Evaluation of Three Vaccination Schemes Against Clostridium perfringens Alpha Toxin and Their Effects on the Performance, Level of Intestinal Lesions, and Serum Antibody Titers in Broilers.
The objective of the trial was to evaluate three vaccination schemes against Clostridium perfringens (CP) alpha-toxoid through drinking water to determine if they can protect against clinical signs of necrotic enteritis and coccidiosis in broiler chickens. Three hundred 1-day-old Cobb 500 male chicks were used in 4 treatments with 10 repetitions. Each group received 1 of the following treatments over the course of 29 days: T1, no vaccination; T2, vaccination on Day 1; T3, vaccination on Day 7; and T4, vaccination on Days 7 and 17. The birds were vaccinated with inactivated CP toxoid type A, administered via drinking water. During the first 14 days, a high-protein diet (27%) consisting of corn, soy, and fish meal was fed. On Day 14 Eimeria acervulina (EA), Eimeria maxima (EMx), Eimeria tenella (ET), Eimeria necatrix, and Eimeria brunetti were used in a coccidial challenge. The field isolate CP type A was then inoculated on Days 18, 19, and 20. Ten birds were slaughtered by treatment to obtain serology samples for antibody titers and intestine samples for CP and Eimeria lesion score and gut integrity indicators. Productive performance was assessed using complete randomized design and compared statistically using the Tukey test, whereas intestinal integrity variables and antibodies against CP alpha toxin were assessed using a Kruskal-Wallis nonparametric method. The results revealed that the treatments had an effect on productive performance (P < 0.05); T3 had better body weight and weight gain than T1. In terms of lesion score at Day 21, T4 had a lower lesion score by EA, EMx, and ET than T1. Cell desquamation in T2 was lower than in T4, and excess mucus (EM) in T1 was the worst in gut integrity indicators at Day 21. On the other hand, T2 had more EM than T3 and T4 at Day 25. In the measurement of antibodies, no statistical differences (P > 0.05) were found. These findings indicate that vaccination on Day 7 (T3) outperformed double vaccination on Days 7 and 17 (T4) and single on Day 1 (T2), in terms of productive performance, gut integrity, and lesion scores; and on the last day of the experiment T3 had the best performance in immunology response.


Foraminifera may structure meiobenthic communities.
The cosmopolitan benthic foraminiferan, Ammonia beccarii, is a fervent microfloral predator which often forms densely-populated 2-4 cm2 aggregates in the field. Sediments within aggregate patches become extensively pelletized, mucus bound and depleted in microfloral food. On a West German Wattenmeer mudflat, copepodite and naupliar densities of a predominant harpacticoid copepod, Amphiascoides limicola, were significantly depressed in sediments containing>100 A. beccarii·3 cm-2 suggesting a possible foraminiferal: copepod amensalism. Therefore, I cultured A. beccarii and A. limicola separately in sediment microcosms and then tested if A. limicola's seemingly negative reaction to sediments containing A. beccarii occurs under controlled conditions, how various life stages of A. limicola are affected, and what the repulsive mechanisms of A. beccarii may be. In natural field sediments seeded with a latin-square dispersion of sterile sediment patches containing 0 or 100 A. beccarii, mean A. limicola naupliar and copepodite densities were 2 to 6 times lower in Ammonia-rich patches than Ammonia-poor patches (i.e. patches containing <100 A. beccarii·3 cm-2). Choice experiments directly testing potential A. beccarii inhibitory mechanisms were conducted with A. limicola copepodites: Cubic microcosms containing a latin-square patch dispersion of (1) sterile sediments (SS) seeded with 100 A. beccarii (low microflora), (2) SS bound with sterile mucus (0.0001%) (low microflora), (3) SS seeded with pelletized sediments (high microflora), and (4) SS seeded with mucus and pellets (high microflora), showed that copepodites colonized 1≪2 & 3, but 1 & 4 were not significantly different. Mucus addition by itself, in the absence of pelletization and microflora, strongly facilitated colonization-as did addition of microfloral-rich pelletized sediments. Pelletization and mucousbinding combined, but with low microflora, were least attractive to A. limicola. Pelletization and mucous-binding combined, but with high microflora, were more attractive to A. limicola than its complement, but not significantly so. Thus A. beccarii's inhibition of A. limicola is probably not caused by sediment pelletization and simple mucous exudates but by local microfloral depletion within aggregate foraminiferal patches.


An epoxy resin and silicone impregnation technique for the preservation of oral pathology teaching specimens.
A technique of plastination and its application to the preservation of oral pathology teaching specimens is presented. Advantages of the technique and the methodology are briefly outlined and summarized.


Correction: The novel long non-coding RNA TALNEC2, regulates tumor cell growth and the stemness and radiation response of glioma stem cells.
[This corrects the article DOI: 10.18632/oncotarget.15991.].


[Not Available].
A method for the combined extraction of the mycotoxins aflatoxin B1, B2, G1, G2, ochratoxin A (OTA) und zearalenone (ZEA) in cereals is described. After extraction with acetonitril/water a clean-up for the mycotoxins was made using solid-phase columns (SiOH) or a combination of two immunoaffinity columns (aflaochra- and zearala-test-column from Vicam). The aflatoxins, ochratoxin A and zearalenone were detected after pre-column derivatization with trifluoroacetic acid in one HPLC run. The clean-up using two combined immunoaffinity columns is suitable because the detection and determination limits are low.


Tyrosine administration to pregnant rats induces persistent behavioral modifications in the male offspring.
Pregnant rats were given, by stomach intubation, 1-tyrosine (20 or 500 mg/kg), beginning on day 11 post-coitus. Tyrosine or saline solution administrations were continued on a once-daily basis until day 20 of gestation. When male offspring were seventy days old, the spontaneous locomotor activity, open field test, swim test and motor ability test were performed. The offspring treated with large tyrosine doses showed a marked increase in both spontaneous locomotor activity and open field locomotion as adults. However, activity in the swim test decreased. The number of defecation boluses produced in the open field test and the motor ability in the rotating rod test diminished. The behavior of the rats treated with small doses of tyrosine was similar, in all tests performed, to that of rats treated with saline solution. These findings strongly suggest that a large increase in diet tyrosine during pregnancy modifies the behavior of male offspring.


Is antibiotic use a risk factor for breast cancer? A meta-analysis.
Breast cancer is a disease integrating hormonal and non-hormonal factors. Given the widespread antibiotic use, attention has been recently drawn upon the association between antibiotic use and breast cancer; however, the published studies have yielded contradictory results. In addition, various types of quantification in antibiotic use have been adopted. This meta-analysis aims to examine whether antibiotic use is associated with breast cancer risk presenting two analyses: one on antibiotic ever-use and one on the number of antibiotic prescriptions. Eligible studies were retrieved by a search in MEDLINE, Cochrane, and EMBASE databases till July 2009. Odds ratios (OR) pertaining to antibiotic ever-use were appropriately calculated. The random effects model was used to estimate the pooled OR. Publication bias was assessed through Begg's and Egger's tests. Meta-regression with the number of antibiotic prescriptions was performed. Five case-control studies were eligible at the ever-use versus never-use analysis (13 069 cases and 73 920 controls). Antibiotic ever-use was associated with slightly elevated breast cancer risk (pooled OR = 1.175, 95%CI: 0.994-1.387). No publication bias became apparent. Meta-regression showed a borderline dose-response effect implicating the number of antibiotic prescriptions. Antibiotic use seems associated with slightly elevated breast cancer risk. The underlying nature of the association remains elusive, as it may be direct or due to secondary associations, that is, causal or confounding. At any case, this is a finding with potentially important public health implications, which should be further examined in the literature.


Bevacizumab plus erlotinib versus erlotinib alone for advanced EGFR-mutant non-small cell lung cancer: a meta-analysis of randomized clinical trials.
Previous studies showed that the combination of bevacizumab and erlotinib (combination therapy) significantly prolonged progression-free survival (PFS) but no overall survival (OS) compared to erlotinib alone (monotherapy) for advanced EGFR-mutant non-small cell lung cancer (NSCLC). Two phase III randomized controlled trials (RCTs) had reported the OS results in 2021. This meta-analysis aimed to include the results of the two RCTs to make a decision. We systematically searched relevant databases for RCTs on the use of bevacizumab plus erlotinib in advanced EGFR-mutant NSCLC. The main outcomes of interest were PFS, OS, and the reported hazard ratio (HR). Fixed-effect model was used to estimate pooled HR. Total 5 RCTs with 935 patients were eligible for this meta-analysis. All studies reached their primary study endpoints including PFS and OS. Compared to monotherapy, combination therapy remarkably prolonged PFS (HR = 0.60, 95% confidence interval CI 0.51-0.70; p < 0.00001); however, OS was similar between the two groups (HR = 0.90, 95% CI 0.76-1.08; p = 0.26). Subgroup analysis demonstrated that in deletion within exon 19 (19del) mutation subgroup, the combination therapy could only prolong PFS (HR = 0.60, 95% CI 0.47-0.76; p < 0.0001) but not OS (HR = 1.00, 95% CI 0.73-1.37; p = 1.00), and also in leucine-to-arginine substitution in exon 21 (L858R) mutation subgroup (HR = 0.59, p < 0.0001 and HR = 0.80, p = 0.18, respectively). For patients with brain metastasis at baseline, the combination therapy achieved a significant better PFS than the monotherapy (HR = 0.60, 95% CI 0.39-0.90; p = 0.01), and a better OS with the difference marginally significant (HR = 0.69, 95% CI 0.46-1.02; p = 0.06). Combination of bevacizumab and erlotinib can prolong progression-free survival but not overall survival compared to erlotinib alone in advanced EGFR-mutant non-small cell lung cancer patients. The combination therapy not only can prolong progression-free survival but also has a tendency to prolong overall survival for patients with brain metastasis at baseline.


Trichinella britovi in a red fox (Vulpes vulpes) from Portugal.
Trichinellosis is one of the most important foodborne parasitic zoonoses, caused by nematodes of the genus Trichinella. Pigs and other domestic and wild animals, including red foxes (Vulpes vulpes), are sources of Trichinella infection for human beings. Trichinella britovi is the major agent of infection in sylvatic animals and the most important species circulating in the European wildlife. The present study aimed at assessing Trichinella spp. infection in red foxes from the North of Portugal. Forty-seven carcasses of wild red foxes shot during the official hunting season or killed in road accidents were obtained between November 2008 and March 2010. In order to identify the presence of Trichinella spp. larvae in red foxes, an individual artificial digestion was performed using approximately 30 g of muscle samples. Larvae of Trichinella spp. were detected in one (2.1%) out of the 47 assessed foxes. After a multiplex polymerase chain reaction analysis, T. britovi was molecularly identified as the infecting species. The recognition of T. britovi in a red fox confirms that a sylvatic cycle is present in the North of Portugal and that the local prevalence of Trichinella infection in wildlife must not be ignored due to its underlying zoonotic risks.


