Appetitive and consummatory behaviors in the control of ethanol consumption: a measure of ethanol seeking behavior.
Models of ethanol self-administration in animals have demonstrated that ethanol can reinforce a variety of behaviors, independent of ethanol's caloric or fluid properties. However, the processes that control self-administration remain unclear. Determining factors related to ethanol seeking behavior, independent of consumption, is central to the concepts of intake regulation. The model described in this article proposes a method to separate the initial appetitive (seeking) behavior from the following consummatory (drinking) behavior to assess each behavior type. Rats were trained to lever press to gain access to a drinking tube connected to a fluid bottle containing either 10% ethanol or 3% sucrose for 20 min. When the response requirement to obtain access to the tube was increased, it was found that both solutions supported the same amount of responding (breakpoint was at approximately a fixed ratio 32 requirement), indicating equal reinforcer strength. However, regardless of the response requirement, if access to the fluids occurred, intakes were not changed. This suggests that factors besides those of reinforcer efficacy are important in controlling the size of the consummatory bout. Based on these findings, we believe that this model will be useful in determining factors related to seeking behaviors and the control of drinking bout size.


Bullying victimization and child sexual abuse among left-behind and non-left-behind children in China.
Bullying is one of the most important factors associated with child abuse. However, robust tests supporting the assumption that being bullied can contribute to child sexual abuse (CSA) among left-behind children (LBC) remain sparse. This study aims to investigate the association of bullying victimization with CSA among LBC in China. A cross-sectional study was conducted in six middle schools of Sichuan and Anhui province in 2015. The bullying victimization was assessed by seven items from the Revised Olweus Bully/Victim Questionnaire. The experience of CSA was measured by ten items CSA scale with good consistency. A total of 1,030 children met the sampling criteria, including 284 LBC and 746 non-LBC. The prevalence of CSA was 22.89% in LBC and 20.19% in non-LBC (p > 0.05). Bullying victimization was related to CSA among both LBC (adjusted Odds Ratio [aOR] = 2.52, 95% CI [1.34-4.73]) and non-LBC (aOR = 2.35, 95% CI [1.58-3.53]). The association between bullying victimization and CSA was much higher among left-behind girls (left-behind girls: aOR = 7.36, 95% CI [2.16-24.99]; non-left-behind girls: aOR = 2.38, 95% CI [1.08-5.27]). Also, LBC of a young age (11-15), children with siblings, living in rural areas and non-traditional family structure who were bullied were more likely to suffer CSA than their non-LBC peers. Bullying victimization is associated with a significant increase in CSA among both LBC and non-LBC. Anti-bullying programs should target vulnerable populations including female LBC and LBC with siblings to reduce the risk of CSA.


The effects of low-intensity narrow-band blue-light treatment compared to bright white-light treatment in sub-syndromal seasonal affective disorder.
The discovery of a novel photoreceptor in the retinal ganglion cells with a highest sensitivity of 470-490 nm blue light has led to research on the effects of short-wavelength light in humans. Several studies have explored the efficacy of monochromatic blue or blue-enriched light in the treatment of SAD. In this study, a comparison has been made between the effects of broad-wavelength light without ultraviolet (UV) wavelengths compared to narrow-band blue light in the treatment of sub-syndromal seasonal affective disorder (Sub-SAD). In a 15-day design, 48 participants suffering from Sub-SAD completed 20-minute sessions of light treatment on five consecutive days. 22 participants were given bright white-light treatment (BLT, broad-wavelength light without UV 10 000 lux, irradiance 31.7 Watt/m(2)) and 26 participants received narrow-band blue light (BLUE, 100 lux, irradiance 1.0 Watt/m(2)). All participants completed daily and weekly questionnaires concerning mood, activation, sleep quality, sleepiness and energy. Also, mood and energy levels were assessed by means of the SIGH-SAD, the primary outcome measure. On day 15, SIGH-SAD ratings were significantly lower than on day 1 (BLT 54.8 %, effect size 1.7 and BLUE 50.7 %, effect size 1.9). No statistically significant differences were found on the main outcome measures. Light treatment is an effective treatment for Sub-SAD. The use of narrow-band blue-light treatment is equally effective as bright white-light treatment. This study was registered in the Dutch Trial Register (Nederlands Trial Register TC = 4342 ) (20-12-2013).


Impact of stents and abciximab on survival from cardiogenic shock treated with percutaneous coronary intervention.
This retrospective observational review compares patient characteristics and in-hospital and long-term outcomes of cohorts of patients undergoing percutaneous coronary intervention (PCI) for cardiogenic shock complicating acute myocardial infarction (MI) prior to the use of stents (as well as glycoprotein IIb/IIIa inhibitor and dual-antiplatelet therapy) with PCI in the stent era. Cardiogenic shock remains the leading cause of hospital mortality from acute MI. This is a report of consecutive patients with cardiogenic shock complicating acute MI, without mechanical complication, referred for emergency catheterization to a single operator at two consecutive Veterans Affairs medical centers over a 15-year period (1988 to August 2003). PCI was attempted in all 93 cases: 44 consecutive patients in the present era and 49 consecutive patients in the stent era. Patients with comparable extent of coronary disease, more ST elevation myocardial infarction, multiple areas of infarction, and greater comorbidity underwent PCI in the stent era. Nevertheless, PCI in the stent era was associated with higher rates of acute success and improved in-hospital survival. Kaplan-Meier curves and log-rank testing showed highly significant improvement in overall survival (P < 0.0001). Logistic regression of in-hospital survival demonstrated that stent use (colinear with glycoprotein IIb/IIIa use and dual-antiplatelet therapy) was significantly associated with survival in a model adjusting for extent of coronary disease and comorbidities (P = 0.007). Stents and abciximab have been associated with improved acute angiographic and procedural success of PCI for cardiogenic shock, leading to improved survival.


A mannoprotein constituent of Candida albicans that elicits different levels of delayed-type hypersensitivity, cytokine production, and anticandidal protection in mice.
To identify major immunogenic constituents of Candida albicans, the effect of a mannoprotein fraction (MP-F2) on the elicitation of a delayed-type hypersensitivity (DTH) reaction, cytokine production, and protection from a virulent Candida challenge in a mouse candidiasis model was studied. In mice immunized with whole cells of a low-virulence strain of C. albicans and thus protected against a challenge with a highly virulent strain of this fungus, MP-F2 was able to elicit a strong DTH response that was accompanied by splenocyte proliferation in vitro in the presence of Candida antigen. The supernatants of MP-F2-stimulated splenocyte cultures contained gamma interferon (IFN-gamma, a typical CD4+ T helper-1 (Th1) cytokine, but no interleukin-4, (IL-4), a typical CD4+ Th2 cytokine. IFN-gamma was produced by CD4+ cells, and its level could be greatly increased by the addition of anti-IL-4 or, mostly, anti-IL-10 antibodies to the CD4+ cell cultures. Upon a suitable schedule of immunization, MP-F2 was also able to induce a vigorous DTH response in Candida-uninfected mice, a response that could be efficiently transferred into naive recipients by CD4+ cells from the spleens of MP-F2-immunized mice. The immunization described above also conferred to mice a low degree of protection against a virulent Candida challenge, both in terms of median survival time and in the number of Candida cells in the kidney. However, while DTH induction by MP-F2 was as strong as that induced by whole cells, MP-F2-induced protection was significantly weaker than that conferred by Candida whole-cell immunization. Mice immunized with either MP-F2 or Candida whole cells had an inverted ratio between the number of CD4+ splenocytes producing IFN-gamma and that of cells producing IL-4, compared with nonimmunized animals. However, the number of IL-4-producing CD4+ cells was significantly higher in MP-F2-vaccinated, weakly protected mice than in Candida whole-cell-vaccinated, highly protected animals. Overall, our data suggest that the MP-F2 fraction contains one or more major immunogens of C. albicans which are capable of interfering with the balance of CD4+ Th1 and Th2 responses that is so critical in the outcome of host-Candida relationship and are thus potentially relevant in the mechanisms of Candida-specific DTH regulation and protection.


Design for a massive all-optical bidirectional associative memory: the big BAM.
An optical bidirectional associative memory offering a potential of operating up to 10(6) neurons with 10(12) interconnections is described. Except possibly for input and output all operations are optical and parallel.


Immunohistochemical evidence that follicle-stimulating hormone and luteinizing hormone reside in separate cells in the chicken pituitary.
As is the case in other tetrapod species, the chicken gonadotropins LH and FSH consist of a common alpha subunit and a hormone-specific beta subunit. Gonadotrophs containing LH were shown earlier to be distributed throughout both the caudal and cephalic lobes of the chicken anterior pituitary, but the cellular distribution of FSH in avian species is still uncertain. The purpose of this study was to determine the cellular distribution of FSH-containing chicken gonadotrophs by use of FSH-specific monoclonal antibodies (mAbs). Three new mAbs toward chicken FSH were proven hormone specific by immunodetection of purified hormones on dot blots and by dual-label immunohistochemistry (IHC) on sagittal sections of chicken pituitaries. A rabbit antibody was used to detect chicken LH. Results showed that LH-containing gonadotrophs were densely distributed throughout the anterior pituitary, whereas gonadotrophs containing FSH were much less numerous; in addition, while also present in both lobes, FSH-positive cells were largely absent from the outer margin of the gland. Dual-label IHC revealed that LH and FSH reside almost exclusively in separate gonadotrophs. The identity of FSH-containing cells was further confirmed through use of an antibody to the chicken alpha subunit, which showed that FSH immunoreactivity was always colocalized with the alpha subunit. Our results suggest the possibility that production and secretion of LH and FSH may be regulated differently in chickens than in most other species studied to date.


