Prospective study of the need for long-term antisecretory therapy in patients with Zollinger-Ellison syndrome following successful curative gastrinoma resection.
A long-term cure is now possible in more than 30% of selected patients with Zollinger-Ellison syndrome who undergo gastrinoma resection. The need, however, for continued gastric acid antisecretory therapy in these patients remains controversial. The current study was designed to determine whether post-operative antisecretory therapy is needed in patients who have undergone successful gastrinoma resection and, if so, to attempt to define criteria with which to identify patients who require therapy. Twenty-eight consecutive patients who had previously undergone curative gastrinoma resection were prospectively studied. When antisecretory therapy was discontinued, 43% (12/28) of these patients developed gastro-oesophageal reflux, diarrhoea, acid-peptic symptoms or endoscopic evidence of acid-peptic disease within 2 weeks and were deemed to have failed a trial of antisecretory drug withdrawal. The remaining 57% (16/28) of patients who successfully discontinued antisecretory therapy were followed for a mean time of 31 months after withdrawal of therapy. Analysis of acid output studies pre-operatively, as well as at the time of drug withdrawal, demonstrated that patients who were unable to discontinue antisecretory therapy exhibited higher pre-operative maximal acid output values and higher basal acid output values at the time of attempted drug withdrawal than patients who were able to discontinue therapy. Despite these findings, there was significant overlap in acid output values between groups so that it was not possible to define specific acid output criteria for successful drug withdrawal. Pre-operative clinical characteristics, such as the presence or absence of gastro-esophageal reflux or acid-peptic disease, or post-operative laboratory values, such as the fasting serum gastrin level, did not correlate with the ability to discontinue antisecretory therapy. We conclude that following successful curative gastrinoma resection, 40% of patients still require antisecretory therapy and that both symptom evaluation as well as upper endoscopy should be used to guide attempted drug withdrawal. Although patients who are not able to discontinue therapy have significantly higher acid output measurements than those who are able to discontinue therapy, neither acid output criteria nor any other laboratory or clinical characteristics are able to predict the need for continued antisecretory therapy in these patients.


Granulocyte macrophage colony stimulating factor produced in lesioned peripheral nerves induces the up-regulation of cell surface expression of MAC-2 by macrophages and Schwann cells.
Peripheral nerve injury is followed by Wallerian degeneration which is characterized by cellular and molecular events that turn the degenerating nerve into a tissue that supports nerve regeneration. One of these is the removal, by phagocytosis, of myelin that contains molecules which inhibit regeneration. We have recently documented that the scavenger macrophage and Schwann cells express the galactose-specific lectin MAC-2 which is significant to myelin phagocytosis. In the present study we provide evidence for a mechanism leading to the augmented expression of cell surface MAC-2. Nerve lesion causes noneuronal cells, primarily fibroblasts, to produce the cytokine granulocyte macrophage-colony stimulating factor (GM-CSF). In turn, GM-CSF induces Schwann cells and macrophages to up-regulate surface expression of MAC-2. The proposed mechanism is based on the following novel observations. GM-CSF mRNA was detected by PCR in in vitro and in vivo degenerating nerves, but not in intact nerves. The GM-CSF molecule was detected by ELISA in medium conditioned by in vitro and in vivo degenerating peripheral nerves as of the 4th h after injury. GM-CSF activity was demonstrated by two independent bioassays, and repressed by activity blocking antibodies. Significant levels of GM-CSF were produced by nerve derived fibroblasts, but neither by Schwann cells nor by nerve derived macrophages. Mouse rGM-CSF enhanced MAC-2 production in nerve explants, and up-regulated cell surface expression of MAC-2 by Schwann cells and macrophages. Interleukin-1 beta up-regulated GM-CSF production thus suggesting that injury induced GM-CSF production may be mediated by interleukin-1 beta. Our findings highlight the fact that fibroblasts, by producing GM-CSF and thereby affecting macrophage and Schwann function, play a significant role in the cascade of molecular events and cellular interactions of Wallerian degeneration.


The birth of clinical body plethysmography: it was a good week.
Nearly fifty years ago, Arthur B. DuBois, Julius H. Comroe Jr., and their colleagues published two papers on the use of body plethysmography to measure lung volume and airway resistance. These two articles in the JCI are almost the most-cited doublet in the Journal's entire archive. Remarkably, the methods described then are still in use today in clinical pulmonary function laboratories. Though body plethysmography had been used before, there were serious technical problems; it was extraordinary that DuBois managed to solve most of these in one week. Times have changed and molecular medicine now dominates the JCI, but these articles remind us that biomedical research goes beyond the molecular.


Optimisation of TP53 reporters by systematic dissection of synthetic TP53 response elements.
TP53 is a transcription factor that controls multiple cellular processes, including cell cycle arrest, DNA repair and apoptosis. The relation between TP53 binding site architecture and transcriptional output is still not fully understood. Here, we systematically examined in three different cell lines the effects of binding site affinity and copy number on TP53-dependent transcriptional output, and also probed the impact of spacer length and sequence between adjacent binding sites, and of core promoter identity. Paradoxically, we found that high-affinity TP53 binding sites are less potent than medium-affinity sites. TP53 achieves supra-additive transcriptional activation through optimally spaced adjacent binding sites, suggesting a cooperative mechanism. Optimally spaced adjacent binding sites have a ∼10-bp periodicity, suggesting a role for spatial orientation along the DNA double helix. We leveraged these insights to construct a log-linear model that explains activity from sequence features, and to identify new highly active and sensitive TP53 reporters.


Cellular basis for age-related changes in fracture repair.
The goal of this work was to define cellular and molecular changes that occur during fracture healing as animals age. We compared the molecular, cellular, and histological progression of skeletal repair in juvenile (4 weeks old), middle-aged (6 months old), and elderly (18 months old) mice at 3, 5, 7, 10, 14, 21, 28, and 35 days post-fracture, using a non-stabilized tibia fracture model. Our histological and molecular analyses demonstrated that there was a sharp decline in fracture healing potential between juvenile and middle-aged animals, while a more subtle decrease in healing potential was apparent between middle-aged and elderly mice. By three days after fracture, chondrocytes expressing Collagen type II, and osteoblasts expressing osteocalcin, were present in calluses of juvenile, but not middle-aged or elderly, mice. At day 5 immature chondrocytes and osteoblasts were observed in calluses of middle-aged and elderly mice. While at this time, chondrocytes in juvenile mice were expressing Collagen type X (ColX) indicating that chondrocyte maturation was already underway. At day 7, chondrocytes expressing ColX were abundant in middle-aged mice while a small domain of ColX-positive chondrocytes were observed in elderly mice. Further, in juvenile and middle-aged mice, but not elderly mice, vascular invasion of the cartilage was underway by day 7. Juvenile mice had replaced nearly all of the cartilage by day 14, while cartilage was still present in the callus of middle-aged mice at day 21 and in elderly mice at day 28. In addition to these delays, histomorphometry revealed that elderly and middle-aged mice formed less bone than juveniles (p<0.001), while cartilage production was unaffected (p>0.22). Collectively, these data suggest that enhancing cell differentiation, improving osteoblast function, and accelerating endochondral ossification may significantly benefit the elderly.


Molecular characterization of the SUMO-1 modification of RanGAP1 and its role in nuclear envelope association.
The mammalian guanosine triphosphate (GTP)ase-activating protein RanGAP1 is the first example of a protein covalently linked to the ubiquitin-related protein SUMO-1. Here we used peptide mapping, mass spectroscopy analysis, and mutagenesis to identify the nature of the link between RanGAP1 and SUMO-1. SUMO-1 is linked to RanGAP1 via glycine 97, indicating that the last 4 amino acids of this 101- amino acid protein are proteolytically removed before its attachment to RanGAP1. Recombinant SUMO-1 lacking the last four amino acids is efficiently used for modification of RanGAP1 in vitro and of multiple unknown proteins in vivo. In contrast to most ubiquitinated proteins, only a single lysine residue (K526) in RanGAP1 can serve as the acceptor site for modification by SUMO-1. Modification of RanGAP1 with SUMO-1 leads to association of RanGAP1 with the nuclear envelope (NE), where it was previously shown to be required for nuclear protein import. Sufficient information for modification and targeting resides in a 25-kD domain of RanGAP1. RanGAP1-SUMO-1 remains stably associated with the NE during many cycles of in vitro import. This indicates that removal of RanGAP1 from the NE is not a required element of nuclear protein import and suggests that the reversible modification of RanGAP1 may have a regulatory role.


Patient reported outcomes and neuropsychological testing in patients with chronic non-cancer pain in long-term opioid therapy: a pilot study.
Background and aims Opioid consumption has increased dramatically in patients with chronic non-cancer pain (CNCP), but long-term consequences are still unclear. The aim of this study is to investigate the effects of long-term opioid treatment on pain, cognition, mood, sleep and quality of life in CNCP patients. Methods In this cross-sectional pilot study, two groups of patients with CNCP treated in a multidisciplinary pain center were selected: (1) opioid group: ≥30 mg morphine equivalent/day for >4 weeks, and (2) control group: no opioid consumption for >4 weeks. Socio-demographic data, alcohol consumption, smoking habits and body mass index (BMI) were registered and pain (brief pain inventory), mood (Hospital Anxiety and Depression Scale), sleep (Pittsburgh Sleep Quality Index) and quality of life (RAND 36-Item Health Survey) were assessed. Continuous Reaction Time and the Digit Span Test were used to evaluate cognitive function. Data was analyzed with a Fisher's exact test and Wilcoxon two-sample test. Results Forty-two patients with CNCP were included (21 in each group). No differences regarding socio-demographics, smoking/alcohol habits and duration, type, or intensity of pain were found. More patients in the opioid group had significantly higher BMI (62% above BMI 25 vs. 33.3%, p = 0.042). Consequently, the subsequent data analyses were controlled for BMI. The two groups did not differ in pain, cognition, anxiety, depression, sleep or quality of life but both showed lower values than the normal standards. Further, the opioid group presented a tendency to lower ratings regarding pain and social function and performed below the normal cut off in the continuous reaction time. Conclusions No significant differences between the two groups were found regarding any of the above-mentioned variables. Interestingly, the patients assessed, regardless of taking opioids or not, could be classified with moderate pain intensity, anxiety and low quality of sleep and life compared to norm standards. Implications The findings of this pilot study suggested that long-term opioid treatment may influence pain and quality of life among CNCP patients. A larger cohort is needed to verify these findings.


