RecA-like activity in mammalian cell extracts of different origin.
The occurrence of a RecA-like activity similar to the one detected in the fibroblast cell line GM1492 derived from a patient suffering from the autosomal recessive disease Bloom's syndrome has been investigated in cell extracts of different origin. The formation of D-loop containing joint molecules from phi X174 RFI DNA and fragments of phi X174 single-stranded DNA by partially purified extracts was measured by a filter binding assay. The RecA-like activity, dependent on ATP and Mg2+, was detected at an elevated level only in the human and rodent cell lines, GM1492 and CHO respectively. The level of activity in DNA-cellulose-purified cell extracts from these cell lines was 4-7-fold higher compared to normal human fibroblasts. Low levels of activity were also detected in extracts from two additional Bloom's syndrome fibroblast cell lines, Fanconi's anemia fibroblasts, virus- (Epstein-Barr virus, Simian virus 40) transformed human cells and human placenta. Cell extracts from rat testis, spleen and calf thymus were also of low activity.


Concerted stimulation of PI-turnover, Ca2+-influx and histamine release in antigen-activated rat mast cells.
Phospholipid metabolism in rat mast cells activated by antigen was examined with reference to phosphatidylinositol (PI) turnover. Upon antigen stimulation, histamine release from passively sensitized mast cells with IgE was potentiated by adding phosphatidylserine (PS). The addition of antigen to [3H]glycerol-prelabeled and sensitized mast cells induced a marked loss of radioactivity of PI and a concurrent accumulation of 1,2-diacylglycerol (DG) and phosphatidic acid (PA) within 5 to 60 sec. Furthermore, this antigen-induced PI breakdown was enhanced in the presence of Mg2+. Histamine release occurred in parallel with PI breakdown. On the other hand, the transient Ca2+ influx into mast cells, as measured by uptake of 45Ca2+, was found to occur quickly after cells were activated by antigen, which was concerted with PI breakdown. These results suggest that enhanced PI turnover may be an important step in the biochemical sequence of events leading to release of histamine, and that not only Ca2+ but also Mg2+ appears to take a part in stimulus-response coupling in rat mast cells.


Nationwide classification of forest types of India using remote sensing and GIS.
India, a mega-diverse country, possesses a wide range of climate and vegetation types along with a varied topography. The present study has classified forest types of India based on multi-season IRS Resourcesat-2 Advanced Wide Field Sensor (AWiFS) data. The study has characterized 29 land use/land cover classes including 14 forest types and seven scrub types. Hybrid classification approach has been used for the classification of forest types. The classification of vegetation has been carried out based on the ecological rule bases followed by Champion and Seth's (1968) scheme of forest types in India. The present classification scheme has been compared with the available global and national level land cover products. The natural vegetation cover was estimated to be 29.36% of total geographical area of India. The predominant forest types of India are tropical dry deciduous and tropical moist deciduous. Of the total forest cover, tropical dry deciduous forests occupy an area of 2,17,713 km(2) (34.80%) followed by 2,07,649 km(2) (33.19%) under tropical moist deciduous forests, 48,295 km(2) (7.72%) under tropical semi-evergreen forests and 47,192 km(2) (7.54%) under tropical wet evergreen forests. The study has brought out a comprehensive vegetation cover and forest type maps based on inputs critical in defining the various categories of vegetation and forest types. This spatially explicit database will be highly useful for the studies related to changes in various forest types, carbon stocks, climate-vegetation modeling and biogeochemical cycles.


[Demonstration of the sources of several descending forebrain systems using the horseradish peroxidase retrograde axonal transport technic].
Cells of cortical and diencephalic fibres descending to the mesencephalic and bulbar reticular formation and to the dorsal column nuclei were identified. According to findings neurons sending fibres to the mesencephalic reticular formation are located in orbitofrontal pole and in area 6 of the pericruciate cortex, mainly ipsilaterally. Neurons which distribute fibres to the bulbar reticular formation are concentrated mainly in area 6 and 4 of the both hemispheres, while those distributing fibres to dorsal column nuclei are arranged in areas 1, 2, 3 and 4, mainly contralaterally. Fibres descending to reticular formation from the limbic cortex, septum, substantia innominata and amygdala were also found. The functional significance of the investigated descending pathways of forebrain is discussed.


Investigation of the influence of acetylsalicylic acid on the steady state of long-term therapy with theophylline in elderly male patients with normal renal function.
The risk inherent in the clinical control of patients with theophylline is widely recognized. Elderly patients may present an additional risk because of altered pharmacokinetics and the use of concomitant medication. Acetylsalicylic acid has been proposed for primary and secondary prevention of myocardial infarction and possible strokes. This investigation was undertaken to determine if concomitant administration of acetylsalicylic acid in elderly patients would alter steady-state levels of theophylline. A population of smoking male patients older than 60 years of age under long-term control of chronic obstructive pulmonary disease (COPD) with theophylline were evaluated for a baseline period of 3 days. Serum levels were measured at 6:00 AM and 6:00 PM. An enteric-coated acetylsalicylic acid preparation, 650 mg by mouth, was added to the daily slow-release theophylline, 6:00 AM hour dose regimen for 4 weeks. The serum levels of theophylline and salicylates were measured at 6:00 PM after dosing and at 6:00 AM the following day, at weekly intervals for 4 weeks. Urine specimens collected before administration of medication at 6:00 AM were analyzed for salicylates to further confirm dosage compliance. All volunteers continued to be clinically controlled throughout the treatment period and no symptoms of either overdose or underdose of either medication occurred. Plateau or trough theophylline serum levels did not change significantly during the salicylate treatment period. Salicylate serum levels did show during treatment self-induced metabolism. It is concluded that in elderly male patients, a daily concomitant therapeutic salicylate regimen does not alter steady-state serum theophylline levels and therefore does not per se necessitate the assay of theophylline blood levels in elderly patients.


Racial and Ethnic Abortion Disparities Following Georgia's 22-Week Gestational Age Limit.
Georgia's 2012 House Bill 954 (HB954) prohibiting abortions after 22 weeks from last menstrual period (LMP) has been associated with a significant decrease in abortions after 22 weeks. However, the policy's effects by race or ethnicity remain unexplored. We investigated whether changes in abortion numbers and ratios (per 1,000 live births) in Georgia after HB954 varied by race or ethnicity. Using Georgia Department of Public Health induced terminations of pregnancy data from 2007 to 2017, we examined changes in number of abortions and abortion ratios (per 1,000 live births) by race and ethnicity following HB954 implementation. After full implementation of HB954 in 2015, the number of abortions and abortion ratios at or after 22 weeks (from last menstrual period) decreased among White (bNumber = -261.83, p < .001; bRatio = -3.31, p < .001), Black (bNumber = -416.17, p < .001; bRatio = -8.84, p < .001), non-Hispanic (bNumber = -667.00, p = .001; bRatio = -5.82, p < .001), and Hispanic (bNumber = -56.25, p = .002; bRatio = -2.44, p = .002) people. However, the ratio of abortions before 22 weeks increased for Black people (bLessThan22Weeks = 44.06, p = .028) and remained stable for White (bLessThan22Weeks = -6.78, p = .433), Hispanic (bLessThan22Weeks = 21.27, p = .212), and non-Hispanic people (bLessThan22Weeks = 26.93, p = .172). The full implementation of HB954 had differential effects by race/ethnicity and gestational age. Although abortion at 22 weeks or more decreased for all groups, abortion at less than 22 weeks increased among Black people. Additional research should elucidate the possible causes, consequences, and reactions to differential effects of abortion restrictions by race and ethnicity.


Anatomy of the distal biceps tendon: an in vivo 3-T magnetic resonance imaging study.
On the basis of the current literature, the optimal surgical technique for distal biceps tendon tears remains controversial. Cadaveric studies have investigated distal biceps anatomy but are limited by cohort size and tissue factors. We sought to investigate distal biceps anatomy in vivo by retrospectively reviewing magnetic resonance imaging (MRI) scans. An improved understanding of the anatomy of the distal biceps tendon will lead to better definition of the optimal anatomic surgical repair. Two independent observers retrospectively reviewed 3-T MRI scans of elbows. Basic demographic data were collected, and measurements of tendon length, footprint width, footprint length, and footprint angle were taken using simultaneous tracker lines and a standardized technique. From the biceps muscle belly distally, the presence of a single tendon or double tendons was recorded and the tendon interdigitation point was measured if relevant. A total of 106 3-T MRI scans of 106 elbows of 103 patients were included. There were 71 male and 32 female patients, and the mean age was 44.7 years. Most distal biceps tendons exited the biceps muscle belly as separate entities (91%, 96 of 106 elbows) and then coalesced prior to insertion on the radial tuberosity (91%, 87 of 96 elbows). There was a positive correlation between tendon length and footprint length (P < .05), as well as between tendon length and footprint width (P < .05). The mean tendon length was 65.2 mm (95% confidence interval [CI], 63.3-66.8 mm; range, 44.3-86.8 mm), the mean distance from the musculotendinous junction to the interdigitation point was 38.3 mm (95% CI, 35.8-40.9 mm; range, 8.9-64.8 mm), the mean footprint width was 10.3 mm (95% CI, 9.9-10.7 mm; range, 5.9-16.3 mm), the mean footprint length was 16.2 mm (95% CI, 15.6-16.9; range, 7.3-25.4 mm), and the mean footprint angle was 32.1° (95% CI, 29.5°-34.6°; range, 8.5°-84.3°). An in vivo, high-resolution study of the anatomy of the distal biceps tendon improves our understanding of its complex morphology and hence our ability to perform an anatomic "footprint repair."


Embryo-fetal distribution of a biopharmaceutical IgG2 during rat organogenesis.
Embryo-fetal biodistribution of a maternally administered humanized IgG2 in rats was evaluated by enzyme-linked immunosorbent assay in dose response and time course studies. Fetal and maternal plasma IgG2 levels increased with dose from 10 to 300mg/kg but fetal:maternal ratio decreased with increasing dose. Plasma IgG2 levels decreased in fetal rat with increasing time post-dose but more slowly than maternal levels. This difference in post-dose kinetics resulted in an increased fetal:maternal ratio with increasing days since last dose. Lastly, IgG2 in embryo-fetal tissue was detected at very low levels on gestation day (GD) 10-12 and levels increased over 100-fold by GD 17. The profile of increasing IgG2 levels as gestation progressed continued in extra-embryonic fluid (GD 12-19) until the end of gestation in fetal plasma (GD 19-21). Based on the current study, there is a potential for direct effects on rat embryo-fetal development following maternal administration of a biopharmaceutical IgG2.


