10.07) compared with patients with intact cognitive function. The familial correlation coefficient between pairs of index patients and their siblings was 0.27 (P = 0.003). The cognitive profiles identified in the current study might be suitable as endophenotypes and could be used in future genetic studies and predicting functional and clinical outcomes.


Effect of whitening toothpastes and activated charcoal powder on enamel wear and surface roughness.
This study aimed to evaluate surface roughness (Sa), roughness profile (Rv), and enamel wear after brushing with different whitening toothpastes and charcoal powders. Sixty (n = 10) bovine enamel blocks (6 × 6 × 3 mm) were randomly distributed into six groups according to toothpaste type: regular toothpaste (CONT), toothpaste containing 2% hydrogen peroxide (HP), toothpaste containing titanium dioxide (TiO2), toothpaste containing charcoal (COAL), toothpaste containing charcoal and TiO2 (COAL+TiO2), and activated charcoal powder (COAL_PWD). Each block was subjected to 30,000 reciprocal cycles at a 1:3 proportion slurry. After brushing, the blocks were analyzed using an optical profilometer to determine Sa, Rv, and enamel wear. In addition, representative 3D images of each group and wear profiles were obtained. Sa was analyzed using generalized linear models followed by Bonferroni correction, whereas Rv was analyzed using one-way analysis of variance. After brushing, COAL and COAL+TiO2 showed higher Sa values than COAL_PWD. However, no significant difference was observed in Sa between whitening toothpaste and COAL_PWD, and CONT (p > 0.05). In addition, no differences were observed among the groups in Rv (p > 0.05). Conversely, enamel wear was higher for TiO2, COAL, COAL+TiO2, and COAL_PWD than for CONT. CONT showed the least enamel wear, whereas HP showed intermediate values. Representative 3D images and line profiles showed lower step-height and lower mean surface losses for the CONT and HP groups than for the other groups. Whitening toothpastes and COAL_PWD did not increase Sa or Rv compared with CONT, while CONT demonstrated lower enamel wear.


Injury and Illness Rates During Ultratrail Running.
This study aimed to describe injury/illness rates in ultratrail runners competing in a 65-km race to build a foundation for injury prevention and help race organizers to plan medical provision for these events. Prospectively transcribed medical records were analysed for 77 athletes at the end of the race. Number of injuries/illnesses per 1 000 runners and per 1 000-h run, overall injury/illness rate and 90% confidence intervals and rates for major and minor illnesses, musculoskeletal injuries, and skin disorders were analysed. A total of 132 injuries/illnesses were encountered during the race. The overall injuries/illnesses were 1.9 per runner and 13.1 per 1 000-h run. Medical illnesses were the most prominent medical diagnoses encountered (50.3%), followed by musculoskeletal injuries (32.8%), and skin-related disorders (16.9%). Despite the ultra-long nature of the race, the majority of injuries/illnesses were minor in nature. Medical staff and runners should prepare to treat all types of injuries and illnesses, especially the fatigue arising throughout the course of an ultratrail run and injuries to the lower limbs. Future studies should attempt to systematically identify injury locations and mechanisms in order to better direct injury prevention strategies and plan more accurate medical care.


Comparison of electron paramagnetic resonance and atomic absorption serum copper measurements in human normal control and cancer patients.
Serum copper levels of 132 controls and 122 cancer patients (including Hodgkin's disease, lung cancer, breast cancer, leukemia, untreated patients, and patients in progression) were measured using both atomic absorption (AA) and electron paramagnetic resonance (EPR) techniques. The data pairs were compared using linear regression analysis, EPR versus AA, and all the data (controls and cancers) fit a single regression line with a squared correlation coefficient (r2) of 0.80. Comparison of the subpopulations revealed possible small differences, but none great enough to be of diagnostic value for individual patients. Thus, in a number of cases of practical interest, EPR-determined serum copper levels were essentially redundant with respect to AA measurements. Previous reports recommending the use and possible superiority of EPR for serum copper determinations appear not to have compared the EPR and AA techniques adequately or correctly. EPR serum copper measurements may yet provide unique data in these diseases, but a more detailed analysis of the spectral parameters will be required. EPR-determined serum transferrin levels are also reported.


Common epithelial tumors of borderline malignancy (carcinomas of low malignant potential).
The creation of the category of ovarian borderline tumors has been a step forward in classification because it has segregated from the general group of common epithelial cancers a subgroup with an unusually good prognosis. Of all borderline tumors, the serous variety is the least difficult for the pathologist to diagnose. The mucinous borderline tumor is not as easy to recognize when an absence of invasion is used as the sole diagnostic criterion, but evaluation of other architectural as well as cytological features is helpful in making the diagnosis. Although the treatment of the majority of serous and mucinous borderline tumors is well standardized, therapy of residual serous borderline tumor is highly controversial and the treatment for pseudomyxoma peritonei, unsatisfactory. Borderline tumors exist in the endometrioid, clear cell, Brenner, and mixed common epithelial categories, but these tumors have been too rare to date in order to clearly characterize their clinical and pathological features. It is hoped that more can be learned about this general group of tumors by a more widespread recognition of their distinctive clinico-pathologic features and by their acceptance as a special subgroup of ovarian cancer. Their behavior differs strikingly from that of other types of malignant ovarian tumors and it is clear that their management should differ accordingly.


Kir4.1/Kir5.1 in the DCT plays a role in the regulation of renal K+ excretion.
The aim of this mini review is to provide an overview regarding the role of inwardly rectifying potassium channel 4.1 (Kir4.1)/Kir5.1 in regulating renal K+ excretion. Deletion of Kir4.1 in the kidney inhibited thiazide-sensitive NaCl cotransporter (NCC) activity in the distal convoluted tubule (DCT) and slightly suppressed Na-K-2Cl cotransporter (NKCC2) function in the thick ascending limb (TAL). Moreover, increased dietary K+ intake inhibited, whereas decreased dietary K+ intake stimulated, the basolateral potassium channel (a Kir4.1/Kir5.1 heterotetramer) in the DCT. The alteration of basolateral potassium conductance is essential for the effect of dietary K+ intake on NCC because deletion of Kir4.1 in the DCT abolished the effect of dietary K+ intake on NCC. Since potassium intake-mediated regulation of NCC plays a key role in regulating renal K+ excretion and potassium homeostasis, the deletion of Kir4.1 caused severe hypokalemia and metabolic alkalosis under control conditions and even during increased dietary K+ intake. Finally, recent studies have suggested that the angiotensin II type 2 receptor (AT2R) and bradykinin-B2 receptor (BK2R) are involved in mediating the effect of high dietary K+ intake on Kir4.1/Kir5.1 in the DCT.


Bilateral Sertoli Cell Tumors in a Patient with Androgen Insensitivity Syndrome.
Androgen insensitivity syndrome is the most common cause of male pseudohermaphroditism and the third most common cause of primary amenorrhea. This genetic alteration is a consequence of inherited defects on the X chromosome causing total or partial damage to the intrauterine virilization process due to functional abnormalities in the androgen receptors. The present report describes a 22-year-old patient with a female phenotype and a 46, XY karyotype, presenting with bilateral inguinal tumors. The tumors were surgically removed at the Santa Casa de Misericórdia Hospital in Vitória, Espírito Santo, Brazil. Pathology revealed bilateral testicles with Sertoli cell tumors. According to the international literature, prophylactic gonadectomy following puberty is recommended due to the progressive risk of neoplastic transformation in the residual gonads.


