Clinical and Neurochemical Effects of Transcranial Magnetic Stimulation (TMS) in Multiple Sclerosis: A Study Protocol for a Randomized Clinical Trial.
Background: Transcranial Magnetic Stimulation (TMS) is a technique based on the principles of electromagnetic induction. It applies pulses of magnetic radiation that penetrate the brain tissue, and it is a non-invasive, painless, and practically innocuous procedure. Previous studies advocate the therapeutic capacity of TMS in several neurodegenerative and psychiatric processes, both in animal models and in human studies. Its uses in Parkinson's disease, Alzheimer's disease and in Huntington's chorea have shown improvement in the symptomatology and in the molecular profile, and even in the cellular density of the brain. Consequently, the extrapolation of these TMS results in the aforementioned neurodegenerative disease to other entities with etiopathogenic and clinical analogy would raise the relevance and feasibility of its use in multiple sclerosis (MS). The overall objective will be to demonstrate the effectiveness of the TMS in terms of safety and clinical improvement, as well as to observe the molecular changes in relation to the treatment. Methods and Design: Phase II clinical trial, unicentric, controlled, randomized, single blind. A total of 90 patients diagnosed with relapsing-remitting multiple sclerosis (RRMS) who meet all the inclusion criteria and do not present any of the exclusion criteria that are established and from which clinically evaluable results can be obtained. The patients included will be assigned under the 1:1:1 randomization formula, constituting three groups for the present study: 30 patients treated with natalizumab + white (placebo) + 30 patients treated with natalizumab + TMS (1 Hz) + 30 patients treated with natalizumab + TMS (5 Hz). Discussion: Results of this study will inform on the efficiency of the TMS for the treatment of MS. The expected results are that TMS is a useful therapeutic resource to improve clinical status (main parameters) and neurochemical profile (surrogate parameters); both types of parameters will be checked. Ethics and Dissemination: The study is approved by the Local Ethics Committee and registered in https://clinicaltrials.gov (NCT04062331). Dissemination will include submission to a peer-reviewed journal, patients, associations of sick people and family members, healthcare magazines and congress presentations. Trial Registration: ClinicalTrials.gov ID: NCT04062331 (registration date: 19th/ August/2019). Version Identifier: EMTr-EMRR, ver-3, 21/11/2017.


Mass spectral determination of phosphopantetheinylation specificity for carrier proteins in Mycobacterium tuberculosis.
Phosphopantetheinyl transferases (PPTases) are key elements in the modular syntheses performed by multienzyme systems such as polyketide synthases. PPTases transfer phosphopantetheine derivatives from Coenzyme A to carrier proteins (CPs), thus orchestrating substrate supply. We describe an efficient mass spectrometry-based protocol for determining CP specificity for a particular PPTase in organisms possessing several candidate PPTases. We show that the CPs MbtL and PpsC, both involved in synthesis of essential metabolites in Mycobacterium tuberculosis, are exclusively activated by the type 2 PPTase PptT and not the type 1 AcpS. The assay also enables conclusive identification of the reactive serine on each CP.


Prediction and detection of freezing of gait in Parkinson's disease from plantar pressure data using long short-term memory neural-networks.
Freezing of gait (FOG) is a walking disturbance in advanced stage Parkinson's disease (PD) that has been associated with increased fall risk and decreased quality of life. Freezing episodes can be mitigated or prevented with external intervention such as visual or auditory cues, activated by FOG prediction and detection systems. While most research on FOG detection and prediction has been based on inertial measurement unit (IMU) and accelerometer data, plantar-pressure data may capture subtle weight shifts unique to FOG episodes. Different machine learning algorithms have been used for FOG detection and prediction; however, long short-term memory (LSTM) deep learning methods hold an advantage when dealing with time-series data, such as sensor data. This research aimed to determine if LSTM can be used to detect and predict FOG from plantar pressure data alone, specifically for use in a real-time wearable system. Plantar pressure data were collected from pressure-sensing insole sensors worn by 11 participants with PD as they walked a predefined freeze-provoking path. FOG instances were labelled, 16 features were extracted, and the dataset was balanced and normalized (z-score). The resulting datasets were classified using long short-term memory neural-network models. Separate models were trained for detection and prediction. For prediction models, data before FOG were included in the target class. Leave-one-freezer-out cross validation was used for model evaluation. In addition, the models were tested on all non-freezer data to determine model specificity. The best FOG detection model had 82.1% (SD 6.2%) mean sensitivity and 89.5% (SD 3.6%) mean specificity for one-freezer-held-out cross validation. Specificity improved to 93.3% (SD 4.0%) when ignoring inactive state data (standing) and analyzing the model only on active states (turning and walking). The model correctly detected 95% of freeze episodes. The best FOG prediction method achieved 72.5% (SD 13.6%) mean sensitivity and 81.2% (SD 6.8%) mean specificity for one-freezer-held-out cross validation. Based on FOG data collected in a laboratory, the results suggest that plantar pressure data can be used for FOG detection and prediction. However, further research is required to improve FOG prediction performance, including training with a larger sample of people who experience FOG.


Estimation of the proportion of true null hypotheses under sparse dependence: Adaptive FDR controlling in microarray data.
The proportion of non-differentially expressed genes is an important quantity in microarray data analysis and an appropriate estimate of the same is used to construct adaptive multiple testing procedures. Most of the estimators for the proportion of true null hypotheses based on the thresholding, maximum likelihood and density estimation approaches assume independence among the gene expressions. Usually, sparse dependence structure is natural in modelling associations in microarray gene expression data and hence it is necessary to develop methods for accommodating the sparse dependence well within the framework of existing estimators. We propose a clustering based method to put genes in the same group that are not coexpressed using the estimated high dimensional correlation structure under sparse assumption as dissimilarity matrix. This novel method is applied to three existing estimators for the proportion of true null hypotheses. Extensive simulation study shows that the proposed method improves an existing estimator by making it less conservative and the corresponding adaptive Benjamini-Hochberg algorithm more powerful. The proposed method is applied to a microarray gene expression dataset of colorectal cancer patients and the results show gain in terms of number of differentially expressed genes. The R code is available at https://github.com/aniketstat/Proportiontion-of-true-null-under-sparse-dependence-2021.


Prophylactic versus selective antibiotics for term newborn infants of mothers with risk factors for neonatal infection.
Early onset bacterial infection is an important cause of morbidity and mortality in newborn infants. Various factors that increase the risk of neonatal infection have been identified. It is unclear whether asymptomatic newborn infants born to mothers with one or more of these risk factors should receive antibiotics prophylactically rather than selectively if only clinical or microbiological evidence of sepsis emerges. To assess the effect of prophylactic versus selective antibiotic treatment for asymptomatic term neonates born to mothers with risk factors for neonatal infection. We used the standard methods of the Cochrane Neonatal Review Group. We searched MEDLINE (1966 - May 2004), EMBASE (1980 - May 2004), LILACS (1982 - 2003), SciELO (1997 - 2003), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2004), and Centers for Disease Control and Prevention protocols and guidelines on the subject. Randomized controlled trials, or trials using quasi-random methods of allocation, comparing the use of prophylactic versus selective antibiotics in asymptomatic neonates born to mothers with one or more risk factors for infection. We extracted the data using the standard methods of the Cochrane Neonatal Review Group, with separate evaluation of trial quality and data extraction by three reviewers and synthesis of data using relative risk and risk difference. The pre-specified primary outcomes were neonatal mortality, systemic neonatal infection, and need for admission to a neonatal intensive care unit. We identified two small trials undertaken in the 1970s. Both trials had methodological weaknesses. There was no evidence of an effect on any of the primary outcomes, but because the trials were underpowered, clinically important effect sizes may have been missed. There are insufficient data from randomized controlled trials to guide clinical practice. A large randomized controlled trial is needed in asymptomatic term infants born to mothers with risk factors for infection in their babies, which compares the effect of prophylactic versus selective antibiotics on morbidity, mortality and costs.


Effects of different water quality regulators on growth performance, immunologic function, and domestic water quality of GIFT tilapia.
Water quality regulation is widely recognized as a highly effective strategy for disease prevention in the field of aquaculture, and it holds significant potential for the development of sustainable aquaculture. Herein, four water quality regulators, including potassium monopersulfate (KMPS), tetrakis hydroxymethyl phosphonium sulfate (THPS), bacillus subtilis (BS), and chitosan (CS), were added to the culture water of Oreochromis niloticus (GIFT tilapia) every seven days. Subsequently, the effects of these four water quality regulators on GIFT tilapia were comprehensively evaluated by measuring the water quality index of daily growth-related performance and immune indexes of GIFT tilapia. The findings indicated that implementing the four water quality regulators resulted in a decrease in the content of ammonia nitrogen, active phosphate, nitrite, total organic carbon (TOC), and chemical oxygen demand (COD) in the water. Additionally, these regulators were found to maintain dissolved oxygen (DO) levels and pH of the water effectively. Furthermore, using these regulators demonstrated positive effects on various physiological parameters of GIFT tilapia, including improvements in final body weight, weight gain rate (WGR), specific growth rate (SGR), condition factor (CF), feed conversion ratio (FCR), spleen index (SI), hepato-somatic index (HSI), immune cell count, the activity of antioxidant-related enzymes (Nitric oxide, NO and Superoxide dismutase, SOD), and mRNA expression levels of immunity-related factors (Tumor Necrosis Factor-alpha, TNF-α and Interleukin-1 beta, IL-1β) in the liver and spleen. Notably, the most significant improvements were observed in the groups treated with the BS and CS water quality regulators. Moreover, BS and CS groups exhibited significantly higher serum levels of albumin (ALB) and total protein (TP) (P < 0.05), whereas the other indicators showed no significant difference (P > 0.05) compared to the control group. However, the KMPS and THPS groups of GIFT tilapia exhibited significantly higher serum levels of aspartate aminotransferase (AST), alanine transaminase (ALT), creatinine (CRE) and blood urea nitrogen (BUN) (P < 0.05), whereas they exhibited significantly decreased HSI (P < 0.05). In addition, the partially pathological observations revealed the presence of cell vacuolation, nuclear shrinkage, and pyknosis within the liver. In conclusion, these four water quality regulators, mainly BS and CS, could improve the growth performance and immunity of GIFT tilapia to varying degrees by regulating the water quality and then further increasing the expression levels of immune-related factors or the activity of antioxidant-related enzymes of GIFT tilapia. On the contrary, the prolonged use of KMPS and THPS may gradually diminish their growth-enhancing properties and potentially hinder the growth of GIFT tilapia.