Reduced phosphorylation of Stat3 at Ser-727 mediated by casein kinase 2 - protein phosphatase 2A enhances Stat3 Tyr-705 induced tumorigenic potential of glioma cells.
Signal transducer and activator of transcription 3 (Stat3) is a transcription factor that is involved in cell survival and proliferation and has been found to be persistently activated in most human cancers mainly through its phosphorylation at Tyr-705. However, the role and regulation of Stat3 Ser-727 phosphorylation in cancer cells have not been clearly evaluated. In our findings, correlation studies on the expression of CK2 and Stat3 Ser-727 phosphorylation levels in human glioma patient samples as well as rat orthotopic tumor model show a degree of negative correlation. Moreover, brain tumor cell lines were treated with various pharmacological inhibitors to inactivate the CK2 pathway. Here, increased Stat3 Ser-727 phosphorylation upon CK2 inhibition was observed. Overexpression of CK2 (α, α' or β subunits) by transient transfection resulted in decreased Stat3 Ser-727 phosphorylation. Stat3 Tyr-705 residue was conversely phosphorylated in similar situations. Interestingly, we found PP2A, a protein phosphatase, to be a mediator in the negative regulation of Stat3 Ser-727 phosphorylation by CK2. In vitro assays prove that Ser-727 phosphorylation of Stat3 affects the transcriptional activity of its downstream targets like SOCS3, bcl-xl and Cyclin D1. Stable cell lines constitutively expressing Stat3 S727A mutant showed increased survival, proliferation and invasion which are characteristics of a cancer cell. Rat tumor models generated with the Stat3 S727A mutant cell line formed more aggressive tumors when compared to the Stat3 WT expressing stable cell line. Thus, in glioma, reduced Stat3 Ser-727 phosphorylation enhances tumorigenicity which may be regulated in part by CK2-PP2A pathway.


Ultra-sensitive immunosensor for detection of hepatitis B surface antigen using multi-functionalized gold nanoparticles.
The signal amplification for analytical purposes has considerable potential in detecting trace levels of analytes for clinical, security or environmental applications. In the present report a strategy based on a sandwich type immunoassay system was designed for the detection of hepatitis B surface antigen which exploits the specific affinity interaction between streptavidin and biotin recognition systems. The method involves the specific coupling of multi-functionalized gold nanoparticles (bearing biotin and luminol molecules) to the streptavidin modified by secondary antibody. The chemiluminescent signal is produced by the gold nanoparticles in the presence of HAuCl4 as catalyst and hydrogen peroxide as oxidant. The immunosensor was able to detect hepatitis B surface antigen in the linear concentration range from 1.7 to 1920 pg mL(-1) and the detection limit of 0.358 pg mL(-1), at signal/noise = 3.


Minor diterpenoids from Halimium viscosum.
Two new diterpenic acids with an ent-halimane skeleton have been isolated from the aerial parts of Halimium viscosum (Villarino de los Aires chemotype) and separated as methyl esters. These diterpenes were 13-oxo-14, 15-dinor-1(10),11E-ent-halimadien-18-oic acid and 15-hydroxy-1(10),13Z-ent-halimadien-18-oic acid.


Concomitant activation of the PI3K-Akt and the Ras-ERK signaling pathways is essential for transformation by the V-SEA tyrosine kinase oncogene.
V-SEA is the transforming component of S13 Avian Erythroblastosis Retrovirus that causes erythroblastosis and anemia in chicken. Like all members in the family (MET, RON, SEA), its cytosolic domain possesses two tyrosine autophosphorylation sites in the tandemly arranged bidentate motif that serve as docking sites for SH2 domain-containing proteins. Here, we investigated phosphotyrosine-dependent activation of signaling pathways and their significance in V-SEA-induced transformation and/or proliferation. We demonstrated that V-SEA activates the PI3K-Akt signaling pathway primarily in Y557- and secondarily in Y564-dependent manner. V-SEA was also shown to induce the tyrosine phosphorylation of the Gab2 protein, leading to PI3K association and thus providing an alternative route for PI3K activation. On the other hand, activation of the Ras-ERK pathway is primarily via Y564 and secondarily via Y557. A dominant-negative form of Ras inhibited V-SEA-induced ERK phosphorylation in concentration dependent manner suggesting the importance of the Grb2-Ras signaling axis in V-SEA-induced ERK activation. The biological significance of activation of the PI3K-Akt and the Ras-ERK pathways in V-SEA-induced transformation was analysed in the V-SEA-RAT1 and V-SEA-3T3 cell lines by employing specific inhibitors, LY294002 and PD98059 compounds. Both the PD and LY compounds inhibited cell growth, but only the PD compound caused reversion of the transformed phenotype. In addition, both compounds inhibited focal colony formation by the transformants in soft agar. Thus, transformation by the V-SEA oncogene is a function of the concomitant activation of, at least, the PI3K-Akt and Ras-ERK signaling pathways that regulate cell growth and morphology.


Antibodies against gonadotropin-releasing hormone (GnRH) in patients with diabetes mellitus is associated with lower body weight and autonomic neuropathy.
Esophageal dysmotility and gastroparesis are common secondary complications in patients with diabetes mellitus. Patients with dysmotility express antibodies against gonadotropin-releasing hormone (GnRH) in serum. The aim of the present study was to scrutinize patients with diabetes mellitus with regard to the presence of GnRH antibodies, and to examine associations between antibodies and clinical findings. Thirty-nine consecutive patients with diabetes mellitus were included in the study after clinical examination and examination by esophageal manometry and gastric emptying scintigraphy. Serum was analyzed for the presence of antibodies against GnRH using an ELISA, and values are expressed as relative units (RU). Two age- and gender-matched healthy subjects per each patient served as controls. The prevalence of IgM GnRH antibodies in patients was 33% compared to 14% in controls (p = 0.027), with a higher antibody titer; 1.2 (0.6-5.0) and 0.2 (0.1-0.3) RU, respectively (p = 0.000). The expression of IgG antibodies was 15% in patients and none in controls (p = 0.000). Lower body mass index was associated with the presence of IgM antibodies (OR = 0.835, 95% CI = 0.699-0.998), and autonomic neuropathy with the presence IgG antibodies (OR = 9.000, 95% CI = 1.327-61.025). Esophageal dysmotility (69%) or gastroparesis (18%) were not associated with the presence of IgM antibodies (OR = 0.589, 95% CI = 0.143-2.424 and OR = 3.407, 95% CI = 0.633-18.350, respectively). Neither was esophageal dysmotility associated with IgG antibodies (OR = 2.500, 95% CI = 0.259-24.096). Antibodies against GnRH are more common in patients with diabetes mellitus compared with healthy controls. IgM antibodies are associated with lower body mass index and IgG antibodies are associated with autonomic neuropathy.


Organophosphorous and organochlorine pesticides affect human placental phosphoinositides metabolism and PI-4 kinase activity.
The objective of this work was to describe the effect of organophosphorous and organochlorine pesticides on phosphoinositides metabolism in human placenta. Pesticides concentration (10 microM) was used for in vitro incubations of cell-free homogenates labelled with (32)P orthophosphate. Heptachlor (HC) and dichloro-diphenyl-trichloroethane (o-p' DDT) increased phosphatidyl-inositol, phosphatidylinositolphosphate, and phosphatidyl-inositolbiphosphate phosphorylation while azinphosmethyl (AM) increased phosphatidylinositolbiphosphate labeling. Decreased (32)P incorporation in phosphatidylinositol was found with phosmet (PM), AM, and chlorpyriphos (CHL). The effects of these xenobiotics on PI4-kinase activity using different subcellular fractions were also examined. Both type of pesticides affected the postmembrane supernatant enzyme activity. A biphasic effect on membrane and nuclear PI4-kinase activity was seen with HC. The strongest effect found was seen with o-p' DDT in nuclear kinase activity while substantial changes were also observed in membrane. These data demonstrate the sensitivity of human placental PI4-kinase to pesticides currently found in human tissues and suggest deleterious consequences in different processes regulated by 4-phosphoinositides.


Crosstalk between dopamine D₂ receptors and cannabinoid CB₁ receptors regulates CNR1 promoter activity via ERK1/2 signaling.
Previously, we found that chronic methamphetamine treatment altered cannabinoid type 1 receptor (CB₁R)-dependent cAMP/PKA/dopamine and cAMP-regulated phosphoprotein of Mr 32,000 (DARPP-32)/T34/PP2B signaling and decreased levels of CB₁R protein and mRNA in the nucleus accumbens. These findings suggested the existence of signaling interplay between mesolimbic dopamine and CB₁R. In this study, we further investigate interactions between CB₁R and dopamine D2 receptor (D₂R) signaling. Activation of either CB₁R or D₂R increased extracellular signal-regulated kinases 1 and 2 (ERK1/2) phosphorylation, while co-stimulation of CB₁R and D2 R evoked an additive effect on the phospho-ERK1/2 signal. This effect was mediated through a pertussis toxin-sensitive Gαi/o pathway in primary striatal cells. Furthermore, the mRNA level of CB₁R was increased via dopamine D2 receptor short form (D(2S)R) by treatment with D₂R agonist quinpirole in D(2S)R/C6 glioma cells. This effect could be suppressed by co-treatment with the ERK1/2 inhibitor U0126. To test if D(2S)R could transcriptionally regulate CB₁R, the 5'-untranslated region (5'-UTR) of the cannabinoid receptor 1 (CNR1) gene was sequenced from rat brain. Results showed that the CNR1 gene includes two exons, which contain 375 bp of 5'-UTR and are separated by a 17-kb intron. A luciferase reporter assay showed that the maximal D(2S)R-responsive promoter activity is located in the -1 to -222 region of CNR1 promoter. Overall, we demonstrate previously unidentified crosstalk between D₂R and CB₁R via ERK1/2 signaling that enhances the expression of CB₁R by modulating its promoter activity.


Shared genetic background for regulation of mood and sleep: association of GRIA3 with sleep duration in healthy Finnish women.
Sleeping 7 to 8 hours per night appears to be optimal, since both shorter and longer sleep times are related to increased morbidity and mortality. Depressive disorder is almost invariably accompanied by disturbed sleep, leading to decreased sleep duration, and disturbed sleep may be a precipitating factor in the initiation of depressive illness. Here, we examined whether, in healthy individuals, sleep duration is associated with genes that we earlier found to be associated with depressive disorder. Population-based molecular genetic study. Regression analysis of 23 risk variants for depressive disorder from 12 genes to sleep duration in healthy individuals. Three thousand, one hundred, forty-seven individuals (25-75 y) from population-based Health 2000 and FINRISK 2007 samples. We found a significant association of rs687577 from GRIA3 on the X-chromosome with sleep duration in women (permutation-based corrected empirical P=0.00001, β=0.27; Bonferroni corrected P=0.0052; f=0.11). The frequency of C/C genotype previously found to increase risk for depression in women was highest among those who slept for 8 hours or less in all age groups younger than 70 years. Its frequency decreased with the lengthening of sleep duration, and those who slept for 9 to 10 hours showed a higher frequency of C/A or A/A genotypes, when compared with the midrange sleepers (7-8 hours) (permutation-based corrected empirical P=0.0003, OR=1.81). The GRIA3 polymorphism that was previously found to be associated with depressive disorder in women showed an association with sleep duration in healthy women. Mood disorders and short sleep may share a common genetic background and biologic mechanisms that involve glutamatergic neurotransmission.


