Dynamically disordered hydrogen bonds in the hureaulite-type phosphatic oxyhydroxide Mn5[(PO4)2(PO3(OH))2](HOH)4.
We report the temperature evolution of hydrogen bond (HB) chains and rings in Mn5[(PO4)2(PO3(OH))2](HOH)4 to reveal conduction pathways based on difference Fourier maps with neutron- and synchrotron x-ray diffraction data. Localized proton dynamics for the five distinct hydrogen sites were observed and identified in this study. Their temperature evaluation over ten orders of magnitude in time was followed by means of quasielastic neutron scattering, dielectric spectroscopy, and ab initio molecular dynamics. Two out of the five hydrogen sites are geometrically isolated and are not suitable for long-range proton conduction. Nevertheless, the detected dc conductivity points to long-range charge transport at elevated temperatures, which occurs most likely (1) over H4-H4 sites between semihelical HB chains (interchain-exchanges) and (2) by rotations of O1-H1 and site-exchanging H4-O10-O5 groups along each semihelical HB chain (intrachain-exchanges). The latter dynamics freeze into a proton-glass state at low temperatures. Rotational and site-exchanging motions of HOH and OH ligands seem to be facilitated by collective motions of framework polyhedra, which we detected by inelastic neutron scattering.


Pregnancy outcomes following maternal or paternal exposure to teriflunomide in the Danish MS population.
Background Teriflunomide (TFL) is an oral drug used for treatment of multiple sclerosis (MS). Due to possible teratogenicity it is contraindicated in women of childbearing potential. Additionally, a low risk of male-mediated embryo-fetal toxicity has been described as the drug can be transmitted via semen. This study investigated the association of adverse perinatal outcomes in newborns with either maternal or paternal exposure to TFL. Methods The Danish Multiple Sclerosis Registry was used to identify all patients treated with teriflunomide from 1st of September 2013 to 31st of December 2018. Data were merged with other nationwide national registries to identify all pregnancies with potential exposure to TFL. Exposure was defined as conception occurring after at least 30 consecutive days of treatment either during treatment or within two years of treatment discontinuation. Exposed pregnancies were matched 1:4 with controls from the general population. Individual outcomes of adverse perinatal events, namely preterm birth, congenital malformations, small for gestational age (SGA), stillbirth or low Apgar score were used to form a composite outcome, any adverse event, which was used for the analysis. Logistic regression was used to estimate the association of having any adverse event in newborns with either maternal or paternal exposure to TFL. Results A total of 112 TFL-exposed pregnancies were included of which 49 had maternal exposure and 63 paternal exposure. Among women, 21/49 pregnancies were terminated - 18 electively and three spontaneously. The remaining 28 pregnancies resulted in healthy newborns of which ≤3 were preterm. None of the newborns presented with malformations, being SGA or with low Apgar score. Among men, all 63 pregnancies resulted in birth of which 4/63 (6.3%) were preterm. Major malformations were registered in ≤3 event, and no newborn presented with low Apgar score or being SGA. No increased association of any adverse event was found in newborns with TFL exposure relative to controls (OR 1.03, 95% CI 0.50-2.13). Conclusion We did not find an increased prevalence of spontaneous abortion, preterm birth, congenital malformations, low Apgar score of being SGA in newborns with maternal or paternal exposure to TFL when compared with the general population. However, the sample was too small to draw firm conclusions.


A comparison of von Willebrand Factor antigen with platelet activity in vitro in normal and venous occlusion blood.
Von Willebrand Factor (vWF) is essential for normal haemostasis involving platelet aggregation induced by high shear forces. In vitro a functional test of platelet aggregation using the filterometer is abnormal in von Willebrand's disease. However in normal people there is no significant correlation between the antigenic assay of vWF and the filter results. To study this discrepancy normal blood before and during venous occlusion, and blood before and after infusion of 1 deamino-(8-D-arginine) vasopressin was studied. During venous occlusion (VO) the increase in vWF due to the release of large multimers correlated precisely with the increase in the filterometer results. That this was due to the plasma vWF and not to any change induced in the platelets was shown as follows: The methodology was altered so that a small amount of the donor's platelet-poor plasma (PPP) was added to homologous normal substrate blood. The effect of the added donor's PPP was then shown to be closely correlated to the increase in the antigenic assay. Analysis of vWF multimer size showed during VO an increase in large multimers. We conclude that the effect of vWF on normal blood may be obscured by variation in platelet aggregability. In the filterometer system as elsewhere the large active multimers probably play a major part in causing platelet adhesion, aggregation and filter blocking. The filterometer test is influenced by the amount of vWF antigen, by the molecular size and activity of the vWF and by platelet sensitivity. Clinically this is a useful global test.


Reference distributions for serum iron and transferrin saturation: a practical, simple, and clinically relevant approach in a large cohort.
The principal considerations driving iron status evaluation are clinical concern for anemia and the possibility of iron-storage disease. Most often, the circulating levels of transferrin (or total iron binding capacity) and serum iron are measured and the percentage of transferrin saturation (TSAT) is then computed. Optimally, reference ranges for these analytes should exclude the effects of the acute phase response, nutritional status, estrogen effect, specific genetic disorders, liver disease, and blood transfusion. The current study reports reference ranges for serum iron and TSAT within a cohort of over 55,000 Caucasians from northern New England, tested in our laboratory between 1994 and 1999. Measurements were standardized against serum reference material (SRM) 937 (for iron) and certified reference material (CRM) 470 (also called reference preparation for proteins in human serum (RPPHS)) (for transferrin), and analyzed using a previously published approach. Individual cases with evidence of inflammation (C-reactive protein > or =10 mg/L), or iron overload (TSAT >80% for males and >70% for females) or serum iron values <5 micro mol/L, were removed. Among the referent individuals, iron and TSAT levels rose slightly until the teen years, at which time levels in males increased while those in females remained essentially constant. Between 20 and 70 years of age, males had 10-15% higher iron levels and 15-20% higher TSAT levels than females. When values were expressed as multiples of the age- and gender-specific median levels, the serum iron and TSAT observations fit log-Gaussian distributions reasonably well from the 20th to 99th centile, and the 10th to the 99th centile, respectively. After normalization, the Gaussian parameters can be used to assign a corresponding centile to an individual's measurement, simplifying interpretation. These data provide new and more detailed reference ranges for serum iron and TSAT.


Hydrogen Peroxide Versus Sodium Hypochlorite: All a Matter of pH?
Hydrogen peroxide (H2O2) and sodium hypochlorite (NaOCl) solutions are similar in that they contain oxidizing agents with a bleaching effect. NaOCl solutions are stable at a high pH, at which they also exert increased cleansing/proteolysis. On the other hand, H2O2 solutions are natively acidic, yet gain bleaching power on organic stains when alkalized. It was investigated whether alkalizing a H2O2 solution would also let it dissolve soft tissue or increase its bleaching power on blood-stained dentin. The stability of alkalized H2O2 solutions was assessed by iodometric titration. Soft tissue dissolution was investigated on porcine palatal mucosa. The bleaching effect (ΔL∗) after 60 minutes of exposure was monitored in blood-stained human dentin using a calibrated spectrophotometer. To compare similar molarities, 2.5% H2O2 solutions were used here, and 5.0% NaOCl was used as the positive control, whereas nonbuffered saline solution served as the negative control. Adding alkali (NaOH) to the H2O2 solutions rendered them unstable in a dose-dependent manner. A H2O2 solution of pH 11.1 was chosen for the main experiments (tissue dissolution and bleaching effect) and compared with a native counterpart (pH = 4.7). Alkalizing the H2O2 solution had no discernible effect on its soft tissue dissolution or bleaching power (P = .75 compared with the native H2O2 solution). The NaOCl solution of similar molar concentration had a considerably (P < .001) higher tissue dissolving and bleaching effect under current conditions. The proteolytic/bleaching effects of NaOCl solutions are unique and cannot be achieved by altering the pH of peroxide solutions.


Hormonal regulation and distribution of peroxidase isoenzymes in the Cucurbitaceae.
Ethylene enhanced the levels of peroxidases in the roots, stems, leaves, and cotyledons of 2-week-old cucumber Cucumis sativus cv Poinsett 76 seedlings. Antibodies to the isoelectric point (pl) 9 and pl 4 isoenzymes were used in a radial immuno-diffusion assay to demonstrate that ethylene induced similar peroxidases in other cultivars of C. sativus, other species of Cucumis and other genera of Cucurbitaceae. Examination of ethylene-induced peroxidases, using isoelectric focusing gels, demonstrated the presence of a series of other peroxidases, mostly slightly acidic, whose isoelectric focusing pH was approximately 6. These pl 6 peroxidases were partially purified on a cation exchange column. Ouchterlony double diffusion gels indicated that these proteins cross-reacted with antibodies to both the pl 9 and pl 4 peroxidase. The data presented here suggest that the induction of peroxidase isoenzymes during ethylene-induced senescence is a common response in this family of plants. In addition, antibody and isoelectric focusing studies indicate that both acidic and basic peroxidase are highly conserved in members of this family.


[Anatomy of the heart and coronary arteries].
Orientation and morphology of the heart and coronary vessels are the basis of cardiac imaging. Knowledge of the configuration of cardiac cavities within the thorax and of the course of coronary vessels is mandatory in order to plan and carry out magnetic resonance imaging acquisitions and computed tomographic reformations. These anatomical features are described, with focus on useful data for acquisition and interpretation of imaging studies. MR and CT images will be presented.


Color Doppler sonography of uterine disorders.
Color Doppler sonography (CDS) of uterine disorders has clinical applications for the evaluation of uterine fibroids, polyps, and vascular malformations. This review describes and illustrates these applications as well as the use of 3D CDS.


Pressure-Induced Polymerization of Polycyclic Arene-Perfluoroarene Cocrystals: Single Crystal X-ray Diffraction Studies, Reaction Kinetics, and Design of Columnar Hydrofluorocarbons.
Pressure-induced polymerization of aromatic compounds leads to novel materials containing sp3 carbon-bonded networks. The choice of the molecular species and the control of their arrangement in the crystal structures via intermolecular interactions, such as the arene-perfluoroarene interaction, can enable the design of target polymers. We have investigated the crystal structure compression and pressure-induced polymerization reaction kinetics of two polycyclic 1:1 arene-perfluoroarene cocrystals, naphthalene/octafluoronaphthalene (NOFN) and anthracene/octafluoronaphthalene (AOFN), up to 25 and 30 GPa, respectively, using single-crystal synchrotron X-ray diffraction, infrared spectroscopy, and theoretical computations based on density-functional theory. Our study shows the remarkable pressure stability of the parallel arene-perfluoroarene π-stacking arrangement and a reduction of the interplanar π-stacking separations by ca. 19-22% before the critical reaction distance is reached. A further strong, discontinuous, and irreversible reduction along the stacking direction at 20 GPa in NOFN (18.8%) and 25 GPa in AOFN (8.7%) indicates the pressure-induced breakdown of π-stacking by formation of σ-bonded polymers. The association of the structural distortion with the occurrence of a chemical reaction is confirmed by a high-pressure kinetic study using infrared spectroscopy, indicating one-dimensional polymer growth. Structural predictions for the fully polymerized high-pressure phases consisting of highly ordered rods of hydrofluorocarbons are presented based on theoretical computations, which are in excellent agreement with the experimentally determined unit-cell parameters. We show that the polymerization takes place along the arene-perfluoroarene π-stacking direction and that the lateral extension of the columns depends on the extension of the arene and perfluoroarene molecules.