Impact of c-MYC protein expression on outcome of patients with early-stage HER2+ breast cancer treated with adjuvant trastuzumab NCCTG (alliance) N9831.
This study investigated the association between tumor MYC protein expression and disease-free survival (DFS) of patients randomized to receive chemotherapy alone (Arm A) or chemotherapy with sequential (Arm B) or concurrent trastuzumab (Arm C) in the N9831 (Alliance) adjuvant HER2(+) trastuzumab breast cancer trial. This analysis included 1,736 patients randomized to Arms A, B, and C on N9831. Nuclear MYC protein expression was determined in tissue microarray sections containing three biopsies per patient or whole tissue sections using standard immunohistochemistry (clone 9E10). A tumor was considered positive for MYC protein overexpression (MYC(+)) if the nuclear 3+ staining percentage was more than 30%. Five hundred and seventy-four (33%) tumors were MYC(+). MYC(+) was associated with hormone receptor positivity (χ(2), P = 0.006), tumors 2 cm or more (χ(2), P = 0.02), and a higher rate of nodal positivity (χ(2), P < 0.001). HRs for DFS (median follow-up: 6.1 years) for Arm C versus A were 0.52 (P = 0.006) and 0.65 (P = 0.006) for patients with MYC(+) and MYC(-) tumors, respectively (P(interaction) = 0.40). For Arm B versus A, HRs for patients with MYC(+) and MYC(-) tumors were 0.79 (P = 0.21) and 0.74 (P = 0.04), respectively (P(interaction) = 0.71). For Arm C versus B, HRs for patients with MYC(+) and MYC(-) tumors were 0.56 (P = 0.02) and 0.89 (P = 0.49), respectively (P(interaction) = 0.17). Our data do not support an impact of tumor MYC protein expression on differential benefit from adjuvant trastuzumab.


Wertheim's hysterectomy after neoadjuvant carboplatin-based chemotherapy in patients with cervical cancer stage IIB and IIIB.
To improve local response and survival, a prospective study was designed to determine the effects of neoadjuvant chemotherapy in the management of cervical carcinoma stage IIB and IIIB. Fourteen patients were treated with preoperative neoadjuvant chemotherapy. Three courses of carboplatin were administered in combination with ifosfamide in 11/14 patients, whereas 3 patients received three courses of carboplatin and paclitaxel. After neoadjuvant chemotherapy, there were 8/14 clinical responses while 6/14 patients had no change. In 8 cases, Wertheim's hysterectomy was possible after neoadjuvant chemotherapy. Six of these 8 patients are still alive after a duration of 32 months median follow-up, 2 patients died of metastatic disease. In 6 cases with no change after chemotherapy, Wertheim's hysterectomy was impossible. In this subgroup, the median survival time was 15.5 months, and 4/6 patients died of metastatic disease. Neoadjuvant chemotherapy with carboplatin/ifosfamide or carboplatin/paclitaxel is safe, well-tolerated, effective and useful to enable Wertheim's hysterectomy.


Occlusion of silastic broviac catheters as a result of twisting between the catheter and hub assembly.
Occlusion is a common cause of catheter malfunction during home parenteral nutrition (HPN). We report 5 cases of central venous catheter occlusion, encountered over a 24 month period, which were associated with twisting of the catheter at the hub assembly. One catheter was replaced before the cause of the occlusion was identified. In 4 cases, twisting was noted prior to catheter removal, and this was corrected in three, allowing HPN to continue without catheter replacement. In 1 case the catheter was repaired. The current design of silastic Broviac catheters allows the catheter to twist around the hub assembly. Over-enthusiastic tightening of the cap of the catheter leads to twisting which causes catheter occlusion. A high index of suspicion should be maintained when dealing with catheter occlusion associated with silastic Broviac catheters. Recognition of the problem allows catheter salvage without recourse to catheter replacement.


Congenital dilatation of the bile duct: changes in diagnostic tools over the past 19 years.
Because of recent improvements in diagnostic procedures, many cases of congenital dilatation of the bile duct (CDBD) have been diagnosed in early life. To determine the mode of presentation and changes in diagnostic tools, medical records of 34 children (25 girls, nine boys) with CDBD who were treated between 1982 and 2000 were reviewed. The age at presentation ranged from 0 to 16 years (median 4.9 +/- 0.7 years), with two patients being diagnosed using prenatal ultrasonography. Of the 32 patients diagnosed post-natally, 21 (66%) complained of abdominal pain. There were also 21 (66%) cases of vomiting. Sixteen patients (50%) experienced both these symptoms. Ten (31%) cases presented with jaundice and three (9%) presented with a palpable mass. Ultrasonography was used as a diagnostic tool in 29 cases (85%). The finding of a dilated common bile duct on abdominal ultrasonography was helpful for early diagnosis. Spiral computed tomography was also a useful and accurate imaging method for diagnosis. Anomalous pancreaticobiliary junction (PBJ) was demonstrated in 44% of patients with CDBD. Magnetic resonance cholangiopancreatography, which can be performed non-invasively, is useful for the diagnosis and pre-operative assessment of CDBD in children. The average length of time from presentation to diagnosis could be shortened from 46 days (1982-1988) to 13 days (1995-2000). Recent improvements in diagnostic procedures make immediate, non-invasive diagnosis of CDBD and PBJ possible.


Myelin basic protein: a component of circulating immune complexes in multiple sclerosis.
Myelin basic protein (MBP) is an antigenic component of circulating immune complexes (CIC) in patients with multiple sclerosis (MS). Immune complexes were isolated from the sera by adsorption to Raji cells and then acid eluted. Final identification of MBP from Raji eluates was done by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) followed by MBP radioimmunoassay (RIA) of gel eluates and by an immunoblot technique.


Anthraquinone Derivatives and Other Aromatic Compounds from Marine Fungus Asteromyces cruciatus KMM 4696 and Their Effects against Staphylococcus aureus.
New anthraquinone derivatives acruciquinones A-C (1-3), together with ten known metabolites, were isolated from the obligate marine fungus Asteromyces cruciatus KMM 4696. Acruciquinone C is the first member of anthraquinone derivatives with a 6/6/5 backbone. The structures of isolated compounds were established based on NMR and MS data. The absolute stereoconfigurations of new acruciquinones A-C were determined using ECD and quantum chemical calculations (TDDFT approach). A plausible biosynthetic pathway of the novel acruciquinone C was proposed. Compounds 1-4 and 6-13 showed a significant antimicrobial effects against Staphylococcus aureus growth, and acruciquinone A (1), dendryol B (4), coniothyrinone B (7), and ω-hydroxypachybasin (9) reduced the activity of a key staphylococcal enzyme, sortase A. Moreover, the compounds, excluding 4, inhibited urease activity. We studied the effects of anthraquinones 1, 4, 7, and 9 and coniothyrinone D (6) in an in vitro model of skin infection when HaCaT keratinocytes were cocultivated with S. aureus. Anthraquinones significantly reduce the negative impact of S. aureus on the viability, migration, and proliferation of infected HaCaT keratinocytes, and acruciquinone A (1) revealed the most pronounced effect.


Alternate hydroxylating activities in newborn rat adrenal cells in primary culture.
During the course of a study to produce reference compounds, the metabolism of tetrahydrogenated derivatives (ring A reduced) of progesterone, 6 alpha-hydroxyprogesterone, 11-deoxycorticosterone and corticosterone in newborn rat adrenal cells in primary culture was studied. Analysis of the metabolites was made by gas chromatography-mass spectrometry. Most products resulted from the enzymatic reactions of 11 beta-, 18- and 21-hydroxylation, reduction of the 20-oxo group and oxidoreduction of the 3-hydroxyl group. However, unexpected metabolites were produced from the incubation of 3 beta, 5 alpha-tetrahydroprogesterone and 6 alpha-hydroxy-3 alpha, 5 beta-tetrahydroprogesterone. They resulted from the 16 alpha-hydroxylation of the precursors and probably from the 15 alpha-, 16 beta- and 17 alpha-hydroxylation of 6 alpha-hydroxy-3 alpha, 5 beta-tetrahydroprogesterone. These hydroxylating activities are weak and were not detected from the endogenous steroidogenesis. They were not detected either from the incubation of exogenous steroids with a 3-oxo-4-ene structure or from steroids with a 21-hydroxyl substituent. They result only from substrates showing diminished or no affinity towards the 11 beta/18- and 21-steroid hydroxylase systems. These unusual hydroxylations could be catalyzed by monooxygenase systems in the endoplasmic reticulum similar to those present in the liver or by the monooxygenase systems specific to steroidogenesis. In particular, the reaction specificity of cytochrome P-450(11) beta could be altered by the presence of a 6 alpha-hydroxyl group in a tetrahydrogenated steroid.


Anthropometrics and maturity status: A preliminary study of youth football head impact biomechanics.
There is a paucity of head impact biomechanics research focusing on youth athletes. Little is known about how youth subconcussive head impact tolerances are related to physical size and maturation. To examine the effects of age, anthropometric and maturational status variability on head impact biomechanics. Cross-sectional. Outdoor youth football facilities in South Carolina. Thirty-four male recreational youth football players, 8 to 13yrs. Categorized by CDC standards, independent variables were: age, height, mass, BMI, and estimated peak height velocity (PHV). Participants wore a designated head impact sensor (xPatch) on their mastoid process during practices and games. Linear acceleration (g) and rotational acceleration (rad/s2). Boys in the older age category had a greater linear (F=17.72; P<0.001) and rotational acceleration (F=10.74; P<0.001) than those in the younger category. Post-PHV boys had higher linear (F=9.09, P=0.002) and rotational (F=5.57, P=0.018) accelerations than those who were pre-PHV. Rotational, but not linear acceleration differed by height category with lowest impacts found for the tallest category, whereas both linear and rotational accelerations by mass differences favored average and heavy categories. BMI overweight boys, had the greatest linear (F=5.25; P=0.011) and rotational acceleration (F=4.13; P=0.260) means. Post-PHV boys who were older, taller and had longer legs, but who were not heavier, had higher impacts perhaps due to the type of impacts sustained. Taller boys' heads are above their peers possibly encouraging hits in the torso region resulting in lower impact accelerations. Obese boys did not have sequential results compared to boys in the other BMI categories probably due to league rules, player position, and lack of momentum produced.


Are those phospholipids in your pocket?
The identification of phospholipids ligands for the nuclear receptors SF-1 and LRH-1 raise exciting new questions in the areas of signaling and metabolism. Do these receptors provide cells with a mechanism to alter genomic activities in response to phospholipid flux? The tools now exist to address these questions, and more.


