Global regurgitant volume: approaching the critical mass in valvular-driven heart failure.
Recent progress in the diagnosis of functional valve regurgitation forms a coherent perception of severity thresholds by quantitative assessment. However, thresholds focused on either valve in isolation-not accounting for the global haemodynamic burden arising from concomitant functional regurgitation of the mitral and tricuspid valves. We sought to determine whether the global regurgitant volume is associated with adverse cardiac remodelling and mortality. This long-term observational study included 414 patients on guideline-directed medical therapy. Baseline global regurgitant load defined as the sum of mitral and tricuspid regurgitant volume was assessed by the proximal flow convergence method. All-cause mortality during 5 years follow-up served as the primary endpoint. The median global regurgitant load was 30 mL (interquartile range 15-49) with 67% accounting for mitral and 33% accounting for tricuspid regurgitant volume. The global regurgitant load had significant impact on outcome with a crude hazard ratio of 1.46 (1.28-1.66; P < 0.001) for a 1-SD increase in global regurgitant volume, results that remained virtually unchanged after bootstrap or clinical confounder-based adjustment (P < 0.001 for adjusted models). Spline curve analysis showed a linearly increasing risk with a threshold of 50 mL and sustained increasing risk thereafter. The present study demonstrates the detrimental effect of the global regurgitant load in patients with heart failure with reduced ejection fraction. The threshold where heart failure is driven by the valve lesions is a global regurgitant volume of 50 mL with continuously increasing risk beyond that threshold. Future studies need to address whether an attempt to reduce the global regurgitant volume can improve outcome.


Factors of the Fusarium verticillioides-maize environment modulating fumonisin production.
Fumonisins are mycotoxins mainly produced by two Fusarium species: F. verticillioides and F. proliferatum. These toxins are of great concern due to their widespread contamination in maize and their adverse effects on animal and human health. In the past decade, progress was made in identifying the genes required for fumonisin biosynthesis. Additionally, molecular mechanisms involved in the regulation of fumonisin production have been very recently elucidated. By covering the latest advances concerning the factors modulating fumonisin production, this review aims at presenting an integrated approach of the overall mechanisms involved in the regulation of fumonisin biosynthesis during maize kernel colonization.


Effects of different types of pharyngeal packing in patients undergoing nasal surgery: A comparative study.
Postoperative throat complaints such as postoperative sore throat (POST), dysphagia, and hoarseness frequently arises after tracheal intubation and throat packing for patient undergoing general anesthesia. This condition is very disturbing to patient. Avoiding POST is a major priority for these patients because preventing postoperative complications contributes to patient satisfaction. To describe and analyze the postoperative throat effects of nasopharyngeal packing and oropharyngeal packing in patients undergoing nasal surgery. A randomized comparative study. After obtaining approval of Ethical Committee 40 patients were included in study. After this patient were randomly allocated into two groups of 20 each. Group A - in which the oropharynx was packed and Group B - inwhich the nasopharynx was packed. General anesthesia were given and throat packing was done and patients were interviewed postoperatively for any throat complications such as sore throat, difficulty in swallowing (dysphagia), hoarseness of voice, throat irritation, and any other symptom pertaining to the study were noted and data were analyzed. T-test to compare the age, while Chi-square test and Fisher's exact test were used to compare sex distribution, sore throat, dysphagia, hoarseness, and throat irritation. Results showed statistically significant difference in incidence and severity of POST in Group A patients when compared to Group B patients to be more. Patients in Group A had a higher incidence of dysphagia when compared to their Group B counterparts. With respect to the incidence of hoarseness and throat irritation, there was no statistical significance between the groups. We concluded that the site of pharyngeal packing influences the incidence and severity of POST and as well as the incidence of dysphagia after general anesthesia. The use of nasopharyngeal packing in the patients undergoing nasal surgeries might lead to a reduction of the same.


Regulation of luteinizing hormone secretion in male sheep by endogenous estrogen.
Both androgens and estrogens are implicated in the regulation of gonadotropin secretion in the male. Three experiments were conducted to determine the physiological importance of estradiol (E2) in the feedback regulation of LH secretion in male sheep. In the first experiment, LH secretion in castrate rams (wethers) was shown to be susceptible to the picomolar concentrations of E2 found in intact rams. In the second experiment, aminoglutethimide (AG) was administered to testosterone-implanted wethers to block aromatization of testosterone and ascertain the possible consequences of E2 deprivation on testosterone-mediated LH suppression. AG had no apparent effect on serum testosterone, but reduced serum E2 by half and increased serum LH approximately 3-fold. These data suggest that aromatization of testosterone to E2 is a physiologically important step in the regulation of LH secretion in the ram and that aromatization occurs, at least in part, in peripheral tissues. The relative contributions of peripherally and centrally derived E2 in the regulation of LH remain uncertain. In the third experiment, immunoneutralization of endogenous E2 in intact rams by active immunization against E2 was shown to stimulate pulsatile LH secretion and elevate basal and mean LH concentrations. Associated with this LH response was a significant increase in serum testosterone, such that immunized rams exposed to a nonstimulatory 16-h light, 8-h dark photoperiod had testosterone concentrations equivalent to those of control rams exposed to a stimulatory 8-h light, 16-h dark photoperiod. Together, these findings emphasize the importance of E2 in the control of male reproduction and suggest the possibility of improving year-round reproductive performance of the domestic ram through E2 immunoneutralization.


Absence of the articular disc in the tasmanian devil temporomandibular joint.
The articular disc of the temporomandibular joint is a constant structure in mammals. According to Parsons' report in 1900, however, it is absent in four animals: the armadillo, two kinds of monotremes and the Tasmanian devil. Thereafter, no research was performed to confirm this observation. The aim of this study was to determine by anatomical and histological examination whether the Tasmanian devil has an articular disc in its temporomandibular joint. Six fresh frozen corpses and one dry skull of Tasmanian devils were obtained from the School of Zoology, University of Tasmania. The corpses were dissected and the morphology of the temporomandibular joint was carefully observed by gross anatomical and histological examination. The structure of the temporomandibular joint of the dry skull was examined macroscopically and by micro-computed tomography. In all cases, absence of the articular disc in the Tasmanian devil temporomandibular joint was morphologically confirmed. The surface layer of both the condyle and the glenoid fossa comprised a thick fibrous tissue. Micro-computed tomography revealed dense and fine trabecular bone in the condyle. The thick fibrous tissue covering the condyle and high-density trabecular bone in the condyle might play a role in absorption against powerful mastication and heavy loading of the Tasmanian devil temporomandibular joint.


Current research problems of chronic arsenicosis in China.
Chronic arsenicosis is a newly-emerged public-health issue in China and many other Asian countries. Over 200 million people are estimated to be at the risk of high arsenic exposure from drinking-water in the Asian region. To protect people from the hazards of chronic arsenic poisoning, the Chinese Government has been providing low-arsenic drinking-water to some seriously-affected rural areas, such as Inner Mongolia autonomous province. Results of follow-up studies showed that both the average values of arsenic, including inorganic arsenic (iAs), monomethylated arsenic, dimethylated arsenic and trimethylated arsenic, and 8-hydroxydeoxyguanine in urine, decreased significantly after drinking low-arsenic water for one year, and arsenic-specific skin lesions also improved to some extent. However, a five-year follow-up study showed no more significant improvement of skin lesions, while the potential risk of arsenic-induced cancers after cutting off high-arsenic exposure was still uncertain and indefinite. The susceptibility of children compared to adults to chronic arsenic exposure and the need to re-evaluate the appropriate standard of arsenic in drinking-water were also discussed in this paper.


Expression of alpha and beta estrogen receptors in the chicken ovary.
The role of estrogens in hen reproduction is well established. However, the distribution of estrogen receptors in the chicken ovary is unknown. Therefore, the mRNA expression of alpha (ERaalpha) and beta (ERbeta) estrogen receptors was examined within the ovaries of laying hens. Expression of ERs was determined by RT-PCR analysis. The presence of ERalpha and ERbeta mRNAs was found in the ovarian stroma and white, yellowish, small yellow and the largest preovulatory (F3-F1) follicles. ERalpha and ERbeta mRNAs were detected in the granulosa and theca layers of the walls of preovulatory follicles. The expression of ERalpha mRNA was markedly higher than ERbeta mRNA in all examined ovarian compartments. Within the ovary, the relative expression of both ER mRNAs depends on the follicular diameter and the layer of the follicular wall. The results demonstrate the expression of both ERalpha mRNA and ERbeta mRNA in all compartments of the chicken ovary, suggesting different pathways of estrogen action in the avian ovary. Much higher expression of ERalpha mRNA indicates that this form of estrogen receptor is predominant in the chicken ovary. The clarification of the mechanism of ERalpha and ERbeta participation in the ovarian functions of birds necessitates further experiments examining ERs at the protein level.


Is there a code for protein-DNA recognition? Probab(ilistical)ly. . .
Transcriptional regulation of all genes is initiated by the specific binding of regulatory proteins called transcription factors to specific sites on DNA called promoter regions. Transcription factors employ a variety of mechanisms to recognise their DNA target sites. In the last few decades, attempts have been made to describe these mechanisms by general sets of rules and associated models. We give an overview of these models, starting with a historical review of the somewhat controversial issue of a "recognition code" governing protein-DNA interaction. We then present a probabilistic framework in which advantages and disadvantages of various models can be discussed. Finally, we conclude that simplifying assumptions about additivity of interactions are sufficiently justified in many situations (and can be suitably extended in other situations) to allow a unifying concept of a "probabilistic code" for protein-DNA recognition to be defined.


Genetic diversity of three donkey populations in the Croatian coastal region.
Genetic variation in three Croatian donkey populations, Istrian (IS), North Adriatic (NA) and Littoral-Dinaric (LD), was analysed using eight microsatellite loci and by sequence and SSCP analysis of the proximal portion of the mtDNA D-loop region. The analysis of microsatellite loci revealed observed heterozygosities in the range of 0.37 (MPZ002 in LD) to 0.85 (AHT21 in LD) and polymorphic information content values in the range of 0.36 (MPZ002 in NA) to 0.78 (AHT21 in LD). The overall probability of exclusion was 0.991. Two populations (IS and NA) were closely related (Fst=0.0034), whereas genetic distances between IS and LD (Fst=0.021) and NA and LD (Fst=0.027) were higher. Using AMOVA, 97.6% of the total genetic variance was portioned within populations, while 2.7% was portioned between the Littoral-Dinaric population and the Istrian/North Adriatic population group. Sequencing of the proximal part of the mtDNA D-loop region revealed 36 polymorphic sites representing 19 haplotypes which clustered into three haplotype groups (Y, W, Ws). Only the Y haplotype was found in the IS population which is characterized by a large body size. Haplotypes W and Ws were found in the NA and LD populations which include smaller animals. All three haplotypes were found in the LD population, indicating sporadic migration events from the IS into LD donkey population.