Regulation of c-myc stability by selective stress conditions and by MEKK1 requires aa 127-189 of c-myc.
C-myc availability is central for its ability to serve as a regulator of cell growth and death. Here we study the regulation of c-myc protein stability and identify domains of c-myc that are important for its stabilization in response to stress kinases activated following selective stress conditions. UV-irradiation elicited an increase in c-myc protein levels, which could be attenuated by inhibitors of stress kinases but also by actinomycin D-inhibitor of transcription. Inhibition of protein synthesis results in a noticeable decrease in c-myc levels, further pointing to the short half-life of the protein. However, in combination with tumor necrosis factor-alpha (TNF-alpha), cycloheximide efficiently increases steady-state levels of c-myc, suggesting that selective stress conditions are required to increase c-myc protein stability. Expression of MEKK1, an upstream regulator of protein kinases that has been implicated in mediating the response to diverse stress conditions, also results in an efficient increase in the half-life of c-myc protein. To map c-myc domains that are responsive to stress kinases, we monitored changes in the level of c-myc deletion mutants following MEKK1 expression. Of the seven c-myc deletion mutants analysed, the domain spanning amino acids 127-189 was found to be required for MEKK1-dependent increase in c-myc stability. In all, the present study identifies a novel domain that is important for the regulation of c-myc stability by stress kinases in response to selective stress conditions.


The use of Trizol reagent (phenol/guanidine isothiocyanate) for producing high quality two-dimensional gel electrophoretograms (2-DE) of dinoflagellates.
Two-dimensional gel electrophoresis (2-DE) is one of the most efficient ways of resolving complex protein mixtures based on the isoelectric point (pI) and molecular mass (M(r)). Although it has been used extensively in proteomic studies on samples from the animal and plant kingdoms, there is limited information on its use on algae, such as dinoflagellates. The preparation of high-quality samples from dinoflagellate cells for 2-DE is difficult due to high endogenous levels of salts, nucleic acids, polysaccharides, phenolic compounds, pigments, and other interfering compounds. Desalting and concentrating steps are usually required for the preparation of dinoflagellate protein sample prior to 2-DE and these steps can be lengthy and complicated. In this study, we report the use of Trizol (a monophasic solution of phenol and guanidine isothiocyanate) for the extraction of proteins from dinoflagellate cells for 2-DE. The method is simple and fast. 2-DE profiles obtained with Trizol treatment are of very high quality in terms of resolution, spot number and spot intensity. This method greatly simplifies protein extraction procedures on dinoflagellate samples for obtaining a high quality and reproductive 2-DE profile. This methodology is generally applicable to algal samples.


Primary congenital aphakia and the rubella syndrome.
Four embryos from women infected by rubella virus early in pregnancy were investigated histologically. In three of the patients the serological tests were positive; in the fourth the diagnosis of rubella was based solely on the clinical picture. Three of the four embryos showed unilateral severe microphthalmia and primary congenital aphakia. In addition to this defect the right eye of one of the embryos showed a central liquefaction of the lens (cataract). Damage to the internal ear in the form of discontinuities in the epithelium of the cochlear duct were also observed (in two of the three embryos; in the fourth both internal ears were absent in the curettage material). In three of the four hearts there were cells in the myocardium with a markedly eosinophilic cytoplasm.


The impact of comorbidities on mortality in patients with non-traumatic major lower extremity amputation.
Major lower limb amputation is generally associated with a high risk of early and late-term mortality. In this study, 30-day, one-year and three-year mortality of non-traumatic major lower extremity amputations and comorbidities affecting the mortality rate were investigated. Patients who underwent a major lower limb amputation secondary to diabetes or peripheral artery disease between the years 2010-2015 were retrospectively evaluated. Additional to patient demographic data and comorbidities, amputation level, survival and mortality time were extracted. Mortality rates after 30 days, one year and three years were analysed. The associations of the survival to different parameters were evaluated with Kaplan-Meier analysis and log rank test, while the impact of the risk factors on mortality was evaluated with the Cox regression test. A total of 193 patients were enrolled in the study. Approximately 60% of patients were aged ≥65 years, and 65.8% were male. Below-knee amputation was performed in 64.8% of patients and above-knee amputation in 35.2% of patients. The mean follow-up of patients was 29.48 months (range: 0-101 months). After non-traumatic major lower extremity amputation, 30-day, one-year and three-year mortality were 16.6%, 38.3% and 60.1%, respectively. On Cox regression analysis, age ≥65 years was the only variable that had significant impact on the 30-day mortality (hazard ratio (HR): 3.4; p=0.012), while age ≥65 years (HR: 2.5, p=0.000), diabetes (HR: 2, p=0.006) and renal failure (HR: 2, p=0.001) were found to have significant impacts on three-year mortality. The findings of this study showed that >50% of patients with non-traumatic major lower limb amputations died within three years. Advanced age, diabetes and renal failure were the risk factors that increased the mortality. The high mortality rates revealed the importance of employing all hard-to-heal wound treatment options before making an amputation decision. Further, prospective studies are needed to determine the effects of primary disease status and timing of amputation on mortality.


Inflammation-induced changes in rabbit CRP and plasma lipoproteins.
Inflammation is accompanied by changes in the plasma concentrations of "acute phase reactants" including the C-reactive proteins of man and other species. Previous results in our laboratory showed that CRP in rabbit acute phase serum may circulate in association with very low density lipoproteins (VLDL), which influence both the apparent m.w. and electrophoretic mobility of CRP. We now show that the ability of VLDL to interact with CRP varies with time during the acute phase response. Before the induction of inflammation, the factor(s) responsible for the beta-mobility of CRP is present at low levels in the VLDL. During the first 24 hr of the acute phase response, the activity can no longer be demonstrated in the VLDL fraction. By 36 to 48 hr after inflammatory stimulation, a significantly increased level of this factor(s) is measurable in VLDL. Furthermore, during the acute phase response, the alpha-lipoproteins decrease, and the beta- and pre-beta lipoproteins increase. The increase in beta- and pre-beta-lipoproteins is due to an accumulation of VLDL isolated at d less than 1.006 g/ml. These changes are accompanied by marked hypertriglyceridemia and a significant increase in phosphocholine-containing phospholipids. A non-CRP apoprotein present in low amounts in VLDL from normal rabbit plasma appears to increase in VLDL as inflammation progresses. This VLDL apoprotein increases in response to multiple acute phase stimuli and may be a newly recognized acute phase reactant in the rabbit.


Solution structural studies and low-resolution model of the Schizosaccharomyces pombe sap1 protein.
Sap1 is a DNA-binding protein involved in controlling the mating type switch in fission yeast Schizosaccharomyces pombe. In the absence of any significant sequence similarity with any structurally known protein, a variety of biophysical techniques has been used to probe the solution low-resolution structure of the sap1 protein. First, sap1 is demonstrated to be an unusually elongated dimer in solution by measuring the translational diffusion coefficient with two independent techniques: dynamic light-scattering and ultracentrifugation. Second, sequence analysis revealed the existence of a long coiled-coil region, which is responsible for dimerization. The length of the predicted coiled-coil matches estimates drawn from the hydrodynamic experimental behaviour of the molecule. In addition, the same measurements done on a shorter construct with a coiled-coil region shortened by roughly one-half confirmed the localization of the long coiled-coil region. A crude T-shape model incorporating all these information was built. Third, small-angle X-ray scattering (SAXS) of the free molecule provided additional evidence for the model. In particular, the P(r) curve strikingly demonstrates the existence of long intramolecular distances. Using a novel 3D reconstruction algorithm, a low resolution 3D model of the protein has been independently constructed that matches the SAXS experimental data. It also fits the translation diffusion coefficients measurements and agrees with the first T-shaped model. This low-resolution model has clearly biologically relevant new functional implications, suggesting that sap1 is a bifunctional protein, with the two active sites being separated by as much as 120 A; a tetrapeptide repeated four times at the C terminus of the molecule is postulated to be of utmost functional importance.


Single intramuscular injection of diclofenac sodium in febrile pediatric patients.
There are few reports on the effectiveness and safety of intramuscular (IM) antipyretic injections in pediatric patients. This study reports the efficacy and adverse effects of a single IM injection of diclofenac sodium in pediatric patients. This was an observational study in which records of febrile pediatric patients presenting to the emergency department were analyzed. Subjects included pediatric patients presenting to the emergency department with a temperature of 38°C or higher. Infants under 12 months of age were excluded. Patients were excluded if they received antipyretics within 4 h prior to presenting to the emergency department. Body temperature was measured at 30-60 min intervals following diclofenac sodium injections. Fever alleviation was defined as the temperature decline to 1°C below the temperature at presentation. Patients who received diclofenac sodium twice or more on different days were observed for side effects such as allergic reaction. Records from the emergency department and outpatient clinics were analyzed. The dose of diclofenac sodium injected was approximately 2 mg/kg. The average time elapsed until antipyresis was 69.1 ± 23.8 min. The average temperature reduction after 1 h was 1.1 ± 0.6°C. The average proportion of temperature change after 1 h was 40.6 ± 22.2%. During the period at the emergency department, there were no reported serious side effects. A single dose of diclofenac sodium provided effective antipyresis in pediatric patients. Serious side effects were not observed.


Review of sensory modalities of sirenians and the other extant Paenungulata clade.
Extant members of Paenungulata (sirenians, proboscideans, and hyracoideans) form a monophyletic clade which originated in Africa. While paenungulates are all herbivorous, they differ greatly in size, life history, and habitat. Therefore, we would expect both phylogenetically related similarities and ecologically driven differences in their use and specializations of sensory systems, especially in adaptations in sirenians related to their fully aquatic habitat. Here we review what is known about the sensory modalities of this clade in an attempt to better elucidate their sensory adaptations. Manatees have a higher frequency range for hearing than elephants, who have the best low-frequency hearing range known to mammals, while the hearing range of hyraxes is unknown. All paenungulates have vibrissae assisting in tactile abilities such as feeding and navigating the environment and share relatively small eyes and dichromatic vision. Taste buds are present in varying quantities in all three orders. While the olfactory abilities of manatees and hyraxes are unknown, elephants have an excellent sense of smell which is reflected by having the relatively largest cranial nerve related to olfaction among the three lineages. Manatees have the relatively largest trigeminal nerve-the nerve responsible for, among other things, mystacial vibrissae-while hyraxes have the relatively largest optic nerve (and therefore, presumably, the best vision) among the Paenungulata. All three orders have diverged significantly; however, they still retain some anatomical and physiological adaptations in common with regard to sensory abilities.