The use of MM3 monoclonal antibodies for the early immunodiagnosis of ovine fascioliasis.
This study reports a new capture ELISA (MM3-SERO) for the serodiagnosis of sheep fascioliasis, based on the use of the monoclonal antibody (mAb) MM3. Like our previously reported indirect ELISA method, based on the use of a FPLC-purified fraction (fraction IV) of the Fasciola hepatica excretion/secretion antigens (ESAs), this new test was able to detect animals infected with very small numbers of metacercariae (5-40) and showed no cross-reaction with sera from sheep infected with other parasites, i.e., Moniezia spp., Cysticercus tenuicollis, and Dicrocoelium dendriticum. In contrast with these 2 methods, some sera (mainly those obtained from animals infected with D. dendriticum) showed high reactivities in indirect ELISA with whole F. hepatica ESAs used as control. Interestingly, the MM3-SERO ELISA has a better signal-to-noise ratio than the fraction-IV ELISA, thus allowing detection of seroconversion in infected sheep on average 1 wk earlier (3.2 +/- 0.4 wk postinfection [PI] for MM3-SERO ELISA vs. 4.2 +/- 0.9 wk PI for fraction IV ELISA). Moreover, the antibody response detected with MM3-SERO ELISA was more uniform, with seroconversion always occurring at 4 wk PI in sheep with 1-2 flukes and at 3 wk PI in sheep with more than 2 flukes. The MM3-SERO ELISA was also used to evaluate the kinetics of antibody response against MM3-recognized antigens in sera from sheep experimentally infected with F. hepatica and then treated with triclabendazole. Our results showed that antibody levels dropped by about 25% during the 4-wk observation period following the flukicide treatment, whereas they remained invariably high in all sheep left untreated. We conclude that the MM3-SERO ELISA is a 100% sensitive and 100% specific test for the early serodiagnosis of sheep fascioliasis. Preliminary studies in our laboratory seem to indicate that this method may also be useful for the determination of anti-F. hepatica antibodies in serum and milk of other ruminants. A commercial version of MM3-SERO is currently available from BIO X Diagnostics (La Jemelle, Belgium).


Beam characteristics of upper and lower physical wedge systems of Varian accelerators.
The beam characteristics of a dual physical wedge system, upper and lower, for Varian accelerators are studied over the energy range 6-18 MV. Wedge factors for both systems are measured in a water phantom as a function of field size, depth and source-to-wedge (SWD) distance. Our results indicate that apart from their physical differences, dosimetrically, the two wedge systems have <2% difference in central axis percentage depth dose beyond the build-up region. The lower wedge central axis percentage depth dose is consistently lower than that of the corresponding upper wedge, with the effect more pronounced for large field sizes. The wedge profiles are identical within 2% for all field sizes, depths and energies. The wedge factors for both wedge systems are also within 2% for all field sizes and depths for both 6 and 15 MV photons and slightly higher for the 18 MV beam and 45 degrees-60 degrees wedge angle. The wedge factor variation with SWD reveals an interesting fact that thinner wedges (15 degrees and 30 degrees) result in a higher surface dose in the central axis region than thicker wedges. As the SWD increases beyond 80 cm, the reverse is true, i.e. thicker wedges produce higher surface dose than thinner wedges. It is also verified that the wedge factor at any depth and for any field size can be calculated from the wedged and open field central axis percentage depth dose, and the wedge factor at dmax, resulting in nearly 44% reduction in water phantom scanning and 80% reduction in point measurements during commissioning.


Down-regulation of JARID1B expression inhibits cell proliferation, induces apoptosis and blocks cell cycle in human acute lymphoblastic leukemia cells.
Acute lymphocytic leukemia (ALL) is a multi-factorial blood disease with unknown pathogenesis. Histone H3K4 methylation was significantly reduced in ALL patients, whereas jumonji AT-rich interactive domain 1B (JARID1B) was the specific demethylase of H3K4me. This study explores the expression level of JARID1B in ALL patients and down-regulated JARID1B expression in ALL cells to explore the function of JARID1B in ALL. JARID1B mRNA expression level in ALL patients was detected by Real-time PCR. The peripheral blood mononuclear cells from healthy volunteers were selected as control. JARID1B shRNA was transfected with MOLT-4 cells and BALL-1 cells. JARID1B protein expression and H3K4me2 and H3K4me3 levels were detected by Western blot assay. Cell proliferation was assessed by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay. Cell apoptosis and cell cycle were determined by flow cytometry. Bcl-2, Bax, Procaspase 3, and cyclin P21 expressions were evaluated by Western blot assay. JARID1B mRNA expression in primary bone marrow cells from ALL patients was significantly higher than that of healthy volunteers (p<0.05). The levels of histone H3K4me3 and H3K4me2 were up-regulated after JARID1B shRNA transfection. JARID1B shRNA significantly inhibited the proliferation of MOLT-4 and BALL-1 cells, induced apoptosis, and blocked cell cycle in G0/G1 phase compared with the control group (p<0.05). JARID1B is highly expressed in ALL. Down-regulating its expression inhibited leukemia cell proliferation, promoted apoptosis, and blocked cell cycle in G0/G1 phase through histone H3K4 methylation. JARID1B is an oncogene in ALL.


Spatial refuge from intraguild predation: implications for prey suppression and trophic cascades.
The ability of predators to elicit a trophic cascade with positive impacts on primary productivity may depend on the complexity of the habitat where the players interact. In structurally-simple habitats, trophic interactions among predators, such as intraguild predation, can diminish the cascading effects of a predator community on herbivore suppression and plant biomass. However, complex habitats may provide a spatial refuge for predators from intraguild predation, enhance the collective ability of multiple predator species to limit herbivore populations, and thus increase the overall strength of a trophic cascade on plant productivity. Using the community of terrestrial arthropods inhabiting Atlantic coastal salt marshes, this study examined the impact of predation by an assemblage of predators containing Pardosa wolf spiders, Grammonota web-building spiders, and Tytthus mirid bugs on herbivore populations (Prokelisia planthoppers) and on the biomass of Spartina cordgrass in simple (thatch-free) and complex (thatch-rich) vegetation. We found that complex-structured habitats enhanced planthopper suppression by the predator assemblage because habitats with thatch provided a refuge for predators from intraguild predation including cannibalism. The ultimate result of reduced antagonistic interactions among predator species and increased prey suppression was enhanced conductance of predator effects through the food web to positively impact primary producers. Behavioral observations in the laboratory confirmed that intraguild predation occurred in the simple, thatch-free habitat, and that the encounter and capture rates of intraguild prey by intraguild predators was diminished in the presence of thatch. On the other hand, there was no effect of thatch on the encounter and capture rates of herbivores by predators. The differential impact of thatch on the susceptibility of intraguild and herbivorous prey resulted in enhanced top-down effects in the thatch-rich habitat. Therefore, changes in habitat complexity can enhance trophic cascades by predator communities and positively impact productivity by moderating negative interactions among predators.


A randomized, double-blind, placebo-controlled trial of augmentation topiramate for chronic combat-related posttraumatic stress disorder.
Topiramate, a novel anticonvulsant, has been reported to rapidly reduce symptoms of posttraumatic stress disorder (PTSD) in an open-label trial. The present study was designed as a test of topiramate's efficacy as adjunctive therapy in a 7-week, randomized, double-blind, placebo-controlled trial. Forty male veterans with PTSD in a residential treatment program were randomized to flexible-dose topiramate or placebo augmentation. The primary outcome measures were PTSD symptom severity and global symptom improvement. Baseline Clinician-Administered PTSD Scale scores were 62.1 +/- 13.9 for placebo and 61.0 +/- 22.2 for topiramate. There was a high dropout rate from the study (55% topiramate; 25% placebo), with 40% of topiramate and 10% of placebo dropping because of adverse events (AEs). No significant treatment effects of topiramate versus placebo were observed for the primary treatment outcomes. Subjects reporting central nervous system-related AEs and with higher baseline severity of depression were more likely to discontinue because of AEs. Primary outcome measures failed to demonstrate a significant effect for topiramate over placebo; however, high dropout rate in the treatment group prohibits definitive conclusions about the efficacy of topiramate in this population.


[Factors Influencing Adolescent Lifetime Smoking and Current Smoking in South Korea: Using data from the 10th (2014) Korea Youth Risk Behavior Web-Based Survey].
The purpose of this study was to investigate factors influencing lifetime smoking and current smoking among adolescents in South Korea. Hierarchical logistic regression was conducted based on complex sample analysis using statistics from the 10th (2014) Korea Youth Risk Behavior Web-Based Survey. The study sample comprised 72,060 adolescents aged 12 to 18. The significant factors influencing adolescent lifetime smoking were female gender, older age, higher stress, higher weekly allowance, lower economic status, living apart from parents, parental smoking, sibling smoking, peer smoking, observation of school personnel smoking, and coed school compared to boys' school. The significant factors influencing adolescent current smoking were female gender, older age, higher stress, higher weekly allowance, both higher and lower economic status compared to middle economic status, living apart from parents, parental smoking, sibling smoking, peer smoking, observation of school personnel smoking, and coed school compared to boys' school. Factors identified in this study need to be considered in programs directed at prevention of adolescent smoking and smoking cessation programs, as well as policies.


Epidemiology of delirium: an overview of research issues and findings.
This paper provides a review of research issues and findings on the epidemiology of delirium. Despite the fact that research on this important geriatric syndrome has been conducted for many decades, several methodological issues make it difficult to compare findings across studies. In this paper we first discuss broadly methodological issues related to diagnosis, case-finding, and populations studied. We next review data on the occurrence and consequences of the syndrome. A discussion of the design and preliminary results of the Commonwealth-Harvard Study of Delirium in Elderly Hospitalized Patients documents both how we responded to the methodological issues outlined and how these choices influenced our findings. We conclude with a discussion of the needs for further research on the epidemiology of delirium.


Mach-Zehnder interferometer for piston and tip-tilt sensing in segmented telescopes: theory and analytical treatment.
A study is presented of a Mach-Zehnder interferometer for the measurement of phasing errors of the type found in segmented telescopes. We show that with a pinhole much larger than the Airy disk and an optical path difference between the arms equal to a quarter of the wavelength, the interferometric signal is related to the second derivative of the wave front. In this condition the signal is produced mostly by the segmentation errors and is marginally sensitive to other aberrations including atmospheric turbulence. The signal has distinguishable symmetric and antisymmetric properties that are related to segment aberrations. We suggest using the antisymmetric component of the signal to retrieve piston, tip, and tilt. The symmetric component of the signal serves as an estimate of the measurement error. In this way we proceed with a study of the errors associated with the misalignment of the interferometer, the segment edge imperfections, and the nonaveraged atmospheric perturbations. The entire study is performed on a theoretical basis, and numerical simulations are used to cross check the analytical results.