Genetic Diagnosis of Pyruvate Kinase Deficiency in Undiagnosed Iranian Patients with Severe Hemolytic Anemia, using Whole Exome Sequencing.
After ruling out the most common causes of severe hemolytic anemia by routine diagnostic tests, certain patients remain without a diagnosis. The aim of this study was to elucidate the genetic cause of the disease in these patients using next generation sequencing (NGS). Four unrelated Iranian families including six blood transfusion dependent cases and their parents were referred to us from a specialist center in Tehran. There was no previous history of anemia in the families and the parents had no abnormal hematological presentations. All probands presented severe congenital hemolytic anemia, neonatal jaundice and splenomegaly. Common causes of hemolytic anemia were ruled out prior to this investigation in these patients and they had no diagnosis. Whole exome sequencing (WES) was performed in the probands and the results were confirmed by Sanger sequencing and subsequent family studies. We identified five variants in the PKLR gene, including a novel unpublished frameshift in these families. These variants were predicted as pathogenic according to the ACMG guidelines by Intervar and/or Varsome prediction tools. Subsequent family studies by Sanger sequencing supported the diagnosis of pyruvate kinase deficiency (PKD) in six affected individuals and the carrier status of disease in their parents. These findings show that PKD is among the rare blood disorders that could remain undiagnosed or even ruled out in Iranian population without performing NGS. This could be due to pitfalls in clinical, hematological or biochemical approaches in diagnosing PKD. Furthermore, genotyping PKD patients in Iran could reveal novel mutations in the PKLR gene.


Risk factors for a serious adverse outcome in neonates: a retrospective cohort study of vaginal births.
To investigate the hypothesis that risk factors in addition to an abnormal fetal heart rate pattern (aFHRp) are independently associated with adverse neonatal outcomes of labour. Observational prospective cohort study. 17 UK maternity units. 585 291 pregnancies between 1988 and 2000 inclusive. Adjusted odds ratios (OR) with 95% confidence intervals (95% CI) were estimated from multivariable logistic regression. Adverse neonatal outcome at term (5-minute Apgar score <7, and a composite measure comprising 5-minute Apgar score <7, resuscitation by intubation and/or perinatal death). Analysis was based on 302 137 vaginal births at 37-42 weeks inclusive. We found a higher odds of Apgar score at 5 minutes <7 with suspected fetal growth restriction (OR 1.34, 95% CI 1.16-1.53), induction of labour (OR 1.41, 95% CI 1.25-1.58), nulliparity (OR 1.48, 95% CI 1.34-1.63), booking body mass index ≥30 (OR 1.18, 95% CI 1.02-1.37), maternal age <25 (OR 1.23, 95% CI 1.10-1.39), black ethnicity (OR 1.21, 95% CI 1.03-1.43), early-term birth at 37-38 weeks (OR 1.13, 95% CI 1.02-1.25), late-term birth at 41-42 weeks (OR 1.14, 95% CI 1.01-1.28), use of oxytocin (OR 1.27, 95% CI 1.14-1.41), maternal pyrexia (OR 1.87, 95% CI 1.46-2.40), aFHRp and presence of meconium (aFHRp without meconium: OR 2.40, 95% CI 2.15-2.69; meconium without aFHRp: OR 2.20, 195% CI.94-2.49; both aFHRp and meconium: OR 4.26, 95% CI 3.74-4.87). The results were similar when the composite adverse outcome was considered. A range of risk factors, including suspicion of fetal growth restriction, maternal pyrexia and presence of meconium, are implicated in poor birth outcomes in addition to aFHRp. Interpretation of the fetal heart rate pattern alone is insufficient as a basis for decisions about escalation and intervention.


Thiamin mono- and pyrophosphatase activities from brain homogenate of Guamanian amyotrophic lateral sclerosis and parkinsonism-dementia patients.
Thiamin-pyrophosphatase (TPPase) and thiamin-monophosphatase (TMPase) were determined using a spectrophotometric method at various pH values (5.5, 7.5, and 9.0) in brain tissue obtained at autopsy from amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia (PD) patients from Guam and from Guamanian patients who died from other diseases (controls). TPPase separation by thin-layer polyacrylamide gel isoelectric focusing (IEF) was also performed using both gray and white matter. TPPase content, chemically determined at pH 9.0, was found to be significantly reduced in the frontal cortex of ALS and PD patients compared to controls. TMPase content, on the contrary, was unchanged. IEF analysis showed 9 clear-cut bands with TPPase activity in the pH range 5.4-7.2 and a broad band at pH 4.7-5.2. The enzymatic activity was higher in gray than in white matter. In one patient the pattern was clearly different, with two additional bands observed at pH 7.1 and 6.7, and thought to be due to genetic microheterogeneity.


New approaches to EGFR inhibition for locally advanced or metastatic squamous cell carcinoma of the head and neck (SCCHN).
Despite recent advances in radiotherapy and chemotherapy, survival rates for squamous cell carcinoma of the head and neck (SCCHN) have remained poor. The focus of SCCHN therapy has more recently shifted to the molecular level, particularly the epidermal growth factor receptor (EGFR/ErbB) pathway. Several agents that target the EGFR pathway, including monoclonal antibodies and tyrosine kinase inhibitors, are under investigation for SCCHN. Searches of PubMed and results of key oncology congresses were performed to identify relevant articles and abstracts. The EGFR-targeted monoclonal antibody cetuximab is approved for the treatment of locally advanced SCCHN in combination with radiotherapy, for first-line treatment of recurrent or metastatic SCCHN in combination with platinum-based chemotherapy and 5-fluorouracil, and for recurrent or metastatic SCCHN following progression with platinum-based chemotherapy. Other investigational EGFR-targeted monoclonal antibodies (e.g., panitumumab, nimotuzumab, zalutumumab) are in clinical development for SCCHN. Inhibition of the tyrosine kinase domain of EGFR has also been explored as a therapeutic approach in SCCHN using small-molecule reversible inhibitors, such as gefitinib and erlotinib. However, a key challenge in SCCHN is the development of resistance, and strategies are being pursued to delay or overcome resistance to EGFR-targeted agents. These strategies include development of agents that inhibit multiple ErbB receptors simultaneously (e.g., lapatinib) or that bind multiple ErbB family receptors irreversibly (e.g., afatinib, PF-00299804) and investigation of combinations of agents that target multiple pathways implicated in the pathogenesis of SCCHN. Ongoing large clinical trials are evaluating these emerging agents and combinations for the treatment of SCCHN.


Senescence-associated secretory phenotype constructed detrimental and beneficial subtypes and prognostic index for prostate cancer patients undergoing radical prostatectomy.
Cellular senescence is growing in popularity in cancer. A dual function is played by the senescence-associated secretory phenotype (SASP) that senescent cells produce in the development of pro-inflammatory niches, tissue regeneration or destruction, senescence propagation, and malignant transformation. In this study, we conducted thorough bioinformatic analysis and meta-analysis to discover detrimental and beneficial subtypes and prognostic index for prostate cancer (PCa) patients using the experimentally confirmed SASP genes. We identified differentially expressed and prognosis-related SASP genes and used them to construct two molecular subtypes and risk score. Another two external cohorts were used to confirm the prognostic effect of the above subtypes and risk score and meta-analysis was further conducted. Additionally, functional analysis, tumor stemness and heterogeneity and tumor microenvironment were also evaluated. We completed analyses using software R 3.6.3 and its suitable packages. Meta-analysis was performed by software Stata 14.0. Through multivariate Cox regression analysis and consensus clustering analysis, we used VGF, IGFBP3 and ANG to establish detrimental and beneficial subtypes in the TCGA cohort, which was validated through other two independent cohorts. Meta-analysis showed that detrimental SASP group had significantly higher risk of biochemical recurrence (BCR) than beneficial SASP group (HR: 2.48). Moreover, we also constructed and validated risk score based on these genes to better guide clinical practice. DNA repair, MYC target, oxidative phosphorylation, proteasome and ribosome were highly enriched in detrimental SASP group. Detrimental SASP group had significantly higher levels of B cells, CD8+ T cells, homologous recombination deficiency, loss of heterozygosity, microsatellite instability, purity, tumor mutation burden, mRNAsi, differentially methylated probes and epigenetically regulated RNA expression than beneficial SASP group. The top mutation genes between detrimental and beneficial SASP groups were SPOP, FOXA1, KMT2C, APC, BSN, DNAH17, MYH6, EPPK1, ZNF536 and ZC3H13 with statistical significance. From perspective of SASP, we found detrimental and beneficial tumor subtypes which were closely associated with BCR-free survival for PCa patients, which might be important for the furture research in the field of PCa.


Vitamin D and functional arterial parameters in postmenopausal women with metabolic syndrome.
Our cross sectional study aimed to identify the relation between vitamin D level and functional arterial parameters in postmenopausal women with metabolic syndrome. 100 postmenopausal women at age 50-65 with diagnosed metabolic syndrome were included in this study. Laboratory tests were performed to determine lipid profile, serum glucose, creatinine, C-reactive protein, serum levels of 25(OH) D, ionized calcium and urine albumin/creatinine ratio. Also non-invasive assessment of arterial function (arterial stiffness, flow-mediated dilatation and carotid artery ultrasound examinations) was performed. The mean vitamin D blood concentration was 47.4±16.9nmol/l. The prevalence of modest insufficiency and deficiency of vitamin D was 62%. Vitamin D concentration in samples assembled from January to March was significantly lower than concentration levels from September to November. No significant relationship was observed between vitamin D and endothelial function, arterial stiffness, carotid intima-media thickness. Week negative correlation was stated between mean arterial pressure and 25(OH) D concentration (p=0.04). A positive correlation was found between high density lipoprotein cholesterol and vitamin 25(OH) D (r=0.3, p<0.05). No significant difference between 25(OH) D and other lipoproteins, calcium ions, glucose, albumin/creatinine ratio and C-reactive protein blood concentrations were found. The prevalence of vitamin D deficiency in postmenopausal women with metabolic syndrome is high. No relation was found between vitamin D levels and parameters that indicate atherosclerotic vascular lesions. Nevertheless our study revealed the relation between concentrations of vitamin D and mean blood pressure and high density lipoprotein cholesterol.