Insulin stimulation of rat ventricular K+ currents depends on the integrity of the cytoskeleton.
1. The effect of insulin on K+ currents was studied with enzymatically dispersed ventricular myocytes from insulin-deficient (type I) diabetic rats. Diabetic conditions were induced by a single intravenous injection of streptozotocin (100 mg kg-1) given 8-13 days before the experiments. Measurements of plasma glucose and insulin levels confirmed the diabetic status of the animals. 2. A Ca2+-independent transient outward K+ current, It, and a slowly inactivating, quasi-steady-state current, Iss, which are depressed in diabetic myocytes, could be restored by exposure to 1, 10 or 100 nM insulin. This was only observed after a delay of 5-6 h, although an insulin exposure of only 1 h was sufficient to initiate its stimulatory action on It and Iss. The stimulatory effect of insulin on these K+ currents was prevented by 2 microM cycloheximide, which in itself had no direct effect on these currents. 3. Disruption of the actin microfilament network with 1 microM cytochalasin D (CD) also prevented the stimulatory effect of 100 nM insulin on both It and Iss. Since CD was added 1 h after insulin, inhibitory effects on insulin signalling were ruled out. Adding CD (1 microM) 5-9 h after insulin, when currents were already augmented, had no effect (up to 50 min exposure). Incubating control cells for 6-10 h with 1 microM CD had no effect on any of the currents measured. 4. Stabilization of the actin network by pre-exposure to 2.5 microM phalloidin restored the stimulatory effect of insulin, in the continued presence of CD, ruling out any effects of CD on components other than the cytoskeleton. 5. The stimulatory effect of insulin was also prevented by incubating cells with insulin in the presence of the microtubule-disrupting agent colchicine (5 microM). 6. These results suggest that the insulin-mediated augmentation of K+ currents in diabetic myocytes requires protein synthesis, possibly of K+ channels, as well as an intact cytoskeleton. The possibility that newly formed channels translocate to the plasma membrane in a process dependent on different elements of the cytoskeleton is discussed.


Expression analysis of a cold responsive transcript from trifoliate orange by real-time PCR and RT-PCR.
CLTa and CLTb are two transcripts produced by the citrus CLT gene. CLTb is constitutively expressed, while CLTa is a low temperature responsive transcript expressed in temperatures below 10 degrees C during the acclimation process of some species of citrus. Real-time PCR was used to study CLTa expression pattern in trifoliate orange during acclimation, gradual deacclimation and abrupt deacclimation. A standard curve of nine dilution series from 10 x 10(6) to 10 x 10(-3) fg was constructed, using part of the CLTa transcript, which enabled us to determine the concentration of the transcript at different temperatures and conditions. It was found that during acclimation, CLTa expression is first detected at 10 degrees C, reaching a maximum after 24 h of exposure at -1 degrees C. During gradual deacclimation, the transcript accumulated at 5 degrees C and after this point it degrades, reaching a low level at 10 degrees C. When the plants were abruptly transferred to room temperature after being acclimated to -1 degrees C, the transcript reduced from 11,303 fg to levels below the threshold 3 h later, indicating a rapid degradation and how the expression of CLTa is dependent on low temperature. Exposure of trifoliate plants to abscisic acid (ABA) and salts indicated that CLTa is not induced by these treatments at the concentrations used. CLTa expression was also verified in other citrus species and was not detected in the acclimated cold-sensitive species "Mexican lime" (Citrus aurantifolia Swing.) and in the cold hardy "Satsuma mandarin (C. unchiu Marc.).


Development of a safety index of transarterial chemoembolization for hepatocellular carcinoma to prevent acute liver damage.
Transarterial chemoembolization (TACE) is the most effective palliative treatment for hepatocellular carcinoma (HCC), but may cause acute liver damage. One hundred and ninteen patients with unresectable HCCs, undergoing TACE, were studied prospectively. A safety index to prevent acute liver damage was developed by using logistic regression. Acute liver damage by TACE was not related to the gender or age, but was mostly correlated to Child's classification (beta = 1.89, OR = 6.6, CI: 2.07, 21.01) and the amount of Lipiodol (beta = 0.09, OR = 1.09, CI: 1.02, 1.16) used for the TACE. In treatment of a Child's B/C patient by TACE, no more than 20 ml Lipiodol should be used.


Risk-Stratified Therapy for Pediatric Acute Myeloid Leukemia.
Acute Myeloid Leukemia (AML) is the second most common type of leukemia in children. Recent advances in high-resolution genomic profiling techniques have uncovered the mutational landscape of pediatric AML as distinct from adult AML. Overall survival rates of children with AML have dramatically improved in the past 40 years, currently reaching 70% to 80% in developed countries. This was accomplished by the intensification of conventional chemotherapy, improvement in risk stratification using leukemia-specific cytogenetics/molecular genetics and measurable residual disease, appropriate use of allogeneic hematopoietic stem cell transplantation, and improvement in supportive care. However, the principle therapeutic approach for pediatric AML has not changed substantially for decades and improvement in event-free survival is rather modest. Further refinements in risk stratification and the introduction of emerging novel therapies to contemporary therapy, through international collaboration, would be key solutions for further improvements in outcomes.


Isolation and characterization of a DNA synthesome from a neuroblastoma cell line.
Despite significant analysis of the chromosomal abnormalities associated with neuroblastoma (NB), the role that NB DNA replication may play in the accumulation of genetic damage is poorly understood. For that matter, the mechanisms involved in NB DNA synthesis have yet to be elucidated. In an effort to investigate this process in NB, we have isolated and purified a multiprotein DNA replication complex from human NB cells (IMR-32). Using a series of subcellular fractionations, ion-exchange chromatography, and gradient sedimentation steps, we have isolated a simian virus 40 replication competent multiprotein complex from IMR-32 NB cells, which has been designated the DNA synthesome. Enzymatic and immunodetection techniques were used to characterize the multiple components of the multiprotein DNA replication complex. The NB DNA synthesome was found to remain intact and functional through all the steps of its purification. The proteins and enzymatic activities that were found to copurify with the NB DNA synthesome include: DNA polymerases alpha , delta , and epsilon , proliferating cell nuclear antigen, replication factor A, replication factor C, topoisomerases I and II, flap endonuclease 1, and DNA ligase I. Although the cooperative integration of a DNA replication macromolecular complex (DNA synthesome) is not new, we extend the view of the DNA synthesome mediating DNA synthesis for human NB. The data reported here characterize the human NB DNA synthesome for the first time and provide the groundwork for investigating whether the NB DNA synthesome contributes to faulty DNA replication and tumor pathogenesis for this childhood malignancy.


Complete Response after Chemoradiotherapy in Rectal Cancer (Watch-and-Wait): Have we Cracked the Code?
Patients with locally advanced rectal cancer receive preoperative chemoradiation as the standard of care, producing a pathological complete response in 10-20% and a complete clinical response (CCR) in 20-30%. Small observational studies suggest a selective non-operative management with rigorous surveillance is an option and is increasingly being advocated in many parts of the world for patients who achieve a CCR or near CCR. The assumption is that oncological outcomes for good responders, who are observed, compare favourably with patients subjected to radical surgery. Late regrowth of the primary is rare, almost invariably endoluminal and, hence, can be salvaged. However, concerns remain among some surgeons and oncologists regarding the reproducibility of published results in routine practice. We have previously reviewed this topic. The aim of this brief overview was to re-assess the feasibility and safety of a non-operative approach based on the currently available literature. We make recommendations as to the quality of care required to undertake this management. Significant heterogeneity remains in the initial inclusion criteria, staging and restaging methods, study design, timing of assessment, duration and rigour of follow-up of the trials reviewed - all of which obscure the validity of the results.


High-performance size-exclusion chromatographic determination of the potency of biosynthetic human growth hormone products.
A new high-performance size-exclusion chromatography method has been developed for the determination of potency of human growth hormone products. This method has been extensively validated and shown to correlate well with the hypophysectomized rat bioassay which has been used traditionally. The method is much more precise than the traditional bioassay and thus provides more reliable means of producing consistent biosynthetic human growth hormone batches.


Verification of Biaryl-Structure Axial Chirality Produced in Ellagitannins by Chemical Oxidation.
The axial chirality of hexahydroxydiphenoyl (HHDP) groups contained in ellagitannins depends on the bridging position of d-glucose. The 4,6-O-HHDP group predominantly exhibits S-type chirality. This study elucidated the formation of the 4,6-O-(R)-HHDP group and subsequent axial isomerization by means of oxidative coupling of galloyl groups, which resulted in S chirality.


PPREMO: a prospective cohort study of preterm infant brain structure and function to predict neurodevelopmental outcome.
More than 50 percent of all infants born very preterm will experience significant motor and cognitive impairment. Provision of early intervention is dependent upon accurate, early identification of infants at risk of adverse outcomes. Magnetic resonance imaging at term equivalent age combined with General Movements assessment at 12 weeks corrected age is currently the most accurate method for early prediction of cerebral palsy at 12 months corrected age. To date no studies have compared the use of earlier magnetic resonance imaging combined with neuromotor and neurobehavioural assessments (at 30 weeks postmenstrual age) to predict later motor and neurodevelopmental outcomes including cerebral palsy (at 12-24 months corrected age). This study aims to investigate i) the relationship between earlier brain imaging and neuromotor/neurobehavioural assessments at 30 and 40 weeks postmenstrual age, and ii) their ability to predict motor and neurodevelopmental outcomes at 3 and 12 months corrected age. This prospective cohort study will recruit 80 preterm infants born ≤ 30 week's gestation and a reference group of 20 healthy term born infants from the Royal Brisbane & Women's Hospital in Brisbane, Australia. Infants will undergo brain magnetic resonance imaging at approximately 30 and 40 weeks postmenstrual age to develop our understanding of very early brain structure at 30 weeks and maturation that occurs between 30 and 40 weeks postmenstrual age. A combination of neurological (Hammersmith Neonatal Neurologic Examination), neuromotor (General Movements, Test of Infant Motor Performance), neurobehavioural (NICU Network Neurobehavioural Scale, Premie-Neuro) and visual assessments will be performed at 30 and 40 weeks postmenstrual age to improve our understanding of the relationship between brain structure and function. These data will be compared to motor assessments at 12 weeks corrected age and motor and neurodevelopmental outcomes at 12 months corrected age (neurological assessment by paediatrician, Bayley scales of Infant and Toddler Development, Alberta Infant Motor Scale, Neurosensory Motor Developmental Assessment) to differentiate atypical development (including cerebral palsy and/or motor delay). Earlier identification of those very preterm infants at risk of adverse neurodevelopmental and motor outcomes provides an additional period for intervention to optimise outcomes. Australian New Zealand Clinical Trials Registry ACTRN12613000280707. Registered 8 March 2013.