Evaluation of the Cytotoxicity and Genotoxicity of Flavonolignans in Different Cellular Models.
Flavonolignans are the main components of silymarin, which represents 1.5-3% of the dry fruit weight of Milk thistle (Silybum marianum L. Gaernt.). In ancient Greece and Romania, physicians and herbalists used the Silybum marianum to treat a range of liver diseases. Besides their hepatoprotective action, silymarin flavonolignans have many other healthy properties, such as anti-platelet and anti-inflammatory actions. The aim of this study was to evaluate the toxic effect of flavonolignans on blood platelets, peripheral blood mononuclear cells (PBMCs) and human lung cancer cell line-A549-using different molecular techniques. We established that three major flavonolignans: silybin, silychristin and silydianin, in concentrations of up to 100 µM, have neither a cytotoxic nor genotoxic effect on blood platelets, PMBCs and A549. We also saw that silybin and silychristin have a protective effect on cellular mitochondria, observed as a reduction of spontaneous mitochondrial DNA (mtDNA) damage in A549, measured as mtDNA copies, and mtDNA lesions in ND1 and ND5 genes. Additionally, we observed that flavonolignans increase the blood platelets' mitochondrial membrane potential and reduce the generation of reactive oxygen species in blood platelets. Our current findings show for the first time that the three major flavonolignans, silybin, silychristin and silydianin, do not have any cytotoxicity and genotoxicity in various cellular models, and that they actually protect cellular mitochondria. This proves that the antiplatelet and anti-inflammatory effect of these compounds is part of our molecular health mechanisms.


Mineral matter distribution on coal surface and its effect on coal wettability.
Coal is an organic sedimentary rock composed of organic macerals and mineral matter. As it is demonstrated in this paper the discrete mineralogical nature of coal largely influences the wetting of the coal surface by water. Both advancing and receding contact angles were measured using the captive-bubble technique with an automatic bubble shape analysis software. The distribution and amount of mineral inclusions on the coal surface were determined by scanning electron microscopy and examined using the image analysis system. To determine the amount and size distribution of mineral grains, the coal surface layer, on which the contact angles were measured, was separated from the larger piece used in the measurements by microslicing. The separated surface layer was subjected to a low-temperature ashing followed by particle size analysis. As expected, a significant scatter of contact angle values was obtained for the same coal samples. Increasing the amount of mineral matter on the coal surface reduced the value of both advancing and receding contact angles. Also, the scatter of contact angle values increased with the increasing mineral matter content from about 1 to 50 wt%. The results reveal that an important factor in analysis of contact angle variation on coal surfaces is the size of the hydrophilic mineral inclusions. Both the advancing and the receding contact angles decrease with increasing size of the mineral grains. Additionally, the scatter of contact angle values increase with increasing size of the mineral matter grains. Finally, the results of fractal dimension analysis of mineral matter grains distributed over the coal surface indicate that there is no significant effect from the shape of hydrophilic mineral inclusions on both advancing and receding contact angles.


Use of lidocaine patch for percutaneous endoscopic lumbar discectomy.
Lidocaine patch (L5P) has demonstrated short-term efficacy in treating both acute surgical pain and chronic neuropathic pain with tolerable side effects. Percutaneous endoscopic lumbar discectomy (PELD) is the mainstay of minimally invasive spine surgery (MISS). Sufficient analgesia during PELD surgery makes the patient consider it real MISS. This study was performed to evaluate the efficacy and adverse effects of lidocaine patch in patients who underwent PELD under local anesthesia. L5P (L group) or placebo (P group) was randomly applied on the skin of the back covering the anticipated path of the working channel before 1 hour of surgery in 100 patients who underwent a single level PELD at L4-L5. Efficacy of the lidocaine patch was assessed by patient's numeric rating scale (NRS) of pain at each stage during the surgery and by a 5-scale grading of the satisfaction with the anesthesia of the operator and patients after surgery. Mean NRS scores at the stages of needle insertion, skin incision, serial dilation and insertion of working channel, and subcutaneous suture were significantly lower in the L group than the P group. Postoperative operator's and patients' satisfaction scores were also significantly higher in L group than in the P group. There were subtle adverse effects in both groups. L5P provided better pain relief during PELD, especially at the stage of needle insertion, skin incision, serial dilation and insertion of working channel, and subcutaneous suture. It also provided higher patient and operator postoperative satisfaction, with only subtle adverse effects.


What is the role of balloon dilatation for severe aortic stenosis during pregnancy?
Severe aortic stenosis in pregnancy creates several challenges for the physician. In recent years, balloon valvuloplasty has become more widely used, though the indications for its use in this setting are unclear. A review of the available evidence is presented, and a suggested management strategy illustrated. Available literature on the subject was reviewed via Medline search and reference lists from the identified articles. Particular attention was paid to prediction of risk, management options and outcome. The data suggest the importance of early symptoms in determining management, as there is a high risk of complications if left untreated. This group should be considered for valvuloplasty, whereas asymptomatic patients are at low risk, and can be managed expectantly. This is illustrated with two contrasting cases from the authors' practice: the symptomatic patient underwent aortic balloon valvuloplasty as a palliative procedure, using transesophageal and minimal fluoroscopic guidance, with good medium-term results. Both patients required aortic valve replacement in the medium to long-term. The use of aortic balloon valvuloplasty in pregnancy is useful as a palliative procedure, allowing deferral of valve replacement until after birth. Echocardiographic features alone are not enough to decide on management, and symptoms play a vital role in determining risk. The use of transesophageal echocardiography during the procedure significantly reduces fluoroscopy time.


Adrenal ganglioneuroma in a patient presenting with severe hypertension and diarrhea.
Ganglioneuromas (GNs) are neural crest cell-derived tumors and rarely occur in the adrenal gland. There are presently no markers that can reliably distinguish benign and malignant neuroendocrine tumors. Here we describe a 63-year-old woman who developed sudden chest pain and hypertension combined with increased stool frequency. An incidental adrenal mass 5 cm in size with a bright signal on T2-weighted magnetic resonance imaging was discovered. Biochemical evaluation and (131)I-metaiodobenzylguanidine (MIBG) scintigraphy were negative. Histopathological examination revealed a mature adrenal GN. Neuroblastoma, the immature form of a GN, is known for deletions on chromosomal locus 1p36, and adrenal tumors frequently show allele loss on 17p. To further elucidate the histo- and pathogenesis of adrenal GN, we performed loss of heterozygosity studies on chromosomal loci 1p34-36 and 17p13 (the p53 gene locus) after careful microdissection of tumor and normal tissue. We did not detect allelic losses at these loci with the informative polymorphic markers used, suggesting that these loci are not involved in tumorigenesis. In addition, immunohistochemical investigation of the GN was positive for vasoactive intestinal peptide, a hormone commonly expressed in ganglion cells. We suggest that in our patient with an adrenal GN, the combination of biochemical, scintigraphic, molecular, immunohistochemical, and histopathological findings are all consistent with the benign morphology of this tumor.


Faunal turnover of marine tetrapods during the Jurassic-Cretaceous transition.
Marine and terrestrial animals show a mosaic of lineage extinctions and diversifications during the Jurassic-Cretaceous transition. However, despite its potential importance in shaping animal evolution, few palaeontological studies have focussed on this interval and the possible climate and biotic drivers of its faunal turnover. In consequence evolutionary patterns in most groups are poorly understood. We use a new, large morphological dataset to examine patterns of lineage diversity and disparity (variety of form) in the marine tetrapod clade Plesiosauria, and compare these patterns with those of other organisms. Although seven plesiosaurian lineages have been hypothesised as crossing the Jurassic-Cretaceous boundary, our most parsimonious topology suggests the number was only three. The robust recovery of a novel group including most Cretaceous plesiosauroids (Xenopsaria, new clade) is instrumental in this result. Substantial plesiosaurian turnover occurred during the Jurassic-Cretaceous boundary interval, including the loss of substantial pliosaurid, and cryptoclidid diversity and disparity, followed by the radiation of Xenopsaria during the Early Cretaceous. Possible physical drivers of this turnover include climatic fluctuations that influenced oceanic productivity and diversity: Late Jurassic climates were characterised by widespread global monsoonal conditions and increased nutrient flux into the opening Atlantic-Tethys, resulting in eutrophication and a highly productive, but taxonomically depauperate, plankton. Latest Jurassic and Early Cretaceous climates were more arid, resulting in oligotrophic ocean conditions and high taxonomic diversity of radiolarians, calcareous nannoplankton and possibly ammonoids. However, the observation of discordant extinction patterns in other marine tetrapod groups such as ichthyosaurs and marine crocodylomorphs suggests that clade-specific factors may have been more important than overarching extrinsic drivers of faunal turnover during the Jurassic-Cretaceous boundary interval.


Larch arabinogalactan for dry eye protection and treatment of corneal lesions: investigations in rabbits.
The aim of the present study was to investigate the corneal protective and healing properties of arabinogalactan (AG), a natural polysaccharide present in conifers of the genus Larix (Larch). AG was tested in comparison with other two polysaccharides possessing well-established properties in the treatment of dry eye: tamarind seed polysaccharide and hyaluronic acid. The AG formulation was subjected to the following investigations: rheologic measurements; evaluation of mucoadhesive properties by rheologic interaction with mucin; ferning test; and in vivo evaluation on rabbits, including treatment of an experimental dry eye; evaluation of the preocular retention; and evaluation of healing rate of experimental corneal wound. AG dispersions showed a newtonian nonviscous behavior, eta = 1.6 mPa . s for 10% w/w solution; it possessed good mucoadhesive properties useful for retention on the eye surface. In fact, a prolonged time of residence in rabbit eyes was ascertained using fluorescein-labeled AG. Five percent (5.0%) w/w AG exerted a good protective effect against the appearance of corneal dry spots. It also reduced significantly the healing time of an experimental corneal lesion since 27 h after the first treatment. These findings suggest that AG may be a potential therapeutic product for dry eye protection and for the treatment of corneal wounds.


Effective treatment of early Barrett's neoplasia with stepwise circumferential and focal ablation using the HALO system.
The aim of the current study was to evaluate the efficacy and safety of stepwise circumferential and focal ablation using the HALO system for Barrett's esophagus containing flat, high-grade dysplasia (HGD) or residual dysplasia after endoscopic resection for HGD or intramucosal cancer (IMC). Visible abnormalities were removed with endoscopic resection prior to ablation. Persistence of dysplasia and absence of IMC were confirmed with biopsy after endoscopic resection. A balloon-based electrode was used for primary circumferential ablation and an endoscope-mounted electrode was used for secondary focal ablation. Twelve patients (nine men; median age 70 years) were treated (median Barrett's length 7 cm). Visible abnormalities were removed by endoscopic resection in seven patients. The worst pathological grade of residual Barrett's esophagus after resection and prior to ablation was low-grade dysplasia (LGD) (n = 1) and HGD (n = 11). Patients underwent a median of one circumferential and two focal ablation sessions. Complete remission of dysplasia was achieved in 12/12 patients (100%). Complete endoscopic and histological removal of Barrett's esophagus was achieved in 12/12 patients (100%). There were no ablation-related stenoses, and no subsquamous Barrett's esophagus was observed in 363 biopsies obtained from post-ablation neo-squamous mucosa. Protocolized cleaning of the ablation zone and electrode in between ablations resulted in superior regression of Barrett's esophagus compared with previous studies. During a median follow-up of 14 months no recurrence of dysplasia or Barrett's esophagus was observed. Stepwise circumferential and focal ablation for Barrett's esophagus with flat HGD or for Barrett's with residual dysplasia after endoscopic resection for HGD/IMC is a safe and effective treatment modality. Its success rate and safety profile compare favorably with alternatives such as esophagectomy, widespread endoscopic resection or photodynamic therapy.