Renal Damage in Recurrent Atypical Hemolytic Uremic Syndrome Associated with C3 p.Ile1157Thr Gene Mutation.
Patients with atypical hemolytic uremic syndrome (aHUS) associated with a C3 p.Ile1157Thr mutation show a relatively high renal survival and low mortality rates, but renal histopathological findings after recurrence have been rarely reported. A 30-year-old man with a C3 p.Ile1157Thr mutation experienced a third recurrence of thrombotic microangiopathies with neurological and gastrointestinal disorders. A renal biopsy performed during the recovery phase of acute kidney injury revealed collapsed glomeruli and arteriolar vacuolization. Approximately 10% of glomeruli were globally sclerotic, despite the absence of arterio-/arteriolo-sclerosis. These findings suggest substantial progression of irreversible injuries in multiple organs, including kidneys, which occurs in aHUS patients with repeated thrombotic microangiopathies.


Correlates of alcohol abstinence and at-risk alcohol consumption in older adults with depression: the NESDO study.
To compare alcohol use between depressed and nondepressed older adults, and to investigate correlates of alcohol abstinence and at-risk alcohol consumption in depressed older adults. Cross-sectional study. Netherlands Study of Depression in Older Persons (NESDO). A total of 373 participants (mean [standard deviation] age: 70.6 [7.3] years; 66% women) diagnosed with a depressive disorder, and 128 nondepressed participants. Alcohol use was assessed with the Alcohol Use Disorders Identification Test (AUDIT). Participants were categorized into abstainers (AUDIT score: 0), moderate drinkers (AUDIT score: 1-4), and at-risk drinkers (AUDIT score: ≥5). Multinomial logistic regression analysis was performed with AUDIT categories as outcome, and demographic, social, somatic, and psychological variables as determinants. The depressed group consisted of 40.2% abstainers, 40.8% moderate drinkers, and 19.0% at-risk drinkers. The depressed participants were more often abstinent and less often moderate drinkers than the nondepressed participants; they did not differ in at-risk drinking. Depressed abstainers more often used benzodiazepines but less often used antidepressants, and they had a poorer cognitive function than depressed moderate drinkers. Depressed at-risk drinkers were more often smokers and had fewer functional limitations but more severe depressive symptoms than depressed moderate drinkers. Although alcohol abstinence was more common in depressed than in nondepressed older adults, 19% of depressed persons were at-risk drinkers. Because at-risk drinking is associated with more severe depression and may have a negative impact on health and treatment outcome, it is important that physicians consider alcohol use in depressed older adults.


Valley Fever (Coccidioidomycosis) Awareness - California, 2016-2017.
Valley fever (coccidioidomycosis) is endemic in the southwestern United States and caused by inhalation of Coccidioides spp. fungal spores from soil or dust; 97% of U.S. Valley fever cases are reported from Arizona and California (1). In California, Valley fever incidence increased 213% from 2014 to 2018 (2). In 2016, the California Department of Public Health (CDPH) added three questions to the adult California Behavioral Risk Factor Surveillance System (BRFSS) survey to better understand whether Californians had heard of Valley fever, knew the environmental risk where they live, and knew who is at risk for severe disease. A total of 2,893 BRFSS respondents aged ≥18 years answered at least one Valley fever question. Using the weighted California population, 42.4% of respondents reported general awareness of Valley fever; awareness was lowest among adults aged 18-44 years (32.9%) and Hispanic persons (26.4%). In addition, despite higher percentages reporting awareness of Valley fever, only 25.0% of persons living in a high-incidence region and 3.0% of persons living in a moderate-incidence region were aware that they lived in areas where Coccidioides spp. exist. Among persons with one or more risk factors for severe disease, 50.8% reported having heard about Valley fever, but only 3.5% knew they were at increased risk for severe disease. The findings from this survey helped to inform a statewide Valley fever awareness campaign implemented during 2019-2020 and to guide outreach to persons living in high- and moderate-incidence regions in California and potentially other southwestern states or who are at risk for severe disease.


[Common variable immunodeficiency and total villous atrophy regressive after gluten-free diet].
A patient with a commun variable immunodeficiency (CVID) is hospitalized for chronic symptoms of malabsorption (weigh loss and diarrhea). The duodenal histology show a total villous atrophy. Investigations are negative and a gluten free diet is given. Symptoms of malabsorption disappear and improvement is histologically confirmed. Our observation suggest that the coincidence of gluten sensitive enteropathy and CVID is possible and clinicians should be aware of this association and should consider giving a gluten free diet. The sensitivity of serologic testing in this conditions is unknown.


Prostaglandin-F2 alpha levels in normal saline-induced mid-trimester abortions.
In 20 mid-trimester abortion seekers induced by extra-amniotic instillation of normal saline, serial estimation of prostaglandin F2 alpha (PGF2 alpha) in the plasma and extra-ovular space were carried out. It was observed that PGF2 alpha was undetectable in both plasma and the extra-ovular space prior to the onset of induction, and was first detected in the extra-ovular fluid 2 hours after the onset of induction, prior to oxytocin infusion. In the subsequent samples, the prostaglandin concentration in plasma as well as in the extra-ovular fluid was found to rise, with levels in the latter showing a more significant rise with time as compared to the former. Thus, this study confirms the hypothesis that the mechanism of action of extra-ovular normal saline instillation in mid-trimester termination of pregnancy is the result of separation of fetal membranes from the uterine wall, leading to the release of prostaglandins which, in turn, causes uterine contractions leading to abortion.


Thymomas and thymic carcinomas. A retrospective investigation with histological reclassification.
The morphological heterogeneity of thymomas has caused much confusion respecting their classification. Recently Kirchner & Müller-Hermelink (4) proposed a histological subclassification which has been claimed to represent an independent prognostic factor: medullary and mixed thymomas are benign; organoid and cortical type as well as well-differentiated thymic carcinomas are low-grade malignant tumors, which have the capacity to recur and spread, even if they are clinically benign. High-grade malignant thymomas are always malignant. We present the clinicopathological data on 10 clinically benign and 14 clinically malignant thymomas. Having reclassified the thymomas, we found four low-grade malignant examples among the clinically benign thymomas. It is important to identify this group of patients as they are at risk of tumor recurrence. However, further investigation is needed to support the validity of this subclassification system.


Prevention of in vitro protein thermal aggregation by the Sulfolobus solfataricus chaperonin. Evidence for nonequivalent binding surfaces on the chaperonin molecule.
We have studied the effects of the Sulfolobus solfataricus chaperonin on the aggregation and inactivation upon heating of four model enzymes: chicken egg white lysozyme (one 14.4-kDa chain), yeast alpha-glucosidase (one 68.5-kDa chain), chicken liver malic enzyme (four 65-kDa subunits), and yeast alcohol dehydrogenase (four 37.5-kDa subunits). When the proteins were heated in the presence of an equimolar amount of chaperonin, 1) the aggregation was prevented in all solutions; 2) the inactivation profiles of the single-chain enzymes were comparable with those detected in the absence of the chaperonin, and enzyme activities were regained in the solutions heated in the presence of the chaperonin upon ATP hydrolysis (78 and 55% activity regains for lysozyme and alpha-glucosidase, respectively); 3) the inactivation of the tetrameric enzymes was completely prevented, whereas the activities decreased in the absence of the chaperonin. We demonstrate by gel filtration chromatography that the chaperonin interacted with the structures occurring during thermal denaturation of the model proteins and that the interaction with the single-chain proteins (but not that with the tetrameric proteins) was reversed upon ATP hydrolysis. The chaperonin had nonequivalent surfaces for the binding of the model proteins upon heating: the thermal denaturation intermediates of the single-chain proteins share Surfaces I, while the thermal denaturation intermediates of the tetrameric proteins share Surfaces II. ATP binding to the chaperonin induced a conformation that lacked Surfaces I and carried Surfaces II. These data support the concept that chaperonins protect native proteins against thermal aggregation by two mechanistically distinct strategies (an ATP-dependent strategy and an ATP-independent strategy), and provide the first evidence that a chaperonin molecule bears functionally specialized surfaces for the binding of the protein substrates.


Neuropsychiatric side effects of cyclobenzaprine.
Cyclobenzaprine is commonly used as a muscle relaxant and analgesic. Given its tricyclic properties, serotonin syndrome is a potential side effect of this drug. We report an unusual case of a patient who experienced symptoms of delirium and hyperkinetic movement disorders shortly after initiating treatment with cyclobenzaprine and oxycodone. Symptoms resolved within 48 h of discontinuing cyclobenzaprine. This case serves to remind clinicians to monitor for serotonin syndrome when initiating cyclobenzaprine, and when adding opiate or antidepressant medications to the regimen.


Dissociation between metabolic and efficiency effects of perhexiline in normoxic rat myocardium.
The antianginal agent perhexiline inhibits rat cardiac carnitine palmitoyltransferase-1 (CPT-1) and CPT-2, key enzymes for mitochondrial transport of long-chain fatty acids. We tested the hypothesis that perhexiline, in therapeutic concentrations (2 microM), inhibits palmitate oxidation and enhances glucose oxidation in isolated rat cardiomyocytes and in the working rat heart, thereby increasing efficiency of oxygen utilization. In isolated cardiomyocytes, perhexiline (2 microM) exerted no acute effects on palmitate oxidation, but after 48 hours pre-exposure oxidation was inhibited by perhexiline (2 to 10 microM) by 15% to 35% (P < 0.0002). In non-ischemic working rat hearts (3%BSA, 0.4 mM palmitate, 11 mM glucose, 100 microU/mL insulin) perhexiline (2 microM) had no significant acute effect on cardiac efficiency, palmitate or glucose oxidation, but 24 hours pretreatment with transdermal perhexiline increased cardiac work (by 29%, P < 0.05) and cardiac efficiency (by 30%, P < 0.02) without significant effects on palmitate oxidation. The selective CPT-1 inhibitor oxfenicine (2 mM) inhibited palmitate oxidation and enhanced glucose oxidation, but failed to enhance cardiac efficiency. In conclusion, in the non-ischemic working rat heart, perhexiline increases myocardial efficiency by a mechanism(s) that is largely or entirely independent of its effects on CPT. Effects on cardiac efficiency during ischemia, and with changes in fatty acid oxidation after longer perhexiline pretreatment remain to be determined.