[New approaches to hygienic assessment of machines used in the construction of railways].
The stock of railway machines has been greatly replaced by that new-generation ones that have a high capacity and can themselves move at high speeds. This changes the working conditions of the staff and the conditions of their driving. The new conditions promotes the development of new standard requirements and the methods of tests and assessing the indices of unfavorable working conditions.


Changes in villin synthesis and subcellular distribution during intestinal differentiation of HT29-18 clones.
Brush border in enterocytes is a cell surface specialization intimately associated with terminal differentiation of these cells. HT29-18, a clone derived from the HT-29 human colonic adenocarcinoma cell line, and HT29-18-C1, a subclone from HT29-18 described in the companion paper (Huet, C., C. Sahuquillo-Merino, E. Coudrier, and D. Louvard, 1987, J. Cell Biol., 105:345-357), undergo terminal differentiation with brush borders in the absence of glucose or upon replacement of glucose by galactose in the medium. Taking advantage of this clone and its subclone which can be manipulated in vitro, we have studied the synthesis and subcellular distribution of villin, one major protein in the microvillus core of the brush border. For this study, a monoclonal antibody against villin (BDID2C3) has been isolated and characterized in detail. In addition an ELISA has been set up to measure villin accurately in total cell extracts. Villin content in differentiated HT29-18 cells is close to that seen in normal human colonic cells but 10 times lower in undifferentiated HT29-18 cells. The rate of villin synthesis is dramatically increased in the course of enterocytic differentiation, while villin is remarkably stable after synthesis. We have recently shown, using a cDNA probe for villin, that this change is controlled either at the transcription level or by RNA stabilization (Pringault, E., M. Arpin, A. Garcia, J. Finidori, and D. Louvard, 1986, EMBO (Eur. Mol. Biol. Organ.) J., 5:3119-3124). As shown by immunofluorescence and immunogold labelings, villin is targeted to the brush border area of differentiated HT29-18 cells but remains diffusely distributed in undifferentiated ones.


Incidence and risk factors for Contegra graft infection following right ventricular outflow tract reconstruction: long-term results.
The aim of this study was to evaluate the risk factors associated with Contegra graft (Medtronic Minneapolis, MN, USA) infection after reconstruction of the right ventricular outflow tract. One hundred and six Contegra grafts were implanted between April 1999 and April 2010 for the Ross procedure (n = 46), isolated pulmonary valve replacement (n = 32), tetralogy of Fallot (n = 24), double-outlet right ventricle (n = 7), troncus arteriosus (n = 4), switch operation (n = 1) and redo of pulmonary valve replacement (n = 2). The median age of the patients was 13 years (range 0-54 years). A follow-up was completed in all cases with a median duration of 7.6 years (range 1.7-12.7 years). There were 3 cases of in-hospital mortality. The survival rate during 7 years was 95.7%. Despite the lifelong endocarditis prophylaxis, Contegra graft infection was diagnosed in 12 (11.3%) patients at a median time of 4.4 years (ranging from 0.4 to 8.7 years). Univariate analysis of preoperative, perioperative and postoperative variables was performed and the following risk factors for time to infection were identified: female gender with a hazard ratio (HR) of 0.19 (P = 0.042), systemic-to-pulmonary shunt (HR 6.46, P < 0.01), hypothermia (HR 0.79, P = 0.014), postoperative renal insufficiency (HR 11.97, P = 0.015) and implantation of permanent pacemaker during hospitalization (HR 5.29, P = 0.075). In 2 cases, conservative therapy was successful and, in 10 patients, replacement of the infected valve was performed. The Contegra graft was replaced by a homograft in 2 cases and by a new Contegra graft in 8 cases. Cox's proportional hazard model indicated that time to graft infection was significantly associated with tetralogy of Fallot (HR 0.06, P = 0.01), systemic-to-pulmonary shunt (HR 64.71, P < 0.01) and hypothermia (HR 0.77, P < 0.01). Contegra graft infection affected 11.3% of cases in our cohort, and thus may be considered as a frequent entity that can be predicted by both intraoperative and early postoperative factors. After the diagnosis of infection associated with the Contegra graft was confirmed, surgical treatment was the therapy of choice.


[Risk factors for Alzheimer's disease].
Alzheimer disease (AD) is the most common cause of dementia in elderly patients. Identification of risk factors for AD would contribute to the understanding of AD pathogenesis and thus, help in the development of preventive methods. Early-onset familial AD is associated with mutations of the genes encoding amyloid precursor protein (APP), presenilin 1 (PS-1), or PS-2, resulting in the overproduction of amyloid beta-protein. Epidemiological and case-control studies have led to the identification of several risk factors for sporadic AD. The most concrete genetic risk factor for AD is the epsilon4 allele of apolipoprotein E gene (APOE). In addition, several genes such as CTNNA3, GAB2, PVRL2, TOMM40, and APOC1 are known to be the risk factors that contribute to AD pathogenesis. On the other hand, nongenetic risk factors, such as age, sex, alcohol consumption, smoking, depression, head injury, and nutrition have also been reported. Although aging is the strongest risk factor for AD, the mechanisms underlying the development of AD as a result of ageing remain to be elucidated.


One stop clinic for assessment of risk for fetal anomalies: a report of the first year of prospective screening for chromosomal anomalies in the first trimester.
To evaluate the introduction of a one stop multidisciplinary clinic for screening for fetal chromosomal abnormalities in the first trimester by a combination of maternal serum biochemistry and ultrasonography providing a risk of chromosomal abnormalities within a one hour clinic visit. One year retrospective review of screening performance. All women attending for routine antenatal care. The population included 4,190 singleton pregnancies in women of all ages screened between 10 weeks and 3 days and 13 weeks and 6 days of gestation between the periods 1 June 1998 and 31 May 1999 in a district general hospital antenatal clinic. All women booked into the clinic were offered screening by a combination of maternal serum free beta human chorionic gonadotrophin (hCG) and pregnancy associated plasma protein A (PAPP-A) and fetal nuchal translucency thickness. Women at increased risk of carrying a fetus with trisomy 21 or trisomy 18/13 (> or =1 in 300 at sampling) were offered counselling and an invasive diagnostic procedure. Follow up of the outcome of all pregnancies was carried out. The detection rate for trisomy 21, trisomy 18/13 and all aneuploides, false positive rate, uptake of screening, uptake of chorionic villus sampling in women identified at increased risk and fetal loss after chorionic villus sampling. Overall 97.6% of the women (4,088/4,190) accepted first trimester screening. The rate of detection of trisomy 21 was 86% (6/7), for trisomy 18/13 100% (9/9) and for all aneuploides 95% (18/19). Fetal death at presentation was found in 1.6% of pregnancies (69/4,088). Of women who accepted screening, 6.1% (257/4,088) presented too late for fetal nuchal translucency measurement and 6.5% of the women (271/4,088) presented too early. The false positive rate was 6.7% (253/3,762). Uptake of invasive testing was 83% (207/253). First trimester prenatal screening for chromosomal abnormalities using a combination of maternal serum biochemistry and fetal nuchal translucency thickness can achieve detection rates in excess of 90%. These services can be provided in a one stop multidisciplinary clinic.


Heterozygous Variants in the Mechanosensitive Ion Channel TMEM63A Result in Transient Hypomyelination during Infancy.
Mechanically activated (MA) ion channels convert physical forces into electrical signals. Despite the importance of this function, the involvement of mechanosensitive ion channels in human disease is poorly understood. Here we report heterozygous missense mutations in the gene encoding the MA ion channel TMEM63A that result in an infantile disorder resembling a hypomyelinating leukodystrophy. Four unrelated individuals presented with congenital nystagmus, motor delay, and deficient myelination on serial scans in infancy, prompting the diagnosis of Pelizaeus-Merzbacher (like) disease. Genomic sequencing revealed that all four individuals carry heterozygous missense variants in the pore-forming domain of TMEM63A. These variants were confirmed to have arisen de novo in three of the four individuals. While the physiological role of TMEM63A is incompletely understood, it is highly expressed in oligodendrocytes and it has recently been shown to be a MA ion channel. Using patch clamp electrophysiology, we demonstrated that each of the modeled variants result in strongly attenuated stretch-activated currents when expressed in naive cells. Unexpectedly, the clinical evolution of all four individuals has been surprisingly favorable, with substantial improvements in neurological signs and developmental progression. In the three individuals with follow-up scans after 4 years of age, the myelin deficit had almost completely resolved. Our results suggest a previously unappreciated role for mechanosensitive ion channels in myelin development.


ALUMINUM CHLORIDE EFFECT ON Ca2+,Mg(2+)-ATPase ACTIVITY AND DYNAMIC PARAMETERS OF SKELETAL MUSCLE CONTRACTION.
We studied enzymatic activity and measured strain-gauge contraction properties of the frog Rana temporaria m. tibialis anterior muscle fascicles during the action of aluminum chloride solution. It was shown that AlCl3 solutions did not affect the dynamic properties of skeletal muscle preparation in concentrations less than 10(-4) M Increasing the concentration of AlCl3 to 10(-2) M induce complete inhibition of muscle contraction. A linear correlation between decrease in Ca2+,Mg(2+)-ATPase activity of sarcoplasmic reticulum and the investigated concentrations range of aluminum chloride was observed. The reduction in the dynamic contraction performance and the decrease Ca2+,Mg(2+)-ATPase activity of the sarcoplasmic reticulum under the effect of the investigated AlCl3 solution were minimal in pre-tetanus period of contraction.


Parent binge eating and depressive symptoms as predictors of attrition in a family-based treatment for pediatric obesity.
Attrition is a significant problem in family-based treatment (FBT) for childhood obesity. Despite this, very few studies have examined factors associated with attrition. The current study examined parent symptoms of depression and binge eating as predictors of attrition in FBT. Participants included 77 parents of overweight children enrolled in FBT for childhood obesity. Data were collected at baseline and post-treatment. Binary logistic regression was used to assess associations between parent binge eating symptoms, depressive symptoms, and attrition. Results showed that parent binge eating symptoms (p=0.02), but not depressive symptoms (p=0.07), were significantly associated with attrition, after controlling for parent BMI, treatment group assignment, and family income. Higher reported parent binge eating symptoms were significantly related to attrition in FBT. Assessment of parent binge eating may be important in identifying families at risk for dropping out of FBT. Further, FBT may need to be adapted for families with parents who have a high level of psychopathology.


