Binding of synthetic beta-human atrial natriuretic peptide to cultured rat vascular smooth muscle cells.
We have studied the effects of synthetic beta-human atrial natriuretic peptide (beta-hANP), an antiparallel dimer of alpha-hANP, on receptor binding and cGMP generation in cultured rat vascular smooth muscle cells and compared the effects with those of alpha-hANP. Characteristics of temperature-dependent binding and degradation of 125I-beta-hANP were similar to those of 125I-alpha-hANP. Scatchard analysis indicated a single class of binding sites for beta-hANP with a maximal binding capacity one-half that of alpha-hANP. Parallel and antiparallel dimers were equipotent in inhibiting the binding and stimulating intracellular cGMP formation, of which the maximal effect was about one-half that of alpha-hANP. Reverse-phase high performance liquid chromatography revealed that most of beta-hANP added to cells was converted to a small molecular mass component corresponding to alpha-hANP after incubation. These data suggest that the less potent effect of beta-hANP in receptor binding and cGMP generation may be partly accounted for by the possible conversion of beta-hANP to alpha-hANP at the site of target cells.


A comparison of the efficacy and tolerability of single doses of HFA 134a albuterol and CFC albuterol in mild-to-moderate asthmatic patients.
After the signing of the Montreal Protocol in 1987, new propellants for use in pressurized metered-dose inhalers that are non-ozone-depleting have been developed. This study was designed to compare the efficacy and tolerability of single doses of albuterol/HFA 134a with albuterol/CFC and to demonstrate a dose-response among the different doses of both formulations. A single-center, randomized, double-blind, placebo-controlled, cross-over study. Sixty-three adolescent and adult asthmatic patients were randomized to receive at separate treatment visits single doses via a pressurized metered-dose inhaler of either placebo/hydrofluoroalkane (HFA) 134a; 100 microg, 200 microg, or 400 microg albuterol/HFA 134a; 100 microg or 200 microg albuterol/chlorofluorocarbon (CFC). Triplicate measurements of forced expiratory volume in 1 second (FEV1) were made immediately before dosing and 15 minutes, 30 minutes, 1, 2, 3, 4, 5, and 6 hours postdose. The primary efficacy variables were area under the entire 6-hour FEV1 curve, relative to baseline subtracted from the area above baseline (AUC(0-6)) and peak effect (derived from serial FEV1 measurements). Analysis of AUC(0-6) and peak effect showed that all doses of albuterol had a significantly greater effect than placebo (HFA 134a propellant). Comparisons of the two formulations at 100 microg and 200 microg showed no difference in AUC(0-6) (100 microg, -0.23 Lhr, P = 0.114 and 200 microg -0.08 Lhr, P = 0.590) or in peak effect, percentage of baseline (100 microg, -1.3%, P = 0.354 and 200 microg, 0.17%, P = 0.902). There were no differences seen among formulations in the incidence of adverse events or with any of the other safety parameters, including electrocardiograms, vital signs, clinical laboratory assessments, and asthma exacerbations. The study demonstrated comparability in terms of efficacy and safety between albuterol/HFA 134a and albuterol/CFC.


Silver nanoparticles functionalized with ampicillin.
The resistance of pathogenic bacteria to antibiotics has become a serious problem. The emphasis is placed on the development of new, effective antimicrobial strategies. One of them is the use of AgNPs in association with antibiotic drugs. The aim of this study was to obtain silver nanoparticles functionalized with ampicillin and to investigate the mechanism of binding antibiotics to nanoparticle using high-performance liquid chromatography approach. To confirm the occurrence of silver nanoparticles functionalization, FTIR, MALDI-TOF MS, and DLS analysis and zeta potential measurements were performed. Moreover we assessed the antibacterial activity of biologically synthesized nanoparticles functionalized with ampicillin against a range of gram (+) and gram (-) bacteria strains such as Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, Staphylococcus epidermidis, and Escherichia coli.


Expansion of the CD4-, CD8- gamma delta T cell subset in the spleens of mice during non-lethal blood-stage malaria.
Splenic gamma delta T cells (CD4-, CD8-) increased more than 10-fold upon resolution of either Plasmodium chabaudi adami or P.c. chabaudi infections in C57BL/6 mice compared to controls. Similarly, a 10- to 20-fold expansion of the gamma delta T cell population was observed in beta 2-microglobulin deficient (beta 2-m0/0) mice that had resolved P.c. adami, P.c. chabaudi or P. yoelii yoelii infections. In contrast, increases in the number of splenic alpha beta T cells in these infected mice were only two to three-fold indicating a differential expansion of the gamma delta T cell subset during malaria. Because nucleated cells of beta 2-m0/0 mice lack surface expression of major histocompatibility complex class I and class Ib glycoproteins, our findings suggest that antigen presentation by these glycoproteins is not necessary for the increasing number of gamma delta T cells. Our observation that after resolution of P.c. adami malaria, C57BL/6 mice depleted of CD8+ cells by monoclonal antibody treatment had lower numbers of gamma delta T cells than untreated controls suggests that the demonstrated lack of CD8+ cells in beta 2-m0/0 mice does not contribute to the expansion of the gamma delta T cell population during non-lethal malaria.


[Ventriculomegaly at the gestational age of 20 weeks; research into its incidence and related abnormalities].
To describe the incidence and the prognostic value of foetal ventriculomegaly identified between 18-23 weeks of gestational age in the northeastern part of the Netherlands during the 2002-2010 period. Retrospective cohort study. From the database of the University Medical Centre Groningen in the Netherlands, we selected all cases of singleton pregnancies in which ventriculomegaly was diagnosed at 18-23 weeks of gestation. In 2002, ventriculomegaly was diagnosed prenatally in 1:7000 foetuses; the incidence increased to 1:1750 in 2010. In 33 (51%) of 65 affected foetuses, an associated severe physical abnormality was detected, in 5 (8%) a subtle sonomarker (subtle ultrasound finding) and in 8 (12%), a chromosomal defect. In 47% of the pregnancies where ventriculomegaly was associated with other defects, the parents opted for termination of pregnancy. In the group with isolated mild ventriculomegaly (10-12 mm), termination was performed in 1 of 19 cases; and in the group with the greater ventricular width of 13-14 mm, this decision was made for 5 of the 8 pregnancies. All continued pregnancies of foetuses with isolated ventriculomegaly resulted in live births. Isolated ventriculomegaly was diagnosed relatively more frequently in male foetuses. The introduction of ultrasound scans as part of standard prenatal care has resulted in an increased incidence of foetal ventriculomegaly. Important factors for predicting the outcome of the pregnancy are the degree of ventricular dilatation, the foetus' gender and the presence or absence of associated abnormalities. It is therefore important to use a standardised protocol for measuring ventricular width, record the biparietal diameter and foetal gender, perform a systematic physical examination and use karyotyping.


Spontaneous intraventricular haemorrhage in utero.
The authors report three cases of unexplained prenatal intraventricular haemorrhage (IVH) in three term infants. In the first two cases the suspected diagnosis of prenatal IVH was made a few hours after delivery, in accordance with the ultrasonographic feature of clots in the ventricles, whereas in the third case prenatal ultrasonography was suggestive of hydrocephalus with intraventricular clots.


Noradrenaline upregulates T-type calcium channels in rat pinealocytes.
The mammalian pineal gland is a neuroendocrine organ that responds to circadian and seasonal rhythms. Its major function is to secrete melatonin as a hormonal night signal in response to nocturnal delivery of noradrenaline from sympathetic neurons. Culturing rat pinealocytes in noradrenaline for 24 h induced a low-voltage activated transient Ca(2+) current whose pharmacology and kinetics corresponded to a CaV3.1 T-type channel. The upregulation of the T-type Ca(2+) current is initiated by β-adrenergic receptors, cyclic AMP and cyclic AMP-dependent protein kinase. Messenger RNA for CaV3.1 T-type channels is significantly elevated by noradrenaline at 8 h and 24 h. The noradrenaline-induced T-type channel mediated an increased Ca(2+) entry and supported modest transient electrical responses to depolarizing stimuli, revealing the potential for circadian regulation of pinealocyte electrical excitability and Ca(2+) signalling. Our basic hypothesis is that mammalian pinealocytes have cycling electrical excitability and Ca(2+) signalling that may contribute to the circadian rhythm of pineal melatonin secretion. This study asked whether the functional expression of voltage-gated Ca(2+) channels (CaV channels) in rat pinealocytes is changed by culturing them in noradrenaline (NA) as a surrogate for the night signal. Channel activity was assayed as ionic currents under patch clamp and as optical signals from a Ca(2+)-sensitive dye. Channel mRNAs were assayed by quantitative polymerase chain reaction. Cultured without NA, pinealocytes showed only non-inactivating L-type dihydropyridine-sensitive Ca(2+) current. After 24 h in NA, additional low-voltage activated transient Ca(2+) current developed whose pharmacology and kinetics corresponded to a T-type CaV3.1 channel. This change was initiated by β-adrenergic receptors, cyclic AMP and protein kinase A as revealed by pharmacological experiments. mRNA for CaV3.1 T-type channels became significantly elevated, but mRNA for another T-type channel and for the major L-type channel did not change. After only 8 h of NA treatment, the CaV3.1 mRNA was already elevated, but the transient Ca(2+) current was not. Even a 16 h wait without NA following the 8 h NA treatment induced little additional transient current. However, these cells were somehow primed to make transient current as a second NA exposure for only 60 min sufficed to induce large T-type currents. The NA-induced T-type channel mediated an increased Ca(2+) entry during short depolarizations and supported modest transient electrical responses to depolarizing stimuli. Such experiments reveal the potential for circadian regulation of excitability.


Evaluation of Alternative Methods for Testing the Bioefficacy of Household Ambient Insecticide Products Against Aedes albopictus.
Ambient insecticides are receiving increasing attention in many developed countries because of their value in reducing mosquito nuisance. As required by the European Union Biocidal Products Regulation 528/2012, these devices require appropriate testing of their efficacy, which is based on estimating the knockdown and mortality rates of free-flying (free) mosquitoes in a test room. However, evaluations using free mosquitoes present many complexities. The performances of 6 alternative methods with mosquitoes held in 2 different cage designs (steel wire and gauze/plastic) with and without an operating fan for air circulation were monitored in a test room through a closed-circuit television system and were compared with the currently recommended method using free mosquitoes. Results for caged mosquitoes without a fan showed a clearly delayed knockdown effect, whereas outcomes for caged mosquitoes with a fan recorded higher mortality at 24 h, compared to free mosquitoes. Among the 6 methods, cages made of gauze and plastic operating with fan wind speed at 2.5-2.8 m/sec was the only method without a significant difference in results for free mosquitoes, and therefore appears as the best alternative to assess knockdown by ambient insecticides accurately.