Noncontact diffuse optical assessment of blood flow changes in head and neck free tissue transfer flaps.
Knowledge of tissue blood flow (BF) changes after free tissue transfer may enable surgeons to predict the failure of flap thrombosis at an early stage. This study used our recently developed noncontact diffuse correlation spectroscopy to monitor dynamic BF changes in free flaps without getting in contact with the targeted tissue. Eight free flaps were elevated in patients with head and neck cancer; one of the flaps failed. Multiple BF measurements probing the transferred tissue were performed during and post the surgical operation. Postoperative BF values were normalized to the intraoperative baselines (assigning "1") for the calculation of relative BF change (rBF). The rBF changes over the seven successful flaps were 1.89 ± 0.15, 2.26 ± 0.13, and 2.43 ± 0.13 (mean ± standard error), respectively, on postoperative days 2, 4, and 7. These postoperative values were significantly higher than the intraoperative baseline values (p<0.001), indicating a gradual recovery of flap vascularity after the tissue transfer. By contrast, rBF changes observed from the unsuccessful flaps were 1.14 and 1.34, respectively, on postoperative days 2 and 4, indicating less flow recovery. Measurement of BF recovery after flap anastomosis holds the potential to act early to salvage ischemic flaps.


A diversified role for γδT cells in vector-borne diseases.
Vector-borne diseases have high morbidity and mortality and are major health threats worldwide. γδT cells represent a small but essential subpopulation of T cells. They reside in most human tissues and exert important functions in both natural and adaptive immune responses. Emerging evidence have shown that the activation and expansion of γδT cells invoked by pathogens play a diversified role in the regulation of host-pathogen interactions and disease progression. A better understanding of such a role for γδT cells may contribute significantly to developing novel preventative and therapeutic strategies. Herein, we summarize recent exciting findings in the field, with a focus on the role of γδT cells in the infection of vector-borne pathogens.


New Anti-Inflammatory Metabolites by Microbial Transformation of Medrysone.
Microbial transformation of the anti-inflammatory steroid medrysone (1) was carried out for the first time with the filamentous fungi Cunninghamella blakesleeana (ATCC 8688a), Neurospora crassa (ATCC 18419), and Rhizopus stolonifer (TSY 0471). The objective was to evaluate the anti-inflammatory potential of the substrate (1) and its metabolites. This yielded seven new metabolites, 14α-hydroxy-6α-methylpregn-4-ene-3,11,20-trione (2), 6β-hydroxy-6α-methylpregn-4-ene-3,11,20-trione (3), 15β-hydroxy-6α-methylpregn-4-ene-3,11,20-trione (4), 6β,17α-dihydroxy-6α-methylpregn-4-ene-3,11,20-trione (5), 6β,20S-dihydroxy-6α-methylpregn-4-ene-3,11-dione (6), 11β,16β-dihydroxy-6α-methylpregn-4-ene-3,11-dione (7), and 15β,20R-dihydroxy-6α-methylpregn-4-ene-3,11-dione (8). Single-crystal X-ray diffraction technique unambiguously established the structures of the metabolites 2, 4, 6, and 8. Fungal transformation of 1 yielded oxidation at the C-6β, -11β, -14α, -15β, -16β positions. Various cellular anti-inflammatory assays, including inhibition of phagocyte oxidative burst, T-cell proliferation, and cytokine were performed. Among all the tested compounds, metabolite 6 (IC50 = 30.3 μg/mL) moderately inhibited the reactive oxygen species (ROS) produced from zymosan-induced human whole blood cells. Compounds 1, 4, 5, 7, and 8 strongly inhibited the proliferation of T-cells with IC50 values between <0.2-10.4 μg/mL. Compound 7 was found to be the most potent inhibitor (IC50 < 0.2 μg/mL), whereas compounds 2, 3, and 6 showed moderate levels of inhibition (IC50 = 14.6-20.0 μg/mL). Compounds 1, and 7 also inhibited the production of pro-inflammatory cytokine TNF-α. All these compounds were found to be non-toxic to 3T3 cells (mouse fibroblast), and also showed no activity when tested against HeLa (human epithelial carcinoma), or against PC3 (prostate cancer) cancer cell lines.


Prevalence and risk factors of alcohol abuse among university students from eastern Croatia: questionnaire study.
The aim of the study was to examine the prevalence of alcohol abuse among university students in Osijek, Croatia and its possible interconnections with gender, year of study, repetition of year of study, faculty subject area, sources of financing and type of residence during study. A validated questionnaire was self-administered to cross-faculty representative student sample of "J. J. Strossmayer" University of Osiek in June 2006. General demographic data, as well as data on academic features and student socio-economical status were obtained. The Alcohol Use Disorders Identification Test (AUDIT) was used for assessing the extent of alcohol consumption, with cut off value of 8 indicating possible alcohol problems. The majority of study participants 90.9% (755/831) had tried alcohol at least once in their life. Among this group, 43.8% (331/755) had an AUDIT total score of 8 or more: 69.2% (229/331) were males and 30.8% (102/331) were females. Among the study participants who screened positive, 70.4% (233/331) responded positively to simple advice focused on the reduction of hazardous drinking (AUDIT 8-15), 14.5% (48/331) needed brief counseling and continued monitoring (AUDIT 16-19), and 15.1% (50/331) clearly warranted further diagnostic evaluation for alcohol dependence (AUDIT 20 and above). Significantly different statistical data was found within the following factors: gender, repetition of year of study, faculty subject area and type of residence (chi2 = 76.232, p = 0.0000; Fisher exact test = 31.828, p = 0.0000; chi2 = 11.667, p = 0.0086 and chi2 = 6.639, p = 0.0362 respectively). Alcohol consumption resulting in risk behaviors is common among university students from eastern Croatia. These findings emphasize the need for comprehensive and effective preventative strategies directed towards student population.


Efficacy of recombinant human macrophage colony-stimulating factor in combination with whole-body hyperthermia in the treatment of mice infected with the polycythemia-inducing strain of the Friend virus complex.
Macrophage colony-stimulating factor (M-CSF, CSF-1) and whole-body hyperthermia (WBH) were evaluated, alone or in combination, for their capability to influence disease progression in mice inoculated with the polycythemia-inducing strain of the Friend virus complex (FVC-P). DBA/2 mice were injected i.v. with FVC-P and were treated with 20 micrograms/dose M-CSF s.c. twice a day for 5 days beginning 6 days after injection of FVC-P and/or with WBH (between 38.8 degrees C and 40.2 degrees C) given on days 5 and 12 after FVC-P injection. Fourteen days after viral inoculation, mice were sacrificed and spleen cells evaluated for: 1) spleen focus-forming virus (SFFV), by the spleen focus-forming unit assay (SFFU); 2) SFFV mRNA and genomic DNA using, respectively, Northern and Southern analysis with a B-E-SFFV DNA probe; and 3) natural killer (NK) cell activity, by 51Cr-release assay. Treatment with M-CSF or WBH alone had a small effect on SFFU numbers but little or no effect on SFFV mRNA expression and SFFV-specific DNA. However, dramatically decreased levels of SFFU and SFFV mRNA and specific DNA fragments were observed in mice treated with M-CSF in combination with WBH, and NK cell activity was restored to normal. These results suggest the possibility that M-CSF may have a therapeutic effect in combination with WBH in the in vivo treatment of certain hematologic malignancies and/or retroviral infections.


[Molecular structure of allelic variants of microsatellite loci Du281 and Du47 in unisexual and bisexual lizard species of the genus Darevskia].
Experimental data on the molecular structure and variability of microsatellite loci in unisexual and bisexual lizard species of the genus Darevskia were analyzed. The allelic variants of Du281 and Du47 were found to differ in the number of monomers, the structure of microsatellite clusters, and point mutations in these clusters and flanking DNA. Interspecific comparison of alleles of these loci revealed both variable regions in the microsatellite clusters and allele-specific evolutionarily conserved nucleotide groups. In general, the results of comparative structural analysis of allelic variants testify to a high genetic similarity of the unisexual and bisexual lizard species studied and reveals the characteristic features of their interspecies variability.


Protonation of non-Watson-Crick base pairs and encapsidation of turnip yellow mosaic virus RNA.
The 5' UTR of turnip yellow mosaic virus RNA contains two conserved hairpins with internal loops consisting of C.C and C.A mismatches. In this article, evidence is presented indicating that the 5' proximal hairpin functions as an encapsidation initiation signal. Extensive mutagenesis studies on this hairpin and sequencing of virus progeny showed a clear preference for C.C and C.A mismatches within the internal loop. The importance of these mismatches lies in their pH-dependent protonation and stable base pair formation. Encapsidation efficiency was found to be severely affected for several mutants lacking the protonatable mismatches in the internal loop of the 5' proximal hairpin. Furthermore, gel mobility-shift assays were performed with various RNA hairpins and empty capsids with a hole. Protonatable hairpins containing C.C and/or C.A pairs were found to bind specifically to the interior of the protein shell under acidic conditions (pH 4.5) in the presence of spermidine. Based on these results we propose that this binding of protonated cytosines to the coat protein of turnip yellow mosaic virus may represent a new motif in RNA-protein interactions.


Environmental Parameters Affecting Dark Response of Rice Seedlings (Oryza sativa L.) to Triacontanol.
Triacontanol applied to IR-8 rice (Oryza sativa L.) seedlings in nutrient solution caused an increase in dry weight during a 6-hour dark period. This increase was altered by atmospheric CO(2) and O(2) concentrations. The largest growth response occurred from 200 to 350 muliters/liter CO(2) with 5% O(2). The treated seedlings did not fix atmospheric CO(2) in the dark, and the immediate products of photosynthesis were not involved in the dry weight increase. The growth response was characterized by an increase in soluble and insoluble Kjeldahl-N, and soluble carbohydrates. The response curve for dry weight increase was a linear function of log presentation time of triacontanol. The response exhibited an apparent K(dose) of 25 minutes in 10 mug/liter triacontanol in the dark and 18 minutes in the light. Concentrations of 50 mug/liter and higher inhibited growth.


Iron deposition in the integument of lampreys.
The integument of larval, parasitic adult, and upstream-migrant lampreys (Petromyzon marinus) was examined for iron deposition using light microscopic histochemistry and routine and histochemical procedures in the electron microscope. Ferritin particles, representing ferric iron, are present throughout most of the cytoplasmic matrix and within dense granules and vacuoles of epidermal mucous cells, but are not located in skein or granular cells. These particles are abundant in mucous cells of the dorsal surface but not the ventral surface and are more concentrated in adult lampreys compared to larva. Histochemistry revealed only sparse amounts of ferrous iron. Iron is not present in the dermis but is found in adipocytes of a subcutaneous layer. The deposition of integumentary iron is discussed with reference to body pigmentation and excretion of this metal.


