Neurochemistry evaluated by magnetic resonance spectroscopy in a patient with FBXO28-related developmental and epileptic encephalopathy.
Mutations in the FBXO28 gene, which encodes FBXO28, one of the F-box protein family, may cause developmental and epileptic encephalopathy (DEE). FBXO28-related DEE is radiologically characterized by cerebral atrophy, delayed/abnormal myelination, and brain malformation; however, no neurochemical analyses have been reported. A female Japanese infant presented with severe psychomotor delay, epileptic spasms, and visual impairment. Whole-exome sequencing revealed a de novo variant of the FBXO28 gene, leading to the diagnosis of FBXO28-related DEE. Magnetic resonance (MR) spectroscopy at 6, 12, and 32 months revealed decreased N-acetylaspartate and choline-containing compounds and increased levels of myoinositol. MR spectroscopy revealed neurochemical derangement in FBXO28-related DEE, that is, disturbed myelination secondary to neuronal damage with astrogliosis.


Kinetic studies on partially liganded species of carboxyhemoglobin: alpha 2 CO beta 2 and alpha 2 beta 2CO.
The valency hybrids of Hb A, alpha 2CO beta 2+, and alpha 2+ beta 2CO have been prepared by a new high pressure liquid chromatography method, and the kinetics of their CO-combination and dissociation reactions have been studied by double mixing and microperoxidase methods. Both reactions are biphasic. The slow phase in CO-combination and the fast phase in CO-dissociation are due to the reactions of alpha CO2 beta T2 or alpha 2 beta 2CO,T. The fast phase in CO-combination reaction has two components, one due to the dimers of the hybrid and the other due to the R-state tetramer. Immediately after the reduction of the valency hybrids, the overall system is represented by the equation: 2 alpha CO beta in equilibrium alpha 2CO beta 2R in equilibrium alpha 2CO beta 2T or (formula: see text) If the solutions are aged for 3-11 s, the R-state population is reduced gradually to a very small size, and the main species after 11 s of aging are dimers and T-state tetramers. Analysis of the kinetic data indicates slow R in equilibrium T equilibria in the absence of phosphates and significant dissociation of the T-state tetramer. It is concluded that the subunit contacts alpha 1-beta 2 (or alpha 2-beta 1) are impaired seriously in the hybrids. Very slow R in equilibrium T relaxation makes these hybrids unlikely intermediates in the sequential binding of CO to Hb tetramer.


Perceptions of surgical difficulty in liver transplantation: A European survey and development of the Pitié-Salpêtrière classification.
Significant variations exist regarding the definition of difficult liver transplantation. The study goals were to investigate how liver transplant surgeons evaluate the surgical difficulty of liver transplantation and to use the identified factors to classify liver transplantation difficulty. A Web-based online European survey was presented to liver transplant surgeons. The survey was divided into 3 parts: (1) participant demographics and practices; (2) various situations based on recipient, liver disease, tumor treatment, and technical factors; and (3) 8 real-life clinical vignettes with different levels of complexity. In part 3 of the survey, respondents were asked whether they would perform liver transplantation but were not aware that these patients eventually underwent liver transplantation. A total of 143 invites were sent out, and 97 (67.8%) participants completed the survey. Most participants considered previous spontaneous bacterial peritonitis, previous supra-mesocolic surgery, hypertrophy of segment I, and obesity to be recipient factors for high-difficulty liver transplantation. Most participants considered liver transplantation to be challenging in patients with Budd-Chiari syndrome, Kasai surgery, polycystic liver disease, diffuse portal vein thrombosis, and a history of open hepatectomy. The proportion of participants indicating that liver transplantation was warranted varied across the 8 cases, from 69% to 100%. Our classification of the surgical difficulty of liver transplantation employed these recipient-related, surgical history-related, and liver disease-related variables and 3 difficulty groups were identified: low, intermediate, and high difficulty groups. This survey provides an overview of the surgical difficulty of various situations in liver transplantation that could be useful for further benchmark and textbook outcome studies.


A Rising Tide Lifts "Related" Boats-Post-Acute Care Quality Improvement is Associated with Improvement in Long-Term Care Quality in Nursing Homes.
To examine the relationship between post-acute care (PAC) quality improvement and long-term care (LTC) quality changes. Observational study using national nursing home data from Nursing Home Compare linked to Brown University's LTCFocus data. Free-standing nursing homes serving PAC and LTC residents in the United States. This study used pooled cross-sectional analysis with nursing home-level data from 2005 to 2010 (12,150 unique nursing homes). We used fixed effects models to examine the association between a 1-year change in PAC quality and a 1-year change in LTC quality, with a specific focus on related care domains. Strong and positive associations were found between related PAC and LTC care domains, particularly between the PAC and LTC influenza vaccination care domains (β = 0.30, P < .001) and the PAC and LTC pneumococcal vaccination care domains (β = 0.55, P < .001). Meanwhile, model results showed PAC quality changes essentially had no associations with unrelated LTC care domains. This is the first study that examines the association of changes in quality between 2 overlapping but different care domains (ie, PAC and LTC) using multiple quality measures. Our findings indicate that nursing homes can manage concurrent quality improvement in PAC and LTC, particularly on care domains that are related. More research is needed to examine the mechanism that enables such concurrent quality improvement.


Mitochondrial superoxide disrupts the metabolic and epigenetic landscape of CD4+ and CD8+ T-lymphocytes.
While the role of mitochondrial metabolism in controlling T-lymphocyte activation and function is becoming more clear, the specifics of how mitochondrial redox signaling contributes to T-lymphocyte regulation remains elusive. Here, we examined the global effects of elevated mitochondrial superoxide (O2-) on T-lymphocyte activation using a novel model of inducible manganese superoxide dismutase (MnSOD) knock-out. Loss of MnSOD led to specific increases in mitochondrial O2- with no evident changes in hydrogen peroxide (H2O2), peroxynitrite (ONOO-), or copper/zinc superoxide dismutase (CuZnSOD) levels. Unexpectedly, both mitochondrial and glycolytic metabolism showed significant reductions in baseline, maximal capacities, and ATP production with increased mitochondrial O2- levels. MnSOD knock-out T-lymphocytes demonstrated aberrant activation including widespread dysregulation in cytokine production and increased cellular apoptosis. Interestingly, an elevated proliferative signature defined by significant upregulation of cell cycle regulatory genes was also evident in MnSOD knock-out T-lymphocytes, but these cells did not show accelerated proliferative rates. Global disruption in T-lymphocyte DNA methylation and hydroxymethylation was also observed with increased mitochondrial O2-, which was correlated to alterations in intracellular metabolite pools linked to the methionine cycle. Together, these results demonstrate a mitochondrial redox and metabolic couple that when disrupted may alter cellular processes necessary for proper T-lymphocyte activation.


A concise synthesis of (+)-batzelladine B from simple pyrrole-based starting materials.
Alkaloids, secondary metabolites that contain basic nitrogen atoms, are some of the most well-known biologically active natural products in chemistry and medicine. Although efficient laboratory synthesis of alkaloids would enable the study and optimization of their biological properties, their preparation is often complicated by the basicity and nucleophilicity of nitrogen, its susceptibility to oxidation, and its ability to alter reaction outcomes in unexpected ways--for example, through stereochemical instability and neighbouring group participation. Efforts to address these issues have led to the invention of a large number of protecting groups that temper the reactivity of nitrogen; however, the use of protecting groups typically introduces additional steps and obstacles into the synthetic route. Alternatively, the use of aromatic nitrogen heterocycles as synthetic precursors can attenuate the reactivity of nitrogen and streamline synthetic strategies. Here we use such an approach to achieve a synthesis of the complex anti-HIV alkaloid (+)-batzelladine B in nine steps (longest linear sequence) from simple pyrrole-based starting materials. The route uses several key transformations that would be challenging or impossible to implement using saturated nitrogen heterocycles and highlights some of the advantages of beginning with aromatic reagents.


Maternal and perinatal risk factors associated with congenital syphilis.
Mother-to-child transmission of syphilis remains an important global public health problem. Untreated intrauterine infection may result in adverse events for the fetus or newborn (NB). Maternal risk factors, such as prenatal care, early diagnosis, and appropriate treatment, significantly impact the likelihood of vertical transmission of syphilis. The purpose of this review is to evaluate maternal risk factors for congenital syphilis and the characteristics of exposed NB. A total of 14 studies were evaluated, including 8 cohort studies, 4 cross-sectional and 2 control cases. A total of 12,230 women were included, with confirmed or highly probable congenital syphilis outcome, and 2285 NB. The studies evaluated risk factors for congenital syphilis, which were maternal, demographic, obstetric factors and characteristics of the exposed NB. Included in the risk factors studied, inadequate prenatal care and late onset, as well as inadequate or late treatment of maternal syphilis were significant risk factors for the outcome of congenital syphilis. When the time set of maternal diagnosis was correlated with neonatal infection, there was a tendency to worsen prognosis (more infected NB) in women diagnosed later in pregnancy, as well as in women who underwent few prenatal consultations and inadequate treatment. Women with recent syphilis with high VDRL titres had a higher rate of vertical transmission. The prior history of syphilis with adequate treatment was identified as a protective factor, resulting in lower rates of congenital syphilis. Among the epidemiological and demographic aspects surveyed, it was observed that young age, lower schooling, unemployment, low family income and no fixed residence were associated with higher risk of congenital syphilis. The association of syphilis with adverse socio-economic conditions and inadequate prenatal care suggests that the improvement of the population's living conditions and equitable access to quality health services may have an impact on the reduction of congenital syphilis.