Are we prepared for animal cell technology in the 21st century?
Large scale animal cell culture for the production of complex therapeutic proteins has been a major success of the biotechnology industry. Today, approximately half of the $ 5 billion annual turnover of the biotechnology industry is based upon this technology, in many cases with reactors of more than 10 m(3). As we look towards the 21 st century, however, we can see novel approaches to the production of therapeutic proteins, by means of gene and cellular therapies. These technologies present new engineering challenges to the animal cell technologist. Are we prepared to meet these challenges? The needs include: small-scale reactors for the preparation of autologous cell lines, methods for the production of viruses to be used as vectors in gene therapy, artificial organ and the processing of xenogenic cell lines and tissues for cellular implants in humans. More attention should be given to three-dimensional cell cultures. Mass transfer considerations need to be extended beyond just oxygen transfer, to include cellular communication in small systems; this is becoming increasingly important for the control and optimise growth and product formation. Apart from improvements of large-scale systems, substantial advantages could be gained by studying new methods for the production and delivery of therapeutic proteins, using small-scale cell culture systems. We should adapt teaching, regulatory, patent and clinical infrastructure to meet this challenge in a harmonious way.


[A comparison of effects of four modes of death on health, depression and grief of the bereaved].
To evaluate how the mode of death affect health and emotional reaction. We analyzed 178 responses to a questionnaire from the bereaved. The respondents were divided into 4 groups: bereaved by suicide, accident, acute death (less than a day from onset), and illness-related death (less than a year from onset). The suicide, accident and acute death groups indicated averages higher than or as high as the clinical threshold on both general health scale and depression scale. Differences among groups appeared on all but the subscales of somatic symptoms and of anxiety & insomnia. The cause-of-death factor has an effect on the bereavement reaction. The effect seemed more apparent on emotion than on physical health.


Changes in chronotype and social jetlag during adolescence and their association with concurrent changes in BMI-SDS and body composition, in the DONALD Study.
Adolescence is a critical period for both the development of overweight and the transition toward a later chronotype, often accompanied by an increase in social jetlag. This study assessed whether changes in chronotype and social jetlag, are linked to changes in body composition during adolescence. We used data from the DONALD open cohort study, collected between 2014 and 2019, from 213 adolescents (9-17 years at baseline, 45% females) having at least two measures of chronotype and anthropometry (N = 572). Chronotype was assessed with the Munich Chronotype Questionnaire and defined as: midpoint of sleep corrected for sleep-debt (MSFsc) accumulated over the week (later MSFsc represents later chronotype). Social jetlag (SJL) defines the difference between midpoint of sleep during week and weekend. Calculations for Fat Free Mass Index (FFMI [kg/m2)]) and Fat Mass Index (FMI) [kg/m2)]) were based on body fat percentage, weight, and height. To analyze the associations, we used linear mixed-effect regression models. Finally, the total cohort was split into three biologically relevant age groups (cut-off set at <12 years, ≥12 to ≤15 years and >15 years). Median follow-up was 2.1 years. Overall, change toward a later chronotype was significantly related with an increase in FMI (ß: 0.05, 95% CI: 0.01-0.08). A 1 h increase in social jetlag predicted an increase in BMI-SDS of 0.08 SDS units (95% CI: 0.01-0.14) and in FMI of 0.04 kg/m2 (95% CI: 0.003-0.08). Associations were stronger for the age group ≥12 to ≤15 years (p for interaction: <0.001). No relationship was found with FFMI. Changes in MSFsc and SJL during adolescence were associated with concurrent changes in BMI-SDS and FMI. The age ≥12 to ≤15 years appears to be a sensitive period in which chronobiological changes were clearly associated with increasing body fatness.


The effect modification of supplemental insurance on the relationship between race and bone mineral density screening in female Medicare beneficiaries.
To determine the effect modification of supplemental insurance on the relationship between race and bone mineral density (BMD) in female Medicare beneficiaries. Retrospectively analyzing hospital administrative claim and clinical data of female Medicare beneficiaries (n = 1,398), we performed multivariate logistic regressions of BMD testing including data from all study participants and the subsets of health insurance. Significantly fewer Black than White female Medicare beneficiaries received the BMD testing in the overall sample (odds ratio, OR = 0.63; p = 0.02) and those without supplementary health insurance (n = 709; OR = 0.38; p = 0.004). By contrast, the magnitude of this racial disparity in the BMD testing was diminished among those with supplementary private health insurance (n = 689). We found a significant racial disparity in BMD testing for Black and White female Medicare beneficiaries. This disparity became more pronounced among those without supplementary private health insurance.


Statistical validation of normal tissue complication probability models.
To investigate the applicability and value of double cross-validation and permutation tests as established statistical approaches in the validation of normal tissue complication probability (NTCP) models. A penalized regression method, LASSO (least absolute shrinkage and selection operator), was used to build NTCP models for xerostomia after radiation therapy treatment of head-and-neck cancer. Model assessment was based on the likelihood function and the area under the receiver operating characteristic curve. Repeated double cross-validation showed the uncertainty and instability of the NTCP models and indicated that the statistical significance of model performance can be obtained by permutation testing. Repeated double cross-validation and permutation tests are recommended to validate NTCP models before clinical use.


Embryonic stem cell-derived osteocytes are capable of responding to mechanical oscillatory hydrostatic pressure.
Osteoblasts can be derived from embryonic stem cells (ESCs) by a 30 day differentiation process, whereupon cells spontaneously differentiate upon removal of LIF and respond to exogenously added 1,25α(OH)2 vitamin D3 with enhanced matrix mineralization. However, bone is a load-bearing tissue that has to perform under dynamic pressure changes during daily movement, a capacity that is executed by osteocytes. At present, it is unclear whether ESC-derived osteogenic cultures contain osteocytes and whether these are capable of responding to a relevant cyclic hydrostatic compression stimulus. Here, we show that ESC-osteoblastogenesis is followed by the generation of osteocytes and then mechanically load ESC-derived osteogenic cultures in a compression chamber using a cyclic loading protocol. Following mechanical loading of the cells, iNOS mRNA was upregulated 31-fold, which was consistent with a role for iNOS as an immediate early mechanoresponsive gene. Further analysis of matrix and bone-specific genes suggested a cellular response in favor of matrix remodeling. Immediate iNOS upregulation also correlated with a concomitant increase in Ctnnb1 and Tcf7l2 mRNAs along with increased nuclear TCF transcriptional activity, while the mRNA for the repressive Tcf7l1 was downregulated, providing a possible mechanistic explanation for the noted matrix remodeling. We conclude that ESC-derived osteocytes are capable of responding to relevant mechanical cues, at least such that mimic oscillatory compression stress, which not only provides new basic understanding, but also information that likely will be important for their use in cell-based regenerative therapies.


Methotrexate and methotrexate polyglutamates in human sarcoma metastases after high-dose methotrexate therapy.
The methotrexate concentrations in the lungs or cutaneous metastases of patients with osteogenic or soft-tissue sarcoma were determined at different times after a high-dose methotrexate therapy. The levels in the metastases were 0.964 to 2.96 X 10(-7) molar six to nine days after the end of MTX infusion. They were thus 7.8 to 28 times higher than the corresponding serum levels. At the same time, an appreciable rise of dihydrofolate reductase activity was observed in the metastases. After chromatographic separation over Sephadex G15, MTX polyglutamates could be demonstrated in all tumor samples investigated so far; these amounted up to 68.3% of the total MTX. Taking into account the slower efflux of MTX polyglutamates compared to unchanged MTX, a new hypothesis for the principle of action of high-dose methotrexate therapy is discussed: the very high MTX doses lead to such high intracellular MTX concentrations even in transport-resistant tumor cells that at least part of the MTX is converted into MTX polyglutamates. Unchanged MTX flows relatively rapidly out of the cells, whereas the MTX polyglutamates only break down very slowly and thus can be cytostatically effective over a long period of time.


Occurrences and spatial distributions of dioxin-like polychlorinated biphenyls in chlorobenzene and chloroethylene manufacturing processes in China.
As a group of pollutants listed in the Stockholm Convention, polychlorinated biphenyls (PCB) should be eliminated and their releases should be controlled. For this purpose, a complete PCB emission inventory is urgently required. Current unintentional releases of PCB were dominantly focused on waste incineration and non-ferrous metal production industries. The formation of PCB in chlorinated chemical manufacturing processes is poorly understood. In this study, occurrences and inventory of dioxin-like PCB (dl-PCB) in three typical chemical manufacturing processes, including chlorobenzene and chloroethylene production processes, were investigated. The bottom residues, which were high boiling point by-products after rectification tower, contained higher concentration of PCB than other stage samples in monochlorobenzene production and trichloroethylene production processes. The PCB concentrations were as high as 1.58 ng/mL and 152.87 ng/mL, respectively, which should be further concerned. The toxic equivalent quantities (TEQ) of dl-PCB in monochlorobenzene, trichloroethylene, and tetrachloroethylene products were 0.25 μg TEQ/t, 1.14 μg TEQ/t, and 5.23 μg TEQ/t, respectively. The mass concentration and TEQ of dl-PCB determined in this research can be used for the further development of dl-PCB emission inventory from these chemical manufacturing industries. In addition, temporal and spatial trends of PCB releases from typical chemical manufacturing processes from 1952 to 2018 in China were clarified. The releases increased rapidly in the latest two decades and presented an expansion tendency from the southeast coastal areas to northern and central areas. The continuing upward trend for the output and the high dl-PCB TEQ of chloroethylene indicated significant releases of PCB from chemical manufacturing processes and should receive more attention.


Plasticity-driven gene expression in the rat retina.
Animals exposed to an enriched environment display features of neural plasticity such as an increased brain volume, enhanced number of dendritic spines, as well as enlarged synapses. Here we report the first description of molecular plasticity in the mammalian retina, as revealed by gene expression. A marked upregulation of both NGFI-A and Arc, two candidate-plasticity genes, was observed in adult rats that had been exposed to an enriched environment for 3 weeks. This increase was paralleled by an increase in the expression of the late genes GAP-43 and Synapsin I, which also indicated changes in retinal connectivity. Our results suggest that both NGFI-A and Arc may regulate mechanisms of plasticity that had been invoked by heightened complexity of the visual environment.