Structure and Function of Renal Organic Cation Transporters.
Polyspecific transport systems in the kidney mediate the excretion and reabsorption of organic cations. Electrogenic import systems and electroneutral export systems in the basolateral and luminal plasma membranes of proximal renal tubules are involved. Two subtypes of electrogenic import systems have been cloned from rats and humans and functionally characterized.


Whey protein hydrolysate augments tendon and muscle hypertrophy independent of resistance exercise contraction mode.
In a comparative study, we investigated the effects of maximal eccentric or concentric resistance training combined with whey protein or placebo on muscle and tendon hypertrophy. 22 subjects were allocated into either a high-leucine whey protein hydrolysate + carbohydrate group (WHD) or a carbohydrate group (PLA). Subjects completed 12 weeks maximal knee extensor training with one leg using eccentric contractions and the other using concentric contractions. Before and after training cross-sectional area (CSA) of m. quadriceps and patellar tendon CSA was quantified with magnetic resonance imaging and a isometric strength test was used to assess maximal voluntary contraction (MVC) and rate of force development (RFD). Quadriceps CSA increased by 7.3 ± 1.0% (P < 0.001) in WHD and 3.4 ± 0.8% (P < 0.01) in PLA, with a greater increase in WHD compared to PLA (P < 0.01). Proximal patellar tendon CSA increased by 14.9 ± 3.1% (P < 0.001) and 8.1 ± 3.2% (P = 0.054) for WHD and PLA, respectively, with a greater increase in WHD compared to PLA (P < 0.05), with no effect of contraction mode. MVC and RFD increased by 15.6 ± 3.5% (P < 0.001) and 12-63% (P < 0.05), respectively, with no group or contraction mode effects. In conclusion, high-leucine whey protein hydrolysate augments muscle and tendon hypertrophy following 12 weeks of resistance training - irrespective of contraction mode.


Dietary intake of lead and cadmium by children and adults - Result calculated from dietary recall and available lead/cadmium level in food in comparison to result from food duplicate diet method.
The dietary intakes of lead and cadmium by 30 children and 30 adults living in Jinhu area in China were determined by the duplicate method with a 3-day sampling period. Dietary recall and available lead/cadmium level in food were also used to calculate dietary intakes. Lead intakes based on duplicate method were 15.66μg(kg(bw))(-1)week(-1) for children and 8.83μg(kg(bw))(-1)week(-1) for adults. Cadmium intakes were 2.07μg(kg(bw))(-1)week(-1) for children and 1.49μg(kg(bw))(-1)week(-1) for adult. The results from the dietary record method were as follows: lead intakes were 11.84μg(kg(bw))(-1)week(-1) for children and 7.70μg(kg(bw))(-1)week(-1) for adult. Cadmium intakes were 2.20μg(kg(bw))(-1)week(-1) for children and 1.44μg(kg(bw))(-1)week(-1) for adults. Children's dietary intakes were higher than those of adults'. The results of the dietary intakes calculated from two methods did not have significant difference. Compared to the FAO/WHO PTWIs for lead and cadmium, the average lead and cadmium dietary intakes are all below PTWIs. It was concluded that dietary record method can give comparatively accurate result for lead and cadmium dietary intakes compared with duplicate method. The average lead and cadmium dietary intakes for children and adults in Jinhu area are considered safe. However, the high level of dietary lead and cadmium intakes of children in this area deserves our attention.


Brain olfactory activation measured by near-infrared spectroscopy in humans.
In recent years, near-infrared spectroscopy (NIRS) has been used to study functional activation of various areas of the brain. This is based on the assumption that an increase in the recorded oxygenated haemoglobin (HbO2) concentration represents an increase in blood flow, which in turn reflects neuronal activation. The aim of this preliminary study was to use NIRS to monitor the activity of the olfactory cortex, as mirrored by the haemodynamic response, when subjects were exposed to olfactory stimuli. A NIRO 300 (Hamamatsu Photonics, Hamamatsu, Japan) device was used. The optodes were placed on the right forehead and right temporal, parietal and occipital regions. Changes in the concentration of HbO2 and deoxygenated haemoglobin during olfactory stimulation were monitored. Olfactory stimulation was performed with vanilla essence, strawberry essence and scatol. During olfactory stimulation, cerebral HbO2 concentration increased over the frontal region. However, in the temporal, parietal and occipital regions, little or no HbO2 changes were recorded. This study shows that human brain cortical activation following olfactory stimulation can be recorded by NIRS. This NIRS analysis may therefore provide the basis for future development of an objective olfactory test in humans.


Tuberculous dacryoadenitis in a child.
Orbital tuberculosis is rare even in endemic areas. The disease may involve soft tissue, lacrimal gland, or the periosteum or bones of the orbital wall. We present an Indian girl, who presented with a slowly growing left-sided superotemporal orbital mass, with no significant previous medical history. The swelling turned to an abscess and burst spontaneously giving rise to a discharging sinus. The discharge was negative for any organism on Gram and Giemsa staining. A tuberculin skin test was strongly positive. Incisional biopsy showed caseating granuloma and Langhan 's giant cells suggestive of tubercular aetiology. The patient responded well to tuberculous chemotherapy. Although tuberculous dacryoadenitis is a very rare manifestation of tuberculosis,still the possibility should be entertained in a slowly growing mass of the lacrimal gland, especially in developing countries where the prevalence of tuberculosis is high.


[Liver damage caused by hepatitis C viral infection and ethyl alcohol consumption].
Hepatitis C virus infection (HCV) is a complex disease, most commonly chronicle (80-85%). The aim of this research was to determinate the level of the liver damage in the patients cansed by HCV in conjunction with consuming ethyl alcohol. The research included 15 patients with chronic HCV infection supported by the misuse of ethyl alcohol, as well. The diagnosis of C infection hepatitis was proved using the ELISA test and PCR method. The results of the study showed the liver damage by both HCV infection and ethyl alcohol, which was verified by the presence of biochemical changes and patohystological processing of the patients (liver biopsy and prosection). Patohystological changes were at the level of liver cirrhosis and carcinoma (2 patients). There was a signficant difference between the two subgroups (p < 0.001) regarding the examined values gamma-GT, PLT and PTV. The basic therapeutic procedure was to introduce this category of patients into alcohol abstinence, and, in a few patients, to apply the antivirus therapy, as well. Based on the number of the examined patients (n = 15), we could conclude that a prolonged ethyl alcohol misuse with the presence of HCV infection was in a correlation with the liver disease progression.


Anti-TNF antibodies in inflammatory bowel disease: do we finally know how it works?
Tumor necrosis factor (TNF) is a central pro-inflammatory cytokine that regulates the expression of numerous signaling pathways implicated in the progression of the immunological reaction. Unraveling the importance of TNF on the pathogenesis of inflammatory bowel disease (IBD) promoted anti-TNF antibodies as novel therapeutic agents. Initially, the main hypothesis behind the clinical application of anti-TNF antagonists in the clinic was that they exert their effects solely through neutralization of TNF. Anti-TNF antibodies induce and maintain clinical remission in patients with minimal side-effects. However, the cellular and molecular mechanisms of actions of the anti-TNF antibodies remain unknown. Various mechanisms of action have been proposed such as activation of transmembrane TNF mediated reverse signaling, induction of apoptosis, pro-inflammatory cytokine down-regulation, complement dependent cytotoxicity, antibodydependent cell-mediated cytotoxicity, and finally activation of regulatory immune cells via interactions with the Fc receptors. The observed discrepancies in the clinical efficacies as well as the differences in the structure of the various TNF antagonists nourish the investigation for additional modes of function.


Isolation and expression of a maize type 1 protein phosphatase.
The dephosphorylation of phosphoproteins by protein phosphatases represents an important mechanism for regulating specific cellular processes in eukaryotic cells. The aim of the present study was to examine the structural and biochemical characteristics of a specific class of protein Ser/Thr phosphatases (type 1 protein phosphatases) which have received very little attention in higher plants. A cDNA clone (ZmPP1) was isolated from a maize (Zea mays L.) cDNA library. The deduced amino acid sequence is 80% identical with a 292-amino acid core region of rabbit and yeast type 1 protein phosphatase catalytic subunit. Southern blot analysis indicates that ZmPP1 may belong to a family of related genes in maize. ZmPP1 RNA was present in all maize tissues examined, indicating that it may play a fundamental role in cellular homeostasis. To demonstrate that ZmPP1 encodes an active protein phosphatase and, in an effort to characterize this gene product biochemically, high levels of ZmPP1 were expressed in Escherichia coli. Active ZmPP1 enzyme dephosphorylates rabbit phosphorylase a and is strongly inhibited by okadaic acid and by the mammalian inhibitor-2. These data show that ZmPP1 is structurally and biochemically very similar to the corresponding enzyme in animal cells. These results also suggest that the function and regulation of the higher plant type 1 protein phosphatases may be similar to the mammalian protein phosphatases.


A Quest for New Cancer Diagnosis, Prognosis and Prediction Biomarkers and Their Use in Biosensors Development.
Traditional techniques for cancer diagnosis, such as nuclear magnetic resonance, ultrasound and tissue analysis, require sophisticated devices and highly trained personnel, which are characterized by elevated operation costs. The use of biomarkers has emerged as an alternative for cancer diagnosis, prognosis and prediction because their measurement in tissues or fluids, such as blood, urine or saliva, is characterized by shorter processing times. However, the biomarkers used currently, and the techniques used for their measurement, including ELISA, western-blot, polymerase chain reaction (PCR) or immunohistochemistry, possess low sensitivity and specificity. Therefore, the search for new proteomic, genomic or immunological biomarkers and the development of new noninvasive, easier and cheaper techniques that meet the sensitivity and specificity criteria for the diagnosis, prognosis and prediction of this disease has become a relevant topic. The purpose of this review is to provide an overview about the search for new cancer biomarkers, including the strategies that must be followed to identify them, as well as presenting the latest advances in the development of biosensors that possess a high potential for cancer diagnosis, prognosis and prediction, mainly focusing on their relevance in lung, prostate and breast cancers.