Altered cytokine (receptor) mRNA expression as a tool in immunotoxicology.
Molecular immunotoxicology is aimed at analysing exposure effects on the temporal expression of important immunoregulatory genes. Cytokines play key roles in the immune system and thus molecular immunotoxicology has focused on the analysis of cytokine (expression) levels. These targets offer important new avenues to explore both in terms of mechanistic understanding of immunotoxicity and in terms of developing new assays and tests for predicting the immunotoxic potential of novel compounds. Effects on cytokine levels can be analysed on two different levels, these being mRNA and protein. The choice essentially depends on the aim of the study. Proteins comprise the biological activity so they are a more direct measure than mRNA. mRNA on the other hand, measures at a specific point in time within a tissue or organ, whereas protein is measured in a body fluid, possibly as a spill-over from tissue, or in a supernatant as a summation over a culture period. mRNA levels are assayed using Northern or dot blotting that both comprise hybridisation and using reverse transcription-polymerase chain reaction (RT-PCR). Although the latter technique has both enormous sensitivity and relative ease of operation as important advantages, it requires much more effort in terms of quantitation. References to the nucleic acid sequences of human, murine, and rat cytokines and their receptors are presented (with accession numbers). Examples in which molecular techniques were successfully employed to assess immunotoxicity and (in some cases) understand mechanisms of action are also presented.


Methods to Discover Alternative Promoter Usage and Transcriptional Regulation of Murine Bcrp1.
Gene expression in different tissues is often controlled by alternative promoters that result in the synthesis of mRNA with unique - usually untranslated - first exons. Bcrp1 (Abcg2), the murine orthologue of the ABC transporter Breast Cancer Resistance Protein (BCRP, ABCG2), has at least four alternative promoters that are designated by the corresponding four alternative first exons produced: E1U, E1A, E1B, and E1C. Herein, in-silico protocols are presented to predict alternative promoter usage for Bcrp1. Furthermore, reporter assay methods are described to produce reporter constructs for alternative promoters and to determine the functionality of putative promoters upstream of the alternative first exons that are identified.


Stimulation of CFU-Mk colony growth by normal plasma and plasma from myelodysplastic patients.
The ability of plasma from myelodysplastic patients to support the clonal growth of normal megakaryocyte progenitors (CFU-Mk) was compared with that of plasma from normal subjects. The resultant megakaryocyte colonies were expressed as a plasma factor index megakaryocyte (PFI-Mk). All cultures included PHA-LCM and medium conditioned by the human bladder carcinoma cell line 5637, and some of them had EPO. PFI-Mk (MDS) was significantly lower than PFI-Mk (normal), both with and without EPO. A positive correlation was found between megakaryocyte and platelet count in normal subjects, but was not present in MDS patients. There was no correlation between platelet count and PFI-Mk in neither group. In MDS there was a negative correlation between megakaryocyte number and PFI-Mk, both with and without EPO. Although, the mean megakaryocyte number in MDS and in normal bone marrow was similar, the proportion of immature megakaryocytes was much higher in MDS. Previous work indicates an abnormal clonal origin of megakaryocytes in MDS. The present study suggests that abnormal plasma factors affects megakaryocytopoiesis in this condition.


The signalling pathway for BCG-induced interleukin-6 production in human bladder cancer cells.
Intravesical bacillus Calmette-Guerin (BCG) is currently the therapy of choice for superficial bladder cancer with a 60-70% response rate. Induction of cytokine production (e.g. IL-6, etc.) by BCG has been found in patient's urine in vivo as well as bladder cancer cell lines. However, the signalling mechanisms are still unclear. In this study, we investigated the effect of BCG on cAMP production and its role in regulating interleukin-6 expression in the human bladder cancer cell line, MGH. After 1 hr exposure to BCG, IL-6 gene expression in MGH cells increased by 2.5-3-fold and cAMP production increased by 8-10-fold in a time- and dose-dependent manner. BCG-induced cAMP production was inhibited by both antifibronectin antibody and an adenylate cyclase inhibitor, SQ22536 in a dose-dependent way. In the presence of SQ22536, IL-6 expression in MGH cells was also greatly reduced. Furthermore, cAMP-dependent kinase inhibitors H7 and HA1004 also inhibited BCG-induced IL-6 expression in MGH, with HA1004 being much less effective than H7. Thus, BCG induces cAMP production and may regulate interleukin-6 expression partially via a cAMP-dependent pathway in human bladder cancer cells.


The RNA m6A modification might participate in microglial activation during hypoxic-ischemic brain damage in neonatal mice.
The RNA m6A modification has been implicated in multiple neurological diseases as well as macrophage activation. However, whether it regulates microglial activation during hypoxic-ischemic brain damage (HIBD) in neonates remains unknown. Here, we aim to examine whether the m6A modification is involved in modulating microglial activation during HIBD. We employed an oxygen and glucose deprivation microglial model for in vitro studies and a neonatal mouse model of HIBD. The brain tissue was subjected to RNA-seq to screen for significant changes in the mRNA m6A regulator. Thereafter, we performed validation and bioinformatics analysis of the major m6A regulators. RNA-seq analysis revealed that, among 141 m6A regulators, 31 exhibited significant differential expression (FC (abs) ≥ 2) in HIBD mice. We then subjected the major m6A regulators Mettl3, Mettl14, Fto, Alkbh5, Ythdf1, and Ythdf2 to further validation, and the results showed that all were significantly downregulated in vitro and in vivo. GO analysis reveals that regulators are mainly involved in the regulation of cellular and metabolic processes. The KEGG results indicate the involvement of the signal transduction pathway. Our findings demonstrate that m6A modification of mRNA plays a crucial role in the regulation of microglial activation in HIBD, with m6A-associated regulators acting as key modulators of microglial activation.


Temperature responses of growth and photosynthetic CO2 exchange rates in coastal and desert races of Atriplex lentiformis.
Comparative measurements of CO2 exchange and growth rates were made on Atriplex lentiformis (Torr.) Wats. plants from populations native to coastal as well as desert habitats in southern California. While both had similar CO2 exchange rates at moderate growth temperatures, the desert plants had a substantially greater capacity to acclimate to high growth temperatures indicating that clear ecotypic differences in acclimation capacity are present in this species. This large capacity for photosynthetic acclimation resulted in nearly equal CO2 exchange rates of the desert plants under the different day temperatures characteristic of the desert habitat during the summer and winter months. In contrast, the photosynthetic CO2 exchange rates of the coastal plants was markedly reduced by high growth temperatures. The large acclimation capacity of the desert plants may function to maintain high productivities during both the winter and summer months but would not be required in the coastal plants because of the moderate temperatures throughout the year in their native habitat.Relative growth rates (RGR) of the coastal and desert plants were similar at 23°C day/18°C night and 33°C day/25°C night growth temperatures. At 43°C day/30°C night temperatures, however, the RGR of the desert plants was higher than that of the coastal plants. Thus, the larger acclimation capacity of the desert plants is related to a greater ability to maintain high growth rates over a wide range of temperatures as compared to the coastal plants. Small differences in allocation patterns could account for differences in the comparative photosynthetic responses and growth rates in each temperature regime.


The effect of flicker on foveal and peripheral thresholds for oscillatory motion.
This study evaluated the influence of superimposed luminance flicker on the detection of oscillatory motion. Thresholds for oscillatory motion were determined in the fovea and at 2, 6 and 25 deg in the right field for a small luminous target with and without sinusoidal luminance flicker. At the fovea, flicker modulation up to 80% at frequencies from 1.5 to 9 Hz had no effect on motion detection, except for oscillatory motion at a frequency of 8 Hz, for which thresholds were elevated by about 0.2 log units. In the periphery, flicker elevated motion thresholds up to 0.3-0.4 log units at low and moderate frequencies of oscillation at all locations tested. However, both foveal and peripheral motion thresholds were unaffected by flicker when the luminance of the target was reduced. The absence of a robust effect of target flicker on motion thresholds may be accounted for in part by the comparison of activity across a large population of motion-detecting neurons with different direction preferences. Another contributing factor may be the existence of foveal velocity- and position-detecting mechanisms with similar sensitivities.