[Evaluation of tumor necrosis factor-alpha and tumor necrosis factor-beta in serum of patients with endometriosis].
To evaluate the levels of tumor necrosis factor-alpha (TNF-alpha) and tumor necrosis factor-beta (TNF-beta) before and after conservative laparoscopic surgery in patients with endometriosis. The levels of TNF-alpha and TNF-beta in the serum of both 82 patients with EMS and 68 controls were determined by ELISA. The levels of TNF-alpha and TNF-beta in the serum of patients with EMS were significantly higher than those of the controls (P < 0.01), and they increased with the clinical terms ( P < 0.05). After clearance of endometrosis foci with laparoscopic conservative surgery, the TNF-alpha levels decreased significantly in EMS III - IV, and TNF-beta levels decreased significantly in EMS I - IV. Measuring TNF-alpha and TNF-beta levels in the serum of patients with EMS may have important value in postoperative follow-up, surveillance and evaluation of the effectiveness of the surgery.


Cre/CysC ratio may predict muscle composition and is associated with glucose disposal ability and macrovascular disease in patients with type 2 diabetes.
Since the ratio of creatinine to cystatin C (Cre/CysC) can reflect muscle volume, it has been proven to be a predictor of sarcopenia in patients with or without diabetes. Here, we investigated the predictive value of Cre/CysC for the skeletal muscle composition and its correlations with glucose disposal ability and diabetic complications in patients with type 2 diabetes. The skeletal muscle index (SMI) and mean skeletal muscle attenuation (MMA) values of 193 patients with type 2 diabetes were obtained through analyses of CT images at the lumbar 3 level. Serum Cre/CysC was significantly correlated with both the SMI (r=0.375, p<0.001) and MMA (r=0.378, p<0.001). Multiple stepwise linear regression analysis demonstrated that Cre/CysC was the only biochemical predictor of the SMI (β=0.48 (95% CI 0.02 to 0.94)) and MMA (β=0.57 (95% CI 0.14 to 1.01)). Furthermore, the fat mass index (FMI) was significantly associated with the MMA (r=-0.481, p<0.001) but not the SMI (r=0.101, p=0.164). In the diabetic complications analysis, Cre/CysC was significantly lower in patients with cardiovascular disease (95% CI (-1.47 to -0.22), p=0.008) and lower extremity arterial disease (95% CI (-1.44 to -0.29), p=0.004). Moreover, in the 100 g steamed bun test, Cre/CysC was significantly correlated with glucose levels at 60 min (r=-0.162, p=0.045), 120 min (r=-0.287, p<0.001) and 180 min (r=-0.313, p<0.001). Cre/CysC may be a valuable predictor of skeletal muscle composition in type 2 diabetes. Patients with a higher Cre/CysC may have a better ability to dispose of postprandial glucose and are at a lower risk of macrovascular disease.


Late complication in patients undergoing pancreatic resection with intraoperative radiation therapy: gastrointestinal bleeding with occlusion of the portal system.
There are few reports of late complications in patients who have undergone pancreatic resection with intraoperative radiation therapy (IORT), because carcinoma of the pancreas (PCa) and the bile duct (BCa) have a poor prognosis. The purpose of the present paper was to review gastrointestinal (GI) bleeding occurring with occlusion of the portal system (PVs) as a complication of IORT in patients surviving long term without recurrence. From 1990 to 1999, 45 patients underwent surgical resection of the pancreas with IORT. Eleven of these patients survived >3 years without recurrence, and occlusion of PVs was recognized in five patients at follow-up examination. Three of these five patients received repeated blood transfusions for GI bleeding. One patient had BCa and two had PCa, and pancreatoduodenectomy was carried out. The delivered radiation doses of IORT were 30 Gy (two patients) and 35 Gy (one patient). The postoperative periods to initial GI bleeding were 36, 26 and 9 months, respectively. In all cases, angiography revealed occlusion of PVs and the collateral circulation. The bleeding points were esophageal varix (case 1), remnant stomach varix (case 2) and a jejunal ulcer (case 3), and blood transfusions were carried out totaling 44, 60 and 16 units, respectively. The GI bleeding disappeared spontaneously in case 1, developed sporadically in case 2 and was stopped by metallic stent insertion in PVs in case 3. During long-term follow up after pancreatectomy with IORT, it is necessary to monitor patients for GI bleeding. A clinical trial on optimum doses, long-term safety and benefit of IORT is necessary.


Frailty status and cardiovascular disease risk profile in middle-aged and older females.
Frailty and pre-frailty are known to increase the risk of developing cardiovascular disease (CVD). However, the risk profiles of females are not well characterized. The aim of this study is to characterize the CVD risk profiles of robust, pre-frail and frail females. Cross-sectional analysis of 985 females ≥55 years with no self-reported history of CVD were recruited. Frailty was assessed using the Fried Criteria with the cut-points standardized to the cohort. Framingham risk scores (FRS), the 4-test Rasmussen Disease Score (RDS), and the CANHEART health index were used to characterize composite CVD risk. Individual measures of CVD risk included blood lipids, artery elasticity assessments, exercise blood pressure response, 6-min walk test (6MWT), sedentary time and PHQ-9 score. The cohort comprised of 458 (46.4%) robust, 464 (47.1%) pre-frail and 63 (6.4%) frail females with a mean age of 66 ± 6 (SD) years. Pre-frail females were at increased odds of taking diabetes medications (OR 3.04; 95% CI 1.27-7.27), hypertension medications (OR 2.02; 95% CI 1.44-2.82), having an exaggerated blood pressure response to exercise (OR 1.878; 95% CI 1.39-2.50), mild depression symptoms (OR 2.38; 95% CI 1.68-338), and lower fitness as assessed by 6MWT (OR 5.74; 95% CI 3.18-10.37), even after controlling for age and relevant medications. Pre-frail females were also at increased odds for having CVD risk scores indicating higher risk with the FRS (OR 1.52; 95% CI 1.12-2.05), the RDS (OR 1.60; 95% CI 1.21-2.10) and the CANHEART risk score (OR 3.07; 95% CI 2.04-4.62). These odds were higher when frail females were compared to their robust peers. Frailty and pre-frailty were associated with higher odds of presenting with CVD risk factors as compared to robust females, even after controlling for age.


Clinical performance comparison between lithium disilicate and hybrid resin nano-ceramic CAD/CAM onlay restorations: a two-year randomized clinical split-mouth study.
A total of 20 lithium disilicate glass-ceramics (IPS e.max CAD, Ivoclar Vivadent) and 20 resin nano-ceramic (Voco Grandio Blocks) onlay restorations were performed in 20 patients using a split-mouth design to compare the two-year clinical performance of lithium disilicate and resin nano-ceramic onlay restorations. Both restorations were evaluated at baseline, one-year, and two-year clinical follow-ups based on the modified United States Public Health Service (USPHS) criteria. Chi-square and Fisher's exact tests showed no statistically significant difference between Voco Grandio and IPS e.max ceramic restorations for all evaluated parameters during the different follow-up periods (p > 0.05). Cochrane's and MC-Nemar's tests indicated statistically significant differences regarding color match within the Voco Grandio group. They also indicated statistically significant differences in marginal discoloration, marginal adaptation, surface texture, and postoperative hypersensitivity within both ceramic material groups (p < 0.05). Kaplan-Meier curve indicated that the survival rate of both ceramic materials was 90%. After two years of clinical service, IPS e.max CAD and Voco Grandio onlay restorations exhibited similar clinical performance.


[Special features of mental and somatic status of the employees of law-enforcement bodies of the Chechen Republic].
With the purpose of study of features of psychical and somatic prosperity of employees of organs of internal affairs of Chechen Republic the inspection of 64 employees was conducted. It is set that a posttraumatic stress disorder (PTSR) was exposed for 3% inspected employees-contracters. The separate symptoms of PTSR were observed for 2/5 contracters and at 1/4 workings on permanent basis. Complaints about somatic disfunctions were present at more than 1/2 employees, dischargings official duties by contract, and 2/5--workings on permanent basis. Presence of intercommunications of complaints with the subscales of questionnaire of traumatic stress, specifies on psychosomatic nature of violations of somatic health because of finding in extreme battle conditions.


Haematologists and palliative care: a multicentric qualitative study.
Early palliative care leads to meaningful improvements in physical and psychosocial symptoms, as well as quality of life, in patients with advanced cancer. Patients with haematological malignancies, despite a high level of distress, continue to have less access to palliative care services. The aim of this study was to identify haematologists' perceptions of palliative care, as well as barriers to patient referral. We used a qualitative grounded theory methodology. Twenty-four medical haematologists involved in clinical practice from two French centres in Lyon-the Lyon Sud University Hospital and the Léon Bérard Cancer Center-were included. The interview guide questions aimed to establish the clinical situations which triggered referral to palliative care and how participants perceived palliative care. Data saturation was reached after 14 interviews. The data analysis highlighted four themes. The aim of palliative care was clearly identified as alleviating severe suffering. Palliative care was identified as a separate specialty, and respondents expressed the need for collaboration. Early intervention was perceived as beneficial to avoid certain situations such as hospitalisation or emergency department visits at the end of life. The main barrier to palliative care referral remained the negative connotations associated with the term 'palliative', which was overwhelmingly associated with the end of life. Our results suggest that the principal barrier to palliative care referral is the term 'palliative care'; haematologists would prefer 'supportive care' instead.


Respiratory water loss and oxygen consumption in full-term infants exposed to cold air on the first day after birth.
Respiratory water loss, oxygen consumption, carbon dioxide production and skin blood flow were measured continuously in nine full-term infants on the first day after birth. After at least 18 min of measurements with the infant asleep in an incubator, with an air temperature of 33 degrees C and a relative humidity of 50%, the temperature of the incubator air was lowered to less than 27.5 degrees C. This resulted in a significant decrease in skin temperature and peripheral skin blood flow, while the infant's core temperature remained unchanged. At the same time, mean respiratory water loss increased from 3.7 to 6.1 mg/kg.min, which can be explained partially by the decrease in ambient humidity that accompanied the decrease in air temperature. In addition, mean oxygen consumption increased from 5.3 to 7.9 ml/kg.min and mean carbon dioxide production increased from 3.8 to 5.9 ml/kg.min. There was no concomitant increase in motor activity. Thus, when the newborn infants were exposed to cool air, they reacted with an increase in respiratory water loss, oxygen consumption and carbon dioxide production before their core temperature was affected and without increasing their motor activity.