Differential involvement of projection neurons during emergence of spontaneous activity in the developing avian hindbrain.
To better characterize the emergence of spontaneous neuronal activity in the developing hindbrain, spontaneous activity was recorded optically from defined projection neuron populations in isolated preparations of the brain stem of the chicken embryo. Ipsilaterally projecting reticulospinal (RS) neurons and several groups of vestibuloocular (VO) neurons were labeled retrogradely with Calcium Green-1 dextran amine and spontaneous calcium transients were recorded using a charge-coupled-device camera mounted on a fluorescence microscope. Simultaneous extracellular recordings were made from one of the trigeminal motor nerves (nV) to register the occurrence of spontaneous synchronous bursts of activity. Two types of spontaneous activity were observed: synchronous events (SEs), which occurred in register with spontaneous bursts in nV once every few minutes and were tetrodotoxin (TTX) dependent, and asynchronous events (AEs), which occurred in the intervals between SEs and were TTX resistant. AEs occurred developmentally before SEs and were in general smaller and more variable in amplitude than SEs. SEs appeared at the same stage as nV bursts early on embryonic day 4, first in RS neurons and then in VO neurons. All RS neurons participated equally in SEs from the outset, whereas different subpopulations of VO neurons participated differentially, both in terms of the proportion of neurons that exhibited SEs, the fidelity with which the SEs in individual neurons followed the nV bursts, and the developmental stage at which SEs appeared and matured. The results show that spontaneous activity is expressed heterogeneously among hindbrain projection neuron populations, suggesting its differential involvement in the formation of different functional neuronal circuits.


Management and modeling approaches for controlling raccoon rabies: The road to elimination.
Rabies is an ancient viral disease that significantly impacts human and animal health throughout the world. In the developing parts of the world, dog bites represent the highest risk of rabies infection to people, livestock, and other animals. However, in North America, where several rabies virus variants currently circulate in wildlife, human contact with the raccoon rabies variant leads to the highest per capita population administration of post-exposure prophylaxis (PEP) annually. Previous rabies variant elimination in raccoons (Canada), foxes (Europe), and dogs and coyotes (United States) demonstrates that elimination of the raccoon variant from the eastern US is feasible, given an understanding of rabies control costs and benefits and the availability of proper tools. Also critical is a cooperatively produced strategic plan that emphasizes collaborative rabies management among agencies and organizations at the landscape scale. Common management strategies, alone or as part of an integrated approach, include the following: oral rabies vaccination (ORV), trap-vaccinate-release (TVR), and local population reduction. As a complement, mathematical and statistical modeling approaches can guide intervention planning, such as through contact networks, circuit theory, individual-based modeling, and others, which can be used to better understand and predict rabies dynamics through simulated interactions among the host, virus, environment, and control strategy. Strategies derived from this ecological lens can then be optimized to produce a management plan that balances the ecological needs and program financial resources. This paper discusses the management and modeling strategies that are currently used, or have been used in the past, and provides a platform of options for consideration while developing raccoon rabies virus elimination strategies in the US.


Conjugal transfer of transposon Tn916 from Streptococcus faecalis to Mycoplasma hominis.
Transposon Tn916 was transferred from Streptococcus faecalis to Mycoplasma hominis by a mating process resembling conjugation with a frequency of 10(-6) to 10(-7). Tn916 was inserted into the mycoplasmal chromosome in single and multiple copies.


The timing of do-not-resuscitate orders and hospital costs.
The relation between the timing of do-not-resuscitate (DNR) orders and the cost of medical care is not well understood. This prospective observational study compares hospital costs and length of stay of 265 terminally ill patients with admission DNR orders, delayed DNR orders (occurring after 24 hours), or no DNR orders (full code). Patients whose orders remained full code throughout a hospital stay had similar lengths of stay, total hospital costs, and daily costs as patients with admission DNR orders. Patients with delayed DNR orders, by contrast, had a greater mortality, longer length of stay, and higher total costs than full code or admission DNR patients, but similar daily costs. The causes of delay in DNR orders and the associated higher costs are a matter for future research.


TNFRSF10C copy number variation is associated with metastatic colorectal cancer.
Genetic markers for distant metastatic disease in patients with colorectal cancer (CRC) are not well defined. Identification of genetic alterations associated with metastatic CRC could help to guide systemic and local treatment strategies. We evaluated the association of tumor necrosis factor receptor superfamily member 10C (TNFRSF10C) copy number variation (CNV) with distant metastatic disease in patients with CRC using The Cancer Genome Atlas (TCGA). Genetic sequencing data and clinical characteristics were obtained from TCGA for all available patients with CRC. There were 515 CRC patient samples with CNV and clinical outcome data, including a subset of 144 rectal adenocarcinoma patient samples. Using the TCGA CRC dataset, CNV of TNFRSF10C was evaluated for association with distant metastatic disease (M1 vs. M0). Multivariate logistic regression analysis with odds ratio (OR) using a 95% confidence interval (CI) was performed adjusting for age, T stage, N stage, adjuvant chemotherapy, gender, microsatellite instability (MSI), location, and surgical margin status. TNFRSF10C CNV in patients with CRC was associated with distant metastatic disease [OR 4.81 (95% CI, 2.13-10.85) P<0.001] and positive lymph nodes [OR 18.83 (95% CI, 8.42-42.09)]; P<0.001) but not MSI (OR P=0.799). On multivariate analysis, after adjusting for pathologic T stage, N stage, adjuvant chemotherapy, gender, and MSI, TNFRSF10C CNV remained significantly associated with distant metastatic disease (OR P=0.018). Subset analysis revealed that TNFRSF10C CNV was also significantly associated with distant metastatic disease in patients with rectal adenocarcinoma (OR P=0.016). TNFRSF10C CNV in patients with CRC is associated with distant metastatic disease. With further validation, such genetic profiles could be used clinically to support optimal systemic treatment strategies versus more aggressive local therapies in patients with CRC, including radiation therapy for rectal adenocarcinoma.


New data on the distribution of aquatic bugs (Hemiptera) from eastern Morocco with notes on chorology.
New faunistic and distributional data on aquatic Hemiptera from the Oriental Region of Morocco and the Moulouya River basin, covering an area of 119,268 km2, are presented. An annotated list of 45 species, 21 genera and 11 families is provided. Nine species are new records for the entire studied area, and two for the Moulouya River basin. We rediscovered Velia noualhieri iberica and Notonecta viridis after eight decades. We also provide novel records for Aphelocheirus pemae and Hebrus atlas, which were recently described from Morocco, and for the invasive corixid Trichocorixa verticalis verticalis. The dominance of species with broad distributions points to the high dispersal dynamics of the Hemiptera community in the study area, similar to that of other areas where a semiarid climate prevails.


Mathematical models for cytarabine-derived myelosuppression in acute myeloid leukaemia.
We investigate the personalisation and prediction accuracy of mathematical models for white blood cell (WBC) count dynamics during consolidation treatment using intermediate or high-dose cytarabine (Ara-C) in acute myeloid leukaemia (AML). Ara-C is the clinically most relevant cytotoxic agent for AML treatment. We extend a mathematical model of myelosuppression and a pharmacokinetic model of Ara-C with different hypotheses of Ara-C's pharmacodynamic effects. We cross-validate the 12 model variations using dense WBC count measurements from 23 AML patients. Surprisingly, the prediction accuracy remains satisfactory in each of the models despite different modelling hypotheses. Therefore, we compare average clinical and calculated WBC recovery times for different Ara-C schedules as a successful methodology for model discrimination. As a result, a new hypothesis of a secondary pharmacodynamic effect on the proliferation rate seems plausible. Furthermore, we demonstrate the impact of treatment timing on subsequent nadir values based on personalised predictions as a possibility for influencing/controlling myelosuppression.


Neuroanatomical patterns of the mu, delta, and kappa opioid receptors of rat brain as determined by quantitative in vitro autoradiography.
Highly specific radioligands and quantitative autoradiography reveal strikingly different neuroanatomical patterns for the mu, delta, and kappa opioid receptors of rat brain. The mu receptors are most densely localized in patches in the striatum, layers I and III of the cortex, the pyramidal cell layer of the hippocampal formation, specific nuclei of the thalamus, the pars reticulata of the substantia nigra, the interpeduncular nucleus, and the locus coeruleus. In contrast, delta receptors are highly confined, exhibiting selective localization in layers I, II, and VIa of the neocortex, a diffuse pattern in the striatum, and moderate concentration in the pars reticulata of the substantia nigra and in the interpeduncular nucleus. delta receptors are absent in most other brain structures. This distribution is unexpected in that the enkephalins, the putative endogenous ligands of the delta receptor, occur essentially throughout the brain. The kappa receptors of rat brain exhibit a third pattern distinct from that of the mu and delta receptors. kappa receptors occur at low density in patches in the striatum and at particularly high density in the nucleus accumbens, along the pyramidal and molecular layers of the hippocampus, in the granular cell layer of the dentate gyrus, specific midline nuclei of the thalamus, and hindbrain regions. kappa receptors appear to be uniformly distributed across regions in the neocortex with the exception of layer III, which revealed only trace levels of binding. An important conclusion of the present study is that delta receptors occur at high density only in the forebrain and in two midbrain structures, whereas mu and kappa receptors exhibit discrete patterns in most major brain regions.


Bid solicitation and contract negotiation.
The process of soliciting bid prices for drug products and of negotiating contracts with pharmaceutical vendors is reviewed. The primary purpose of bid purchasing is to obtain drugs at the lowest price and to have these prices remain fixed for a predetermined period of time. A successful bid-purchasing process depends on the institution's implementation of a formulary brand-standardization policy, prior identification of acceptable vendors and drug products, and establishment of criteria for evaluating drugs under a bid-purchasing system. Specific information to be included in the invitation to bid and useful data other than drug prices that may be solicited from vendors are outlined. Manual and computerized systems for organizing bid-request data are described. Bid evaluations should maintain the confidentiality of bid and contract prices. Selection of winning bids is based on lowest price or, in cases where prices are identical, on selected vendor characteristics or services. Negotiation of unacceptable bid prices should be conducted with a thorough knowledge of the needs and goals of the institution and the vendor. Procedures for establishing contracts and the timing of various phases of the bid process are discussed. An optimal bid-purchasing system is achieved only when the system is carefully planned and designed and when each prospective vendor is given an equal opportunity to establish a contractual relationship with the institution.