The effects of sevoflurane, halothane, enflurane, and isoflurane on hepatic blood flow and oxygenation in chronically instrumented greyhound dogs.
Inhalational anesthetics produce differential effects on hepatic blood flow and oxygenation that may impact hepatocellular function and drug clearance. In this investigation, the effects of sevoflurane on hepatic blood flow and oxygenation were compared with those of enflurane, halothane, and isoflurane in ten chronically instrumented greyhound dogs. Each dog randomly received enflurane, halothane, isoflurane, and sevoflurane, each at 1.0, 1.5, and 2.0 MAC concentrations. Mean arterial blood pressure and cardiac output decreased in a dose-dependent fashion during all four anesthetics studied. Heart rate increased compared to control during enflurane, isoflurane, and sevoflurane anesthesia and did not change during halothane anesthesia. Hepatic arterial blood flow and portal venous blood flow were measured by chronically implanted electromagnetic flow probes. Hepatic O2 delivery and consumption were calculated after hepatic arterial, portal venous, and hepatic venous blood gas analysis. Hepatic arterial blood flow was maintained with sevoflurane and isoflurane. Halothane and enflurane reduced hepatic arterial blood flow during all anesthetic levels compared to control (P less than 0.05), with marked reductions occurring with 1.5 and 2.0 MAC halothane concomitant with an increase in hepatic arterial vascular resistance. Portal venous blood flow was reduced with isoflurane and sevoflurane at 1.5 and 2.0 MAC. A somewhat greater reduction in portal venous blood flow occurred during 2.0 MAC sevoflurane (P less than 0.05 compared to control and 1.0 MAC values for sevoflurane). Enflurane reduced portal venous blood flow at 1.0, 1.5, and 2.0 MAC compared to control. Halothane produced the greatest reduction in portal venous blood flow (P less than 0.05 compared to sevoflurane).(ABSTRACT TRUNCATED AT 250 WORDS)


Randomized controlled trial of intralesional corticosteroid and griseofulvin vs. griseofulvin alone for treatment of kerion.
We studied 30 children with tinea capitis and kerion to define the epidemiology of the disease and to compare the efficacy of intralesional steroid injection and griseofulvin to griseofulvin alone for treatment of this disorder. Patients ranged in age from 1 year to 12 years, 1 month (mean, 5 years, 7 months). All patients were black and 23 (77%) were female. (The racial composition of our clinic population is 45% black, 18% Latin American, 34% Caucasian and 3% Asian.) Fungus cultures were positive in all but one patient and Trichophyton tonsurans was isolated from 26 of 30 (87%) of the pretreatment hair cultures. Direct microscopic examinations of KOH-treated hair samples were negative in 13 of 29 (43%) culture-positive patients. Patients were randomly assigned to receive intralesional steroid injection (2.5 mg) and griseofulvin (14 patients) or griseofulvin only (16 patients). The treatment groups were comparable with regard to age, sex, duration of lesions before treatment and type of lesions. There were no significant differences between the two treatment groups in the time to negative culture, time of onset of new hair growth, complete regrowth of hair and time to scalp clearing. We conclude that intralesional injection of corticosteroid is an unnecessary adjunct to therapy for patients with tinea capitis with kerion.


Functional analysis of bladder cancer-related protein gene: a putative cervical cancer tumor suppressor gene in cervical carcinoma.
Our previous study has suggested thatthe bladder cancer-associated protein gene (BLCAP) was among the differentially expressed genes in cervical cancer. We confirm here that BLCAP is expressed in all noncancerous cervical tissues (10/10), but it is greatly lost in primary cervical cancer tissue (31/39). In order to further investigate the functional roles of BLCAP, we stably transfected BLCAP cDNA into HeLa cells. The HeLa cells expressing BLCAP show reduced cell growth and clone genicity compared to the vector-transfected cognate cells. BLCAP expression in HeLa cells leads to growth arrest and significantly enhanced apoptosis in vitro and reduced tumor formation in vivo. Thus, BLCAP might be a potential tumor suppressor gene in cervical carcinoma.


Influence of patient positioning on dose-volume histogram and normal tissue complication probability for small bowel and bladder in patients receiving pelvic irradiation: a prospective study using a 3D planning system and a radiobiological model.
A prospective study was undertaken to evaluate the influence of patient positioning (prone position using a belly board vs. supine position) on the dose-volume histograms (DVHs) of organs of risk, and to analyze its possible clinical relevance using radiobiological models. From November 1996 to August 1997 a computed tomography (CT) scan was done in the prone position using a belly board and in supine position in 20 consecutive patients receiving postoperative pelvic irradiation because of rectal cancer. Using a three-dimensional (3D) planning system (Helax, TMS) the DVH for small bowel, bladder, a standard planning target volume (PTV) of postoperative irradiation of rectal cancer, the intersection of volume of PTV and small bowel (PTV intersection V(SB), respectively, of PTV and bladder (PTV intersection V(B)) were defined in each axial CT slice. The normal tissue complication probability (NTCP) was determined by the radiobiological model of Lyman and Kutcher using the tolerance data of Emami. For evaluation of late toxicity alpha/beta ratio was 2.5; for evaluation of acute toxicity, it was 10. Total dose was 50.4 Gy (1.8 Gy/fraction) (ICRU 50). Using the prone position compared to the supine position, the median volume of PTV intersection V(B) was reduced by 18.5 cm3 (62%). Median dose (related to the reference dose) to the bladder was 44.5% (22.4 Gy) in prone and 66.05% (33.3 Gy) in supine position (p<0.001). Median V(B) within the 90% (45.4 Gy), 80% (40.3 Gy), 60% (30.2 Gy), and 40% (20.2 Gy) isodose was significantly lower in the prone position when compared to the supine position. Using the radiobiological models, however, there was no difference of NTCP between prone position or supine position. In the prone position, median volume of PTV intersection V(SB) was reduced by 32.5 cm3 (54%). The median dose to small bowel was 30.85% (15.4 Gy) in the prone position and 47.35% (23.9Gy) in the supine position (p<0.001). Significant differences between prone and supine position were found for median V(SB) within the 90% (45.4 Gy), 80% (40.3 Gy), 60% (30.2 Gy), and 40% (20.2 Gy) isodose. According to the method of Lyman, median NTCP of small bowel was significant lower in prone than in supine position. The prone position with a standard belly board should be the standard positioning technique for patients receiving adjuvant postoperative radiation therapy following surgery of rectal cancer. Both irradiated volume and total dose to the organs of risk can be reduced significantly. As a consequence of this, radiation induced toxicity will be minimized.


Two-dimensional metal-organic frameworks with blue luminescence.
Three new isostructural two-dimensional metal-organic frameworks (MOFs), [M(bpydc)(H(2)O).H(2)O](n) where M = Zn (1); Co (2); Ni (3) and the bpydc is 2,2'-bipyridine-5,5'-dicarboxylate), were prepared by various methods such as hydrothermal, ultrasonic and microwave-assisted synthetic methods. Microcrystalline could be obtained by using ultrasonification or microwave irradiation in a short time. Their solid-state structures were revealed by X-ray crystallography. The coordination environment of the metal ions is distorted octahedral geometry. The metal ions are coordinated by two nitrogen atoms from the bipyridyl moiety, two oxygen atoms from one carboxylate in a bidentate manner, one oxygen atom from another carboxylate in a monodentate manner, and one oxygen atom from the aqua ligand. The multiple coordination modes of the bpydc ligand led to a novel topologically interesting two-dimensional sheet structure; a 6-connected uninodal net with Schläfli symbol of 3(3).4(4).5(5).6(2).7. Thermal and luminescence properties of the three MOFs were also investigated. The weight maintained constant in the range 290-342 degrees C for 1, 250-470 degrees C for 2, and 275-470 degrees C for 3 after the initial weight loss related to the dehydration steps. In particular, [Zn(bpydc)(H(2)O).H(2)O](n) (1) displays strong solid state blue luminescence.


The effect of infant vitamin B12 supplementation on neurodevelopment: a follow-up of a randomised placebo-controlled trial in Nepal.
The most critical period for brain development is before a child's second birthday. Standardised tests measuring neurodevelopment are more reliable when administered after this period. Severe vitamin B12 deficiency affects brain development and function. In a randomised, double-blind, placebo-controlled trial in 600 Nepalese infants (6-11 months at enrolment), we found no effect of 2 µg vitamin B12 daily for a year on neurodevelopment. The primary objective of the current study was to measure the effect of the intervention on the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-IV) full scale intelligence quotient (FSIQ). We measured the effect on the Bayley Scales of Infant and Toddler Development 3rd edition at age 30-35 months (n 555). At age 42-47 months (n 533), we used the WPPSI-IV and subtests from the Neuropsychological Assessment, 2nd edition (NEPSY-II). We also used the FSIQ to estimate subgroup specific effects. The mean (sd) WPPSI-IV FSIQ in the vitamin B12 group was 84·4 (8·4) and 85·0 (8·6) in the placebo group (mean difference -0·5 (95 % CI -1·97, 0·94), P = 0·48). There were no effect of the vitamin B12 on any of the other neurodevelopmental outcomes and no beneficial effect in any of the subgroups. In conclusion, providing 2 µg of vitamin B12 for a year in infants at risk of vitamin B12 deficiency does not improve preschool cognitive function.


The Application of MEVEC 3D Doppler Ultrasound Technique for a New Classification of Morpho-Functional Phenotypes in Lower Limbs Venous Diseases.
MEVEC 2.1 is a novel 3D mapping software dedicated to the evaluation of the venous vascular three of the lower limbs. It has already proven as a sensitive, specific, and accurate technique able to provide better morphologic and functional details of the lower limb venous system than standard reports. The aim of this study was to identify specific morpho-functional graphic phenotypes in lower limb venous diseases by means of MEVEC 2.1. Three-hundred eleven consecutive outpatients underwent lower limb Doppler ultrasound examination by means of the MEVEC 2.1 technique. All of them showed at least one among these pathological findings: venous insufficiency, thrombosis, incompressibility, and/or incompetent. We tried to evaluate possible clusters among the different morpho-functional findings from the venous maps in order to outline reproducible phenotypes. Correlation indexes allowed us to provide a classification in morpho-functional phenotypes in order to standardize the data from examinations performed by different physicians. Twelve phenotypes had been proposed. The study showed that the MEVEC 2.1 technique provides a standardized classification that allows physicians identifying phenotypes yielded by 3D mapping of the veins of the lower limbs.