An overview of the pharmacokinetics, efficacy and safety of liraglutide.
Incretin-based therapies, including glucagon-like peptide 1 (GLP-1) receptor agonists, are the latest addition to the range of available medications for the management of patients with type 2 diabetes. The GLP-1 analog liraglutide has been approved for use in Europe and the US for over a year and has undergone evaluation in several pharmacokinetic/pharmacodynamics studies and in an extensive phase 3 clinical program. The aim of this review is to assess the pharmacokinetics, efficacy and safety of the phase 3 data. Data are presented from the pharmacokinetics/pharmacodynamics studies of liraglutide and from nine published phase 3 studies, including the six Liraglutide Effect and Action in Diabetes (LEAD) studies. Liraglutide is effective at improving indices of glycemic control, and has a good tolerability and safety profile. Beneficial effects on weight (mean reduction of 1-3.4 kg) and blood pressure (systolic blood pressure decreased by 2.1-6.7 mmHg) are also observed. Liraglutide is an effective and well tolerated option for the treatment of type 2 diabetes.


Molecular and Immune Biomarkers for Cutaneous Melanoma: Current Status and Future Prospects.
Advances in the genomic, molecular and immunological make-up of melanoma allowed the development of novel targeted therapy and of immunotherapy, leading to changes in the paradigm of therapeutic interventions and improvement of patients' overall survival. Nevertheless, the mechanisms regulating either the responsiveness or the resistance of melanoma patients to therapies are still mostly unknown. The development of either the combinations or of the sequential treatment of different agents has been investigated but without a strongly molecularly motivated rationale. The need for robust biomarkers to predict patients' responsiveness to defined therapies and for their stratification is still unmet. Progress in immunological assays and genomic techniques as long as improvement in designing and performing studies monitoring the expression of these markers along with the evolution of the disease allowed to identify candidate biomarkers. However, none of them achieved a definitive role in predicting patients' clinical outcomes. Along this line, the cross-talk of melanoma cells with tumor microenvironment plays an important role in the evolution of the disease and needs to be considered in light of the role of predictive biomarkers. The overview of the relationship between the molecular basis of melanoma and targeted therapies is provided in this review, highlighting the benefit for clinical responses and the limitations. Moreover, the role of different candidate biomarkers is described together with the technical approaches for their identification. The provided evidence shows that progress has been achieved in understanding the molecular basis of melanoma and in designing advanced therapeutic strategies. Nevertheless, the molecular determinants of melanoma and their role as biomarkers predicting patients' responsiveness to therapies warrant further investigation with the vision of developing more effective precision medicine.


Tomato golden net virus and tomato yellow net virus: two novel New World begomoviruses with monopartite genomes.
Two novel tomato-infecting begomoviruses were discovered via high-throughput sequencing in Brazil. Both viruses were also Sanger-sequenced and displayed DNA-A components phylogenetically related to New World bipartite begomoviruses. The names tomato golden net virus (ToGNV) and tomato yellow net virus (ToYNV) were proposed. The majority of the New World begomoviruses has bipartite genomes. However, extensive analyses revealed that ToGNV and ToYNV have monopartite genomes, because no cognate DNA-B components were detected. Hence, they may comprise a unique group of monopartite New World begomoviruses, which have enormous biological, molecular, and plant breeding interest.


Affordable Care Act and Diabetes Mellitus.
The Affordable Care Act (ACA) has the potential for great impact on U.S. health care, especially for chronic disease patients requiring long-term care and management. The act was designed to improve insurance coverage, health care access, and quality of care for all Americans, which will assist patients with diabetes mellitus in acquiring routine monitoring and diabetes-related complication screening for better health management and outcomes. There is great potential for patients with diabetes to benefit from the new policy mandating health insurance coverage and plan improvement, Medicaid expansion, minimum coverage guarantees, and free preventative care. However, policy variability among states and ACA implementation present challenges to people with diabetes in understanding and optimizing ACA impact. This paper aims to select the most influential components of the ACA as relates to people with diabetes and discuss how the ACA may improve health care for this vulnerable population.


Decreased serum levels of oestradiol, testosterone and prolactin during prolonged physical strain and sleep deprivation, and the influence of a high calorie diet.
The changes in oestradiol, testosterone and prolactin, and the effects of a high calorie diet, were investigated in eleven young males cadets participating in a 5 days' ranger training course involving heavy and continuous physical activities with less than 1500 kcal . day-1 and almost without sleep. Prolactin decreased continuously during the first 24 h to 25% of precourse values. Testosterone decreased during the day time and reached below 25% of precourse values after 48 h. Oestradiol did not change during the first 48 h but then decreased to about 50% of precourse values. In conclusion, oestradiol, testosterone and prolactin are strongly reduced during prolonged strain. These changes were not reversed by a high calorie diet.


Topical Nystatin for the Prevention of Catheter-Associated Candidiasis in ELBW Infants.
Catheter-associated Candida bloodstream infections are a common and serious problem in the neonatal intensive care unit (NICU). Several prophylactic regimens have been developed including oral administration of nonabsorbable antifungals and intravenous infusions. No reports to date have employed a topical regimen. To evaluate the effectiveness of topical nystatin cream in preventing catheter-associated Candida sepsis. A retrospective descriptive design was used to determine the incidence of Candida sepsis in extremely low-birth weight (ELBW, <1000 g at birth) infants who were treated with topical nystatin cream for Candida bloodstream infection prophylaxis between January 1, 2000, and December 31, 2010. The electronic medical records of study infants were reviewed to establish the incidence of Candida sepsis. A total of 464 ELBW infants were admitted to the NICU during the study period. Three infants (0.65%) developed Candida sepsis. These data demonstrate that a topical nystatin cream protocol is associated with a very low rate of Candida sepsis in ELBW infants with central catheters. The use of this protocol may contribute to a decrease in the morbidity and mortality rate associated with catheter-associated Candida infections in ELBW infants. Before generalizations can be made as to the safety and efficacy of this protocol as compared to enteral and parenteral prophylactic treatments and in other institutions, large multicenter randomized controlled trials are required.


Chloride intracellular channel 1 regulates migration and invasion in gastric cancer by triggering the ROS-mediated p38 MAPK signaling pathway.
Mol Med Rep 12:[Related article:] 8041–8047, 2015; DOI: 10.3892/mmr.2015.4459 Following the publication of this article, an interested reader drew to our attention anomalies associated with the presentation of Fig. 4A. In the original presentation of the Figure, different representations of the same photomicrograph were inadvertently used for the panels labelled 'N', 'H-R', 'H-R + NAC' and 'H-R + SB203580'. This error arose as a consequence of an incorrect ordering of our original image numbers. A corrected version of Fig. 4A is provided below, featuring the appropriate data for each of the five panels listed above. This Figure was intended to show how, compared with the normoxic control group, the invasiveness of the SGC-7901 gastric cancer cells was markedly increased under hypoxia-reoxygenation (H-R) conditions, although pretreatment with N-acetyl cysteine (NAC; 30 mmol/l) or indanyloxyacetic acid 94 (IAA-94; 40 μmol/l), inhibited the invasiveness resulting from H-R exposure. Similarly, treatment with the inhibitor of p38 mitogen-activated protein kinase, SB203580 (10 μmol/l), also inhibited the cell invasiveness induced under the H-R conditions. We sincerely apologize for this mistake, and thank the reader of our article who drew this matter to our attention. Furthermore, we regret any inconvenience this mistake has caused.


Engaging Operational Partners Is Critical for Successful Implementation of Research Products: a Coincidence Analysis of Access-Related Projects in the Veterans Affairs Healthcare System.
The Veterans Health Administration (VHA) has prioritized timely access to care and has invested substantially in research aimed at optimizing veteran access. However, implementing research into practice remains challenging. Here, we assessed the implementation status of recent VHA access-related research projects and explored factors associated with successful implementation. We conducted a portfolio review of recent VHA-funded or supported projects (1/2015-7/2020) focused on healthcare access ("Access Portfolio"). We then identified projects with implementable research deliverables by excluding those that (1) were non-research/operational projects; (2) were only recently completed (i.e., completed on or after 1/1/2020, meaning that they were unlikely to have had time to be implemented); and (3) did not propose an implementable deliverable. An electronic survey assessed each project's implementation status and elicited barriers/facilitators to implementing deliverables. Results were analyzed using novel Coincidence Analysis (CNA) methods. Among 286 Access Portfolio projects, 36 projects led by 32 investigators across 20 VHA facilities were included. Twenty-nine respondents completed the survey for 32 projects (response rate = 88.9%). Twenty-eight percent of projects reported fully implementing project deliverables, 34% reported partially implementing deliverables, and 37% reported not implementing any deliverables (i.e., resulting tool/intervention not implemented into practice). Of 14 possible barriers/facilitators assessed in the survey, two were identified through CNA as "difference-makers" to partial or full implementation of project deliverables: (1) engagement with national VHA operational leadership; (2) support and commitment from local site operational leadership. These findings empirically highlight the importance of operational leadership engagement for successful implementation of research deliverables. Efforts to strengthen communication and engagement between the research community and VHA local/national operational leaders should be expanded to ensure VHA's investment in research leads to meaningful improvements in veterans' care. The Veterans Health Administration (VHA) has prioritized timely access to care and has invested substantially in research aimed at optimizing veteran access. However, implementing research findings into clinical practice remains challenging, both within and outside VHA. Here, we assessed the implementation status of recent VHA access-related research projects and explored factors associated with successful implementation. Only two factors were identified as "difference-makers" to adoption of project findings into practice: (1) engagement with national VHA leadership or (2) support and commitment from local site leadership. These findings highlight the importance of leadership engagement for successful implementation of research findings. Efforts to strengthen communication and engagement between the research community and VHA local/national leaders should be expanded to ensure VHA's investment in research leads to meaningful improvements in veterans' care.


Should children with suspected obstructive sleep apnea syndrome and normal nap sleep studies have overnight sleep studies?
Overnight polysomnography (ONP) is the "gold standard" for the diagnosis of sleep-disordered breathing, but it is expensive and time-consuming. Thus, daytime nap studies have been used as screening tests. If the findings of a nap study are normal or mildly abnormal, should ONP be performed? Do specific abnormalities in nap studies predict abnormal findings in ONP? To answer these questions, we conducted this study. Retrospective chart review. Children's hospital. One hundred forty-three children with suspected obstructive sleep apnea syndrome secondary to isolated adenotonsillar hypertrophy, who had normal or mildly abnormal nap studies, and underwent ONP. We compared daytime nap and overnight polysomnograms in 143 children (52 girls; mean [+/- SD] age, 5.6 +/- 3.1 years). Total sleep time was 1 h in daytime nap, and 5.1 +/- 1.3 h in ONP. The interval between the two studies was 5.9 +/- 4.8 months. The findings of 59% of the nap studies were mildly abnormal, while 66% of overnight studies were abnormal. No individual nap study parameter (including short obstructive apneas, hypopneas, hypoxemia, hypoventilation, snoring, paradoxical breathing, gasping, retractions) had good sensitivity at predicting abnormal overnight polysomnograms, but most had good specificity and positive predictive value. We conclude that individual nap study parameters are not very sensitive in predicting abnormal ONP findings. However, when nap study parameters are abnormal, the chance of obstructive sleep apnea syndrome is high.