[Mnemonic complaints and chronic migraine].
INTRODUCTION. Patients with chronic migraine often report lower cognitive performance, which affects their quality of life. AIMS. To analyse whether the mnemonic capacity of patients with chronic migraine is altered or not. SUBJECTS AND METHODS. A cross-sectional study was conducted in patients with chronic migraine evaluated consecutively in our unit, and paired by age (18-60 years) and gender with a control group consisting of cognitively healthy volunteers. The following cognitive instruments were administered: Folstein Minimental State Examination (MMSE), Memory Alteration Test (M@T), Montreal Cognitive Assessment (MoCA) and working memory. RESULTS. A total of 30 patients with chronic migraine were included (mean age: 49.33 ± 10.05 years) paired with a control group of 30 healthy volunteers (mean age: 44.83 ± 10.91 years). The mean elapsed time since onset of the patients with chronic migraine was 4.47 ± 2.74 years. On performing a comparative analysis between the two groups, significant differences were found with overall lower scores in the group of patients with chronic migraine in the MoCA (24.16 versus 29), M@T (43.76 versus 48.8) and working memory tests (17.5 versus 24.26). Performance in the MMSE was similar in both groups. CONCLUSIONS. Patients with chronic migraine can have lower cognitive performance regardless of distracting elements, such as pharmacological factors or psychiatric comorbidity, since chronic migraine can be understood as yet another element within the spectrum of chronic pain.


The effects of different hormone treatment on endothelial function in healthy postmenopausal women.
We aimed to compare the effects of different types of hormone treatment (HT) on endothelial function by means of brachial artery ultrasonographic examination in postmenopausal women. Sixty-two healthy postmenopausal women were included in this study. Subjects were assigned to one of the five groups receiving 6 months of treatment [estrogen (conjugated estrogen), estrogen (conjugated estrogen) plus progesterone (medroxyprogesterone acetate; MPA), raloxifene, tibolone or control]. Endothelial function was assessed by measurement of flow-mediated dilatation (FMD) and nitrate-dependent dilatation in the brachial artery. At the end of 6 months, FMD values were found to be significantly increased in women with HT use than the control group (p = 0.001). In subgroups, FMD increased significantly in the estrogen [12 ± 7 versus 25 ± 8, p = 0.001] and raloxifene groups [7 ± 5 versus 11 ± 3, p < 0.01] compared to tibolone and estrogen plus progesterone groups. In conclusion, endothelial function is impaired in postmenopausal women. Both estrogen and raloxifene regimens may improve endothelial functions in healthy postmenopausal women. The direct protective effects of these HT on the healthy endothelium may be more remarkable than the favorable effects on lipid profile.


Identification of risk factors for falls in postmenopausal women: a systematic review and meta-analysis.
The purpose of this study was to identify risk factors for falls in postmenopausal women and provide evidence for the primary prevention of falls in postmenopausal women. The protocol for this meta-analysis is registered with PROSPERO (CRD42020170927). We searched PubMed, the Cochrane Library and EMBASE for observational studies on the risk factors for falls in postmenopausal women. Review Manager 5.3 was used to calculate the relative risk (RR) or weighted mean difference (WMD) of potential risk factors related to falls. STATA 14.0 was used for the quantitative evaluation of publication bias. Eleven studies with 42,429 patients from 7 countries were included. The main risk factors for falls in postmenopausal women were patient sociodemographic risk factors (age: WMD = 0.37, 95% CI 0.07 to 0.68; body weight: WMD = 0.88, 95% CI 0.56 to 1.12; BMI: WMD = 0.34, 95% CI 0.21 to 0.46; exercise: RR = 0.97, 95% CI 0.94 to 0.99; and FES-I: WMD = 6.60, 95% CI 0.72 to 12.47) and medical risk factors (dietary calcium intake: WMD = - 16.91, 95% CI - 25.80 to - 8.01; previous fracture history: RR = 1.21, 95% CI 1.13 to 1.29; previous falls: RR = 2.02, 95% CI 1.91 to 2.14; number of diseases, ˃ 2: RR = 1.17, 95% CI 1.11 to 1.23; and number of reported chronic health disorders: WMD = 0.30, 95% CI 0.10 to 0.49). Knowledge of the many risk factors associated with falls in postmenopausal women can aid in fall prevention. However, we cannot rule out some additional potential risk factors (age at the onset of menopause, years since last menstruation, hormone therapy and BMD) that need further clinical research.


Does short-term fasting promote pathological eating patterns?
Fasting, or going a significant amount of time without eating, has been identified as a risk factor for the development of pathological eating patterns. Findings from several studies examining the impact of fasting on subsequent eating behaviors have been mixed. The current study recruited college students to record food intake, episodes of binge eating, and use of compensatory behaviors before, throughout, and following a 24-hour fast. Participants attended an initial appointment in which they completed measures of dietary restraint and disinhibition and received instructions on self-monitoring and fasting. Participants (N=122) self-monitored their eating behaviors for 96 h, including a 24-hour fasting period. Participants did not demonstrate significant increases in disordered eating behaviors following the fast (e.g., objective binge episodes, self-defined excessive eating or compensatory behavior use). Baseline disinhibition predicted excessive eating as well as objective binge episodes both before and after fasting. Altogether, findings have implications for research seeking to further understand how fasting may contribute to the development of pathological eating patterns; specifically, it seems that the ED risk associated with fasting is derived from the behavior's interaction with other individual difference variables.


Transition-Metal-Free Decarboxylative Iodination: New Routes for Decarboxylative Oxidative Cross-Couplings.
Constructing products of high synthetic value from inexpensive and abundant starting materials is of great importance. Aryl iodides are essential building blocks for the synthesis of functional molecules, and efficient methods for their synthesis from chemical feedstocks are highly sought after. Here we report a low-cost decarboxylative iodination that occurs simply from readily available benzoic acids and I2. The reaction is scalable and the scope and robustness of the reaction is thoroughly examined. Mechanistic studies suggest that this reaction does not proceed via a radical mechanism, which is in contrast to classical Hunsdiecker-type decarboxylative halogenations. In addition, DFT studies allow comparisons to be made between our procedure and current transition-metal-catalyzed decarboxylations. The utility of this procedure is demonstrated in its application to oxidative cross-couplings of aromatics via decarboxylative/C-H or double decarboxylative activations that use I2 as the terminal oxidant. This strategy allows the preparation of biaryls previously inaccessible via decarboxylative methods and holds other advantages over existing decarboxylative oxidative couplings, as stoichiometric transition metals are avoided.


A facile synthesis of p- and m-(amidinomethyl)phenyl esters derived from amino acid and tryptic hydrolysis of these synthetic inverse substrates.
A facile synthetic method for p- and m-(amidinomethyl)phenyl esters derived from a variety of amino acids is presented. We analyzed the kinetic behavior of trypsin towards these synthetic esters, which are inverse substrates. The substituent (meta- and para-isomers) and isosteric effects of (amidinomethyl)phenyl esters are discussed.


Destructive subependymal cysts following ventriculitis-pathomechanisms and treatment.
Ventriculitis may complicate neurosurgical procedures, for example, due to shunt or external ventricular drainage infection. Clearance of the infection with subsequent intravenous antibiotic therapy and shunt reinsertion, if necessary, are the standard treatment procedures with a high rate of success. Here, we report on a protracted complication, the development of destructive subependymal cysts, illustrate its treatment and discuss the pathomechanisms. The 2-year-and-9-month-old girl was admitted 5 weeks after a shunt revision with symptoms of shunt infection. Ventriculitis caused by Streptococcus salivarius (S. salivarius) was diagnosed and intravenous antibiotic treatment was performed. A new shunt system was implanted after clearance of infection and the girl did not show clinical signs of infection thereafter. A routine follow-up magnetic resonance imaging (MRI) revealed progressive and space-occupying multifocal subependymal cysts with partial destruction of the corpus callosum including compression of the ventricular system. Endoscopic broad-based laser fenestration of all cysts resulted in sustained regression of cavity formation. The cognitive development of the girl assessed 2 years afterward was completely normal. We conclude that routine follow-up MRI investigations are recommended 6 months after successful treatment of ventriculitis to detect protracted postinflammatory destructive subependymal cyst formations. Endoscopic broad-based laser-assisted cyst fenestration can stop progression and lead to regression of postinfectious subependymal cysts.


Dynalign II: common secondary structure prediction for RNA homologs with domain insertions.
Homologous non-coding RNAs frequently exhibit domain insertions, where a branch of secondary structure is inserted in a sequence with respect to its homologs. Dynamic programming algorithms for common secondary structure prediction of multiple RNA homologs, however, do not account for these domain insertions. This paper introduces a novel dynamic programming algorithm methodology that explicitly accounts for the possibility of inserted domains when predicting common RNA secondary structures. The algorithm is implemented as Dynalign II, an update to the Dynalign software package for predicting the common secondary structure of two RNA homologs. This update is accomplished with negligible increase in computational cost. Benchmarks on ncRNA families with domain insertions validate the method. Over base pairs occurring in inserted domains, Dynalign II improves accuracy over Dynalign, attaining 80.8% sensitivity (compared with 14.4% for Dynalign) and 91.4% positive predictive value (PPV) for tRNA; 66.5% sensitivity (compared with 38.9% for Dynalign) and 57.0% PPV for RNase P RNA; and 50.1% sensitivity (compared with 24.3% for Dynalign) and 58.5% PPV for SRP RNA. Compared with Dynalign, Dynalign II also exhibits statistically significant improvements in overall sensitivity and PPV. Dynalign II is available as a component of RNAstructure, which can be downloaded from http://rna.urmc.rochester.edu/RNAstructure.html.