Homologies of the anterior teeth in Indriiadae and a functional basis for dental reduction in primates.
In a recent paper Schwartz ('74) proposes revised homologies of the deciduous and permanent teeth in living lemuriform primates of the family Indriidae. However, new evidence provided by the deciduous dentition of Avahi suggests that the traditional interpretations are correct, specifically: (1) the lateral teeth in the dental scraper of Indriidae are homologous with the incisors of Lemuriadae and Lorisidae, not the canines; (2) the dental formula for the lower deciduous teeth of indriids is 2.1.3; (3) the dental formula for the lower permanent teeth of indriids is 188.8.131.52; and (4) decrease in number of incisors during primate evolution was usually in the sequence I3, then I2, then I1. It appears that dental reduction during primate evolution occurred at the ends of integrated incisor and cheek tooth units to minimize disruption of their functional integrity.


Occupational Exposure to Mycotoxins: Current Knowledge and Prospects.
Occupational exposure to mycotoxins is supposedly very frequent, but it is rarely reported in the scientific literature. Several recent studies described occupational exposure to the aflatoxin B1 (AFB1) mycotoxin in different occupational settings. Previously, exposure to other mycotoxins was shown in the animal husbandry and food processing sectors, confirming that occupational exposure cannot be negligible. However, no guidelines or standard methodologies are available for helping occupational hygienists to consider mycotoxin exposure in their interventions. This article reviews the literature on this problem and recommends some actions for the better management of this risk factor in occupational settings, especially where environmental conditions are favorable to fungal presence.


Investigating the renoprotective effect of C21 in male mice with sepsis via modulation of p-AKT/PI3K expression.
This study aimed to investigate if C21 could prevent acute renal injury induced by sepsis by regulating the expression of p-AKT/PI3K. Five equal groups of 25 adult male Swiss-albino mice were randomly divided (n=5): sham (laparotomy without CLP), CLP, vehicle (equivalent amount of DMSO one hour before CLP), and C21 (0.03 mg/kg, one hour before CLP). ELISA was used to measure serum inflammatory mediators, and the expression of PI3K and P-AKT was determined using PCR and immunohistochemistry (IHC), respectively. TNF, TNF receptor, F8-isoprostane, urea, creatinine, and IL-6 blood levels were considerably lower in the CLP group (p<0.05) compared to the sham group, whereas the C21 treated group had significantly (p<0.05) greater levels of these inflammatory mediators. The IHC analysis revealed that P-AKT expression was significantly lower (p<0.05) in the CLP group compared to the sham group, while the C21 pretreatment group had significantly higher levels of P-AKT expression compared to the CLP group (p<0.05). The PI3K expression in the CLP group was significantly lower than in the sham group (p<0.05), according to PCR results, whereas the PI3K expression in the C21 pretreatment group was significantly greater than in the CLP group (p<0.05). This study showed that C21 might reduce levels of pro-inflammatory cytokines, including TNF-, IL-6, and TNF receptor, by modulating the PI3K/AKT signaling pathways, which can, in turn, reduce renal dysfunction during CLP-induced sepsis in male mice.


Obesity, Dietary Factors, Nutrition, and Breast Cancer Risk.
To synthesize the critical role of obesity-associated inflammation, dietary factors, and nutrition in determining breast cancer risk. Obesity-associated inflammation is strongly linked to breast cancer risk and progression, largely via two processes: inflammatory pathways and dysregulated metabolism. Cytokine production in excess adipose tissues creates a chronic inflammatory microenvironment, which favors tumor development. Lifestyle factors, including diet, have long been recognized as important determinants of breast cancer risk and mortality. Obesity increases the risk of developing breast cancer in both pre- and postmenopausal women and also negatively affects breast cancer recurrence and survival. Poor dietary habits characterized by the high intake of refined starches, sugar, and both saturated and trans-saturated fats, as well as the low intake of omega-3 fatty acids, natural antioxidants, and fiber, modulate inflammation and, thereby, appear to be linked to increased risk of breast cancer and mortality.


A versatile X-ray diffraction station at LNLS (Brazil).
Versatility was a major consideration in the project to provide an X-ray diffraction station at LNLS. At least two techniques are possible at the station: powder diffraction and multiple single-crystal diffraction. A two-crystal monochromator based on monolithic elastic translators, developed at LNLS, with sagittal focusing by the second crystal, allows 10 mrad of a >/=2 keV monochromatic beam to be used on the diffractometer. The station is equipped with a fast scintillation detector, imaging plates, a high-energy-resolution pin-diode detector, an ionization chamber and a high-angular-resolution soller slit. The data collection and control hardware and software were also developed at LNLS. The theta-2theta goniometry for powder diffraction on this 1 m-diameter diffractometer is based on commercial rotation tables. The multiple single-crystal goniometry is realized by an independent elastic axis driven by differential micrometers for both high- and low-resolution angular movements. At least four independent axes can be positioned as necessary on the diffractometer table. Powder diffractograms and double-crystal rocking curves collected with the synchrotron beam show the expected quality.


Drug development for liver diseases: focus on picroliv, ellagic acid and curcumin.
The use of herbal drugs for the treatment of liver diseases has a long tradition in many eastern countries. The easy accessibility without the need for laborious pharmaceutical synthesis has drawn increased attention towards herbal medicines. Few herbal preparations exist as standardized extracts with major known ingredients or even as pure compounds. Some of the herbals, which show promising activity, are ellagic acid for antifibrotic treatment, phyllanthin for treating chronic hepatitis B, glycyrrhizin to treat chronic viral hepatitis and picroliv for liver regeneration. These compounds, which have proven antioxidant, antiviral or anticarcinogenic properties, can serve as primary compounds for further development as hepatoprotective drugs. This review provides the chemistry, pharmacology and future aspects of picroliv, ellagic acid and curcumin with focus on hepatoprotective properties. These phytochemicals may prove to be very useful in the treatment of hepatotoxicity induced by viral agents, toxic drugs and plant poisons. The high safety profile may be an added advantage. However, poor bioavailability and temperature and light sensitivity can reduce the efficacy of drugs like curcumin. In future, the derivatives or new combinations of these drugs may prove to be useful.


Identifying Patients in Need of Goals of Care Conversations: Reliability, Acceptability, and Prognostic Significance of the Preference-Aligned Communication and Treatment Conversation Trigger Tool for Patients with Cancer.
Background: Simple methods to help teams identify patients with goals of care (GOC) conversation needs are lacking. Objectives: To develop a tool to identify hospitalized patients who may benefit from GOC conversations. Methods: The Preference-Aligned Communication and Treatment (PACT) Conversation Trigger Tool was implemented as part of a quality improvement initiative in 10 Illinois hospitals and validated in a cohort of patients admitted to the coordinating site's oncology unit (n = 135). Results: The tool was reliable and acceptable to clinicians using it across sites. Thirty percent (n = 40) of patients screened at the coordinating site's oncology unit triggered positive. These patients were more likely to have a do-not-resuscitate order (43% vs. 11%) and palliative care consult (53% vs. 20%) and had lower mean survival time (125 vs. 248 days) than those who did not trigger (p < 0.001). Conclusions: The tool is reliable, acceptable, and can identify hospitalized oncology patients who may benefit from GOC conversations.


Dimerization and Structural Stability of Amyloid Precursor Proteins Affected by the Membrane Microenvironments.
The lipid raft microenvironment is implicated in the generation of the pathological amyloid-β (Aβ) species in amyloid precursor protein (APP) that is associated with neurodegenerative diseases. Evidence shows that APP forms a transmembrane homodimer with changeable structures as a function of the membrane compositions. However, the molecular responsibility of the dimerization and structural alteration for the amyloidogenic process in segregated membranes remains largely unclear. Here, we performed multiple coarse grained (CG) simulations to explore the behavioral preference of the transmembrane domain of APP (called C99) that is affected by the lipid raft microenvironment. The results showed that C99 was anchored at the boundary of the lipid raft relying on the conserved hydrophobic motif of V710xxA713xxxV717xxxV721. Moreover, the dimerization of C99 was greatly destabilized by the lipid raft, which led to a susceptible switching packing conformation. The molecular driving forces were derived from the combined regulation of the saturated lipids and cholesterols rather than from the simple binding competition of cholesterol in the C99 dimerization. The molecular details of the differential dimerization in the raft-forming and bulk fluid bilayer environments were compared, and the structural information was helpful for further understanding the enzymolysis responsiveness of APP.


Single-cell transcriptomics reveals specific RNA editing signatures in the human brain.
While RNA editing by A-to-I deamination is a requisite for neuronal function in humans, it is under-investigated in single cells. Here we fill this gap by analyzing RNA editing profiles of single cells from the brain cortex of living human subjects. We show that RNA editing levels per cell are bimodally distributed and distinguish between major brain cell types, thus providing new insights into neuronal dynamics.


The knowledge, attitudes and practices on influenza among medical college students in Northwest China.
Objective This study aimed to understand the knowledge, attitudes and practices (KAP) on seasonal influenza among medical college students in a low-income multiethnic society. Methods A cross-sectional questionnaire survey collected information of KAP related to influenza. A knowledge score was calculated according to the total number of correct points out of 9 questions. Logistic regression was used to identify factors associated with influenza vaccine uptake. Results 856 valid questionnaires were obtained. The average knowledge score was 14.8 ± 3.1 out of 22 correct points. Han Chinese got higher score than minorities (p < 0.001). Knowledge score increased with grade (p < 0.001). Students majoring in pharmacy had lower score than others. Questions on mode of transmission, symptoms, precautions, high risk groups and vaccination schedule had a correct rate lower than 50%. Hand hygiene was practiced by less than 40% of students after touching objects in public areas or sneezing. The proportion of participants received influenza vaccine in the past 3 y was 4.1%, 9.2% and 6.1% respectively. Willingness to receive free vaccine (OR = 2.49, 95% CI 1.31∼4.28), and awareness of the vaccine effectiveness (OR = 1.67, 95% CI 1.08∼2.56) were significantly associated with vaccine uptake, while the general knowledge about influenza, perceived susceptibility and severity, and demographic factors were not. The top 3 reasons for not being vaccinated were poor knowledge of the vaccine (46%), no perceived need due to good health (45%) and worry about adverse reactions (33%). Conclusion Health education is needed to improve the awareness of basic facts about influenza and vaccine, and more attention should be paid to minority groups. The coverage of seasonal influenza vaccine is quite low. Besides individual level behavior change, social and structural factors should be considered to increase the uptake of influenza vaccine.