Complete amino acid sequence of a mouse epidermal keratin subunit and implications for the structure of intermediate filaments.
We have determined the complete primary structure of an intermediate filament subunit, the 59,000 molecular weight subunit of mouse epidermal keratin, from the nucleotide sequence of cDNA clones. The central portion of the sequence forms extended tracts of a coiled-coil alpha-helical conformation. This is flanked at both termini by similar non-alpha-helical sequences that are extremely rich in glycine residues, frequently configured in tandem peptide repeats. Limited chymotryptic digestion of keratin filaments containing this protein suggests a structural organization whereby the terminal glycine-rich sequences protrude from a conserved core structure into which the coiled-coil alpha-helical segments are packed.


Alterations of systemic endotoxemia over the course of acute edematous pancreatitis. correlation to the advent of an infection?
To define whether bacterial translocation occurs over the course of acute edematous pancreatitis and to correlate its presence to the advent of an infection since data in humans are lacking. Thirty-three patients hospitalized over the period January 2000-January 2001 were subjected to venipuncture at regular time intervals for the collection of blood samples for blood culture and for determination of endotoxins and of C-reactive protein. Endotoxins were measured by the Limulus assay and C-reactive protein by nephelometry. A wide range of concentrations of endotoxins was observed over the first 3 days of the disease. Mean (+/-SE) of endotoxins was 4.01 +/- 1.36 and 2.42 +/- 0.95 EU/ml 3 and 6 h, respectively, after admission of afebrile patients. Respective values 3 and 6 h after admission of febrile patients were 3.03 +/- 1.14 and 5.84 +/- 2.28 EU/ml (normal <0.1 EU/ml); these values gradually decreased after the second day. No correlation was found between endotoxins and C-reactive protein. Endotoxins were increased as a result of the occurrence of an infection on the third day. A significant level of endotoxemia is observed over the course of acute edematous pancreatitis, which might be correlated to the advent of the systemic inflammatory response.


The design and evaluation of a simulated-patient teaching programme to develop the consultation skills of undergraduate pharmacy students.
This study aimed to identify the key skills and knowledge required for the delivery of an ideal patient consultation in order to develop a training programme (using simulated-patients) to teach consultation skills to undergraduate pharmacy students. Participants included all third year undergraduate Pharmacy students (MPharm, level III) at the School of Pharmacy & Biomolecular Sciences, University of Brighton (from October 1999 to March 2000). Working in groups of 12, students participated in two 4 hour seminars. A structured questionnaire was designed to assess students' perceptions of the difficulty of conducting a consultation and their confidence in delivering a structured consultation. Questionnaires were administered before and after delivery of the teaching programme to assess changes in students' confidence and ability to consult with patients. Twelve volunteers satisfied the criteria set to serve as simulated patients and then received appropriate training. Six scenarios were developed which focused on the key skills and knowledge identified from the adherence and consultation skills literature. A total of 91 students participated in the programme (mean age = 23 years, SD = 4.5). Following participation in the programme students' perceived 'confidence' for conducting an effective consultation significantly increased (t = -5.9, p < 0.01) while a statistically significant decrease was seen in students' perceived level of 'difficulty' when conducting a consultation (t = 4.0, p < 0.01). This study has shown that the use of a structured teaching programme improves students' perceptions of their ability and confidence in conducting an effective consultation. Providing skills training around the consultation process, using simulated patients, provides pharmacists with a good framework around which to practice pharmaceutical care.


In situ study of active and passive mechanical properties of rat tail artery.
The present study constitutes an effort to close the gap still existing between in vivo and in vitro experiments in vascular mechanics. Active and passive mechanical properties of the rat tail artery were studied in situ under conditions as close as possible to the natural in vivo state of the vessel. At constant pressure levels, changes in diameter as caused after dilatation by papaverine and constriction by norepinephrine, were automatically and continuously registered using a contact free measurement technique (Video Dimension Analyzer). In order to check consistency of the in situ findings with analogous results from in vitro studies, pressure-diameter and stress-strain data were compared with results from our own and other authors. The results show that, quite similarly to in vitro, the maximum isobaric response of the tail artery in situ occurs in the physiological pressure range of some 100 mm Hg. Although the results focus the attention on the importance of both the experimental protocols and the definitions used, they confirm the validity of in vitro investigations as a powerful tool in arterial rheology.


Association of the Mandatory Medicare Bundled Payment With Joint Replacement Outcomes in Hospitals With Disadvantaged Patients.
Medicare's Comprehensive Care for Joint Replacement (CJR) model rewards or penalizes hospitals on the basis of meeting spending benchmarks that do not account for patients' preexisting social and medical complexity or high expenses associated with serving disadvantaged populations such as dual-eligible patients (ie, those enrolled in both Medicare and Medicaid). The CJR model may have different implications for hospitals serving a high percentage of dual-eligible patients (termed high-dual) and hospitals serving a low percentage of dual-eligible patients (termed low-dual). To examine changes associated with the CJR model among high-dual or low-dual hospitals in 2016 to 2017. This cohort study comprised 3 analyses of high-dual or low-dual hospitals (n = 1165) serving patients with hip or knee joint replacements (n = 768 224) in 67 treatment metropolitan statistical areas (MSAs) selected for CJR participation and 103 control MSAs. The study used Medicare claims data and public reports from 2012 to 2017. Data analysis was conducted from February 1, 2019, to August 31, 2019. The CJR model holds participating hospitals accountable for the spending and quality of care during care episodes for patients with hip or knee joint replacement, including hospitalization and 90 days after discharge. The primary outcomes were total episode spending, discharge to institutional postacute care facility, and readmission within the 90-day postdischarge period; bonus and penalty payments for each hospital; and reductions in per-episode spending required to receive a bonus for each hospital. In total, 1165 hospitals (291 high-dual and 874 low-dual) and 768 224 patients with joint replacement (494 013 women [64.3%]; mean [SD] age, 76 [7] years) were included. An episode-level triple-difference analysis indicated that total spending under the CJR model decreased at high-dual hospitals (by $851; 95% CI, -$1556 to -$146; P = .02) and low-dual hospitals (by $567; 95% CI, -$933 to -$202; P = .003). The size of decreases did not differ between the 2 groups (difference, -$284; 95% CI, -$981 to $413; P = .42). Discharge to institutional postacute care settings and readmission did not change among both hospital groups. High-dual hospitals were less likely to receive a bonus compared with low-dual hospitals (40.3% vs 59.1% in 2016; 56.9% vs 76.0% in 2017). To receive a bonus, high-dual hospitals would be required to reduce spending by $887 to $2231 per episode, compared with only $89 to $215 for low-dual hospitals. The study found that high- and low-dual hospitals made changes in care after CJR implementation, and the magnitude of these changes did not differ between the 2 groups. However, high-dual hospitals were less likely to receive a bonus for spending cuts. Spending benchmarks for CJR would require high-dual hospitals to reduce spending more substantially to receive a financial incentive.


Incorporation of project-based learning into an occupational health course.
Use of an appropriate teaching approach is a major concern for faculty members who are involved in occupational health and safety academic education. The challenge is to explore teaching tools to equip students with knowledge and skills to prepare them for their practices, in which they will encounter occupational health and safety issues in various occupational settings. The current study presents the design and implementation of a team project-based learning approach for undergraduate occupational health students to examine the appropriateness and perceptions of students and educators with regard to such a learning experience. Steps were taken to guide the educators and students through the learning process based on projects completed in teams. The research tools for collecting data were a questionnaire and semi-structured interviews with participants. The results illustrated that use of the proposed teaching approach as part of occupational health education may have the potential to motivate and enhance the active roles of educators and students in the learning process, and improve students' technical and social skills that are crucial for practice in the occupational health field. The study findings showed that project-based learning may provide a promising teaching strategy in the education and training of occupational health students. In addition, academic institutions should encourage educators to plan, introduce and evaluate the effectiveness of project-based learning.


Doses of epinephrine causing arrhythmia during enflurane, methoxyflurane and halothane anaesthesia in dogs.
The arrhythmogenic dosage of epinephrine, administered by constant intravenous infusion, was measured in five dogs during enflurane, methoxyflurane and halothane anaesthesia. While premature ventricular contractions were observed in only one of five dogs with enflurane and methoxyflurane, epinephrine-induced arrhythmias were seen in all animals during halothane anaesthesia. Epinephrine dosage and the resultant increase in mean arterial blood pressure at which arrhythmias occurred during halothane anaesthesia were significantly less (p less than 0.05) than with the other anaesthetics. These observations indicate that enflurane and methoxyflurane, as compared to halothane, possess relatively less arrhythmogenic potential as sensitizing agents in the presence of increased circulating catecholamines.


Functional characterisation of the pharmacological profile of the putative alpha1B-adrenoceptor antagonist, (+)-cyclazosin.
We studied the functional pharmacological profile of (+)-cyclazosin, which has been characterised as a selective, high-affinity (pKi = 9.68) alpha1B-adrenoceptor ligand in binding experiments with rat liver membranes. The pKa/pA2 values for antagonism of contractions mediated via alpha1A/L-adrenoceptors of rat small mesenteric artery, alpha1B-adrenoceptors of rat aorta and alpha1B-adrenoceptors of rat spleen were 7.78 +/- 0.04, 6.86 +/- 0.07 and 7.96 +/- 0.08, respectively. Furthermore, in mouse spleen, which is also regarded as an alpha1B-adrenoceptor preparation, (+)-cyclazosin displayed low potency and did not act as a competitive antagonist. Thus, in contrast with results obtained in radioligand binding experiments, (+)-cyclazosin does not behave as a selective alpha1B-adrenoceptor antagonist in functional tissues. Whether this discrepancy has consequences for the classification of alpha1-adrenoceptors requires further investigation.


A novel electropolymerized fluorescent film probe for TNT based on electro-active conjugated copolymer.
A novel electro-active conjugated copolymer (PFPCz) has been designed, synthesized and used as the precursor of electropolymerization (EP) directly. By optimizing the EP condition, the PFPCz EP films have been prepared and displayed high fluorescent sensitivity to TNT, whose fluorescent intensity could be quenched 68.6% exposed to TNT (50 μM) in aqueous medium. These results suggest PFPCz EP film a promising candidate for TNT detection. Furthermore, this work provides not only a new precursor to EP but also a promising fluorescence film sensor candidate.