Increased IL-10 production and HLA-DR suppression in the lungs of injured patients precede the development of nosocomial pneumonia.
The incidence of nosocomial pneumonia (NP) among injured patients is substantial. We hypothesize that traumatic injury induces alterations in local organ effector cell function that may predispose the lungs of injured patients to infection. It is the objective of this study to compare the systemic and alveolar effector cell response to injury and assess the relationship these have to the development of NP. Peripheral blood and bronchoalveolar lavage fluid (BAL) were collected from 10 elective surgery patients (controls) and 16 multitrauma patients at 12, 36, and 60 h post-injury. Systemic and alveolar levels of IL-8 and IL-10 were measured. CD11b expression on peripheral blood neutrophils (PBN) and alveolar neutrophils (AN) and HLA-DR expression on peripheral blood monocytes (PBM) and alveolar macrophages (AM) were measured. Alveolar levels of IL-8 and IL-10 were significantly higher than systemic levels after injury. HLA-DR expression was reduced on both PBM and AM after injury but was lowest on the AM. Six of 16 patients (38%) developed NP (NP+). There were no differences in cytokine levels (IL-8 and IL-10) or effector cell phenotype (CD11b and HLA-DR expression) within the systemic circulation of NP+ and NP- patients. In contrast, NP+ and NP- patients differed significantly in alveolar cytokine levels and alveolar effector cell phenotype. IL-8 was significantly higher in BAL form NP+ patients at all time points after injury. Furthermore, alveolar levels of IL-10 decreased in NP- patients but increased in NP+ patients. In all patients, AM HLA-DR expression was significantly reduced from normal controls 12 h post-injury. In NP-patients, AM HLA-DR expression returned to normal 60 h post-injury, whereas in NP+ patients, expression remained suppressed. These findings identify distinct trends in local organ cytokine production and alterations in effector cell phenotype that precede NP. The persistence of reduced HLA-DR expression amidst increasing levels of IL-10 in NP+ patients suggest that cell-mediated immune function is being suppressed. As such, local organ immunosuppression may be responsible for the development of nosocomial pneumonia in injured patients.


Covalent attachment of acetylene and methylacetylene functionality to Si(111) surfaces: scaffolds for organic surface functionalization while retaining Si-C passivation of Si(111) surface sites.
Si(111) surfaces have been functionalized with Si-CC-R species, where R = H or -CH3, using a two-step reaction sequence involving chlorination of H-Si(111) followed by treatment with Na-CC-H or CH3-CC-Na reagents. The resulting surfaces showed no detectable oxidation as evidenced by X-ray photoelectron spectroscopic (XPS) data in the Si 2p region, electrochemical measurements of Si-H oxidation, or infrared spectroscopy. The Si-CC-R-terminated surfaces exhibited a characteristic CC stretch in the infrared at 2179 cm-1, which was strongly polarized perpendicular to the Si(111) surface plane. XPS measurements in the C 1s region showed a low binding energy peak indicative of Si-C bonding, with a coverage that was, within experimental error, identical to that of the CH3-terminated Si(111) surface, which has been shown to fully terminate the Si atop sites on an unreconstructed Si(111) surface. The Si-CC-H-terminated surfaces were further functionalized by exposure to n-C4H9Li followed by exposure to para Br-C6H5-CF3, allowing for introduction of para -C6H5CF3 groups while maintaining the desirable chemical and electrical properties that accompany complete Si-C termination of the atop sites on the Si(111) surface.


Abdominoplasty with direct resection of deep fat.
Suction-assisted lipectomy is an integral component of abdominoplasty for many surgeons. Its potential to affect the vascularity of the abdominal flap is usually offset by limiting the extent of undermining and not suctioning the central flap. The authors address whether these guidelines apply to direct excision of subscarpal fat and whether direct excision provides aesthetically superior abdominoplasty results with fewer complications. A 10-year review of consecutive abdominoplasty patients (n = 181) was conducted. Undermining was done to the xyphoid and just beyond the lower rib margins superiorly and at least as far as the anterior axillary line laterally. Fat deep to Scarpa's fascia was removed by tangential excision in all zones of the abdominal flap, including those considered at high risk for vascular compromise if subjected to liposuction after similar undermining. Concurrent liposuction of the abdominal flap was not done. Thirty patients had concurrent flank liposuction. No patients experienced major full-thickness tissue loss. The incidence of limited necrosis at the incision line requiring subsequent scar revision was 0.7 percent in the 151 patients having abdominoplasty and 6.7 percent in the 30 patients having abdominoplasty combined with flank liposuction. Erythema and/or epidermolysis was seen in 4.8 percent of the abdominoplasty patients and 10 percent of the abdominoplasty/ flank liposuction group. The rate of seroma formation in both groups was approximately 16.5 percent. Direct excision of subscarpal fat does not subject any zone of the abdominoplasty flap to increased risks of vascular compromise. It is a safe technique that provides excellent abdominoplasty results.


A novel prodrug strategy for beta-dicarbonyl carbon acids: syntheses and evaluation of the physicochemical characteristics of C-phosphoryloxymethyl (POM) and phosphoryloxymethyloxymethyl (POMOM) prodrug derivatives.
The C-phosphoryloxymethyl (POM) and phosphoryloxymethyloxymethyl (POMOM) prodrugs resulting from derivatization at the reactive alpha-carbon of beta-dicarbonyl carbon acid drugs represent a unique approach for improving their chemical stability and aqueous solubility. This work evaluates the physicochemical and in vitro enzymatic bioconversion lability of selected prodrugs of phenylbutazone and phenindione. The POM and POMOM prodrug derivatives of phenylbutazone are highly water soluble (>or=250 mg/mL), chemically stable with projected shelf-lives of 4.5 years (pH 3.5, 25 degrees C) and 1.1 years (pH 6.0, 25 degrees C), respectively. Interestingly, both prodrug derivatives do not display a pH-dependency typical of many phosphate monoesters, although the similarities of their apparent thermodynamic activation parameters indicate a hydrolysis mechanism similar to other phosphates. These prodrugs undergo alkaline phosphatases catalyzed bioconversion to their respective carbon acids with an expected faster rate exhibited by the POMOM derivatives. Additionally, in marked contrast to the oxidative instability of phenindione, its POM prodrug is stable. The results from these studies reaffirm the rationale of transiently "masking" the reactive alpha-carbon/proton bond by covalently incorporating a POM or POMOM promoiety. This prodrug strategy presents a twofold advantage, enhancement of aqueous solubility and prevention of oxidative instability, two intrinsic formulation limitations found for beta-dicarbonyl carbon acid drugs.


Crystal structure of 4-bromo-N-(2-bromo-3-nitro-benz-yl)-2-nitro-naphthalen-1-amine.
In the title compound, C17H11Br2N3O4, the dihedral angle between the planes of the naphthalene system and the benzene ring is 52.86 (8)°. The nitro substituent and the attached naphthalene system are almost coplanar [dihedral angle = 5.6 (4)°], probably as a consequence of an intra-molecular N-H⋯O hydrogen bond with the amine group. The nitro substituent attached to the benzene ring is disordered over two sets of sites with occupancies of 0.694 (3) and 0.306 (3). The major component deviates significantly from the ring plane [dihedral angle = 53.6 (2)°]. In the crystal, the mol-ecules are linked into a three-dimensional array by extensive π-π inter-actions involving both the naphthalene and benzene rings [range of centroid-centroid distances = 3.5295 (16)-3.9629 (18) Å] and C-H⋯O inter-actions involving the methyl-ene H atoms and the phenyl-attached nitro group.


Trauma-Focused Cognitive Behavioural Therapy for Children and Parents.
Trauma-focused cognitive behavioural therapy (TF-CBT) for children and parents is an evidence based treatment approach for traumatised children. Evaluation of TF-CBT includes several randomised controlled trials, effectiveness studies and ongoing studies for children experiencing sexual abuse, domestic violence, traumatic grief, terrorism, disasters and multiple traumas. The model of TF-CBT described here is a flexible, components-based model that provides children and parents with stress management skills prior to encouraging direct discussion and processing of children's traumatic experiences. TF-CBT components are summarised by the acronym PRACTICE: Psychoeducation, Parenting skills, Relaxation skills, Affective modulation skills, Cognitive coping skills, Trauma narrative and cognitive processing of the traumatic event(s), In vivo mastery of trauma reminders, Conjoint child-parent sessions, and Enhancing safety and future developmental trajectory. Currently this model of TF-CBT is being adapted and implemented both within the USA and internationally.


APC mutations in colorectal tumors with mismatch repair deficiency.
We have investigated the influence of genetic instability [replication error (RER) phenotype] on APC (adenomatous polyposis coli), a gene thought to initiate colorectal tumorigenesis. The prevalence of APC mutations was similar in RER and non-RER tumors, indicating that both tumor types share this step in neoplastic transformation. However, in a total of 101 sequenced mutations, we noted a substantial excess of APC frameshift mutations in the RER cases (70% in RER tumors versus 47% in non-RER tumors, P < 0.04). These frameshifts were characteristic of mutations arising in cells deficient in DNA mismatch repair, with a predilection for mononucleotide repeats in the RER tumors (P < 0.0002), particularly (A)n tracts (P < 0.00007). These findings suggest that the genetic instability that is reflected by the RER phenotype precedes, and is responsible for, APC mutation in RER large bowel tumors and have important implications for understanding the very earliest stages of neoplasia in patients with tumors deficient in mismatch repair.


Inhibition of terminal differentiation of B cells mediated by CD27 and CD40 involves signaling through JNK.
B cells responding to cognate Ag in vivo undergo clonal expansion that is followed by differentiation into Ab-secreting plasma cells or into quiescent restimulable memory. Both these events occur in the germinal center and require that cells exit from proliferation, but the signals that lead to one or the other of these mutually exclusive differentiation pathways have not been definitively characterized. Previous experiments have shown that signals transduced through the TNFRs CD27 and CD40 at the time of B cell stimulation in vitro or in vivo can influence this cell fate decision by inhibiting terminal differentiation and promoting memory. In this study, we show that the PIQED domain of the cytoplasmic tail of murine CD27 and the adapter molecule TNFR-associated factor 2 are involved in this effect. Using pharmacological inhibitors of signaling intermediates, we identify JNK as being necessary and sufficient for the observed inhibition of terminal differentiation. While JNK is involved downstream of CD40, inhibition of the MEK pathway can also partially restore plasma cell generation, indicating that both signaling intermediates may be involved. We also show that inhibition of induction of IFN regulatory factor 4 and B lymphocyte induced maturation protein 1 are downstream events common to both receptors.


Sulfur-Rich Phosphorus Sulfide Molecules for Use in Rechargeable Lithium Batteries.
A new family of sulfur-rich phosphorus sulfide molecules (P4 S10+n ) and their electrochemical reaction mechanism with metallic Li has been explored. These P4 S10+n molecules are synthesized by the reaction between P4 S10 and S. For Li batteries, the P4 S40 molecule in the series of P4 S10+n molecules provides the highest capacity, which has a first discharge capacity of 1223 mAh g-1 at 100 mA g-1 and stabilizes at approximately 720 mAh g-1 at 500 mA g-1 after 100 cycles. This new class of sulfur-rich P4 S10+n molecules and its electrochemical behavior for room-temperature Li+ storage could provide novel insights for phosphorus sulfide molecules and high-energy batteries.