Replacement of dopaminergic medication with subthalamic nucleus stimulation in Parkinson's disease: long-term observation.
Stimulation of the subthalamic nucleus (STN) is an effective treatment for advanced Parkinson's disease (PD), but the medication requirements after implant are poorly known. We performed a long-term prospective evaluation of 20 patients maintained at stable dopaminergic therapy for 5 years after bilateral STN implants, who were evaluated 6 months, 1 year, 3 years, and 5 years after surgery. We measured, during the entire observation period, the effect of deep brain stimulation on motor and functional outcome measures, the levodopa equivalent daily dose and the total electrical energy delivered. At 5 years, the UPDRS motor score had improved by 54.2% and levodopa equivalent dose was reduced by 61.9%, compared with preimplant. Dopaminergic medication remained stable during the observation period, but energy was progressively increased over time. Rest tremor, rigidity, gait, lower and upper limb akinesia, and total axial score were improved in decreasing order. Postural stability and speech improved transiently, whereas on-period freezing of gait, motor fluctuations and dyskinesias recovered durably. Functional measures did not show improvement in autonomy and daily living activities after STN implant. Chronic STN stimulation allows to replace for dopaminergic medications in the long-term at the expense of an increase of the total energy delivered. This is associated with marked improvement of motor features without a matching benefit in functional measures.


Automatic-Scoring Actigraph Compares Favourably to a Manually-Scored Actigraph for Sleep Measurement in Healthy Adults.
Introduction Actigraphy has been used widely in sleep research due to its non-invasive, cost-effective ability to monitor sleep. Traditionally, manually-scored actigraphy has been deemed the most appropriate in the research setting; however, technological advances have seen the emergence of automatic-scoring wearable devices and software. Methods A total of 60-nights of sleep data from 20-healthy adult participants (10 male, 10 female, age: 26 ± 10 years) were collected while wearing two devices concomitantly. The objective was to compare an automatic-scoring device (Fatigue Science Readiband™ [AUTO]) and a manually-scored device (Micro Motionlogger® [MAN]) based on the Cole-Kripke method. Manual-scoring involved trained technicians scoring all 60-nights of sleep data. Sleep indices including total sleep time (TST), total time in bed (TIB), sleep onset latency (SOL), sleep efficiency (SE), wake after sleep onset (WASO), wake episodes per night (WE), sleep onset time (SOT) and wake time (WT) were assessed between the two devices using mean differences, 95% levels of agreement, Pearson-correlation coefficients ( r ), and typical error of measurement (TEM) analysis. Results There were no significant differences between devices for any of the measured sleep variables ( p ≥0.05). All sleep indices resulted in very-strong correlations ( all r ≥0.84) between devices. A mean difference between devices of <1 minutes for TST was associated with a TEM of 15.5 minute (95% CI =12.3 to 17.7 minutes). Conclusion Given there were no significant differences between devices in the current study, automatic-scoring actigraphy devices may provide a more practical and cost-effective alternative to manually-scored actigraphy in healthy populations.


Histone acetyltransferase NAA40 modulates acetyl-CoA levels and lipid synthesis.
Epigenetic regulation relies on the activity of enzymes that use sentinel metabolites as cofactors to modify DNA or histone proteins. Thus, fluctuations in cellular metabolite levels have been reported to affect chromatin modifications. However, whether epigenetic modifiers also affect the levels of these metabolites and thereby impinge on downstream metabolic pathways remains largely unknown. Here, we tested this notion by investigating the function of N-alpha-acetyltransferase 40 (NAA40), the enzyme responsible for N-terminal acetylation of histones H2A and H4, which has been previously implicated with metabolic-associated conditions such as age-dependent hepatic steatosis and calorie-restriction-mediated longevity. Using metabolomic and lipidomic approaches, we found that depletion of NAA40 in murine hepatocytes leads to significant increase in intracellular acetyl-CoA levels, which associates with enhanced lipid synthesis demonstrated by upregulation in de novo lipogenesis genes as well as increased levels of diglycerides and triglycerides. Consistently, the increase in these lipid species coincide with the accumulation of cytoplasmic lipid droplets and impaired insulin signalling indicated by decreased glucose uptake. However, the effect of NAA40 on lipid droplet formation is independent of insulin. In addition, the induction in lipid synthesis is replicated in vivo in the Drosophila melanogaster larval fat body. Finally, supporting our results, we find a strong association of NAA40 expression with insulin sensitivity in obese patients. Overall, our findings demonstrate that NAA40 affects the levels of cellular acetyl-CoA, thereby impacting lipid synthesis and insulin signalling. This study reveals a novel path through which histone-modifying enzymes influence cellular metabolism with potential implications in metabolic disorders.


Effect of high tyrosine content on the determination of tryptophan in protein by the acidic ninhydrin method. Application to chicken ovoinhibitor.
Colorimetric determination of tryptophan in intact proteins by the acidic ninhydrin method of Gaitonde & Dovey (1970) gives high apparent tryptophan contents for proteins having high tyrosine/tryptophan ratios. Correction for this interference by tyrosine can be achieved by plotting the ratio of observed to expected tryptophan content as a function of tyrosine/tryptophan ratio for proteins of known composition. The equation of the line is: [Formula: see text] Application of this correction to chicken ovoinhibitor, which contains 17 tyrosine residues per molecule, gave results that agree with tryptophan content determined by other methods.


Prenatal and postnatal findings in a case with the autosomal recessive type of Robinow syndrome.
Our aim was to present a prenatally diagnosed case with Robinow syndrome in a consanguineous couple and discuss possible differential diagnosis in view of the literature. A 28-year-old pregnant woman gravida 2 para 1 was referred to the obstetric clinic of Kahramanmaras Sutcu Imam University presenting with a fetus having shortened upper and lower limbs at 33 weeks of gestation. Her medical history was unremarkable except for consanguinity. Prenatal ultrasonographic examination revealed a reduced humerus and femur length. Further, shortening of the forearm, frontal bossing, mild hypertelorism, reduced thoracic perimeter and hemivertebrae at the thoracic level were present. Meticulous neonatal examination was performed following an uncomplicated vaginal delivery at 39 weeks of gestation. Distinct facial appearance in addition to the prenatal findings argued in favor of the diagnosis of Robinow syndrome. Additionally, radiological survey revealed and confirmed shortening of the upper extremities and thoracic hemivertebrae. We are documenting the case on the account of its rarity and additional features. The main approach in the differential diagnosis of Robinow syndrome should determine whether hemivertebrae is isolated or part of a syndrome or association.


Determining the clinical significance of errors in pediatric radiograph interpretation between emergency physicians and radiologists.
Emergency physicians (EPs) interpret plain radiographs for management and disposition of patients. Radiologists subsequently conduct their own interpretations, which may differ. The purposes of this study were to review the rate and nature of discrepancies between radiographs interpreted by EPs and those of radiologists in the pediatric emergency department, and to determine their clinical significance. We conducted a retrospective review of discrepant radiology reports from a single-site pediatric emergency department from October 2012 to December 2014. All radiographs were interpreted first by the staff EP, then by a radiologist. The report was identified as a "discrepancy" if these reports differed. Radiographs were categorized by body part and discrepancies classified as false positive, false negative, or not a discrepancy. Clinically significant errors that required a change in management were tracked. There were 25,304 plain radiographs completed during the study period, of which 252 (1.00%) were identified as discrepant. The most common were chest radiographs (41.7%) due to missed pneumonia, followed by upper and lower extremities (26.2% and 17.5%, respectively) due to missed fractures. Of the 252 discrepancies, 207 (82.1%) were false negatives and 45 (17.9%) were false positives. In total, 105 (0.41% of all radiographs) were clinically significant. There is a low rate of discrepancy in the interpretation of pediatric emergency radiographs between emergency department physicians and radiologists. The majority of errors occur with radiographs of the chest and upper extremities. The low rate of clinically significant discrepancy allows safe management based on EP interpretation.


The Impact of Staging by Positron-Emission Tomography on Overall Survival and Progression-Free Survival in Patients With Locally Advanced NSCLC.
We investigated the potential impact of stage migration because of positron-emission tomography (PET) scan staging on survival in the locally advanced (stage IIIA/B) NSCLC setting. In PROCLAIM, 598 patients with stage IIIA/B nonsquamous NSCLC (intent-to-treat population) were randomized to either pemetrexed plus cisplatin and concurrent thoracic radiotherapy for 3 cycles followed by 4 cycles of pemetrexed consolidation or etoposide plus cisplatin and concurrent thoracic radiotherapy for 2 cycles followed by a consolidation platinum-based doublet regimen for up to 2 cycles. Baseline PET scan (PET Yes versus No) was one of the stratification factors. Subgroup analyses (PET Yes versus No) of overall survival (OS) and progression-free survival (PFS) were conducted on the intent-to-treat population regardless of treatment, as the study did not show superior efficacy for either arm. Majority (491 of 598; 82.1%) of patients had a baseline PET scan staging performed. A longer median OS (PET Yes versus No: 27.2 versus 20.8; hazard ratio = 0.81, p = 0.130) and an improved median PFS (PET Yes versus No: 11.3 versus 9.2; hazard ratio = 0.73, p = 0.012) were observed for patients with PET scans compared to those with conventional staging in both treatment arms. Both a significantly improved PFS and a numerically longer OS in the PET Yes subgroup, compared to patients with conventional staging, are consistent with improved survival due to stage migration. The magnitude of differences in OS and PFS based on PET scan is a reminder of the potential for factors other than the therapeutic intervention to affect outcomes.