Tracking of atrial flutter during DDD pacing: another form of pacemaker-mediated tachycardia.
Two patients who had DDD pacemakers inserted for symptomatic sick sinus syndrome developed sustained upper-rate limit pacing. It was demonstrated in these two patients that pacemaker-mediated tachycardia was due to tracking of atrial flutter. DDD pacemakers should be used with caution in patients with the sick sinus syndrome and associated atrial tachyarrhythmias. Medical treatment of recurrent atrial tachyarrhythmias may allow patients to remain in the DDD mode.


Principles for computational design of binding antibodies.
Natural proteins must both fold into a stable conformation and exert their molecular function. To date, computational design has successfully produced stable and atomically accurate proteins by using so-called "ideal" folds rich in regular secondary structures and almost devoid of loops and destabilizing elements, such as cavities. Molecular function, such as binding and catalysis, however, often demands nonideal features, including large and irregular loops and buried polar interaction networks, which have remained challenging for fold design. Through five design/experiment cycles, we learned principles for designing stable and functional antibody variable fragments (Fvs). Specifically, we (i) used sequence-design constraints derived from antibody multiple-sequence alignments, and (ii) during backbone design, maintained stabilizing interactions observed in natural antibodies between the framework and loops of complementarity-determining regions (CDRs) 1 and 2. Designed Fvs bound their ligands with midnanomolar affinities and were as stable as natural antibodies, despite having >30 mutations from mammalian antibody germlines. Furthermore, crystallographic analysis demonstrated atomic accuracy throughout the framework and in four of six CDRs in one design and atomic accuracy in the entire Fv in another. The principles we learned are general, and can be implemented to design other nonideal folds, generating stable, specific, and precise antibodies and enzymes.


Metabolomics-derived marker metabolites to characterize Phaeocystis pouchetii physiology in natural plankton communities.
Phaeocystis pouchetii (Hariot) Lagerheim, 1893 regularly dominates phytoplankton blooms in higher latitudes spanning from the English Channel to the Arctic. Through zooplankton grazing and microbial activity, it is considered to be a key resource for the entire marine food web, but the actual relevance of biomass transfer to higher trophic levels is still under discussion. Cell physiology and algal nutritional state are suggested to be major factors controlling the observed variability in zooplankton grazing. However, no data have so far yielded insights into the metabolic state of Phaeocystis populations that would allow testing this hypothesis. Therefore, endometabolic markers of different growth phases were determined in laboratory batch cultures using comparative metabolomics and quantified in different phytoplankton blooms in the field. Metabolites, produced during exponential, early and late stationary growth of P. pouchetii, were profiled using gas chromatography-mass spectrometry. Then, metabolites were characterized that correlate with the growth phases using multivariate statistical analysis. Free amino acids characterized the exponential growth, whereas the early stationary phase was correlated with sugar alcohols, mono- and disaccharides. In the late stationary phase, free fatty acids, sterols and terpenes increased. These marker metabolites were then traced in Phaeocystis blooms during a cruise in the Barents Sea and North Norwegian fjords. About 50 endometabolites of P. pouchetii were detected in natural phytoplankton communities. Mannitol, scyllo-inositol, 24-methylcholesta-5,22-dien-3β-ol, and several free fatty acids were characteristic for Phaeocystis-dominated blooms but showed variability between them. Distinct metabolic profiles were detected in the nutrient-depleted community in the inner Porsangerfjord (< 0.5 µM NO3-, < 0.1 µM PO 4 3- ), with high relative amounts of free mono- and disaccharides indicative for a limited culture. This study thereby shows how the variable physiology of phytoplankton can alter the metabolic landscape of entire plankton communities.


The endocrinology of varicoceles.
There is good evidence of an associated abnormality in testicular hormone production and spermatogenesis in some men with varicoceles. This abnormality can be demonstrated with dynamic tests of the hypothalamic-pituitary-testicular axis and by measuring seminal plasma androgen levels. A high proportion of oligozoospermic men who have abnormal hormone profiles will respond favorably to correction of their varicosities. Several oligozoospermic men with varicoceles have normal hormonal profiles. To date, in our unit, none of these men has had an improvement in seminal characteristics after varicocelectomy. This result would suggest that these men have incidental varicoceles. It is not clear what the testicular defect is leading to abnormal spermatogenesis in these men. Clearly, more studies are required in this group of men and in the men with sperm densities greater than 30 X 10(6)/ml, the majority of whom have normal responses to GnRH infusion. More information is needed regarding the intratesticular control of hormone production and spermatogenesis. As our knowledge of the paracrine system within the testis increases, so should our understanding of the mechanisms involved in the association of varicoceles and infertility.


Proximal femoral osteotomies in children.
The aim of proximal femoral osteotomies (PFO) in children is to restore normal anatomy and optimal joint congruency to prevent medium and long-terms degenerative deterioration of the hip. They play an important role in the treatment of neurological subluxations or dislocations of the hip. Advances in modern imaging and surgical techniques have improved understanding of the anatomical factors associated with a number of disorders of the growing hip and their sequelae. The indications for isolated PFO or associated with other intra- or extraarticular procedures have become more rational and better adapted to the various architectural defects and the femoroacetabular impingements. Two types of osteotomies are described: intertrochanteric osteotomies (varus and valgus correction, valgisation, flexion, extension), and osteotomies of the greater trochanter, either simple or double with lengthening of the femoral neck. Primary stability of the osteosynthesis is the major problem, as it is often affected by osteopenia. The development of new implants (LCP plate) avoids this inconvenience, resulting in geometrically precise osteotomies and a more stable fixation. Even when it is correctly performed, articular congruence is not always managed by PFO alone, it is sometimes necessary to associate acetabular procedures.


The relationship of biological and immunological activities of factor VIII.
Factor VIII is an essential blood clotting factor which consists of two protein moieties, each with distinct biological functions and antigenic determinants. The immunological markers were originally seen as indicators of the biological activities; however this view has been increasingly challenged. We have investigated the biological and immunological properties of Factor VIII to clarify these relationships. Plasma stored at room temperature for 21 days lost biological activity, but retained immunological activity: The procoagulant activity was reduced to 35% and the ristocetin cofactor activity to 75.4% of their original levels; but the reactivities of both procoagulant antigen and Factor VIII related antigen were maintained. A dissociation of activities was also demonstrated in serum, in which the procoagulant activity was 10% and the procoagulant antigen 72% of corresponding plasma values. These results indicate that the antigenic reactivities are not appropriate markers for Factor VIII biological activity.


Resistance profiles of Neisseria gonorrhoeae isolates in Vienna, Austria: a phenotypic and genetic characterization from 2013 to 2020.
International surveillance data show a constant rise in the number of Neisseria gonorrhoeae infections and an increase in drug resistance of N. gonorrhoeae. As recent N. gonorrhoeae surveillance data in Austria are scarce, this study investigated phenotypic and genotypic antimicrobial resistance in N. gonorrhoeae isolates. In total, 440 N. gonorrhoeae samples were collected at the Medical University of Vienna, and the minimal inhibitory concentrations (MICs) for a range of different antibiotics were determined. Sampling sites and treatments were recorded, and whole-genome sequencing of N. gonorrhoeae isolates was performed using allele libraries to determine genotypic resistance. The median MICs for ceftriaxone, cefixime, azithromycin, ciprofloxacin, tetracycline and penicillin were <0.002 µg/mL, <0.016 µg/mL, 0.25 µg/mL, 2.0 µg/mL, 1.5 µg/mL and 0.25 µg/mL, respectively. Annual comparison showed that MICs were generally stable for all antimicrobial agents except azithromycin, for which an increase in median MIC was observed from 2017 (0.25 µg/mL). There was no genetic resistance to ceftriaxone; 8% of samples displayed resistance mutations against cefixime, primarily located in the penA gene. Resistance to azithromycin increased from 2% in 2013 to 12% in 2020. MtrD mosaic had the highest impact on azithromycin susceptibility; 47% of the resistant isolates showed this mutation. The majority of cases of gonorrhoea were treated successfully with either ceftriaxone or a ceftriaxone/azithromycin regime. Two treatment failures occurred under monotherapy with doxycycline. Overall, genotypic resistance corresponded significantly to all respective MICs. The resistance rate of N. gonorrhoeae to antibiotics has remained stable in Vienna over the last decade, except for azithromycin. The strong correlation found between genetic and phenotypic patterns in this study holds promise for future diagnostics of N. gonorrhoeae resistance based on genotypes.


Oxidative removal of aqueous steroid estrogens by manganese oxides.
This study investigated the oxidative removal of steroid estrogens from water by synthetic manganese oxide (MnO2) and the factors influencing the reactions. Using 1 x 10(-5)M MnO2 at pH 4, estrone (E1), 17beta-estradiol (E2), estriol (E3) and 17alpha-ethinylestradiol (EE2), all at 4 x 10(-6)M, were rapidly removed within 220 min, indicating the effectiveness of MnO2 as an oxidizing agent towards estrogens. E2 removal increased with decreasing pH over the tested range of 4-8, due most likely to increased oxidizing power of MnO2 and a cleaner reactive surface in acidic solutions. Coexisting metal ions of 0.01 M (Cu(II), Zn(II), Fe(III) and Mn(II)) and Mn(II) released from MnO2 reduction competed with E2 for reactive sites leading to reduced E2 removal. Observed differential suppression on E2 removal may be related to different speciations of metals, as suggested by the MINTEQ calculations, and hence their different adsorptivities on MnO2. By suppressing the metal effect, humic acid substantially enhanced E2 removal. This was attributed to complexation of humic acid with metal ions. With 0.01 M ZnCl2 in solutions containing 1 mg l(-1) humic acid, the binding of humic acid for Zn(II) was determined at 251 mmol g(-1). An in vitro assay using human breast carcinoma MCF-7 cells indicated a near elimination of estrogenic activities without secondary risk of estrogen solutions treated with MnO2. Synthetic MnO2 is therefore a promising chemical agent under optimized conditions for estrogen removal from water. Metal chelators recalcitrant to MnO2 oxidation may be properly used to further enhance the MnO2 performance.


Identification of a human mitochondrial ABC transporter, the functional orthologue of yeast Atm1p.
We have sequenced the entire coding region of the human ABC transporter ABC7. The protein represents a 'half-transporter' and displays high sequence similarity to the mouse ABC7 protein and to the mitochondrial ABC transporter Atm1p of Saccharomyces cerevisiae. As shown by immunostaining using a specific antibody, the human ABC7 protein (hABC7) is a constituent of mitochondria. The N-terminus of hABC7 contains the information for targeting and import into the organelles. When synthesised in yeast cells defective in Atm1p (strain delta atm1/hABC7), hABC7 protein can revert the strong growth defect observed for delta atm1 cells to near wild-type behaviour. The known phenotypical consequences of inactivation of the ATM1 gene are almost fully amended by expression of hABC7 protein. delta atm1/hABC7 cells harbour wild-type levels of cytochromes and extra-mitochondrial heme-containing proteins, they contain normal levels of mitochondrial iron, and the cellular content of glutathione is substantially reduced relative to the high levels detected in delta atm1 cells. Our results suggest that hABC7 is a mitochondrial protein, and represents the functional orthologue of yeast Atm1p.