Denosumab Use as a Predictor Variable for External Cervical Resorption: A Case-Control Study.
The objective of this case-control study was to investigate the association between denosumab use and the risk of developing external cervical resorption (ECR). Thirty-three patients ≥45 years old who were diagnosed with ECR were selected. Controls were matched to the cases based on sex and age (±5 years) in a 1:1 ratio. Confounders were classified into systemic factors, including a history of systemic sclerosis, hepatitis B, denosumab use, and bisphosphonate use, or local factors, including a history of traumatic occlusion, periodontal procedures (scaling and root planing and periodontal surgeries), and tooth extraction (excluding third molar extraction). Additionally, the number of remaining teeth in each subject was recorded using panoramic radiographs. The baseline characteristics of the 2 groups, including age, sex, and the number of remaining teeth, were compared using the chi-square and Mann-Whitney U tests. Binary logistic regression was used to determine the possible association between denosumab use and the risk of developing ECR (α < 0.05). No significant differences in baseline characteristics were observed between the case and control groups (P > .05). After adjusting for systemic and local cofounders, denosumab use was significantly associated with the occurrence of ECR (odds ratio = 7.317; 95% confidence interval, 1.410-37.966; P < .05). Based on the binary logistic regression model, denosumab use could significantly predict the risk of developing ECR.


[Drug treatment of immune hyperthyroidism (Basedow disease). Patient selection, long-term follow-up and prevention of recurrence].
Since theraphy of Graves' disease is not directed towards the cause of the disease, medical theraphy is still the first choice and symptomatically effective in treating hyperthyroidism. Antithyroid drugs are effective in restoring euthyroidism in >90% of the patients durning 4-6 weeks, but 30-50% of the patients experience relapse after withdrawal. Previous prospective randomized studies evaluated prognostic parameters and the use of levothyroxine for prevention of relapse of hyperthyroidism. Recent studies have addressed the period after withdrawal amd focused on the natural course of disease. The results of a recent prospective randomized and controlled multicenter study were as follows: supplementation of levothroxine does not prevent relapse of hyperthyroidism. Basal TSH (4 weeks after withdrawal of antithyroid drugs) is the best prognostic marker. Smoking and positive TSH-receptor-antibodies at the end of antithyroid theraphy are other risk factors.


Population differences in the timing of diapause: adaptation in a spatially heterogeneous environment.
Populations of the planktonic copepod, Diaptomus sanguineus, live in permanent and temporary freshwater ponds in Rhode Island. All ponds in which they occur become uninhabitable at some time during the year, but the nature and timing of the harsh period varies both spatially and temporally. Females produce discrete clutches either of subitaneous eggs which hatch immediately or of diapausing eggs which hatch the following season. The two egg types show distinct chorion morphologies under transmission electron microscopy. In permanent ponds the copepods start making diapausing eggs in March, one month before rising water temperatures induce planktivorous sunfish to become active. In temporary ponds diapausing eggs are produced, in a complex pattern from May to July, before the water disappears in late summer or early fall.We investigated the spatial scale at which D. sanguineus is adapted to this complex environment. In a reciprocal transfer experiment between temporary and permanent bodies of water, female copepods placed in new ponds made subies of water, female copepods placed in new ponds made subitaneous and diapausing eggs in the same sequence as control females retained in their home ponds. The copepod populations enter diapause at times appropriate for the local habitat conditions they experience, but inappropriate for other, nearby ponds. Transplanted females were unable to sense a change in pond type or to adjust egg production accordingly. We conclude that D. sanguineus populations are adapted to the specific conditions of isolated ponds rather than to a broader geographical region containing several pond types.


Effectiveness of the COVID-19 vaccines on preventing symptomatic SARS-CoV-2 infections and hospitalizations in Southwestern Alaska, January-December 2021.
The population in rural southwest Alaska has been disproportionately affected by COVID-19. To assess the benefit of COVID-19 vaccines, we analyzed data from the regional health system. We estimated vaccine effectiveness (VE) during January 16-December 3, 2021, against symptomatic SARS-CoV-2 infection after a primary series or booster dose, and overall VE against hospitalization. VE of a primary series against symptomatic infection among adult residents was 91.3% (95% CI: 85.7, 95.2) during January 16-May 7, 2021, 50.3% (95% CI, 41.1%-58.8%) during July 17-September 24, and 37.0% (95% CI, 27.8-45.0) during September 25-December 3, 2021; VE of a booster dose during September 25-December 3, 2021, was 92.1% (95% CI: 87.2-95.2). During the overall study period, VE against hospitalization was 91.9% (95% CI: 85.4-95.5). COVID-19 vaccination offered strong protection against hospitalization and a booster dose restored protection against symptomatic infection.


Optimizing the selection of technically unresectable colorectal liver metastases.
The prediction of conversion surgery in patients with technically unresectable colorectal liver metastases has not been generalized or well-established. We developed a predictive model for conversion surgery and assessed the long-term outcomes of patients with technically unresectable colorectal liver metastases. In this single-center, retrospective study, we analyzed the perioperative parameters and outcomes of 892 consecutive patients (2014-2021). Conversion surgery was indicated when the chemotherapy response allowed the complete resection of colorectal liver metastases with negative margins and adequate remnant liver volume. Of the 892 patients, 122 had technically unresectable colorectal liver metastases; 61 underwent conversion surgery (conversion surgery group) and 61 did not (nonconversion surgery group). The median overall survival was significantly higher in the conversion surgery group than in the nonconversion surgery group (5.6 vs 1.8 years, P < .001). After univariate and multivariate analyses, the predictive model for conversion surgery was constructed using 4 predictive factors: Rat sarcoma viral oncogene homolog status (mutant, +2 points), tumor number (≥15, +1), hepatic vein contact (≥2 hepatic veins, +1), and the presence of preservable sections (absence of preservable sections, +2). The area under the curve for conversion surgery was 0.889. Patients were graded according to the scores (A [0-2], B [3-4], and C [5-6]), and the conversion rates were 91.5% (A), 32.6% (B), and 10.3% (C) (P < .001). Grade A patients (median survival time, 5.7 years) had significantly better overall survival than grade B and C patients (median survival time, 2.2 and 1.6 years, respectively; P < .001). Patients who underwent conversion surgery for technically unresectable colorectal liver metastases had better prognoses, and our novel predictive model was useful in predicting conversion surgery and prognosis.


Suboptimal performance of LI-RADS v2018 on gadoxetic acid-enhanced MRI for detecting hepatocellular carcinoma in liver transplant candidates.
To evaluate the diagnostic performance for hepatocellular carcinoma (HCC) detection of the Liver Imaging Reporting and Data System (LI-RADS) version 2018 on gadoxetic acid-enhanced MRI, comparing liver transplant candidates (LT group) with patients who underwent surgical resection (SR group), and to determine significant clinical factors for diagnostic performance of LI-RADS v2018. Patients who underwent gadoxetic acid-enhanced MRI and subsequent SR or LT for HCC were retrospectively included between January 2019 and December 2020. The sensitivity and specificity of LI-RADS LR-5 for HCC were compared between the two groups using generalized estimating equations. The accuracy of patient allocation according to the Milan criteria was calculated for the LT group. Univariable and multivariable logistic regression analyses were performed to determine significant clinical factors associated with the sensitivity of LI-RADS. Of the 281 patients, 237 were assigned to the SR group, and 44 were assigned to the LT group. The LT group showed significantly lower per-patient (48.5% vs. 79.6%, p < .001) and per-lesion sensitivity (31.0% vs. 75.9%, p < .001) than the SR group, whereas no significant difference in both per-patient (100.0% vs. 91.7%, p > .99) and per-lesion specificities (100.0% vs. 94.1%, p > .99). The accuracy of patient allocation was 50.0%. Sensitivity was significantly lower in patients with a smaller lesion size (p < .001), a larger lesion number (p = .002), and a higher Child-Pugh score (p = .009). LI-RADS v2018 on gadoxetic acid-enhanced MRI might be insufficient in liver transplant candidates and other diagnostic imaging tests should be considered in patients with these significant clinical factors. In liver transplant candidates with a smaller lesion size, a larger lesion number, and a higher Child-Pugh score, imaging tests other than gadoxetic acid-enhanced MRI may be clinically useful to determine the transplant eligibility. • The sensitivity of the Liver Imaging Reporting and Data System (LI-RADS) was lower in liver transplant candidates than in those who underwent surgical resection. • With the use of gadoxetic acid-enhanced MRI, the accuracy of patient allocation for liver transplantation on the basis of the Milan criteria was suboptimal. • The sensitivity of LI-RADS v2018 was significantly associated with lesion size, lesion number, and Child-Pugh classification.


Phase I study of chidamide (CS055/HBI-8000), a new histone deacetylase inhibitor, in patients with advanced solid tumors and lymphomas.
Chidamide (CS055/HBI-8000) is a new benzamide class of histone deacetylase inhibitor with marked anti-tumor activity. This study reports the phase I results. Patients with advanced solid tumors or lymphomas received oral doses of 5, 10, 17.5, 25, 32.5, or 50 mg chidamide either twice (BIW) or three times (TIW) per week for 4 consecutive weeks every 6 weeks. Safety, characteristics of pharmacokinetics (PK) and pharmacodynamics (PD), and preliminary efficacy were evaluated. A total of 31 patients were enrolled. No DLTs were identified in the BIW cohorts up to 50 mg. DLTs were grade 3 diarrhea and vomiting in two patients in the TIW cohort at 50 mg, respectively. PK analysis revealed t(1/2) of 16.8-18.3 h, T(max) of 1-2 h in most cases, and a dose-related increase in C(max) and AUC. Significant induction of histone H3 acetylation in peripheral white blood cells was observed after a single dose of chidamide. Four patients with T-cell lymphomas and 1 patient with submandibular adenoid cystic carcinoma achieved a partial response. Chidamide was generally well tolerated in patients with advanced solid tumors or lymphomas in the tested regimens. Favorable PK and PD profiles, as well as encouraging preliminary anti-tumor activity, were demonstrated.