Treatment of a partially thrombosed giant aneurysm of the vertebral artery by aneurysm trapping and direct vertebral artery-posterior inferior cerebellar artery end-to-end anastomosis: technical case report.
The purpose of this article is to focus for the first time on the operative management of a direct vertebral artery (VA)-posterior inferior cerebellar artery (PICA) end-to-end anastomosis in a partially thrombosed giant VA-PICA-complex aneurysm and to underline its usefulness as an additional treatment option. The operative technique of a direct VA-PICA end-to-end anatomosis is described in detail. The VA was entering the large aneurysm sack. Distally, the PICA originated from the aneurysm sack-VA-complex. The donor and recipient vessel were cut close to the aneurysm. Whereas the VA was cut in a straight manner, the PICA was cut at an oblique 45-degree angle to enlarge the vascular end diameter. Vessel ends were flushed with heparinized saline and sutured. The thrombotic material inside the aneurysm sack was removed and the distal VA clipped, leaving the anterior spinal artery and brainstem perforators free. The patient regained consciousness without additional morbidity. Magnetic resonance imaging scans revealed a completely decompressed brainstem without infarction. The postoperative angiograms demonstrated a good filling of the anastomosed PICA. Despite the caliber mistmatch of these two vessels the direct VA-PICA end-to-end anastomosis provides an accurate alternative in addition to other anastomoses and bypass techniques, when donor and recipient vessels are suitable and medullary perforators do not have to be disrupted.


Surgical experience of intratemporal facial nerve neurofibromas.
The first presentation of intratemporal facial neurofibromas was variable, with facial palsy most common. The tumors often involve two or more segments of facial nerve. Outcomes of the tumors were closely related to nerve integrity, preoperative facial nerve function level, and follow-up period. The aim of this study was to present surgical experience of 11 cases with intratemporal facial neurofibroma. Clinical data of the 11 cases with the tumors was retrospectively collected and analyzed. They were followed up for 37.9 ± 1.7 months, range 13-59 months, except for one case that was only followed up for 5 months and was excluded from the analysis of outcomes. Facial palsy was the first presentation in 10 cases, with repetitive facial palsy and vertigo in 1 case; 6 cases (54.5%) were insidious and 5 (45.5%) were sudden in terms of onset. Ear pain around the onset of facial palsy was found in four cases (36.4%). The tumor involved more than one segment in six cases. Among the non-grafted cases one patient with grade V facial nerve function recovered to grade III and another patient with grade VI facial nerve function recovered to grade IV, whereas only one case with grade VI recovered to grade IV among the grafted cases.


The effect of genome-wide association scan quality control on imputation outcome for common variants.
Imputation is an extremely valuable tool in conducting and synthesising genome-wide association studies (GWASs). Directly typed SNP quality control (QC) is thought to affect imputation quality. It is, therefore, common practise to use quality-controlled (QCed) data as an input for imputing genotypes. This study aims to determine the effect of commonly applied QC steps on imputation outcomes. We performed several iterations of imputing SNPs across chromosome 22 in a dataset consisting of 3177 samples with Illumina 610 k (Illumina, San Diego, CA, USA) GWAS data, applying different QC steps each time. The imputed genotypes were compared with the directly typed genotypes. In addition, we investigated the correlation between alternatively QCed data. We also applied a series of post-imputation QC steps balancing elimination of poorly imputed SNPs and information loss. We found that the difference between the unQCed data and the fully QCed data on imputation outcome was minimal. Our study shows that imputation of common variants is generally very accurate and robust to GWAS QC, which is not a major factor affecting imputation outcome. A minority of common-frequency SNPs with particular properties cannot be accurately imputed regardless of QC stringency. These findings may not generalise to the imputation of low frequency and rare variants.


Olfactory tracking strategies in a neotropical fruit bat.
Many studies have characterized olfactory-tracking behaviors in animals, and it has been proposed that search strategies may be generalizable across a wide range of species. Olfaction is important for fruit- and nectar-feeding bats, but it is uncertain whether existing olfactory search models can predict the strategies of flying mammals that emit echolocation pulses through their nose. Quantitative assessments of how well echolocating bats track and localize odor sources are lacking, so we developed a behavioral assay to characterize the olfactory detection and tracking behavior of crawling northern yellow-shouldered bats (Sturnira parvidens), a common neotropical frugivore. Trained bats were presented with a choice between control and banana-odor-infused solutions in a series of experiments that confirmed that bats are able to locate a reward based on odor cues alone and examined the effect of odor concentration on olfactory search behaviors. Decision distance (the distance from which bats made their change in direction before directly approaching the target) was distinctly bimodal, with an observed peak that coincided with an inflection point in the odor concentration gradient. We observed two main search patterns that are consistent with both serial sampling and learned route-following strategies. These results support the hypothesis that bats can combine klinotaxis with spatial awareness of experimental conditions to locate odor sources, similar to terrestrial mammals. Contrary to existing models, bats did not display prominent head-scanning behaviors during their final approach, which may be due to constraints of nasal-emitted biosonar for orientation.


Safety and tolerability of DIM-based therapy designed as personalized approach to reverse prostatic intraepithelial neoplasia (PIN).
It has been shown previously that novel formulation of 3,3'-diindolylmethane (DIM) substance with high bioavailability (Infemin) inhibits tumor development due to the tumor growth rate reduction in the xenograft model of prostate cancer. Prostatic intraepithelial neoplasia (PIN) is considered to be promising as a personalized and preventive treatment strategy of prostate cancer (PC). We assessed the safety of Infemin in men with PIN and discussed the interim results. A total of 14 patients with PIN were enrolled. They were randomized to 900 mg DIM or placebo daily for 3 months. Safety was evaluated by adverse events (AEs), laboratory tests and physical examinations. The trial revealed that Infemin treatment is associated with minimal toxicity and no serious adverse events when administered orally for 3 months. We noted three adverse events including nausea and diarrhea in two patients (14%). Combined 95% confidence interval (CI) was 1.8%-42.8%. Therapy was continued in all cases of adverse events. Good tolerability of DIM-based formulation allows us to recommend it for further clinical trials among men diagnosed with PIN for its efficacy and long-term safety parameters.


Distinct roles of the two tumor necrosis factor (TNF) receptors in modulating TNF and lymphotoxin alpha effects.
The role for the two tumor necrosis factor (TNF) receptors in discriminating TNF and lymphotoxin alpha (LTalpha) effects has been studied. TNF and LTalpha were equally mitogenic in Fs4 fibroblasts, which express a high amount of the p55 compared to the p75 TNF receptors (TNFRs). In contrast, TNF was more potent than LTalpha in mediating gene regulation and cytotoxicity in SW480-betaGal cells and KYM-1 cells, which have a high p75/p55 TNFR ratio. Both TNF and LTalpha showed comparable affinities for the two TNFRs. However, in contrast to LTalpha, TNF dissociated rapidly from the p75 TNFR, whereas both cytokines dissociated slowly from the p55 TNFR. Soluble p55 TNFR was much more potent than soluble p75 TNFR in inhibiting TNF cytotoxicity, whereas both soluble receptors moderately decreased LTalpha-mediated cytotoxicity with comparable efficacy. Antagonistic monoclonal antibodies against either TNFR types markedly inhibited TNF effects. However, only the p55 TNFR antagonistic antibody significantly decreased LTalpha-mediated cytotoxicity and cytomegalovirus promoter activation, whereas blocking of the p75 TNFR enhanced the LTalpha effects. These data suggest that whereas the p75 TNFR can both directly propagate TNF signals and "pass" TNF to the p55 TNFR, it attenuates LTalpha and may serve as a decoy receptor for this cytokine.


Everolimus Versus Mycophenolate Mofetil De Novo After Lung Transplantation: A Prospective, Randomized, Open-Label Trial.
The role of mammalian target of rapamycin (mTOR) inhibitors in de novo immunosuppression after lung transplantation is not well defined. We compared Everolimus versus mycophenolate mofetil in an investigator-initiated single-center trial in Hannover, Germany. A total of 190 patients were randomly assigned 1:1 on day 28 posttransplantation to mycophenolate mofetil (MMF) or Everolimus combined with cyclosporine A (CsA) and steroids. Patients were followed up for 2 years. The primary endpoint was freedom from bronchiolitis obliterans syndrome (BOS). The secondary endpoints were incidence of acute rejections, infections, treatment failure and kidney function. BOS-free survival in intention-to-treat (ITT) analysis was similar in both groups (p = 0.174). The study protocol was completed by 51% of enrolled patients. The per-protocol analysis shows incidence of bronchiolitis obliterans syndrome (BOS): 1/43 in the Everolimus group and 8/54 in the MMF group (p = 0.041). Less biopsy-proven acute rejection (AR) (p = 0.005), cytomegalovirus (CMV) antigenemia (p = 0.005) and lower respiratory tract infection (p = 0.003) and no leucopenia were seen in the Everolimus group. The glomerular filtration rate (GFR) decreased in both groups about 50% within 6 months. Due to a high withdrawal rate, the study was underpowered to prove a difference in BOS-free survival. The dropout rate was more pronounced in the Everolimus group. Secondary endpoints indicate potential advantages of Everolimus-based protocols but also a potentially higher rate of drug-related serious adverse events.


Microcolony formation by single-cell Synechococcus strains as a fast response to UV radiation.
UV radiation (UVR) has different effects on prokaryotic cells, such as, for instance, filamentation and aggregation in bacteria. Here we studied the effect of UVR on microcolony formation in two freshwater Synechococcus strains of different ribotypes (group B and group I) and phycobiliprotein compositions (phycoerythrin [PE] and phycocyanin [PC]). Each strain was photoacclimated at two light intensities, low light (LL) (10 μmol m⁻² s⁻¹) and moderate light (ML) (100 μmol m⁻² s⁻¹). The cultures were exposed for 6 days to treatments with UVR or without UVR. PE-rich Synechococcus acclimated to LL had a low carotenoid/chlorophyll a (car/chl) ratio but responded faster to UVR treatment, producing the highest percentages of microcolonies and of cells in microcolonies. Conversely, the same strain acclimated to ML, with a higher car/chl ratio, did not aggregate significantly. These results suggest that microcolony formation by PE-rich Synechococcus is induced by UVR if carotenoid levels are low. PC-rich Synechococcus formed a very low percentage of microcolonies in both acclimations even with low car/chl ratio. The different responses of the two Synechococcus strains to UVR depend on their pigment compositions. On the other hand, this study does not exclude that UVR-induced microcolony formation could also be related to specific ribotypes.