Identification and functional analysis of odorant-binding proteins of the parasitoid wasp Scleroderma guani reveal a chemosensory synergistic evolution with the host Monochamus alternatus.
Scleroderma guani is a generalist ectoparasitoid of wood-boring insects. The chemosensory genes expressed in its antennae play crucial roles in host-seeking. In the present study, we identified 14 OBP genes for the first time from the antennae transcriptomes and genomic data of S. guani. The expression profiles of 14 OBPs were tested by RT-qPCR, and the RT-qPCR results showed that SguaOBP2/5/6/11/12/13 were specifically highly expressed in the female antennae. Then we performed ligand binding assays to test the interactions between six selected SguaOBPs with host specific chemical compounds from M. alternatus and pines. The binding results indicated that SguaOBP12 had a higher binding affinity with longifolene, β-caryophyllene, α-pinene, β-pinene, myrcene, butylated hydroxytoluene, and 3-carene. SguaOBP11 had a high or medium binding affinity with them. Furthermore, both SguaOBP11 and SguaOBP12 had a medium binding affinity with the aggregation pheromone of Monochamus species, 2-undecyloxy-1-ethanol. Finally, by using molecular docking and RNAi, we further explored the molecular interactions and behavioral functions of SguaOBP11 and SguaOBP12 with these vital odor molecules. Our study contributes to the further understanding of chemical communications between S. guani and its host, and further exploration for its role as a more effective biological control agent.


Phase 1 study of XL119, a rebeccamycin analog, in patients with refractory hematologic malignancies.
XL119 is a water-soluble derivative of rebeccamycin with dose-dependent myelosuppression as dose-limiting toxicity in phase 1 studies of solid tumors. A phase 1 study was conducted to determine the maximum tolerated dose and toxicities of XL119 in patients with advanced myelodysplastic syndrome and relapsed or refractory acute leukemias. Thirty-one patients were treated at 7 dose levels ranging from 140 to 260 mg/m(2)/daily times 5 in a 21-day cycle. Consenting patients had correlative biologic parameters studied. Dose-limiting toxicity was grade 3/4 mucositis. The recommended phase 2 dose in hematologic malignancies is 240 mg/m(2)/daily times 5 in a 21-day cycle. Clinically significant reduction in bone marrow blasts were seen in 5 patients and additional patients had reductions in peripheral blood blasts. However, the responses were transient. Changes of plasma vascular endothelial growth factor levels from Day 1 to Day 7 correlated negatively with changes in peripheral blood blasts from Day 1 to Day 7. Further assessment of XL119 in combination with other agents in patients with acute leukemias and high-risk myelodysplastic syndrome is warranted.


Long noncoding RNA OVAAL enhances nucleotide synthesis through pyruvate carboxylase to promote 5-fluorouracil resistance in gastric cancer.
5-Fluorouracil (5-FU) is widely used in gastric cancer treatment, yet 5-FU resistance remains an important clinical challenge. We established a model based on five long noncoding RNAs (lncRNA) to effectively assess the prognosis of gastric cancer patients; among them, lncRNA OVAAL was markedly upregulated in gastric cancer and associated with poor prognosis and 5-FU resistance. In vitro and in vivo assays confirmed that OVAAL promoted proliferation and 5-FU resistance of gastric cancer cells. Mechanistically, OVAAL bound with pyruvate carboxylase (PC) and stabilized PC from HSC70/CHIP-mediated ubiquitination and degradation. OVAAL knockdown reduced intracellular levels of oxaloacetate and aspartate, and the subsequent pyrimidine synthesis, which could be rescued by PC overexpression. Moreover, OVAAL knockdown increased sensitivity to 5-FU treatment, which could be reversed by PC overexpression or repletion of oxaloacetate, aspartate, or uridine. OVAAL overexpression enhanced pyrimidine synthesis to promote proliferation and 5-FU resistance of gastric cancer cells, which could be abolished by PC knockdown. Thus, OVAAL promoted gastric cancer cell proliferation and induced 5-FU resistance by enhancing pyrimidine biosynthesis to antagonize 5-FU induced thymidylate synthase dysfunction. Targeting OVAAL-mediated nucleotide metabolic reprograming would be a promising strategy to overcome chemoresistance in gastric cancer.


The use of immobilized ferrite to enhance the depth selectivity of in vivo surface coil NMR spectroscopy.
Ferrite particles immobilized on a flexible support and arranged in a specific pattern will produce localized gradients in the homogeneous B0 magnetic field. The screening gradients are strong enough to cause inhomogeneous broadening of the NMR signals arising from the region of a specimen which is adjacent to the ferrite particles. This technique allows improvement of the depth selectivity in non-invasive surface coil NMR spectroscopy while optimizing both the signal-to-noise ratio and the data acquisition time of in vivo NMR experiments. The ferrite screen method also facilitates the routine application of high resolution NMR pulse sequences to in vivo experiments. The technique is readily implemented without special hardware or software and displays a great versatility in the size, shape and depth of the screening effect.


Cerebrospinal fluid absorption in the rabbit. Optic pathways.
Fifteen rabbits were intrathecally perfused with horseradish peroxidase at normal cerebrospinal fluid pressures. Horseradish peroxidase was found in the subarachnoid space around the optic nerve; it permeated the pia and penetrated within the nerve, occupying extracellular spaces between myelinated axons and glial cells up to the area of the lamina cribrosa. Horseradish peroxidase also crossed the perineural sclera and the border tissue of Elschnig to spread into the choroid where it was mostly seen within choriocapillaris, venules, and veins crossing through interendothelial spaces. "Bulk" cerebrospinal fluid absorption in the eye appears to occur through venous drainage in the choroid and SAS.


Women with polycystic ovary syndrome have elevated serum concentrations of and altered GABA(A) receptor sensitivity to allopregnanolone.
Several studies have reported that γ-aminobutyric acid (GABA) ergic circuits are involved in the pathophysiology of polycystic ovary syndrome (PCOS). The progesterone metabolite allopregnanolone is a potent GABA(A) -receptor-modulating steroid, and patients may have increased concentrations of allopregnanolone or altered GABAA receptor sensitivity. We investigated both of these possibilities in this study. We enrolled 9 women with PCOS and 24 age-matched eumenorrhoeic controls, who were divided into two groups by body mass index (BMI) (16 normal weight and 8 overweight). We investigated the effects of allopregnanolone injection on GABA(A) receptor sensitivity in both groups of women. All women received a single intravenous dose of allopregnanolone (0·050 mg/kg). GABA(A) receptor sensitivity was assessed with the saccadic eye velocity (SEV) over 30° (SEV30°), the SEV30°/allopregnanolone concentration ([Allo]) ratio, and sedation, which were measured together with serum allopregnanolone at intervals for 180 min after injection. The controls were tested in the follicular phase of the menstrual cycle. Baseline allopregnanolone concentrations were higher in the PCOS women than in the normal-weight (P = 0·034) and overweight controls (P = 0·004). The allopregnanolone concentrations after injection were higher in the PCOS women (P = 0·006) and overweight controls (P = 0·037) than in the normal-weight controls. All groups showed a decline in the SEV30°/[Allo] ratio after injection. Allopregnanolone had a smaller effect on the SEV30°/[Allo] ratio in the overweight women (PCOS, P = 0·032; controls, P = 0·007) than in the normal-weight controls. The sedation score after allopregnanolone injection was lower in the PCOS patients than in the controls, but was not different between the two control groups. PCOS women had elevated baseline allopregnanolone concentrations compared with follicular-phase controls. All overweight women (PCOS and controls) were less sensitive to allopregnanolone than normal-weight controls.


An essential overview of orofacial clefting.
An appreciation of the embryologic development of the face is essential to understanding the anatomic variation observed in this phenotypically broad condition. Embryologically, the nose, lip and palate are separated into the primary and secondary palate, which are divided anatomically by the incisive foramen. The epidemiology of orofacial clefting is reviewed together with the contemporaneous cleft classification systems that enable comparisons to be made between international centres for audit and research purposes. A detailed examination of the clinical anatomy of the lip and palate informs the surgical priorities for the primary reconstruction of both form and function. The pathophysiology of the submucous cleft palate is also explored. The seismic impact of the 1998 Clinical Standards Advisory Group report on the organisation of UK cleft care provision is outlined. The importance of the Cleft Registry and Audit Network database in auditing UK cleft outcomes is highlighted. The potential for the Cleft Collective study to establish the causes of clefting, the optimal treatment protocols, and the impact of cleft on patients is tremendously exciting for all health care professionals involved in the management of this challenging congenital deformity.


Female ejaculation: its relationship to disturbances of erotic function.
It is hypothesised that function of the female prostate homologue in small girls may be associated with shame resulting in inhibition of erotic function and sexual disturbance. This inhibition may explain the great variation to be found in female sexual experience.


Localization of antigenic activity and immunogenic capacity in different conformational domains of procollagen peptide.
The antibody response to the amino-terminal CNBr peptide of sheep procollagen which consists of a globular and a collagenous segment, was studied in inbred strains of mice. The determinants reacting with antibody could be localized in the globular domain and were lost by reduction of disulfide bridges. The ability to induce an antibody response required the collagen-like sequences and was independent of the triple-helical conformation of this segment. The data were interpreted as indicating a different conformation dependence of hapten and carrier determinants.


Prognostic value of glycemic gap in patients with spontaneous intracerebral hemorrhage.
Glycemic gap (GG), as a novel biomarker showing the acute glycemic change after the onset of acute illness, has been found to be associated with adverse outcomes in many diseases. This study aimed to explore the prognostic value of GG on long-term outcomes of spontaneous intracerebral hemorrhage (sICH). The current study included 528 patients from a multicenter, prospective, consecutive, observational cohort study. Poor clinical outcome was defined as modified Rankin Scale ≥ 3. GG was calculated using admission blood glucose minus hemoglobin A1c-derived average blood glucose. Logistic regression analyses were performed to determine the association between GG and poor clinical outcomes at 30 days, 90 days, and 1 year. Glycemic gap was significantly associated with poor clinical outcomes at 30 days, 90 days, and 1 year (p < 0.05 for all models), where patients with higher GG were more likely to have poor clinical outcome. Restricted cubic splines revealed a positive association between GG and poor clinical outcome. In addition, patients with higher GG were more likely to have a higher 1-year mortality rate. The addition of GG to the intracerebral hemorrhage score improved the discrimination and calibration properties for the prediction of poor clinical outcome. Glycemic gap was independently associated with poor outcomes and may be a valuable prognostic factor in patients with sICH.