Clonal genetic alterations in the lungs of current and former smokers.
Genetic damage has been identified at multiple chromosomal sites (i.e., loci) in lung cancer cells. We questioned whether similar damage could be detected in the bronchial epithelial cells of chronic smokers who do not have this disease. Biopsy specimens from six different bronchial regions were obtained from 54 chronic smokers (40 current smokers and 14 former smokers). The presence of squamous metaplasia and dysplasia (abnormal histologic changes) in the specimens was documented by examination of hematoxylin-eosin-stained sections, and a metaplasia index ([number of biopsy specimens with metaplasia/total number of biopsy specimens] x 100%) was calculated for each subject. Loss of heterozygosity (i.e., loss of DNA sequences from one member of a chromosome pair) involving microsatellite DNA at three specific loci-chromosome 3p14, chromosome 9p21, and chromosome 17p13-was evaluated by means of the polymerase chain reaction. Fisher's exact test and logistic regression analysis were used to assess the data. Reported P values are two-sided. Data on microsatellite DNA status at chromosomes 3p14, 9p21, and 17p13 were available for 54, 50, and 44 subjects, respectively. The numbers of individuals who were actually informative (i.e., able to be evaluated for a loss of heterozygosity) at the three loci were 36 (67%), 37 (74%), and 34 (77%), respectively. DNA losses were detected in 27 (75%), 21 (57%), and six (18%) of the informative subjects at chromosomes 3p14, 9p21, and 17p13, respectively. Fifty-one subjects were informative for at least one of the three loci, and 39 (76%) exhibited a loss of heterozygosity. Forty-two subjects were informative for at least two of the loci, and 13 (31%) exhibited losses at a minimum of two loci. Loss of heterozygosity at chromosome 3p14 was more frequent in current smokers (22 [88%] of 25 informative) than in former smokers (five [45%] of 11 informative) (P = .01) and in subjects with a metaplasia index greater than or equal to 15% (21 [91%] of 23 informative) than in subjects with a metaplasia index of less than 15% (six [46%] of 13 informative) (P = .003). In five informative individuals among nine tested nonsmokers, a loss of heterozygosity was detected in only one subject at chromosome 3p14 (P = .03), and no losses were detected at chromosome 9p21 (P = .05). Genetic alterations at chromosomal sites containing putative tumor-suppressor genes (i.e., 3p14 and the FHIT gene, 9p21 and the p16 gene [also known as CDKN2], and 17p13 and the p53 gene [also known as TP53]) occur frequently in the histologically normal or minimally altered bronchial epithelium of chronic smokers.


PS6K amplification characterizes a small subset of anaplastic meningiomas.
PS6K, a putative oncogene mapped to chromosome 17q23, encodes a serine/threonine kinase, which phosphorylates ribosomal subunit 6 and is part of the insulin receptor signal transduction pathway involved in the regulation of messenger RNA translation, protein synthesis, cell cycle progression, and cell size. Comparative genomic hybridization studies have detected 17q23 amplifications in a subset of meningiomas, particularly those with aggressive histologic features. PS6K amplifications have been reported in breast cancer, another hormonally driven neoplasm. We assessed PS6K dosage in 94 archival paraffin-embedded meningiomas using dual-color fluorescence in situ hybridization. We found high-level PS6K amplifications in 3 of 22 anaplastic grade III meningiomas. Amplification was confirmed by differential polymerase chain reaction in 1 of these cases. In contrast, no amplifications were identified in 37 benign (grade I) and 35 atypical (grade II) meningiomas. To our knowledge, this represents the first report of gene amplification in primary human meningiomas. Given its exclusive association with anaplastic meningiomas, PS6K amplification likely occurs during the malignant progression of a small subset of anaplastic tumors. Further studies are needed to map the 17q23 amplicon to determine whether additional genes in this region are amplified in high-grade meningiomas.


Genome sequence and comparative analysis of a putative entomopathogenic Serratia isolated from Caenorhabditis briggsae.
Entomopathogenic associations between nematodes in the genera Steinernema and Heterorhabdus with their cognate bacteria from the bacterial genera Xenorhabdus and Photorhabdus, respectively, are extensively studied for their potential as biological control agents against invasive insect species. These two highly coevolved associations were results of convergent evolution. Given the natural abundance of bacteria, nematodes and insects, it is surprising that only these two associations with no intermediate forms are widely studied in the entomopathogenic context. Discovering analogous systems involving novel bacterial and nematode species would shed light on the evolutionary processes involved in the transition from free living organisms to obligatory partners in entomopathogenicity. We report the complete genome sequence of a new member of the enterobacterial genus Serratia that forms a putative entomopathogenic complex with Caenorhabditis briggsae. Analysis of the 5.04 MB chromosomal genome predicts 4599 protein coding genes, seven sets of ribosomal RNA genes, 84 tRNA genes and a 64.8 KB plasmid encoding 74 genes. Comparative genomic analysis with three of the previously sequenced Serratia species, S. marcescens DB11 and S. proteamaculans 568, and Serratia sp. AS12, revealed that these four representatives of the genus share a core set of ~3100 genes and extensive structural conservation. The newly identified species shares a more recent common ancestor with S. marcescens with 99% sequence identity in rDNA sequence and orthology across 85.6% of predicted genes. Of the 39 genes/operons implicated in the virulence, symbiosis, recolonization, immune evasion and bioconversion, 21 (53.8%) were present in Serratia while 33 (84.6%) and 35 (89%) were present in Xenorhabdus and Photorhabdus EPN bacteria respectively. The majority of unique sequences in Serratia sp. SCBI (South African Caenorhabditis briggsae Isolate) are found in ~29 genomic islands of 5 to 65 genes and are enriched in putative functions that are biologically relevant to an entomopathogenic lifestyle, including non-ribosomal peptide synthetases, bacteriocins, fimbrial biogenesis, ushering proteins, toxins, secondary metabolite secretion and multiple drug resistance/efflux systems. By revealing the early stages of adaptation to this lifestyle, the Serratia sp. SCBI genome underscores the fact that in EPN formation the composite end result - killing, bioconversion, cadaver protection and recolonization- can be achieved by dissimilar mechanisms. This genome sequence will enable further study of the evolution of entomopathogenic nematode-bacteria complexes.


Spiritual well-being and health-related quality of life in colorectal cancer: a multi-site examination of the role of personal meaning.
Individuals diagnosed and treated for cancer often report high levels of distress, continuing even after successful treatment. Spiritual well-being (SpWB) has been identified as an important factor associated with positive health outcomes. This study had two aims: (1) examine the associations between SpWB (faith and meaning/peace) and health-related quality of life (HRQL) outcomes and (2) examine competing hypotheses of whether the relationship among distress, SpWB, and HRQL is better explained by a stress-buffering (i.e., interaction) or a direct (main effects) model. Study 1 consisted of 258 colorectal cancer survivors (57% men) recruited from comprehensive cancer centers in metropolitan areas (age, M=61; months post-diagnosis, M=17). Study 2 consisted of 568 colorectal cancer survivors (49% men) recruited from a regional cancer registry (age, M=67; months post-diagnosis, M=19). Participants completed measures of SpWB (functional assessment of chronic illness therapy-spiritual well-being (FACIT-Sp)) and HRQL (functional assessment of cancer therapy-colorectal) in both studies. Measures of general distress (profile of mood states-short form) and cancer-specific distress were also completed in study 1 and study 2, respectively. After controlling for demographic and clinical variables, faith and meaning/peace were positively associated with HRQL. However, meaning/peace emerged as a more robust predictor of HRQL outcomes than faith. Planned analyses supported a direct rather than stress-buffering effect of meaning/peace. This study provides further evidence of the importance of SpWB, particularly meaning/peace, to HRQL for people with colorectal cancer. Future studies of SpWB and cancer should examine domains of the FACIT-Sp separately and explore the viability of meaning-based interventions for cancer survivors.


Post-transcriptional regulation of ribosome formation in the nucleus of regenerating rat liver.
Kinetic experiments on RNA labelling in vivo with [14C]orotate were performed with normal and 12h-regenerating rat liver. The specific radioactivities of nucleolar, nucleoplasmic and cytoplasmic rRNA species were analysed by computer according to the models of rRNA processing and nucleo-cytoplasmic migration given previously [Dudov, Dabeva, Hadjiolov & Todorov, Biochem. J. (1978) 171, 375-383]. The rates of formation and the half-lives of the individual pre-rRNA and rRNA species were determined in both normal and regenerating liver. The results show clearly that the formation of ribosomes in regenerating rat liver is post-transcriptionally activated: (a) the half-lives of all the nucleolar pre-rRNA and rRNA species are decreased by 30% on average; (b) the pre-rRNA processing is directed through the shortest maturation pathway: 45 S leads to 32 S + 18 S leads to 28 S; (c) the nucleo-cytoplasmic transfer of ribosomes is accelerated. As a consequence, the time for formation and appearance of ribosomes in the cytoplasm is shortened 1.5-fold for the large and 2-fold for the small subparticle. A new scheme for endonuclease cleavage of 45 S pre-rRNA is proposed, which explains the alterations in pre-rRNA processing in regenerating liver. Its validity for pre-rRNA processing in other eukaryotes is discussed. It is concluded that: (i) the control sites in the intranucleolar formation of 28 S and 18 S rRNA are the immediate precursor of 28 S rRNA, 32 S pre-rRNA, and the primary pre-rRNA, 45 S pre-rRNA, respectively; (ii) the limiting step in the post-transcriptional stages of ribosome biogenesis is the pre-rRNA maturation.