Antidepressant Prescribing and Suicide/Self-Harm by Young Australians: Regulatory Warnings, Contradictory Advice, and Long-Term Trends.
In 2004, the US Food and Drug Administration (FDA) controversially issued a black box warning that antidepressants were associated with an increased risk of suicidal thoughts and behaviours in people aged under 18 years. In 2007, the warning was expanded to include young adults aged under 25 years. In 2005, the Australian Therapeutic Goods Administration responded to the FDA warning by requiring Product and Consumer Information leaflets to be updated to reflect the risk. However, there was considerable debate, and at times emotive backlash, in academic journals and the international media. Prominent US and Australian mental health organisations and psychiatrists challenged the FDA warning. They argued that, on balance, antidepressant use was likely to reduce the risk of suicide. Several ecological studies were cited misleadingly as evidence that decreasing antidepressant use increases suicide risk. From 2008 to 2018, Australian per-capita child, adolescent and young adult antidepressant dispensing (0-27 years of age) and suicide (0-24 years) rates have increased approximately 66% and 49%, respectively. In addition, there was a 98% increase in intentional poisonings among 5 to 19 year-olds in New South Wales and Victoria between 2006 and 2016, with substantial overlap between the most commonly dispensed psychotropics and the drugs most commonly used in self-poisoning. These results do not support claims that increased antidepressant use reduces youth suicide risk. They are more consistent with the FDA warning and the hypothesis that antidepressant use increases the risk of suicide and self-harm by young people. Causal relationships cannot be established with certainty until there is a vast improvement in post-marketing surveillance. However, there is clear evidence that more young Australians are taking antidepressants, and more young Australians are killing themselves and self-harming, often by intentionally overdosing on the very substances that are supposed to help them.


[Present knowledge of human spleen function].
The human spleen is an important lymphoid organ participating in immune reactions against all types of circulating antigens. It also removes particles of nonantigenic nature from blood circulation. The structure of the spleen, containing specialized cells types, provides a microenvironment where various intercellular interactions occur and determines the course of development of immune and nonimmune reactions. Though the spleen significantly participates in host defense reactions it is not inevitable for life. However, removing of the spleen increases the risk of overwhelming infections by bacteria with polysaccharide capsules.


Suitability of Foxtail Millet (Setaria italica) and Barnyard Millet (Echinochloa frumentacea) for Development of Low Glycemic Index Biscuits.
Millets have been neglected despite their nutritive value and therapeutic use. The present study was undertaken with the aim of preparing biscuits based on foxtail millet and barnyard millet and to evaluate their sensory quality and acceptability, nutritional value and glycemic index by comparing with biscuits made from refined wheat flour. The biscuits made from millet were prepared using 45% of millet flour and 55% of refined wheat flour. All the three types of biscuits were found to be acceptable by a trained panel and diabetic subjects. The shelf life study indicated that the biscuits made from both types of millet flour can be successfully stored for a period of 60 days in a thermally sealed single polyethylene bag at room conditions. The millet flour and biscuits had higher content of crude fibre, total ash and total dietary fibre than refined wheat flour and biscuits. Biscuits from foxtail millet flour had the lowest GI of 50.8 compared to 68 for biscuits from barnyard millet flour and refined wheat flour. Thus, besides its traditional use in making chapatti and porridge, millet can be exploited for the development of low GI therapeutic food products like biscuits. Further studies are needed to determine long term effects of consumption of foxtail millet biscuits on blood lipid profile and glycosylated haemoglobin of diabetics and cardiovascular patients.


Safety and pharmacokinetics of single intravenous dose of MGAWN1, a novel monoclonal antibody to West Nile virus.
West Nile Virus (WNV) is a neurotropic flavivirus that can cause debilitating diseases, such as encephalitis, meningitis, or flaccid paralysis. We report the safety, pharmacokinetics, and immunogenicity of a recombinant humanized monoclonal antibody (MGAWN1) targeting the E protein of WNV in a phase 1 study, the first to be performed on humans. A single intravenous infusion of saline or of MGAWN1 at escalating doses (0.3, 1, 3, 10, or 30 mg/kg of body weight) was administered to 40 healthy volunteers (30 receiving MGAWN1; 10 receiving placebo). Subjects were evaluated on days 0, 1, 3, 7, 14, 21, 28, 42, 56, 91, 120, and 180 by clinical assessments, clinical laboratory studies, electrocardiograms (ECGs), and pharmacokinetic and immunogenicity assays. All 40 subjects tolerated the infusion of the study drug, and 39 subjects completed the study. One serious adverse event of schizophrenia occurred in the 0.3-mg/kg cohort. One grade 3 neutropenia occurred in the 3-mg/kg cohort. Six MGAWN1-treated subjects experienced 11 drug-related adverse events, including diarrhea (1 subject), chest discomfort (1), oral herpes (1), rhinitis (1), neutropenia (2), leukopenia (1), dizziness (1), headache (2), and somnolence (1). In the 30-mg/kg cohort, MGAWN1 had a half-life of 26.7 days and a maximum concentration in serum (C(max)) of 953 microg/ml. This study suggests that single infusions of MGAWN1 up to 30 mg/kg appear to be safe and well tolerated in healthy subjects. The C(max) of 953 microg/ml exceeds the target level in serum estimated from hamster studies by 28-fold and should provide excess WNV neutralizing activity and penetration into the brain and cerebrospinal fluid (CSF). Further evaluation of MGAWN1 for the treatment of West Nile virus infections is warranted.


Effect of increased wood harvesting and utilization on required greenhouse gas displacement factors of wood-based products and fuels.
A displacement factor (DF) may be used to describe the efficiency of using wood-based products or fuels instead of fossil-based ones to reduce net greenhouse gas (GHG) emissions. However, the DFs of individual products and their production volumes could not be used alone to evaluate the climate impacts of forest utilization. For this reason, in this study we have developed a methodology to assess a required displacement factor (RDF) for all wood products and bioenergy manufactured and harvested in a certain country in order to achieve zero CO2 equivalent emissions from increased forest utilization over time in comparison with a selected baseline harvesting scenario. Input data for calculations were produced with the simulation model, Monsu, capable of predicting the carbon stocks of forests and wood-based products. We tested the calculations in Finnish conditions in a 100-year time horizon and estimated the current average DF of manufactured wood-based products and fuels in Finland for the interpretation of RDF results. The results showed that if domestic wood harvesting will be increased by 17-33% compared to the basic scenario, the RDF will be 2.0 to 2.4 tC tC-1 for increased wood use in 2017-2116. However, the estimated average DF of manufactured wood-based products and fuels currently in Finland was less than 1.1 tC tC-1. The results indicate strongly that the increased harvesting intensity from the current situation would represent a challenge for the Finnish forest-based bioeconomy from the viewpoint of climate change mitigation. For this reason, there is an immediate need to improve reliability and applicability of the RDF approach by repeating corresponding calculations in different circumstances and by improving estimations of DFs on country levels.


Amino acid residues that define both the isoprenoid and CAAX preferences of the Saccharomyces cerevisiae protein farnesyltransferase. Creating the perfect farnesyltransferase.
Studies of the yeast protein farnesyltransferase (FTase) have shown that the enzyme preferentially farnesylates proteins ending in CAAX (C = cysteine, A = aliphatic residue, X = cysteine, serine, methionine, alanine) and to a lesser degree CAAL. Furthermore, like the type I protein geranylgeranyltransferase (GGTase-I), FTase can also geranylgeranylate methionine- and leucine-ending substrates both in vitro and in vivo. Substrate overlap of FTase and GGTase I has not been determined to be biologically significant. In this study, specific residues that influence the substrate preferences of FTase have been identified using site-directed mutagenesis. Three of the mutations altered the substrate preferences of the wild type enzyme significantly. The ram1p-74D FTase farnesylated only Ras-CIIS and not Ras-CII(M,L), and it geranylgeranylated all three substrates as well or better than wild type. The ram1p-206DDLF FTase farnesylated Ras-CII(S,M,L) at wild type levels but could no longer geranylgeranylate the Ras-CII(M,L) substrates. The ram1p-351FSKN FTase farnesylated Ras-CIIS and Ras-CIIM but not Ras-CIIL. The ram1p-351FSKN FTase was not capable of geranylgeranylating the Ras-CII(M,L) substrates, giving this mutant the attributes of the dogmatic FTase that only farnesylates non-leucine-ending CAAX substrates and does not geranylgeranylate any substrate. These results suggest that the isoprenoid and protein substrate specificities of FTase are interrelated. The availability of a mutant FTase that lacked substrate overlap with the protein GGTase-I made possible an analysis of the role of substrate overlap in normal cellular processes of yeast, such as mating and growth at elevated temperatures. Our findings suggest that neither farnesylation of leucine-ending CAAX substrates nor geranylgeranylation by the FTase is necessary for these cellular processes.


Myocardial blood flow and oxygen consumption in patients with Friedreich's ataxia prior to the onset of cardiomyopathy.
We tested the hypothesis, in patients with Friedreich's ataxia and no overt structural heart disease, that impairment of cardiac oxidative metabolism may be compensated for either by increased rest myocardial blood flow or more efficient oxygen consumption in performance of external work. Friedreich's ataxia is characterized by a mutant frataxin gene, which causes mitochondrial iron overload and impaired energy production. Further, it is frequently associated with cardiomyopathy. Studies using magnetic resonance spectroscopy, however, suggest impaired cardiac energetics even in the absence of structural heart disease. Positron emission tomography measured rest myocardial blood flow (N-13-ammonia method) and myocardial oxygen consumption (11-C-acetate, Kmono) in Friedreich's ataxia patients (n=8; 31+/-5 years, mean+/-SD, four women) and healthy controls (n=8; 30+/-7 years, five women) matched for stroke work index and age. Stroke work index and power were determined by electrocardiogram gated positron emission tomography N-13-ammonia using modified Simpson's rule to compute left ventricular volumes. Neither stroke work index nor rest myocardial blood flow differed significantly between the groups. Although myocardial oxygen consumption was lower in Friedreich's ataxia (P<0.001), Kmono/rest myocardial blood flow, an index of myocardial oxygen extraction, did not differ between the groups. Power/Kmono, an index of the efficiency of myocardial oxygen consumption, was greater in Friedreich's ataxia (P<0.04). Rest myocardial blood flow normalized to rate pressure product was lower in Friedreich's ataxia (P<0.05). Prior to the onset of cardiomyopathy, selected patients with Friedreich's ataxia may compensate for impaired cardiac energetics through more efficient oxygen consumption rather than increased rest myocardial blood flow. The data illustrate a more general mechanism pertaining to metabolic regulation of myocardial blood flow and myocardial oxygen consumption.