Some lessons learned from the COVID-19 pandemic: Subjective well-being before and during the pandemic among Brazilian adults.
Image, graphical abstract.


The pharmaceutical stability of trastuzumab after short-term storage at room temperature assessed by analytical techniques and tumour imaging by microSPECT/CT.
We report the pharmaceutical stability of trastuzumab stored for a short time (12 h) at room temperature (RT; 20-25 °C) compared to trastuzumab stored at 2-8 °C. The physicochemical properties were evaluated by UV-visible and FTIR spectroscopy, SDS-PAGE and size-exclusion HPLC (SE-HPLC). Trastuzumab was reacted with benzylisothiocyanate diethylenetriaminepentaacetic acid (BzDTPA) to complex 111In. The HER2-binding affinity of 111In-BzDTPA-trastuzumab synthesised from trastuzumab stored at RT or at 2-8 °C was measured using HER2-positive SK-Br-3 human breast cancer (BC) cells. The tumour and normal tissue uptake of 111In-BzDTPA-trastuzumab was studied by microSPECT/CT imaging and biodistribution studies in CD1 athymic mice with s.c. HER2-positive SK-Ov-3 human ovarian cancer xenografts. There were no differences in λmax or molar absorptivity (ε) values in the UV-visible spectra of trastuzumab stored at RT or at 2-8 °C. FTIR spectroscopy suggested no differences in secondary structure. SDS-PAGE revealed protein bands corresponding to the expected molecular weights. SE-HPLC showed identical properties for trastuzumab stored at RT or at 2-8 °C. The dissociation constant (Kd) for binding of 111In-BzDTPA-trastuzumab to HER2 on SK-Br-3 cells (2.2-4.4 nM) was not significantly different when the radioimmunoconjugates were synthesised from trastuzumab stored at RT or at 2-8 °C. MicroSPECT/CT demonstrated high uptake in SK-Ov-3 tumours in mice that was not significantly different using trastuzumab stored at RT or at 2-8 °C (33.7 ± 8.8% vs. 22.2 ± 8.1% i.d./g, respectively; P = 0.36). There were no significant differences in normal tissue uptake or in tumour/normal tissue (T/NT) ratios. We conclude that short-term storage of trastuzumab at RT for 12 h did not affect the physicochemical or biological properties of the drug.


Cosmetics in the treatment of acne vulgaris.
This article describes scenarios of patients who have acne vulgaris have tried over-the-counter products and cosmetics and are disheartened by the persistence of their disease and the resulting scars. They may have seen an aesthetician, plastic surgeon, or even a general practitioner before seeing a well-informed skin specialist. Patients perceive the dermatologist to be the skin care expert and seek guidance to obtain otherwise unobtainable results. Therefore, practicing dermatologists should take advantage of the available tools to treat patients aggressively and completely. Appropriately applied cosmetics can play a role in achieving this goal. This article describes scenarios that integrate cosmetics into an anti-acne treatment regimen that is effective and safe for all ethnic groups and is well tolerated by both male and female patients.


Reduction of predation risk under the cover of darkness: Avoidance responses of mayfly larvae to a benthic fish.
Mayfly larvae of Paraleptophlebia heteronea (McDunnough) had two antipredator responses to a nocturnal fish predator (Rhinichthys cataractae (Valenciennes)): flight into the drift and retreat into interstitial crevices. Drift rates of Paraleptophlebia abruptly increased by 30 fold when fish were actively foraging in the laboratory streams but, even before fish were removed, drift began returning to control levels because larvae settled to the substrate and moved to areas of low risk beneath stones. This drifting response was used as an immediate escape behavior which likely decreases risk of capture from predators which forage actively at night. Surprisingly, drift most often occurred before contact between predator and prey, and we suggest that in darkness this mayfly may use hydrodynamic pressure waves for predator detection, rather than chemical cues, since fish forage in an upstream direction. Although drifting may represent a cost to mayfly larvae in terms of relocation to a new foraging area with unknown food resources, the immediate mortality risk probably out-weighs the importance of staying within a profitable food patch because larvae can survive starvation for at least 2 d. In addition to drifting, mayflies retreated from upper, exposed substrate surfaces to concealed interstitial crevices immediately after a predator encounter, or subsequent to resettlement on the substrate after predator-induced drift. A latency period was associated with this response and mayflies remained in these concealed locations for at least 3 h after dace foraging ceased. Because this mayfly feeds at night and food levels are significantly lower in field refugia under stones, relative to exposed stone surfaces, predator avoidance activity may limit foraging time and, ultimately, reduce the food intake of this stream mayfly.


[Confocal microscopy as an early relapse marker after keratoplasty due to Fusarium solani keratitis].
In the case of therapy-resistant keratitis an infection with Fusarium solani should be taken into consideration as a rare but very severe eye disease. In the majority of cases Fusarium solani keratitis will result in a protracted clinical course despite aggressive medicinal and surgical interventions. We describe the case of a referred patient after intensive topical, intracameral and systemic antibacterial and antimycotic therapy as well as surgical treatment with emergency keratoplasty à chaud because of Fusarium solani keratitis. The patient presented to our department with persistent discomfort for further therapeutic interventions. Using confocal microscopy we were able to demonstrate the presence of fungal hyphae in the host cornea and the graft, which was important for making further surgical decisions. Furthermore, this emphasizes the role of confocal microscopy as an early relapse marker during the clinical monitoring.


Muscarinic depolarization of SH-SY5Y human neuroblastoma cells as determined using oxonol V.
Membrane potential was measured in the suspension of SH-SY5Y cells using the anionic potentiometric probe, oxonol V. The relation of fluorescence to membrane potential was assessed by increasing the external [K+] in the presence of the K+ ionophore valinomycin. The response was linear in the range of 5 to 30 mM K+ (membrane potential change of approximately 40 mV). Muscarine increased the fluorescence indicating a depolarization. The competitive inhibitory constant (112 nM) of the muscarinic antagonist pirenzepine (5,11-dihydro-11-([4-methyl-1-piperazinyl]acetyl)-6H-pyrido[2,3-b] (1,4)benzodiazepin-6-one-dihydrochloride) suggests that Hm1 receptors are not involved. The protein kinase C inhibitor, GF 109203X (3-[1-(3-demethylaminopropyl)-indol-3-yl]-3-(indol-3-yl)-maleimide ), and a reduction of extracellular Na+ both produced an additive partial inhibition. The results suggest that muscarinic receptors depolarize these cells by separate Na(+)-dependent and -independent mechanisms, the Na(+)-independent mechanism being protein kinase C-dependent.


Binding of defined regions of a polypeptide to GroEL and its implications for chaperonin-mediated protein folding.
Unfolded rhodanese in a complex with the chaperonin GroEL was subjected to limited proteolysis. Sequence analysis indentified a GroEL-bound fragment of approximately 11,000 M(r) and a well defined fragment of approximately 7,000 M(r) from the two homologous domains of rhodanese. The shorter segment contains one hydrophobic and one amphiphilic alpha-helix mapping to the domain interface while the other fragment contains the homologous regions and an additional hydrophobic helix. Our results suggest a mechanism for the GroEL-mediated folding of rhodanese in which the domain-forming regions of the polypeptide are kept apart and are then released, perhaps sequentially, resulting in correct folding.


Time to include the gut microbiota in the hygienic standardisation of laboratory rodents.
The gut microbiota (GM) composition and its impact on animal experiments has become currently dramatically relevant in our days: (1) recent progress in metagenomic technologies, (2) the availability of large scale quantitative analyses to characterize even subtle phenotypes, (3) the limited diversity of laboratory rodent GM due to strict barriers at laboratory animal vendors, and (4) the availability of up to 300.000 different transgenic mouse strains from different sources displaying a huge variety in their GM composition. In this review the GM is described as a variable in animal experiments which need to be reduced for scientific as well as ethical reasons, and strategies how to implement this in routine diagnostic procedures are proposed. We conclude that we have both enough information available to state that the GM has an essential impact on animal models, as well as the methods available to start dealing with these impacts.


Ultrasound elastography of the prostate: state of the art.
Prostate cancer is the cancer exhibiting the highest incidence rate and it appears as the second cause of cancer death in men, after lung cancer. Prostate cancer is difficult to detect, and the treatment efficacy remains limited despite the increase use of biological tests (prostate-specific antigen [PSA] dosage), the development of new imaging modalities, and the use of invasive procedures such as biopsy. Ultrasound elastography is a novel imaging technique capable of mapping tissue stiffness of the prostate. It is known that prostatic cancer tissue is often harder than healthy tissue (information used by digital rectal examination [DRE]). Two elastography techniques have been developed based on different principles: first, quasi-static (or strain) technique, and second, shear wave technique. The tissue stiffness information provided by US elastography should improve the detection of prostate cancer and provide guidance for biopsy. Prostate elastography provides high sensitivity for detecting prostate cancer and shows high negative predictive values, ensuring that few cancers will be missed. US elastography should become an additional method of imaging the prostate, complementing the conventional transrectal ultrasound and MRI. This technique requires significant training (especially for quasi-static elastography) to become familiar with acquisition process, acquisition technique, characteristics and limitations, and to achieve correct diagnoses.