Special considerations for assessing and caring for autism in girls and women.
As the specificities of autistic women are increasingly recognized, this review aims to highlight emerging areas of research. These areas primarily focus on measurement bias of diagnostic tools, the physical and mental health of autistic women, and the unique aspects of the lives of autistic women, both personally and professionally across all life stages. Conventional diagnostic tools struggle to capture the specificities of autism in females, but more sensitive instruments like the GQ-ASC (Girls' Questionnaire for Autism Spectrum Conditions), later also referred to as Q-ASC (Questionnaire for Autism Spectrum Conditions) in the scientific literature, show better performances. Autistic women face particular challenges, including an increased risk of physical and mental health problems throughout their lives as women (puberty, motherhood, menopause). Autistic women also encounter specific difficulties in their employment that require greater consideration. The findings of this review identify research areas that need to be developed to better understand and support autistic girls and women and to enhance clinical practice for them.


[Gene silencing with RNA interference: a novel tool for the study of physiology and pathophysiology of adrenal cortex].
Loss-of-function approaches such as gene knock-out or gene silencing are extremely powerful strategies for assigning function to a gene and for mapping the interconnections of intracellular regulatory pathways. Post-transcriptional gene silencing can be obtained via activation of a double-stranded RNA (dsRNA) mediated mechanism termed RNA interference (RNAi). RNAi has revealed an extremely versatile tool in Biomedical research that can be used in both single silencing gene experiments and in large-scale Functional Genomics studies and has been used as a tool for gene therapy. In the present paper the authors discuss the intracellular mechanisms underlying the RNAi phenomenon, as well the different strategies and their limitations for RNAi gene silencing in mammalian cells. The use of RNAi in the treatment of human diseases and in the investigation of both physiology and pathophysiology of adrenal cortex has also been reviewed.


Magnetic resonance imaging of normal and abnormal brain perfusion.
The brain is highly susceptible to injury from any process that deprives its cells of oxygen, glucose, and other essential nutrients, and is therefore critically dependent on blood flow or perfusion. With hypoperfusion or ischemia, blood flow to the brain may be diminished to a level incompatible with normal function, eventually leading to acute ischemic stroke. Magnetic resonance (MR) imaging is one of several imaging methods used to evaluate brain perfusion and stroke. Using a multisequence approach comprised of conventional spin echo, inversion recovery, and heme-sensitive gradient echo pulse sequences, MR angiography, and diffusion and perfusion sensitive techniques, MR imaging is capable of identifying vascular lesions, measuring abnormal blood flow, and depicting the metabolic and structural consequences of ischemia. MR imaging objectives and strategies for the diagnosis of acute ischemic stroke in humans and animals, terminology, pathophysiology, and normal vascular anatomy are reviewed.


Effect of alendronate on immature human dental root explants.
This study investigated the use of alendronate in the formation of new dentin in vitro. Extracted human premolar and molar teeth with immature apices were grown in tissue culture medium for 60 days. Six control specimens were grown without alendronate in the medium, and 22 experimental specimens were grown with alendronate at [10(-9) M] in the medium. Newly formed dentin was stained with tetracycline and procion brilliant red at days 1 to 3, 30 to 33, and 60. Specimens were decalcified and 5-micron sections were prepared for examination using fluorescent microscopy. New dentin formation was measured in microns at the most apical region, at 125-micron from the apical measurement and at 250-micron from the apical measurement. The alendronate group had 57.15% more growth than the control group at the most apical region, and this difference was significant (p = 0.0001). The results indicate that alendronate at [10(-9) M] is effective in accelerating dentin formation in vitro.


Activity-Dependent Regulation of the Proapoptotic BH3-Only Gene egl-1 in a Living Neuron Pair in Caenorhabditis elegans.
The BH3-only family of proteins is key for initiating apoptosis in a variety of contexts, and may also contribute to non-apoptotic cellular processes. Historically, the nematode Caenorhabditis elegans has provided a powerful system for studying and identifying conserved regulators of BH3-only proteins. In C. elegans, the BH3-only protein egl-1 is expressed during development to cell-autonomously trigger most developmental cell deaths. Here we provide evidence that egl-1 is also transcribed after development in the sensory neuron pair URX without inducing apoptosis. We used genetic screening and epistasis analysis to determine that its transcription is regulated in URX by neuronal activity and/or in parallel by orthologs of Protein Kinase G and the Salt-Inducible Kinase family. Because several BH3-only family proteins are also expressed in the adult nervous system of mammals, we suggest that studying egl-1 expression in URX may shed light on mechanisms that regulate conserved family members in higher organisms.


Trifluoperazine as a modulator of multidrug resistance in refractory breast cancer.
Overexpression of P-glycoprotein (P-gp) has been implicated as the mechanism of multidrug resistance (MDR) in a number of human cancers, including carcinoma of the breast. We conducted a clinical trial to determine whether the P-gp inhibitor, trifluoperazine, could sensitize patients with refractory breast cancer to vinblastine chemotherapy. Adult patients with histologically confirmed, refractory, advanced breast cancer were treated with vinblastine at a dose of 1.7 mg/m2 per day by continuous infusion for five consecutive days. Patients who did not respond after two cycles were subsequently treated with vinblastine plus trifluoperazine at a dose of 8 mg twice daily during the five days of chemotherapy. In patients from whom tumor samples were available, the expression of P-gp was determined by immunocytochemistry. Of 35 patients enrolled, 30 were evaluable, 2 of whom (7%) achieved a partial response to vinblastine alone. Among the 16 patients treated with vinblastine plus trifluoperazine there was one response (6%) which lasted 16 weeks. Tumor samples were available from 16 patients, and 14 (87%) were immunoreactive for P-pg. P_pg expression was detected both in the patient who responded to vinblastine plus trifluoperazine and in one of the two patients who responded to vinblastine alone. Continuous-infusion vinblastine demonstrated limited activity in this study. Furthermore, trifluoperazine did not effectively reverse established resistance to vinblastine. This failure may be related the presence of multiple mechanisms of drug resistance in the heavily pretreated population, or because ineffective concentrations of the modulator were achieved in vivo. Future studies should evaluate more effective modulators, and attempt to reverse MDR earlier in the course of treatment, before other forms of resistance can develop.


Angiopoietin-like 3 in lipoprotein metabolism.
Triglycerides and cholesterol circulate in the bloodstream as part of various lipoprotein particles. Three members of the angiopoietin-like (ANGPTL) protein family - ANGPTL3, ANGPTL4 and ANGPTL8 - have emerged as important regulators of plasma lipoprotein levels by inhibiting the enzyme lipoprotein lipase. Here, I review the role of ANGPTL3 in lipoprotein metabolism. In contrast to ANGPTL4 and ANGPTL8, ANGPTL3 is exclusively produced in the liver and can therefore be classified as a true hepatokine. ANGPTL3 cooperates with ANGPTL8 to inhibit lipoprotein lipase and is mostly active after feeding, whereas ANGPTL4 is mostly active after fasting. Inactivation of ANGPTL3 in mice reduces plasma triglyceride and free fatty acid levels and suppresses atherosclerosis. In humans, homozygous loss-of-function mutations in ANGPTL3 lead to low plasma levels of low-density lipoproteins, high-density lipoproteins and triglycerides, a condition referred to as familial combined hypolipidaemia. Heterozygous carriers of loss-of-function mutations in ANGPTL3 have a lower risk of coronary artery disease than non-carriers. At present, researchers are investigating antisense oligonucleotide and monoclonal antibody-based inactivation of ANGPTL3 in human clinical trials for the therapeutic management of dyslipidaemia and atherosclerosis. Thus, ANGPTL3 is an important liver-derived regulator of lipoprotein metabolism that holds considerable promise as a target for atherosclerosis.