Why Open-Ended Survey Questions Are Unlikely to Support Rigorous Qualitative Insights.
Health professions education researchers are increasingly relying on a combination of quantitative and qualitative research methods to explore complex questions in the field. This important and necessary development, however, creates new methodological challenges that can affect both the rigor of the research process and the quality of the findings. One example is "qualitatively" analyzing free-text responses to survey or assessment instrument questions. In this Invited Commentary, the authors explain why analysis of such responses rarely meets the bar for rigorous qualitative research. While the authors do not discount the potential for free-text responses to enhance quantitative findings or to inspire new research questions, they caution that these responses rarely produce data rich enough to generate robust, stand-alone insights. The authors consider exemplars from health professions education research and propose strategies for treating free-text responses appropriately.


Quality of Life of Cohabitants of People Living with Acne.
The aim of this study was to analyse the levels of anxiety, depression, and quality of life of individuals living with acne patients (cohabitants). The study included patients, cohabitants, and controls; a total of 204 participants. Patients' health-related quality of life was measured with the Dermatology Life Quality Index (DLQI), while cohabitants' quality of life was measured with the Family Dermatology Life Quality Index (FDLQI). The psychological state of all participants was measured with the Hospital Anxiety and Depression Scale (HADS). Presence of acne impaired the quality of life of 89.4% of the cohabitants. The FDLQI scores of cohabitants were significantly associated with the DLQI scores of the patients (rp = 0.294; p = 0.044). Anxiety and depression levels in cohabitants were significantly higher than in controls (p < 0.01). In conclusion, acne may have a negative impact on quality of life and psychological well-being of patients and their cohabitants.


Modelling interrupted time series to evaluate prevention and control of infection in healthcare.
The most common methods for evaluating interventions to reduce the rate of new Staphylococcus aureus (MRSA) infections in hospitals use segmented regression or interrupted time-series analysis. We describe approaches to evaluating interventions introduced in different healthcare units at different times. We compare fitting a segmented Poisson regression in each hospital unit with pooling the individual estimates by inverse variance. An extension of this approach to accommodate potential heterogeneity allows estimates to be calculated from a single statistical model: a 'stacked' model. It can be used to ascertain whether transmission rates before the intervention have the same slope in all units, whether the immediate impact of the intervention is the same in all units, and whether transmission rates have the same slope after the intervention. The methods are illustrated by analyses of data from a study at a Veterans Affairs hospital. Both approaches yielded consistent results. Where feasible, a model adjusting for the unit effect should be fitted, or if there is heterogeneity, an analysis incorporating a random effect for units may be appropriate.


[Supervised physical activity interventions in the management of cancer-related fatigue: a systematic review].
Cancer-related fatigue is the most common and distressing symptom among cancer survivors; physical activity has been proposed as a safe and effective intervention to control it. This study aimed to determine the effectiveness of supervised physical activity interventions for the management of cancer-related fatigue (CRF). Systematic review of randomized controlled trials. Adults (>20 years old) diagnosed with any type of cancer regardless of treatment or diagnosis stage. Physical activity interventions (aerobic and resistance training) supervised by health professionals. CRF was the primary outcome measure, whilst secondary outcomes included depression, the comparison between supervised and non-supervised interventions, physical and functional wellbeing. Risk of bias and methodological quality were evaluated using the PEDro scale. Fourteen studies (n=14) were included (n=1638) with low risk of bias (PEDro mean score=6,5 ± 1). Supervised physical activity significantly improved CRF; similar results were found for resistance training. Further, supervised physical activity was more effective than conventional care for improving CRF among breast cancer. Supervised physical activity interventions provide an overall reduction on CRF. These findings suggest that guidelines of aerobic and resistance training should be included in oncologic rehabilitation programs.


Associations between subjective social status and DSM-IV mental disorders: results from the World Mental Health surveys.
The inverse social gradient in mental disorders is a well-established research finding with important implications for causal models and policy. This research has used traditional objective social status (OSS) measures, such as educational level, income, and occupation. Recently, subjective social status (SSS) measurement has been advocated to capture the perception of relative social status, but to our knowledge, there have been no studies of associations between SSS and mental disorders. To estimate associations of SSS with DSM-IV mental disorders in multiple countries and to investigate whether the associations persist after comprehensive adjustment of OSS. Face-to-face cross-sectional household surveys of community-dwelling adults in 18 countries in Asia, South Pacific, the Americas, Europe, and the Middle East (N=56,085). Subjective social status was assessed with a self-anchoring scale reflecting respondent evaluations of their place in the social hierarchies of their countries in terms of income, educational level, and occupation. Scores on the 1 to 10 SSS scale were categorized into 4 categories: low (scores 1-3), low-mid (scores 4-5), high-mid (scores 6-7), and high (scores 8-10). Objective social status was assessed with a wide range of fine-grained objective indicators of income, educational level, and occupation. The Composite International Diagnostic Interview assessed the 12-month prevalence of 16 DSM-IV mood, anxiety, and impulse control disorders. The weighted mean survey response rate was 75.2% (range, 55.1%-97.2%). Graded inverse associations were found between SSS and all 16 mental disorders. Gross odds ratios (lowest vs highest SSS categories) in the range of 1.8 to 9.0 were attenuated but remained significant for all 16 disorders (odds ratio, 1.4-4.9) after adjusting for OSS indicators. This pattern of inverse association between SSS and mental disorders was significant in 14 of 18 individual countries, and in low-, middle-, and high-income country groups but was significantly stronger in high- vs lower-income countries. Significant inverse associations between SSS and numerous DSM-IV mental disorders exist across a wide range of countries even after comprehensive adjustment for OSS. Although it is unclear whether these associations are the result of social selection, social causation, or both, these results document clearly that research relying exclusively on standard OSS measures underestimates the steepness of the social gradient in mental disorders.


First Report of Goss's Bacterial Leaf Blight and Wilt of Corn Caused by Clavibacter michiganensis subsp. nebraskensis in North Dakota.
In August of 2011, the North Dakota State University Plant Diagnostic Lab received a hybrid corn (Zea mays) leaf sample from Burleigh County in south-central North Dakota (ND). The leaf had long, irregular, water-soaked lesions consistent with Goss's leaf blight of corn. Using a light microscope at 10× magnification, bacterial streaming was observed from the excised edge of leaf tissue. A bacterial suspension was created, streaked onto a semi-selective CNS medium (1), and incubated at 22°C. Dark yellow-orange colonies appeared on the medium after 5 days. Single colonies were subcultured onto additional CNS media. To verify the identity of the bacterial isolate, PCR amplification of the 16S ribosomal DNA from this isolate along with a known Clavibacter michiganensis spp. nebraskensis (Cmn) isolate collected in Indiana (4) was performed using the eubacterial universal primers 27f and 1525r (3). The 1,431-bp 16S rDNA region was obtained for each isolate and they were compared with each other and with those deposited in NCBI GenBank. Sequence alignment identified only one nucleotide difference between the ND isolate and the Indiana isolate. BLASTn search against the NCBI database showed the first 100 hits were described as C. michiganensis or unidentified Clavibacter sp. The ND isolate had a two-nucleotide difference with Cmn isolate NCPPB2581 (HE614873), and a three nucleotide difference was found with the C. michiganensis spp. michiganensis isolate NCPPB 382 (AM711867). To satisfy Koch's postulates, eight corn plants (Golden Cross Bantam) were grown in the greenhouse at 22 to 24°C. Four corn plants were inoculated at growth stage V4-V5 using a suspension of approximately 1 × 109 CFU/ml from cultures grown on CNS for 6 days. Wounds were created on the fifth leaf approximately 7 cm from the leaf tip using a tongue-seizing forceps outfitted with a rubber stopper composed of pins (2). Simultaneously, 1 ml of the bacterial suspension was delivered into the wounds through a hole on top of the rubber stopper. Four control plants were inoculated with sterile water in a similar fashion. No symptoms were observed on the control plants. After 6 days, long water-soaked symptoms were observed on leaves inoculated with the bacterial suspension. Using leaves with water-soaked lesions, the pathogen was re-isolated onto CNS media and subjected to PCR amplification, and the resulting amplicons were sequenced as before. The sequence of the amplicon from the re-isolation matched that of the original ND isolate. To our knowledge, this is the first account of Goss's leaf blight and wilt identified in ND. As the corn acreage and no-till production systems in the state have increased, the economic implications of this disease may become more significant. Recognition of symptoms and proper identification of this bacterial disease in the field should help reduce unnecessary foliar fungicide sprays. References: (1) D. C. Gross and A. K. Vidaver. Phytopathology 69:82, 1979. (2) W. A. Hagborg. Can. J. Bot. 48:1135, 1970. (3) X. Li and S. H. DeBoer. Can. J. Microbiol. 41:925, 1995. (4) G. Ruhl et al. Plant Dis. 93:841, 2009.


Proteome analysis of tobacco bright yellow-2 (BY-2) cell culture plastids as a model for undifferentiated heterotrophic plastids.
We analyzed the proteome of undifferentiated plastids from a tobacco BY-2 cell culture by shotgun proteomics following multidimensional protein fractionation. The fractionation strategy initiated with the serial extraction of proteins from membranes which allowed us to distinguish soluble, peripheral, and integral membrane proteins. The majority of the identified proteins have a function in the cellular metabolism and most of them are active in amino acid synthesis pathways. A significant number of the identified proteins was not identified in chloroplast proteome analyses before. This suggests BY-2 plastid specific functions that differ from the major activities of chloroplasts. We have used the BY-2 plastid proteins reported here to assess the metabolic activities of undifferentiated heterotrophic plastids and compared the functional profile with that of differentiated heterotrophic amyloplasts. Comparative shotgun proteome analyses as reported here provide information about prevalent metabolic activities of different plastid types.