Two hour blood glucose levels in at-risk babies: An audit of Canadian guidelines.
The Canadian guidelines recommend blood glucose (BG) screening starting at 2 h of age in asymptomatic 'at-risk' babies (including small-for-gestational-age [SGA] and large-for-gestational-age [LGA] infants), with intervention cut-offs of 1.8 mmol/L and 2.6 mmol/L. The present study reviews and audits this practice in full-term newborn populations. A literature review meta-analyzed BG values in appropriate-for-gestational age (AGA) term newborns to establish normal 1 h, 2 h and 3 h values. A clinical review audited screening of 'at-risk' SGA and LGA term newborns, evaluating both clinical burden and validity. The review included six studies, although none clearly defined the plasma glucose standard. The pooled mean (plasma) BG level in AGA babies 2 h of age was 3.35 mmol/L (SD=0.77), significantly higher than 1 h levels (3.01 mmol/L, SD=0.96). In the audit, 78 SGA and 142 LGA babies each had an average of 6.0 and 4.7 BG tests, respectively. The mean 2 h BG levels for SGA (3.42 mmol/L, SD=1.02) and LGA (3.31 mmol/L, SD=0.66) babies did not differ significantly from the AGA pooled mean. Receiver operating characteristic curves showed that 2 h BG levels in LGA and SGA babies predicted later hypoglycemia (defined as a BG level lower than 2.6 mmol/L), but sensitivities and specificities were poor. Published 2 h BG levels for AGA babies are higher than 1 h values and are similar to audited 2 h levels in SGA and LGA babies. Clinically, 2 h levels are predictive of later hypoglycemia but may require repeat BG testing. Audit is an important tool to validate national guidelines, to minimize their burden and to maximize their utility.


Analysis of glycoproteins in human serum by means of glycospecific magnetic bead separation and LC-MALDI-TOF/TOF analysis with automated glycopeptide detection.
Comprehensive proteomic analyses require efficient and selective pre-fractionation to facilitate analysis of post-translationally modified peptides and proteins, and automated analysis workflows enabling the detection, identification, and structural characterization of the corresponding peptide modifications. Human serum contains a high number of glycoproteins, comprising several orders of magnitude in concentration. Thereby, isolation and subsequent identification of low-abundant glycoproteins from serum is a challenging task. selective capturing of glycopeptides and -proteins was attained by means of magnetic particles specifically functionalized with lectins or boronic acids that bind to various structural motifs. Human serum was incubated with differentially functionalized magnetic micro-particles (lectins or boronic acids), and isolated proteins were digested with trypsin. Subsequently, the resulting complex mixture of peptides and glycopeptides was subjected to LC-MALDI analysis and database searching. In parallel, a second magnetic bead capturing was performed on the peptide level to separate and analyze by LC-MALDI intact glycopeptides, both peptide sequence and glycan structure. Detection of glycopeptides was achieved by means of a software algorithm that allows extraction and characterization of potential glycopeptide candidates from large LC-MALDI-MS/MS data sets, based on N-glycopeptide-specific fragmentation patterns and characteristic fragment mass peaks, respectively. By means of fast and simple glycospecific capturing applied in conjunction with extensive LC-MALDI-MS/MS analysis and novel data analysis tools, a high number of low-abundant proteins were identified, comprising known or predicted glycosylation sites. According to the specific binding preferences of the different types of beads, complementary results were obtained from the experiments using either magnetic ConA-, LCA-, WGA-, and boronic acid beads, respectively.


Association of anxiety and depressive symptoms and adiposity among adolescent females, using dual energy X-ray absorptiometry.
The purpose of this study is to evaluate the association between anxiety and depressive symptoms and obesity among adolescent females using objective measures of adiposity and evaluate for moderating effects of race and age. This is a cross-sectional analysis of 198 females aged 11, 13, 15, and 17 years (mean = 14.6, standard deviation = 2.2). Adiposity measures include BMI, BMI Z score, percentage body fat from dual energy X-ray absorptiometry (DXA), and fat distribution (fat mass upper vs lower body regions from DXA). Symptoms of anxiety are measured with the State-Trait Anxiety Inventory and depressive symptoms with the Children's Depression Inventory. Trait anxiety and depressive symptoms are positively associated with BMI and percentage body fat. No interaction of anxiety/ depressive symptoms with race or age on measures of adiposity was detected. Symptoms of anxiety and depression are associated with percentage body fat among adolescent females, linking psychological distress with a physiological measure of adiposity.


The moral status of animals and their use in research: a philosophical review.
In this article I offer a philosophical review of (1) leading theories of the moral status of animals, (2) pivotal theoretical issues on which more progress needs to be made, and (3) applications to the setting of animal research. Such an examination demonstrates, I believe, that the practical implications of leading theories converge far more than might be expected. In addition, I hope this review helps to clarify particularly troubling issues that remain so they can be treated adequately.


Early Opiate Analgesic Requirements Following Nonsurgically Managed Tibial Fractures in Children.
Many children with tibial fractures are currently being managed as outpatients. It is unclear how much opiates should be prescribed to ensure adequate analgesia at home without overprescription. This study aimed to evaluate the risk factors for requiring opiates following admission for tibial fractures and to estimate opiate requirements for children being discharged directly from the emergency department (ED). All children aged 4 to 16 years admitted with closed tibial fractures being treated in a molded circumferential above-knee plaster cast between October 2015 and April 2020 were included. Case notes were reviewed to identify demographics, analgesic prescriptions, and complications. Risk factors were analyzed using logistic regression. A total of 75 children were included, of which 64% were males. The mean age was 9.5 (SD 3.4) years. Opiates were required by 36 (48%) children in the first 24 hours following admission. The median number of opiate doses in the first 48 hours was 0 (range: 0 to 5), with 93% of children receiving ≤3 doses. The odds of requiring opiates in the first 24 hours were unchanged for age above 10 years [odds ratio (OR)=0.85, 95% confidence interval (CI): 0.33-2.23], male sex (OR=1.58, 95% CI: 0.59-4.19), high-energy injury (OR=1.65, 95% CI: 0.45-6.04), presence of a fibula fracture (OR=2.21, 95% CI: 0.72-6.76), or need for fracture reduction in the ED (OR=0.57, 95% CI: 0.20-1.65). No children developed compartment syndrome, and the mean length of stay was 1.4 (SD 1.2) days. No children were readmitted following discharge. We have found no cases of compartment syndrome or extensive requirement for opiates following closed tibial fractures treated in plaster cast. These children are candidates to be discharged directly from the ED. We have not identified any specific risk factors for the targeting of opiate analgesics. We recommend a guideline prescription of 6 doses of opiates for direct discharge from the ED to ensure adequate analgesia without overprescription. Level IV-case series.


Antineoplastic potential of mycotoxins.
Fungal toxins are secondary metabolites, in which many of them were mycotoxins, affecting eukaryotic cells with a broad range of structural and functional variety contributing to the multitude of their classification. This refers to the harmful genotoxic (mutagenic, teratogenic, and carcinogenic) effects of mycotoxins on the one hand, and their cytocidic and antineoplastic properties on the other hand. This "double edged sword" effect could be utilized against the spread of tumors in older patients when the survival is much more important than the mutagenic side effects. To decide which fungal toxins could be used as combined cytotoxic and antimetastatic agents, mycotoxins were divided into three categories: (a) highly genotoxic (mutagenic, teratogenic, and carcinogenic), (b) adversely toxic, and (c) antitumorigenic agents. Highly cytotoxic mycotoxins with tolerable side effects, combined with an antineoplastic character, could be potential candidates against metastasis. From the structure-function relationship of antimetastatic mycotoxins, only general conclusions have been drawn. The presence of ring structures containing heteroatoms, functional groups, and the cumulative presence of oxygen atoms contributed to the oxidative stress and cytotoxicity of mycotoxins. The preselection of mycotoxins excluded category (a), and only the categories (b) and


The high frequency of manic symptoms in fibromyalgia does influence the choice of treatment?
Mood disorders were found associated with fibromyalgia (FM) and clinical studies have revealed the efficacy of antidepressant drugs in the treatment of FM. However no specific instruments to identify manic symptoms were used. To assess the frequency of anxiety and mood disorders (particularly bipolar disorders and manic symptoms) in a consecutive sample of women affected by FM using standardized diagnostic tools and to compare the prevalence of these disorders with that observed in a sample of healthy controls from the general population. consecutive series of women (N = 37, mean age 50.1 +/- 21.0) attending a Rheumatology outpatient Unit at the University of Cagliari. 148 women, drawn from the data bank of an epidemiological study matched for sex and age with controls according to a randomisation "after blocks" method. The Italian version of the Composite International Diagnostic Interview Simplified were carried out by physicians. Psychiatric diagnosis was formulated according to DSM-IV criteria. The Italian version of the Mood Disorder Questionnaire (MDQ) was administered to identify manic symptoms and bipolar disorders. Diagnosis of FM were carried out by rheumatologist according to the criteria of American College of Rheumatology. Subjects with FM showed a higher comorbidity with Generalised Anxiety Disorder, Panic Disorder and Major Depressive Disorder than controls. The study showed a high frequency of manic symptoms (MDQ positive) in the sample of fibromyalgic patients (59%), approximately double that found in the control sample (P < 0.001). Clinical studies have shown the efficacy of antidepressants, especially tricyclic antidepressants, in the treatment of FM. The clinical difficulty in identifying hypomanic episodes is well known particularly where previous and not present episodes are concerned as in depressive patients. These data would suggest further studies on the subject are needed and more caution also in prescribing antidepressants in a population apparently at high risk for bipolar disorders.


Cognitive variations among vascular dementia subtypes caused by small-, large-, or mixed-vessel disease.
Vascular dementia (VaD) is a heterogeneous disease that can vary in clinical presentation and cognitive profile. The cognitive profiles of different VaD subtypes depend on the anatomical distribution of the vascular insults that have been documented. We reviewed demographic, cognitive, and imaging data in 402 patients who were clinically diagnosed with VaD between January 2002 and June 2012 at the First Affiliated Hospital of Gan Nan Medical College in Ganzhou, China. Based on magnetic resonance imaging (MRI) results, patients were classified as having large- (24.1%), small- (70.4%), or mixed-vessel VaD (5.5%). Hypertension was the most prevalent risk factor (81%), followed by smoking (37%), hyperlipidemia (35%), and diabetes (27%). Hyperlipidemia, cardiac risk factors (history of cardiovascular disease, heart valve disorder) and carotid stenosis were more frequent in patients with large-vessel disease compared to those with small-vessel or mixed-vessel disease (p < 0.001). A median of 4 (maximum 11) cognitive domains were impaired in each VaD patient. After memory dysfunction, executive defects were the most prevalent (68.9%), and neurobehavioral dysfunction was the most rare (13.2%). Patients with small-vessel VaD showed more executive dysfunction than patients with large-vessel and mixed-vessel VaD (p < 0.05), whereas patients with large-vessel VaD had a higher prevalence of visuospatial or language dysfunction (p < 0.05). The results indicate that specific subtypes and underlying vascular mechanisms will help predict clinical courses and produce more focused treatment and prevention of VaD.