Relationship between Helicobacter pylori infection and Alzheimer disease.
The authors investigated the association between Helicobacter pylori infection (Hp-I) and Alzheimer disease (AD) by using histology for diagnosis of Hp-I. Fifty patients with AD and 30 iron deficiency anemic control participants without AD were included. The histologic prevalence of Hp-I was 88% in patients with AD and 46.7% in controls (p < 0.001).


A genome-wide linkage scan reveals CD53 as an important regulator of innate TNF-alpha levels.
Cytokines are major immune system regulators. Previously, innate cytokine profiles determined by lipopolysaccharide stimulation were shown to be highly heritable. To identify regulating genes in innate immunity, we analyzed data from a genome-wide linkage scan using microsatellites in osteoarthritis (OA) patients (The GARP study) and their innate cytokine data on interleukin (IL)-1beta, IL-1Ra, IL-10 and tumor necrosis factor (TNF)alpha. A confirmation cohort consisted of the Leiden 85-Plus study. In this study, a linkage analysis was followed by manual selection of candidate genes in linkage regions showing LOD scores over 2.5. An single-nucleotide polymorphism (SNP) gene tagging method was applied to select SNPs on the basis of the highest level of gene tagging and possible functional effects. QTDT was used to identify the SNPs associated with innate cytokine production. Initial association signals were modeled by a linear mixed model. Through these analyses, we identified 10 putative genes involved in the regulation of TNFalpha. SNP rs6679497 in gene CD53 showed significant association with TNFalpha levels (P=0.001). No association of this SNP was observed with OA. A novel gene involved in the innate immune response of TNFalpha is identified. Genetic variation in this gene may have a role in diseases and disorders in which TNFalpha is closely involved.


Problems with serological diagnosis of Toxoplasma gondii infections in heart transplant recipients.
Of the first 128 patients to receive either heart or heart and lung transplants at Papworth Hospital, four developed Toxoplasma gondii infections acquired from the donor heart and two died. Six patients had passively acquired T gondii antibody as a result of blood transfusions around the time of transplantation. Eight patients developed antibodies against T gondii, which were detectable by changes in the latex agglutination test titres but not by those of the dye test. These false positive latex agglutination reactions occurred simultaneously with cytomegalovirus infection and were associated with the IgM serum fraction in the patients' sera. These reactions were not associated with cytomegalovirus specific IgM, Paul-Bunnell antibody, nor detectable rheumatoid factor. These findings emphasise the need for T gondii dye test confirmation of latex agglutination test titre rises in heart transplant recipients.


Reduction of comminuted metatarsal fractures utilizing circular wire fixation.
The comminuted fracture of a metatarsal shaft provides a greater challenge to clinicians in relationship to stabilization and and fixation then does the simple noncomminuted type of fracture. Comminuted fractures may result in gross displacement or fragmentation of the bony segments calling for more dramatic methods of fixation to insure proper union with optimal bone healing and minimal postfrature complications. Adequate approximation of fractured bone segments is essential to insure proper restoration of function and stability to fractured bones. Open reduction with circular wire fixation is one method by which proper approximation of comminuted fracture bone segments can be accomplished.


Anti-inflammatory and antitumor action of hydrogen via reactive oxygen species.
Hydrogen (H2) has advantages that lead it to be used as a novel antioxidant in preventive and therapeutic applications. H2 can permeate into biomembranes, cytosol, mitochondria and nuclei, and can be dissolved in water or saline to produce H2 water or H2-rich saline. H2 selectively reduces oxidants of the detrimental reactive oxygen species (ROS), including hydroxyl radicals (·OH) and peroxynitrite (ONOO-), which serve a causative role in the promotion of tumor cell proliferation, invasion and metastasis, but do not disturb metabolic oxidation-reduction reactions in cell signaling. Compared with traditional antioxidants, H2 is a small molecule that can easily dissipate throughout the body and cells; thus, it may be a safe and effective antioxidant for inflammatory diseases and cancer, since ROS usually initiates tumor progression. Treatment with H2 may involve correction of the oxidative/anti-oxidative imbalance and suppression of inflammatory mediators. Therefore the present review will discuss the anti-inflammatory and anti-tumorigenic action of H2 via ROS.


Probing smoking craving with a multidimensional approach: validation of the 12-item French-language version of the Questionnaire on Smoking Urges.
The current study examined the psychometric properties of the 12-item French-language version of the Questionnaire on Smoking Urges (QSU-12), a widely used multidimensional measure of cigarette craving. Daily smokers (n=230) completed the QSU-12, the Fägerstrom Test for Nicotine Dependence, and items about addiction-related symptoms. Additional participants (n=40) completed the QSU-12 and the Fägerstrom Test for Nicotine Dependence and were assessed for expired carbon monoxide. Consistent with studies validating the English version of the scale, confirmatory factor analyses supported a two-factor solution in the French version of the scale. Good scale and subscales reliabilities were observed, and convergent validity was evidenced through relationships with dependence and addiction-related symptoms. The French-language version of the QSU-12 is an adequate instrument to assess the multidimensional construct of craving in both research and clinical practice.


Cyberbullying among children and youth in Türkiye: A systematic review and meta-analysis.
It has been reported in various studies that identifying risk and protective factors and outcomes of cyberbullying perpetration (CP) and cyberbullying victimization (CV) is crucial for educational strategies to fight against cyberbullying. The main purpose of the present study is to conduct a meta-analysis and systematic review to identify which risk and protective factors are more strongly associated with CP/CV and possible consequences of CP/CV among children and youth in Türkiye. Various databases, including PubMed, Web of Science (WoS), ProQuest, ERIC, SCOPUS, Turkish Psychiatry Index, DergiPark, and National Dissertation/Thesis Center of Türkiye were searched to identify relevant studies. Fifty-nine studies met the inclusion criteria included in the present study. Results revealed that the strongest risk factor was traditional bullying for CP (r = 0.47, p < .001) and traditional victimization for CV (r = 0.43, p < .001). The strongest protective factor was social skill for CP (r = -0.45, p < .001) and empathy for CV (r = -0.25, p < .001). In addition, involvement in CP behaviors had the strongest effect on negative self-concept (r = 0.28, p < .001), while exposure to CV on anxiety (r = 0.35, p < .001). Although this study has some limitations, the study's findings are important source of information for many professionals, such as pediatric nurses, school psychological counselors, psychologists, and policymakers to further educational strategies for children and young people in Türkiye. The study findings would be useful for developing educational programs to strengthen protective factors and reduce risk factors to prevent cyberbullying perpetration behaviors.


Income inequality and adult nutritional status: anthropometric evidence from a pre-industrial society in the Bolivian Amazon.
Evidence has been accumulated about the adverse effects of income inequality on individual health in industrial nations, but we know less about its effect in small-scale, pre-industrial rural societies. Income inequality should have modest effects on individual health. First, norms of sharing and reciprocity should reduce the adverse effects of income inequality on individual health. Second, with sharing and reciprocity, personal income will spill over to the rest of the community, attenuating the protective role of individual income on individual health found in industrial nations. We test these ideas with data from Tsimane' Amerindians, a foraging and farming society in the Bolivian Amazon. Subjects included 479 household heads (13+ years of age) from 58 villages. Dependent variables included anthropometric indices of short-run nutritional status (body-mass index (BMI), and age- and sex-standardized z-scores of mid-arm muscle area and skinfolds). Proxies for income included area deforested per person the previous year and earnings per person in the last 2 weeks. Village income inequality was measured with the Gini coefficient. Income inequality did not correlate with anthropometric indices, most likely because of negative indirect effects from the omission of social-capital variables, which would lower the estimated impact of income inequality on health. The link between BMI and income and between skinfolds and income resembled a U and an inverted U; income did not correlate with mid-arm muscle area. The use of an experimental research design might allow for better estimates of how income inequality affects social capital and individual health.