Development and Validation of a Quantitative, One-Step, Multiplex, Real-Time Reverse Transcriptase PCR Assay for Detection of Dengue and Chikungunya Viruses.
Dengue virus (DENV) and chikungunya virus (CHIKV) are important human pathogens with common transmission vectors and similar clinical presentations. Patient care may be impacted by the misdiagnosis of DENV and CHIKV in areas where both viruses cocirculate. In this study, we have developed and validated a one-step multiplex reverse transcriptase PCR (RT-PCR) to simultaneously detect, quantify, and differentiate between four DENV serotypes (pan-DENV) and chikungunya virus. The assay uses TaqMan technology, employing two forward primers, three reverse primers, and four fluorophore-labeled probes in a single-reaction format. Coextracted and coamplified RNA was used as an internal control (IC), and in vitro-transcribed DENV and CHIKV RNAs were used to generate standard curves for absolute quantification. The diagnostic 95% limits of detection (LOD) within the linear range were 50 and 60 RNA copies/reaction for DENV (serotypes 1 to 4) and CHIKV, respectively. Our assay was able to detect 53 different strains of DENV, representing four serotypes, and six strains of CHIKV. No cross-reactivity was observed with related flaviviruses and alphaviruses, To evaluate diagnostic sensitivity and specificity, 89 clinical samples positive or negative for DENV (serotypes 1 to 4) and CHIKV by the standard virus isolation method were tested in our assay. The multiplex RT-PCR assay showed 95% sensitivity and 100% specificity for DENV and 100% sensitivity and specificity for CHIKV. With an assay turnaround time of less than 2 h, including extraction of RNA, the multiplex quantitative RT-PCR assay provides rapid diagnosis for the differential detection of two clinically indistinguishable diseases, whose geographical occurrence is increasingly overlapping.


How far can we go? Quantum-chemical investigations of oxidation state +IX.
The highest known oxidation state of any element is +VIII. After the recent discovery of Ir(VIII)O(4) under cryogenic conditions, we have investigated the stability of cationic species [MO(4)](+) (M=Rh,Ir,Mt). Such compounds would formally represent the new oxidation state +IX, which is experimentally unknown so far for the whole periodic table. [IrO(4)](+) is predicted to be the most promising candidate. The calculated spin-orbit (SO) coupling shows only minor effects on the stability of the iridium species, whereas SO-coupling increases enormously for the corresponding Eka-Iridium (Meitnerium) complexes and destabilizes these.


Genome-Wide SNP Discovery in Indigenous Cattle Breeds of South Africa.
Single nucleotide polymorphism arrays have created new possibilities for performing genome-wide studies to detect genomic regions harboring sequence variants that affect complex traits. However, the majority of validated SNPs for which allele frequencies have been estimated are limited primarily to European breeds. The objective of this study was to perform SNP discovery in three South African indigenous breeds (Afrikaner, Drakensberger, and Nguni) using whole genome sequencing. DNA was extracted from blood and hair samples, quantified and prepared at 50 ng/μl concentration for sequencing at the Agricultural Research Council Biotechnology Platform using an Illumina HiSeq 2500. The fastq files were used to call the variants using the Genome Analysis Tool Kit. A total of 1,678,360 were identified as novel using Run 6 of 1000 Bull Genomes Project. Annotation of the identified variants classified them into functional categories. Within the coding regions, about 30% of the SNPs were non-synonymous substitutions that encode for alternate amino acids. The study of distribution of SNP across the genome identified regions showing notable differences in the densities of SNPs among the breeds and highlighted many regions of functional significance. Gene ontology terms identified genes such as MLANA, SYT10, and CDC42EP5 that have been associated with coat color in mouse, and ADAMS3, DNAJC3, and PAG5 genes have been associated with fertility in cattle. Further analysis of the variants detected 688 candidate selective sweeps (ZHp Z-scores ≤ -4) across all three breeds, of which 223 regions were assigned as being putative selective sweeps (ZHp scores ≤-5). We also identified 96 regions with extremely low ZHp Z-scores (≤-6) in Afrikaner and Nguni. Genes such as KIT and MITF that have been associated with skin pigmentation in cattle and CACNA1C, which has been associated with biopolar disorder in human, were identified in these regions. This study provides the first analysis of sequence data to discover SNPs in indigenous South African cattle breeds. The information will play an important role in our efforts to understand the genetic history of our cattle and in designing appropriate breed improvement programmes.


Hsp90 chaperonins possess ATPase activity and bind heat shock transcription factors and peptidyl prolyl isomerases.
Heat shock proteins of the 82-90 kDa class (hsp82 and hsp90) are abundant, conserved, and ubiquitous from prokaryotes to eukaryotes. Although proposed to be chaperones, they had not been reported to possess enzymatic activity until our recent observation that pure trypanosomatid hsp83 had potent ATPase activity (Nadeau, K., Sullivan, M., Engman, D., and Walsh, C. T. (1992) Protein Sci. 1, 970-979). We have now purified the hsp90 homolog from Escherichia coli (HtpG) and from Saccharomyces cerevisiae (hsp82) to homogeneity and observe ATPase activity with kcat values of 3 min-1 and 140 min-1. In addition, examinations of purified rat hsp90 and human hsp90 detect ATPase activity with a kcat of 0.6 min-1 and 10 min-1. Each of these hsp90s undergoes autophosphorylation on serine or threonine residues. In prokaryotes and eukaryotes, the induction of hsps during heat shock is controlled, respectively, by the binding of an alternate sigma 32 or a transcriptional activator (heat shock factor or HSF) at heat shock promoter elements. Here we show that E. coli HtpG immobilized to Affi-Gel beads selectively retains sigma 32 while the yeast hsp90 and rat hsp90 retain HSF. The peptidyl prolyl isomerase hsp59 of the FK506 binding class is known to bind to hsp90. We also detect binding of the other family of PPIases, the cyclophilins, to immobilized hsp90, consistent with a functional convergence of protein foldases.


Paresis acquired in the intensive care unit: a prospective multicenter study.
Although electrophysiologic and histologic neuromuscular abnormalities are common in intensive care unit (ICU) patients, the clinical incidence of ICU-acquired neuromuscular disorders in patients recovering from severe illness remains unknown. To assess the clinical incidence, risk factors, and outcomes of ICU-acquired paresis (ICUAP) during recovery from critical illness in the ICU and to determine the electrophysiologic and histologic patterns in patients with ICUAP. Prospective cohort study conducted from March 1999 to June 2000. Three medical and 2 surgical ICUs in 4 hospitals in France. All consecutive ICU patients without preexisting neuromuscular disease who underwent mechanical ventilation for 7 or more days were screened daily for awakening. The first day a patient was considered awake was day 1. Patients with severe muscle weakness on day 7 were considered to have ICUAP. Incidence and duration of ICUAP, risk factors for ICUAP, and comparative duration of mechanical ventilation between ICUAP and control patients. Among the 95 patients who achieved satisfactory awakening, the incidence of ICUAP was 25.3% (95% confidence interval [CI], 16.9%-35.2%). All ICUAP patients had a sensorimotor axonopathy, and all patients who underwent a muscle biopsy had specific muscle involvement not related to nerve involvement. The median duration of ICUAP after day 1 was 21 days. Mean (SD) duration of mechanical ventilation after day 1 was significantly longer in patients with ICUAP compared with those without (18.2 [36.3] vs 7.6 [19.2] days; P =.03). Independent predictors of ICUAP were female sex (odds ratio [OR], 4.66; 95% CI, 1.19-18.30), the number of days with dysfunction of 2 or more organs (OR, 1.28; 95% CI, 1.11-1.49), duration of mechanical ventilation (OR, 1.10; 95% CI, 1.00-1.22), and administration of corticosteroids (OR, 14.90; 95% CI, 3.20-69.80) before day 1. Identified using simple bedside clinical criteria, ICUAP was frequent during recovery from critical illness and was associated with a prolonged duration of mechanical ventilation. Our findings suggest an important role of corticosteroids in the development of ICUAP.


Phenotyping and genotyping of coagulation factor V Leiden.
The currently used activated Protein C resistance test demonstrated to be of limited diagnostic value for the detection of the mutant Factor V Leiden. Moreover, this assay is not useful for patients under anticoagulant therapy. A modification of the APC resistance test, applying Factor V deficient plasma is described which demonstrates a specificity and sensitivity of 1.0. The superiority of the modified APC resistance test over the existing APC resistance test was verified by genotyping. For that purpose, the Amplification Refractory Mutation System (ARMS) was applied to the detection of the G to A mutation at position 1691 in the gene encoding coagulation Factor V. The mutation at that position could be easily detected by using each of two allele-specific oligonucleotide primers concomitantly with one common primer in two separate polymerase chain reactions, thereby amplifying a fragment of 186 base-pairs of the Factor V gene.


[PROGNOSIS - The PROspective German NOn-CF BronchiectaSIS Patient Registry].
Bronchiectasis not due to cystic fibrosis (Non-CF bronchiectasis) represents a heterogeneous disorder with many different underlying diseases. Reliable and mature data referring to prevalence and incidence of Non-CF bronchiectasis in Germany are lacking. Bronchiectasis is often mentioned as rare or orphan disease, although it might be more often than supposed to be. Up to now (May 2015) there is no approved therapy for this disease in Germany. After some preliminary work the German bronchiectasis registry PROGNOSIS (The PROspective German NOn-CF bronchiectaSIS patient registry) will start recruiting patients by the beginning of July. The goals of PROGNOSIS are to build up a national, representative, prospective, observing (non-interventional) and longitudinal patient registry with at least 750 patients within three years in 25-35 centers, to evaluate important epidemiological questions. In addition a German-language guideline for diagnostic and management of Non-CF bronchiectasis will be developed in cooperation with the German respiratory society (DGP).


[The impact of the economic crisis on health systems of OECD countries].
This paper describes measures adopted by OECD countries in the health sector in response to the economic crisis which began in 2008: increase and diversification of revenues collected for health, increases in user charges, reductions in staff, salaries and prices of health goods and services; and policies aiming to increase health systems efficiency. It then reviews the impact of these policies on health spending trends.


Gamma frequency activation of inhibitory neurons in the acute phase after stroke attenuates vascular and behavioral dysfunction.
Alterations in gamma oscillations occur in several neurological disorders, and the entrainment of gamma oscillations has been recently proposed as a treatment for neurodegenerative disease. Optogenetic stimulation enhances recovery in models of stroke when applied weeks after injury; however, the benefits of acute brain stimulation have not been investigated. Here, we report beneficial effects of gamma-frequency modulation in the acute phase, within 1 h, after stroke. Transgenic VGAT-ChR2 mice are subject to awake photothrombotic stroke in an area encompassing the forelimb sensory and motor cortex. Optogenetic stimulation at 40 Hz in the peri-infarct zone recovers neuronal activity 24 h after stroke in motor and parietal association areas, as well as blood flow over the first week after stroke. Stimulation significantly reduces lesion volume and improves motor function. Our results suggest that acute-phase modulation of cortical oscillatory dynamics may serve as a target for neuroprotection against stroke.