Anomalous diffraction of light with geometrical path statistics of rays and a Gaussian ray approximation.
The anomalous-diffraction theory (ADT) of extinction of light by soft particles is shown to be determined by a statistical distribution of the geometrical paths of individual rays inside the particles. Light extinction depends on the mean and the mean-squared geometrical paths of the rays. Analytical formulas for optical efficiencies from a Gaussian distribution of the geometrical paths of rays are derived. This Gaussian ray approximation reduces to the exact ADT in the intermediate case of light scattering for an arbitrary soft particle and describes well the extinction of light from a system of randomly oriented and (or) polydisperse particles. The implications for probing of the sizes and shapes of particles by light extinction are discussed.


[Undifferentiated basal cell cancer of the skin (the ultrastructural and histochemical aspects of its histogenesis and diagnosis)].
Twenty-eight undifferentiated basal-cell carcinomas were studied electron microscopically and histochemically. It is established that the cells of which the tumours are formed, retain a number of tissue- and cell-specific features of the epidermis and skin appendages cells. 4 groups of undifferentiated basal-cell carcinoma are distinguished on the basis of this study that histogenetically are connected with the cells of epidermis, hair follicle, secretory parts of the eccrine sweat or sebaceous glands respectively.


Opening up connectivity between documents, structures and bioactivity.
Bioscientists reading papers or patents strive to discern the key relationships reported within a document "D" where a bioactivity "A" with a quantitative result "R" (e.g., an IC50) is reported for chemical structure "C" that modulates (e.g., inhibits) a protein target "P". A useful shorthand for this connectivity thus becomes DARCP. The problem at the core of this article is that the community has spent millions effectively burying these relationships in PDFs over many decades but must now spend millions more trying to get them back out. The key imperative for this is to increase the flow into structured open databases. The positive impacts will include expanded data mining opportunities for drug discovery and chemical biology. Over the last decade commercial sources have manually extracted DARCP from ≈300,000 documents encompassing ≈7 million compounds interacting with ≈10,000 targets. Over a similar time, the Guide to Pharmacology, BindingDB and ChEMBL have carried out analogues DARCP extractions. Although their expert-curated numbers are lower (i.e., ≈2 million compounds against ≈3700 human proteins), these open sources have the great advantage of being merged within PubChem. Parallel efforts have focused on the extraction of document-to-compound (D-C-only) connectivity. In the absence of molecular mechanism of action (mmoa) annotation, this is of less value but can be automatically extracted. This has been significantly accomplished for patents, (e.g., by IBM, SureChEMBL and WIPO) for over 30 million compounds in PubChem. These have recently been joined by 1.4 million D-C submissions from three major chemistry publishers. In addition, both the European and US PubMed Central portals now add chemistry look-ups from abstracts and full-text papers. However, the fully automated extraction of DARCLP has not yet been achieved. This stands in contrast to the ability of biocurators to discern these relationships in minutes. Unfortunately, no journals have yet instigated a flow of author-specified DARCP directly into open databases. Progress may come from trends such as open science, open access (OA), findable, accessible, interoperable and reusable (FAIR), resource description framework (RDF) and WikiData. However, we will need to await the technical applicability in respect to DARCP capture to see if this opens up connectivity.


Outcomes following Peripheral Nerve Decompression with and without Associated Double Crush Syndrome: A Case Control Study.
Double crush syndrome, the association between proximal and distal nerve lesions, has been established. This investigation compares the outcomes of nerve surgery in patients with isolated peripheral compression versus those with double crush syndrome treated with peripheral nerve and cervical spine operations. This case-controlled study enrolled 80 patients: 40 underwent carpal or cubital tunnel surgery and cervical spine surgery (double crush group); and 40 controls, matched by age and sex, underwent only peripheral nerve decompression (peripheral nerve group). A minimum of 18 months was required after peripheral nerve and cervical spine surgery for office assessment (mean, 4.9 years and 6.0 years, respectively). Statistical analysis compared postoperative function and symptom severity questionnaires, physical examination, and patient-reported satisfaction between groups. Patients in the double crush group reported significantly more disability and persistent symptoms on the QuickDASH questionnaire (29 versus 13) and Levine Katz symptom severity (2.0 versus 1.4) and functional status scales (1.9 versus 1.4). Double crush patients reported significantly lower satisfaction. The double crush group exhibited a greater frequency of persistent signs of nerve irritability and muscle weakness compared with the control group. At a minimum of 18 months after peripheral nerve surgery, patients with a history of cervical spine surgery are likely to have inferior patient-reported outcomes, persistent nerve dysfunction, and lower satisfaction after peripheral nerve release compared with patients following isolated peripheral nerve surgery. Double crush syndrome was associated with poorer outcome after peripheral nerve surgery despite treatment of cervical spine nerve compression. Therapeutic, III.


Bracketing phenogenotypic limits of mammalian hybridization.
An increasing number of mammalian species have been shown to have a history of hybridization and introgression based on genetic analyses. Only relatively few fossils, however, preserve genetic material, and morphology must be used to identify the species and determine whether morphologically intermediate fossils could represent hybrids. Because dental and cranial fossils are typically the key body parts studied in mammalian palaeontology, here we bracket the potential for phenotypically extreme hybridizations by examining uniquely preserved cranio-dental material of a captive hybrid between grey and ringed seals. We analysed how distinct these species are genetically and morphologically, how easy it is to identify the hybrids using morphology and whether comparable hybridizations happen in the wild. We show that the genetic distance between these species is more than twice the modern human-Neanderthal distance, but still within that of morphologically similar species pairs known to hybridize. By contrast, morphological and developmental analyses show grey and ringed seals to be highly disparate, and that the hybrid is a predictable intermediate. Genetic analyses of the parent populations reveal introgression in the wild, suggesting that grey-ringed seal hybridization is not limited to captivity. Taken together, we postulate that there is considerable potential for mammalian hybridization between phenotypically disparate taxa.


Three-Dimensional (3D)-Printed Zero-Order Released Platform: a Novel Method of Personalized Dosage Form Design and Manufacturing.
In 2017, there are 451 million people with diabetes worldwide. These figures were expected to increase to 693 million by 2045. The research and development of hypoglycemic drugs has become a top priority. Among them, sulfonylurea hypoglycemic drugs such as glipizide are commonly used in non-insulin-dependent type II diabetes. In order to adapt to the wide range of hypoglycemic drugs and the different individual needs of patients, this topic used glipizide as a model drug, and prepared glipizide preparations with 3D printing technology. The purpose of this study was to investigate the prescription applicability and control-release behavior of structure and explore the application prospects of 3D printing personalized drug delivery formulations. This article aims to establish a production process for personalized preparations based on 3D printing technology. The process is easy to obtain excipients, universal prescriptions, flexible dosages, exclusive customization, and integrated automation. In this paper, the UV method was used to determine the in vitro release and content analysis method of glipizide; the physical and chemical properties of the glipizide were investigated. The established analysis method was inspected and evaluated, and the experimental results met the methodological requirements. Glipizide controlled-release tablets were prepared by the semisolid extrusion (SSE) method using traditional pharmaceutical excipients combined with 3D printing technology. The formulation composition, in vitro release, and printing process parameters of the preparation were investigated, and the final prescription and process parameters (traveling speed 6.0-7.7 mm/s and extruding speed 0.0060-0.0077 mm/s) were selected through comprehensive analysis. The routine analysis results of the preparation showed that the performance of the preparation meets the requirements. In order for 3D printing technology to play a better role in community medicine and telemedicine, this article further explored the universality of the above prescription and determined the scope of application of prescription drugs and dosages. Glipizide, gliclazide, lornoxicam, puerarin, and theophylline were used as model drugs, and the range of drug loading percentage was investigated. The results showed when the solubility of the drug is 9.45 -8.34 mg/mL, and the drug loading is 3-43%; the release behavior is similar.


Osteoprogenitor response to defined topographies with nanoscale depths.
In the development of the next generation of orthopaedic implants for load-bearing applications, an ability to influence osteoprogenitor population activity and function will be highly desirable. This will allow the formation of hard-tissue directly onto the implant, i.e. osseointegration, rather than the formation of fibrous capsules which form around many of the current, non-bioactive, prosthesis. The formation of capsules leads to micromotion due to modulus mismatch and ultimately to fracture and the need for revision surgery. Microtopography and latterly nanotopography have been shown to elicit influence over adhesion, proliferation and gene expression of a wide number of cell types. This study has examined the possibility of modulating cell adhesion using a range of nanometric scale shallow pits and grooves. The topographies were manufactured using photolithography followed by the production of nickel shims and finally embossing into polymethylmethacrylate. Cell testing with human osteoprogenitor populations showed that the nanotopographies allowed control of cell adhesion, cytoskeleton, growth and production of the osteoblastic markers osteocalcin and osteopontin. It is concluded that the human bone marrow stromal cells are highly responsive to nanoscale features.


Control of differentiation-induced calbindin-D9k gene expression in Caco-2 cells by cdx-2 and HNF-1alpha.
Calbindin D9k (CaBP) is critical for intestinal calcium absorption; its in vivo expression is restricted to differentiated enterocytes of the small intestine. Our goal was to identify factors controlling the transcriptional regulation of this gene in the human intestine. Both the natural gene and a 4600-bp promoter construct were strongly regulated by differentiation (>100-fold) but not by treatment with 1,25(OH)2 vitamin D (<2-fold) in the Caco-2 clone TC7. Deletion-mutation studies revealed that conserved promoter sequences for cdx-2 (at -3158 bp) and hepatocyte nuclear factor (HNF)-1 (at -3131 and at -98 bp) combined to control CaBP expression during differentiation. Other putative response elements were not important for CaBP regulation in TC7 cells (CCAAT enhancer binding protein, pancreatic duodenal homebox-1 (pdx-1), a proximal cdx-2 element). Mutation of the distal HNF-1 site had the greatest impact on CaBP gene expression through disruption of HNF-1alpha binding; both basal and differentiation-mediated CaBP expression was reduced by 80%. In contrast, mutation of the distal cdx-2 element reduced only basal CaBP expression. Whereas a 60% reduction of CaBP mRNA in the duodenum of HNF-1alpha null mice confirmed the physiological importance of HNF-1alpha for CaBP gene regulation, additional studies showed that maximal CaBP expression requires the presence of both HNF-1alpha and cdx-2. Our data suggest that cdx-2 is a permissive factor that influences basal CaBP expression in enterocytes and that HNF-1alpha modulates CaBP gene expression during cellular differentiation.