The Michigan Appropriateness Guide for Intravenous Catheters in Pediatrics: miniMAGIC.
Vascular access device decision-making for pediatric patients remains a complex, highly variable process. To date, evidence-based criteria to inform these choices do not exist. The objective of the Michigan Appropriateness Guide for Intravenous Catheters in pediatrics (miniMAGIC) was to provide guidance on device selection, device characteristics, and insertion technique for clinicians, balancing and contextualizing evidence with current practice through a multidisciplinary panel of experts. The RAND Corporation and University of California, Los Angeles Appropriateness Method was used to develop miniMAGIC, which included the following sequential phases: definition of scope and key terms, information synthesis and literature review, expert multidisciplinary panel selection and engagement, case scenario development, and appropriateness ratings by an expert panel via 2 rounds. The appropriateness of the selection, characteristics, and insertion technique of intravenous catheters commonly used in pediatric health care across age populations (neonates, infants, children, and adolescents), settings, diagnoses, clinical indications, insertion locations, and vessel visualization devices and techniques was defined. Core concepts including vessel preservation, insertion and postinsertion harm minimization (eg, infection, thrombosis), undisrupted treatment provision, and inclusion of patient preferences were emphasized. In this study, we provide evidence-based criteria for intravenous catheter selection (from umbilical catheters to totally implanted venous devices) in pediatric patients across a range of clinical indications. miniMAGIC also highlights core vascular access practices in need of collaborative research and innovation.


[Association between genetic polymorphisms of interleukin 6 (IL6), IL6R and IL18 with metabolic syndrome in obese Chilean children].
Metabolic Syndrome (MS) is highly prevalent among obese children and adolescents and is considered a predictor for the development of type 2 diabetes mellitus and cardiovascular disease. Obesity is associated with an increase in circulating levels of interleukins 6 (IL6) and 18 (IL18), which in turn would depend on polymorphisms of IL6, IL6R and IL18 genes. To evaluate the association between genetic polymorphisms of IL6 (rs1800795, rs1800796 and rs1800797), IL6R (rs2228145) and IL18 (rs360719, rs187238 and rs204355) and MS and/or its components in a sample of Chilean obese children. These polymorphisms were genotyped in 259 obese children aged 10 ± 2 years with a body mass index of 26.1 ± 4.1 kg/m². Sixty eight had metabolic syndrome (26.3%). The association of their alleles, genotypes and haplotypes with the MS and its components was assessed. IL6, IL6R and IL18 variants showed no association with SM nor with any of the phenotypes that compose it. However, IL18 haplotypes (rs360719-rs187238-rs204355) TCT and CGT were associated with triglycerides ≤ 110 mg/dL and HDL < 40 mg/dL, respectively. IL6 and IL6R variants are not associated with MS or with any of its phenotypes. Although an association between IL18 haplotypes and certain MS component has been detected herein, it is necessary to replicate our findings in independent studies due to the low frequency of these allele combinations detected in our sample.


Predicting Disease Onset from Mutation Status Using Proband and Relative Data with Applications to Huntington's Disease.
Huntington's disease (HD) is a progressive neurodegenerative disorder caused by an expansion of CAG repeats in the IT15 gene. The age-at-onset (AAO) of HD is inversely related to the CAG repeat length and the minimum length thought to cause HD is 36. Accurate estimation of the AAO distribution based on CAG repeat length is important for genetic counseling and the design of clinical trials. In the Cooperative Huntington's Observational Research Trial (COHORT) study, the CAG repeat length is known for the proband participants. However, whether a family member shares the huntingtin gene status (CAG expanded or not) with the proband is unknown. In this work, we use the expectation-maximization (EM) algorithm to handle the missing huntingtin gene information in first-degree family members in COHORT, assuming that a family member has the same CAG length as the proband if the family member carries a huntingtin gene mutation. We perform simulation studies to examine performance of the proposed method and apply the methods to analyze COHORT proband and family combined data. Our analyses reveal that the estimated cumulative risk of HD symptom onset obtained from the combined data is slightly lower than the risk estimated from the proband data alone.


Properties of iridoviruses from ornamental fish.
An iridovirus from 2 species of freshwater tropical imported fish was examined for its antigenic and biochemical properties and virulence for 3 species of food fish. The virus was found in both guppy (Poecilia reticulata) and doctor fish (Labroides dimidatus). The virus replicated in numerous fish cell lines including BF-2, CCO and EPC. Virus titers reached 10(8) TCID50/ml in each cell line. The virions had similar size and morphology to those previously reported to cause systemic infections among catfish in Europe and from redfin perch and rainbow trout in Australia. A comparison of the ornamental fish iridovirus with these systemic agents indicated that all share common antigens detected by indirect fluorescent antibody tests and Western blots. Additionally, polymerase chain reactions using primer sets developed for the red fin perch virus, amplified a segment of genomic DNA from the ornamental fish isolate. An examination of the virulence of the ornamental fish isolate for 2 important food fish species, rainbow trout (Oncorhynchus mykiss) and channel catfish (Ictalurus punctatus), indicated the former species was susceptible although mortality was low. Dead fish had significant lesions in the liver and kidney and had titers of virus greater than 10(8) TCID50/g. We speculate that these iridoviruses, first detected in Australia in redfin perch, are all related strains in the Ranavirus genus that may have reached these geographically distant sites by movements of ornamental fish.


Identification of a 43-kDa outer-membrane protein as an adhesin in Aeromonas caviae.
Aeromonas spp. are associated with intestinal and extra-intestinal infections. However, the virulence factors of A. caviae remain, for the most part, poorly known. This study examined the interactions involved in the adherence of A. caviae isolates Ae56, Ae391 and Ae398 to HEp-2 cells. All strains expressed high levels of aggregative adherence. Maximum adhesion occurred with bacteria grown at 22 degrees C, but transmission electron microscopy did not reveal the presence of fimbrial structures on the bacterial cell surface. Outer-membrane proteins (OMPs) extracted from isolate Ae398, grown at 22 degrees C and 37 degrees C, showed similar SDS-PAGE protein profiles. Most proteins were < 60 kDa. A major 43-kDa protein was seen only in the boiled OMP extract. The biotinylated 43-kDa protein bound specifically to HEp-2 cells. Microbeads coated with the 43-kDa protein were also adherent to HEp-2 cells, and anti-43-kDa protein antibody blocked adherence of 43-kDa protein-coated latex beads. These data suggest that the 43-kDa OMP functions as an adhesin in A. caviae.


Comorbid Psychiatric Disorders in Children and Adolescents with Nocturnal Enuresis.
The present study was conducted with the aim of identifying the frequency of comorbid psychiatricdisorders in children and adolescents with nocturnal enuresis (NE). In this descriptive-analytical study, 183 children and adolescents aged 5-18 years withNE referred to psychiatric clinics at Tabriz University of Medical Sciences were selected in 2015. A structuredclinical diagnostic interview, the kiddie-schedule for affective disorders and schizophrenia (K-SADS), was employedbased on the diagnostic and statistical manual of mental disorders (DSM-IV-TR) for the diagnosis of NEand comorbid psychiatric disorders. In this study, 39 participants (21.3%) were female and 144 (78.7%) were male. The mean age of participantswas 8.69 ± 2.34 years. The lifelong incidence of mental disorders among enuretic children and adolescentswas 79.23%. The highest incidence belonged to attention deficit/hyperactivity disorder (ADHD) with 74.9%, oppositional-defiant disorder (ODD) with 53%, and tic disorders with 12% (motor tics together with a single caseof vocal tic). The lowest incidence was for conduct disorder, bipolar affective disorder, and post-traumatic stressdisorder (PTSD) with 5%. Based on the Fisher exact test, there was no significant difference between girls andboys in terms of psychiatric disorders incidence (P > .05). Comorbid psychiatric disorders with NE are common among children and adolescents. Therefore,in-depth examination of other psychiatric disorders needs to be carried out in enuretic children and adolescents,which will affect the treatment and prognosis of NE.