Solid-state NMR spectroscopy of proteins.
Solid-state NMR spectroscopy proved to be a versatile tool for characterization of structure and dynamics of complex biochemical systems. In particular, magic angle spinning (MAS) solid-state NMR came to maturity for application towards structural elucidation of biological macromolecules. Current challenges in applying solid-state NMR as well as progress achieved recently will be discussed in the following chapter focusing on conceptual aspects important for structural elucidation of proteins.


Fasting plasma glucose level to guide the need for an OGTT to screen for gestational diabetes mellitus.
To determine the fasting plasma glucose (FPG) level at which an oral glucose tolerance test (OGTT) could be avoided to screen for gestational diabetes (GDM) and to evaluate the characteristics of women across this FPG threshold. A multi-centric prospective cohort study with 1843 women receiving universal screening for GDM with a 75 g OGTT. In the total population, GDM prevalence was 12.5% (231). A FPG < 78 mg/dL was the cut-off with best trade-off to limit the number of missed GDM cases [44 (19.0%)] with a negative predictive value of 97.3% (95% CI 96.5-98.0) for GDM, while avoiding 52.2% OGTTs. Compared to GDM with FPG ≥ 78 mg/dL [187 (81.0%)], GDM women with FPG < 78 mg/dL had a significantly lower BMI (27.1 ± 4.5 vs. 29.6 ± 5.2 kg/m2, p = 0.003), less insulin resistance [Matsuda: 0.4 (0.4-0.7) vs. 0.3 (0.2-0.5), p < 0.001] and better β-cell function [ISSI-2: 0.13 (0.08-0.25) vs. 0.09 (0.04-0.15), p = 0.004]. Compared to NGT women (1612) with FPG ≥ 78 mg/dL [846 (52.5%)], NGT with FPG < 78 mg/dL [766 (47.5%)] had a significantly lower BMI (26.0 ± 3.9 vs. 27.8 ± 4.7 kg/m2, p < 0.001), less insulin resistance [Matsuda: 0.7 (0.5-0.9) vs. 0.5 (0.4-0.7), p < 0.001], better β-cell function [ISSI-2: 0.17 (0.10-0.30) vs. 0.12 (0.07-0.21), p < 0.001], and less often large-for-gestational age infants [9.2 (70) vs. 16.2% (136), p < 0.001]. FPG < 78 mg/dL can be used to limit the number of OGTTs when screening for GDM. Women with FPG < 78 mg/dL had a better metabolic profile and in NGT women also less fetal overgrowth.


Recapitulating pathophysiology of skeletal muscle diseases in vitro using primary mouse myoblasts on a nanofibrous platform.
Tissue engineering approaches are used to mimic the microenvironment of the skeletal muscle in vitro. However, the validation of a bioengineered muscle as a model to study diseases is inadequate. Here, we present polycaprolactone nanofibers as a robust platform that mimics cellular organization and recapitulates critical functions of the myotubes observed in vivo. We isolated myoblasts from mice following a simplified protocol and cultured them on aligned nanofibers. Myotubes grown on aligned nanofibers maintained alignment for 14 days and exhibited a time-dependent increase in levels of p-AKT upon insulin stimulation. Treatment with matrix-assisted integrin inhibitor led to reduction in p-AKT levels, underscoring the critical role of environment on the biological processes. We demonstrate the suitability of myotubes grown on nanofibrous platform to study corticosteroid-induced muscle degeneration. This study, thus, demonstrates that aligned nanofibers retain myotubes in culture for longer duration and recapitulate the functions of skeletal muscle under pathophysiological conditions.


Contribution of dysregulated serum magnesium to mortality in hemodialysis patients with secondary hyperparathyroidism: a 3-year cohort study.
The extent of contribution of disturbed magnesium balance to mortality remains unclear among hemodialysis patients. This was a cohort study involving 3276 patients on maintenance hemodialysis at 86 facilities in Japan from 2008 to 2010 who had secondary hyperparathyroidism (SHPT). Baseline serum magnesium (sMg) values were categorized into quintiles (≤2.3, >2.3-2.5, >2.5-2.7, >2.7-3.0 and >3.0 mg/dL), and the middle quintile was set as the reference. Outcome was all-cause death. Independent contribution to all-cause death was assessed via Cox regression to generate population-attributable fractions (PAFs). A total of 2165 patients from 68 facilities were analyzed. The lowest quintile of sMg was positively associated with lower serum potassium and albumin levels, higher C-reactive protein (CRP) levels and prevalence of atrial fibrillation and cerebrovascular disease than the other quintiles. The highest sMg quintile was positively associated with higher potassium levels, and negatively associated with lower serum albumin levels and higher intact parathyroid hormone and CRP levels and prevalence of cerebrovascular disease than the other quintiles. During a median follow-up of 3 years, the lowest and the second lowest quintiles of sMg were associated with all-cause death [adjusted hazard ratio (HR) 1.737, 95% confidence interval (95% CI) 1.200-2.512 and HR 1.675, 95% CI 1.254-2.238, respectively). Point estimates of adjusted HRs of the highest and the second highest sMg quintiles were higher than those of the middle quintile for all-cause death. Adjusted PAFs of lower sMg and of higher and lower sMg for all-cause death were 24.0% (95% CI 13.0-35.0%) and 30.7% (95% CI 14.5-46.8%), respectively. In hemodialysis patients with SHPT, dysregulated sMg is an important contributor to all-cause death. Further studies are warranted to examine whether or not correction of sMg improves survival.


Effects of half-dose and full-dose GnRH antagonists on IVF-ET outcomes: a retrospective study.
Gonadotropin-releasing hormone antagonist(GnRH-ant) has been shown to have a negative effect on endometrial receptivity. Therefore, the use of lower doses of GnRH-ant during controlled ovarian stimulation (COS) may improve endometrial receptivity and clinical pregnancy rate. However, the GnRH-ant dose is relatively flexible and there is no fixed requirement for guidance. In this retrospective study, we determined the effects of half-dose and full-dose GnRH-ant on IVF-ET outcomes. Of the 316 cycles in the 314 patients analyzed in this study, 149 received GnRH-ant half-dose (Group1), while 167 received GnRH-ant full-dose (Group2). The groups were further classified based on age and BMI. Age subgroups, were divided as age ≤ 35(subgroup A) and age > 35(subgroup B): 180 cycles in subgroup A (107 cycles in subgroup A1,73 cycles in subgroup A2), 136 cycles in subgroup B (42 cycles in subgroup B1,94 cycles in subgroupB2). The subgroups based on BMI were divided as BMI < 25 (subgroup C)and BMI ≥ 25 (subgroup D):208 cycles in subgroup C (94 cycles in subgroup C1,114 cycles in subgroup C2), 108 cycles in subgroup D (55 cycles in subgroup D1,53 cycles in subgroup D2). The number of fertilized oocytes, superior-quality embryos, clinical pregnancy rate, and live birth rate differed significantly between the two groups. However, the number of retrieved oocytes and available embryos were significantly higher in Group 1 than Group 2 (8.17 ± 4.10 vs. 7.07 ± 4.05, 2.96 ± 2.03 vs. 2.52 ± 1.62, respectively,p<0.05). Differences between the age subgroups were not statistically significant. However, in the subgroups based on BMI, the fertilized oocytes, available embryos, the number of superior-quality embryos, and the live birth rate differed significantly between the four subgroups. The number of retrieved oocytes was higher in subgroup C1 than in subgroup C2 (8.24 ± 4.04 vs. 6.83 ± 3.92,p < 0.05), In addition, the clinical pregnancy rate was slightly higher in subgroup D1 than in subgroup D2(45.45 vs. 24.53%, P < 0.05). The results showed that half-dose GnRH-ant was as effective as full-dose GnRH-ant for most patients. Moreover, half-dose GnRH-ant may be more suitable in patients with BMI greater than or equal to 25. The findings of this study need to be validated in a large sample RCT. Retrospectively registered.


The MRP2/cMOAT transporter and arsenic-glutathione complex formation are required for biliary excretion of arsenic.
Worldwide, millions of people are exposed to arsenic in drinking water that exceeds the World Health Organization standard of 10 microg/liter by as much as 50-300-fold, yet little is known about the molecular basis for arsenic excretion. Here we show that transport of arsenic into bile depends on the MRP2/cMOAT transporter and that glutathione is obligatory for such transport. Using reversed phase liquid chromatography/mass spectrometry, we demonstrate that two arsenic-glutathione complexes not previously identified in vivo, arsenic triglutathione and methylarsenic diglutathione, account for most of the arsenic in the bile. The structure of the compounds was also confirmed by nuclear magnetic resonance spectroscopy. Our findings may help explain the increased susceptibility of malnourished human populations to arsenic.