Cross-linked polyethylene glycol beads to separate 99mTc-pertechnetate from low-specific-activity molybdenum.
We report a kit-based approach for the purification of sodium pertechnetate ((99m)TcO4 (-)) from solutions with high MoO4 (2-) content. Cross-linked polyethylene glycol resins (ChemMatrix) were used to separate (99m)Tc and molybdenum in 4N NaOH. The resins were loaded at various flow rates and eluted with water to release (99m)Tc. The (99m)Tc solution was passed through a cation exchange resin and an alumina cartridge, followed by saline elution. This process was tested with cyclotron-produced (99m)Tc using an automated system and disposable kits. Optimal results were obtained by loading 500 mg of resin at flow rates of up to 3.1 mL/min, with quantitative extraction of (99m)Tc from the molybdate solution and complete release of (99m)Tc after elution with water. The automated system was highly efficient at isolating Na(99m)TcO4 within minutes, with a recovery rate of 92.7% ± 1.1% (mean ± SD) using cyclotron-produced (99m)Tc. ChemMatrix resins were highly effective at separating (99m)TcO4 (-) from molybdate solutions.


The specificity of UV-induced mutations at an endogenous locus in mammalian cells.
We have used a rapid in vivo recombinational method to clone and completely sequence 34 UV-induced mutants at the adenine phosphoribosyltransferase (APRT) locus of Chinese hamster ovary cells. Among the mutants recovered, 26 were single base substitutions including 17 G.C----A.T transitions and a single A.T----G.C transition. Three of the 4 possible transversions accounted for the remaining 8 mutations. The G.C----T.A transversion was not recovered. Six tandem double or closely neighboring double-base substitutions, one double mutation consisting of a G.C----T.A transversion and an adjacent frameshift, as well as one single frameshift mutation were also recovered. UV-induced mutation appears to be targeted to dipyrimidine sites with only two exceptions. These include two double mutations where only one of the base substitutions occurred at a dipyrimidine site. The observed specificity of UV-light-induced mutations at the APRT locus is consistent with the argument that G.C----A.T transitions result primarily from the (6-4) pyrimidine pyrimidone lesion. A striking resemblance in the distribution of UV-induced mutants and a collection of 30 spontaneous mutants identified recently in our laboratory was noted. Both share a common strong site of multiple occurrence and a considerable degree of overlap with respect to site specificity. We speculate therefore that DNA context plays a significant role in mutation fixation in mammalian cells.


Characterization of Cryopreserved Canine Amniotic Membrane.
Amniotic membrane is an effective corneal reconstruction material in veterinary surgery. Cryopreserved amniotic membrane is widely used in practice. Properties of cryopreserved canine amniotic membranes are currently not well studied. This study aimed to compare three properties between canine amniotic membranes cryopreserved for 7 days and 30 days, including tensile strength, transparency, and cell viability. After their respective cryopreservation time, stress-strain curves of the cryopreserved membranes' tensile strength were assessed using a universal testing machine. Both groups produced J-shaped stress-strain curves with statistically comparable parameters, including maximum stress, strain, and Young's modulus. The percentage of cell viability was observed by trypan blue staining under a light microscope. Membrane transparency was tested with a spectrophotometer. Transparency tests showed high levels of light transmission and low haze, with no statistical difference between groups. Cell viability was statistically lower in the 30-day cryopreserved group. Tensile strength and transparency of cryopreserved CAM were not significantly impeded for up to 30 days. For CAM to be used as an alternative corneal transplant material in veterinary and regenerative medicine, further research on cell biology, biomechanical properties of the membrane, and cell viability should be conducted.


Mammary carcinogen-protein binding potentials: novel and biologically relevant structure-activity relationship model descriptors.
Previously, SAR models for carcinogenesis used descriptors that are essentially chemical descriptors. Herein we report the development of models with the cat-SAR expert system using biological descriptors (i.e., ligand-receptor interactions) rat mammary carcinogens. These new descriptors are derived from the virtual screening for ligand-receptor interactions of carcinogens, non-carcinogens, and mammary carcinogens to a set of 5494 target proteins. Leave-one-out validations of the ligand mammary carcinogen-non-carcinogen model had a concordance between experimental and predicted results of 71%, and the mammary carcinogen-non-mammary carcinogen model was 72% concordant. The development of a hybrid fragment-ligand model improved the concordances to 85 and 83%, respectively. In a separate external validation exercise, hybrid fragment-ligand models had concordances of 81 and 76%. Analyses of example rat mammary carcinogens including the food mutagen and oestrogenic compound PhIP, the herbicide atrazine, and the drug indomethacin; the ligand model identified a number of proteins associated with each compound that had previously been referenced in Medline in conjunction with the test chemical and separately with association to breast cancer. This new modelling approach can enhance model predictivity and help bridge the gap between chemical structure and carcinogenic activity by descriptors that are related to biological targets.


Assessment of Chemical Impact of Invasive Bryozoan Pectinatella magnifica on the Environment: Cytotoxicity and Antimicrobial Activity of P. magnifica Extracts.
Pectinatella magnifica, an invasive bryozoan, might significantly affect ecosystem balance due to its massive occurrence in many areas in Europe and other parts of the world. Biological and chemical analyses are needed to get complete information about the impact of the animal on the environment. In this paper, we aimed to evaluate in vitro cytotoxic effects of five extracts prepared from P. magnifica using LDH assay on THP-1 cell line. Antimicrobial activities of extracts against 22 different bacterial strains were tested by microdilution method. Our study showed that all extracts tested, except aqueous portion, demonstrated LD50 values below 100 μg/mL, which indicates potential toxicity. The water extract of P. magnifica with LD50 value of 250 μg/mL also shows potentially harmful effects. Also, an environmental risk resulting from the presence and increasing biomass of potentially toxic benthic cyanobacteria in old colonies should not be underestimated. Toxicity of Pectinatella extracts could be partially caused by presence of Aeromonas species in material, since we found members of these genera as most abundant bacteria associated with P. magnifica. Furthermore, P. magnifica seems to be a promising source of certain antimicrobial agents. Its methanolic extract, hexane, and chloroform fractions possessed selective inhibitory effect on some potential pathogens and food spoiling bacteria in the range of MIC 0.5-10 mg/mL. Future effort should be made to isolate and characterize the content compounds derived from P. magnifica, which could help to identify the substance(s) responsible for the toxic effects of P. magnifica extracts.


Local electronic structure of aqueous zinc acetate: oxygen K-edge X-ray absorption and emission spectroscopy on micro-jets.
Oxygen K-edge X-ray absorption, emission, and resonant inelastic X-ray scattering spectra were measured to site selectively gain insights into the electronic structure of aqueous zinc acetate solution. The character of the acetate ion and the influence of zinc and water on its local electronic structure are discussed.


The assessment of skeletal maturation.
The measurement of skeletal maturity is important for the analysis of growth and growth disorders. Several methods are available for the assessment of skeletal age. They are all based on the recognition of maturity indicators, that is, of changes in the radiographic appearance of hand-wrist bones. The most commonly used methods are the Greulich and Pyle Atlas and the Tanner-Whitehouse (TW2) method. More recently, the FELS method has been described by Roche and coworkers. The assessments made using the Greulich and Pyle Atlas are often very inaccurate, whereas experience with the FELS method is still very limited. At the present time, the TW2 is still the method of choice. It is hoped that the development of a computerized method of assessment will lead to greater accuracy in the determination of skeletal maturity.


Pivotal Advance: Eosinophilia in the MES rat strain is caused by a loss-of-function mutation in the gene for cytochrome b(-245), alpha polypeptide (Cyba).
MES is a rat strain that spontaneously develops severe blood eosinophilia as a hereditary trait. Herein, we report that eosinophilia in MES rats is caused by a loss-of-function mutation in the gene for cytochrome b(-245), alpha polypeptide (Cyba; also known as p22(phox)), which is an essential component of the superoxide-generating NADPH oxidase complex. The MES rat has a deletion of four nucleotides, including the 5' splice donor GpT of intron 4 of the Cyba gene. As a consequence of the deletion, a 51-nucleotide sequence of intron 4 is incorporated into the Cyba transcripts. Leukocytes from the MES strain lack both CYBA protein and NADPH oxidase activity. Nevertheless, unlike patients with chronic granulomatous disease, who suffer from infections with pathogens due to similar genetic defects in NADPH oxidase, MES rats retain normal innate immune defense against Staphylococcus aureus infection. This is due to large quantities of peritoneal eosinophils in MES rats, which phagocytose and kill the bacteria. MES rat has a balance defect due to impaired formation of otoconia in the utricles and saccules. Eosinophilia of the MES rat was normalized by introduction of a normal Cyba transgene. The mechanisms by which impairment of NADPH oxidase leads to eosinophilia in the MES rat are elusive. However, our study highlights the essential role of NADPH oxidase in homeostatic regulation of innate immunity beyond conventional microbicidial functions.


Bone mineral density in patients with endogenous subclinical hyperthyroidism: is this thyroid status a risk factor for osteoporosis?
The aim of the present study was to elucidate whether endogenous subclinical hyperthyroidism due to a solitary autonomously functioning thyroid nodule affects bone metabolism and is a risk factor for osteoporosis. In a cross-sectional study measurements of bone mineral density were performed in premenopausal and post-menopausal women. Patients were categorized into non-toxic nodular goitre (n = 32), subclinical hyperthyroid (n = 37) and toxic solitary autonomous thyroid nodule (n = 22) subgroups and the results were compared with those of sex and age-matched control reference population (n = 68). Lumbar spine and femoral neck bone mineral densities were measured by dual energy X-ray absorptiometry. Single-photon absorptiometry was applied to the measurement of bone mineral content in the midshaft of the radius. In the non-toxic nodular goitre group, bone densities for all the scanned sites did not differ from the sex and age-matched reference population. At the L2-4 scanning site a significant decrease in the bone mineral density could be observed only in the toxic nodular goitre group and this decrease was more marked in the postmenopausal (P < 0.001) than in the premenopausal females (P < 0.05). At the femoral neck and midshaft radius the mean densitometric values were slightly, but significantly, lower only in the post-menopausal subclinical hyperthyroid group compared with the reference population (P < 0.01). The bone mineral density of the femoral neck, as well as the bone mineral content of the midshaft radius, was significantly decreased in both the premenopausal and post-menopausal patients with a toxic solitary nodule. This study indicates that the bone mineral density of the lumbar spine, femoral neck and the midshaft of the radius are not significantly decreased in premenopausal patients with endogenous subclinical hyperthyroidism resulting from a solitary autonomously functioning thyroid nodule. Conversely, findings hint at the possibility that long-lasting endogenous subclinical hyperthyroidism may be a contributing factor to the development of osteoporosis in some post-menopausal women, mostly at sites where cortical bone preponderates.