Single-cell transcriptomics reveals cell type diversity of human prostate.
Extensive studies have been performed to describe the phenotypic changes occurring during malignant transformation of the prostate. However, the cell types and associated changes that contribute to the development of prostate diseases and cancer remain elusive, largely due to the heterogeneous composition of prostatic tissues. Here, we conduct a comprehensive evaluation of four human prostate tissues by single-cell RNA sequencing (scRNA-seq) to analyze their cellular compositions. We identify 18 clusters of cell types, each with distinct gene expression profiles and unique features; of these, one cluster of epithelial cells (Ep) is found to be associated with immune function. In addition, we characterize a special cluster of fibroblasts and aberrant signaling changes associated with prostate cancer (PCa). Moreover, we provide insights into the epithelial changes that occur during the cellular senescence and aging. These results expand our understanding of the unique functional associations between the diverse prostatic cell types and the contributions of specific cell clusters to the malignant transformation of prostate tissues and PCa development.


The psychological symptoms of patients with mild symptoms of coronavirus disease (2019) in China: A cross-sectional study.
To determine psychological symptoms of patients with mild symptoms of coronavirus disease 2019 in China and to explore the influencing factors. A cross-sectional study. A convenience sample of 296 mild coronavirus disease 2019 patients were recruited from a Fangcang hospital in Wuhan, Hubei Province, from 3-5 March, 2020. Participants were assessed using a sociodemographic and clinical characteristics questionnaire, and Symptom Check List 90. The binary logistic regression was utilized to explore the influencing factors of psychological symptoms of patients with mild symptoms of coronavirus disease 2019. In total, 296 of 299 patients with mild symptoms of coronavirus disease 2019 participated in the study (response rate: 99.0%). The findings revealed that 12.8% patients with mild symptoms have mental health problems; the most common psychological symptoms are phobic anxiety (58.4%), paranoid ideation (50.7%) and psychoticism (40.2%). Female patients [OR = 3.587, 95% CI (1.694-7.598)] and those having physical symptoms currently [OR = 2.813, 95% CI (1.210-6.539)] are at higher risk, while those in the middle duration of hospitalization [OR = 0.278, 95% CI (0.121-0.639)] protect against mental-health problems. The minority of patients with mild symptoms of coronavirus disease 2019 were still suffering from psychological symptoms. Healthcare providers are recommended to pay particular attention to screening these high-risk groups (women, those in the initial stages of hospitalization and those with physical symptoms currently) and implement targeted psychological care as required. This study found that most patients of coronavirus disease 2019 in Fangcang hospital exhibited normal mental health at par with the general Chinese norm and the minority of them were suffering from psychological symptoms. The findings can provide a reference for healthcare providers to screen high-risk psychological symptoms groups and implement targeted psychological intervention for patients with coronavirus disease 2019.


Testosterone and the prostate: implications for the treatment of hypogonadal men.
Late-onset hypogonadism (LOH) and testosterone replacement therapy (TRT) are subjects of much recent research. Because aging men are at risk for benign prostatic hyperplasia (BPH) and prostate cancer, elucidating the relationship between testosterone and these diseases is crucial to ensure its safe administration. It is known that testosterone supplementation may worsen active prostate cancer and that its blockade or removal slows the disease's progression. However, recent studies have attempted to show that, in individuals in whom prostate cancer has been ruled out, TRT may simply restore serum testosterone levels to within normal limits without significant adverse affects on the prostate. Patients undergoing TRT should be monitored carefully for any evidence of prostatic disease.


Mechanism of pentoxifylline mediated down-regulation of killer lineage cell functions.
The authors reported recently that endotoxaemia mediated elevated levels of tumour necrosis factor (TNF-alpha) and interleukin-1alpha (IL-1alpha) were involved in the pathophysiology of acute heat stroke patients. Pentoxifylline (PTX) is known to modulate neutrophil functions. In the present study the effects of PTX on lipopolysaccharide (LPS) and cytokine induced T-cell and macrophage (PhiM) activation, and on natural killer (NK) cell and lymphokine activated killer (LAK) cell mediated cytotoxicity were examined. Finally, the effect of PTX on the expression of adhesion molecules (LFA-1, Mac-1 and ICAM-1), and cytokine (IL-1alpha, IL-2, TNF-alpha, IL-6 and IFN-gamma) production and their surface receptor expression in response to LPS activation was investigated. PTX free cultures served as a control. Results revealed that PTX can down-regulate all the above-mentioned immunological parameters in a dosedependent manner. These findings might have far reaching clinical implications.


Therapy-associated genetic aberrations in patients treated for non-Hodgkin lymphoma.
Therapy-associated myelodysplastic syndromes and acute myeloid leukaemia (t-AML/MDS) following high dose chemotherapy are significant problems, with a cumulative incidence of 20% or more in myeloablative treatment regimen. Retrospective findings indicated that t-AML/MDS associated genetic aberrations can be observed directly after exposure to chemotherapy and can precede t-AML by several months. To determine the incidence of post-therapeutic aberrations and their predictive value, we prospectively investigated 316 samples of 95 patients with non-Hodgkin lymphoma (NHL) who were treated with intermediate and high dose chemotherapy (Arm A and B of the megaCHOEP (cyclophosphamide, doxorubicin, etoposide, vincristine, prednisolone) trial of the German High Grade NHL study group). Molecular aberrations (RUNX1/RUNX1T1, PML-RARA, CBFB-MYH11, MLL-MLLT1, BCR-ABL1) were observed in 33.3% (Arm A) and 55.4% (Arm B) of patients and in 14.9% and 28.7% of respective samples. Cytogenetic analysis of 53 NHL patients after high dose therapy showed frequent chromosomal breakage. Clonal aberrations were found in three patients. None of these patients developed a t-AML/MDS during a 3-year clinical follow up period. We concluded that the high incidence of genetic aberrations reflected a dose-dependent, transient therapy-induced genetic damage which is not predictive of a t-AML/MDS.


In vivo efficacy of anti-malarial drugs against clinical Plasmodium vivax malaria in Ethiopia: a systematic review and meta-analysis.
Ethiopia is one of the few countries in Africa where Plasmodium vivax commonly co-exists with Plasmodium falciparum, and which accounts for ~ 40% of the total number of malaria infections in the country. Regardless of the growing evidence over many decades of decreasing sensitivity of this parasite to different anti-malarial drugs, there has been no comprehensive attempt made to systematically review and meta-analyse the efficacy of different anti-malarial drugs against P. vivax in the country. However, outlining the efficacy of available anti-malarial drugs against this parasite is essential to guide recommendations for the optimal therapeutic strategy to use in clinical practice. The aim of this study was to synthesize evidence on the efficacy of anti-malarial drugs against clinical P. vivax malaria in Ethiopia. All potentially relevant, peer-reviewed articles accessible in PubMed, Scopus, Web of Science, and Clinical Trial.gov electronic databases were retrieved using a search strategy combining keywords and related database-specific subject terms. Randomized controlled trials (RCTs) and non-randomized trials aiming to investigate the efficacy of anti-malarial drugs against P. vivax were included in the review. Data were analysed using Review Manager Software. Cochrane Q (χ2) and the I2 tests were used to assess heterogeneity. The funnel plot and Egger's test were used to examine risk of publication bias. Out of 1294 identified citations, 14 articles that presented data on 29 treatment options were included in the analysis. These studies enrolled 2144 clinical vivax malaria patients. The pooled estimate of in vivo efficacy of anti-malarial drugs against vivax malaria in Ethiopia was 97.91% (95% CI: 97.29-98.52%), with significant heterogeneity (I2 = 86%, p < 0.0001) and publication bias (Egger's test = -12.86, p < 0.001). Different anti-malarial drugs showed varied efficacies against vivax malaria. The duration of follow-up significantly affected the calculated efficacy of any given anti-malarial drug, with longer duration of the follow-up (42 days) associated with significantly lower efficacy than efficacy reported on day 28. Also, pooled PCR-corrected efficacy and efficacy estimated from altitudinally lower transmission settings were significantly higher than PCR-uncorrected efficacy that estimated for moderate transmission settings, respectively. The overall efficacy of anti-malarial drugs evaluated for the treatment of vivax malaria in Ethiopia was generally high, although there was wide-ranging degree of efficacy, which was affected by the treatment options, duration of follow-up, transmission intensity, and the confirmation procedures for recurrent parasitaemia. Regardless of evidence of sporadic efficacy reduction reported in the country, chloroquine (CQ), the first-line regimen in Ethiopia, remained highly efficacious, supporting its continuous utilization for confirmed P. vivax mono-infections. The addition of primaquine (PQ) to CQ is recommended, as this is the only approved way to provide radical cure, and thus ensure sustained efficacy and longer protection against P. vivax. Continuous surveillance of the efficacy of anti-malarial drugs and clinical trials to allow robust conclusions remains necessary to proactively act against possible emergence and spread of drug-resistant P. vivax in Ethiopia.


Commotio cordis as a result of a fight: report of a case considered to be imprudent homicide.
Commotio cordis is a clinic-pathological syndrome related to sudden death in young people involved in sports activities. It has been described, mainly, in athletes without previous cardiac anomalies who received a minor blow to the chest which produces ventricular fibrillation and cardiac arrest in the absence of structural damage to the ribs, sternum, or heart. There are few reported cases of commotio cordis associated with violent, non-sports related actions, which are commonly considered to be imprudent homicides. We present the case of a 20-year-old man, who was kicked in the chest during a fight; he suddenly collapsed although advanced cardio-respiratory resuscitation started shortly. Autopsy showed no cardiac lesions concluding that death was due to commotio cordis (blunt trauma to the chest). Toxicological analysis determined the presence of 5.14 mg/L benzoylecgonine in blood. On the basis of medico-legal investigation, the official prosecution considered the death to be imprudent homicide and the aggressor was sentenced to 4 years in prison. We emphasize the importance of the knowledge of the death circumstances through the witnesses' testimony, prior to beginning the autopsy, to confirm this important medico-legal diagnosis. Arrhythmogenic effects of cocaine and its contribution in the production of these deaths are also exposed.


Efficacy and safety assessment of mineralocorticoid receptor antagonists in patients with chronic kidney disease.
The objective of our study is to evaluate the efficacy and safety of mineralocorticoid receptor antagonists (MRAs) and determine the optimal MRA treatment regimen in patients with chronic kidney disease (CKD). We searched PubMed, Embase, Web of Science, and the Cochrane Library from their inception to June 20, 2022. The composite kidney outcome, cardiovascular events, urinary albumin to creatinine ratio (UACR), estimated glomerular filtration rate (EGFR), serum potassium, systolic blood pressure (SBP), diastolic blood pressure (DBP), creatine and creatine clearance were included for analysis. We conducted pairwise meta-analyses and Bayesian network meta-analyses (NMA) and calculated the surface under the cumulative ranking curve (SUCRA). We included 26 studies with 15,531 participants. By pairwise meta-analyses, we found that MRA treatment could significantly reduce UACR in CKD patients with or without diabetes. Notably, compared to placebo, Finerenone was associated with a lower risk of composite kidney outcome and cardiovascular events. Data from NMA demonstrated an overt UACR reduction without increasing serum potassium by Apararenone, Esaxerenone, and Finerenone in CKD patients. Spironolactone decreased SBP and DBP but elevated CKD patients' serum potassium. Compared to placebo, Apararenone, Esaxerenone, and Finerenone might ameliorate albuminuria in CKD patients without causing elevated serum potassium levels. Remarkably, Finerenone conferred a cardiovascular benefit, and Spironolactone lowered blood pressure in CKD patients.