CHCHD10 mutations in patients with amyotrophic lateral sclerosis in Mainland China.
Many genes have been found to be pathogenic for amyotrophic lateral sclerosis (ALS). Among them, the coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10) has been reported to play a controversial role in ALS. We examined the coding region of this gene in 424 unrelated Chinese sporadic ALS subjects, 73 familial ALS subjects, and 204 healthy controls using a polymerase chain reaction-direct sequencing strategy. Two types of variants were identified, and of these, one variant (g.877C>T, p.P23L) was identified to be damaging, and the other one was (g.648G>A) in intron. The mutation (g.877C>T, p.P23L) has been previously reported in a Chinese frontotemporal dementia patient. Our study is the first to report the clinical heterogeneity of specific mutations in CHCHD10 in ALS in an Asian population and to report the possible new mutation hotspot. Our findings support the major role of CHCHD10 in the frontotemporal dementia-amyotrophic lateral sclerosis disease spectrum and stress the importance of mitochondrial abnormalities in the pathogenesis of diseases in Asian cohorts.


Transformation of animal cells with human T-cell leukemia virus type II.
Human T-cell leukemia virus type II (HTLV-II) was tested for its ability to transform normal animal cells. The HTLV-II-infected human T-cell line, HTLV-IIA was lethally X-irradiated and cocultivated with normal leukocytes of rabbit and crab-eating monkey and spleen cells of hamster. The transformed cell lines, designated Ra-IIA, Si-IIA and Ham-IIA, were established. These cell lines were shown to be infected with HTLV-II by the polymerase chain reaction method combined with the digoxigenin-enzyme-linked immunosorbent assay method. These cell lines were examined for viral antigens by the indirect immunofluorescence method. Although the cytoplasma of over 90% of the cells of Si-IIA cell line was brilliantly stained, Ra-IIA and Ham-IIA cells were not stained. Electron microscopy of cells of the Si-IIA line revealed C-type virus particles in the extracellular spaces.


Leukotriene C4 increases the susceptibility of adult mice to Shiga toxin-producing Escherichia coli infection.
Shiga toxin-producing Escherichia coli (STEC) is a food-borne pathogen that causes hemorrhagic colitis. Under some circumstances, Shiga toxin (Stx) produced within the intestinal tract enters the bloodstream, leading to systemic complications that may cause the potentially fatal hemolytic-uremic syndrome (HUS). Despite STEC human infection is characterized by acute inflammation of the colonic mucosa, little is known regarding the role of proinflammatory mediators like cysteine leukotrienes (cysLTs) in this pathology. Thus, the aim of this work was to analyze whether leukotriene C4 (LTC4) influences STEC pathogenesis in mice. We report that exogenous LTC4 pretreatment severely affected the outcome of STEC gastrointestinal infection. LTC4-pretreated (LTC4+) and STEC-infected (STEC+) mice showed an increased intestinal damage by histological studies, and a decreased survival compared to LTC4-non-pretreated (LTC4-) and STEC+ mice. LTC4+/STEC+ mice that died after the infection displayed neutrophilia and high urea levels, indicating that the cause of death was related to Stx2-toxicity. Despite the differences observed in the survival between LTC4+ and LTC4- mice after STEC infection, both groups showed the same survival after Stx2-intravenous inoculation. In addition, LTC4 pretreatment increased the permeability of mucosal intestinal barrier, as assessed by FITC-dextran absorption experiments. Altogether these results suggest that LTC4 detrimental effect on STEC infection is related to the increased passage of pathogenic factors to the bloodstream. Finally, we showed that STEC infection per se increases the endogenous LTC4 levels in the gut, suggesting that this inflammatory mediator plays a role in the pathogenicity of STEC infection in mice, mainly by disrupting the mucosal epithelial barrier.


Malignant meningioma within the third ventricle: a case report.
A case of a malignant meningioma within the 3rd ventricle is presented. Although malignant transformation of meningiomas has been described, occurrence within the ventricular system is extremely rare.


Approaches for enhanced phytoextraction of heavy metals.
The contamination of the environment with toxic metals has become a worldwide problem. Metal toxicity affects crop yields, soil biomass and fertility. Soils polluted with heavy metals pose a serious health hazard to humans as well as plants and animals, and often requires soil remediation practices. Phytoextraction refers to the uptake of contaminants from soil or water by plant roots and their translocation to any harvestable plant part. Phytoextraction has the potential to remove contaminants and promote long-term cleanup of soil or wastewater. The success of phytoextraction as a potential environmental cleanup technology depends on factors like metal availability for uptake, as well as plants ability to absorb and accumulate metals in aerial parts. Efforts are ongoing to understand the genetics and biochemistry of metal uptake, transport and storage in hyperaccumulator plants so as to be able to develop transgenic plants with improved phytoremediation capability. Many plant species are being investigated to determine their usefulness for phytoextraction, especially high biomass crops. The present review aims to give an updated version of information available with respect to metal tolerance and accumulation mechanisms in plants, as well as on the environmental and genetic factors affecting heavy metal uptake. The genetic tools of classical breeding and genetic engineering have opened the door to creation of 'remediation' cultivars. An overview is presented on the possible strategies for developing novel genotypes with increased metal accumulation and tolerance to toxicity.


Subtropical adaptation of a temperate plant (Brassica oleracea var. italica) utilizes non-vernalization-responsive QTLs.
While many tropical plants have been adapted to temperate cultivation, few temperate plants have been adapted to the tropics. Originating in Western Europe, Brassica oleracea vernalization requires a period of low temperature and BoFLC2 regulates the transition to floral development. In B. oleracea germplasm selected in Taiwan, a non-vernalization pathway involving BoFLC3 rather than BoFLC2 regulates curd induction. In 112 subtropical breeding lines, specific haplotype combinations of BoFLC3 and PAN (involved in floral organ identity and a positional candidate for additional curd induction variation) adapt B. oleracea to high ambient temperature and short daylength. Duplicated genes permitted evolution of alternative pathways for control of flowering in temperate and tropical environments, a principle that might be utilized via natural or engineered approaches in other plants. New insight into regulation of Brassica flowering exemplifies translational agriculture, tapping knowledge of botanical models to improve food security under projected climate change scenarios.


The paired homeodomain transcription factor Pax-2 is expressed in the endocrine pancreas and transactivates the glucagon gene promoter.
Glucagon gene expression is controlled by at least four DNA elements within the promoter; G2, G3, and G4 confer islet-specific expression, while G1 restricts glucagon transcription to alpha cells. Two islet-specific complexes are formed on G3, the insulin-responsive element of the glucagon gene; one of these corresponds to the paired homeodomain protein Pax-6, a major glucagon gene transactivator that plays a crucial role in alpha cell development. We describe here the identification of the second complex as Pax-2, another member of the paired box family. Pax-2 is known to be crucial for the development of the urogenital tract and of the central nervous system, but its presence in the endocrine pancreas has not been reported. We detected Pax-2 gene expression by RT-PCR; in islets, Pax-2 is present as two alternative splicing isoforms, Pax-2A and Pax-2B, whereas in the glucagon- and insulin-producing cell lines alphaTC1 and Min6, a distinct isoform, Pax-2D2, is found in addition to Pax-2B. Both islet-specific isoforms bind to the enhancer element G3 and to the alpha-specific promoter element G1 that also interacts with Pax-6. Pax-2A and Pax-2B dose-dependently activate transcription from the G3 and the G1 elements both in heterologous and in glucagon-producing cells. Our data indicate that Pax-2 is the third paired domain protein present in the endocrine pancreas and that one of its roles may be the regulation of glucagon gene expression.


Biocompatible nanostructured magnesium oxide-chitosan platform for genosensing application.
A novel organic-inorganic platform comprising of chitosan (CH) modified nanostructured magnesium oxide (nanoMgO) has been electrophoretically deposited on the indium-tin-oxide (ITO) substrate. The single stranded probe DNA (ssDNA) sequence of Vibrio cholerae has been covalently functionalized onto CH-nanoMgO/ITO surface. The cytotoxicity assay of nanoMgO particles, examined using human intestinal cell line (INT 407), reveals no significant cytotoxicity at the given doses in the range of 50-350 μg/mL. The X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR) and various microscopic techniques have been employed for the structural and morphological analysis of the fabricated electrodes. The electrochemical response studies of ssDNA and fragmented genomic DNA hybridized electrode (dsGDNA/CH-nanoMgO/ITO) have been carried out using cyclic voltammetry (CV) and differential pulse voltammetry (DPV) techniques. The dsGDNA/CH-nanoMgO/ITO bioelectrode exhibits a linear response in the range 100-500 ng/μL with improved sensitivity of 36.72 nA/ng/cm(2), faster response time of 3s and high stability of 3-4 months under refrigerated condition. The lower detection limit of fabricated genosensor has been estimated as 35.20 ng/μL and it shows good reproducibility/repeatability.