Alzheimer's Disease Sequencing Project discovery and replication criteria for cases and controls: Data from a community-based prospective cohort study with autopsy follow-up.
The Alzheimer's Disease Sequencing Project (ADSP) used different criteria for assigning case and control status from the discovery and replication phases of the project. We considered data from a community-based prospective cohort study with autopsy follow-up where participants could be categorized as case, control, or neither by both definitions and compared the two sets of criteria. We used data from the Adult Changes in Thought (ACT) study including Diagnostic and Statistical Manual-IV criteria for dementia status, McKhann et al. criteria for clinical Alzheimer's disease, and Braak and Consortium to Establish a Registry for AD findings on neurofibrillary tangles and neuritic plaques to categorize the 621 ACT participants of European ancestry who died and came to autopsy. We applied ADSP discovery and replication definitions to identify controls, cases, and people who were neither controls nor cases. There was some agreement between the discovery and replication definitions. Major areas of discrepancy included the finding that only 40% of the discovery sample controls had sufficiently low levels of neurofibrillary tangles and neuritic plaques to be considered controls by the replication criteria and the finding that 16% of the replication phase cases were diagnosed with non-AD dementia during life and thus were excluded as cases for the discovery phase. These findings should inform interpretation of genetic association findings from the ADSP. Differences in genetic association findings between the two phases of the study may reflect these different phenotype definitions from the discovery and replication phase of the ADSP.


Autoimmunity in hepatitis C and D virus infection.
A large number of viruses are capable of inducing acute or chronic hepatitis. The syndrome of chronic hepatitis encompasses not only viral but also autoimmune liver diseases. The hepatitis C virus, and recently also the hepatitis D virus have been found to be associated with an array of autoimmune syndromes, diseases and markers of autoimmunity. The relationship of hepatotropic virus infection and the immune system leading to virus-associated autoimmunity, and its distinction from genuine autoimmune disease represents a fascinating field of research. Clinically, the differentiation between autoimmune liver diseases, virus infection and virus-associated autoimmunity is difficult and epidemiological evaluations have not come up with universally applicable and valid classification criteria. However, both autoimmune liver diseases and viral hepatitis can readily be diagnosed and distinguished through precise and molecularly determined immunological testing systems. The overlap of both, virus-associated autoimmunity, is still at the centre of research activities aimed at establishing diagnostic and risk-assessment criteria. Studies of molecular autoantigens and autoepitopes have begun to define the differences of the B-cell response in autoimmune disease and virus-associated autoimmunity. This provides data that may contribute to the safe application of therapeutic strategies as different as immunosuppression and interferon-alpha (IFN-alpha). The present review focuses on the clinical, epidemiological and molecular aspects of these disease entities.


On the mechanistic reasons for the dual positional specificity of the reticulocyte lipoxygenase.
A set of octadecadienoic acid isomers and selected eicosatrienoic acids were tested as substrates for the lipoxygenases from soybeans and reticulocytes. Among the dienoic fatty acids, 8Z,11Z-octadecadienoic acid containing a n - 9 doubly allylic methylene group turned out to be the best substrate for the reticulocyte enzyme. This substrate was converted to its corresponding n - 7 hydroperoxy derivative. The soybean lipoxygenase, in contrast, prefers the 9Z,12Z-octadecadienoic acid (linoleic acid) which is oxygenated to its n - 6 hydroperoxy derivative. In both cases a strong preference for the LS-isomer has been observed. Analysis of the oxygenation products formed from various eicosatrienoic acids indicated that 8Z,11Z,14Z-eicosatrienoic acid was converted by the reticulocyte enzyme to its 12S- and 15S-hydroperoxy derivative in a ratio of about 1:7 (dual positional specificity), whereas the 7Z,10Z,13Z-isomer was oxygenated predominantly (greater than 97%) to its 14S-hydroperoxy derivative (singular positional specificity). 9Z,12Z,15Z-eicosatrienoic acid was oxygenated with a dual positional specificity to the corresponding 13- and 16-hydroperoxy compounds in a ratio of about 7:1. The soybean lipoxygenase converts the 8Z,11Z,14Z-isomer with a singular positional specificity to the corresponding 15S-hydroperoxy derivatives. The 9Z,12Z,15Z-eicosatrienoic acid, however, was oxygenated with a dual positional specificity to its 13S-hydroperoxy and 16S-hydroperoxy derivative in a ratio of about 1:4.


Effects of various tachykinins on pituitary LH secretion, feeding, and sexual behavior in the rat.
Our investigations of the four tachykinines tested have shown that NPK characteristically evoked a spectrum of biological effects in male and female rats. NPK suppressed pituitary LH release by inhibiting the release of hypothalamic LHRH, presumably by activation of NK-2 tachykinin receptor subtypes. However, NPK may also act at the level of gonadotrophs to stimulate LH release in male rats. Central injection of NPK rapidly disrupted copulatory behavior in sexually active male rats. NPK also suppressed feeding, but, in this case, peripheral injections were more effective than central injections. Taken together, these observations strongly imply that NPK may be an inhibitory messenger molecule in the hypothalamic control of reproduction, sexual, and feeding behaviors.


Peak bone mass, a growing problem?
The focus of attention in osteoporosis research has been on factors influencing bone fragility and the propensity for trauma (falls) during adulthood and old age. The purpose of this review is to change the focus of this attention toward consideration of skeletal growth in the first 20 years of life and to demonstrate the importance of mineral accrual (and the factors influencing this accrual) in determining bone density in adulthood and old age. We suggest that the epidemiology of fractures may be unified by a central role of reduced peak bone density in the pathogenesis of the low bone density found in patients with fractures. The reduced peak bone density establishes the relevance of age-related and sex hormone-dependent bone loss. Risk and protective factors in the first 20 years of life may have quantitatively larger, and qualitatively different effects on the axial and appendicular skeleton than exposure during adulthood. Public health measures focussed on optimising mineral accrual in the first 20 years of life may be more important than health care measures more proximate to the age at which fractures occur.


Complex regulation and nuclear localization of JRK protein.
The mouse jerky gene and its human orthologue, JRK/JH8, encode a putative DNA-binding protein with homology to the CENP-B (centromere-binding protein B). Disruption of the mouse jerky gene by transgene insertion causes generalized recurrent seizures reminiscent of human idiopathic generalized epilepsy. In addition (and similar to a cenp-b null mouse) jerky null mice exhibit postnatal weight loss and reduced fertility. Using fluorescence confocal microscopy, the cellular localization of a JRK-GFP fusion (where GFP stands for green fluorescent protein) was investigated in HeLa cells. JRK-GFP has a dynamic expression pattern in the interphase nucleus, localizing in a small number of punctate nuclear foci and in the nucleolus. The JRK-GFP foci number changes during the cell cycle, but a distinct pattern of three JRK-GFP foci is observed at G(2). The endogenous protein behaves in a similar manner to the GFP-fusion protein. JRK-GFP was found to co-localize with CREST antigens (which recognize the centromere-binding proteins, CENP-A, -B and -C) through S and G(2) phases of interphase and co-localized completely with a subset of PML nuclear bodies at G(2). We speculate that JRK protein associates with a specific chromosomal centromeric locus in G(2), where it associates fully with PML bodies. Research is underway to identify this locus.


Regulation of G protein-initiated signal transduction in yeast: paradigms and principles.
All cells have the capacity to evoke appropriate and measured responses to signal molecules (such as peptide hormones), environmental changes, and other external stimuli. Tremendous progress has been made in identifying the proteins that mediate cellular response to such signals and in elucidating how events at the cell surface are linked to subsequent biochemical changes in the cytoplasm and nucleus. An emerging area of investigation concerns how signaling components are assembled and regulated (both spatially and temporally), so as to control properly the specificity and intensity of a given signaling pathway. A related question under intensive study is how the action of an individual signaling pathway is integrated with (or insulated from) other pathways to constitute larger networks that control overall cell behavior appropriately. This review describes the signal transduction pathway used by budding yeast (Saccharomyces cerevisiae) to respond to its peptide mating pheromones. This pathway is comprised by receptors, a heterotrimeric G protein, and a protein kinase cascade all remarkably similar to counterparts in multicellular organisms. The primary focus of this review, however, is recent advances that have been made, using primarily genetic methods, in identifying molecules responsible for regulation of the action of the components of this signaling pathway. Just as many of the constituent proteins of this pathway and their interrelationships were first identified in yeast, the functions of some of these regulators have clearly been conserved in metazoans, and others will likely serve as additional models for molecules that carry out analogous roles in higher organisms.


GIS-based spatial, temporal, and space-time analysis of haemorrhagic fever with renal syndrome.
We obtained a list of all reported cases of haemorrhagic fever with renal syndrome (HFRS) in Shenyang, China, during 1990-2003, and used GIS-based scan statistics to determine the distribution of HFRS cases and to identify key areas and periods for future risk-factor research. Spatial cluster analysis suggested three areas were at increased risk for HFRS. Temporal cluster analysis suggested one period was at increased risk for HFRS. Space-time cluster analysis suggested six areas from 1995 to 1996 and four areas from 1998 to 2003 were at increased risk for HFRS. We also discussed the likely reasons for these clusters. We conclude that GIS-based scan statistics may provide an opportunity to classify the epidemic situation of HFRS, and we can pursue future investigations to study the likely factors responsible for the increased disease risk based on the classification.


Tetraprenyltoluquinols from the brown alga Cystophora fibrosa.
Six cyclised tetraprenyltoluquinols and five stereoisomers with the previously reported amentol skeleton have been isolated from the lipophilic extract of the South African brown alga Cystophora fibrosa. Structures and relative stereochemistry were determined using spectrometric techniques, particularly 1D and 2D NMR, and molecular modelling experiments. The compounds isolated appear to be enantiomeric to compounds with the same skeleton isolated from brown algae of the genus Cystoseira collected in northern Africa and the Mediterranean Sea. The isolation of tetraprenyltoluquinols with the amentol skeleton from this alga suggests that C. fibrosa should be moved from the genus Cystophora into the Cystoseira.