Effect of aliskiren treatment on endothelium-dependent vasodilation and aortic stiffness in essential hypertensive patients.
Aliskiren is a new oral non-peptide renin inhibitor. Its effects on vascular function in human hypertension are unknown. We assessed whether aliskiren may improve peripheral endothelial function and arterial stiffness in essential hypertensive patients (EH), when compared with the angiotensin-converting enzyme-inhibitor ramipril. Fifty EH received treatment with aliskiren (150-300 mg/daily) or ramipril (5-10 mg/daily) for 12 weeks, according to a randomized, open with blind endpoints, parallel group design. We studied the forearm blood flow (straingauge plethysmography) response to intrabrachial acetylcholine, repeated under the nitric oxide synthase inhibitor N(G)-monomethyl-l-arginine (l-NMMA) (4 μmol/min), or the antioxidant ascorbic acid (8 mg/100 mL/min). Carotid-to-femoral pulse wave velocity (PWV), central blood pressure and augmentation index (AIx) were obtained by applanation tonometry. Brachial blood pressure was similarly normalized by aliskiren (from 149/94 to 136/86 mmHg) and ramipril (from 148/92 to 135/85 mmHg), as well as central blood pressure. Aliskiren increased (P < 0.001) the vasodilation to acetylcholine and restored the inhibitory effect of l-NMMA on acetylcholine. Ascorbic acid, which at baseline potentiated the response to acetylcholine, no longer improved endothelium-dependent relaxation after aliskiren treatment. In contrast, ramipril failed to affect the response to acetylcholine, the lacking inhibitory effect of l-NMMA, or the potentiating effect of ascorbic acid. Pulse wave velocity was significantly (P < 0.05) and similarly reduced by both drugs. Aliskiren induced a significantly (P < 0.05) greater AIx reduction than ramipril. Aliskiren increased nitric oxide availability in the forearm resistance arterioles of EH, an effect probably determined by an antioxidant activity, which can also contribute to improved peripheral wave reflection.


Effects of catchment and riparian landscape setting on water chemistry and seasonal evolution of water quality in the upper Han River basin, China.
Six-year (2005-2010) evolution of water chemistry (Cl(-), NO(3)(-), SO(4)(2-), HCO(3)(-), Na(+), K(+), Ca(2+) and Mg(2+)) and their interactions with morphological properties (i.e., slope and area), land cover, and hydrological seasonality were examined to identify controlling factors and processes governing patterns of stream water quality in the upper Han River, China. Correlation analysis and stepwise multiple regression models revealed significant correlations between ions (i.e., Cl(-), SO(4)(2-), Na(+) and K(+)) and land cover (i.e., vegetation and bare land) over the entire catchment in both high- and low-flow periods, and in the buffer zone the correlation was much more stronger in the low-flow period. Catchment with steeper slope (>15°) was negatively correlated with major ions, largely due to multicollinearity of basin characteristics. Land cover within the buffer zone explained slightly less of major elements than at catchment scale in the rainy season, whereas in the dry season, land cover along the river networks in particular this within 100 m riparian zone much better explained major elements rather than this over the entire catchment. Anthropogenic land uses (i.e., urban and agriculture) however could not explain water chemical variables, albeit EC, TDS, anthropogenic markers (Cl(-), NO(3)(-), SO(4)(2)), Na(+), K(+) and Ca(2+) significantly increased during 2005-2010, which was corroborated by principal component analyses (PCA) that indicated anthropogenic inputs. Observations demonstrated much higher solute concentrations in the industrial-polluted river. Our results suggested that seasonal evolution of water quality in combined with spatial analysis at multiple scales should be a vital part of identifying the controls on spatio-temporal patterns of water quality.


Stability of isoflavones during extrusion processing of corn/soy mixture.
The influence of extrusion processing in the presence of corn on the quantity and quality of genistein, daidzein, and their respective beta-glucoside, acetyl glucoside, and malonyl glucoside derivatives was evaluated. Products of 100% soy (textured) and a blend of 20% soy protein concentrate (SPC) and 80% corn meal (direct-expanded) were extruded, with evaluations before and after extrusion. In addition, a 3 x (3 x 3) split-plot factorial experiment investigated the influence of barrel temperature (110, 130, 150 degrees C), moisture content (22, 24, 26%), and relative residence time (1, 0.8, 0.6) on extruder response and isoflavone profile. The extrusion barrel temperature had the most influence on isoflavone profile, especially decarboxylation of the malonyl beta-glucoside, followed by the moisture content. The amount of extractable isoflavones decreased after extrusion for both the SPC and SPC/corn meal blend when extracted with 80% aqueous methanol but remained approximately the same when first hydrated with water before extraction. However, initially hydrating with water produced enzymatic glycolysis in the unextruded samples, increasing the aglycons dramatically.


Mangiferin suppresses endoplasmic reticulum stress in perivascular adipose tissue and prevents insulin resistance in the endothelium.
Mangiferin is a naturally occurring glucosylxanthone with beneficial effects on glucose and lipid homeostasis. This study investigates the potential therapeutic effect of Mangiferin in perivascular adipose tissue (PVAT) and whether it contributes to regulating insulin action in the endothelium. Palmitate challenge evoked ROS-associated endoplasmic reticulum stress (ER stress) and NLRP3 inflammasome activation in PVAT. The conditioned medium from PA-stimulated PVAT was prepared to induce endothelial insulin resistance, and improved endothelium-dependent vasodilation in response to insulin was detected in vitro and in vivo. Mangiferin treatment enhanced LKB1-dependent AMPK activity and suppressed ER stress with downregulation of TXNIP induction, leading to the inhibition of NLRP3 inflammasome activation evidenced by attenuated NLRP3 and cleaved caspase-1 expression as well as reduced IL-1β secretion. Moreover, Mangiferin restored insulin-mediated Akt and eNOS phosphorylations with increased NO production, immunohistochemistry examination of adipocytes, and endothelial tissue in high-fat diet-fed mice also showed that oral administration of Mangiferin inhibited ER stress and NLRP3 induction in PVAT, and then effectively prevented insulin resistance in the vessel endothelium. Taken together, these results revealed that Mangiferin suppressed ER stress-associated NLRP3 inflammasome activation in PVAT through regulation of AMPK activity, which prevented endothelial insulin resistance. These findings suggested that the amelioration of PVAT dysfunction may be a therapeutic strategy for the prevention of endothelial insulin resistance.


Interaction between hepatitis delta virus-encoded proteins and hepatitis B virus envelope protein domains.
Hepatitis delta virus (HDV) packaging requires prenylation of the HDV large protein (p27), as well as a direct protein-protein interaction between HDV proteins and hepatitis B virus (HBV) envelope protein domains. To investigate this interaction, we have analysed the binding capacity of baculovirus-expressed delta p24 and p27 proteins to synthetic peptides specific for the HBV envelope. Although a higher degree of binding was observed with p27, both p24 and p27 could bind HBV envelope peptides. One such peptide corresponded to residues 56-80 located in the cytosolic loop of the small HBV envelope protein, and another corresponded to 23 carboxy-terminal residues of the pre-S1 specific to the large HBV envelope protein. This indicates that in addition to p27, p24 may contribute to packaging of HDV through a protein-protein interaction with HBV envelope domains, and that an interaction between the pre-S1 polypeptide and delta proteins may play a role in infectivity.


Multifunctional microbubbles for image-guided antivascular endothelial growth factor therapy.
We synthesize multifunctional microbubbles (MBs) for targeted delivery of antivascular endothelial growth factor (antiVEGF) therapy with multimodal imaging guidance. Poly-lactic-co-glycolic acid (PLGA) MBs encapsulating Texas Red dye are fabricated by a modified double-emulsion process. Simultaneous ultrasound and fluorescence imaging are achieved using Texas Red encapsulated MBs. The MBs are conjugated with Avastin, an antiVEGF antibody for treating neovascular age-related macular degeneration (AMD). The conjugation efficiency is characterized by enzyme-linked immunosorbent assay (ELISA). The efficiency for targeted binding of Avastin-conjugated MBs is characterized by microscopic imaging. Our work demonstrates the technical potential of using multifunctional MBs for targeted delivery of antiVEGF therapy in the treatment of exudative AMD.


Differential stimulation of three forms of hyaluronan synthase by TGF-beta, IL-1beta, and TNF-alpha.
This study compares the regulation of three isoforms of hyaluronan synthase (HAS1, HAS2, and HAS3) transcripts and hyaluronan (HA) production by cytokines in human synovial fibroblastic cells derived from tissue from patients with rheumatoid arthritis (RA) and osteoarthritis (OA). Levels of HAS mRNA of the cells with or without stimulation were detected using a real-time fluorescence polymerase chain reaction detection system. Concentrations of HA in the culture supernatants of the cells were measured by a sandwich binding protein assay. Molecular weight of HA was evaluated by agarose gel electrophoresis. The relative proportions of the expression pattern of HAS isoforms was similar between RA and OA tissue-derived cells. HAS1 mRNA was upregulated by transforming growth factor-beta and HAS3 mRNA was upregulated by interleukin-1beta and somewhat by tumor necrosis factor-alpha in the RA cells. HAS2 remained unchanged. Differences in the expression pattern of HAS1, HAS2, and HAS3 mRNA by cytokines suggest that these three isoforms are independently and differentially regulated, and each isoform of HAS may have a different role in arthritic joint disease.


Factors associated with adoption of beneficial newborn care practices in rural Eastern Uganda: a cross-sectional study.
Beneficial newborn care practices can improve newborn survival. However, little is known about the factors that affect adoption of these practices. Cross-sectional study conducted among 1,616 mothers who had delivered in the past year in two health sub-districts (Luuka and Buyende) in Eastern Uganda. Data collection took place between November and December 2011. Data were collected on socio-demographic and economic characteristics, antenatal care visits, skilled delivery attendance, parity, distance to health facility and early newborn care knowledge and practices. Descriptive statistics were computed to determine the proportion of mothers who adopted beneficial newborn care practices (optimal thermal care; good feeding practices; weighing and immunizing the baby immediately after birth; and good cord care) during the neonatal period. We conducted multivariable logistic regression to assess the covariates of adoption of all beneficial newborn care practices. Analysis was done using STATA statistical software, version 12.1. Of the 1,616 mothers enrolled, 622 (38.5%) were aged 25-34; 1,472 (91.1%) were married; 1,096 (67.8%) had primary education; while 1,357 (84%) were laborers or peasants. Utilization of all beneficial newborn care practices was 11.7%; lower in Luuka (9.4%, n = 797) than in Buyende health sub-district (13.9%, n = 819; p = 0.005). Good cord care (83.6% in Luuka; 95% in Buyende) and immunization of newborn (80.7% in Luuka; 82.5% in Buyende) were the most prevalent newborn care practices reported by mothers. At the multivariable analysis, number of ANC visits (3-4 vs. 1-2: Adjusted (Adj.) Odds Ratio (OR) = 1.69, 95% CI = 1.13, 2.52), skilled delivery (Adj. OR = 2.66, 95% CI = 1.92, 3.69), socio-economic status (middle vs. low: Adj. OR = 1.57, 95% CI = 1.09, 2.26) were positively associated with adoption of all beneficial newborn care practices among mothers. Adoption of all beneficial newborn care practices was low, although associated with higher ANC visits; middle-level socio-economic status and skilled delivery attendance. These findings suggest a need for interventions to improve quality ANC and skilled delivery attendance as well as targeting of women with low and high socio-economic status with newborn care health educational messages, improved work conditions for breastfeeding, and supportive policies at national level for uptake of newborn care practices.