Intervention effects on stage transitions for adolescent smoking and alcohol use acquisition.
The health impacts of smoking and alcohol abuse have been long established with smoking representing one of the most preventable causes of disease and alcohol use the most popular psychoactive substance among adolescents. The current study evaluated stage of change progression in a large (N = 4,158) school-based, computer-delivered, transtheoretical model (TTM)-tailored multiple behavior intervention focused on preventing acquisition of smoking and alcohol use in adolescents. Assessments began in sixth grade and continued yearly until eighth grade, with a follow-up in ninth grade. Markov modeling was used to (a) characterize the best pattern of stage movement (e.g., no stage change, stage-sequential change, stages skipped), (b) test whether the identified pattern was stable over time (e.g., between assessments and after intervention completion), and (c) to determine whether the substance use prevention (SP) intervention effectively kept adolescents in acquisition stages (e.g., prevents stage movement toward substance use), relative to the comparison intervention. Major findings supported positive effects for both the intervention and comparison condition, which focused on energy balance (EB) behaviors and provided no direct intervention on substance use behaviors. Substantial differences in stage membership and transitions across intervention conditions highlighted the process of smoking and alcohol use acquisition in middle school students across each intervention condition. (PsycINFO Database Record


G protein-coupled receptor signaling complexity in neuronal tissue: implications for novel therapeutics.
The manipulation of transmembrane signaling by G protein-coupled receptors (GPCRs) constitutes perhaps the single most important therapeutic target in medicine. Therapeutics acting on GPCRs have traditionally been classified as agonists, partial agonists, or antagonists based on a two state model of receptor function embodied in the ternary complex model. Over the past decade, however, many lines of investigation have shown that GPCR signaling exhibits greater diversity and 'texture' than previously appreciated. Signal diversity arises from numerous factors, among them the ability of receptors to adopt multiple 'active' states with different effector coupling profiles, the formation of receptor dimers that exhibit unique pharmacology, signaling, and trafficking, the dissociation of receptor 'activation' from desensitization and internalization, and the discovery that non-G protein effectors mediate some aspects of GPCR signaling. At the same time, clustering of GPCRs with their downstream effectors in membrane microdomains, and interactions between receptors and a plethora of multidomain scaffolding proteins and accessory/chaperone molecules confers signal preorganization, efficiency, and specificity. More importantly it is likely that alteration in the interactions of these proteins with GPCRs may occur in aging or neurodegenerative disorders, thus defining a distinct 'pharmacology' from that seen in young organisms or normal physiology. In this context, the concept of agonist selective trafficking of receptor signaling, which recognizes that a bound ligand may select between a menu of 'active' receptor conformations and induce only a subset of the possible response profile, presents the opportunity to develop drugs that change the quality as well as the quantity of efficacy and enhance these qualities for specific disorders or other paradigms. As a more comprehensive understanding of the complexity of GPCR signaling is developed, the rational design of ligands possessing increased specific efficacy and attenuated side effects may become the standard mode of drug development.


Exposure to concentrated ambient air particles alters hematologic indices in humans.
Descriptions of changes in hematological indices have contested the premise that the biological effects of suspended particulate matter (PM) are restricted to the lung. Employing approximately 40 hematologic parameters reflecting blood cells, chemistries, mediators, and coagulation factors, we tested the hypothesis that exposure to concentrated ambient air particles (CAPs) can be associated with changes in hematologic indices in normal humans. Twenty healthy young volunteers were exposed to either filtered air (n = 5) or CAPs (n = 15) with a mean PM mass of 120.5 +/- 14.0 microg/m3 and a range from 15.0-357.6 microg/m3. Hematologic indices were measured. Changes in all parameters are expressed as the absolute value either immediately after or 24 h after exposure. Differences between responses of those individuals exposed to filtered air and CAPs were tested using the T-test of independent means. If significant differences between the two groups were suggested by the T-test (p < .10), the relationship was further evaluated employing linear regression techniques. Regression analysis verified significant linear relationships between particle mass the individual was exposed to and (1) decrements in WBC count 24 h later, (2) decreases in lactate dehydrogenase (LDH) concentration 24 h later, and (3) elevations in fibrinogen levels 24 h later. There were no changes in either inflammatory mediators in the blood or indices of coagulation/fibrinolysis other than fibrinogen. We conclude that exposure of healthy volunteers to CAPs can be associated with decreases of both white blood cell (WBC) count and LDH and increased concentrations of fibrinogen in the blood.


Isolation and identification of a neuroactive factor from Lathyrus latifolius.
A neuroactive principle of Lathyrus latifolius has been isolated in crystalline form as a monohydrochloride and has been identified as L-alpha,gamma-diaminobutyric acid. This amino acid has also been found in very high concentration in the toxic seed of Lathyrus sylvestris Wagneri. A structural relationship between this factor, the lathyrus factor from Lathyrus odoratus, and, beta-cyano-L-alanine, a new, synthetic neuroactive amino acid nitrile, is pointed out, and a possible biosynthetic pathway relating these is indicated.


Whether co-administration of garlic has negative influence on Scutellaria baicalensis Georgi in treating models rats with pelvic inflammation?
The research was to explore whether co-administration of garlic has negative influence on Scutellaria baicalensis Georgi (Scutellaria baicalensis) in treating models rats with pelvic inflammation. Twelve model rats were randomized into a Scutellaria baicalensis group and a Scutellaria baicalensis+garlic group with six in each group for pharmacokinetic analysis. Twenty-four rats were randomized into a Scutellaria baicalensis group, a Scutellaria baicalensis+garlic group, a model control group and a normal control group with six rats in each group for detecting the serum levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin 6 (IL-6) with enzyme-linked immunosorbent assay (ELISA). The results showed that in the Scutellaria baicalensis group, the maximum concentration (C(max)) of baicalin, area under the plasma concentration-time curve (AUC) and the time to C(max) (T(max)) were significantly higher and apparent clearance (CL/F) were significantly lower than those of Scutellaria baicalensis+garlic group. The serum levels of TNF-alpha and IL-6 in the Scutellaria baicalensis group were both significantly lower than Scutellaria baicalensis+garlic group. It was then concluded that garlic not only had negative influence on the absorption of active compounds in Scutellaria baicalensis, but decreased the curative effects of Scutellaria baicalensis in treating model rats with pelvic inflammation. Garlic should not be co-administered with Scutellaria baicalensis.


Effectiveness of porcine dermal collagen in giant hernia closure in patients with deleterious fascia constitution after orthotopic liver transplantation.
Incisional hernias (IHs) occur universally after orthotopic liver transplantation (OLT). This study aimed to investigate the effectiveness of porcine dermal collagen (PDC) as a closing aid in giant hernias after OLT in a prospective trial. If direct closure (DC) was not feasible due to the hernia size and abdominal wall constitution, a PDC mesh was implanted. All patients from the PDC and DC groups were followed prospectively for 24 months. IH recurrence rates served as the primary endpoint, and the development of infections and wound healing disorders served as the secondary endpoints. Recurrence rate was 21% (4/19) in DC patients and 12% (2/16) in PDC patients (P = 0.045). Implant site infections occurred in five of PDC and one of DC patients (P < 0.05). All of them were managed with antibiotics; two of the PDC patients required surgical drainage. Histological analysis of PDC mesh biopsies indicated good angiogenesis and integration of the PDC into the abdominal wall. PDC was effective in our study for incisional hernia repair, and our results compared favourably with those of patients in whom direct hernia closure was feasible.


Physical fatty acid deficiency signs in children with ADHD symptoms.
Fatty acid deficiency symptoms (FADS) of dry hair and skin, frequent thirst and urination have been observed to be higher in children with attention deficit hyperactivity disorder (ADHD). Two studies investigated FADS in 7-12-year-old children; Study 1 in a general population (N=347) and Study 2 in children with ADHD symptoms (N=104). Correlations between FADS and ADHD-related symptoms were found at baseline in Study 1 but not Study 2. FADS did not improve after supplementation with omega-3 and omega-6 polyunsaturated fatty acids (PUFA) versus placebo after 15 weeks in Study 2, and were not related to improvements in ADHD symptoms in the PUFA groups. However, FADS did improve in all groups, possibly attributable to the linoleic acid present in both the PUFA and placebo (palm oil) supplements. FADS are not a reliable selection criterion for children with ADHD who might benefit from omega-3 PUFA supplementation.