Relationship between abnormal P-wave terminal force in lead V1 and left ventricular diastolic dysfunction in hypertensive patients: the LIFE study.
Abnormal P-wave terminal force in lead V1 (PTF-V1) is an ECG marker of increased left atrial (LA) volume, elevated LA filling pressures and/or LA systolic dysfunction. Because left ventricular (LV) diastolic dysfunction is one of the potential mechanisms driving LA remodelling, we hypothesized that PTF-V1 might be an additional ECG marker of diastolic dysfunction. LV diastolic function after 3 years' systematic antihypertensive treatment was examined in relation to baseline PTF-V1 in 431 hypertensive patients undergoing protocol-driven blood pressure reduction who had baseline and year-3 ECG and echocardiographic data and a preserved LV ejection fraction (EF >45%) at year-3. Abnormal diastolic function was defined by the tenth or 90th percentile values from 405 normotensive, non-obese and non-diabetic adults without overt cardiovascular disease. Abnormal PTF-V1, defined by the presence of a negative terminal P-wave in lead V1 ≥ 4000 μV·ms, was present in 167 patients (38.7%). Abnormal PTF-V1 was associated with worse year-3 mean diastolic first third filling time (0.43 ± 0.08 vs 0.40 ± 0.07 sec, p = 0.039), first half filling time (0.55 ± 0.07 vs 0.53 ± 0.07 sec, p = 0.041), mitral valve A velocity (86 ± 27 vs 76 ± 19 cm/sec, p = 0.009) and mitral valve E/A ratio (0.85 ± 0.22 vs 0.94 ± 0.27, p = 0.007) after adjusting for other potential predictors of diastolic dysfunction including race, and heart rate, systolic blood pressure and severity of ECG LVH by Cornell product criteria at baseline. In parallel multivariate logistic regression analysis, abnormal PTF-V1 was associated with significantly increased odds of abnormal mitral valve E/A ratio (OR 1.55, 95%CI 1.04-2.32 p = 0.032), and a trend toward higher odds of abnormal half filling time (OR 1.42, 95%CI 0.94-2.15, p = 0.098) at year-3 of follow-up. Abnormal P-wave terminal force in lead V1 is associated with worse diastolic function and predicts abnormal LV diastolic behaviour in patients with preserved EF after 3 years of blood pressure reductive therapy.


Low seroprevalence of bartonella species in danish elite orienteers.
In the 1990s, studies were conducted to investigate 16 episodes of sudden unexpected cardiac death (SUCD) among Swedish elite orienteers during the period from 1979 to 1992. A case control study revealed that a significantly higher proportion of Swedish elite orienteers were B. elizabethae seropositive compared to controls. The aim of our study, designed as a case-control study, was to determine whether similarly high rates of B. elizabethae seropositivity were present among Danish elite orienteers. Cases were 43 elite orienteers; controls were 159 blood donors and 63 elite indoor sportsmen. All participants were tested for antibodies against B. henselae, B. quintana and B. elizabethae using immunofluorescent antibody tests. Surprisingly, Bartonella antibodies were only detected in sera from 5 persons: B. henselae from 1 elite orienteer, 1 handball player and 1 blood donor. B. elizabethae antibodies were detected in 1 handball player and 1 basketball player. We found no association between elite orienteers and the prevalence of Bartonella antibody positivity. This is in contrast to the Swedish study, and might be explained by the use of different serological methods in the 2 studies; to determine whether it is a true difference, a new study is needed.


[Exposure risk assessment of plasticizer in dietary food in Xiamen].
To understand the dietary consumption of residents in Xiamen and the content of phthalic acid esters (PAEs) in food, and to assess the plasticizer exposure risk of diet in Xiamen. The survey was conducted by stratified cluster random sampling method in Xiamen from September to October in 2010. According to the Xiamen administrative division, six neighborhood communities were selected as sampling units, then 25 families were randomly chosen from each sampling units.From the above 150 families, the permanent residents over the age of six were permitted to our study. The survey included 495 residents totally. These participants' information, such as basic personal information, physical activity levels, meal frequency and the average consumption of 33 kinds of food in 13 categories were collected using questionnaires. Thirteen categories included cereal and tubers, beans, vegetables, fungi and algae, fruits, dairy products, meat, seafood, eggs, snacks, beverages, cooking oil and spices. The height and weight of residents were measured and the average daily dietary intake was calculated. Thirty-three kinds of food in 13 categories were collected in supermarkets in Xiamen. According to the annual sales ranking, the top three-five brands of each kinds of food were selected and numbered, then two or three brands were chosen by random number table method from them; three completely individual packed samples in the same batch of each brand were detected; 243 samples were included in our study.100-500 g solid samples or 100-500 ml liquid samples were collected. The content of diethyl phthalate (DEP), dibutyl phthalate (DBP), di (2-ethylhexyl) phthalate (DEHP) in food were detected by liquid chromatography mass spectrometry, which expressed by median (minimum-maximum). The exposure dose, contribution rate and risk index of PAEs were calculated by point estimation method. According to the average daily dietary intake of residents in Xiamen, the top three ones in 13 categories of food were cereal and tubers (337.16 g/d, 18.21%), vegetables (309.12 g/d, 16.69%) and fruits (213.20 g/d, 11.51%). The content of DEP, DBP or DEHP among different categories of food was significantly different (χ² values were 58.05, 50.19 and 102.10, P < 0.01). Among 13 categories of food, seafood contained the most DEP (0.090 (0.000-0.324)mg/kg); cooking oil had the most DBP (0.700(0.000-2.980) mg/kg) and DEHP (5.115(0.000-24.160) mg/kg). DEP, DBP and DEHP exposure(0.19, 4.20, 18.10 µg × kg⁻¹ ×d ⁻¹)in dietary food in Xiamen were less than the reference dose(RfD) (800, 100, 20 µg × kg⁻¹ × d⁻¹) proposed by the United States Environmental Protection Agency (EPA), and the risk indexes were 0.02%, 4.20% and 90.50%, respectively. Among 13 categories of foods, seafood was the main source of DEP dietary exposure. The exposure dose and contribution rate of DEP in seafood were 0.18 µg × kg⁻¹ × d⁻¹ and 94.74%, respectively.Vegetables were the main source of DBP and DEHP dietary exposure. The exposure dose and contribution rate of DBP and DEHP were 1.48 µg × kg⁻¹ × d⁻¹, 35.24% and 6.07 µg × kg⁻¹ × d⁻¹, 33.54%, respectively. The food consumed by residents in Xiamen was overall in a safe state, but to some extent, there still exists DEHP exposure risk in foods.


Ultraviolet B irradiation-induced G2 cell cycle arrest in human keratinocytes by inhibitory phosphorylation of the cdc2 cell cycle kinase.
In response to genotoxic stress, cell cycle progression can be arrested at certain checkpoints which serve to maintain genomic integrity. We have investigated the mechanism of ultraviolet B (UVB) irradiation-induced cell cycle arrest in normal human keratinocytes and in the HaCaT keratinocyte cell line which carries mutant p53 tumour suppressor protein. While only normal keratinocytes showed a delay in G1 following sublethal UVB irradiation both cell types exhibited prolonged G2 arrest attributable to rapid inhibition of cyclin B-associated cdc2 kinase activity. This inhibition coincided with increased tyrosine phosphorylation of cdc2 and was reversed by the cdc25C phosphatase in vitro. The data indicate that UVB-induced G2 arrest in mammalian cells is mediated by inhibitory tyrosine phosphorylation of cdc2 and acts as a defense mechanism against DNA damage irrespective of the cells' p53 status.


T cells from Jak3-deficient mice have intact TCR signaling, but increased apoptosis.
The Jak family tyrosine kinase, Jak3, is involved in signaling through cytokine receptors utilizing the common gamma-chain (gamma(c)). Mice and humans lacking Jak3 have severe immune deficiencies, including defects in B and T lymphocyte development and function. In particular, Jak3-deficient mice have mature T cells with an activated phenotype, yet these cells are functionally nonresponsive. In this work, we show that Jak3-deficient T cells have no gross defects in early T cell signaling, as measured by TCR-induced tyrosine phosphorylation and calcium mobilization responses. Furthermore, we find that Jak3-deficient mice expressing a transgenic TCR have extremely low numbers of peripheral T cells with a naive phenotype, indicating that both peripheral activation and expansion of Jak3-/- T cells are driven by antigenic signals. We show that, similar to gamma(c)-deficient mice, T cells from Jak3-deficient mice have an increased susceptibility to apoptosis. Previously, we showed that when stimulated in vitro by CD3 plus CD28 cross-linking, Jak3-/- T cells secrete greatly reduced amounts of IL-2, and fail to proliferate. However, by measuring intracellular IL-2 levels, we find that Jak3-/- T cells produce amounts of IL-2 similar to activated T cells from control mice, further supporting the notion that there is no defect in TCR signaling in Jak3-/- T cells.


Federal policy on criminal offenders who have substance use disorders: how can we maximize public health and public safety?
The Obama Administration is striving to promote both public health and public safety by improving the public policy response to criminal offenders who have substance use disorders. This includes supporting drug courts, evidence-based probation and parole programs, addiction treatment and re-entry programs. Scientists and clinicians in the addiction field have a critical role to play in this much-needed effort to break the cycle of addiction, crime and incarceration.


Properties of carbonate-containing aluminum hydroxide produced by precipitation at constant pH.
Carbonate-containing aluminum hydroxide was precipitated at constant pH at intervals of 0.5 pH units from pH 6 to 10 by pumping 0.5 M AlCl3 into the reaction vessel at a constant rate of 2 mL/min and infusing 2 M Na2CO3 at a rate necessary to maintain the desired pH. The pH of precipitation affected both the particle size and the composition of the precipitate. The particle size of the precipitate decreased as the pH of precipitation was increased from 6 to 10. The precipitates formed between pH 7.5 and 9.5 contained crystalline sodium aluminum hydroxycarbonate (dawsonite) in addition to amorphous carbonate-containing aluminum hydroxide.


Endoscopic examination in patients with acquired immunodeficiency syndrome: Taiwan experience.
Endoscopic experience in patients with acquired immunodeficiency syndrome (AIDS) has rarely been reported in Taiwan. We present our experience in 9 AIDS patients (8 male and 1 female, age from 26 to 63 years) with 12 examinations. The risk factor of these patients were bisexual in 3, homosexual in 2, hemophilia in 1, drug abuse in 1, and paid-sex in 2. Odynophagia or dysphagia was the major complaints. Oral ulcers or/and thrush were noted in 8 patients. Endoscopic findings included negative (6/12), candidiasis (3/12), erosions (1/12), ulcers (1/12) and ulcer scar (1/12) in esophagus; negative (8/12), gastritis (1/12), erosions (1/12), ulcers (1/12) and Kaposi's sarcoma (1/12) in stomach; and negative (11/12) and duodenitis (1/12) in duodenum. Patients with esophageal candidiasis always had oral thrush. Dysphagia was highly correlated with positive endoscopic findings in esophagus. It is important for an endoscopist to identify clinical symptoms and to examine patient's oral cavity before an endoscopic examination. The endoscopist must keep himself from being infected by exposure to contaminated blood and secretion and avoid dissemination of this horrible disease by undisinfected instruments.