Endoscopic decompression of L3 nerve root in a case of adult spinal deformity correction with post-operative neurological deficit: a case report.
Adult spinal deformities (ASD) have a very high incidence of postoperative neurological decline. Spine surgeons all over the world are broadening the indications of endoscopic spine surgery (ESS) with similar/better outcomes to other conventional spine surgeries. In this report we present a case of L3-radiculopathy post ASD correction and its management with ESS. A 78-year-old female operated for ASD presented with backache, and right-side-dominant radiating leg pain. Imaging showed distal junctional failure with left rod fracture between L5-S1 and screw loosening with gross sagittal imbalance. She was treated with L4 pedicle subtraction osteotomy (PSO) with T10-iliac posterior fixation with use of satellite rods at PSO site. Post-operatively she developed left-sided L3 motor deficit. Imaging revealed left L3 root compression by bone fragment near the left L3 pedicle screw-head. We presume that, since the L3 pedicular screw had to be inserted deeper than the other screws to accommodate the satellite-rod, the bone in the area near the screw head (part of either the pedicle or facet) caused compression of the left L3 nerve root. The patient was treated with interlaminar ESS under awake anaesthesia and the compressing bone was drilled out. Post-operatively, patient had rapid relief of the radicular pain and improvement in the left quadriceps (L3) power with no recurrence at 1-year follow-up. Thus, post-operative iatrogenic neurological deficits can be treated successfully using ESS when the exact cause of the deficit is identified and is amenable to endoscopic removal. We could successfully treat a case of left-sided L3-radiculopathy, caused due to protruding bony spur after ASD correction surgery with ESS.


Image-based modeling and scoring of Howell-Jolly Bodies in human erythrocytes.
The spleen selectively removes cells with intracellular inclusions, for example, detached nuclear fragments in circulating erythrocytes, called Howell-Jolly Bodies (HJBs). With absent or deficient splenic function HJBs appear in the peripheral blood and can be used as a simple and non-invasive risk-indicator for fulminant potentially life-threatening infection after spleenectomy. However, it is still under debate whether counting of the rare HJBs is a reliable measure of splenic function. Investigating HJBs in premature erythrocytes from patients during radioiodine therapy gives about 10 thousand times higher HJB counts than in blood smears. However, we show that there is still the risk of false-positive results by unspecific nuclear remnants in the prepared samples that do not originate from HJBs, but from cell debris residing above or below the cell. Therefore, we present a method to improve accuracy of image-based tests that can be performed even in non-specialized medical institutions. We show how to selectively label HJB-like clusters in human blood samples and how to only count those that are undoubtedly inside the cell. We found a "critical distance" dcrit referring to a relative HJB-Cell distance that true HJBs do not exceed. To rule out false-positive counts we present a simple inside-outside-rule based on dcrit -a robust threshold that can be easily assessed by combining conventional 2D imaging and straight-forward image analysis. Besides data based on fluorescence imaging, simulations of randomly distributed HJB-like objects on realistically modelled cell objects demonstrate the risk and impact of biased counting in conventional analysis. © 2017 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of ISAC.


Assisting the translation of SNOMED CT into French using UMLS and four representative French-language terminologies.
To provide a semantics-based method to assist the translation of SNOMED CT into French. To do so, we selected four French-language terminologies: ICD-10, SNOMED International, MedDRA, MeSH, as they are dedicated to different uses - epidemiology, clinical medicine, adverse reactions, medical literature, respectively - in order to map them to SNOMED Clinical Terms (CT), and thus associate French terms with SNOMED CT concepts. In this way, we measured the number of SNOMED CT concepts to be found in French-language terminologies. We used the UMLS Metathesaurus. The mapping method was based on the coincidence of identifiers and on the explicit mappings present in the Metathesaurus. The study dealt exclusively with preferred terms (PTs) in the terminologies. The terminologies are mapped with varying success as regards PTs mapped to SNOMED terms (from 52% to 96%). Conversely, 45% of SNOMED CT terms are mapped by uniting the four terminologies. A more effective mapping technique than the current method is under consideration. The method presented will be refined. It could certainly provide useful assistance in the translation of SNOMED CT into French. Due to its general nature, it could be used to translate SNOMED CT into other languages than French.


The Regulation of the Practice of Acupuncture by Physicians in the United States.
Introduction: The landscape of acupuncture regulation has greatly evolved since the National Institutes of Health Consensus Statement in 1997. In recent decades, acupuncture treatment has become increasingly integrated with conventional medical care. Healthcare practitioners often utilize acupuncture as an adjunctive therapy to help alleviate symptoms of many conditions, such as nausea and pain. The popularity of this complementary and alternative modality has elevated the importance and urgency for states to regulate its practice and safety. Materials and Methods: The authors comprehensively examined the regulation of the practice of acupuncture by licensed physicians in the United States. Current statutes were evaluated with respect to those from past decades. Requirements were compared with the World Health Organization's recommendations for acupuncture basic training and safety. Results: Most physicians are permitted to practice acupuncture within the scope of their medical practices. Many states mandate that they complete additional education and training. Three states require that physicians obtain acupuncture licenses through the same process as non-physicians. Compared to prior decades, many states have changed their requirements. Conclusions: This article provides current, individual state regulations for the practice of acupuncture by physicians.


Autopsy case of the cerebellar form of progressive multifocal leukoencephalopathy without immunodeficiency.
A case of the cerebellar form of progressive multifocal leukoencephalopathy (PML) without remarkable immune depression or immune deficiency is reported here. The patient was a 74-year-old-woman who had complications of chronic renal failure and renal anemia for several years. Seven months before her death she had symptoms of general fatigue, gait disturbance and articulation disorder. During her hospitalization period her neurological disorder gradually progressed irreversibly with failure of consciousness and she died of respiratory failure. She did not have remarkable clinical signs of immunodeficiency nor did she receive immunosuppressive therapy. Clinically she had not been diagnosed with PML. At the post-mortem examination different degrees of demyelination were observed in the brain white matter: diffuse and severe in the cerebellum, moderate and coalescent in the brainstem, and light and patchy in the cerebrum. JC virus antigen-positive cells were frequently observed in the demyelinated lesions in the cerebrum and sometimes observed in the brainstem, but were rarely found in the cerebellum. These findings suggest that PML lesions may be present with different degrees of demyelination that are inversely correlated with the number of JC virus-infected cells. This fact should be considered when evaluating the brain biopsies of PML patients.


Low patient satisfaction scores: the five stages of response.
When faced with poor patient satisfaction scores, emergency department physicians and medical directors have similar reactions. Ironically, the emotions experienced mimic the stages of grief.


Retrospective serosurvey of leptospirosis among patients with acute febrile illness and hepatitis in Egypt.
The epidemiologic status of leptospirosis in Egypt has not been well defined because of difficulties in disease diagnosis. A retrospective study was conducted to detect leptospiral antibodies among undiagnosed acute febrile illness (AFI) and hepatitis cases. Approximately 16% of both AFI (141/886) and acute hepatitis (63/392) cases showed seroreactivity to Leptospira IgM by ELISA and microscopic agglutination test (MAT). Canicola, Djasiman, Grippotyphosa, Pyrogenes, Icterohemorrhagiae, and Pomona were the most commonly reactive serovars among patients with AFI. Djasiman, Grippotyphosa and Icterohemorrhagiae were the most reactive among patients with acute hepatitis. This study represents the first systematic report of Leptospira associated with patients with AFI and hepatitis in Egypt. Physicians need to have increased awareness about the importance of leptospirosis in the differential diagnosis of AFI and acute hepatitis in Egypt. In addition, laboratory capacity should be developed at fever hospitals to diagnose leptospirosis.


The role of endoscopy in the management of hereditary diffuse gastric cancer syndrome.
Hereditary diffuse gastric cancer (HDGC) syndrome is an inherited cancer risk syndrome associated with pathogenic germline CDH1 variants. Given the high risk for developing diffuse gastric cancer, CDH1 carriers are recommended to undergo prophylactic total gastrectomy for cancer risk reduction. Current guidelines recommend upper endoscopy in CDH1 carriers prior to surgery and then annually for individuals deferring prophylactic total gastrectomy. Management of individuals from HDGC families without CDH1 pathogenic variants remains less clear, and management of families with CDH1 pathogenic variants in the absence of a family history of gastric cancer is particularly problematic at present. Despite adherence to surveillance protocols, endoscopic detection of cancer foci in HDGC is suboptimal and imperfect for facilitating decision-making. Alternative endoscopic modalities, such as chromoendoscopy, endoscopic ultrasound, and other non-white light methods have been utilized, but are of limited utility to further improve cancer detection and risk stratification in HDGC. Herein, we review what is known and what remains unclear about endoscopic surveillance for HDGC, among individuals with and without germline CDH1 pathogenic variants. Ultimately, the use of endoscopy in the management of HDGC remains a challenging arena, but one in which further research to improve surveillance is crucial.


Improved stability bound for steady-state flow in a car-following model of road traffic on a circular route.
This note revisits a car-following model of road traffic on a circular route that was studied in recent literature, and improves a stability result for steady-state flows that was obtained in this literature. It will be shown through a counter example that the stability bound obtained in the literature only gives a sufficient condition for stability, which only becomes necessary when the number of cars on the route tends to infinity. We will further present a result that gives a necessary and sufficient condition for stability.


Anatomic vascular considerations in uterine artery ligation at its origin during laparoscopic hysterectomies.
Pelvic pathology such as fibroids, endometriosis, adhesions from previous pelvic surgeries, or ovarian remnants can distort anatomy and pose technical challenges during laparoscopic hysterectomies. Retroperitoneal dissection to ligate the uterine artery at its vascular origin can circumvent these obstacles, resulting in a safer procedure. However, detailed anatomic knowledge of the course of the uterine artery and understanding of vascular variations are essential for optimal dissection. We frequently encounter a C-shaped uterine artery variation during retroperitoneal dissection. We describe the key steps in identification and isolation of this variant, approaching the uterine artery origin either from the pararectal space or by utilizing the medial umbilical ligament coursing through the paravesical space. We also review other known uterine artery configurations. These techniques allow for safe completion of complex laparoscopic hysterectomies performed for various gynecologic diseases.