Relationship between high-sensitivity cardiac troponin T and the prognosis of elderly inpatients with non-acute coronary syndromes.
Low-level high-sensitivity cardiac troponin T (hs-cTnT) increases in elderly population. In this study, the relationship between hs-cTnT level and all-cause death of elderly inpatients with non-acute coronary syndrome (non-ACS) after discharge from the hospital was investigated. Non-ACS patients aged >65 years admitted in the General Practice Wards and Department of Geriatrics of Fuxing Hospital Affiliated to Capital Medical University were enrolled in the study. The patients were grouped according to the tertiles of hs-cTnT levels. Biochemical markers, hs-cTnT, and amino-terminal pro-brain natriuretic peptide were measured. The median follow-up period was 47 months, and all-cause deaths of the patients were observed. A total of 722 patients, including 473 males and 249 females, aged 65-98 (82.43±5.98) years were enrolled in the study. The level of hs-cTnT was found to be higher in males, and increased with age and comorbidities (P<0.01). Compared with low-level group, NT-proBNP level of patients in high-level group was higher, while hemoglobin (Hb), estimated glomerular filtration rate (eGFR), and left ventricular ejection fraction (LVEF) levels were lower (P<0.001). The mortality rate increased significantly with increased hs-cTnT levels (P<0.001). The total number of deaths was 136 (18.8%), and of these, 108 (79.4%) were noncardiac deaths. Risk of all-cause deaths in the highest hs-cTnT level group was 7.3 times higher than that of the lowest hs-cTnT level group (95% CI: 4.29-12.51, P<0.001). After adjusting for gender, age, comorbidities, NT-proBNP, Hb, eGFR, and LVEF, hs-cTnT level still affected the patient's survival time (HR: 3.01, 95% CI: 1.67-5.43, P<0.001). These findings suggest that low-level hs-cTnT was increased in elderly inpatients without ACS. They further highlight that baseline hs-cTnT level was associated with increased risk of all-cause deaths among patients after their discharge, and most deaths were from non-cardiovascular diseases.


X-ray structure of a trimeric 5,5'-biaryl/erythro-beta-O-4-ether lignin model: evidence for through-space weak interactions.
The crystal structure of a trimeric lignin model 1 presenting the characteristic pattern of biphenyl (5,5') and aryl-alkyl-ether (beta-O-4) linkages has been determined. The crystal system is triclinic and the crystallographic unit cell consists of two monomeric molecules. These results are compared with crystal data from the literature of simple models of the 5,5' and beta-O-4 structure type. The availability of a terminal aldehyde function on the model affords some interesting intermolecular interactions by weak hydrogen bonding which controls the conformation of the molecule and the aromatic ring orientation in particular; an unexpected cisoïd conformation of the biaryl unit is observed based on the 64.4 degrees value found for the torsion angle between the two 5,5' aromatic rings.


Correlates and moderators of child pornography consumption in a community sample.
This study compares pornography users who report child pornography (CP) consumption with those who do not on demographic characteristics (age, ethnicity, and education level), psychological characteristics (e.g., loneliness, attachment style, anxiety, and sensation seeking), frequency of pornography use, and intentions to engage in contact sexual abuse. Participants were recruited on the Internet to complete an online anonymous survey about "problematic pornography use." Approximately, one fifth of the recruited male pornography users (21%, n = 37) reported consuming CP. The two groups were similar on all demographic and psychological characteristics. However, the probability of CP consumption was the greatest among men scoring high on a measure of sensation seeking who reported frequent pornography use (i.e., statistical moderation). CP consumers also reported a greater interest in engaging in sexual contact with a minor than non-CP consumers.


Soluble adenosine diphosphate glucose- -1,4-glucan -4-glucosyltransferases from spinach leaves.
Multiple forms of ADP-glucose-alpha-1,4-glucan alpha-4-glucosyltransferase were obtained from spinach leaves by gradient elution from a DEAE-cellulose column. In the presence of high concentrations of some salts and bovine serum albumin, unprimed activity was found in one (transglucosylase III) of the four fractions eluted from the column. In addition to having unprimed activity, transglucosylase III had a lower K(m) for ADP-glucose, a much higher K(m) for oyster glycogen, greater heat sensitivity and lower affinity for maltose, maltotriose and amylopectin beta-limit dextrin than fractions I, II and IV. In addition, the kinetics at low concentrations of amylose, amylopectin and rabbit liver glycogen were non-linear for transglucosylase III. The properties of transglucosylases I, II and IV were generally similar to each other. Rates of the unprimed reaction at physiological concentrations of ADP-glucose were greater than those found for the primed reaction of fraction III. The product formed by the unprimed reaction was a glucan containing principally alpha-1,4 linkages with some alpha-1,6 linkages. The primer, maltose, at a concentration of 0.5m inhibited the synthesis of the unprimed product.


Diffusion-modulated colorimetric sensor for continuous gas detection.
Due to their high sensitivity and selectivity, low cost, and good compatibility for sensor array integration, colorimetric gas sensors are widely used in hazardous gas detection, food freshness assessment, and gaseous biomarker identification. However, colorimetric gas sensors are usually designed for one-time discrete measurement because the sensing materials are entirely exposed to analytes during the sensing process. The fast consumption of sensing materials limits colorimetric sensors' applications in continuous analytes monitoring, increases the operation complexity and brings challenges for calibration. In this work, we reported a novel sensor design to prolong the lifetime of colorimetric gas sensors by engineering the gas diffusion process to preserve the sensing materials. We compared two geometries for gas diffusion control in a sensing matrix through simulation and experiment on an ammonia sensing platform. We found that the 2-dimensional gas diffusion geometry enabled a better sensor performance, including more stable and higher sensitivity and a more linear response to ammonia concentration compared to 1-dimensional gas diffusion geometry. We also demonstrated the usability of this diffusion-modulated colorimetric sensor for continuous environmental ammonia monitoring.


[Urethane inhibition of DNA synthesis in the hepatocytes of the regenerating liver in mice].
Hepatocarcinogen urethane (ethyl carbamate) inhibits DNA synthesis in the regenerating mice liver when administered at the peak of stimulated proliferation--46 hours after partial hepatectomy. The inhibition is temporary and reversible. The maximum inhibition of 3H-thymidine incorporation in the cells is observed 12 hours after urethane administration, and the effect is removed following 20 hours after administration. Another effect of urethane consists in the lengthening of the period of DNA synthesis by 1.38 times, as estimated by the Quastler-Sherman method, though it does not affect the length of G2-period or mitosis. Possible mechanisms of the effect of urethane on the initiation of DNA synthesis and on the rate of DNA replication are discussed.


Evaluating the morphology of the left atrial appendage by a transesophageal echocardiographic 3-dimensional printed model.
The novel 3-dimensional printing (3DP) technique has shown its ability to assist personalized cardiac intervention therapy. This study aimed to determine the feasibility of 3D-printed left atrial appendage (LAA) models based on 3D transesophageal echocardiography (3D TEE) data and their application value in treating LAA occlusions.Eighteen patients with transcatheter LAA occlusion, and preprocedure 3D TEE and cardiac computed tomography were enrolled. 3D TEE volumetric data of the LAA were acquired and postprocessed for 3DP. Two types of 3D models of the LAA (ie, hard chamber model and flexible wall model) were printed by a 3D printer. The morphological classification and lobe identification of the LAA were assessed by the 3D chamber model, and LAA dimensions were measured via the 3D wall model. Additionally, a simulation operative rehearsal was performed on the 3D models in cases of challenging LAA morphology for the purpose of understanding the interactions between the device and the model.Three-dimensional TEE volumetric data of the LAA were successfully reprocessed and printed as 3D LAA chamber models and 3D LAA wall models in all patients. The consistency of the morphological classifications of the LAA based on 3D models and cardiac computed tomography was 0.92 (P < .01). The differences between the LAA ostium dimensions and depth measured using the 3D models were not significant from those measured on 3D TEE (P > .05). A simulation occlusion was successfully performed on the 3D model of the 2 challenging cases and compared with the real procedure.The echocardiographic 3DP technique is feasible and accurate in reflecting the spatial morphology of the LAA, which may be promising for the personalized planning of transcatheter LAA occlusion.


Treatment of hepatitis C infections with interferon: a historical perspective.
Interferons were first described in 1957, but it was not until 34 years after their discovery that sufficient quantities of it were available for treatment of hepatitis C virus (HCV) infections, Clinicians now have an excellent understanding of the basis for the effectiveness of interferon alpha (IFN-α) in the therapy of this disease. Treatment with IFN-α is more efficient when it complemented by the antiviral ribavirin and the IFN-α is conjugated with polyethylene glycol to form peginterferon. In the near future treatment of HCV with IFN-α may involve new anti-HCV agents that are currently under development.


Sexual barrier acceptability among multiethnic HIV-positive and at-risk women.
Sexual behavior interventions have been found to reduce sexual risk among HIV-seropositive and high-risk HIV-seronegative women. This study examined the influence of ethnicity and HIV serostatus on sexual barrier acceptability and use at short-term and long-term follow-up among African American and Hispanic (n=457) women participating in a gender and culturally tailored sexual risk reduction intervention. We hypothesized that sexual barrier acceptability and use would differ between ethnic groups but that this difference would dissipate after intervention participation. We further postulated that HIV-seropositive women would report greater acceptability and use of sexual barriers than seronegative women at baseline and that after participation in the intervention, acceptability and use would increase for both serostatus groups. We enrolled 317 African American and 140 Hispanic women, 273 (60%) seropositive and 184 (40%)seronegative. Ethnic differences in the frequency of male and female condom use existed at baseline but were not found at 12-month follow-up. Male condom acceptability was higher among African American women than Hispanic women at baseline and 12-month follow-up. Seropositive women reported higher levels of consistent male condom use, but both ethnic and serostatus groups reported high levels (positive, 40%; negative, 52%) of inconsistent condom use. Most women had little experience with female condoms or lubricating gels and suppositories at baseline. No differences between ethnicities were identified in lubricant use. Results support the use of a culturally tailored intervention among these populations to increase sexual barrier use and reduce sexual risk.