Punching Glass: A 10-Year Consecutive Series.
Punching glass can cause severe and debilitating injuries. The literature is scant in regards to the injury patterns, optimal management, and preventative strategies. We have reviewed our experience of these injuries at a regional Australian hospital. A retrospective chart review of all patients who had punched glass and presented to Cairns Base Hospital between January 2003 and December 2012. Data collected included age, gender, marital status, employment status, alcohol consumption, side of injury, intent, time of presentation, damaged structures, treatment required, operative time, total hospital stay, and required follow-up. 137 eligible patients were identified during the 10-year study period. Mean age was 26.3 years. Most were men (n = 113), single (n = 122), unemployed (n = 95), and intoxicated (n = 91). Most of these injuries presented outside of normal working hours (P < 0.001). Ninety-one patients had superficial skin lacerations only and did not require operative intervention. The remaining 46 patients had a total of 46 tendon, 18 muscle, 12 nerve, 8 vessel and 5 bone injuries, and all required operative intervention. Tendon, nerve and vessel injuries were strongly associated with each other (P < 0.05). This represents the largest case series of glass punching injuries in the English literature. Punching glass can cause significant morbidity in a young age group and is therefore a major public health concern. Thorough physical examination, appropriate imaging and operative repair can improve outcomes. Preventative measures such as stricter legislation and safety glass will reduce the burden of these injures on the individual and healthcare system in Australia.


Origin of Magnetically Induced Optical Transmission of Magnetic Nanocomposite Films.
Herein, we present an investigation on the origin of the magnetically induced optical transmission of composite films comprised of polydimethylsiloxane and magnetic nanofillers via experiment and simulation. Structured and unstructured films were used in the study, which were fabricated with and without magnetic fields, respectively. Altered optical transmittance was observed from both types of films when they were subjected to an external magnetic field. Numerical analyses were performed to investigate the effect of the particle movement under magnetic field and the film magnetostriction on the film optical transmittance. The simulation results show that the changed light transmission under magnetic field is mainly due to a variation in the film thickness resulting from the film magnetostriction. The ellipsometric analysis results confirm the altered film thickness in response to the external magnetic field, and the measurements of the film magnetostrictive stresses validate that there is magnetostriction in the magnetic composite films. Additionally, it is indicated that there might be some relationship between the magnetically induced optical transmission and the film magnetostrictive stress under certain conditions.


Lack of gonadal protection by medroxyprogesterone acetate-induced transient medical castration during chemotherapy for testicular cancer.
The serum FSH levels were analysed in 24 testicular cancer patients 3 to 9 years after intensive chemotherapy. Sperm cell counts were performed in 12 patients. In all cases a temporary medical castration had been achieved during intensive chemotherapy by the use of medroxyprogesterone acetate (MPA) (500 mg daily per os). The hormone treatment was initiated on day 1 of the first chemotherapy cycle. Thirteen additional patients did not receive this hormone treatment but were treated by similar chemotherapy. The latter patients served as a control group. There was a tendency towards higher FSH levels in the MPA-treated patients than in the controls. Following treatment, serum testosterone was significantly lower in patients who had received MPA during their intensive chemotherapy than in the controls. There was no difference between the groups with regard to recovery of sperm cell production after chemotherapy. An MPA-induced medical castration during intensive chemotherapy in testicular cancer patients is ineffective in protecting the remaining testis against treatment-induced damage to spermatogenesis, at least if hormone treatment is started simultaneously with chemotherapy.


The UCS family of myosin chaperones.
The canonical UCS (UNC-45/Cro1/She4p) protein, Caenorhabditis elegans UNC-45, was one of the earliest molecules to be shown genetically to be necessary for sarcomere assembly. Genetic analyses of homologues in several fungal species indicate that the conserved UCS domain functionally interacts with conventional type II and unconventional type V myosins. In C. elegans and other invertebrate species, UNC-45 and its orthologues interact with both sarcomeric and non-sarcomeric myosins whereas, in vertebrates, there are two UNC-45 isoforms: a general cell (GC) and a striated muscle (SM) isoform. Although the mechanism of action of UCS proteins is unknown, recent biochemical studies suggest that they may act as molecular chaperones that facilitate the folding and/or maturation of myosin.


Long-standing oral mucosal lesions in solid organ-transplanted children-a novel clinical entity.
Acute oral angioedema is well documented in young pediatric liver-transplanted patients. This is a report of an identified novel entity of long-standing oral mucosal lesions (OML) in children who had undergone solid organ transplantation. In conjunction with routine medical follow-ups, all solid organ-transplanted children were examined annually for OML. Eight children developed a novel entity of long-standing OML after solid organ transplantation. Seven of the eight children had undergone liver transplantation whereas one child was kidney transplanted. The children received tacrolimus immunosuppression after transplantation. All recipients presented with multiple spherical nodules on the dorsum of the tongue, which later on displayed a fissured appearance. Most patients also presented with mucosal tags or ridges and swollen lips similar to those found in patients with orofacial granulomatosis. In addition, most patients had a clinical history of immediate-onset food-induced allergic reactions, including transient angioedema, after transplantation, but this clinical manifestation appeared separately from the long-standing lesions. A novel entity of long-standing OML that share some features with orofacial granulomatosis has been identified in children after solid organ transplantation.


[Effect evaluation of three ELISA kits in detection of fasciolasis].
To evaluate the effect of 3 ELISA kits on detection of human fasciolasis. Twenty-six serum samples from patients with fasciolasis, 180 serum samples from patients with other parasitic diseases as well as 26 serum samples from healthy people were detected by ELISA kits which using soluble antigen of Fasciola gigantica, Fasciola hepatica (Fg-ELISA and Fh-ELISA) as well as IgG antigen ELISA detection kits made by DRG company in Germany. The effects of the 3 kits were evaluated. The sensitivities of Fg-ELISA, Fh-ELISA, and DRG-ELISA were 100.0%, 80.8% (95% CI: 65.7%-95.9%) and 100.0%, respectively; the specificities of the three were 87.9% (95% CI: 83.5%-92.4%), 85.0%(95% CI: 80.1%-89.9%) and 83.5% (95% CI: 78.4%-88.6%), respectively, and Youden indexes of them were 0.88, 0.66 and 0.84, respectively. The detection rate of Fg-ELISA (100%) was significantly higher than that of Fh-ELISA (80.8%) (P < 0.05). The A absolute value (A/CO) of Fg-ELISA was 1.70, which was also significantly higher than the value of Fh-ELISA (1.18) (P < 0.000 1). Fg-ELISA has a good detection effect and low cost, and is more suitable than Fh-ELISA and DRG-ELISA for clinical sample tests as well as massive screening in fasciolasis endemic areas in southwest China.


Photodegradation of penoxsulam.
This study was carried out to characterize the photodegradation of penoxsulam and to evaluate the significance of photolysis for its fate and dissipation. Degradation studies of (14)C-labeled isotopes of penoxsulam in a "merry-go-round" reactor suggest that aqueous photodegradation proceeds via three possible pathways: cleavage of the sulfonamide bridge, stepwise degradation of the triazolopyrimidine system and its substituents, and photooxidation of the sulfonyl group. Seven major photoproducts were found, and six were identified. Two of the identified photodegradation products seem to be either rapidly biodegraded when formed or not formed in significant amounts in environmental conditions.


Targeting CD73 in the tumor microenvironment with MEDI9447.
MEDI9447 is a human monoclonal antibody that is specific for the ectoenzyme CD73 and currently undergoing Phase I clinical trials. Here we show that MEDI9447 is a potent inhibitor of CD73 ectonucleotidase activity, with wide ranging immune regulatory consequences. MEDI9447 results in relief from adenosine monophosphate (AMP)-mediated lymphocyte suppression in vitro and inhibition of mouse syngeneic tumor growth in vivo. In contrast with other cancer immunotherapy agents such as checkpoint inhibitors or T-cell agonists, MEDI9447 drives changes in both myeloid and lymphoid infiltrating leukocyte populations within the tumor microenvironment of mouse models. Changes include significant alterations in a number of tumor micro-environmental subpopulations including increases in CD8(+) effector cells and activated macrophages. Furthermore, these changes correlate directly with responder and non-responder subpopulations within animal studies using syngeneic tumors. Combination data showing additive activity between MEDI9447 and anti-PD-1 antibodies using human cells in vitro and mouse tumor models further demonstrate the potential value of relieving adenosine-mediated immunosuppression. Based on these data, a Phase I study to test the safety, tolerability, and clinical activity of MEDI9447 in cancer patients was initiated (NCT02503774).


Lensless digital holography with diffuse illumination through a pseudo-random phase mask.
Microscopic imaging with a setup consisting of a pseudo-random phase mask, and an open CMOS camera, without an imaging objective, is demonstrated. The pseudo random phase mask acts as a diffuser for an incoming laser beam, scattering a speckle pattern to a CMOS chip, which is recorded once as a reference. A sample which is afterwards inserted somewhere in the optical beam path changes the speckle pattern. A single (non-iterative) image processing step, comparing the modified speckle pattern with the previously recorded one, generates a sharp image of the sample. After a first calibration the method works in real-time and allows quantitative imaging of complex (amplitude and phase) samples in an extended three-dimensional volume. Since no lenses are used, the method is free from lens abberations. Compared to standard inline holography the diffuse sample illumination improves the axial sectioning capability by increasing the effective numerical aperture in the illumination path, and it suppresses the undesired so-called twin images. For demonstration, a high resolution spatial light modulator (SLM) is programmed to act as the pseudo-random phase mask. We show experimental results, imaging microscopic biological samples, e.g. insects, within an extended volume at a distance of 15 cm with a transverse and longitudinal resolution of about 60 μm and 400 μm, respectively.


Effects of accentual fall on phrase-final vowel duration in Japanese.
This study explores the effect of accentual fall on phrase-final vowel duration in read declarative sentences of Standard Japanese. The results show that an intonational phrase-final vowel is significantly shorter when the final phrase has an accentual pitch fall than when it does not. Previous studies have reported a vowel-shortening effect for the final position of Japanese declarative sentences; the new finding reported in this paper is that this shortening effect is enhanced by the pitch fall of an accent in the sentence-final phrase.


Prediction of Bioequivalence and Food Effect Using Flux- and Solubility-Based Methods.
In this work, two different approaches have been developed to predict the food effect and the bioequivalence of marketed itraconazole (ITRA) formulations. Kinetic solubility and simultaneous dissolution-permeation tests of three (ITRA) formulations (Sporanox capsules and solution and SUBA-ITRA capsules) were carried out in simulated fasted and fed states. Fraction of dose absorbed ratios estimating food effect and bioequivalence were calculated based on these results and were compared to the in vivo study results published by Medicines Agencies. The comparison demonstrated that kinetic solubility and flux values could be used as input parameters for biopharmaceutics modeling and simulations to estimate food effect and bioequivalence. Both prediction methods were able to determine a slightly negative food effect in the case of the Sporanox solution and also a pronounced positive food effect for the Sporanox capsule. Superior bioavailability was predicted when the Sporanox solution was compared to the Sporanox capsule (in agreement with in vivo data).