Long-term follow-up of patients with congenital thrombotic thrombocytopenia purpura receiving a plasma-derived factor VIII (Koate) that contains ADAMTS13.
Hereditary thrombotic thrombocytopenia purpura (hTTP) is an ultra-rare disorder resulting from an inherited deficiency of ADAMTS13, a von Willebrand factor (VWF)-cleaving metalloprotease. The plasma-derived factor VIII/VWF Koate (FVIII/VWFKoate ) has been shown to contain ADAMTS13, allowing for its use to treat hTTP at home by the patient/caregiver. Based on prior demonstration of safe and effective use of FVIII/VWFKoate in eight patients with hTTP, we conducted a retrospective study to gather additional data regarding the use of FVIII/VWFKoate for hTTP. This was a multicentre, retrospective, noninterventional chart review of patients who had received FVIII/VWFKoate for the management of hTTP. Data collected included demographics, medical history, relevant family history, past use and tolerability of fresh frozen plasma, and details regarding FVIII/VWFKoate therapy. The cohort included 11 patients (seven males, four females) with hTTP, ranging in age at study entry from 2 to 28 years. The average duration of FVIII/VWFKoate therapy was 4.8 years (range, 0.5-6.5 years). Among nine patients using FVIII/VWFKoate as prophylaxis, the normalized annual rate of breakthrough TTP episodes ranged from 0.2 to 1.1 episodes/year. All nine patients who received FVIII/VWFKoate prophylaxis had thrombocytopenia recorded at baseline, while eight (88.9%) did not have thrombocytopenia after using FVIII/VWFKoate . There was one AE (unspecified) attributed to FVIII/VWFKoate . These data suggest that FVIII/VWFKoate is a safe and well-tolerated source of the missing ADAMTS13 enzyme in patients with hTTP, producing a marked reduction in thrombocytopenia prevalence, low frequency of TTP episodes, and with the added benefit of self- or caregiver-administration.


Prognostic factors of survival and recurrence pattern in differentiated thyroid cancer: a retrospective study from Western Turkey.
The aim of this study was to determine prognostic factors in patients with well-differentiated thyroid cancer (WDTC). This retrospective study included 181 well-differentiated thyroid cancer patients who were operated between Decembers 1996-2007. Total of 181 patients [139 (76.8%) women and 42 (23.2%) men with a mean age of 46.3 years] who were subjected to a complete follow-up, were enrolled in the study. The mean follow-up period was 7.1 years (range 3.1 to 14.9 years). Medical records were reviewed regarding to age, gender, extent of surgery, tumor size, multifocality, clinical stage, capsule infiltration, extracapsular invasion, histological type, lymph node metastasis, distant metastasis, radioactive iodine treatment and prognosis. During follow-up, in 41 (22.6%) patients locoregional recurrences were detected and 5 (2.7%) patients passed away. Determined statistically significant prognostic factors were as follows; tumor size (histopathologically), extent of surgery, histological type, lymph node metastasis, tumor invasion (capsule and extracapsular) and clinical stage. Well-differentiated thyroid cancer is a disease with good prognosis when detected early and appropriate treatment applied. Despite the prognosis, it is good to apply the right treatment and reduce recurrence and mortality rates, prognostic factors are well known and must be considered in patient management.


Nutrigenomics in the context of evolution.
Nutrigenomics describes the interaction between nutrients and our genome. Since the origin of our species most of these nutrient-gene communication pathways have not changed. However, our genome experienced over the past 50,000 years a number of evolutionary pressures, which are based on the migration to new environments concerning geography and climate, the transition from hunter-gatherers to farmers including the zoonotic transfer of many pathogenic microbes and the rather recent change of societies to a preferentially sedentary lifestyle and the dominance of Western diet. Human populations responded to these challenges not only by specific anthropometric adaptations, such as skin color and body stature, but also through diversity in dietary intake and different resistance to complex diseases like the metabolic syndrome, cancer and immune disorders. The genetic basis of this adaptation process has been investigated by whole genome genotyping and sequencing including that of DNA extracted from ancient bones. In addition to genomic changes, also the programming of epigenomes in pre- and postnatal phases of life has an important contribution to the response to environmental changes. Thus, insight into the variation of our (epi)genome in the context of our individual's risk for developing complex diseases, helps to understand the evolutionary basis how and why we become ill. This review will discuss the relation of diet, modern environment and our (epi)genome including aspects of redox biology. This has numerous implications for the interpretation of the risks for disease and their prevention.


Organizational characteristics influencing nursing home social service directors' qualifications: a national study.
This research sought to identify organizational characteristics associated with the amount of professional qualifications among a nationally representative sample of nursing home social service directors. A self-administered survey was sent to directors in 675 facilities randomly sampled from a federal database, excluding facilities with fewer than 120 beds that are not required to staff a full-time social worker. The response rate was 45 percent (N = 299). Univariate results showed that most respondents possessed a social work degree, most lacked licensure, and few were clinically supervised. A multiple regression analysis found that nonprofit, independently owned facilities in rural areas staffed social service directors who were significantly more qualified than directors in for-profit, chain-affiliated facilities in urban and suburban areas. Facilities with fewer psychosocial deficiencies and higher occupancy rates employed social service directors with greater qualifications. The implications of these findings for social work education, practice, policy, and research are discussed.


Exploring the epidemiology of carbapenem-resistant Gram-negative bacteria in west London and the utility of routinely collected hospital microbiology data.
The objective of this study was to identify carbapenem-resistant organisms using routinely collected local microbiology data and describe the epidemiology of carbapenem resistance in two London teaching hospitals. Data on inpatients infected or colonized with Gram-negative organisms between March 2009 and February 2012 were extracted. A computer algorithm was developed incorporating internationally recognized criteria to distinguish carbapenem-resistant organisms. Multivariable analysis was conducted to identify factors associated with infection or colonization with carbapenem-resistant organisms. Binomial regression was performed to detect changes in resistance trends over time. Yearly incidence of carbapenem resistance was observed to be increasing, with significant increasing trends in Acinetobacter baumannii (47.1% in 2009-10 to 77.2% in 2011-12; P<0.001) and Enterobacter spp. (2.2% in 2009-10 to 11.5% in 2011-12; P<0.001). Single-variable and multivariable analysis demonstrated differences in the proportion of carbapenem-resistant isolates across all variables investigated, including age, sex and clinical specialty; in the latter organism-specific niches were identified. Patients in the youngest age group (16-24 years old) had the highest odds of being infected or colonized with carbapenem-resistant isolates of Escherichia coli, Klebsiella spp. or Pseudomonas aeruginosa. Furthermore, proportions of carbapenem-resistant organisms differed between the hospitals. Carbapenem resistance is an emerging problem within the UK inpatient healthcare setting. This is not an issue confined to the Enterobacteriaceae and fine-resolution surveillance is needed to identify at-risk groups. Regular analysis of routinely collected data can provide insight into the evolving carbapenem-resistance threat, with the ability to inform efforts to prevent the spread of resistance.


Proton dynamics in strong (short) intramolecular H-bond. DFT study of the KH maleate crystal.
The structure, harmonic frequencies, and infrared intensities of the fundamental transitions of potassium hydrogen/deuterium maleate crystals have been computed by the density functional theory with periodic boundary conditions. Different functionals with all-electron Gaussian-type orbital (GTO) basis set have been used. It was found that BLYP/GTO approximation provides the best results for the structural parameters of the KH maleate crystal. Within this approximation, the hydrogen-bonded potential in the KH maleate crystal is extremely shallow. Delocalization of the bridging protons complicates a strict definition of the space group of the crystal; the space groups Pbcm and Pbc2(1) represent an equivalent choice. The periodic BLYP/GTO study provides detailed information on the nature of the internal vibrations of the hydrogen maleate anion, which are located in the range 300-1800 cm(-1). Assignment of the vibrational bands in this frequency region has been performed. The two most intensive bands in the infrared spectrum (approximately 500 and approximately 1450 cm(-1)) are caused by the "pure" asymmetric O...H...O stretching vibrations and the stretching motion of the bridging proton heavily mixed with the C-C stretching and CH bending vibrations, respectively. A crystalline environment is found to play an important role in the low-frequency region and is negligible above 1000 cm(-1). The H/D substitution slightly changes the vibration frequencies, involving the stretching motion of the bridging proton because of the strong coupling between this motion and the various internal vibrations of the hydrogen maleate anion.


Mammography of breast carcinoma: experience of 108 cases.
Mammography is the radiographic imaging of the breast and includes screen-film mammography and xeromammography. From September 1987 to March 1990, 108 patients with breast carcinoma received mammographic examinations at Chang Gung Memorial Hospital. The spectrum of mammographic appearance included mass abnormalities (50.9%), calcifications (10.2%), a combination of mass abnormalities and calcifications (25%), asymmetrical increased density (4.6%), and parenchymal distortion (1.9%). The remaining 7.4% of the lesions lacked any radiologic sign of malignancy and primarily appeared as dense breast on the mammogram. In this series, mammography had a sensitivity of 86.1%, a specificity of 77.3% and a positive predictive value of 67.4%. Recognition of these mammographic appearances is beneficial in detecting breast carcinoma and in establishing a correct diagnosis. In addition, knowing the abilities, as well as limitations, of mammography will optimize the efficacy of this examining modality.


MicroRNA-325-3p protects the heart after myocardial infarction by inhibiting RIPK3 and programmed necrosis in mice.
Receptor-interacting serine-threonine kinase 3 (RIPK3)-mediated necroptosis has been implicated in the progression of myocardial infarction (MI), but the underlying mechanisms, particularly whether microRNAs (miRNAs) are involved, remain largely unknown. A microarray analysis was used to screen for miR-325-3p expression in myocardial tissues from MI mice, and the expression was confirmed with qRT-PCR. The levels of myocardial enzymes were measured using commercial kits, and an echocardiography system was utilized for the detection of cardiac function parameters. The pathological features and infarction sizes of cardiac tissues were examined using H&E, TCC and Masson's trichrome staining, and the amount of cell apoptosis was determined using an in situ TUNEL assay. Cardiomyocytes were isolated and then subjected to hypoxia induction in vitro. The expression of the RIPK1, RIPK3 and phosphorylated MLKL (p-MLKL) proteins was measured using a Western blot. The mouse cardiomyocyte cell viability was analyzed by an MTT assay. The mRNA target of miR-325-3p was predicted using TargetScan v7.2 and then validated using a dual-luciferase reporter assay. The overexpression of miR-325-3p evidently decreased the expression levels of lactate dehydrogenase (LDH), phosphocreatine kinase (CK), superoxide dismutase (SOD) and malondialdehyde (MDA), inhibited left ventricular end-diastolic diameter (LVEDD) and left ventricular end-systolic diameter (LVESD), and promoted left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVES). In addition, miR-325-3p overexpression attenuated the degree of injury to the cardiac tissue, decreased the infarct sizes and downregulated the expression of the necrosis-related proteins RIPK1, RIPK3 and p-MLKL. The RIPK1/RIPK3/p-MLKL axis-induced necroptosis that occurred during MI was mediated by a miRNA module, miR-325-3p, which can effectively ameliorate the symptoms of MI by suppressing the expression of RIPK3.