Evaluation of T1-Weighted MRI to Detect Intratumoral Hemorrhage Within Papillary Renal Cell Carcinoma as a Feature Differentiating From Angiomyolipoma Without Visible Fat.
The objective of the present study is to determine whether hemorrhage within papillary renal cell carcinoma (RCC) can be detected using T1-weighted MRI and to ascertain whether it can be used to differentiate papillary RCC from angiomyolipoma (AML) without visible fat. A retrospective case-control study compared 11 AMLs without visible fat with 58 papillary RCCs smaller than 5 cm that were evaluated using MRI between 2003 and 2015. Two blinded radiologists subjectively evaluated MR images to identify the presence of intratumoral hemorrhage on the basis of a decrease in signal intensity (SI) on in-phase, compared with opposed-phase, chemical-shift MRI and also on the basis of the SI of the lesion compared with that of the renal cortex on fat-suppressed T1-weighted MRI. A third radiologist established consensus and measured the ratio of the SI of the lesion to that of the renal cortex (hereafter referred to as the "SI ratio") on T2-weighted MRI; the SI loss index, as calculated using the equation [(SItumorIP - SItumorOP) / SItumorOP] × 100, where IP denotes the in-phase image and OP denotes the opposed-phase image; and the SI ratio on fat-suppressed T1-weighted MRI. Analyses were performed using tests of association and ROCs. When AMLs without visible fat were compared with papillary RCCs, no statistically significant difference in the T2-weighted SI ratio was noted (p = 0.08). Papillary RCCs had a lower mean (± SD) SI loss index (-3.7% ± 17.3%; range, -51.3% to 31.3%) than did AMLs without visible fat (37.8% ± 76.1%; range, -15.6% to 184.4%) (p < 0.001). A mean SI loss index of less than -16% resulted in an AUC of 0.71 (95% CI, 0.52-0.91), with a sensitivity and specificity of 22.8% and 100%, respectively, for the diagnosis of papillary RCC. After consensus review, none of the AMLs without visible fat and 16 of the 58 papillary RCCs (27.6%) were found to have a decrease in SI on subjective analysis (p = 0.06, κ = 0.60). Between groups, no differences were noted in the SI ratio on fat-suppressed T1-weighted MRI (p = 0.58) or in the SI observed on subjective analysis of fat-suppressed T1-weighted MRI (p = 0.20, κ = 0.48). The presence of intratumoral hemorrhage within papillary RCC is a specific feature that differentiates papillary RCCs from AMLs without visible fat. Subjective analysis may be more clinically appropriate than chemical-shift MRI because of limitations in the quantitative measurement of T2* signal with the use of chemical-shift MRI.


Autologous olfactory glial cell transplantation is reliable and safe in naturally occurring canine spinal cord injury.
Intraspinal transplantation of olfactory glial cells (OGC) has produced well-defined beneficial effects in experimental rodent models of spinal cord injury (SCI) and therefore has considerable promise as a treatment for severe SCI in human patients. In this study, we used clinical canine cases of severe SCI to determine whether derivation and transplantation of OGC from an autologous source was feasible. From the nerve fiber layer of a single olfactory bulb, we were able to generate 5 x 10(6) cells from each patient within 3 weeks. Of this population, 72% were p75(+) OGC, 20% were meningeal cells, and the remainder mainly astrocytes. Intraspinal transplantation was not associated with any observable long- or short-term complications.


Modular Synthetic Biology Toolkit for Filamentous Fungi.
Filamentous fungi are highly productive cell factories, often used in industry for the production of enzymes and small bioactive compounds. Recent years have seen an increasing number of synthetic-biology-based applications in fungi, emphasizing the need for a synthetic biology toolkit for these organisms. Here we present a collection of 96 genetic parts, characterized in Penicillium or Aspergillus species, that are compatible and interchangeable with the Modular Cloning system. The toolkit contains natural and synthetic promoters (constitutive and inducible), terminators, fluorescent reporters, and selection markers. Furthermore, there are regulatory and DNA-binding domains of transcriptional regulators and components for implementing different CRISPR-based technologies. Genetic parts can be assembled into complex multipartite assemblies and delivered through genomic integration or expressed from an AMA1-sequence-based, fungal-replicating shuttle vector. With this toolkit, synthetic transcription units with established promoters, fusion proteins, or synthetic transcriptional regulation devices can be more rapidly assembled in a standardized and modular manner for novel fungal cell factories.


Visualizing the mobility and distribution of chlorophyll proteins in higher plant thylakoid membranes: effects of photoinhibition and protein phosphorylation.
The diffusion of proteins in chloroplast thylakoid membranes is believed to be important for processes including the photosystem-II repair cycle and the regulation of light harvesting. However, to date there is very little direct information on the mobility of thylakoid proteins. We have used fluorescence recovery after photobleaching in a laser-scanning confocal microscope to visualize in real time the exchange of chlorophyll proteins between grana in intact spinach (Spinacia oleracea L.) and Arabidopsis chloroplasts. Most chlorophyll proteins in the grana appear immobile on the 10-min timescale of our measurements. However, a limited population of chlorophyll proteins (accounting for around 15% of chlorophyll fluorescence) can exchange between grana on this timescale. In intact, wild-type chloroplasts this mobile population increases significantly after photoinhibition, consistent with a role for protein diffusion in the photosystem-II repair cycle. No such increase in mobility is seen in isolated grana membranes, or in the Arabidopsis stn8 and stn7 stn8 mutants, which lack the protein kinases required for phosphorylation of photosystem II core proteins and light-harvesting complexes. Furthermore, mobility under low-light conditions is significantly lower in stn8 and stn7 stn8 plants than in wild-type Arabidopsis. The changes in protein mobility correlate with changes in the packing density and size of thylakoid protein complexes, as observed by freeze-fracture electron microscopy. We conclude that protein phosphorylation switches the membrane system to a more fluid state, thus facilitating the photosystem-II repair cycle.


Effects of macronutrient intake on the lifespan and fecundity of the marula fruit fly, Ceratitis cosyra (Tephritidae): Extreme lifespan in a host specialist.
In insects, lifespan and reproduction are strongly associated with nutrition. The ratio and amount of nutrients individuals consume affect their life expectancy and reproductive investment. The geometric framework (GF) enables us to explore how animals regulate their intake of multiple nutrients simultaneously and determine how these nutrients interact to affect life-history traits of interest. Studies using the GF on host-generalist tephritid flies have highlighted trade-offs between longevity and reproductive effort in females, mediated by the protein-to-carbohydrate (P:C) ratio that individuals consume. Here, we tested how P and C intake affect lifespan (LS) in both sexes, and female lifetime (LEP), and daily (DEP) egg production, in Ceratitis cosyra, a host-specialist tephritid fly. We then determined the P:C ratio that C. cosyra defends when offered a choice of foods. Female LS was optimized at a 0:1 P:C ratio, whereas to maximize their fecundity, females needed to consume a higher P:C ratio (LEP = 1:6 P:C; DEP = 1:2.5 P:C). In males, LS was also optimized at a low P:C ratio of 1:10. However, when given the opportunity to regulate their intake, both sexes actively defended a 1:3 P:C ratio, which is closer to the target for DEP than either LS or LEP. Our results show that female C. cosyra experienced a moderate trade-off between LS and fecundity. Moreover, the diets that maximized expression of LEP and DEP were of lower P:C ratio than those required for optimal expression of these traits in host-generalist tephritids or other generalist insects.


Deriving Vignettes for the Rare Disease AADC Deficiency Using Parent, Caregiver and Clinician Interviews to Evaluate the Impact on Health-Related Quality of Life.
Aromatic l-amino acid decarboxylase (AADC) deficiency is a rare genetic condition, characterised by movement disorder, and speech and cognitive functioning impairment. To enable economic evaluation of treatments, health-related quality of life or utilities need to be derived. These are currently lacking in the literature. This is challenging, where patient numbers are small, particularly in paediatric populations. This study outlines the 5-stage development of vignettes describing AADC, for use in a subsequent health-state utility elicitation study, with an emphasis on caregiver and clinician engagement. To align with the economic model, 5 vignettes describing 5 AADC deficiency motor milestones were developed, ranging from "bedridden" to "walking with assistance". Stage 1 comprised identification of symptoms/impairments from the literature and AADC deficiency charity websites. Stage 2 comprised group discussion with 3 caregivers. A symptoms matrix was developed, followed by draft vignettes (Stage 3). Eight clinicians reviewed these, alongside the same 3 caregivers via a survey (Stage 4). The vignettes were revised at stage 5. There was high consensus regarding symptoms at Stages 1 and 2, although the literature highlighted behavioural and autonomic symptoms, which caregivers did not. The symptoms were grouped into neuromuscular, autonomic, cognitive, behavioural and functional impairments. Clinician and caregiver vignette feedback highlighted the idiopathic nature of AADC. Despite this, clinicians suggested only 2 additional symptoms. Similarly, caregivers suggested 4 symptoms and a change to the wording used for the cognitive symptoms. Not all changes were included. The differing focus of caregivers, clinicians and the literature reinforces the importance of patient/caregiver engagement. The vignettes need to comprehensively capture what it is like to live with AADC deficiency, in order for the subsequent utilities to be robust. A focus on evidence triangulation, especially for idiopathic conditions, and how engagement is sought from caregivers are important future avenues of research.


The statistical analysis of adherence data obtained from markers.
Adherence markers provide new kinds of clinical trial data. Adherence data on individual participants obtained from markers can be used for designing the trial sample size and stratification, evaluating the adequacy of randomization, directing the management of adherence, and analyzing and interpreting the trial's final results. Examples of these are presented. Analyses of adherence data can employ conventional procedures. Box plot techniques are proposed for flagging extreme values of the distribution of adherence either at a single time point or in a time continuum. The effect of difference in distribution of the markers in two or more groups in a clinical trial is discussed. Survival analysis is illustrated as one technique in univariate and multivariate analysis of markers with covariate effects. Design considerations with markers in a clinical trial are discussed, with particular emphasis on some of the assumptions and biases that must be considered for the analysis.


The single ventricle heart in the fetus: accuracy of prenatal diagnosis and outcome.
The purpose of this study was to determine the diagnostic accuracy of fetal echocardiography in evaluating anatomic details of the single ventricle heart and the outcome of fetuses diagnosed with this anomaly. This is a retrospective study of 57 fetuses in which the results of fetal echocardiography were compared with the diagnoses at postnatal echocardiography, and postnatal surgical outcome was reviewed. Diagnostic accuracy was present in predicting morphology of the predominant ventricle, visceral situs, presence of pulmonary or aortic outflow tract obstruction, and presence of obstructed pulmonary venous outflow (sensitivity 100%). However, the ability to predict for a ductal dependent pulmonary circulation was poor (sensitivity 63%). Errors were made in the fetal assessment of ventricular size and viability such that in three cases, postnatal plans were altered toward a two-ventricular intervention. Of the 57 fetuses, intervention was elected in 37 (75%). Termination or nonintervention was elected in 14, and and 6 died before intervention. Of those operated on, 71% are presently alive after various stages of intervention. Accurate diagnosis of the fetal single ventricle heart is possible, and outcome is improving. Caution must be used in judging ventricular size and in predicting ductal dependent pulmonary circulation.