Suppressive effects of Mimosa pudica (L.) constituents on the production of LPS-induced pro-inflammatory mediators.
The present study deals with the isolation of fourteen compounds from the active ethyl acetate (MPE) extract of M. pudica (L.) whole plant and their subsequent evaluation for the nitric oxide (NO), tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1ß) inhibitory activities in lipopolysaccharide (LPS) stimulated RAW 264.7 and J774A.1 cells. Among the tested compounds, L-mimosine (12; IC50 = 19.23 to 21.15 µM), crocetin (4; IC50 = 23.45 to 25.57 µM), crocin (14; IC50 = 27.16 to 31.53 µM) and jasmonic acid (11; IC50 = 21.32 to 29.42 µM) were identified as potent NO inhibitor when tested on the macrophages. Similarly, towards TNF-α and IL-1ß inhibition, including these four compounds, and ethyl gallate (3), gallic acid (10) and caffeic acid (7) were found to be more active with half maximal concentration, 17.32 to 62.32 µM whereas the other compounds depicted moderate and mild effects (IC50 = 59.32 to 95.01 µM). Also, at a dose of 40 mg/Kg, L-mimosine (12), jasmonic acid (11), crocin (14) and its de-esterified form, crocetin (4) were found to significantly (p < 0.05 and 0.001) reduce 60.7 %, 48.9 %, 48.4 % and 43.6 % respectively of TNF-de-esterified production in female Sprague Dawley rats. However, in case of IL-1ß, with the same dose (40 mg/Kg), jasmonic acid (11) exhibited significant reduction with 54.2 % followed by crocin (14) (50.2 %) and crocetin (4) (39.8 %) while L-mimosine (12) was found to reduce only 16.3 %. Based on the results, it can be estimated that these compounds imparting greatly to anti-inflammatory effects of M. pudica in vitro as well as in vivo through reduction of LPS-induced pro-inflammatory mediators which affirm the ethno-pharmacological use of this plant for prevention of inflammatory-related disorders.


Changes in ankle and foot kinematic after fixed-bearing total ankle replacement.
Ankle osteoarthritis is a chronic debilitating disease marked by cartilage breakdown, pain and significant biomechanical impairment of the entire lower limb. Total ankle replacement (TAR) has been encouraged during the last decade as it has the potential to maintain the existing pre-operative ankle range of motion and to protect the more distally located joints of the foot. Three-dimensional gait analysis using a multi-segment foot model can provide an objective analysis of TAR for the treatment of end-stage ankle osteoarthritis. Thirty-six patients suffering from post-traumatic end-stage ankle osteoarthritis were evaluated before and after TAR. A four-segment kinematic foot model was used to calculate intrinsic foot joint kinematics during gait. Spatio-temporal parameters were also assessed. Kinematic results were compared to a control group of asymptomatic subjects. Differences in waveform patterns were mainly limited to dorsi-/plantarflexion inter-segment angles. At loading response, the Shank-Calcaneus plantarflexion angles as well as the Calcaneus-Midfoot dorsiflexion angle increased slightly in post-operative condition. During propulsion, an increase in Hallux-Metatarsus dorsiflexion angle was observed. Pain improved after surgery as supported by increased spatio-temporal parameters. While multi-segment foot and ankle kinematics were improved, they remained impaired compared to control values. This study confirms that TAR maintains the residual pre-operative range of motion after surgery from midstance to propulsion. Furthermore, the results suggest that the kinematic behavior of the foot joints distal to the affected ankle joint also improves post-operatively. The outcome of this study further emphasizes the clinical relevance of multi-segment foot modeling when assessing the outcome of TAR.


[Abdominal paracentesis].
Abdominal paracentesis is frequently performed in the clinical setting. Every newly developed ascites need to be investigated by abdominal paracentesis. Any clinical or biological deterioration in patients with chronic ascites also requires a new paracentesis. Therapeutically abdominal paracentesis is performed for refractory or symptomatic ascites. As other invasive procedures, it is critical to master its indications, contra-indications and complications. The aim of this article is to review the basics of abdominal paracentesis in order to help physicians to carry out this technical skill.


MRI and thallium features of pigmented villonodular synovitis and giant cell tumours of tendon sheaths: a retrospective single centre study of imaging and literature review.
The purpose of this study was to characterize the MRI and thallium-201 ((201)TI) scintigraphy attributes of pigmented villonodular synovitis (PVNS) and giant cell tumours of tendon sheaths (GCTTS). The epidemiology of these uncommon lesions was also assessed and less commonly encountered pathology reported on including multifocality, necrosis and concurrent malignancy. A retrospective single centre review of MRI and (201)TI scintigraphy findings for 83 surgically proven or biopsy-proven consecutive cases of PVNS was undertaken. Radiological findings including lesion size, (201)TI uptake (as a marker of metabolic activity), location, extent and patient demographics were correlated with biopsy and surgical specimen histology. Typical appearances are described, as well as less common imaging manifestations. The study period encompassed all patients presenting or referred to a tertiary bone and soft-tissue tumour referral centre with PVNS or GCTTS between 1 January 2007 and the 1 December 2013. Lesions occur most commonly around the knee joint in the fourth decade of life, with younger patients showing a tendency to occur in the hip. Features of PVNS and GTTS include bone erosion, ligamentous and cartilage replacement, muscle infiltration and multifocality. MR signal characteristics were variable but post-contrast enhancement was near-universal. 14 of 83 cases showed no uptake of (201)TI and revealed a statistically significant smaller average axial dimension of 19.8 mm than lesions displaying active (201)TI uptake of 36.4 mm, p = 0.016. Four lesions demonstrated central necrosis on gross histology, two of each from both the (201)TI-avid and (201)TI-non-avid groups. MR is the imaging modality of choice when considering the diagnosis of these uncommon tumours. (201)TI scintigraphy as a marker of metabolic activity further adds minimal value although small lesions can appear to lack (201)TI avidity. This article depicts typical imaging findings of PVNS/GCTTS and also a subset of lesions that demonstrate no uptake on metabolic functional imaging, namely smaller sized lesions irrespective of anatomical location. This represents an important departure from previously documented imaging manifestations, whereby an absence of isotope accumulation suggested exclusion of these lesions from the differential diagnosis. These findings have important implications when considering the diagnosis of these uncommon lesions and may be important when interpreting post-treatment response. We suggest that further investigation, for example, with MRI is valuable in order to clarify potential post-treatment response, as well as the use of alternate functional imaging modalities such as positron emission tomography (PET), to further corroborate these findings.


Multispacer typing of Rickettsia prowazekii enabling epidemiological studies of epidemic typhus.
Currently, there is no tool for typing Rickettsia prowazekii, the causative agent of epidemic typhus, currently considered a potential bioterrorism agent, at the strain level. To test if the multispacer typing (MST) method could differentiate strains of R. prowazekii, we amplified and sequenced the 25 most variable intergenic spacers between the R. prowazekii and R. conorii genomes in five strains and 10 body louse amplicons of R. prowazekii from various geographic origins. Two intergenic spacers, i.e., rpmE/tRNA(fMet) and serS/virB4, were variable among tested R. prowazekii isolates and allowed identification of three and two genotypes, respectively. When the genotypes obtained from the two spacers were combined, we identified four different genotypes. MST demonstrated that several R. prowazekii strains circulated in human body lice during an outbreak of epidemic typhus in Burundi. This may help to discriminate between natural and intentional outbreaks. Our study supports the usefulness of MST as a versatile method for rickettsial strain genotyping.


Associations between body image, eating behavior, and diet quality.
Background: Weight-neutral interventions that promote adaptive eating behaviors are becoming a growing area of practice. Understanding whether adaptive eating behaviors are associated with improved diet quality is essential. Body image may be an important factor in this relationship given its close connection to eating behaviors. Aim: The purpose of this study was to develop an understanding of the relationships between positive and negative body image, adaptive and maladaptive eating behaviors, and diet quality. Methods: We recruited 288 adults 18 years and older who were living in the US using Prolific Academic. Participants completed an online survey including measures of positive and negative body image, adaptive and maladaptive eating behaviors, and a dietary screener questionnaire (DSQ). We ran a hierarchical linear regression and tested whether body image and diet quality were mediated by eating behavior. Results: Body image and maladaptive eating behaviors were not associated with diet quality. Body-food choice congruence (B-FCC), an adaptive eating behavior, was associated with diet quality. B-FCC mediated the relationship of positive and negative body image to diet quality. Conclusions: Our findings provide additional support for weight-neutral or adaptive eating interventions as a mechanism to promote diet quality. Additional research may benefit from exploring indirect effects of body image on diet intake, the relationship between eating behavior and diet quality using qualitative data, and the comparison of weight-neutral or non-diet interventions with traditional behavior change interventions.


A quantitative model for the all-or-none permeabilization of phospholipid vesicles by the antimicrobial peptide cecropin A.
The mechanism of the all-or-none release of the contents of phospholipid vesicles induced by the antimicrobial peptide cecropin A was investigated. A detailed experimental study of the kinetics of dye release showed that the rate of release increases with the ratio of peptide bound per vesicle and, at constant concentration, with the fraction of the anionic lipid phosphatidylglycerol in neutral, phosphatidylcholine membranes. Direct measurement of the kinetics of peptide binding and dissociation from vesicles revealed that the on-rate is almost independent of vesicle composition, whereas the off-rate decreases by orders of magnitude with increasing content of anionic lipid. A simple, exact model fits all experimental kinetic data quantitatively. This is the first time that an exact kinetic model is implemented for a peptide with an all-or-none mechanism. In this model, cecropin A binds reversibly to vesicles, which at a certain point enter an unstable state. In this state, a pore probably opens and all vesicle contents are released, consistent with the all-or-none mechanism. This pore state is a state of the whole vesicle, but does not necessarily involve all peptides on that vesicle. No peptide oligomerization on the vesicle is involved; alternative models that assume oligomerization are inconsistent with the experimental data. Thus, formation of well-defined, peptide-lined pores is unlikely.