Exploring the intersection of multiple social determinants of health and disordered eating behaviors in a population-based sample in the United States.
Disordered eating behaviors (DEBs) have long-term, deleterious effects on health and are more prevalent among socially marginalized groups, likely as a result of systemic inequities across social determinants of health (SDoH). This exploratory study aimed to identify subgroups of emerging adults characterized by main and interactive associations between SDoH and two forms of DEB (binge eating, extreme unhealthy weight control behaviors). Participants (n = 1568; age 22.2 ± 2.1 years) from the United States were drawn from the EAT 2010-2018 longitudinal study. Conditional inference tree (CIT) analyses derived main and intersecting SDoH related to DEB across 33 input variables collected during adolescence and emerging adulthood. The binge eating CIT revealed five subgroups (prevalence: 6.3-23.2%) shaped by variables collected during emerging adulthood: appearance-based teasing (p < .001), financial difficulty (p = .003), gender (p < .001), and everyday discrimination (p = .008). The CIT results for extreme unhealthy weight control behaviors derived six subgroups (prevalence: 2.3-45.5%) shaped by weight teasing (p < .001) and gender (p < .001) during emerging adulthood and public assistance (p = .008) and neighborhood safety (p = .007) in adolescence. This exploratory study revealed distinct subgroups of emerging adults with varying DEB prevalence, suggesting that variability in DEB prevalence may be partially explained by intersecting SDoH during adolescence and emerging adulthood. Hypothesis-driven research and replication studies are needed to further explore the associations between SDoH and DEB during emerging adulthood. Disordered eating behaviors are common among young people in the United States and have long-term health consequences. This exploratory study identified subgroups of young people, characterized by combinations of social inequities (e.g., financial difficulties, teasing). Results highlight high-risk subgroups of emerging adults that should be examined further in hypothesis-driven research.


Cardiovascular risk factors among black schoolchildren: comparisons among four Know Your Body studies.
Baseline cardiovascular risk factor variables were obtained from 1,041 black District of Columbia children in Grades 4-6 as part of a Know Your Body evaluation project. Screening included height, weight, triceps skinfold measurements, systolic and diastolic blood pressures, step-test for fitness, serum cholesterol, high-density lipoprotein cholesterol and thiocyanate. Results were compared with those in three other Know Your Body studies, Bronx, New York, Westchester, New York, and Los Angeles, and indicated that District of Columbia black children are more likely to have high cholesterol levels and to fail the fitness test than black children in the other studies. In the District of Columbia, obese children had significantly higher total serum cholesterol, systolic, diastolic, and high-density lipoprotein levels, and were less fit than other District of Columbia children; almost three-fourths of all of the children had one or more risk factors. Socioeconomic status was negatively correlated with diastolic blood pressure, skinfold thickness, and cholesterol levels and was positively correlated with high-density lipoprotein cholesterol. Rates of obesity and diastolic blood pressure were consistent with Bronx and Westchester comparisons suggesting that socioeconomic status interacts with ethnicity to determine risk factor levels. The existence of children with multiple risk factors in all of the Know Your Body studies supports the need for early intervention.


New iodinated progestins as potential ligands for progesterone receptor imaging in breast cancer. Part 2: In vivo pharmacological characterization.
On the basis of the observed high selective binding to both the human and rat progesterone receptor (PR) in vitro, three 17alpha-iodovinyl-substituted nortestosterone derivatives, i.e., the Z-isomer of 17alpha-iodovinyl-19-nortestosterone (Z-IVNT; Z-IPG1) and both the stereoisomers of 17alpha-iodovinyl-18-methyl-11-methylene-19-nortestosterone (E- and Z-IPG2), were selected for radio-iodination and subsequently evaluated as potential radioligands for PR imaging in human breast cancer. Their target tissue uptake, retention, and uptake selectivity were studied in female rats. The distribution studies revealed that PR-mediated uptake in the uterus and ovaries could only be demonstrated for Z-[123I]IPG2. The target tissue uptake selectivity was, however, low, with the highest uterus-to-nontarget tissue uptake ratios observed at 2-4 h postinjection (p.i.), being 4.4, 1.8, and 7.4 for the uterus-to-blood, -fat, and -muscle ratio, respectively. For Z-[123I]IPG2, distribution was also studied in dimethylbenzanthracene (DMBA)-induced mammary tumour-bearing rats and in normal rabbits. Mammary tumour uptake of Z-[123I]IPG2 in the mammary tumour-bearing rat was also found to be PR-specific. In rabbits, higher selective target tissue uptake of Z-[123I]IPG2 was observed than in rats, resulting in uterus-to-blood, -fat, and -muscle ratios of 6.6, 2.2, and 21.3 at 2-4 h p.i., respectively. In conclusion, Z-[123I]IPG2, which displayed high binding affinity for both the human and rat PR in vitro, showed specific PR-mediated target tissue uptake in rats and rabbits in vivo, the uptake selectivity being highest in the latter. Because the binding characteristics appeared to vary between species, a pilot study in breast cancer patients may be needed to decide whether Z-[123I]IPG2 can be of potential use as PR imaging agent in breast cancer.


Valorizing coffee pulp by-products as anti-inflammatory ingredient of food supplements acting on IL-8 release.
Coffee is the second traded food commodity in the world. Beyond roasted seeds, the most part of the original fruit -and in particular pulp- is discarded as waste, with severe environmental and economic consequences in many developing countries. Our research focused on developing an eco-friendly extraction protocol of phytocomplexes from coffee pulp and evaluating their bioactivity and beneficial effects to human health as food supplements. Antioxidant activity assays (Folin-Ciocalteu and DPPH assays) were adopted to select the most effective extraction technique and results show antioxidant activity of coffee pulp extracts. After analysis of cytotoxicity on human epithelial gastric cells, measurements of IL-8 release of treated or pre-treated cells were performed. Results showed that the use of soft technical equipment and sustainable solvents (i.e. maceration process, aqueous extraction) can extract phytocomplexes with antioxidant properties. Moreover, IL-8 measurements showed impairment of this chemokine release at concentrations that may be reached in vivo in the gastrointestinal tract, following consumption of reasonable amount of extract. Pre-treatments analysis demonstrated the ability of coffee pulp extracts to prevent IL-8 release by gastric epithelial cells. Chemical evaluation performed by liquid chromatography mass spectrometry showed that quinic acid derivatives are abundant in coffee pulp extract together with procyanidins derivatives: those compounds might be responsible for the high biological activity. This evidence supports future applications of coffee pulp extracts as food supplement with high added value, starting from a waste that can be valorized through simple yet efficient extraction methods.


Reaction mechanism of bovine heart cytochrome c oxidase.
The 1.9 A resolution X-ray structure of the O2 reduction site of bovine heart cytochrome c oxidase in the fully reduced state indicates trigonal planar coordination of CuB by three histidine residues. One of the three histidine residues has a covalent link to a tyrosine residue to ensure retention of the tyrosine at the O2 reduction site. These moieties facilitate a four electron reduction of O2, and prevent formation of active oxygen species. The combination of a redox-coupled conformational change of an aspartate residue (Asp51) located near the intermembrane surface of the enzyme molecule and the existence of a hydrogen bond network connecting Asp51 to the matrix surface suggest that the proton-pumping process is mediated at Asp51. Mutation analyses using a gene expression system of the Asp51-containing enzyme subunit yield results in support of the proposal that Asp51 plays a critical role in the proton pumping process.


Effect of different types of volatile fatty acids on the performance and bacterial population in a batch reactor performing biological nutrient removal.
Different ratios of four volatile fatty acids (VFAs) were used as the primary feed to a laboratory scale biological nutrient reactor during four operational stages. The reactor performed efficiently over 500 days of operation with over 90% dissolved phosphorus and over 98% ammonium-nitrogen (NH4+-N) removal. Through in the first experimental phase, acetate and propionate were present in a significant proportion as carbon sources, the relative abundance of Candidatus Accumulibacter, a potential polyphosphate accumulating organism, increased from 10% to 57% and the Defluviicoccus genus, a known glycogen accumulating organism (GAO), decreased from 41% to 5%. Further tests indicated the presence of denitrifying phosphorus accumulating organisms (DPAO) belonging to Clade IIC, that could use nitrite as the electron acceptor during P-uptake. In general, VFAs favored the increase of the genus Defluviicoccus and Candidatus Accumulibacter. High relative abundance of Defluviicoccus did not affect the stability and the performance of the BNR process.


[Transformation of tetrahydro-1,3-oxazine into 1,3,5-tris(3-hydroxypropyl)-hexahydro-1,3,5-triazine--a question of stability (author's transl)].
At room temperature tetrahydro-1,3-oxazine (THO) is converted into the very viscous 1,3,5-tris(3-hydroxypropyl)-hexahydro-1,3,5-triazine (THT) over several weeks. On heating to ca. 125 degrees C THO will be reformed from THT. The structure of THT was proven by mass-, 1H- and 13C-NMR spectra.


Stable mixed chimerism after T cell-depleted allogeneic hematopoietic stem cell transplantation using conditioning with low-dose total body irradiation and fludarabine.
Although reduced intensity conditioning (RIC) before allografting is associated with low treatment-related morbidity and mortality, graft-versus-host disease (GVHD) remains a significant complication of hematopoietic stem cell transplantation (HSCT). T cell depletion (TCD) has been successfully used in conventional allotransplantation to reduce the incidence of GVHD, but was associated with an increased rate of engraftment failure. In a small cohort of six patients at high risk of developing GVHD we have determined whether sustained engraftment could be achieved using reduced intensity conditioning and T cell depletion in combination. All patients engrafted and 5/6 developed high levels (i.e. > or =95%) of donor chimerism, even though mismatched related or matched unrelated donors were used. Only one patient developed acute GVHD, as he received donor lymphocyte infusions (DLI) for relapse. In summary, TCD might be a useful prophylactic tool in RIC allogeneic HSCT. Although TCD after RIC might be associated with high relapse rate, as 5/6 patients are not in remission, this combined strategy might be appropriate for patients with less aggressive malignant or non-malignant diseases in which high transplant-related morbidity and mortality is not acceptable.


2'-Deoxy-2'(S)-ethinyl oligonucleotides: a modification which selectively stabilizes oligoadenylate pairing to DNA complements.
Oligonucleotides consisting of 2'-deoxy-2'(S)-ethinyl-thymidine,-uridine, and -adenosine have been prepared. Whereas the modified pyrimidine oligonucleotides uniformly lead to weaker pairing affinity with DNA and RNA complements, the corresponding adenine oligonucleotides show enhanced thermal stability in duplexes with complementary DNA and decreased stability with RNA.