Rape and the Straw Man: A Response to Lindsay Kelland.
Lindsay Kelland has taken issue with a claim I made in a book titled The Second Sexism: Discrimination Against Men and Boys. In response to this claim, she has argued that when a woman is raped, it matters that her rapist is a male because "her situation as a woman under patriarchy is partly constitutive of the harm that she suffers" in being raped. In my response to her article, I show that she has taken my claim out of context and thereby misrepresented it. As a result, her article fails to respond to anything I said.


The proportion of nitrate in leaf nitrogen, but not changes in root growth, are associated with decreased grain protein in wheat under elevated [CO2].
The atmospheric CO2 concentration ([CO2]) is increasing and predicted to reach ∼550ppm by 2050. Increasing [CO2] typically stimulates crop growth and yield, but decreases concentrations of nutrients, such as nitrogen ([N]), and therefore protein, in plant tissues and grains. Such changes in grain composition are expected to have negative implications for the nutritional and economic value of grains. This study addresses two mechanisms potentially accountable for the phenomenon of elevated [CO2]-induced decreases in [N]: N uptake per unit length of roots as well as inhibition of the assimilation of nitrate (NO3-) into protein are investigated and related to grain protein. We analysed two wheat cultivars from a similar genetic background but contrasting in agronomic features (Triticum aestivum L. cv. Scout and Yitpi). Plants were field-grown within the Australian Grains Free Air CO2 Enrichment (AGFACE) facility under two atmospheric [CO2] (ambient, ∼400ppm, and elevated, ∼550ppm) and two water treatments (rain-fed and well-watered). Aboveground dry weight (ADW) and root length (RL, captured by a mini-rhizotron root growth monitoring system), as well as [N] and NO3- concentrations ([NO3-]) were monitored throughout the growing season and related to grain protein at harvest. RL generally increased under e[CO2] and varied between water supply and cultivars. The ratio of total aboveground N (TN) taken up per RL was affected by CO2 treatment only later in the season and there was no significant correlation between TN/RL and grain protein concentration across cultivars and [CO2] treatments. In contrast, a greater percentage of N remained as unassimilated [NO3-] in the tissue of e[CO2] grown crops (expressed as the ratio of NO3- to total N) and this was significantly correlated with decreased grain protein. These findings suggest that e[CO2] directly affects the nitrate assimilation capacity of wheat with direct negative implications for grain quality.


Dose-responses of Bacillus cereus RS87 for growth enhancement in various Thai rice cultivars.
To achieve the goal of reducing the levels of chemical fertilizers applied in rice production, there is a need to develop microorganisms with the capacity to enhance plant growth. Previous studies have demonstrated that Bacillus cereus RS87 promotes growth of various plants in greenhouse and field trials. The objectives of this study were to (i) evaluate the efficacy and determine the optimum concentration of B. cereus RS87 to enhance growth of various Thai rice cultivars, (ii) measure the chlorophyll content in leaves affected by strain RS87, and (iii) investigate the capacity of strain RS87 to solubilize phosphate and produce siderophores. Three concentrations of strain RS87 (log 6.0, log 7.0, and log 8.0 CFU/mL) were applied to each rice cultivar. Superior responses (i.e., enhanced development of roots and shoots of all rice cultivars) were observed using RS87 at log 8.0 CFU/mL compared with lower bacterial concentrations and the water-treated control treatment. In addition, log 8.0 CFU/mL of RS87 provided the greatest root length and plant height of all rice cultivars 45 days after planting in the greenhouse. Rice leaves treated with log 8.0 CFU/mL of RS87 yielded the highest total chlorophyll, specifically chlorophyll a and chlorophyll b, compared with the control. Strain RS87 also solubilized phosphate and produced siderophores. The results of these studies demonstrate that log 8.0 CFU/mL is the optimum concentration of strain RS87 for growth promotion of various Thai rice cultivars.


Nanoparticle-based immunochromatographic test strip with fluorescent detector for quantification of phosphorylated acetylcholinesterase: an exposure biomarker of organophosphorus agents.
A nanoparticle-based fluorescence immunochromatographic test strip (FITS) coupled with a hand-held detector for highly selective and sensitive detection of phosphorylated acetylcholinesterase (AChE), an exposure biomarker of organophosphate (OP) pesticides and nerve agents, is reported. In this approach, OP-AChE adducts were selectively captured by quantum dot-tagged anti-AChE antibodies (Qdot-anti-AChE) and zirconia nanoparticles (ZrO2 NPs). The sandwich-like immunoreactions were performed among the Qdot-anti-AChE, OP-AChE and ZrO2 NPs to form a Qdot-anti-AChE-OP-AChE-ZrO2 complex, which was detected by recording the fluorescence intensity of Qdots captured during the test line. Paraoxon was used as the model OP pesticide. Under optimal conditions, this portable FITS immunosensor demonstrates a highly linear absorption response over the range of 0.01 nM to 10 nM OP-AChE, with a detection limit of 4 pM, coupled with good reproducibility. Moreover, the FITS immunosensor has been validated with OP-AChE spiked human plasma samples. This is the first report on the development of ZrO2 NP-based FITS for the detection of the OP-AChE adduct. The FITS immunosensor provides a sensitive and low-cost sensing platform for on-site screening/evaluating OP pesticides and nerve agents poisoning.


Association of depressive symptoms with ambient PM2.5 in middle-aged and elderly Chinese adults: A cross-sectional study from the China health and Retirement Longitudinal Study wave 4.
Depressive symptoms have become a serious public health issue worldwide. Several studies showed that air pollution, especially fine particulate matter (PM2.5), may be a risk factor of mental disorders. However, existing studies reported inconsistent results and little evidence is available in developing countries, like China. To fill the gap, in this study, we explored the relationship between ambient PM2.5 exposure and depressive symptoms among middle-aged and elderly Chinese adults in the Chinese Health and Retirement Longitudinal Study (CHARLS). The social and demographic variables and depressive symptoms were obtained from the Wave4 of CHARLS in 2018. PM2.5 concentrations were obtained from the national urban air quality real-time release platform of China Environmental Monitoring Station. We applied generalized linear mixed models to determine the association between PM2.5 exposure and depressive symptoms. A total of 15,105 middle-aged and elderly adults from CHARLS Wave4 were included in the analyses. We found positive impact of ambient PM2.5 on depressive symptoms for the exposure windows of 30-day, 60-day, 120-day, 180-day, 1-year and 2-year. The most significant increase was observed for 180-day moving average. For every 10 μg/m3 increment in PM2.5 exposure, the incidence of depressive symptoms increased by 9% (OR = 1.09; 95%CI: 1.05, 1.14) after adjusting for age, sex and residence. In interaction analyses, we found PM2.5 had weaker effect on depressive symptoms among people who used to drink alcohol (OR = 1.05; 95%CI: 1.00, 1.10) and exercise (OR = 1.10; 95%CI: 1.02, 1.18). People living in western China (OR = 1.09; 95%CI: 1.03, 1.16) were more vulnerable than those living in eastern China (OR = 0.99; 95%CI: 0.94, 1.05). In conclusion, exposure to PM2.5 was significantly associated with depressive symptoms in middle-aged and elder Chinese adults, particularly for people who never drink, with lower physical activity levels, or lived in western China.


Hydraulic prediction of drought-induced plant dieback and top-kill depends on leaf habit and growth form.
Hydraulic failure caused by severe drought contributes to aboveground dieback and whole-plant death. The extent to which dieback or whole-plant death can be predicted by plant hydraulic traits has rarely been tested among species with different leaf habits and/or growth forms. We investigated 19 hydraulic traits in 40 woody species in a tropical savanna and their potential correlations with drought response during an extreme drought event during the El Niño-Southern Oscillation in 2015. Plant hydraulic trait variation was partitioned substantially by leaf habit but not growth form along a trade-off axis between traits that support drought tolerance versus avoidance. Semi-deciduous species and shrubs had the highest branch dieback and top-kill (complete aboveground death) among the leaf habits or growth forms. Dieback and top-kill were well explained by combining hydraulic traits with leaf habit and growth form, suggesting integrating life history traits with hydraulic traits will yield better predictions.


Intracellular glutathione-depleting polymeric micelles for cisplatin prodrug delivery to overcome cisplatin resistance of cancers.
The intrinsic or acquired cisplatin resistance of cancer cells frequently limits the final therapeutic efficacy. Detoxification by the high level of intracellular glutathione (GSH) plays critical roles in the majority of cisplatin-resistant cancers. In this report, we designed an amphiphilic diblock copolymer composed of poly(ethylene glycol) (PEG) and polymerized phenylboronic ester-functionalized methacrylate (PBEMA), PEG-b-PBEMA, which can self-assemble into micelles in aqueous solutions to load hydrophobic cisplatin prodrug (Pt(IV)). Pt(IV)-loaded PEG-b-PBEMA micelles (PtBE-Micelle) reverse cisplatin-resistance of cancer cells through improving cellular uptake efficiency and reducing intracellular GSH level. We found that the cellular uptake amount of platinum from PtBE-Micelle was 6.1 times higher than that of free cisplatin in cisplatin-resistant human lung cancer cells (A549R). Meanwhile, GSH concentration of A549R cells was decreased to 32% upon treatment by PEG-b-PBEMA micelle at the phenyl borate-equivalent concentration of 100μM. PtBE-Micelle displayed significantly higher cytotoxicity toward A549R cells with half maximal inhibitory concentration (IC50) of cisplatin-equivalent 0.20μM compared with free cisplatin of 33.15μM and Pt(IV)-loaded PEG-b-poly(ε-caprolactone) micelles of cisplatin-equivalent 0.75μM. PtBE-Micelle can inhibit the growth of A549R xenograft tumors effectively. Accordingly, PEG-b-PBEMA micelles show great potentials as drug delivery nanocarriers for platinum-based chemotherapy toward cisplatin-resistant cancers.