The impact of R&D and innovation on global supply chain transition: GTAP analysis on Japan's public R&D investment.
Policymaking for science, technology, and innovation (R&D) is stepping into a new era in the twenty-first century within a highly integrated production network, making it more challenging to capture the impact of R&D investment from an evidence-based approach. To unfold the paradox of the R&D spillover effect spared in the global supply chain, we use computable general equilibrium model with the GTAP database v10 to analyze the impact of Japan's public R&D investment to the world focus on key sectors of global supply chain, namely chemical and pharmaceutical, electronic equipment, machinery, and transportation equipment to examine its output, external trades, and welfare. The productivity parameters triggered by public R&D investment are calibrated from the SciREX Policymaking Intelligent Assistance System-Economic Simulator (SPIAS-e). The simulation results show significant increase in Japan's output and export for chemical and pharmaceutical, electronic equipment, and transportation equipment. The GDP growth was stimulated by 0.6% and substantial welfare improvement by USD 78,000 million, while other countries such as Malaysia and Taiwan by 0.4-0.6%. In contrast, the economic indicators of China reveal a negative impact, implying a structural change in the composition of the production network. It is notable to see a higher economic integration of Oceania within the region through its vibrant production and trades. The study provides comprehensive global analysis on production networks and insights for evaluating the R&D investment spillover effects.


The Chinese medicine Sini-San inhibits HBx-induced migration and invasiveness of human hepatocellular carcinoma cells.
Sini-San (SNS) is a formulation of four Traditional Chinese Drugs that exhibits beneficial therapeutic effects in liver injury and hepatitis. However, there are no reports describing its effects on the hepatitis B X-protein (HBx)-induced invasion and metastasis in hepatoma cells, and the detailed molecular mechanisms of its actions are still unclear. In this study, we investigated the mechanisms underlying SNS-mediated inhibition of HBx-induced cell invasion and the inhibition of secreted and cytosolic MMP-9 production, using gelatin zymography and Western blot analysis in a human hepatoma cell line (HepG2). Relative luciferase activity was assessed for MMP-9, NF-κB, or AP-1 reporter plasmid-transfected cells. SNS suppressed MMP-9 transcription by inhibiting activator protein (AP)-1 and nuclear factor-κ B (NF-κB) activity. SNS suppressed HBx-induced AP-1 activity through inhibition of phosphorylation in the extracellular signal-related kinase (ERK) and c-Jun N-terminal kinase (JNK) signaling pathways. SNS also suppressed HBx-induced inhibition of NF-κB nuclear translocation through IκB and suppressed HBx-induced activation of ERK/phosphatidylinositol 3-kinase/Akt upstream of NF-κB and AP-1. SNS suppresses the invasiveness and metastatic potential of hepatocellular carcinoma cells by inhibiting multiple signal transduction pathways.


Global public health: a scorecard.
Global health is attracting an unprecedented level of interest. In this paper, we summarise recent trends and identify the unfinished and new agendas in global public health. We propose a global public health scorecard as a simple way to assess progress and suggest actions by public health practitioners and their organisations for improving the effectiveness of public health. Although we find many recent positive developments in global health, the potential for global cooperation and progress is still largely untapped. Compared with other components of development, health improvement should easily foster global cooperation; strong advocacy and political will are keys to continuing progress. We view global public health as a barometer of more general development. Our responses to the current health challenges are at the forefront of the global struggle for survival.


Aspergillosis in hihi (Notiomystis cincta) on Mokoia Island.
An intensive 2-year field study of 65 hihi (or stitchbirds) on Mokoia Island provided an opportunity to investigate the causes of mortality of this endangered species in a free-living environment. The birds were observed daily during the breeding season (October to March) and every 4 weeks during the remainder of the year. Any abnormalities in behaviour, voice and body weight were recorded and all sick or dead birds which could be recovered were taken to the laboratory for necropsy. Thirty-one birds died during the period of this study. Aspergillosis was found to be the cause of death in six of nine adult birds examined post mortem. Some of the affected birds experienced subtle voice changes before becoming ill and all birds had granulomatous lesions in airsacs or lungs at necropsy. A further eight birds for which carcasses could not be found or which were autolysed showed similar clinical signs before death or disappearance. Because Aspergillus is an opportunist pathogen it seems likely that affected birds were immunosuppressed. This may have occurred during the breeding season which in this species is highly stressful. The presence of fungal material in bronchial exudate and the occurrence of the disease in mates, raises the possibility that aspergillosis in hihi may be contagious.


Evaluation of a simple method for storage of blood samples that enables isolation of circulating tumor cells 96 h after sample collection.
Minimizing the effects of transportation on the properties of biological material is a major challenge for the scientific community. The viability of cells is important in cases where their study is urgent for evaluation of treatment response or for the study of cancer progression. Circulating tumor cells (CTCs) constitute a cell subpopulation with great importance for oncologists, because of their prognostic value. Detection and isolation of CTCs from blood samples is a routine activity in many laboratories, but concerns exist with regard to the maintenance of the cells during transportation. In this study, experiments were conducted to determine the stability of gene and protein expression in CTCs over a period of 96 h. Blood samples collected from healthy individuals and patients with cancer were each divided into five aliquots, which were stored at 2-8 °C and analyzed after 0, 24, 48, 72 and 96 h of storage. CTCs from patients and CD45-negative cells from healthy individuals were isolated each day using enrichment protocols, and qPCR was performed to determine expression levels of genes encoding specific biological markers. In addition, cells from breast and colon cancer cell lines were spiked into blood samples from healthy individuals, and these samples were stored and analyzed over a period of 96 h by PCR and by flow cytometry. The markers that were studied included housekeeping genes and genes associated with the response to chemotherapy, as well as genes encoding transcription factors. The results demonstrated that the expression profiles of specific genes and proteins in CTCs were not significantly affected by 72 h of storage. After 96 h of storage, expression of some genes was altered. The transportation of blood at low temperature (2-8 °C) in the presence of the anticoagulant EDTA can protect CTCs from alteration of gene and protein expression for at least 72 h. Furthermore, under these conditions, CTCs can be detected and isolated 96 h after blood collection.


Diagnostic value of gonadal steroid hormones and gonadotropins in ovarian cystic lesions.
During a 12-mo period the fluid aspirated from 32 ovarian cystic lesions was assayed for 17 beta-estradiol (E2), progesterone (P), testosterone (T), follicle-stimulating hormone (FSH), and luteinizing hormone (LH). All cysts were subsequently subjected to histologic or cytologic examination. In 84.6% (11/13) of the proven follicular cysts, the E2 content was greater than 100 pg/ml, in 76.9% (10/13) the P content was greater than 13 ng/ml, and in 69% (9/13) the T content was greater than 0.5 ng/ml. In 94.7% (18/19) of the ovarian cysts of other types, the E2 content was less than 100 pg/ml and the P content was less than 13 ng/ml. The FSH and LH contents of both types of cysts were variable, and no consistent pattern was discerned. In contrast, cytologic examination identified 69.2% (9/13) of the follicular cysts. In conclusion, consideration of the E2 and P contents with cytologic examination allowed the identification of all follicular cysts. Accordingly we recommend the estimation of E2 and P as part of the assessment of all ovarian cyst aspirates obtained from premenopausal patients.


Systematics of the ascomycetous yeasts assessed from ribosomal RNA sequence divergence.
Extent of divergence in partial nucleotide sequences from large and small subunit ribosomal RNAs was used to estimate genetic relationships among ascomycetous yeasts and yeastlike fungi. The comparisons showed four phylogenetically distinct groups comprised of the following taxa: Group 1. The budding yeasts Saccharomyces, Saccharomycopsis, Debaryomyces, Metschnikowia, Saturnospora, and Lipomyces, and the yeastlike genera Ascoidea, Cephaloascus, Dipodascus, Dipodascopsis, and Galactomyces; Group 2. Eremascus, Emericella and Ceratocystis; Group 3. Taphrina and Protomyces; Group 4. Schizosaccharomyces. Because of the genetic relationships indicated by sequence analysis, Group 1 taxa are retained in the order Endomycetales, and Schizosaccharomyces is retained in the Schizosaccharomycetales Prillinger et al. ex Kurtzman.


Loss of nerve fibers in the oviduct isthmus in women with hydrosalpinx.
Apart from the abnormalities of tubal anatomy, the main concern linked to infertility is impaired tubal motility associated with hydrosalpinx, which is thought to be controlled by hormones and nerves. The objective of this study was to determine the distribution of nerve fibers in the oviduct isthmus in women with and without hydrosalpinx. Histological sections of the oviduct isthmus tissue were obtained from 18 women undergoing salpingectomy for hydrosalpinx, and from 15 women undergoing hysterectomy and salpingectomy for benign gynecologic diseases. The tissues were immunohistochemically stained for protein gene product (PGP) 9.5, protein S100, neuropeptide tyrosine (NPY), and vasoactive intestinal peptide (VIP) to reveal all nerve fibers, as well as sympathetic and parasympathetic nerve fibers, in the oviduct isthmus. We detected the presence of PGP9.5, S100, VIP, and NPY-immunoreactive nerve fibers in the oviduct isthmus in all study subjects. However, the densities of PGP9.5, S100, VIP, and NPY-immunoreactive nerve fibers in the oviduct isthmus were all significantly decreased in women with hydrosalpinx compared with those in women without hydrosalpinx (P<0.01). Our results suggest that reduced nerve fibers in the oviduct isthmus in women with hydrosalpinx compared with women without hydrosalpinx may have an important function in the mechanism of hydrosalpinx-associated infertility.