Advanced imaging in stone management.
Stone disease continues to plague humankind. Recent innovations in minimally invasive surgery, however, have decreased morbidity for the treatment of lithiasis, once only amenable to open surgical techniques. These advances in stone management have also been paralleled in the radiographic armamentarium. Herein, we describe the evolution of initial radiographic workup for urolithiasis, from abdominal radiograph to three-dimensional computed tomography and some of the novel applications thereof. Previously, abdominal radiography was the only modality available for the visualization of calculi. Subsequently, the development of intravenous contrast aided in evaluating renal function, detecting the presence and location of obstruction, and in identifying filling defects. Most recently, prospective randomized trials have demonstrated improved sensitivity and specificity using noncontrast helical computed tomography rather than intravenous pyelogram with regard to the initial evaluation of acute flank pain. Further attempts to lower the overall radiation dose without compromising efficacy have also been introduced. Currently, the volume of calculus disease can be better quantified and somewhat qualified from three-dimensional computer software, thereby optimizing stone management. Considerable progress has been made using minimally invasive techniques in the treatment of nephrolithiasis. Furthermore, advances in radiographic computer hard- and software applications allow for a rapid acquisition time and improved image quality without sacrificing diagnostic accuracy. In time, it is likely that the combination of these enhanced imaging modalities will lead to an improvement in stone localization, fragmentation and stone-free rates.


Lateralized activation of Cluster N in the brains of migratory songbirds.
Cluster N is a cluster of forebrain regions found in night-migratory songbirds that shows high activation of activity-dependent gene expression during night-time vision. We have suggested that Cluster N may function as a specialized night-vision area in night-migratory birds and that it may be involved in processing light-mediated magnetic compass information. Here, we investigated these ideas. We found a significant lateralized dominance of Cluster N activation in the right hemisphere of European robins (Erithacus rubecula). Activation predominantly originated from the contralateral (left) eye. Garden warblers (Sylvia borin) tested under different magnetic field conditions and under monochromatic red light did not show significant differences in Cluster N activation. In the fairly sedentary Sardinian warbler (Sylvia melanocephala), which belongs to the same phyolgenetic clade, Cluster N showed prominent activation levels, similar to that observed in garden warblers and European robins. Thus, it seems that Cluster N activation occurs at night in all species within predominantly migratory groups of birds, probably because such birds have the capability of switching between migratory and sedentary life styles. The activation studies suggest that although Cluster N is lateralized, as is the dependence on magnetic compass orientation, either Cluster N is not involved in magnetic processing or the magnetic modulations of the primary visual signal, forming the basis for the currently supported light-dependent magnetic compass mechanism, are relatively small such that activity-dependent gene expression changes are not sensitive enough to pick them up.


Health Effects of Tobacco at the Global, Regional, and National Levels: Results From the 2019 Global Burden of Disease Study.
The purpose was to quantify the health effects of tobacco using data from the 2019 Global Burden of Disease study. We collected detailed information on tobacco consumption overall as well as its individual aspects (smoking, secondhand smoke, and chewing tobacco) for the deaths and disability-adjusted life years (DALYs) for all-cause disease, cardiovascular disease, neoplasms, and chronic respiratory diseases, and their age-standardized rates (ASRs). Tobacco was responsible for 8.71 million deaths and 229.77 million DALYs globally in 2019. The ASRs of all tobacco-related deaths and DALYs declined from 1990 to 2019, to 108.55 deaths per 100 000 population and 2791.04 DALYs per 100 000 population in 2019. During any year the ASRs of all tobacco-related deaths and DALYs were higher in males than in females. The ASRs of all tobacco-related deaths and DALYs were highest in countries with a low-middle sociodemographic index (SDI) and lowest in high-SDI countries in 2019. Cardiovascular disease, neoplasms, and chronic respiratory diseases were the three leading causes of tobacco-related mortality. Although the ASRs of deaths and DALYs related to tobacco have declined, the absolute number remain high. Tobacco control policies need to be strengthened further in order to reduce the heavy health burden of tobacco. This study provides a detailed description on the health effects of tobacco, including maps of the current global burden of tobacco-related disease. Although the ASRs of tobacco-related deaths and DALYs have declined, the absolute numbers remain high-tobacco was responsible for 8.71 million deaths and 229.77 million DALYs globally in 2019. The findings may have implications for tobacco control. Countries where progress has been slower in reducing tobacco-related disease burden should study and consider implementing policies and strategies that have been applied in countries like Singapore which show the greatest declines for recent decades.


A Terrylene-Anthraquinone Dyad as a Chromophore for Photothermal Therapy in the NIR-II Window.
A terrylenedicarboximide-anthraquinone dyad, FTQ, with absorption in the second near-infrared region (NIR-II) is obtained as a high-performance chromophore for photothermal therapy (PTT). The synthetic route proceeds by C-N coupling of amino-substituted terrylenedicarboximide (TMI) and 1,4-dichloroanthraquinone followed by alkaline-promoted dehydrocyclization. FTQ with extended π-conjugation exhibits an optical absorption band peaking at 1140 nm and extending into the 1500 nm range. Moreover, as determined by dielectric spectroscopy in dilute solutions, FTQ achieves an ultrastrong dipole moment of 14.4 ± 0.4 Debye due to intense intramolecular charge transfer. After encapsulation in a biodegradable polyethylene glycol (DSPE-mPEG2000), FTQ nanoparticles (NPs) deliver a high photothermal conversion efficiency of 49% under 1064 nm laser irradiation combined with excellent biocompatibility, photostability, and photoacoustic imaging capability. In vitro and in vivo studies reveal the great potential of FTQ NPs in photoacoustic-imaging-guided photothermal therapy for orthotopic liver cancer treatment in the NIR-II window.


[Abciximab: a new antiplatelet agent for use in coronary angioplasty].
Angioplasty of coronary arteries (PTCA) is an accepted treatment modality for patients with symptomatic coronary artery disease. Despite technological improvements it is still plagued by (mainly thrombotic) complications in around 10% of all patients. A number of new antithrombotic and antiplatelet agents have been tried in the setting of angioplasty. The monoclonal glycoprotein IIb-IIIa receptor blocker abciximab appears to control the thrombotic process most effectively before, during and after the procedure. Three large randomized trials with abciximab in patients with stable, unstable or refractory unstable angina pectoris were conducted. All three showed a relative reduction by 35% to 56% in the primary combined endpoint, consisting of mortality, myocardial infarction or urgent intervention, at 30 days. Severe bleeding, which affected 14.0% of patients on abciximab in the first trial, was reduced, after adjusting heparin dosing and issuing sheath removal guidelines, to 3.8% in the second and 2.0% in the final study. In the placebo groups the percentages of severe bleeding were 6.6, 1.9, and 3.1, respectively. Abciximab appears to reduce the thrombotic complications of PTCA substantially. The extent of this reduction and the severity of complications prevented justifies its more general use during angioplasty.


Validating the psycholinguistic aspects of LITMUS-CLT: Evidence from Polish and Norwegian.
The novel assessment tool Cross-Linguistic Lexical Tasks (LITMUS-CLT) aims for comparable cross-linguistic assessment of multilingual children's lexical skills by basing each language version on two language-specific variables: age of acquisition (AoA) and complexity index (CI), a novel measure related to phonology, morphology, exposure and etymology. This article investigates the validity of this methodology, asking whether the underlying properties are robust predictors of children's performance. The Polish and Norwegian CLTs were used to assess 32 bilingual Polish-Norwegian, 34 monolingual Norwegian and 36 monolingual Polish children. The effects of AoA and CI were contrasted with frequency in child directed speech (CDS) and imageability, two known predictors of lexical development. AoA was a reliable predictor of performance within all parts of CLT, in contrast to CI. Apart from AoA, only exposure and CDS frequency had a significant effect within both monolinguals and bilinguals. These results indicate that CLT assesses lexical skills in a cross-linguistically comparable manner, but suggest a revision of the CI measure.


High serum IgG4 concentrations in patients with sclerosing pancreatitis.
Sclerosing pancreatitis is a unique form of pancreatitis that is characterized by irregular narrowing of the main pancreatic duct, lymphoplasmacytic inflammation of the pancreas, and hypergammaglobulinemia and that responds to glucocorticoid treatment. Preliminary studies suggested that serum IgG4 concentrations are elevated in this disease but not in other diseases of the pancreas or biliary tract. We measured serum IgG4 concentrations using single radial immunodiffusion and an enzyme-linked immunosorbent assay in 20 patients with sclerosing pancreatitis, 20 age- and sex-matched normal subjects, and 154 patients with pancreatic cancer, ordinary chronic pancreatitis, primary biliary cirrhosis, primary sclerosing cholangitis, or Sjögren's syndrome. Serum concentrations of immune complexes and the IgG4 subclass of immune complexes were determined by means of an enzyme-linked immunosorbent assay with monoclonal rheumatoid factor. The median serum IgG4 concentration in the patients with sclerosing pancreatitis was 663 mg per deciliter (5th and 95th percentiles, 136 and 1150), as compared with 51 mg per deciliter (5th and 95th percentiles, 15 and 128) in normal subjects (P<0.001). The serum IgG4 concentrations in the other groups of patients were similar to those in the normal subjects. In patients with sclerosing pancreatitis, serum concentrations of immune complexes and the IgG4 subclass of immune complexes were significantly higher before glucocorticoid therapy than after four weeks of such therapy. Glucocorticoid therapy induced clinical remissions and significantly decreased serum concentrations of IgG4, immune complexes, and the IgG4 subclass of immune complexes. Patients with sclerosing pancreatitis have high serum IgG4 concentrations, providing a useful means of distinguishing this disorder from other diseases of the pancreas or biliary tract.