Antimicrobial resistance in healthcare, agriculture and the environment: the biochemistry behind the headlines.
The crisis of antimicrobial resistance (AMR) is one of the most serious issues facing us today. The scale of the problem is illustrated by the recent commitment of Heads of State at the UN to coordinate efforts to curb the spread of AMR infections. In this review, we explore the biochemistry behind the headlines of a few stories that were recently published in the public media. We focus on examples from three different issues related to AMR: (i) hospital-acquired infections, (ii) the spread of resistance through animals and/or the environment and (iii) the role of antimicrobial soaps and other products containing disinfectants in the dissemination of AMR. Although these stories stem from three very different settings, the underlying message in all of them is the same: there is a direct relationship between the use of antimicrobials and the development of resistance. In addition, one type of antimicrobial could select for cross-resistance to another type and/or for multidrug resistance. Therefore, we argue the case for increased stewardship to not only cover clinical use of antibiotics, but also the use of antimicrobials in agriculture and stewardship of our crucially important biocides such as chlorhexidine.


Action of aldosterone on cultured renal collecting duct cells during the latent period.
The effects of aldosterone on protein synthesis in the latent period were investigated on cultured renal collecting duct cells from neonatal rabbit kidneys. Tissue was incubated with radioactively labelled uridine and amino acids and then precipitated with trichloroacetic acid in order to determine the intracellular precursor pool and identify new synthesis of RNA and protein. During the latent period, aldosterone increased the intracellular radioactive uridine pool and total radioactive RNA content already 20 and 60 min after its application; conversely 40 min after aldosterone introduction, no stimulation was found. Further experiments revealed that the intracellular radioactive amino acid pool was generally increased by aldosterone after 20, 40 and 60 min, while a distinct increased radioactive protein content was found to be induced by aldosterone only after 40 min. This indicates that aldosterone increases the uptake of RNA and protein precursors and the new synthesis of RNA and proteins. These events seem to to be regulated not continuously but intermittently. The induced proteins possibly take part in the mediation of the early hormone response. Experiments with the aldosterone antagonist, spironolactone, provide evidence for the specificity of the described hormone effects. The results after application of the Na+ channel blocker, amiloride, and the Na+/K(+)-ATPase inhibitor, G-strophanthin, indicate that the aldosterone effects are controlled by Na+ channels and Na+ pumps and therefore by the intracellular Na+ content. The inhibitory effect of cycloheximide on the aldosterone-induced protein synthesis indicates the role of these proteins on the hormone-stimulated Na+ transport.


Evaluation of respiratory volume monitoring (RVM) to detect respiratory compromise in advance of pulse oximetry and help minimize false desaturation alarms.
Monitoring respiratory function is important. By continuously monitoring respiratory volumes, respiratory depression could be identified before hypoxemia and drive earlier intervention. Here, we evaluate the temporal relationship of respiratory volume monitoring (providing real-time minute ventilation [MV], tidal volume, and respiratory rate in nonintubated patients) to hypoxemic episodes and its potential to help classify true vs false desaturations (related to patient movement/probe dislodgement). Respiratory volume monitoring data, oxygen saturation (SpO2), oxygen supplementation, and opioid use were analyzed in 259 patients following orthopedic surgery. Detection of "low MV" (<40% of predicted MV) in advance of low SpO2 (<90%) was used to classify true and false desaturations. Patients were also stratified based on opioid use and development of low MV. Patient's length of stay (LOS) and number of SpO2 alarms were compared across groups (± opioids; ± low MV). The electronic health records reported 113 SpO2 alarms; 105 (93%) not preceded by low MV and considered false. Low MV preceded the eight true desaturations by 12.8 ± 2.8 minutes. One hundred ninety-eight patients (76%) of 259 experienced one or more low MV events. Patients with low MV had significantly longer postanesthesia care unit (PACU) LOS than those maintaining "adequate MV": 2.8 ± 0.1 hours vs. 2.4 ± 0.1 hours (p < 0.001). Patients receiving opioids had increased likelihood of low MV (69% vs. 80%; p < 0.05) and had significantly longer PACU LOS than those without opioids (2.9 ± 0.1 hours vs. 2.3 ± 0.1 hours; p < 0.001). In the opioid group, PACU LOS was 75% longer in patients developing low MV versus maintaining adequate MV (3.0 ± 0.1 hours vs. 1.7 ± 0.2 hours; p < 0.001). Respiratory volume monitoring can provide advanced warning of impending oxygen desaturation and potentially reduce the number of false SpO2 alarms. Opioid administration increased low MV events correlating with increased LOS. Respiratory volume monitoring can help clinicians individualize patient care, decrease false alarms, adjust opioid dosing, and increase PACU throughput. Similar benefits may translate to the general care floor and prehospital and posthospital environments. Diagnostic study, level II.


ACCLAIM: A randomized trial of abatacept (CTLA4-Ig) for relapsing-remitting multiple sclerosis.
Costimulatory blockade of T lymphocytes with the CTLA4-Ig fusion protein abatacept could be an effective treatment for the immune-mediated neuroinflammatory disease relapsing-remitting multiple sclerosis (RRMS). To evaluate efficacy and safety of abatacept in RRMS. ACCLAIM (A Cooperative Clinical Study of Abatacept in Multiple Sclerosis) was a Phase II, randomized, double-blind, placebo-controlled, multi-center trial. In all, 65 of 123 planned participants with RRMS were randomized to monthly intravenous infusions of abatacept or placebo for 24 weeks in a 2:1 ratio, switched to the opposite treatment at 28 weeks, and received their final dose of study medication at 52 weeks. Enrollment was closed early due to slow accrual. The primary endpoint was the mean number of new gadolinium-enhancing (Gd+) lesions obtained on magnetic resonance imaging (MRI) scans performed every 4 weeks. No statistically significant differences were observed in mean number of new Gd+ MRI lesions between the abatacept and placebo groups. No statistically significant differences were observed in other MRI and clinical parameters of RRMS disease activity. Abatacept was well tolerated. The ACCLAIM study did not demonstrate efficacy of abatacept in reducing the number of new Gd+ MRI lesions, or clinical measures of disease activity in RRMS.


Surface-enhanced nonlinear four-wave mixing.
We report on a particularly strong third-order nonlinear response from nanostructured gold surfaces. Two incident laser beams with frequencies omega{1} and omega{2} give rise to four-wave mixing (4WM) fields with frequencies 2omega{1}-omega{2} and 2omega{2}-omega{1}. We demonstrate that the nonlinear response can be purely evanescent and that nanostructured surfaces convert the evanescent energy into propagating radiation, thereby increasing the efficiency of frequency conversion. The emitted 4WM radiation is found to be directional, polarized, coherent, and both frequency and angle tunable. The ability to perform efficient frequency conversion in reduced dimensions provides new opportunities for nanophotonics and active plasmonics.


Bulk chemical characteristics of dissolved organic matter in the ocean.
Dissolved organic matter (DOM) is the largest reservoir of reduced carbon in the oceans. The nature of DOM is poorly understood, in part, because it has been difficult to isolate sufficient amounts of representative material for analysis. Tangential-flow ultrafiltration was shown to recover milligram amounts of >1000 daltons of DOM from seawater collected at three depths in the North Pacific Ocean. These isolates represented 22 to 33 percent of the total DOM and included essentially all colloidal material. The elemental, carbohydrate, and carbon-type (by (13)C nuclear magnetic resonance) compositions of the isolates indicated that the relative abundance of polysaccharides was high ( approximately 50 percent) in surface water and decreased to approximately 25 percent in deeper samples. Polysaccharides thus appear to be more abundant and reactive components of seawater DOM than has been recognized.


Eosinophilic fasciitis: a case series with an emphasis on therapy and induction of remission.
Eosinophilic fasciitis is an uncommon connective tissue disorder that affects patients of all ages, resulting in significant morbidity. Systemic corticosteroids can induce remission of disease. However, there is no universally accepted treatment ladder for eosinophilic fasciitis. This case series evaluates treatment efficacy in patients with eosinophilic fasciitis seen at Wake Forest University Department of Dermatology outpatient clinics. Patient charts were screened using ICD-9 diagnosis code 710.9 (unspecified diffuse connective tissue disease) to identify patients with eosinophilic fasciitis (n=10) seen at our institution. Patients were treated for an average 24 months with a combination of methotrexate and prednisone therapy, unless one or both were contraindicated, with each medication tapered conservatively to prevent disease flares. Alternate treatments included mycophenolate mofetil with prednisone, azathioprine with prednisone, prednisone monotherapy, and methotrexate monotherapy. Disease remission off therapy and on low-dose therapy was 66 and 70%, respectively. Our first-line therapy of concomitant methotrexate and prednisone is well-tolerated and effective for managing patients with eosinophilic fasciitis. Our study was limited to cases seen at a single academic institution.


Nonradiologist utilization of American College of Radiology Appropriateness Criteria in a preauthorization center for MRI requests: applicability and effects.
The purpose of this study was to evaluate the effects and applicability of use of the American College of Radiology (ACR) Appropriateness Criteria by nonradiologist physicians in an MRI preauthorization center. All MRI requests received at our preauthorization center during a 19-month period were included in the study. The study period was divided into preintervention and postintervention phases, indicating before and after introduction of the ACR criteria to the general practitioners staffing our center. ACR appropriateness values were classified into three groups: appropriate, indeterminate, and inappropriate. Requests for which a matching ACR value could not be assigned were labeled ACR-noncodable. Multiple parameters evaluated and compared for the two phases included rate of request receipt, total approval and denial rates, and approval and denial rates according to the ACR Appropriateness Criteria and by anatomic region to be evaluated. There was no significant change in rate of request receipt and total approval and denial rates. However, there was an increase in the rate of approval of appropriate requests (phase 1, 71/96 [74%]; phase 2, 74/76 [97%]; p < 0.001) and the rate of denial of inappropriate requests (phase 1, 0/12 [0%]; phase 2, 9/13 [69%]; p < 0.001). More than 40% of requests were marked "ACR-noncodable" because of a lack of a matching clinical condition or variant. Introduction of the ACR Appropriateness Criteria resulted in an increase in the rate of performance of appropriate MRI examinations and a decrease in the rate of performance of inappropriate MRI examinations. ACR Appropriateness Criteria were applicable to approximately 50% of MRI requests.