In utero cocaine exposure: effect on neonatal breathing in guinea pigs.
Cocaine (COC) abuse during pregnancy may be a factor in the development of neonatal breathing abnormalities. To examine this possibility, pregnant Dunkin-Hartley guinea pigs were treated daily with s.c. injections of saline or 2, 6 or 12 mg/kg of COC during the second half of gestation. Treatments were assigned randomly to pregnant dams. Neonatal weight, breathing, ECG and EEG were recorded in unsedated animals using noninvasive techniques at intervals for 3 weeks after birth. Neonatal weight on Day 1 was decreased by exposure to the two highest doses of COC (P less than .05). The effects of drug treatment, day of study and response to inhalation of 5% CO2 were analyzed by repeated measures analysis of variance. A significant drug-, day- and CO2-effect on tidal volume (VT) and inspiratory minute volume (VI) was observed (P less than .01). COC exposure in utero increased the weight-normalized neonatal VT and VI on room air and 5% CO2 during the first 2 weeks of life in the absence of a measurable effect of drug exposure upon breathing frequency, heart rate or EEG power. The increase in VT and VI may be caused by an increase in metabolic rate (hyperpnea) or an alteration of ventilatory control (hyperventilation). Either mechanism could represent functional teratogenesis and either results in a greater ventilatory effort which increases the work of breathing and the consumption of oxygen. An increase in oxygen demand due to an increase in metabolism or an increase in ventilatory effort might compromise some neonates and contribute to an increased incidence of sudden-infant-death.


Hydroxysafflor Yellow A Confers Neuroprotection from Focal Cerebral Ischemia by Modulating the Crosstalk Between JAK2/STAT3 and SOCS3 Signaling Pathways.
Natural bioactive compounds have increasingly proved to be promising in evidence- or target-directed treatment or modification of a spectrum of diseases including cerebral ischemic stroke. Hydroxysafflor yellow A (HSYA), a major active component of the safflower plant, has drawn more interests in recent year for its multiple pharmacological actions in the treatment of cerebrovascular and cardiovascular diseases. Although the Janus kinase signaling, such as JAK2/STAT3 pathway, has been implicated in the modulation of the disease, the inhibition or activation of the pathway that contributed to the neuronal prevention from ischemic damages remains controversial. In this study, a series of experiments were performed to examine the dose- and therapeutic time window-related pharmacological efficacies of HSYA with emphasis on the HSYA-modulated interaction of JAK2/STAT3 and SOCS3 signaling in the MCAO rats. We found that HSYA treatment significantly rescued the neurological and functional deficits in a dose-dependent manner in the MCAO rats within 3 h after ischemia. HSYA treatment with a dosage of 8 mg/kg or higher markedly downregulated the expression of the JAK2-mediated signaling that was activated in response to ischemic insult, while it also promoted the expression of SOCS3 coordinately. In the subsequent experiments with the use of the JAK2 inhibitor WP1066, we found that the treatment of WP1066 alone or combination of WP1066/HSYA all exhibited inhibitory effects on JAK2-mediated signaling, while there was no influence on the SOCS3 activity of corresponding efficacious data in the MCAO rats, suggesting that excessive activation of JAK2/STAT3 might be necessary for HSYA to provoke SOCS3-negative feedback signaling. Taking together, our study demonstrates that HSYA might modulate the crosstalk between JAK2/STAT3 and SOCS3 signaling pathways that eventually contributed to its therapeutic roles against cerebral ischemic stroke.


[Familial translocation t(3;22) detected in a carrier child with mental retardation and other abnormalities].
A case of familial translocation t(3;22) (q21;q13) detected through a boy carrier with various functional and phenotypical alterations is described. The caryotype study (G bands) showed that the mother, one maternal aunt, two maternal uncles, and the brother of the proband were likewise carriers of the same translocation. We discuss the type of segregation and the high familial incidence of the translocation.


Microbial diversity under extreme euxinia: Mahoney Lake, Canada.
Mahoney Lake, British Columbia, Canada, is a stratified, 15-m deep saline lake with a euxinic (anoxic, sulfidic) hypolimnion. A dense plate of phototrophic purple sulfur bacteria is found at the chemocline, but to date the rest of the Mahoney Lake microbial ecosystem has been underexamined. In particular, the microbial community that resides in the aphotic hypolimnion and/or in the lake sediments is unknown, and it is unclear whether the sulfate reducers that supply sulfide for phototrophy live only within, or also below, the plate. Here we profiled distributions of 16S rRNA genes using gene clone libraries and PhyloChip microarrays. Both approaches suggest that microbial diversity is greatest in the hypolimnion (8 m) and sediments. Diversity is lowest in the photosynthetic plate (7 m). Shallower depths (5 m, 7 m) are rich in Actinobacteria, Alphaproteobacteria, and Gammaproteobacteria, while deeper depths (8 m, sediments) are rich in Crenarchaeota, Natronoanaerobium, and Verrucomicrobia. The heterogeneous distribution of Deltaproteobacteria and Epsilonproteobacteria between 7 and 8 m is consistent with metabolisms involving sulfur intermediates in the chemocline, but complete sulfate reduction in the hypolimnion. Overall, the results are consistent with the presence of distinct microbial niches and suggest zonation of sulfur cycle processes in this stratified system.


Sox17 expression confers self-renewal potential and fetal stem cell characteristics upon adult hematopoietic progenitors.
A key question concerns the mechanisms that determine temporal identity in stem cells. Fetal hematopoietic stem cells (HSCs) differ from adult HSCs in terms of gene expression profile, surface marker expression, differentiation, and self-renewal capacity. We previously showed that the transcription factor SOX17 is expressed by fetal, but not adult, HSCs and is required for the maintenance of fetal and neonatal, but not adult, HSCs. In the current study, we show that ectopic expression of Sox17 in adult HSCs and transiently reconstituting multipotent progenitors was sufficient to confer increased self-renewal potential and the expression of fetal HSC genes, including fetal HSC surface markers. Sox17 expression enabled transiently reconstituting adult progenitors to give long-term multilineage reconstitution that resembled fetal hematopoiesis, including increased erythropoiesis, increased myelopoiesis, and decreased lymphopoiesis. Long-term ectopic expression of Sox17 eventually led to leukemogenesis. These data demonstrate that SOX17 is sufficient to confer fetal HSC characteristics to adult hematopoietic progenitors and is therefore a key determinant of fetal HSC identity.


Antibiotic treatment of children with sore throat.
Of children with sore throat, 15% to 36% have pharyngitis caused by group A beta-hemolytic streptococci (GABHS). Performance of a GABHS test prior to antibiotic prescribing is recommended for children with sore throat. Penicillin, amoxicillin, erythromycin, and first-generation cephalosporins are the recommended antibiotics for treatment of sore throat due to GABHS. To measure rates of antibiotic prescribing and GABHS testing and to evaluate the association between testing and antibiotic treatment for children with sore throat. Analysis of visits by children aged 3 to 17 years with sore throat to office-based physicians, hospital outpatient departments, and emergency departments in the National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey, 1995 to 2003 (N = 4158) and of a subset of visits with GABHS testing data (n = 2797). National rates of antibiotic prescribing, prescribing of antibiotics recommended and not recommended for GABHS, and GABHS testing. Physicians prescribed antibiotics in 53% (95% confidence interval [CI], 49%-56%) of an estimated 7.3 million annual visits for sore throat and nonrecommended antibiotics to 27% (95% CI, 24%-31%) of children who received an antibiotic. Antibiotic prescribing decreased from 66% of visits in 1995 to 54% of visits in 2003 (P = .01 for trend). This decrease was attributable to a decrease in the prescribing of recommended antibiotics (49% to 38%; P = .002). Physicians performed a GABHS test in 53% (95% CI, 48%-57%) of visits and in 51% (95% CI, 45%-57%) of visits at which an antibiotic was prescribed. GABHS testing was not associated with a lower antibiotic prescribing rate overall (48% tested vs 51% not tested; P = .40), but testing was associated with a lower antibiotic prescribing rate for children with diagnosis codes for pharyngitis, tonsillitis, and streptococcal sore throat (57% tested vs 73% not tested; P<.001). Physicians prescribed antibiotics to 53% of children with sore throat, in excess of the maximum expected prevalence of GABHS. Although there was a decrease in the proportion of children receiving antibiotics between 1995 and 2003, this was due to decreased prescribing of agents recommended for GABHS. Although GABHS testing was associated with a lower rate of antibiotic prescribing for children with diagnosis codes of pharyngitis, tonsillitis, and streptococcal sore throat, GABHS testing was underused.


[Epidemiological pattern of lymphatic filariasis in children living in endemic areas].
Lymphatic filariasis still represents a major public health problem in the city of Recife. In spite of the fact that previous surveys had already shown high frequency of microfilaraemia in pediatric population, the prevalence of filarial disease and the microfilaraemic pattern of this group were unknown. This paper describes the clinical-epidemiological pattern of filariasis in children and adolescents living in two highly endemic areas of Recife. The parasitological survey was done through a census carried out between December 1990 and July 1991. Thick drop technique (45 micro l) was performed on a total of 1,464 children and adolescents between the ages of 5 and 14, of whom 967 were submitted to clinical examination. Positive cases had their blood recollected (60 micro l) to measure the microfilaraemic density. The microfilaraemia prevalence was 6.4 %. In the age groups of 5 to 9 and 10 to 14 a microfilaraemia prevalence of respectively 4.6% and 8.3% was observed. The microfilaraemic density varied from 3 to 864 microfilariae per 60 microl of blood, there having been no statistically significant difference between the sexes and age groups (p<0.05). 6 cases (0.6 %) of acute filarial disease and 11 of chronic filarial disease (1.1%) were identified, hydrocele being the principal manifestation found. Lymphadenopathy was found in 22% of the children, statistical association with microfilaraemia being observed (p<0.001). The results of the parasitological survey show the strong presence of children in the contingent of microfilaraemic individuals, indicating an early and intense exposure to filariasis in the population studied.


Pulmonary function following feeding in low-birth-weight infants.
Determination of functional residual capacity, arterial gas tensions and pH, and arterial-alveolar differences was carried out in a group of nondistressed premature infants to determine if significant alterations in lung volumes or ventilation perfusion relationships sufficiently large to cause cyanosis could be detected after feeding. The only statistically significant changes observed in these parameters were immediately following feeding, a fall of .01 pH units and a fall of 6 mm Hg in arterial oxygen tension; and 15 minutes after feeding, a fall of .01 pH units and a rise in arterial PCO2 of 3 mm Hg. In addition, significant falls in peripheral blood flow were observed five minutes after feeding in association with marked elevations in peripheral vascular resistance. The mild impairment in pulmonary function in association with the more profound changes in limb blood flow are consistent with other studies in premature and full-term infants. These data suggest that cyanotic attacks following feeding may have a complex etiology and require an aggressive multisystem approach for adequate diagnosis and therapy.