Neurotensin stimulates histamine release from the isolated, spontaneously beating heart of rats.
Neurotensin (NT) evoked a transient, dose-dependent histamine release (ED50 170 ng ml-1) from the rat perfused heart. Histamine release by NT occurred within seconds and lasted less than 2 min. The histamine releasing effect of NT was followed by a dose-dependent increase of the perfusion pressure and a slight tachycardia. The histamine releasing effect of NT was completely abolished in hearts derived from rats pretreated for 3 days with high doses of compound 48/80. The coronary vasoconstrictor effect of NT was increased in hearts derived from compound 48/80-pretreated rats. The mast cell inhibitor cromoglycate markedly inhibited NT-induced histamine release without affecting the coronary vasoconstrictor effect of NT. The histamine releasing effect of NT was inhibited, while its coronary vasoconstrictor effect was markedly potentiated, in hearts derived from rats pretreated with the antiallergic and antiinflammatory steroid dexamethasone. The increase of perfusion pressure evoked by NT was not modified by antihistamine drugs. Infusions of exogenous histamine (10(-6)-10(-5) g ml-1) caused a dose-dependent coronary vasodilation in the rat perfused heart. The results suggest that NT stimulates histamine release from cardiac mast cells. These results together with those obtained in previous studies suggest that mast cell mediators (particularly histamine and serotonin) are unlikely to be responsible for the coronary vasoconstrictor effect of NT in the rat perfused heart.


[Cervical lymph node metastasis and blood metastasis of thyroid cancer].
To evaluate the relevant factors for lymph cervical node metastases and blood metastases of thyroid cancer and to raise the level of diagnosis and treatment. 225 cases of thyroid cancer were treated from Jan. 1984 to Dec. 1992. Their clinical characteristics, treatment, and pathologic features were described. The metastasis of thyroid cancer was related to its pathologic and invasive features. Papillary and squamous cell carcinomas were characterized by local lymph metastasis. Their metastasis rate was 44.7%, and 3/3 respectively. Follicular carcinoma showed good differentiation but vessel metastasis with a metastatic rate of 18.2%. The metastasis rate was high and the prognosis poor, in undifferentiated cancer. Better treatment results may be achieved if proper management of thyroid cancer is based on its pathologic type and extent of local infiltration.


Kinetic study of corn straw pyrolysis: comparison of two different three-pseudocomponent models.
With heating rates of 20, 50 and 100 K min(-1), the thermal decomposition of corn straw samples (corn stalks skins, corn stalks cores, corn bracts and corn leaves) were studied using thermogravimetric analysis. The maximum pyrolysis rates increased with the heating rate increasing and the temperature at the peak pyrolysis rate also increased. Assuming the addition of three independent parallel reactions, corresponding to three pseudocomponents linked to the hemicellulose, cellulose and lignin, two different three-pseudocomponent models were used to simulate the corn straw pyrolysis. Model parameters of pyrolysis were given. It was found that the three-pseudocomponent model with n-order kinetics was more accurate than the model with first-order kinetics at most cases. It showed that the model with n-order kinetics was more accurate to describe the pyrolysis of the hemicellulose.


A paternal protein facilitates sperm RNA delivery to regulate zygotic development.
Sperm contributes essential paternal factors, including the paternal genome, centrosome, and oocyte-activation signals, to sexual reproduction. However, it remains unresolved how sperm contributes its RNA molecules to regulate early embryonic development. Here, we show that the Caenorhabditis elegans paternal protein SPE-11 assembles into granules during meiotic divisions of spermatogenesis and later matures into a perinuclear structure where sperm RNAs localize. We reconstitute an SPE-11 liquid-phase scaffold in vitro and find that SPE-11 condensates incorporate the nematode RNA, which, in turn, promotes SPE-11 phase separation. Loss of SPE-11 does not affect sperm motility or fertilization but causes pleiotropic development defects in early embryos, and spe-11 mutant males reduce mRNA levels of genes crucial for an oocyte-to-embryo transition or embryonic development. These results reveal that SPE-11 undergoes phase separation and associates with sperm RNAs that are delivered to oocytes during fertilization, providing insights into how a paternal protein regulates early embryonic development.


Multilevel quadrature for elliptic problems on random domains by the coupling of FEM and BEM.
Elliptic boundary value problems which are posed on a random domain can be mapped to a fixed, nominal domain. The randomness is thus transferred to the diffusion matrix and the loading. While this domain mapping method is quite efficient for theory and practice, since only a single domain discretisation is needed, it also requires the knowledge of the domain mapping. However, in certain applications, the random domain is only described by its random boundary, while the quantity of interest is defined on a fixed, deterministic subdomain. In this setting, it thus becomes necessary to compute a random domain mapping on the whole domain, such that the domain mapping is the identity on the fixed subdomain and maps the boundary of the chosen fixed, nominal domain on to the random boundary. To overcome the necessity of computing such a mapping, we therefore couple the finite element method on the fixed subdomain with the boundary element method on the random boundary. We verify on one hand the regularity of the solution with respect to the random domain mapping required for many multilevel quadrature methods, such as the multilevel quasi-Monte Carlo quadrature using Halton points, the multilevel sparse anisotropic Gauss-Legendre and Clenshaw-Curtis quadratures and multilevel interlaced polynomial lattice rules. On the other hand, we derive the coupling formulation and show by numerical results that the approach is feasible.


N-acetylcysteine for preventing pump-induced oxidoinflammatory response during cardiopulmonary bypass.
To investigate the effect of N-acetylcysteine on preventing pump-induced oxidoinflammatory response during cardiopulmonary bypass (CPB). Forty patients undergoing coronary artery bypass grafting (CABG) were randomly divided into a study group (n = 20), given 50 mg kg(-1) N-acetylcysteine intravenously for 3 days, and a control group (n = 20) given saline. Serum samples were collected for measurement of myeloperoxidase (MPO), malondialdehyde (MDA), interleukin-6, Alpha1-acid glycoprotein (AAGP), and C-reactive protein (CRP) during surgery and postoperatively. The MPO and MDA values showed a similar pattern during and after CPB in the study group, with significantly less variance than in the control group. Interleukin-6 showed similar patterns in the two groups, but the data from 30 min after the start of CPB and from 6 h post-CPB were significantly different. The AAGP and CRP values were both elevated during CPB in the two groups without a significant difference, but 6 and 24 h post-CPB, the values were significantly higher in the control group than in the study group. N-Acetylcysteine decreased pump-induced oxidoinflammatory response during CPB, suggesting that it could be a novel therapy for assisting in the prevention of CBP-induced oxidoinflammatory damage.


Sodium phenylacetate inhibits the Ras/MAPK signaling pathway to induce reduction of the c-Raf-1 protein in human and canine breast cancer cells.
An aromatic fatty acid, phenylacetate (PA), has been shown to have cytostatic, antitumor and cell differentiation-inducing effects on various kinds of tumors. Previously, we have demonstrated cell growth inhibition, malignant phenotype reduction and cell differentiation effects of sodium phenylacetate (NaPA) treatment in a canine mammary tumor cell line. To clarify the molecular mechanism of these effects, we examined the expression of Ras/MAPK signaling pathway-related molecules in human and canine breast cancer cell lines, and found that the level of c-Raf-1 protein was reduced by 5, 10 and 20 mM of NaPA treatments, though Ras activation was maintained. Dephosphorylation of c-Raf-1 at Serine (Ser) 259, Ser 338, and Ser 621 were also seen in NaPA-treated cells. Downstream factors in the pathway, such as mitogen-activated protein kinase/ERK kinase (MEK)1/2 and ERK1/2, showed decreased activity, and accordingly, expressions of cyclinD1, c-myc, and inactivation of p90 ribosomal S6 kinase (RSK), which are MAPK targets, were reduced. We also observed the reduction of cell-cycle-promoted molecules, such as cdc1/cdk2, cdk4, PCNA cyclin A, and cyclin B, and the increased expression of p27kip1. Furthermore, expression of an epithelial marker, E-cadherin, was increased by NaPA treatment. These results suggest that one of the molecular targets of NaPA treatment was the reduction of c-Raf-1 protein, and that its reduction results in the decrease of malignant characteristics of tumor cells through blockage of the Ras/MAPK signaling pathway.


Validation and adaption of an Information-Motivation-Behavioral Skills model of medication adherence in older patients with multimorbidity.
To test and adapt the Information-Motivation-Behavioral Skills (IMB) model in explaining medication adherence for older patients with multimorbidity. Older patients with at least three chronic conditions (N = 254) were recruited from community health centers in Changsha, China. All participants completed a self-administrated questionnaire assessing adherence information, personal motivation, social motivation, behavioral skills, medication adherence, depressive symptoms, medication treatment satisfaction, treatment burden, and disease burden. Structural equation modeling was used to examine the hypothesized models and relationships between variables. The final extended IMB model could explain 52.0% of the variance in adherence. Personal motivation (β = 0.29, p < 0.001), behavioral skills (β = 0.36, p < 0.001), and medication treatment satisfaction (β = 0.23, p = 0.001) had a positive direct effect on adherence. Information, social motivation, personal motivation, medication treatment satisfaction, and treatment burden could also affect adherence indirectly through multiple pathways. This study demonstrated that an extended IMB model could be used to conceptualize determinants of medication adherence among older patients with multimorbidity. Adherence improvement programs might be more effective if targeting psychosocial factors, including adherence information, motivation, behavioral skills, treatment burden, and medication treatment satisfaction.


The orthosteric GABAA receptor ligand Thio-4-PIOL displays distinctly different functional properties at synaptic and extrasynaptic receptors.
Explorations into the heterogeneous population of native GABA type A receptors (GABAA Rs) and the physiological functions governed by the multiple GABAA R subtypes have for decades been hampered by the lack of subtype-selective ligands. The functional properties of the orthosteric GABAA receptor ligand 5-(4-piperidyl)-3-isothiazolol (Thio-4-PIOL) have been investigated in vitro, ex vivo and in vivo. Thio-4-PIOL displayed substantial partial agonist activity at the human extrasynaptic GABAA R subtypes expressed in Xenopus oocytes, eliciting maximal responses of up to ∼30% of that of GABA at α5 β3 γ2S , α4 β3 δ and α6 β3 δ and somewhat lower efficacies at the corresponding α5 β2 γ2S , α4 β2 δ and α6 β2 δ subtypes (maximal responses of 4-12%). In contrast, it was an extremely low efficacious agonist at the α1 β3 γ2S , α1 β2 γ2S , α2 β2 γ2S , α2 β3 γ2S , α3 β2 γ2S and α3 β3 γ2S GABAA Rs (maximal responses of 0-4%). In concordance with its agonism at extrasynaptic GABAA Rs and its de facto antagonism at the synaptic receptors, Thio-4-PIOL elicited robust tonic currents in electrophysiological recordings on slices from rat CA1 hippocampus and ventrobasal thalamus and antagonized phasic currents in hippocampal neurons. Finally, the observed effects of Thio-4-PIOL in rat tests of anxiety, locomotion, nociception and spatial memory were overall in good agreement with its in vitro and ex vivo properties. The diverse signalling characteristics of Thio-4-PIOL at GABAA Rs represent one of the few examples of a functionally subtype-selective orthosteric GABAA R ligand reported to date. We propose that Thio-4-PIOL could be a useful pharmacological tool in future studies exploring the physiological roles of native synaptic and extrasynaptic GABAA Rs.