Tumor-Selective Cytotoxicity of Nitidine Results from Its Rapid Accumulation into Mitochondria.
We identified a nitidine- (NTD-) accumulating organelle and evaluated the net cytotoxicity of accumulated NTD. To evaluate tumor cell selectivity of the drug, we evaluated its selective cytotoxicity against 39 human cancer cell lines (JFCR39 panel), and the profile was compared with those of known anticancer drugs. Organelle specificity of NTD was visualized using organelle-targeted fluorescent proteins. Real-time analysis of cell growth, proliferation, and cytotoxicity was performed using the xCELLigence system. Selectivity of NTD in the JFCR39 panel was evaluated. Mitochondria-specific accumulation of NTD was observed. Real-time cytotoxicity analysis suggested that the mechanism of NTD-induced cell death is independent of the cell cycle. Short-term treatment indicated that this cytotoxicity only resulted from the accumulation of NTD into the mitochondria. The results from the JFCR39 panel indicated that NTD-mediated cytotoxicity resulted from unique mechanisms compared with those of other known anticancer drugs. These results suggested that the cytotoxicity of NTD is only induced by its accumulation in mitochondria. The drug triggered mitochondrial dysfunction in less than 2 h. Similarity analysis of the selectivity of NTD in 39 tumor cell lines strongly supported the unique tumor cell specificity of NTD. Thus, these features indicate that NTD may be a promising antitumor drug for new combination chemotherapies.


Cystatins of human placenta.
Two low-molecular protein fractions inhibiting cysteine proteases were isolated from human placenta by alkalization to pH 11, acetone fractionation, affinity chromatography on CM-papain-Sepharose 4B, and Sephadex G-75 gel filtration. The results of polyacrylamide gel electrophoresis, isoelectric focusing indicate that one of there fractions in a dimer of cystatins B, and another is a mixture of cystatins A and B.


Arterial baroreceptor and vagal inputs to sympathoexcitatory neurons in rat medulla.
Lumbar sympathetic nerve discharge and unit activity of reticulospinal sympathoexcitatory (SE) neurons located in nucleus paragigantocellularis lateralis (PGCL) were recorded in rats. The sympathoinhibition produced by low-frequency stimulation of vagal afferents was abolished by bilateral microinjections of 20 pmol of bicuculline methiodide (BIC, a GABA-receptor antagonist) into PGCL and was converted into a pressor response by injections of 100 pmol. These BIC injections also inhibited the arterial baroreflex in a dose-dependent manner. In contrast the sympathoexcitation produced by high-frequency stimulation of vagal afferents was selectively blocked by bilateral injections of kynurenic acid (KYN, a Glu-receptor antagonist) into PGCL. Convergence of vagal excitatory, vagal inhibitory, and arterial baroreceptor inputs was detected in all SE neurons recorded. Single-pulse stimulation of vagal afferents produced up to two peaks of excitation of SE neurons, both blocked by iontophoretic applications of KYN and at least one inhibitory period selectively blocked by iontophoresis of BIC. The results emphasize the importance of SE neurons and surrounding area in integrating the brain vasomotor output to spinal preganglionic neurons.


What makes men leak? An investigation of objective and self-report measures of urinary incontinence early after radical prostatectomy.
Pelvic floor muscle training for patients having radical prostatectomy promotes contraction of these muscles in anticipation of activities that may provoke urine leakage. The aims of this study were: to determine the contribution of the individual activities comprising a standardised 1-hour pad test (1HPT) to overall urine leakage early after radical prostatectomy; and to investigate relationships between the 1HPT, 24-hour pad test (24HPT) and the International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF) early after radical prostatectomy. A prospective analysis of patients having radical prostatectomy and receiving pelvic floor muscle training (n = 33). Participants completed the 1HPT, 24HPT and ICIQ-SF at 3 and 6 weeks postoperatively. Participants wore a separate, pre-weighed continence pad for each of the seven activities comprising the 1HPT; pads were weighed separately and together to calculate activity-related and overall urine leakage. Walking at a comfortable speed and drinking while sitting were the two activities contributing most to overall urine leakage, albeit these activities also comprised 75% of 1HPT time. All component activities contributed a minimum 7 ± 5% of overall urine leakage. There were significant and strong to very strong correlations between all of the 1HPT, 24HPT, and ICIQ-SF at 3 weeks postoperatively. There were significant decreases in 24HPT (P = 0.032) and ICIQ-SF (P = 0.001) but no significant change in 1HPT from 3 to 6 weeks postoperatively. Pelvic floor muscle training should include contraction of these muscles in sedentary and walking postures. The 1HPT correlates well with the 24HPT, but may not be sensitive to early postoperative improvements in urinary leakage.


Normal and injury-induced sympathetic innervation of rat dorsal root ganglia increases with age.
In rats, partial injury to a peripheral nerve often leads to sympathetically maintained pain (SMP). In humans, this condition is especially apparent in the elderly. Nerve injury also causes perivascular sympathetic axons to sprout into the dorsal root ganglion (DRG), forming a possible anatomical substrate for SMP. Here, we describe the effects of chronic sciatic nerve constriction injury (CCI) in young (3 months) and old (16 months) rats on neuropathic pain behavior and on sympathetic sprouting in DRG. Behavioral tests assessed changes in thermal allodynia and hyperalgesia and in mechanical allodynia. We found that 1) sympathetic innervation of the DRG increased naturally with age, forming pericellular baskets mainly around large DRG neurons, and that sympathetic fibers were often associated with myelinated sensory axons; 2) sympathetic fiber density following CCI was also greater in old than in young rats; and 3) in old rats, thermal allodynia was less pronounced than in young rats, whereas thermal hyperalgesia and mechanical allodynia were more pronounced. These results highlight the possibility that sympathetic sprouting in the DRG is responsible for the sympathetic generation or maintenance of pain, especially in the elderly.


Female adolescents' perceptions of benefits of and barriers to using oral contraceptives.
A study was conducted to describe 12 female adolescents' oral contraceptive perceptions that were considered first independently and then after facilitation by a nurse. A self-administered decisional balance sheet elicited 44 descriptions of oral contraceptive perceptions, and a structured interview elicited 31 additional descriptions. The data were content-analyzed for common elements. The majority of participants perceived oral contraceptive benefits related to pregnancy prevention and others' approval and barriers related to side effects and others' disapproval. Participants considered additional oral contraceptive perceptions upon facilitation by a nurse after the opportunity for independent consideration. Facilitation of female adolescents' consideration of oral contraceptive perceptions may be an appropriate nursing intervention.


Assembly and peptide binding of major histocompatibility complex class II heterodimers in an in vitro translation system.
In vitro transcription/translation of HLA-DR1 cDNAs in the presence of microsomal membranes was used to study the association of major histocompatibility complex class II molecules with peptide and invariant chain (Ii) in the endoplasmic reticulum (ER). HLA-DR alpha and HLA-DR beta subunits assembled into SDS-unstable heterodimers in the absence of exogenous peptide. The inclusion of synthetic peptides during the alpha/beta assembly process promoted their conversion to SDS-resistant heterodimers. Addition of Ii RNA during the translation of HLA-DR alpha and HLA-DR beta RNAs resulted in the formation of alpha/beta/Ii complexes. Peptide binding by class II molecules was detected even when excess Ii was present during alpha/beta assembly. These findings indicate that peptides can bind alpha/beta heterodimers in the ER microenvironment and suggest that peptides derived from cytosolic proteins that are presented by class II molecules at the cell surface may have bound to HLA-DR in the ER.


Anti-tau vaccine is successful in clinical trial for people with Alzheimer's disease.
Alzheimer's disease progressively impairs cognition and daily function, and death usually occurs five to ten years after diagnosis. There are drugs available to treat the disease's symptoms, but they do not halt or slow its progression.


Methylation of SOCS3 in Myeloproliferative Neoplasms and Secondary Erythrocytosis/Thrombocythemia.
Myeloproliferative neoplasms (MPNs) like essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF) are acquired clonal hematopoietic stem cell disorders and originate from a multipotent hematopoietic stem cell. The SOCS1 and SOCS3 genes are negative regulators of the JAK/STAT signal pathway. In this study we investigate the promoter methylation of these genes in the pathogenesis of MPNs and secondary erythrocytosis/thrombocythemia. Promoter methylation of SOCS1 and SOCS3 genes was analyzed with methylation-specific PCR. PCR products were analyzed by agarose gel electrophoresis. No disease-specific CpG island methylation of SOCS1 was observed. Hypermethylation of the SOCS3 promoter was identified in 5 out of 19 (26.3%) PV cases, 2 out of 21 (9.5%) ET cases, 1 out of 5 (20%) PMF cases, and 9 out of 42 (21.4%) cases of secondary erythrocytosis/thrombocythemia. The results revealed that promoter methylation of the SOCS3 gene suggests a possible role for SOCS3 methylation in the pathogenesis of MPNs and secondary erythrocytosis/thrombocythemia. None declared.


[Absence of occult hepatitis B in Colombian blood donors].
In Colombian blood banks, screening for the surface antigen of hepatitis B is mandatory in all units collected. Testing of antibody against core antigens is not administered, although this method may be useful to detect donors infected with the hepatitis B virus. The prevalence of occult hepatitis B was determined by applying a full-serological profile of hepatitis B virus to blood samples of blood donors. Between April 2008 and October 2009, a prospective cross sectional study was conducted using 628 samples from donors to blood banks located in four Colombian cities. Prevalence for hepatitis B had been previously recorded for these cities. Serological screening was performed for the complete virus; then nucleic acid amplification was tested in sera that were anti-HBc reactive and with a titer of anti-HBs ≤30 mUI/ml. Of the 628 samples tested, 129 met the serological criteria established to be tested nucleic acid amplification. None of them demonstrated evidence of nucleic acid amplification of hepatitis B virus. This is the first study in Colombia to detect the presence of blood donors that may be occult hepatitis B carriers. None was detected.


T Cells in immunodeficiencies as evaluated by an antihuman T-cell serum.
An antihuman T-cell has been prepared in rabbits by infecting lymphocytes from a patient with Bruton-type agammaglobulinemia and absorption with cultured B-lymphoblast cells. Cytotoxicity of the antiserum was assayed with peripheral blood lymphocytes in the presence of rabbit complement and its specificity for T vs B cells was verified. This anti-T-cell serum killed 66% (range 49-78) of normal blood lymphocytes. In patients with Bruton-type agammaglobulinemia the percentage of cells sensitive to the antiserum was above normal (77-89%), whereas it was decreased in some patients with lepromatous leprosy or under antilymphocyte globulin therapy.