Clinical presentation and visual status of retinitis pigmentosa patients: a multicenter study in southwestern Nigeria.
To review the visual status and clinical presentation of patients with retinitis pigmentosa (RP). Multicenter, retrospective, and analytical review was conducted of the visual status and clinical characteristics of patients with RP at first presentation from January 2007 to December 2011. Main outcome measure was the World Health Organization's visual status classification in relation to sex and age at presentation. Data analysis by SPSS (version 15) and statistical significance was assumed at P<0.05. One hundred and ninety-two eyes of 96 patients with mean age of 39.08±18.5 years and mode of 25 years constituted the study population; 55 (57.3%) were males and 41 (42.7%) females. Loss of vision 67 (69.8%) and night blindness 56 (58.3%) were the leading symptoms. Twenty-one (21.9%) patients had a positive family history, with RP present in their siblings 15 (71.4%), grandparents 11 (52.3%), and parents 4 (19.4%). Forty (41.7%) were blind at presentation and 23 (24%) were visually impaired. Blindness in six (15%) patients was secondary to glaucoma. Retinal vascular narrowing and retinal pigmentary changes of varying severity were present in all patients. Thirty-five (36.5%) had maculopathy, 36 (37.5%) refractive error, 19 (20%) lenticular opacities, and eleven (11.5%) had glaucoma. RP was typical in 85 patients (88.5%). Older patients had higher rates of blindness at presentation (P=0.005); blindness and visual impairment rate at presentation were higher in males than females (P=0.029). Clinical presentation with advanced diseases, higher blindness rate in older patients, sex-related difference in blindness/visual impairment rates, as well as high glaucoma blindness in RP patients requires urgent attention in southwestern Nigeria.


Competitive double-switched self-assembled cyclic peptide nanotubes: a dual internal and external control.
"Intelligent" materials based on synthetic small molecules that become functional only under specific conditions provide new opportunities for developing regulated systems aimed at a large number of applications. For instance, biologically active supramolecular entities that are sensitive to environmental conditions, such as the presence of bacterial membranes, are extremely interesting in biomedicine. In this work, we have designed and investigated, using molecular dynamics simulations, a doubly modulable nanotube formed by the self-assembly of cyclic peptides sensitive to both the presence of a lipid membrane and the pH of the aqueous media. The cyclic peptides were designed to self-assemble into peptide nanotubes in the presence of a lipid bilayer and at low pH values. Under these conditions, the residual side chains point outside the cyclic peptides, being exposed to the lipid bilayer, and the inner groups (carboxylic acids) are protonated, thus allowing the permeation of water and preventing that of ions. Higher pH values are expected to create carboxylate groups at the lumen of the peptides, leading to the disassembly of the nanotube, the attraction and translocation of ions towards the hydrophobic core of the bilayer, and eventually killing the target malignant cells. Our results suggest that by introducing a second switch in a membrane sensitive system, it is possible to modulate its interaction with the lipid bilayer. This opens the door to new strategies for the preparation of antimicrobial peptides that interact at the membrane level.


Camp happiness.
In the outside world, children with serious skin conditions often face isolation and loneliness. Their peers give them nicknames, uninformed adults ask difficult questions. Once they get to Camp Horizon, however, they forget their disease, and swim, boat, stargaze, sing around the fire. They meet other children just like themselves. According to one boy, 'This place is like Heaven on Earth for me."


A novel method using a silicone diffusion membrane for continuous ²²²Rn measurements for the quantification of groundwater discharge to streams and rivers.
²²²Rn is a natural radionuclide that is commonly used as tracer to quantify groundwater discharge to streams, rivers, lakes, and coastal environments. The use of sporadic point measurements provides little information about short- to medium-term processes (hours to weeks) at the groundwater-surface water interface. Here we present a novel method for high-resolution autonomous, and continuous, measurement of ²²²Rn in rivers and streams using a silicone diffusion membrane system coupled to a solid-state radon-in-air detector (RAD7). In this system water is pumped through a silicone diffusion tube placed inside an outer air circuit tube that is connected to the detector. ²²²Rn diffuses from the water into the air loop, and the ²²²Rn activity in the air is measured. By optimizing the membrane tube length, wall thickness, and water flow rates through the membrane, it was possible to quantify radon variations over times scales of about 3 h. The detection limit for the entire system with 20 min counting was 18 Bq m⁻³ at the 3σ level. Deployment of the system on a small urban stream showed that groundwater discharge is dynamic, with changes in ²²²Rn activity doubling on the scale of hours in response to increased stream flow.


Influence of Oxygen and Temperature on the Dark Inactivation of Pyruvate, Orthophosphate Dikinase and NADP-Malate Dehydrogenase in Maize.
The influence of oxygen and temperature on the inactivation of pyruvate, Pi dikinase and NADP-malate dehydrogenase was studied in Zea mays. O(2) was required for inactivation of both pyruvate, Pi dikinase and NADP-malate dehydrogenase in the dark in vivo. The rate of inactivation under 2% O(2) was only slightly lower than that at 21% O(2). The in vitro inactivation of pyruvate, Pi dikinase, while dependent on adenine nucleotides (ADP + ATP), did not require O(2).The postillumination inactivation of pyruvate, Pi dikinase in leaves was strongly dependent on temperature. As temperature was decreased in the dark, there was a lag period of increasing length (e.g. at 17 degrees C there was a lag of about 25 minutes) before inactivation proceeded. Following the lag period, the rate of inactivation decreased with decreasing temperature. The half-time for dark inactivation was about 7 minutes at 32 degrees C and 45 minutes at 17 degrees C. The inactivation of pyruvate, Pi dikinase in vitro following extraction from illuminated leaves was also strongly dependent on temperature, but occurred without a lag period. In contrast, NADP-malate dehydrogenase was rapidly inactivated in leaves (half-time of approximately 3 minutes) during the postillumination period without a lag, and there was little effect of temperature between 10 and 32 degrees C. The results are discussed in relation to known differences in the mechanism of activation/inactivation of the two enzymes.


Elevated t/e2 ratio is associated with an increased risk of cerebrovascular disease in elderly men.
To investigate the relationship between sex hormones and the risk of vascular disease in elderly men and to evaluate the advantages and disadvantages of testosterone replacement. A total of 337 men, aged 60 to 91 years, were enrolled in this single-center, cross-sectional study, and their sex hormone levels were assessed. Linear and logistic regression analyses were utilized to compare the sex hormone levels between patients with and without vascular disease. The nonparametric K-sample test was used for inter-group comparisons. Aging and abnormal metabolism were both significantly associated with an increased risk of vascular diseases and changes in sex hormone levels. Primary linear and logistic regression analyses showed no significant differences in sex hormone concentrations between patients with and without vascular diseases after adjusting for age. Logistic regression with abnormal metabolism as categorical variable showed that free testosterone (FT) and free estradiol (FE2) had significant relationships with CEVD risk (P<0.05). In further regression with all metabolic continuous variables included, the testosterone/estradiol (T/E2) ratio replaced FT and FE2 (P<0.05). Trend line analyses showed that T/E2 actually had a binomial linear correlation with the risk of cerebrovascular disease; its best protective effect occurred at values of 0.13-0.15, with an OR value extremely close to those of FT and FE2 (0.23 vs. 0.24-0.25). T/E2 balance plays a key role in the relationship between sex hormones and the risk of cerebrovascular disease. The balance between T and E2 may be more important than their absolute quantities. Extremely low T/E2 and inappropriately high T/E2 ratio can both harm the brain blood vessels. Careful consideration should be given before beginning testosterone replacement treatment, and supplementing with estrogen seems to be a good way to protect blood vessels of the brain in elderly men.


A Randomised Controlled Trial Examining the Effects of Self-Compassion Meditations on Women's Body Image.
Although research has suggested that body image improves following self-compassion meditation training, studies have been limited due to the use of a wait-list control group. This study therefore compared the effects of self-compassion meditations to an active control group. Seventy young adult women (17-35 years) were randomly assigned to receive either self-compassion or nature-focused guided imagery meditations. Over one week, participants engaged in two meditations and completed pre- and post-test measures of trait self-compassion, body appreciation, body shame, and appearance-contingent self-worth. A mixed design analysis of variance revealed a main effect of time; women in both meditation groups demonstrated significant increases in self-compassion and body appreciation, and significant reductions in body shame. No effect was found for appearance-contingent self-worth. There were no interactions or main effects for group. Self-compassion may improve body image in women, although there was no evidence for an advantage of self-compassion over guided imagery meditations. Common elements between self-compassion and guided imagery may be a mechanism for improving body image. However, further research is warranted to isolate the effects of these meditations from other specific and non-specific treatment effects. (This study was pre-registered with the Australian New Zealand Clinical Trials Registry, ACTRN12618001814268).


Protein biomineralized nanoporous inorganic mesocrystals with tunable hierarchical nanostructures.
Mesocrystals with the symmetry defying morphologies and highly ordered superstructures composed of primary units are of particular interest, but the fabrication has proved extremely challenging. A novel strategy based on biomineralization approach for the synthesis of hematite mesocrystals is developed by using silk fibroin as a biotemplate. The resultant hematite mesocrystals are uniform, highly crystalline, and porous nanostructures with tunable size and morphologies by simply varying the concentration of the silk fibroin and iron(III) chloride in this biomineralization system. In particular, we demonstrate a complex mesoscale biomineralization process induced by the silk fibroin for the formation of hematite mesocrystals. This biomimetic strategy features precisely tunable, high efficiency, and low-cost and opens up an avenue to access new novel functional mesocrystals with hierarchical structures in various practical applications.


N-(2-bromophenyl)-2-(4,6-dimethoxypyrimidin-2-yloxy)benzylamine, a new selective postemergent herbicide for weed control in winter oilseed rape.
N-(2-Bromophenyl)-2-(4,6-dimethoxypyrimidin-2-yloxy)benzylamine is a highly active herbicide, which belongs to a novel class of chemistry. The compound is de novo synthesized in good yield, and the structure is confirmed by (1)H NMR, IR, MS, microanalysis, and X-ray. Its herbicidal activity is assessed under greenhouse conditions. It is effective against many grass weed species, as well as broadleaf weeds, under greenhouse conditions. Field trials indicate that it controls major weeds with a good tolerance on oilseed rape by postemergence application at rates of 15-90 g of active ingredient/ha. This compound possesses low mammalian toxicity and favorable environmental profile. These results suggest that the compound has potential as a new selective postemergent herbicide in winter oilseed rape.


The photochemical reaction cycle of retinal reconstituted bacteriorhodopsin.
The function of three types of bacteriorhodopsins was compared: the wild-type, the bleached and retinal reconstituted and retinal deficient bacteriorhodopsin after retinal addition. The apparent pK(a) of the proton acceptor group for the bleached BR and retinal deficient BR shifted toward higher pH values compared to the wild-type BR. Fitting the photocycle model to the absorption kinetic signals for all three proteins showed the existence of the same intermediates, but the time-dependent concentration of the intermediates was different. Although measurements were made at pH 7, the absorption kinetics and photoelectric signals in both retinal reconstituted samples acted as wild-type bacteriorhodopsin at significantly higher pH. Below pH 3 the retinal deficient and reconstituted sample bleached. These results suggested that the added retinal was not able to rebind in the same position in the protein as in native bacteriorhodopsin. This points out that care should be taken, when bleached bacteriorhodopsin is reconstituted with different retinal analogs.