No transplacental passage of standard heparin or an enzymatically depolymerized low molecular weight heparin.
In 21 women who had an abortion by hysterotomy between the 15th and 23rd week of pregnancy, the possibility that unfragmented heparin or low molecular weight heparin (LMWH) passed the placental barrier to the foetus was studied. Laboratory analyses included amidolytic assays of factor Xa inhibitory activity (XaI), antithrombin III (ATIII) and a direct measurement of heparin-like substances in plasma with a competitive binding assay. The ATIII concentration in foetal plasma was about 20% of that in normal human plasma and varied considerably between individuals (2-27%). The XaI activity did not differ between the two treated groups, but the mean XaI activity of the combined groups differed from zero (P less than 0.05). If the XaI activity was corrected for the ATIII concentration, the heparin activities no longer differed significantly from zero. As the concentration of heparin-like substances were above the detection limit (0.35 microgram/ml) in 6/16 analysable samples of foetal plasma, a further 15 women who had not received any heparin were included as controls. In 12/14 analysable foetal plasmas heparin-like substances in concentrations above 0.35 micrograms/ml could be detected. Determination of heparin activity in foetal plasma is thus difficult due to the influence of endogenous ATIII on heparin assays. In conclusion, this study did not demonstrate any evidence for the passage of heparin or LMWH across the placental barrier. No differences were detected whether unfragmented heparin or LMWH had been given to the mothers. Our results also indicate the presence of an endogenous glycosaminoglycan in foetal plasma.


[Case report on a nasal glioma: review of the literature].
A nasal glioma was discovered during routine examination of the nasal cavity patency of a newborn. An excision of the lesion was done by an intranasal approach under general anaesthesia. The intranasal endoscopic approach is strongly recommended for the removal of intranasal gliomas. Angled (30 or 70 degrees) endoscopy allows visualisation of the cribriform plate which helps to rule out an intracranial extension.


[Reintroduction of state activities. Problems of the health sector seen from a renewal's perspective].
Medical knowledge is increasing and calls for a flexible public health service. The counties' responsibility for the public health service makes this difficult. A National Hospital Council would ensure that the decentralized public health services makes full use of the country's total resources, without the transfer of money between different administrative levels at additional cost to the patient during serious illness. The article discusses management and administration of hospitals. The DRG-System is compared with the system of payment for patients' stay in hospital. The previous nationally appointed district doctor arrangement is discussed in relation to the present local community doctor arrangement.


ZPG goals.
1. Zero Population Growth (ZPG) believes that the present population of the U.S. exceeds the optimum level for the continued well-being of its citizens. ZPG therefore advocates the achievement, by voluntary means, of an end to U.S. population growth by 1990, and a reduction in U.S. population size thereafter. Among the conditions necessary to achieve this goal, ZPG stresses: freedom of access for every person to all means of voluntary birth control; a major research effort to develop safer and more effective means of birth control; complete equality of opportunity for all women and men; and removal of all legal and societal pronatalist pressures. The population size should stabilize at a substantially reduced level which will maximize diversity, freedom of choice, and the quality of life for all. 2. ZPG believes that land is a resource too important to human survival to be subjected to misuse. Ecological land use planning is essential in determining the appropriate patterns of distribution of people on the land, and of migration between states and regions. Thoughtful land use planning at all levels of government is necessary to assure the long-range stewardship of the land and well-being of mankind. 3. ZPG believes that human activities are causing the rapid depletion of the world's available stock of mineral resources. Simultaneously those activities are resulting in increased pollution of land, air, and water resources. ZPG therefore recommends 1) reduction in the rate of growth and eventual stabilization of U.S. consumption of nonrenewable resources; and 2) rapid stabilization of total national energy consumption at least until environmentally sound sources are developed. ZPG recognizes that none of its goals can be justified unless concurrently with their achievement adequate levels of income, health care, and educational opportunity are assured to all persons.


[Report of a case of subcutaneous endometriosis].
In this paper, the authors report a case of subcutaneous endometriosis and analyze the main etiopathogenetic theories to give a reason for this anomalous localization.


Intake of dairy products and bone ultrasound measurement in late adolescents: a nationwide cross-sectional study in Japan.
There is little evidence regarding the effects of dairy product intake on bone mineralization among late adolescents, especially in Asians. The aim of this study was to determine the association between dairy product intake and bone strength as measured by quantitative ultrasound (QUS) in a large Japanese population. Subjects were 38,719 high school students (14,996 males and 23,723 females) across 33 prefectures in Japan. Bone stiffness of the calcaneus was measured by QUS densitometry (AOS-100, Aloka). Subjects were given a self-administered questionnaire, which included questions on gender, age, height, weight, consumption of dairy products, and levels of physical activity. Intake of milk and yogurt were classified as none, 1-99, 100-199, 200-399, and>or=400 ml/day. The proportion of subjects who consumed milk 400 ml/day or more was 21% in males and 7.3% in females, while 24% of males and 41.1% of females did not consume milk. After adjusting for physical activity, weight, gender, age, and area of residence, milk intake (R2=2.8%, p<0.0001) and yogurt intake (R2=0.1%, p<0.0001) were independently associated with the QUS measurement. Similar associations were found in males and females when a gender-stratified analysis was conducted. We found a positive dose-effect relationship between milk intake and bone strength in late adolescents, to whom we recommend milk intake of 400 ml/day or more to obtain greater bone mass.


Micropulse Cyclophotocoagulation: A Multicenter Study of Efficacy, Safety, and Factors Associated With Increased Risk of Complications.
PRéCIS:: Micropulse cyclophotocoagulation (MPCP) lowered intraocular pressure (IOP) in the short-term but nearly half required additional intervention. Mydriasis was the most common complication (11%); 15% lost ≥3 Snellen lines of acuity; 11% had persistent complications at last follow-up. The purpose of this study was to evaluate the efficacy and complications of MPCP in a large series of patients with all stages of glaucoma. Multicenter, retrospective chart review of patients from 3 clinical sites. One hundred sixty-seven eyes of 143 patients. MPCP was performed with 2000 mW energy, 31.3% duty cycle and 2 to 4 180-degree applications of 80 seconds duration each per treatment. The procedure was considered a failure if any of the following occurred: additional IOP lowering intervention, <20% IOP reduction from baseline at the last follow-up (with or without medication), or severe complications. Mean age was 71 years, 53% were female, and 53% were Asian. 60% of eyes had POAG, 63% were pseudophakic, 38% had prior glaucoma surgery, and 51% had Snellen visual acuity (VA) of 20/40 or better. Mean follow-up time was 11.9±7.8 months. Mean IOP was 21.9±8.4 mm Hg before intervention, and 17.4±7.2 mm Hg at last follow-up (P<0.0001). There was no change in mean logMAR VA (P=0.0565) but 15% lost ≥3 Snellen lines of VA. The success rate was 36.5% (61/167 eyes) at last follow-up. The probability of survival by Kaplan-Meier analysis was 82%, 71%, and 57% at 3, 6, and 12 months after the procedure, respectively. The reasons for failure were additional intervention in 47%, inadequate IOP reduction in 14%, and severe complication in 1.8%. In a multivariable Cox proportional hazard model, female sex was associated with a 56% decrease in failure rate compared with males (P<0.0001), while a unit increase in baseline IOP corresponded with a 5.7% increase in failure rate (P<0.0001). If repeat MPCP was allowed then success rate increased to 58%. There were no complications in 73% (122/167) but 11% (18/167) had persistent complications at the last follow-up and half of these 18 eyes had decrease in VA of 1 to 6 Snellen lines. Asian race (odds ratio 13.5, P=0.0131) and phakic status (odds ratio 3.1, P=0.0386) were associated with higher odds of developing mydriasis, which was the most common complication. MPCP lowered IOP in the short-term but nearly half required additional IOP lowering intervention. Potential complications should be discussed in detail especially when the procedure is being considered for those with good VA and early stage disease.


HIV testing uptake and acceptability in an inner city polyclinic.
Up to 33% of HIV-infected adults in the UK remain undiagnosed and efforts to increase HIV testing are underway. HIV testing was conducted amongst individuals presenting to a polyclinic at a central London hospital using a point of care test. Demographic and HIV risk data was collected along with a patient feedback questionnaire exploring acceptability of the HIV testing experience. Seventy-one out of 93 (76%) individuals accepted HIV testing. Of those accepting HIV testing, 53/71 (75%) had never previously tested for HIV despite, 45/53 (85%) of these being registered with a GP. Twenty-seven out of 71 (38%) of individuals testing had at least one risk factor associated with HIV acquisition, and of these 17/27 (63%) had never previously tested for HIV infection. There were no new HIV positive diagnoses during the period of testing. Respondents indicated a high level of satisfaction with the service and more than 85% found the service to be helpful, educational and convenient. This small proof of concept pilot showed uptake of HIV testing in this setting to be high and acceptable to patients.


Follow-up protocol for oncological patients at risk of developing multiple primary neoplasms.
Multiple primary neoplasms (MPN) have a growing impact in the outcome of oncological patients given the rising incidence of these entities in daily practice. The early diagnosis of secondary tumors could translate into better survival of patients with MPN. The final objective of this study was the elaboration of a follow-up protocol for oncological patients at risk of developing multiple primary neoplasms. Patients with MPN diagnosed and treated in the Oncology Institute "Prof.Dr.Ion Chiricuta" Cluj-Napoca (OICN) between 2008-2012 were included in this nonrandomized, retrospective study and the clinicopathological characteristics of these patients and the prognostic factors possibly involved in the occurrence of MPN were analyzed. 278 patients with MPN were included in this study. The median age at diagnosis was 60 years. The median interval between the diagnosis of the primary and secondary neoplasm was 30.98 months. Smoking and alcohol consumption were the most frequent environmental factors observed in patients with MPN. Patients diagnosed with breast cancers, head and neck cancers, colorectal cancer, prostate cancer, ovarian cancer or uterine body cancer were the patients with the highest risk of developing MPN. This first follow-up protocol for oncological patients at risk of developing multiple primary neoplasms could be implemented in daily practice with further validation of the protocol.


Preliminary Characterization of Dog Derived Pathogenic Strains of Leptospira interrogans Serovar Australis in Nanchang of Jiangxi Province, China.
Leptospirosis is a global zoonotic disease caused by pathogenic Leptospira, and those infected animals will show a variety of clinical symptoms and even death. The discovery of endemic strains is crucial to produce effective vaccines. In this study, we report that a strain of Leptospira, isolated from a dog, is pathogenic. Using MLST analysis, the serovar of isolated Leptospira was identified and found it belongs to Leptospira interrogation Serovar Australis. Then, the virulence of this strain was researched by using hamsters. After infection, all the hamsters died within 4-5 days. Typical pathological changes were found in the liver, kidney, and lung of hamsters. These results all indicated that the isolated Leptospira was pathogenic. Thus, this study facilitates to identifying local Leptospira strains and develop a more targeted canine Leptospira vaccine.