Reflecting on survivorship outcomes to aid initial decision making in patients treated for IDH-mutated anaplastic glioma.
Patients with anaplastic glioma (AG) harboring an isocitrate dehydrogenase mutation have potential durable survival after intensity-modulated radiotherapy (IMRT) and chemotherapy. Understanding long-term functioning, and the factors that have an impact on later effects, is important for decision making. Consecutive patients with AG who received IMRT were reviewed with regard to 6 survivorship domains, including Eastern Cooperative Oncology Group (ECOG) performance status, Medical Research Council (MRC) neurological status, late toxicity, comorbidity, functional status (employment/driving), and psychosocial events. Assessments were performed at baseline before RT; at month +6; and at years +1, +3, and +5 after RT. The primary endpoints were ECOG at year +3 and employment at year +3. A total of 146 patients were included, with a median follow-up of 5.1 years. The 6-year overall survival rate was 78.7% (95% CI, 71.1%-87.0%). Baseline ECOG performance status was 0 to 1 in 82.2% of patients but improved at year +1 (95.7%) and year +3 (97.2%). Employment rates at year +3 and year +5 were 70.1% and 76.5%, respectively, compared with 61.6% at baseline. Worse ECOG performance status at year +3 was related to the anaplastic astrocytoma subtype (P = .001), delayed RT (P = .081), multiple craniotomies performed before RT (P = .002), worse ECOG performance status before RT (P < .001), worse MRC neurological status before RT (P < .001), seizures (P = .038), neurocognitive disturbance (P < .001), and the presence of recurrent disease (P = .004). Absent or impaired employment at year +3 was found to be related to older age (P = .007), delayed timing of RT (P = .023), multiple craniotomies prior to RT (P = .005), worse ECOG performance status before RT (P < .001), worse MRC neurological status before RT (P < .001), and neurocognitive disturbance (P < .001). Patients with AG with an isocitrate dehydrogenase mutation have the potential for prolonged survival. Functional status appears to be good in patients who are free of disease progression at 3 to 5 years after IMRT, with >95% of patients having high ECOG performance status and >75% being employed.


Friends with social benefits: host-microbe interactions as a driver of brain evolution and development?
The tight association of the human body with trillions of colonizing microbes that we observe today is the result of a long evolutionary history. Only very recently have we started to understand how this symbiosis also affects brain function and behavior. In this hypothesis and theory article, we propose how host-microbe associations potentially influenced mammalian brain evolution and development. In particular, we explore the integration of human brain development with evolution, symbiosis, and RNA biology, which together represent a "social triangle" that drives human social behavior and cognition. We argue that, in order to understand how inter-kingdom communication can affect brain adaptation and plasticity, it is inevitable to consider epigenetic mechanisms as important mediators of genome-microbiome interactions on an individual as well as a transgenerational time scale. Finally, we unite these interpretations with the hologenome theory of evolution. Taken together, we propose a tighter integration of neuroscience fields with host-associated microbiology by taking an evolutionary perspective.


[Not Available].
In recent years, the enactment of uniform national regulations concerning postmortem examination has become a persistent demand. There is strong criticism of the reliability of coroner's inquest. The education of most of the coroners in forensic medicine is found to be insufficient, and many experts report that medical examiners partly are neglectful for the inquest. The classification of the manner of death is also said to be deficient, the rate of misdiagnosis being only little below 50%. Thus much emphasis is put on demanding a reinforced training of doctors in the field of the external examination of corpses. But only few of those reports make allowance for the fact that most of the present deficiencies have their origin in the 19th century. As a matter of fact, from the outset the practice of coroner's inquest gave rise to criticism. Thus the present article traces the historical roots of postmortem examination in Germany. Special emphasis is placed on a comparison between the infancies of coroner's inquest and the current state. Actual and historical imperfections in the system of postmortem examination and striking similarities are pointed out.


Alterations in TNF- and IL-related gene expression in space-flown WI38 human fibroblasts.
Spaceflight, just like aging, causes profound changes in musculoskeletal parameters, which result in decreased bone density and muscular weakness. As these conditions decrease our ability to conduct long-term manned space missions, and increase bone frailty in the elderly, the identification of genes responsible for the apparition of these physiological changes will be of great benefit. Thus, we developed and implemented a new microarray approach to investigate the changes in normal WI38 human fibroblast gene expression that arise as a consequence of space flight. Using our microarray, we identified changes in the level of expression of 10 genes, belonging to either the tumor necrosis factor- (TNF) or interleukin- (IL) related gene families in fibroblasts when WI38 cells exposed to microgravity during the STS-93 Space Shuttle mission were compared with ground controls. The genes included two ligands from the TNF superfamily, TWEAK and TNFSF15; two TNF receptor-associated proteins, NSMAF and PTPN13; three TNF-inducible genes, ABC50, PTX3, and SCYA13; TNF-alpha converting enzyme, IL-1 receptor antagonist, and IL-15 receptor alpha chain. Most of these are involved in either the regulation of bone density, and as such the development of spaceflight osteopenia, or in the development of proinflammatory status.


Position paper on requirements for toxicological studies in the specific case of radiopharmaceuticals.
This is a position paper of the Radiopharmacy Committee of the EANM (European Association of Nuclear Medicine) addressing toxicology studies for application of new diagnostic and therapeutic radiopharmaceuticals (RP) that are not approved (i.e., not having a marketing authorization or a monograph in the European Pharmacopoeia), excluding endogenous and ubiquitous substances in humans. This paper discusses the requirements for clinical trials with radiopharmaceuticals for clinical research applications, not necessarily intended to aim at a marketing authorization. If marketing authorization is intended, scientific advice of the competent authorities is mandatory and cannot be replaced by this position paper. The position paper reflects the view of the Radiopharmacy Committee of the EANM and can be used as a basis for discussions with the responsible authorities.


Receptor cooperation in B cells.
TLR4-stimulated B cell activation is mediated by the tyrosine kinase Syk and depends on the B cell receptor.


Defective oral tolerance promotes nephritogenesis in experimental IgA nephropathy induced by oral immunization.
Oral tolerance, an important feature of the mucosal immune system, appears to protect against immune-mediated disease by blunting production of systemic IgG and IgM antibody directed toward immunogens chronically present at mucosal surfaces. In this study, we explored the role of oral tolerance and mucosal immunoregulation in an experimental model of IgA nephropathy (IgAN), an important form of nephritis in humans. Cyclophosphamide and estradiol were used to inhibit the expression of oral tolerance, which otherwise develops after chronic oral presentation of Ag. BALB/c mice given drinking water containing 0.1% bovine gamma globulin (BGG) continuously for 14 wk were randomly assigned to groups given either 2 mg of cyclophosphamide i.p., 2 mg of estradiol s.c. or both drugs. Groups of control mice received neither BGG nor drugs. In three separate experiments, a low percentage of saline-treated orally immunized mice had microscopic hematuria (0 to 20%), as did nonimmunized controls (0 to 20%). However, 58 to 83% of mice given estradiol and/or cyclophosphamide at appropriate times developed significant hematuria. If drugs were given at suboptimal times, only 25 to 56% of mice developed hematuria. Drug-treated immunized mice also had more serum IgG and IgM anti-BGG antibodies than control and saline groups. Immunofluorescence showed significantly more glomerular deposits of IgG, IgM, and C3 in drug-treated immunized mice compared to saline-treated immunized and normal untreated control mice. Hematuria and glomerular deposits of IgG, IgM, and C3 paralleled serum IgG and IgM antibody. All immunized mice showed significant mesangial IgA and BGG deposits and there were no differences in such deposits between saline- and drug-treated immunized mice. We suggest that blunting of oral tolerance with promotion of systemic IgG and IgM antibody production leads to nephritis in chronically orally immunized mice and that glomerular immune complexes containing IgG and/or IgM promote complement deposition and hematuria in IgAN. Analogous defects in oral (or more generally mucosal) tolerance could play a role in the genesis of symptomatic human IgAN.


The effect of nicotine on pulmonary epithelial permeability in man.
We examined the effect of nicotine on pulmonary epithelial permeability in man. Nicotine was administered from a chewing gum base given over a seven-day period. An index of pulmonary permeability was derived from the rate of clearance from the lung into the blood of 99mTcDTPA (diethylenetriamine pentacetate). In five nonsmoking volunteers there was no change in permeability for the seven-day study period. This lack of effect of nicotine alone was in striking contrast to the increase in epithelial permeability observed in five nonsmoking subjects who took up cigarette smoking.


A methodology for estimating the contribution of malnutrition to child mortality in developing countries.
According to conventional methods of classifying cause of death, approximately 70% of child deaths (0-4 y) worldwide are due to a small number of priority infectious diseases which, in turn, receive the vast majority of donor and national resources in the health sector. Despite the long-recognized synergism between malnutrition and infection in the causation of child mortality, malnutrition does not appear as a major cause of death in health statistics from developing countries. Part of the reason for this has been the difficulty of estimating the percent of deaths due to malnutrition, because the conventional methods of classifying cause of death do not recognize the potentiating effect of malnutrition on the disease. The purpose of this paper is to develop and test a simple methodology to estimate the percent of child deaths in a given country or community that is due to malnutrition's potentiating effects on prevailing infectious diseases. The cornerstone of the methodology is knowledge of the strength of the association between malnutrition and mortality in developing countries, as measured in eight prospective studies. These studies reveal remarkable consistency in relative risk across different grades of malnutrition. The mean and SE of relative risk for severe malnutrition is 8.4 +/- 2.1, for moderate malnutrition it is 4.6 +/- 0.9, and for mild malnutrition it is 2.5 +/- 0.3. When applied to survey data from Ethiopia, Malawi, Guatemala and India for illustrative purposes, this methodology indicates that 42-57% of all child deaths in these samples (6-59 mo) are due to malnutrition's potentiating effects on infectious disease, of which 76-89% is attributable to mild-to-moderate malnutrition. This methodology is recommended for use in a variety of policy and planning applications.


Cyclin-dependent kinase 5 is essential for neuronal cell cycle arrest and differentiation.
Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine kinase with significant homology to cell cycle-related Cdks but is not believed to be active in a typical cell cycle. In Cdk5-deficient embryos and Cdk5 chimeras, migration and survival of postmitotic neurons is compromised in a cell-autonomous manner. In the present study, we show that loss of Cdk5 leads to both failure of neuronal differentiation and loss of cell cycle control. Using specific cytoskeletal proteins as indices of neuronal differentiation, we find that Cdk5-deficient neurons are significantly arrested or delayed in their developmental program both in vivo and in vitro. For example, immunocytochemistry of embryonic day 16 (E16) cortex reveals that the expression of microtubule-associated protein 2c (Map-2c), a marker of mature neurons, is nearly absent in Cdk5(-/-) cells that have migrated to the cortical plate while these same cells continue to express nestin. Similarly, in vitro, Map-2-positive cells are rare in cultures from E16 Cdk5(-/-) embryos. Cell cycle control is also deficient in Cdk5(-/-) cells. In vivo, neurons engaged in cell cycle activities are found in the cortical plate, and, in vitro, class III beta-tubulin-positive cells continue to label with bromodeoxyuridine even after 5 d of incubation. Transfection of a wild-type Cdk5 construct reveals that cell cycle control can be regained in Cdk5(-/-) cells by overexpression of Cdk5. These data indicate that Cdk5 is necessary for both neuronal differentiation and cell cycle inhibition.