Evidence of functional impairment of syngeneically transplanted mouse pancreatic islets retrieved from the liver.
A drawback in pancreatic islet transplantation is the large number of islets needed to obtain insulin independence in patients with diabetes. This most likely reflects extensive posttransplantation islet cell death and functional impairment of the remaining endocrine cells. We aimed to develop an experimental method to retrieve transplanted islets from the mouse liver, which would enable comparisons of transplanted and endogenous islets and provide valuable information on functional changes induced by intraportal transplantation. Transplanted islets were obtained by retrograde perfusion of the liver with collagenase. The identity of retrieved tissue as transplanted islets was confirmed by intravital staining, immunohistochemistry, and electron microscopy. The retrieved islets, irrespective of whether they had resided in diabetic or nondiabetic recipients, had a markedly lower insulin content and glucose-stimulated insulin release when compared with isolated endogenous islets. The glucose oxidation rate was also markedly lower in the retrieved islets, suggesting mitochondrial dysfunction. These disturbances in insulin content, insulin release, and glucose oxidation rate were not reversed by a few days of culture after retrieval. The results implicate changes in islet function after intraportal transplantation. Such dysfunction may contribute to the high number of islets needed for successful transplantation in diabetic individuals.


Bright visible light emission from graphene.
Graphene and related two-dimensional materials are promising candidates for atomically thin, flexible and transparent optoelectronics. In particular, the strong light-matter interaction in graphene has allowed for the development of state-of-the-art photodetectors, optical modulators and plasmonic devices. In addition, electrically biased graphene on SiO2 substrates can be used as a low-efficiency emitter in the mid-infrared range. However, emission in the visible range has remained elusive. Here, we report the observation of bright visible light emission from electrically biased suspended graphene devices. In these devices, heat transport is greatly reduced. Hot electrons (∼2,800 K) therefore become spatially localized at the centre of the graphene layer, resulting in a 1,000-fold enhancement in thermal radiation efficiency. Moreover, strong optical interference between the suspended graphene and substrate can be used to tune the emission spectrum. We also demonstrate the scalability of this technique by realizing arrays of chemical-vapour-deposited graphene light emitters. These results pave the way towards the realization of commercially viable large-scale, atomically thin, flexible and transparent light emitters and displays with low operation voltage and graphene-based on-chip ultrafast optical communications.


Calcified amorphous tumor of the heart: case report.
Calcified amorphous tumor of the heart consists of a cardiac mass of rare nonneoplastic nature that mimics malignancy and causes symptoms due to obstruction or embolization of calcific fragments. We present a case of tumor 17-year-old young, male, in tricuspid valve, with classic pathological findings. It was preferred to approach for classic median esternotomy, installation of the circuit of extracorporal circulation and right atriotomy, exereses of tumor, DeVega's plasty in tricuspid valve and bicuspidization. The amatomopathological study demonstrated presence of extensive calcification and metaplastic bone areas. The patient had an uneventful hospitalization.


Self-schema as a non-drinker: a protective resource against heavy drinking in Mexican-American college women.
Alcohol use is considered less acceptable for women than men in the Mexican culture. However, recent studies of Mexican-American (MA) women show that prevalence and rates of alcohol use are escalating, particularly in those with high acculturation to Western standards. Building on recent studies that demonstrated that drinking-related identities (self-schemas) are important predictors of alcohol use in college populations, this secondary data analysis investigated the association between acculturation, MA cultural values, and acculturative stress, drinking-related self-schemas and heavy drinking over time in college-enrolled MA women. Data were drawn from a 12-month longitudinal study of self-schemas and health-risk behaviors in 477 college-enrolled MA women. Drinking-related self-schemas, acculturation, MA cultural values and acculturative stress were measured at baseline, and heavy drinking was measured at baseline, 3, 6, 9 and 12 months. Thirty-six percent of women had a non-drinker self-schema but only 3% had a drinker self-schema. Higher spirituality was protective against heavy drinking, and this effect can be partially explained by presence of a non-drinker self-schema. Interventions that emphasize the personal relevance of being a non-drinker and support the importance of spirituality may help to prevent heavy drinking in MA college women.


[Ansiform growth of blood vessels as a fundamental principle of angiogenesis].
Succession in formation of blood bed of the greater omentum has been studied in human fetuses (42), in premature children with the body mass of 900-2,500 g (108) and in mature children up to 3 years of age (48). Vasculogenesis in the organ of 12-week-old fetuses and in older ones is demonstrated as an ansiform growth of the vessels. In the vascular loop the afferent geniculum contains differential signs of the arterial, and the different one--the venous part of the blood bed. The top of the loop contains a growth bud and is a zone of growth; it ensures proliferation of the vascular loops and their spreading in the growing tissue mass in the organ. This principle of growth provides a ramified system of arteries and veins, reiterating the course and branching of each other. Against the background of the ansiform growth of the vessels capillary formation begins, at first connective, and then true capillaries are formed. Basing on the data obtained a conception of vasculogenesis in ontogenesis is formulated. Its main stages are--period of ansiform growth of the vessels and period of capillary formation. In the latter should be distinguished appearance of connective capillaries and formation of truely capillary network.


Accelerated free-breathing whole-heart 3D T2 mapping with high isotropic resolution.
To enable free-breathing whole-heart 3D T2 mapping with high isotropic resolution in a clinically feasible and predictable scan time. This 3D motion-corrected undersampled signal matched (MUST) T2 map is achieved by combining an undersampled motion-compensated T2 -prepared Cartesian acquisition with a high-order patch-based reconstruction. The 3D MUST-T2 mapping acquisition consists of an electrocardiogram-triggered, T2 -prepared, balanced SSFP sequence with nonselective saturation pulses. Three undersampled T2 -weighted volumes are acquired using a 3D Cartesian variable-density sampling with increasing T2 preparation times. A 2D image-based navigator is used to correct for respiratory motion of the heart and allow 100% scan efficiency. Multicontrast high-dimensionality undersampled patch-based reconstruction is used in concert with dictionary matching to generate 3D T2 maps. The proposed framework was evaluated in simulations, phantom experiments, and in vivo (10 healthy subjects, 2 patients) with 1.5-mm3 isotropic resolution. Three-dimensional MUST-T2 was compared against standard multi-echo spin-echo sequence (phantom) and conventional breath-held single-shot 2D SSFP T2 mapping (in vivo). Three-dimensional MUST-T2 showed high accuracy in phantom experiments (R2 > 0.99). The precision of T2 values was similar for 3D MUST-T2 and 2D balanced SSFP T2 mapping in vivo (5 ± 1 ms versus 4 ± 2 ms, P = .52). Slightly longer T2 values were observed with 3D MUST-T2 in comparison to 2D balanced SSFP T2 mapping (50.7 ± 2 ms versus 48.2 ± 1 ms, P < .05). Preliminary results in patients demonstrated T2 values in agreement with literature values. The proposed approach enables free-breathing whole-heart 3D T2 mapping with high isotropic resolution in about 8 minutes, achieving accurate and precise T2 quantification of myocardial tissue in a clinically feasible scan time.


The Disordered Linker in p53 Participates in Nonspecific Binding to and One-Dimensional Sliding along DNA Revealed by Single-Molecule Fluorescence Measurements.
The tumor suppressor p53 is a multidomain transcription factor that can quickly bind to its target DNA by sliding along the DNA strand. We hypothesized that the intrinsically disordered and positively charged linker of p53 regulates its search dynamics first by directly interacting with DNA and second by modulating hopping of the core domain. To test the two hypotheses, we prepared five variants of p53 in which the length and charge of the linker were modulated. The affinity for and sliding along nonspecific DNA of p53 were altered by the charge of the linker, but not by the linker length. In particular, charge neutralization significantly reduced the affinity, suggesting that the linker directly contacts the DNA. Charge neutralization eliminated the slow mode of sliding, in which the core domain was assumed to contact nonspecific DNA. In contrast, the affinity of p53 for the target DNA was not affected by linker mutations. These results demonstrate that the linker participates in a target search of p53 by contacting nonspecific DNA and recruiting the core domain to contact DNA.


N-glycan Utilization by Bifidobacterium Gut Symbionts Involves a Specialist β-Mannosidase.
Bifidobacteria represent one of the first colonizers of human gut microbiota, providing to this ecosystem better health and nutrition. To maintain a mutualistic relationship, they have enzymes to degrade and use complex carbohydrates non-digestible by their hosts. To succeed in the densely populated gut environment, they evolved molecular strategies that remain poorly understood. Herein, we report a novel mechanism found in probiotic Bifidobacteria for the depolymerization of the ubiquitous 2-acetamido-2-deoxy-4-O-(β-d-mannopyranosyl)-d-glucopyranose (Man-β-1,4-GlcNAc), a disaccharide that composes the universal core of eukaryotic N-glycans. In contrast to Bacteroidetes, these Bifidobacteria have a specialist and strain-specific β-mannosidase that contains three distinctive structural elements conferring high selectivity for Man-β-1,4-GlcNAc: a lid that undergoes conformational changes upon substrate binding, a tryptophan residue swapped between the two dimeric subunits to accommodate the GlcNAc moiety, and a Rossmann fold subdomain strategically located near to the active site pocket. These key structural elements for Man-β-1,4-GlcNAc specificity are highly conserved in Bifidobacterium species adapted to the gut of a wide range of social animals, including bee, pig, rabbit, and human. Together, our findings uncover an unprecedented molecular strategy employed by Bifidobacteria to selectively uptake carbohydrates from N-glycans in social hosts.


Heterogeneous versus homogeneous crystal nucleation of hard spheres.
Hard-sphere model systems are well-suited in both experiment and simulations to investigate fundamental aspects of the crystallization of fluids. In experiments on colloidal models of hard-sphere fluids, the fluid is unavoidably in contact with the walls of the sample cell, where heterogeneous crystallization may take place. In this work we use simulations to investigate the competition between homogeneous and heterogeneous crystallization. We report simulations of wall-induced nucleation for different confining walls. Combining the results of these simulations with earlier studies of homogeneous crystallization allows us to assess the competition between homogeneous and heterogeneous nucleation as a function of the wall type, fluid density and the system size. On flat walls, heterogeneous nucleation will typically overwhelm homogeneous nucleation. Even for surfaces randomly coated with spheres with a diameter that was some three times larger than that of the fluid spheres - as has been used in some experiments - heterogeneous nucleation is likely to be dominant for volume fractions smaller than ∼0.535. Only for a disordered coating that has the same structure as the liquid did we find that nucleation was likely to occur in the bulk. Hence, such coatings might be used to suppress heterogeneous nucleation in experiments. Finally, we report the apparent homogeneous nucleation rate taking into account the formation of crystallites both in the bulk and at the walls. We find that the apparent overall nucleation rates coincide with those reported in "homogeneous nucleation" experiments. This suggests that heterogeneous nucleation at the walls could partly explain the large discrepancies found between experimental measurements and simulation estimates of the homogeneous nucleation rate.