Chocolate intake and incidence of heart failure: a population-based prospective study of middle-aged and elderly women.
Randomized clinical trials have shown that chocolate intake reduces systolic and diastolic blood pressure, and observational studies have found an inverse association between chocolate intake and cardiovascular disease. The aim of this study was to investigate the association between chocolate intake and incidence of heart failure (HF). We conducted a prospective cohort study of 31,823 women aged 48 to 83 years without baseline diabetes or a history of HF or myocardial infarction who were participants in the Swedish Mammography Cohort. In addition to answering health and lifestyle questions, participants completed a food-frequency questionnaire. Women were followed from January 1, 1998, through December 31, 2006, for HF hospitalization or death through the Swedish inpatient and cause-of-death registers. Over 9 years of follow-up, 419 women were hospitalized for incident HF (n=379) or died of HF (n=40). Compared with no regular chocolate intake, the multivariable-adjusted rate ratio of HF was 0.74 (95% CI, 0.58 to 0.95) for women consuming 1 to 3 servings of chocolate per month, 0.68 (95% CI, 0.50 to 0.93) for those consuming 1 to 2 servings per week, 1.09 (95% CI, 0.74 to 1.62) for those consuming 3 to 6 servings per week, and 1.23 (95% CI, 0.73 to 2.08) for those consuming ≥1 servings per day (P=0.0005 for quadratic trend). In this population, moderate habitual chocolate intake was associated with a lower rate of HF hospitalization or death, but the protective association was not observed with intake of ≥1 servings per day.


A Multiple Primary Malignancy Patient With FANCA Gene Mutation: A Case Report and Literature Review.
Background: Multiple primary malignancies (MPMs) refer to two or more primary malignant tumors in the same individual, the prevalence of which ranges from 0. 734 to 11.7%. The risk factors for MPMs vary and include both genetic and environmental causes. FANCA gene mutation might be a predisposition to the development of a second primary cancer. Here, we report a case in which a patient with a FANCA mutation developed thyroid papillary carcinoma and gastric adenocarcinoma. Case Presentation: A 48-year-old woman was diagnosed with thyroid cancer underwent resection in 2006. In 2008, the patient developed gastric adenocarcinoma and underwent radical gastrectomy. Gastric cancer was completely remitted after radiochemotherapy, but metastasis developed, and she received immunotherapy. The patient died on October 27, 2019. Peripheral blood gene detection showed germline FANCA mutation. Conclusions: Gene detection is of great importance in cancer patients, especially in those with MPMs. FANCA mutation is a predisposition to tumorigenesis that can increase the risk of developing MPMs. Patients with heterozygous FANCA gene mutations have poorer outcomes.


Site-directed serology using synthetic oligopeptides representing the C-terminus of the external glycoproteins of HIV-1, HIV-2, or SIVmac may distinguish subtypes among primate lentiviruses.
In this study the presence of a highly immunogenic domain located at the C-terminus of the external glycoproteins (EGP) of human and simian immunodeficiency viruses (HIV-1, HIV-2, and SIVMAC) is shown using synthetic oligopeptides as antigens in enzyme immunoassays. This epitope is probably located within the last 13 and 15 residues of the EGP of HIV-1 and HIV-2, respectively. The C terminal epitope of the EGP of SIVMAC may involve residues located more upstream. Among the HIV-2/SIV serotype, we observed that the reactivity to the C-terminal epitope of gp120 was dependent of both species and geographical origin of the samples tested. It seems that this gp 120 C-terminal epitope could distinguish subtypes among the HIV-2/SIV serotype. Further studies, using site-directed enzyme immunoassays with synthetic peptides representing the C-terminus of the EGP derived from a wide variety of HIV2/SIV strains must be performed to confirm this observation. These kinds of assays may constitute important tools for use in seroepidemiological studies and broaden our understanding of the distribution and phylogenetic relationship of primate lentiviruses.


Young Children Intuitively Divide Before They Recognize the Division Symbol.
Children bring intuitive arithmetic knowledge to the classroom before formal instruction in mathematics begins. For example, children can use their number sense to add, subtract, compare ratios, and even perform scaling operations that increase or decrease a set of dots by a factor of 2 or 4. However, it is currently unknown whether children can engage in a true division operation before formal mathematical instruction. Here we examined the ability of 6- to 9-year-old children and college students to perform symbolic and non-symbolic approximate division. Subjects were presented with non-symbolic (dot array) or symbolic (Arabic numeral) dividends ranging from 32 to 185, and non-symbolic divisors ranging from 2 to 8. Subjects compared their imagined quotient to a visible target quantity. Both children (Experiment 1 N = 89, Experiment 2 N = 42) and adults (Experiment 3 N = 87) were successful at the approximate division tasks in both dots and numeral formats. This was true even among the subset of children that could not recognize the division symbol or solve simple division equations, suggesting intuitive division ability precedes formal division instruction. For both children and adults, the ability to divide non-symbolically mediated the relation between Approximate Number System (ANS) acuity and symbolic math performance, suggesting that the ability to calculate non-symbolically may be a mechanism of the relation between ANS acuity and symbolic math. Our findings highlight the intuitive arithmetic abilities children possess before formal math instruction.


Chain-length dependence of diblock copolymer micellization kinetics studied by stopped-flow pH-jump.
A series of well-defined poly(ethylene oxide)- b-poly(2-(diethylamino)ethyl methacrylate) (PEO- b-PDEA) diblock copolymers containing PEO block of identical chain length and PDEA block with varying degrees of polymerization (DP, in the range of 32-154) were prepared via atom transfer radical polymerization (ATRP) employing a PEO-based macroinitiator (DP = 113). Upon a pH-jump from 3 to 12 under highly efficient stopped-flow mixing conditions, PEO- b-PDEA copolymers spontaneously form spherical micelles of increasing sizes and aggregation numbers ( N agg) with increasing PDEA chain lengths. Stopped-flow light scattering technique was used to probe the pH-induced micellization kinetics of PEO- b-PDEA copolymers, aiming to elucidate the PDEA chain-length effects on the unimer-to-micelle transition process. Upon a stopped-flow pH-jump from 3 to 12, the obtained dynamic traces can be well-fitted with double exponential functions. The calculated fast and slow characteristic relaxation times (tau 1 and tau 2) can be ascribed to the formation of quasi-equilibrium micelles (fast process) and subsequent relaxation into final equilibrium micelles (slow process), respectively. For PEO 113- b-PDEA 32 and PEO 113- b-PDEA 61, tau 2 is almost independent of polymer concentrations, suggesting that the relaxation from quasi-equilibrium micelles into final equilibrium micelles mainly proceeds via insertion/expulsion of unimer chains. Upon increasing the DP of pH-responsive PDEA block to 89, 117, and 154, the obtained slow relaxation time, tau 2, tends to decrease with increasing polymer concentrations, suggesting that the slow process is dominated by the micelle fusion/fission mechanism. The apparent activation energy ( E a) associated with tau 2 has also been determined from temperature-dependent micellization kinetics for five PEO- b-PDEA copolymers. It was found that during micellization, copolymers with longer PDEA blocks exhibit much lower E a compared to those with shorter blocks. Thus, we observed experimentally for the first time that increasing the hydrophobic block length in double hydrophilic block copolymers (DHBCs) can transform the mechanism of the slow process from unimer insertion/expulsion to micelle fusion/fission.


Small molecule inhibitors of methionine aminopeptidase type 2 (MetAP-2).
The protein processing enzyme, methionine aminopeptidase-2 (MetAP-2), has been identified as a molecular target of fumagillin and its derivative, TNP-470, compounds known to inhibit endothelial cell proliferation and angiogenesis. A high-throughput screening program was undertaken to identify selective, reversible inhibitors of MetAP-2 in an attempt to discover structurally novel anti-angiogenic agents for potential therapeutic use in oncology. Approximately 90 small-molecule, reversible, selective inhibitors of rhMetAP-2 were identified. The most potent of these compounds contained a singly-substituted triazole moiety which exhibited an IC50 of 8 nM (95% confidence limits 5 to 13 nM) and was highly selective for MetAP-2 over MetAP-1 (approximately 60-fold difference in IC50 values). Unlike fumagillin, these MetAP-2 inhibitors failed to significantly inhibit growth factor-stimulated endothelial cell (HUVEC) proliferation or to suppress angiogenesis in the in vitro aortic ring explant model of microvessel outgrowth. The MetAP-2-inhibitory activity of these compounds was dependent on the divalent cation used as the metalloenzyme activating cofactor for MetAP-2. These inhibitors were identified using cobalt(II)-activated recombinant human MetAP-2 for screening compound libraries. When manganese (Mn2+) was substituted for cobalt following EDTA treatment and extensive dialysis of the MetAP-2 protein, these inhibitors were significantly less potent (40-fold increase in IC50) as inhibitors of MetAP-2. These results support the recent hypothesis that cobalt may not be the relevant divalent metal ion cofactor for MetAP-2 in cells and may explain the observed absence of cell-based activity using potent triazole inhibitors of cobalt-activated MetAP-2.


Nerve growth factor induces sensitization of nociceptors without evidence for increased intraepidermal nerve fiber density.
Nerve growth factor (NGF) is involved in the long-term sensitization of nociceptive processing linked to chronic pain. Functional and structural ("sprouting") changes can contribute. Thus, humans report long-lasting hyperalgesia to mechanical and electrical stimulation after intradermal NGF injection and NGF-induced sprouting has been reported to underlie cancer bone pain and visceral pain. Using a human-like animal model we investigated the relationship between the structure and function of unmyelinated porcine nociceptors 3 weeks after intradermal NGF treatment. Axonal and sensory characteristics were studied by in vivo single-fiber electrophysiology and immunohistochemistry. C fibers recorded extracellularly were classified based on mechanical response and activity-dependent slowing (ADS) of conduction velocity. Intraepidermal nerve fiber (IENF) densities were assessed by immunohistochemistry in pigs and in human volunteers using the same NGF model. NGF increased conduction velocity and reduced ADS and propagation failure in mechano-insensitive nociceptors. The proportion of mechano-sensitive C nociceptors within NGF-treated skin areas increased from 45.1% (control) to 71% and their median mechanical thresholds decreased from 40 to 20 mN. After NGF application, the mechanical receptive fields of nociceptors increased from 25 to 43 mm(2). At the structural level, however, IENF density was not increased by NGF. In conclusion, intradermal NGF induces long-lasting axonal and mechanical sensitization in porcine C nociceptors that corresponds to hyperalgesia observed in humans. Sensitization is not accompanied by increased IENF density, suggesting that NGF-induced hyperalgesia might not depend on changes in nerve fiber density but could be linked to the recruitment of previously silent nociceptors.