Making nutrition sense from OASIS.
Assessing nutrition is an integral part of the comprehensive assessment for each patient. Although OASIS does not have a specific section or identified items labeled for nutrition, there are numerous nuances of nutritional status imbedded in the OASIS-B1. This article will identify the many OASIS items that contribute to the nutritional assessment and point out when OASIS responses should trigger a referral to a registered dietitian.


[In situ enrichment and diversity analysis of polycyclic aromatic carbon degrading bacteria in the coastal seawater of Xiamen Island].
The aim of this study is to assess the diversity of polycyclic aromatic carbon (PAH)-degrading bacteria in the coastal seawater of Xiamen Island. The phenanthrene-degrading bacteria were enriched by suspending phenanthrene-coated Polyvinylchloride (PVC) plates in the seawater close to Xiamen International Cruise Dock. PCR-DGGE and 16S rRNA gene clone library were used to analyze the bacteria colonizing on the PVC plates. Further, PAH-degrading bacteria were re-enriched in lab after the in situ enrichment and subjected to diversity analysis and bacterial isolation. After 6 days incubation, the genus Cycloclasticus was shown to be the dominant bacterium on the phenanthrene (Phe)-coated plates, which accounted for 50% of the total clones in 16S rRNA gene clone library. However, on the control plates without Phe-coating, bacteria of Rhodobacteraceae were the dominant member, which accounted for 47% of the total clones. PCR-DGGE results reconfirmed the genus Cycloclasticus as the dominant member on the Phe-coated plates. After re-enrichment with Phe in laboratory, 14 strains were isolated from the consortium, which contained a potential novel species of genus Novosphingobium, named strain B-14 and identified as a Phe degrader. However, the most predominant member Cycloclasticus can not be cultivated into pure culture. Genus Cycloclasticus is the most important PAH-degrading bacterium in the coast sea water of Xiamen Island. This is the first evidence to our knowledge about the in situ enrichment PAH-degrading bacterium in seawater.


Newer formulations of the triptans: advances in migraine management.
Migraine is a common, frequently incapacitating, headache disorder that imposes a substantial burden on both the individual patient and society. The last two decades have witnessed an explosion in our understanding of the pathophysiology of migraine, and in our development of an efficacious and diverse therapeutic armamentarium. There are several routes of drug administration available to patients with migraine. All the serotonin 5-HT(1B/1D) receptor agonists (triptans) are available as oral tablets (sumatriptan, rizatriptan, zolmitriptan, naratriptan, almotriptan, frovatriptan and eletriptan). Only sumatriptan is available as a subcutaneous injection. Some triptans are also available via newer routes of administration, including orally disintegrating tablets (rizatriptan and zolmitriptan), rectal suppositories (sumatriptan) and intranasal sprays (sumatriptan and zolmitriptan). Oral disintegrating tablets and other non-oral triptan routes (subcutaneous, intranasal, rectal) are a useful alternative to conventional oral tablets for patients who have difficulty swallowing pills or prefer not to do so, and for patients whose nausea and/or vomiting precludes swallowing tablets and/or makes the likelihood of complete absorption unpredictable. This is important because epidemiological studies in migraine reveal that the vast majority of patients (>90%) have experienced nausea during a migraine attack and more than 50% have nausea with the majority of attacks. Similarly, most (almost 70%) have vomited at some time during an attack and of these patients, almost one-third vomit in the majority of attacks. The newer formulations, rapidly dissolving tablets and intranasal sprays, afford patients the opportunity to use abortive therapy without the need for liquids, at anytime and anywhere, at the onset of a migraine attack. Furthermore, the intranasal sprays are absorbed rapidly and have a prompt onset of action allowing for significant pain free rates versus placebo as early as 15 minutes post administration. The ability to administer treatment early in a migraine attack and have a rapid onset of action is particularly important in acute migraine treatment in order to prevent the development of central sensitisation. While many patients and physicians choose conventional oral tablets because of familiarity and ease of administration, the newer formulations, oral disintegrating tablets and intranasal sprays, should be given consideration as first-line agents in selected patients.


Apoptotic Resistance of Metastatic Tumor Cells in Triple Negative Breast Cancer: Roles of Death Receptor-5.
Background: Metastasis is a major cause of death from cancer in triple-negative breast cancer (TNBC). Apoptosis evasion is a critical feature of metastatic tumor cells. Chemopreventive and apoptotic potential of curcumin has been shown in breast cancer. However, the precise mechanism of these effects against metastatic tumor cells has not been clearly addressed yet. Methods: 4T1 cell line was used for induction of metastatic animal model of breast cancer. Primary and metastatic tumor cells were extracted from subcutaneous tumor and lung of cancerous mice, respectively. MTT assay was used to determine the effect of curcumin on viability of tumor cells. Quantitative real-time polymerase chain reaction was performed to analyze the effect of curcumin on death receptor-5 (DR-5) gene expression. Results: Our data revealed that, compared with primary tumor cells, metastatic tumor cells were more resistance to apoptosis effects of curcumin. The DR-5 gene expression was up-regulated in both primary and metastatic tumor cells after curcumin treatment, but this up-regulation was significantly higher in primary tumor cells compared with metastatic cells. Conclusion: These findings provided important insights regarding the molecular mechanism of apoptosis resistance of metastatic tumor cells and can be used for designing a targeted therapeutic strategies in combat with metastatic TNBC.


[18p-syndrome with bilateral pyramidal tract signs, dystonia of the lower extremities and concentric visual field defect].
A case, diagnosed as 18p-syndrome by typical clinical appearance and by chromosomal analysis, presented with multiple nervous system defects consisting of bilateral pyramidal tract signs, weakness and focal dystonia of the lower extremities, and concentric visual field defect. Chromosomal analysis revealed karyotype 46, X, dic (Y;18) (p11;p11), inv(9) (p11q13), and the points of chromosomal breakages were thought to be in the short arm of chromosome 18 and in the short arm of Y chromosome. 18p-syndrome is caused by a chromosomal deletion, and presents with a wide variety of clinical appearances. Many cases have been reported since the original descriptions by de Grouchy in 1963, though with few mentions of neurological deficits other than mental retardation. Furthermore, there have been no reports of pyramidal tract signs, weakness and focal dystonia of the lower extremities, or visual field defect, without recognizable anatomical abnormalities. Our case of 18p-syndrome is quite rare because of multiple nervous system abnormalities mentioned above, not accompanied by malformations of the central nervous system.


[Nursing diagnoses in acute psychiatric wards in Switzerland and Austria: commonalities and differences].
In Austria and Switzerland, nursing diagnoses in psychiatric nursing have been used increasingly over the last few years. To date, few empirical studies on the clinical use of nursing diagnoses in psychiatric nursing have been conducted. The purpose of this study was to examine the frequency and content of documented nursing diagnoses and to compare the utilization of nursing diagnoses in Austria and Switzerland. We prospectively registered all documented nursing diagnoses in an unselected sample of 330 patients consecutively discharged from eleven acute (admission) wards in five psychiatric hospitals in Switzerland and Austria. 635 nursing diagnoses were located. 83% of the patients had at least one nursing diagnosis (mean = 2, median = 1). 20% of the nursing diagnoses were documented on admission day and 90% of the diagnoses were formulated using NANDA terminology. The most frequently used categories were coping-related diagnoses, disturbed thought processes, and self care deficits. In comparison to Switzerland, nursing diagnoses are implemented more consequently in Austria. There seem to be differences between the two countries in the application of the diagnostic process. We conclude from the study's results that the application of nursing diagnoses is possible on acute psychiatric wards with a short length of stay of patients. 20 NANDA diagnoses account for a large portion of the care problems of acute psychiatric patients. Local differences in the use of the diagnostic process deserve further examination.


Integrative analysis of super enhancer SNPs for type 2 diabetes.
Clinical studies in type 2 diabetes (T2D) primarily focused on the single nucleotide polymorphisms (SNPs) located in protein-coding regions. Recently, the SNPs located in noncoding regions have also been recognized to play an important role in disease susceptibility. The super enhancer is a cluster of transcriptional enhancers located in noncoding regions. It plays a critical role in cell-type specific gene expression. However, the exact mechanism of the super enhancer SNPs for T2D remains unclear. In this study, we integrated genome-wide association studies (GWASs) and T2D cell/tissue-specific histone modification ChIP-seq data to identify T2D-associated SNPs in super enhancer, followed by comprehensive bioinformatics analyses to further explore the functional importance of these SNPs. We identified several interesting T2D super enhancer SNPs. Interesting, most of them were clustered within the same or neighboring super enhancers. A number of SNPs are involved in chromatin interactive regulation and/or potentially influence the binding affinity of transcription factors. Gene Ontology (GO) analysis showed a significant enrichment in several well-known signaling pathways and regulatory process, e.g. WNT signaling pathway, which plays a key role in T2D metabolism. Our results highlighted the potential functional importance of T2D super enhancer SNPs, which may yield novel insights into the pathogenesis of T2D.


Mortality associated with central nervous system tuberculosis.
Tuberculosis (TB) of the central nervous system (CNSTB) is associated with higher mortality rates than other forms of TB. Epidemiologic associations with and prognostic indicators of CNSTB have not been assessed in a large US population-based study. Between 1995 and 2004 and using a population-based active surveillance study, we compared patients with CNSTB to patients with TB affecting sites other than CNS (non-CNSTB) with respect to sociodemographic, clinical and Mycobacterium tuberculosis genotype variables. Risk factors associated with mortality at 180 days were compared between the 2 groups. We enrolled 92 patients with CNSTB and 3570 with non-CNSTB. HIV co-infection was present in 31 (33.7%) of the CNSTB cases. In a Cox proportion hazard model, we found that CNSTB patients who died within 180 days were more likely to be older (HR 1.06, 95% CI 1.02-1.10), have a positive MTB culture from a CNS source (HR 5.11, 95% CI 1.06-24.62) and have hydrocephalus (HR 10.62, 95% CI 3.28-34.36) than patients who survived CNSTB. HIV co-infection association with mortality was not statistically significant (HR 1.74, 95% CI 0.35-8.62). In our cohort, hydrocephalus was the most important predictor of mortality post-CNSTB diagnosis.