Compensatory mechanisms in congenital nystagmus.
Congenital nystagmus may occur in a manifest or latent form. Since most patients with latent nystagmus also have nystagmus with both eyes open (manifest latent nystagmus), differentiation between these two entities frequently requires electronystagmographic wave form analysis. Such analysis shows distinctive characteristics for manifest and latent or manifest latent congenital nystagmus, suggesting different origins. Several compensation mechanisms exist by which congenital nystagmus is decreased and visual acuity improved. For manifest nystagmus, these mechanisms include version or convergence innervation or a rest point between primary position and maximal lateroversion. In latent or manifest latent nystagmus, the nystagmus decreases when the fixating eye is adducted. Patients with manifest congenital nystagmus may use several of these compensation strategies. Because of the difficulties involved in distinguishing between manifest and manifest latent nystagmus without electronystagmography, confusion has arisen regarding the etiologic relationship between congenital nystagmus and infantile esotropia. Such relationship clearly exists in some patients with manifest nystagmus and convergence dampening. However, in most patients with infantile esotropia and congenital nystagmus, the nystagmus is latent or manifest latent and there is no evidence of a causal relationship between these two entities.


Design of a high affinity peptidomimetic opioid agonist from peptide pharmacophore models.
A pair of diastereomeric peptidomimetics based upon opioid receptor-binding pharmacophore models derived for a series of opioid tetrapeptides was synthesized. Both analogues display high opioid receptor affinity, moderate selectivity for the mu opioid receptor, and are potent, full agonists.


Oxidation of elemental mercury by modified spent TiO2-based SCR-DeNOx catalysts in simulated coal-fired flue gas.
In order to reduce the costs, the recycle of spent TiO2-based SCR-DeNOx catalysts were employed as a potential catalytic support material for elemental mercury (Hg(0)) oxidation in simulated coal-fired flue gas. The catalytic mechanism for simultaneous removal of Hg(0) and NO was also investigated. The catalysts were characterized by Brunauer-Emmett-Teller (BET), scanning electron microscope (SEM), X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS) method. Results indicated that spent TiO2-based SCR-DeNOx catalyst supported Ce-Mn mixed oxides catalyst (CeMn/SCR1) was highly active for Hg(0) oxidation at low temperatures. The Ce1.00Mn/SCR1 performed the best catalytic activities, and approximately 92.80% mercury oxidation efficiency was obtained at 150 °C. The inhibition effect of NH3 on Hg(0) oxidation was confirmed in that NH3 consumed the surface oxygen. Moreover, H2O inhibited Hg(0) oxidation while SO2 had a promotional effect with the aid of O2. The XPS results illustrated that the surface oxygen was responsible for Hg(0) oxidation and NO conversion. Besides, the Hg(0) oxidation and NO conversion were thought to be aided by synergistic effect between the manganese and cerium oxides.


Metabolic pathways enriched according to ERG status are associated with biochemical recurrence in Hispanic/Latino patients with prostate cancer.
The role of ERG-status molecular subtyping in prognosis of prostate cancer (PCa) is still under debate. In this study, we identified differentially expressed genes (DEGs) according to ERG-status to explore their enriched pathways and implications in prognosis in Hispanic/Latino PCa patients. RNA from 78 Hispanic PCa tissues from radical prostatectomies (RP) were used for RNA-sequencing. ERGhigh /ERGlow tumor groups were determined based on the 1.5-fold change median expression in non-tumor samples. DEGs with a False Discovery Rate (FDR) < 0.01 and a fold change >2 were identified between ERGhigh and ERGlow tumors and submitted to enrichment analysis in MetaCore. Survival and association analyses were performed to evaluate biochemical recurrence (BCR)-free survival. The identification of 150 DEGs between ERGhigh and ERGlow tumors revealed clustering of most of the non-BCR cases (60%) into de ERGhigh group and most of the BCR cases (60.8%) in ERGlow group. Kaplan-Meier survival curves showed a worst BCR-free survival for ERGlow patients, and a significant reduced risk of BCR was observed for ERGhigh cases (OR = 0.29 (95%CI, 0.10-0.8)). Enrichment pathway analysis identified metabolic-related pathways, such as the renin-angiotensin system and angiotensin maturation system, the linoleic acid metabolism, and polyamines metabolism in these ERG groups. ERGlow tumor cases were associated with poor BCR-free survival in our Hispanic/Latino patients, with metabolism-related pathways altered in the BCR progression. Our findings suggest the need to dissect the role of diet, metabolism, and lifestyle as risk factors for more aggressive PCa subtypes.


Distribution characteristics of ¹³⁷Cs, Pu isotopes and ²⁴¹Am in soil in Korea.
Cesium-137, Plutonium isotopes and (241)Am were studied in soil samples collected from Korea between 2006 and 2008 to provide information on the distribution and origin of Pu isotopes and (241)Am. The vertical profiles of radionuclides showed higher activity concentrations at the surface layer and then gradually decreased with depth. A good correlation between (137)Cs and (239,240)Pu was observed, whereas a poor relationship between (137)Cs and (241)Am was found. The (238)Pu/(239,240)Pu, (241)Am/(239,240)Pu and (239,240)Pu/(137)Cs activity ratios were concordant to those of the global fallout ratios. Furthermore, the atomic ratios of (240)Pu/(239)Pu in the samples provided the information of Pu depositional history and the origin of Pu isotopes in Korea.


Electrospray encapsulation of water-soluble protein with polylactide. I. Effects of formulations and process on morphology and particle size.
Bovine serum albumin (BSA) was encapsulated with poly (lactide) (PLA) using an electrospray technique in which a sufficiently strong electric field was applied to overcome the surface tension of a droplet and to produce small particles. The influences of PLA solvent type, PLA solution concentrations; the viscosity, electrical conductivity and surface tension of PLA solutions and PLA/BSA emulsions; and the applied voltage and flow rate on the morphology and size of the BSA-loaded PLA particles were examined. 1,2-dichloroethane (DCE) was a better solvent for PLA than dichloromethane. Spherical electrosprayed particles, with smooth surfaces, were observed with both solvents. The electrical conductivity increased and particle size decreased when acetone was mixed with DCE as PLA solvent. However, the particles were no longer spherical. The size of the particles increased and shape became spherical as PLA concentration was increased from 1-3%. Increasing the concentration to 4% resulted in the formation of a mixture of beads and fibres. Particle size decreased as applied voltage was increased from 10-15 kV and increased as flow rate was increased from 0.5-3 ml h(-1).


Carbohydrate (CHO) oxidation in patients with type B insulin resistance.
Total body carbohydrate (CHO) and fat oxidation rates, plasma glucose, free fatty acid, and insulin concentrations were determined in two patients with the type B syndrome of severe insulin resistance and in normal controls in response to insulin infusions (1-100 mU/kg/min) and to a test meal. In addition, insulin was infused at higher rates (10-1000 mU/kg/min) in one of the two patients while plasma glucose concentrations were clamped first at 195 and later at 244 mg/dl. During the postabsorptive state, resting metabolic rates (RMR) were 914 and 979 cal/min/1.73 m2 in the two patients (controls: 1018 +/- 85 cal/min/1.73 m2). Patients met 85% and 83% of their caloric requirements by oxidizing fat (controls: 63 +/- 7%). Protein oxidation accounted for 15% and 13% (controls: 14 +/- 3%) of energy requirements and CHO oxidation for 0% and 0%, respectively, in both patients (controls: 23 +/- 5%). Infusion of insulin at a rate of 10 mU/kg/min raised plasma insulin concentrations from 1400 and 440 microU/ml to 6000 and 2500 microU/ml, respectively, in patients 1 and 2 (controls: from 4 +/- 0.3 to 1288 +/- 50 microU/ml), but had no effects on rates of CHO, fat, or protein oxidation in either patient. By comparison, the rate of CHO oxidation in controls rose about sixfold from 40 +/- 8 to 234 +/- 12 mg/min/1.73 m2. Infusion of 1000 mU/kg/min in combination with an increase in plasma glucose from 195 +/- 1.1 to 244 +/- 1.9 mg/dl in patient 1, however, raised CHO oxidation from 0 to 36 mg/min/1.73 m2 and lowered fat oxidation from 105 to 69 mg/min/1.73 m2.(ABSTRACT TRUNCATED AT 250 WORDS)


Reperfusion injury following single-lung transplantation: the tissue glutathione response.
Parenchymal injury following reperfusion of the donor lung remains a significant problem in clinical lung transplantation. It has been postulated that free oxygen radicals act as local mediators of this event, and that tissue oxidized glutathione levels which reflect local free oxygen radical production, may be useful as an indicator of this regional ischemia-reperfusion injury. The glutathione redox cycle plays a physiologically important role in the endogenous antioxidant defense system. Intracellular glutathione depletion has been shown to render cells vulnerable to oxidant mediated injury. Adequate glutathione stores may be vital in protecting the cell from oxidant injury, especially the relatively exposed pulmonary epithelial cells. Single lung transplantation was carried out in 10 3- to 5-kg mongrel puppies, with a standard 2-hour ischemic time for the donor lung prior to reimplantation. Four hours following transplantation, lung tissue was harvested from both the transplanted and native lung of the recipient animal, and compared to normal lung tissue from the donor animal. Tissue was prepared for histological evaluation and glutathione assay. Tissue glutathione levels were determined via a spectrophotometric assay. For determination of oxidized glutathione (GSSG), samples were prepared with 2-vinylpyridine and N-ethylmaleimide (NEM) to derivatize all reduced glutathione and leave only GSSG for measurement by the fluorometric assay.(ABSTRACT TRUNCATED AT 250 WORDS)


The association of neuroblastoma and myoclonic encephalopathy: an imaging approach.
Myoclonic encephalopathy is a unique clinical syndrome of infants and children that is associated with a neurogenic tumor of ganglion-cell origin in approximately half of cases. A review of the literature as well as our personal experience with two recent infants suggests an imaging approach that includes chest radiography and abdominal computed tomography (CT). Ultrasonography, neck CT, and chest CT myelography may be required in selected patients. An expedient clinical and imaging evaluation of infants and children with opsomyoclonus is important to detect those patients with neurogenic tumors.