Health research capacity development in low and middle income countries: reality or rhetoric? A systematic meta-narrative review of the qualitative literature.
Locally led health research in low and middle income countries (LMICs) is critical for overcoming global health challenges. Yet, despite over 25 years of international efforts, health research capacity in LMICs remains insufficient and development attempts continue to be fragmented. The aim of this systematic review is to identify and critically examine the main approaches and trends in health research capacity development and consolidate key thinking to identify a more coherent approach. This review includes academic and grey literature published between January 2000 and July 2013. Using a predetermined search strategy, we systematically searched PubMed, hand-searched Google Scholar and checked reference lists. This process yielded 1668 papers. 240 papers were selected based on a priori criteria. A modified version of meta-narrative synthesis was used to analyse the papers. 3 key narratives were identified: the effect of power relations on capacity development; demand for stronger links between research, policy and practice and the importance of a systems approach. Capacity development was delivered through 4 main modalities: vertical research projects, centres of excellence, North-South partnerships and networks; all were controversial, and each had their strengths and weaknesses. A plurality of development strategies was employed to address specific barriers to health research. However, lack of empirical research and monitoring and evaluation meant that their effectiveness was unclear and learning was weak. There has been steady progress in LMIC health research capacity, but major barriers to research persist and more empirical evidence on development strategies is required. Despite an evolution in development thinking, international actors continue to use outdated development models that are recognised as ineffective. To realise newer development thinking, research capacity outcomes need to be equally valued as research outputs. While some development actors are now adopting this dedicated capacity development approach, they are in the minority.


Helicobacter pylori VacA induces programmed necrosis in gastric epithelial cells.
Helicobacter pylori is a Gram-negative bacterium that colonizes the human stomach and contributes to the development of peptic ulcer disease and gastric cancer. The secreted pore-forming toxin VacA is one of the major virulence factors of H. pylori. In the current study, we show that AZ-521 human gastric epithelial cells are highly susceptible to VacA-induced cell death. Wild-type VacA causes death of these cells, whereas mutant VacA proteins defective in membrane channel formation do not. Incubation of AZ-521 cells with wild-type VacA results in cell swelling, poly(ADP-ribose) polymerase (PARP) activation, decreased intracellular ATP concentration, and lactate dehydrogenase (LDH) release. VacA-induced death of these cells is a caspase-independent process that results in cellular release of histone-binding protein high mobility group box 1 (HMGB1), a proinflammatory protein. These features are consistent with the occurrence of cell death through a programmed necrosis pathway and suggest that VacA can be included among the growing number of bacterial pore-forming toxins that induce cell death through programmed necrosis. We propose that VacA augments H. pylori-induced mucosal inflammation in the human stomach by causing programmed necrosis of gastric epithelial cells and subsequent release of proinflammatory proteins and may thereby contribute to the pathogenesis of gastric cancer and peptic ulceration.


Lessons learnt in conducting a clinical drug trial in children with Asperger Syndrome.
To describe the authors' experience of conducting a clinical drug trial in children with Asperger Syndrome, including the pitfalls encountered and lessons learnt. The main barrier encountered was in the recruitment of children: it was not possible to recruit the target of 60 patients. The recruitment of children is often the major barrier to the progress of a successful clinical trial. Conducting the clinical drug trial was greatly facilitated by the appropriate setting and experienced clinical pharmacology staff.


The Strength of Alpha Oscillations in the Electroencephalogram Differently Affects Algorithms Used for Anesthesia Monitoring.
Intraoperative patient monitoring using the electroencephalogram (EEG) can help to adequately adjust the anesthetic level. Therefore, the processed EEG (pEEG) provides the anesthesiologist with the estimated anesthesia level. The commonly used approaches track the changes from a fast- and a low-amplitude EEG during wakefulness to a slow- and a high-amplitude EEG under general anesthesia. However, besides these changes, another EEG feature, a strong oscillatory activity in the alpha band (8-12 Hz), develops in the frontal EEG. Strong alpha-band activity during general anesthesia seems to reflect an appropriate anesthetic level for certain anesthetics, but the way the common pEEG approaches react to changes in the alpha-band activity is not well explained. Hence, we investigated the impact of an artificial alpha-band modulation on pEEG approaches used in anesthesia research. We performed our analyses based on 30 seconds of simulated sedation (n = 25) EEG, simulated anesthesia (n = 25) EEG, and EEG episodes from 20 patients extracted from a steady state that showed a clearly identifiable alpha peak in the density spectral array (DSA) and a state entropy (GE Healthcare) around 50, indicative of adequate anesthesia. From these traces, we isolated the alpha activity by band-pass filtering (8-12 Hz) and added this alpha activity to or subtracted it from the signals in a stepwise manner. For each of the original and modified signals, the following pEEG values were calculated: (1) spectral edge frequency (SEF95), (2) beta ratio, (3) spectral entropy (SpEntr), (4) approximate entropy (ApEn), and (5) permutation entropy (PeEn). The pEEG approaches showed different reactions to the alpha-band modification that depended on the data set and the amplification step. The beta ratio and PeEn decreased with increasing alpha activity for all data sets, indicating a deepening of anesthesia. The other pEEG approaches behaved nonuniformly. SEF95, SpEntr, and ApEn decreased with increasing alpha for the simulated anesthesia data (arousal) but decreased for simulated sedation. For the patient EEG, ApEn indicated an arousal, and SEF95 and SpEntr showed a nonuniform change. Changes in the alpha-band activity lead to different reactions for different pEEG approaches. Hence, the presence of strong oscillatory alpha activity that reflects an adequate level of anesthesia may be interpreted differently, by an either increasing (arousal) or decreasing (deepening) pEEG value. This could complicate anesthesia navigation and prevent the adjustment to an adequate, alpha-dominant anesthesia level, when titrating by the pEEG values.


Prochlorperazine Increases KCC2 Function and Reduces Spasticity after Spinal Cord Injury.
In mature neurons, low intracellular chloride level required for inhibition is maintained by the potassium-chloride cotransporter, KCC2. Impairment of Cl- extrusion after KCC2 dysfunction has been involved in many central nervous system disorders, such as seizures, neuropathic pain, or spasticity, after a spinal cord injury (SCI). This makes KCC2 an appealing drug target for restoring Cl- homeostasis and inhibition in pathological conditions. In the present study, we screen the Prestwick Chemical Library® and identify conventional antipsychotics phenothiazine derivatives as enhancers of KCC2 activity. Among them, prochlorperazine hyperpolarizes the Cl- equilibrium potential in motoneurons of neonatal rats and restores the reciprocal inhibition post-SCI. The compound alleviates spasticity in chronic adult SCI rats with an efficacy equivalent to the antispastic agent, baclofen, and rescues the SCI-induced downregulation of KCC2 in motoneurons below the lesion. These pre-clinical data support prochlorperazine for a new therapeutic indication in the treatment of spasticity post-SCI and neurological disorders involving a KCC2 dysfunction.


Profile of betrixaban and its potential in the prevention and treatment of venous thromboembolism.
Venous thromboembolism (VTE), which includes deep vein thrombosis and pulmonary embolism, is a common and potentially preventable cause of morbidity and mortality. Unfractionated heparin, low-molecular-weight heparin, and warfarin have been the cornerstone of VTE prevention and treatment but are being replaced by recently approved non-vitamin K antagonist oral anticoagulants (NOACs): dabigatran, rivaroxaban, apixaban, and edoxaban. The NOACs are at least as effective and as safe as heparins and warfarin for VTE prevention and treatment and are more convenient because they have a low propensity for food and drug interactions and are given in fixed doses without routine coagulation monitoring. The remaining limitations of currently available NOACs include their dependence on renal and hepatic function for clearance, and the lack of an approved antidote. Betrixaban is a new NOAC with distinct pharmacological characteristics: minimal renal clearance, minimal hepatic metabolism, and long half-life. It has undergone successful Phase II studies in orthopedic thromboprophylaxis, and in stroke prevention in atrial fibrillation. Currently, it is being evaluated in a Phase III trial of extended thromboprophylaxis in medical patients (APEX study). In this article, we describe the development of betrixaban, review its pharmacological profile, discuss the results of clinical trials, and examine its potential for VTE prevention and treatment.


Unraveling the Sweet Secrets of HCC: Glucometabolic Rewiring in Hepatocellular Carcinoma.
Hepatocellular carcinoma (HCC) is the primary form of liver cancer. It causes ∼ 800 000 deaths per year, which is expected to increase due to increasing rates of obesity and metabolic dysfunction associated steatotic liver disease (MASLD). Current therapies include immune checkpoint inhibitors, tyrosine kinase inhibitors, and monoclonal antibodies, but these therapies are not satisfactorily effective and often come with multiple side effects and recurrences. Metabolic reprogramming plays a significant role in HCC progression and is often conserved between tumor types. Thus, targeting rewired metabolic pathways could provide an attractive option for targeting tumor cells alone or in conjunction with existing treatments. Therefore, there is an urgent need to identify novel targets involved in cancer-mediated metabolic reprogramming in HCC. In this review, we provide an overview of molecular rewiring and metabolic reprogramming of glucose metabolism in HCC to understand better the concepts that might widen the therapeutic window against this deadly cancer.