Nitric oxide-cGMP pathway is involved in endotoxin-induced contractile dysfunction in rat hearts.
The mechanisms by which endotoxemia causes cardiac depression have not been fully elucidated. The present study examined the involvement of nitric oxide (NO) in this pathology. Rats were infused with lipopolysaccharide (LPS) or saline, and the plasma and myocardial NO(2)(-) and NO(3)(-) (NOx) concentrations were measured before or 3, 6, and 24 h after treatment. The hearts were then immediately isolated and mounted in a Langendorff apparatus, and left ventricular developed pressure (LVDP) was determined before biochemical analysis of the myocardium. LPS injection effected the expression of inducible NO synthase (iNOS) in the myocardium, a marked increase in plasma and myocardial NOx levels, and a significant decline in LVDP compared with saline controls. The LPS-induced NO production and concomitant cardiac depression were most pronounced 6 h after LPS injection and were accompanied by a significant increase in myocardial cGMP content. Myocardial ATP levels were not significantly altered after LPS injection. Significant negative correlation was observed between LVDP and myocardial cGMP content, as well as between LVDP and plasma NOx levels. Aminoguanidine, an inhibitor of iNOS, significantly attenuated the LPS-induced NOx production and contractile dysfunction. Furthermore, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, an inhibitor of soluble guanylate cyclase, significantly decreased myocardial cGMP content and attenuated the contractile depression, although aminoguanidine or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one was not able to completely reverse myocardial dysfunction. Our data suggest that endotoxin-induced contractile dysfunction in rat hearts is associated with NO production by myocardial iNOS and a concomitant increase in myocardial cGMP.


Immunofluorescence and immunoelectron microscopic studies in cicatricial pemphigoid.
We have studied various tissues from 10 patients with cicatricial pemphigoid using direct and indirect immunofluorescence, mechanical suction blister induction, and immunoelectron microscopy. In 8 of the 10 patients, direct immunofluorescence of buccal mucosa showed a linear deposition of immunoreactants, IgG and C3 being those most commonly detected. Direct immunofluorescence of skin was positive in only 4 patients. Only 1 patient had a detectable circulating anti-basement membrane zone antibody. Substitution of normal human oral mucosa for adult skin as the tissue substrate for indirect immunofluorescence did not prove useful in the detection of circulating autoantibodies. Immunoelectron microscopy was performed in the skin or mucosa (buccal or ocular) of 6 patients, revealing lamina lucida localization of in vivo-bound immunoreactants. Indirect immunofluorescence studies on mechanically induced suction blisters in skin of 2 patients with in vivo-bound IgG suggest that the lamina lucida antigen involved in cicatricial pemphigoid may be distinct from the bullous pemphigoid antigen.


Preliminary study of an oral vaccine against infectious hematopoietic necrosis virus using improved yeast surface display technology.
Infectious hematopoietic necrosis virus (IHNV) is a common pathogen that causes severe disease in the salmonid aquaculture industry. Because oral vaccines induce more efficient mucosal immunity than parenteral immunization, an oral vaccine was developed with an improved yeast cell surface display technology to induce an immune response to IHNV. The oral yeast vaccine, designated EBY100/pYD1-bi-G, was delivered orally to rainbow trout (Oncorhynchus mykiss) on days 1 and 32, and the nonspecific and specific immune responses were measured 50days after the first vaccination. In the hindgut, spleen, and head kidney, the expression of IFN-1 and Mx-1 was significantly upregulated after oral vaccination with EBY100/pYD1-bi-G, and the highest expression of IFN-1 and Mx-1 was observed in the spleen (7.5-fold higher than the control group) and head kidney (3.9-fold higher than the control group), respectively. Several markers of the adaptive immune response (IgM, IgT, CD4, and CD8) were also significantly upregulated, and the highest expression of these markers was observed in the hindgut, suggesting that the mucosal immune response was successfully induced by oral vaccination with EBY100/pYD1-bi-G. Sera from the orally vaccinated rainbow trout showed higher anti-IHNV neutralizing antibody titers (antibody titer 81±4) than the control sera (antibody titer 7±3), and the relative percentage survival after IHNV challenge was 45.8% compared with 2% in the control group. Although the protection afforded by this orally delivered vaccine was lower than that of a DNA vaccine (83%-98%), it is a promising candidate vaccine with which to protect larval fish against IHNV, which are most susceptible to the virus and difficult to inject with a DNA vaccine.


The Role of Sub- and Supercritical CO2 as "Processing Solvent" for the Recycling and Sample Preparation of Lithium Ion Battery Electrolytes.
Quantitative electrolyte extraction from lithium ion batteries (LIB) is of great interest for recycling processes. Following the generally valid EU legal guidelines for the recycling of batteries, 50 wt % of a LIB cell has to be recovered, which cannot be achieved without the electrolyte; hence, the electrolyte represents a target component for the recycling of LIBs. Additionally, fluoride or fluorinated compounds, as inevitably present in LIB electrolytes, can hamper or even damage recycling processes in industry and have to be removed from the solid LIB parts, as well. Finally, extraction is a necessary tool for LIB electrolyte aging analysis as well as for post-mortem investigations in general, because a qualitative overview can already be achieved after a few minutes of extraction for well-aged, apparently "dry" LIB cells, where the electrolyte is deeply penetrated or even gellified in the solid battery materials.


Estimating population extinction thresholds with categorical classification trees for Louisiana black bears.
Monitoring vulnerable species is critical for their conservation. Thresholds or tipping points are commonly used to indicate when populations become vulnerable to extinction and to trigger changes in conservation actions. However, quantitative methods to determine such thresholds have not been well explored. The Louisiana black bear (Ursus americanus luteolus) was removed from the list of threatened and endangered species under the U.S. Endangered Species Act in 2016 and our objectives were to determine the most appropriate parameters and thresholds for monitoring and management action. Capture mark recapture (CMR) data from 2006 to 2012 were used to estimate population parameters and variances. We used stochastic population simulations and conditional classification trees to identify demographic rates for monitoring that would be most indicative of heighted extinction risk. We then identified thresholds that would be reliable predictors of population viability. Conditional classification trees indicated that annual apparent survival rates for adult females averaged over 5 years ([Formula: see text]) was the best predictor of population persistence. Specifically, population persistence was estimated to be ≥95% over 100 years when [Formula: see text], suggesting that this statistic can be used as threshold to trigger management intervention. Our evaluation produced monitoring protocols that reliably predicted population persistence and was cost-effective. We conclude that population projections and conditional classification trees can be valuable tools for identifying extinction thresholds used in monitoring programs.


Therapist-oriented home rehabilitation for adults with sickle cell anemia: effects on muscle strength, functional capacity, and quality of life.
Considering the advances in functional rehabilitation in recent decades, therapist-oriented home rehabilitation (TOHR) has been increasingly used in the field of physical therapy because it increases patient compliance and reduces health system costs. The objective of this study was to investigate the effects of TOHR on functional capacity, muscle strength, and quality of life (QoL) in adults with sickle cell anemia (SCA). Forty adults with SCA underwent manually guided TOHR for 12 weeks. Before and at the end of training, the following variables were assessed in the participants: distance covered in the 6-min walk test (6MWD); maximal inspiratory pressure (MIP); maximal expiratory pressure (MEP); handgrip strength (HGS); quadriceps strength (QS); and QoL using the Short Form-36 physical component summary (SF-36PCS) and the Short Form-36 mental component summary (SF-36MCS). After TOHR, significant increases were observed in the mean values for the 6MWD, MIP, MEP, HGS, QS, and SF-36PCS and SF-36MCS scores. The relative delta between the pre- and post-TOHR 6MWDs correlated significantly with the relative deltas of MIP (rs = 0.640, p < 0.0001), MEP (rs = 0.587, p < 0.0001), HGS (rs = 0.360, p = 0.022), and QS (rs = 0.351, p = 0.026). When the participants were separated according to their use of hydroxyurea, significant increases were observed in the relative deltas of the 6MWD, MIP and MEP values. This study shows that TOHR can potentially increase functional capacity, muscle strength, and QoL in adults with SCA. Furthermore, there appears to be a relationship between 6MWD gains and muscle strength gains with TOHR.Trial registration: ClinicalTrials.gov identifier: NCT04705792.


Characterization of the transcriptional activity of the cryptic plasmid pRN1 from Sulfolobus islandicus REN1H1 and regulation of its replication operon.
The plasmid pRN1 from Sulfolobus islandicus REN1H1 belongs to the crenarchaeal plasmid family pRN. The plasmids in this family encode three conserved proteins that participate in plasmid replication and copy number regulation, as suggested by biochemical characterization of the recombinant proteins. In order to deepen our understanding of the molecular biology of these plasmids, we investigated the transcriptional activity of the model plasmid pRN1. We detected five major transcripts present at about 2 to 15 copies per cell. One long transcriptional unit comprises the genes for the plasmid-copy-number control protein Orf56/CopG and the replication protein Orf904. A second transcript with a long 3'-untranslated region codes for the DNA binding protein Orf80. For both transcripts, we identified countertranscripts which could play a regulatory role. The function of the fifth transcript is unclear. For the five transcripts, we determined the start site, the transcript end, the stability, and the abundance in different growth phases. Reporter gene experiments demonstrated that the copy number control protein Orf56 represses transcription of the orf56-orf904 cotranscript in vivo.


Bioinformatic Prediction of Possible Targets and Mechanisms of Action of the Green Tea Compound Epigallocatechin-3-Gallate Against Breast Cancer.
Epigallocatechin-3-gallate (EGCG), a bioactive compound in green tea, is the most abundant and biologically active catechin, and it exerts multiple effects in humans through mechanisms that remain to be clarified. The present study used bioinformatics to identify possible mechanisms by which EGCG reduces risk of breast cancer. Possible human protein targets of EGCG were identified in the PubChem database, possible human gene targets were identified in the NCBI database, and then both sets of targets were analyzed using Ingenuity Pathway Analysis to predict molecular networks affected by EGCG in breast cancer. The results suggest that signaling proteins affected by EGCG in breast cancer, which include JUN, FADD, NFKB1, Bcl-2, GNAO1, and MMP14, are involved primarily in cell death and survival; DNA replication, recombination and repair; and the cell cycle. The main networks affected by EGCG are predicted to involve the cell cycle; cellular assembly and organization; DNA replication, recombination and repair; and cell death and survival. These results identify several specific proteins and pathways that may be affected by EGCG in breast cancer, and they illustrate the power of integrative bioinformatics and chemical fragment analysis for focusing mechanistic studies.