Medical students' exposure to pharmaceutical industry marketing: a survey at one U.S. medical school.
While much is known about the interactions between the pharmaceutical industry and physicians, very little is known about pharmaceutical marketing directed toward medical students. This study sought to characterize the extent and forms of medical students' exposure to pharmaceutical industry marketing. In 2001-02, an anonymous, 17-item questionnaire was distributed to 165 preclinical and 116 clinical students at the University of Minnesota Medical School-Twin Cities. The main outcome measures were the number and forms of exposures to pharmaceutical industry marketing reported by medical students and whether students had discussed these exposures with teachers or advisors. Preclinical and clinical students were compared using chi(2) analysis (p < .05). One hundred fourteen (69.1%) preclinical students and 107 (92.2%) clinical students responded. Nearly all students reported at least one exposure to pharmaceutical industry marketing. Seventy-six (71.7%) clinical students compared to 38 (33.3%) preclinical students recalled over 20 exposures (p < .005). Clinical students were more likely to have received a free meal (p < .01), textbook (p < .005), pocket text (p < .005), or trinket (p < .005) than were their preclinical colleagues. Most students (68.2%) had not discussed pharmaceutical marketing with an instructor or advisor; 59 (55.7%) clinical students as compared to 87 (80.6%) preclinical students recalled no such discussion (p < .005). Medical students have extensive exposure to pharmaceutical industry marketing during their early years of training. Given existing evidence that such exposure influences physicians' practice and prescribing patterns, the authors propose that medical school curricula include formal instruction to prepare students to critically assess these contacts.


Genetic variants of the inflammatory C-reactive protein and schizophrenia in Armenian population: a pilot study.
C-reactive protein (CRP) is an inflammation marker implicated in the pathogenesis of schizophrenia. To investigate association of the CRP rs1417938, rs1800947, rs1205 variants with susceptibility to schizophrenia 208 unrelated Armenians (103 patients and 105 healthy controls) were genotyped. In this pilot study, none of studied variants was associated with schizophrenia.


Rapid down-regulation of GABAA receptors in the gerbil hippocampus following transient cerebral ischemia.
During transient cerebral ischemia, there is a temporary and robust accumulation of extracellular GABA in the hippocampus. We examined whether the acute exposure of GABAA/benzodiazepine receptors to high concentrations of GABA early after ischemia results in receptor down-regulation as observed in vitro. Gerbils were killed 30 and 60 min following a 5-min bilateral carotid occlusion, and their brains were prepared for receptor autoradiography. The hydrophilic, GABAA receptor antagonist [3H]SR-95531 and the hydrophobic benzodiazepine agonist [3H]flunitrazepam were used to distinguish between cell surface and internalized receptors. Ischemia significantly decreased [3H]SR-95531 binding in hippocampal areas CA1 and CA3 and in the dentate gyrus 30 min after ischemia. Scatchard analysis in area CA1 revealed that ischemia decreased the Bmax as low as 44%. The affinity of the remaining sites was increased substantially (72% decrease in KD). As expected, there were no changes in the binding of [3H]flunitrazepam to hippocampus in the early postischemic period because the benzodiazepine could bind to both internalized receptors and those on the cell surface. We hypothesize that prolonged exposure (approximately 30-45 min) of GABAA receptors to high concentrations of synaptic GABA in vivo causes receptor down-regulation, perhaps via receptor internalization.


A systematic review of using and reporting survival analyses in acute lymphoblastic leukemia literature.
Survival analysis is commonly used to determine the treatment effect among acute lymphoblastic leukemia (ALL) patients who undergo allogeneic stem cell transplantation (allo-SCT) or other treatments. The aim of this study was to evaluate the use and reporting of survival analyses in these articles. We performed a systematic review by searching the MEDLINE, EMBASE and Cochrane library databases from inception to April 2015. Clinical trials of patients with ALL comparing allo-SCT compared to another treatment were included. We included only studies that used survival analysis as a part of the statistical methods. There were 14 studies included in the review. Sample size estimation was described in 4 (29 %) studies. Only 4 (29 %) studies reported the list of covariates assessed in the Cox regression and 6 (43 %) studies provided a description of censorship. All studies reported survival curves using the Kaplan-Meier method. The comparisons between groups were investigated using the log-rank test and Wilcoxon test. Crossing survival curves were observed in 11(79 %) studies. The Cox regression model was incorporated in 10 (71 %) studies. None of the studies assessed the Cox proportional hazards assumption or goodness-of-fit. The use and reporting of survival analysis in adult ALL patients undergoing allo-SCT have significant limitations. Notably, the finding of crossing survival curves was common and none of the studies assessed for the proportional hazards assumption. We encourage authors, reviewers and editors to improve the quality of the use and reporting of survival analysis in the hematology literature.


Implications of IL-13Rα2 in atopic skin inflammation.
Atopic dermatitis (AD) is a common eczematous skin disorder characterized by skin inflammation, barrier disruption, chronic pruritus and marked scratching. Th2 cytokines, especially IL-13, play a pathogenic role in AD. IL-13 signals via a heterodimeric receptor composed of IL-4Rα and IL-13 Rα1. A second receptor, IL-13 Rα2, binds to IL-13 with high affinity, but it works as a decoy receptor. IL-13 Rα2 is overexpressed in the lesional skin of AD. Notably, mechanical scratching, as well as IL-13 itself, also upregulates IL-13 Rα2 expression. The scratch-induced IL-13 Rα2 upregulation may attenuate the IL-13-mediated epidermal barrier dysfunction and dermal fibrosis. Recent studies stress an importance of another IL-13 Rα2 ligand, chitinase 3-like 1 or YKL-40 in Th2 differentiation. However, the implications of increased IL-13 Rα2 levels remain elusive in AD. In this review, we summarize the recent topics on IL-13 Rα2 in atopic skin inflammation.


Dietary Insulinemic Potential and Risk of Total and Cause-Specific Mortality in the Nurses' Health Study and the Health Professionals Follow-up Study.
Insulin response is related to overall health. Diet modulates insulin response. We investigated whether insulinemic potential of diet is associated with risk of all-cause and cause-specific mortality. We prospectively followed 63,464 women from the Nurses' Health Study (1986-2016) and 42,880 men from the Health Professionals Follow-up Study (1986-2016). Diet was assessed by food frequency questionnaires every 4 years. The insulinemic potential of diet was evaluated using a food-based empirical dietary index for hyperinsulinemia (EDIH), which was predefined based on predicting circulating C-peptide concentrations. During 2,792,550 person-years of follow-up, 38,329 deaths occurred. In the pooled multivariable-adjusted analyses, a higher dietary insulinemic potential was associated with an increased risk of mortality from all-cause (hazard ratio [HR] comparing extreme quintiles: 1.33; 95% CI 1.29, 1.38; P-trend <0.001), cardiovascular disease (CVD) (HR 1.37; 95% CI 1.27, 1.46; P-trend <0.001), and cancers (HR 1.20; 95% CI 1.13, 1.28; P-trend <0.001). These associations were independent of BMI and remained significant after further adjustment for other well-known dietary indices. Furthermore, compared with participants whose EDIH scores were stable over an 8-year period, those with the greatest increases had a higher subsequent risk of all-cause (HR 1.13; 95% CI 1.09, 1.18; P-trend <0.001) and CVD (HR 1.10; 95% CI 1.01, 1.21; P-trend = 0.006) mortality. Higher insulinemic potential of diet was associated with increased risk of all-cause, CVD, and cancer mortality. Adopting a diet with low insulinemic potential might be an effective approach to improve overall health and prevent premature death.


Detection and diagnostic utilization of placental alkaline phosphatase in muscular tissue and tumors with myogenic differentiation.
Placental alkaline phosphatase (PLAP) is normally produced by primordial germ cells and syncytiotrophoblasts, and the detection of its expression has been useful in the diagnosis of germ cell tumors. We have recently observed PLAP immunoreactivity in normal human adult and fetal muscle tissue. Based on this observation, we explored the possible role of PLAP in the diagnosis of soft tissue tumors. A total of 271 tumors were studied. These included tumors with myogenic, neural, fibrous, myofibroblastic, lipomatous, neuroepithelial, perivascular, and epithelial differentiation. A formalin-fixed, paraffin-embedded section from each tumor was stained with PLAP monoclonal antibody using standard immunohistochemical methods preceded by antigen retrieval. In addition, western blotting with PLAP monoclonal antibodies was performed on fresh samples from a uterine leiomyoma, grossly normal myometrium, and placenta. Also, formalin-fixed sections of fetal skeletal muscle were labeled with double immunohistochemistry techniques using antibodies to myogenin and PLAP. Cytoplasmic PLAP reactivity was detected in all leiomyomas and rhabdomyosarcomas (100%), 7 of 15 (46%) leiomyosarcomas, 15 of 19 (79%) desmoplastic small round cell tumors, 2 of 15 (13%) gastrointestinal stromal tumors, 1 of 8 (13%) Wilms' tumors, 1 of 9 synovial sarcomas (9%), and 2 of 7 (29%) myofibroblastic tumors. No PLAP reactivity was detected in hyperplastic scars, nodular fasciitis, or the other remaining soft tissue and epithelial tumors. Double immunohistochemistry studies showed coexpression of myogenin and PLAP in fetal skeletal muscle cells, and western blot analysis showed a 70-kDa band in samples derived from grossly normal placenta, benign myometrium, and a uterine leiomyoma. PLAP immunoreactivity is detected in soft tissue tumors with known myogenic differentiation. PLAP immunoreactivity seems to relate to the degree of myogenic differentiation in soft tissue tumors and is more frequently expressed in cells with skeletal muscle differentiation and least in those with myofibroblastic features. The biologic function of PLAP in muscle and tumors with myogenic differentiation is unknown and merits further investigation. In addition to its role as a germ cell marker, PLAP may also be used as a myogenic marker in the diagnosis of soft tissue tumors.


[Metabolism of amino acids and urea cycle: animal models of enzymopathies].
This article is a review of the animal models which have been described until now for the inborn errors of amino acid metabolism and urea cycle. Two approaches have been explored to obtain such animal models: firstly oral or parenteral administration of the amino acid(s) accumulated in some enzymatic defects of the amino acid catabolism or urea cycle--specific enzymatic inhibitors have sometimes been used; secondly, the genetic approach, which is often the best method. Systematic screening of rat or mouse mutants obtained by experimental mutagenesis was performed in some cases. The relationships between the metabolic disturbances observed either in the inborn errors of metabolism or in the experimental models are discussed as well as the origin of the discrepancies often observed between human and animal syndromes.