Identification of differentially expressed proteins in murine embryonic and postnatal cortical neural progenitors.
The central nervous system (CNS) develops from a heterogeneous pool of neural stem and progenitor cells (NSPC), the underlying differences among which are poorly understood. The study of NSPC would be greatly facilitated by the identification of additional proteins that mediate their function and that would distinguish amongst different progenitor populations. To identify membrane and membrane-associated proteins expressed by NSPC, we used a proteomics approach to profile NSPC cultured as neurospheres (NS) isolated from the murine cortex during a period of neurogenesis (embryonic day 11.5, E11.5), as compared to NSPC isolated at a peak of gliogenesis (postnatal day 1, P0) and to differentiated E11.5 NS. 54 proteins were identified with high expression in E11.5 NS, including the TrkC receptor, several heterotrimeric G proteins, and the Neogenin receptor. 24 proteins were identified with similar expression in E11.5 and P0 NS over differentiated E11.5 NS, and 13 proteins were identified with high expression specifically in P0 NS compared to E11.5 NS. To illustrate the potential relevance of these identified proteins to neural stem cell biology, the function of Neogenin was further studied. Using Fluorescence Activated Cell Sorting (FACS) analysis, expression of Neogenin was associated with a self-renewing population present in both E11.5 and adult subventricular zone (SVZ) NS but not in P0 NS. E11.5 NS expressed a putative Neogenin ligand, RGMa, and underwent apoptosis when exposed to a ligand-blocking antibody. There are fundamental differences between the continuously self-renewing and more limited progenitors of the developing cortex. We identified a subset of differentially expressed proteins that serve not only as a set of functionally important proteins, but as a useful set of markers for the subsequent analysis of NSPC. Neogenin is associated with the continuously self-renewing and neurogenic cells present in E11.5 cortical and adult SVZ NS, and the Neogenin/RGMa receptor/ligand pair may regulate cell survival during development.


Teaching moral reasoning through gesture.
Stem-cell research. Euthanasia. Personhood. Marriage equality. School shootings. Gun control. Death penalty. Ethical dilemmas regularly spark fierce debate about the underlying moral fabric of societies. How do we prepare today's children to be fully informed and thoughtful citizens, capable of moral and ethical decisions? Current approaches to moral education are controversial, requiring adults to serve as either direct ('top-down') or indirect ('bottom-up') conduits of information about morality. A common thread weaving throughout these two educational initiatives is the ability to take multiple perspectives - increases in perspective taking ability have been found to precede advances in moral reasoning. We propose gesture as a behavior uniquely situated to augment perspective taking ability. Requiring gesture during spatial tasks has been shown to catalyze the production of more sophisticated problem-solving strategies, allowing children to profit from instruction. Our data demonstrate that requiring gesture during moral reasoning tasks has similar effects, resulting in increased perspective taking ability subsequent to instruction. A video abstract of this article can be viewed at http://www.youtube.com/watch?v/gAcRIClU_GY.


Reduction in N-methyl-D-aspartate Receptor-mediated Cell Death in Hippocampal Neurons by Glucose Reduction Preconditioning.
Repeated episodes of reduced glucose availability can precondition the brain against damage caused by severe hypoglycemia. Because N-methyl-D-aspartate (NMDA) receptor activation may contribute to neuronal loss in the hippocampus following glucose deprivation, we tested the hypothesis that preconditioning with reduced glucose decreased NMDA receptor-mediated cell death in hippocampal neurons. Hippocampal slice cultures from 7-day old rats were used to study glucose reduction preconditioning and N-methyl-D-aspartate receptor (NMDAR)-mediated cell death. Preconditioning involved reductions in glucose to the following levels: 0.1 mM, 0.5, or 1.0 mM for 30 minutes, 60 minutes, or 90 minutes on 3 consecutive days. Cell death following 1-hour total glucose deprivation was measured with a vital dye technique (SYTOX fluorescence). As an index of NMDAR activity, cell death following application of 1 mM NMDA, was also measured. A preconditioning protocol of 30 minutes of 0.1 mM glucose per day for 3 days reduced cell death following 1-hour total glucose by 65% to 70%, depending on cellular region. No reduction in NMDAR-mediated cell death was seen following any of the preconditioning treatments. However, when NMDAR-mediated cell death was assessed following preconditioning combined with subsequent total glucose deprivation, cell death was reduced in the cultures that had been preconditioned with 0.1 mM glucose for 30 minutes×3 days. We found that that glucose reduction preconditioning protects hippocampal neurons against severe glucose deprivation-induced neuronal damage. This preconditioning was not associated with reductions in NMDAR-mediated cell death except when the preconditioning was combined with an additional exposure to a period of total glucose deprivation.


A morphological and phylogenetic revision of the Nectria cinnabarina species complex.
The genus Nectria is typified by N. cinnabarina, a wood-inhabiting fungus common in temperate regions of the Northern Hemisphere. To determine the diversity within N. cinnabarina, specimens and cultures from Asia, Europe, and North America were obtained and examined. Their phylogeny was determined using sequences of multiple loci, specifically act, ITS, LSU, rpb1, tef1, and tub. Based on these observations, four species are recognised within the N. cinnabarina complex. Each species is delimited based on DNA sequence analyses and described and illustrated from specimens and cultures. The basionym for N. cinnabarina, Sphaeria cinnabarina, is lectotypified based on an illustration that is part of the protologue, and an epitype specimen is designated. Nectria cinnabarinas. str. is recircumscribed as having 2-septate ascospores and long stipitate sporodochia. Nectria dematiosa, previously considered a synonym of N. cinnabarina, has up to 2-septate ascospores and sessile sporodochia or no anamorph on the natural substrate. A third species, Nectria nigrescens, has up to 3-septate ascospores and short to long stipitate sporodochia. One newly described species, Nectria asiatica with a distribution restricted to Asia, has (0-)1-septate ascospores and short stipitate sporodochia. Young and mature conidia developing on SNA were observed for each species. Mature conidia of N. asiatica, N. cinnabarina, and N. nigrescens but not N. dematiosa bud when the mature conidia are crowded. On PDA the optimal temperature for growth for N. dematiosa is 20 °C, while for the other three species it is 25 °C. Based on our phylogenetic analyses, three subclades are evident within N. dematiosa. Although subtle culture and geographical differences exist, these subclades are not recognised as distinct species because the number of samples is small and the few specimens are insufficient to determine if morphological differences exist in the natural environment.


Structure of Helicobacter pylori L-asparaginase at 1.4 A resolution.
Bacterial L-asparaginases have been used in the treatment of childhood acute lymphoblastic leukaemia for over 30 years. Their therapeutic effect is based on their ability to catalyze the conversion of L-asparagine, an essential amino acid in certain tumours, to L-aspartic acid and ammonia. Two L-asparaginases, one from Escherichia coli and the other from Erwinia chrysanthemi, have been widely employed in clinical practice as anti-leukaemia drugs. However, L-asparaginases are also able to cause severe side effects owing to their intrinsic glutaminase activity. Helicobacter pylori L-asparaginase (HpA) has been reported to have negligible glutaminase activity. To gain insight into the properties of HpA, its crystal structure in the presence of L-aspartate was determined to 1.4 A resolution, which is one of the highest resolutions obtained for an L-asparaginase structure. The final structure has an R(cryst) of 12.6% (R(free) = 16.9%) with good stereochemistry. A detailed analysis of the active site showed major differences in the active-site flexible loop and in the 286-297 loop from the second subunit, which is involved in active-site formation. Accordingly, Glu289, Asn255 and Gln63 are suggested to play roles in modulating the accessibility of the active site. Overall, the structural comparison revealed that HpA has greater structural similarity to E. coli L-asparaginase than to any other L-asparaginase, including Er. carotovora L-asparaginase, despite the fact that the latter is also characterized by low glutaminase activity.