Viruslike particles containing knob-associated histidine-rich protein are secreted into the culture medium of Plasmodium falciparum in vitro cultures.
This report describes the isolation of a viruslike particle from in vitro cultures of the human malaria parasite P. falciparum. Electronmicroscopic observations suggest that the particles are liberated into the culture medium by budding from the erythrocyte membrane. The density of the free particles is 1.16, they contain nucleic acid and two distinct molecular species of the knob-associated Histidine-rich protein. Proteins of the particles are recognized by sera from malaria patients. The previously described knobs may correspond to viral coats inserted in the membrane.


Tumor Volume Staging Provides a Comparable Stratifying for Laryngeal Squamous Cell Cancer According to T Stages.
The prognostic significance of tumor volume (TV) in laryngeal squamous cell cancer (LSCC) has been demonstrated previously. Still, its clinical use is uncertain, and a method for accurate staging for TV is lacking. This study aimed to develop an objective staging and determine the effect of tumor volume on disease outcome after surgical treatment for LSCC. This study was designed retrospectively. Patients with LSCC who underwent laryngectomy were identified. Discretization for optimal scaling level of Tumor Volume (TV) was performed by Catreg Version 3.0. The rate of cancer recurrence, disease-free survival (DFS), and overall survival (OS) rate were calculated and compared between T stage and TV staging. Kaplan-Meier survival analysis was performed for comparison. 206 LSCC patients enrolled in the study. TV was found significantly higher in patients with cartilage invasion, contralateral nodal metastasis, and extranodal extension (p = 0.004, 0.010, and 0.021, respectively). TV and lymph node density LND showed a low significant positive correlation (p = 0.015, r = 0.169). TV was 7.25 + 7.53 ml on average, and TV above the mean value was found to be an independent risk factor for OS and DFS (p = 0.043, HR = 1.8; CI95% for HR: 1.02-3.44 and p < 0.001, HR = 3.7; CI95% for HR: 1.8-7.3, respectively). The optimal scaling level of TV was found in three-level; group 1: TV ≤ 7.07, group 2: 7.07 < TV ≤ 14.09, and group 3: TV ≥ 14.10. This categorization of TV has obtained significant discretization between patients for DFS and OS (Long-Rank = 0.038 and < 0.001). This classification may provide better performance in addition to helping the T stage in determining prognosis, especially in patients with advanced laryngeal SCC.


An Ovarian Carcinoid Tumor With Peptide YY-Positive Insular Component: A Case Report and Review of the Literature.
Ovarian carcinoid tumors are uncommon and account for 1% of all carcinoid tumors. The insular type of ovarian carcinoid tumor is common in western countries; in contrast, the strumal and trabecular types seem to be common in Asian countries. Strumal and trabecular types are associated with peptide YY (PYY) production, which may cause constipation. Here, we report the case of a 70-yr-old Japanese woman with chronic constipation who was referred to Kumamoto University Hospital because of a right adnexal mass. Imaging tests suggested that the solid mass might be malignant; therefore, abdominal total hysterectomy, bilateral salpingo-oophorectomy, and omentectomy were performed. A subsequent histopathologic examination confirmed an insular carcinoid tumor with a trabecular component in the right ovary. Both components were positive for PYY but not for serotonin. The patient complained of diarrhea instead of constipation soon after the surgery. Because PYY-positive insular carcinoid tumor in the ovary has not been previously reported, we reviewed 19 reported cases of patients with PYY-positive ovarian carcinoid tumors. The origins, common histologic types and symptoms caused by specific peptides secreted in ovarian carcinoid tumors differ between western and Asian countries.


Effect of Light at Night on oxidative stress markers in Golden spiny mice (Acomys russatus) liver.
Light at Night (LAN) suppresses melatonin (MLT) production, and effects metabolism, hormone secretion, gene expression and enzyme activity. Changes in antioxidant enzymes glutathione peroxidase (GPx) and superoxide dismutase (SOD), can be used as an indication for oxidative stress level. We assayed activity and expression of these enzymes in the liver of Acomys russatus exposed to LAN and treated with MLT. Short day (SD)-acclimated A. russatus, was exposed to 30min of LAN for two, seven or 21 nights. MLT impact was assessed simultaneously with two and seven nights of LAN exposure. GPx and SOD activities were measured. Gpx1 expression was evaluated by RT-PCR. There was a significant increase in GPx activity following LAN exposure for all acclimation durations, GPx activity was elevated after two nights of LAN and MLT treatment, Gpx1 expression was elevated by MLT after seven nights of LAN. SOD activity increased after two nights of LAN in MLT-treated A. russatus, GPx activity increased with the duration of LAN acclimation, indicating changes in liver redox status. Our results suggest that LAN is a stressor that influences oxidative stress. As in the other studies, MLT increases antioxidant activities, presumably attenuating stress response, in order to restore homeostasis.


A human hepatoma cell line (PCL/PRF/5) produces lung metastases and secretes HBsAg in nude mice.
PLC/PRF/5 is a human liver cancer cell line which synthesizes hepatitis B virus surface antigen (HgsAB). These cells produced tumor in 6 of 8 (75%) congenitally athymic nude mice at 13 of 28 subcutaneous injection sites and in 13 of 14 (93%) mice inoculated intraperitoneally. Tumors were successfully transplanted to 4 of 6 additional nude mice. Tumor growth was rapid. Growth of cephalad tumors was significantly greater than for caudal tumors (0.39 mm/day versus 0.28 mm/day). Microscopic examination of tumors showed moderately well-differentiated hepatocellular carcinoma. Foci of identical cells were present in pulmonary veins in 7 of 14 tumor-bearing animals. Tumor cell karyotype was identical with that of PLC/PRF/5 cells. In addition, HBsAg was detectable in high titer in animals with extensive tumor. Biological features of PLC/PRF/5-induced tumors in nude mice appeared to closely resemble human hepatocellular carcinoma. Moreover, HBsAg may provide a marker of tumor growth.


The medicolegal usefulness of the Kidd system in exclusion of parentage.
The blood samples of 2741 people from Germany were examined. The gene frequencies of Jka was found to be 0.49345 and of Jkb 0.50655. The theoretical probability of exclusion lies at 18,57%, the practical one only at 7.09%, because in many cases, the presumptive father is also the biological father. It is a system of dependable information. The Kidd system can be used as a classical system for exclusion of parentage.


Age-dependent regulation of the polymorphic forms of alpha 2u-globulin.
Hepatic synthesis of alpha 2u-globulin in the male rat shows a gradual decline and ultimate loss during aging and senescence. Northern blot analysis with a cloned cDNA probe showed that the decrease in alpha 2u-globulin synthesis during aging is associated with a corresponding decrease in the concentration of its hepatic mRNA. By means of two-dimensional gel electrophoresis, alpha 2u-globulin is resolved into a family of proteins. A monoclonal mouse antibody can identify at least five major isoelectric variants of alpha 2u-globulin within the total protein synthesized by rat hepatocytes. These isoelectric variants are also present in the in vitro translation products of hepatic mRNA. An examination of the hepatic synthesis of the isoelectric variants of alpha 2u-globulin during aging showed a differential regulation of the variant forms of this protein. Variant 2 (pI 6.1, the most prominent form) is the first to appear at puberty (40 days). The weakest member of the five major isoelectric forms (variant 4, pI 4.1) is the last to disappear at senescence. Although the overall decline in alpha 2u-globulin synthesis during aging seems to be due to an age-dependent decrease in the androgen responsiveness of hepatocytes, it is postulated that the differential regulation of the isoelectric variants may represent changes at the level of the genes coding for this protein.


Biomass production and fatty acid profile of a Scenedesmus rubescens-like microalga.
This investigation examined the effects of nitrogen-phosphate combined deficiency on the biomass yield, fatty acid methyl esters (FAME) production and composition from Scenedesmus rubescens-like microalga. A 15-day indoor culture was performed as a 3 × 3 factorial design (NaNO(3) levels: 3, 10 and 20mM; KH(2)PO(4) levels: 20, 50 and 150 μM). The algae grown under medium nitrogen concentration (10mM) and high phosphate concentration (150 μM) reached the highest biomass (1223.5 ± 152.5mg/L). Both nitrogen and phosphate had a significant influence on the FAME yield (P<0.05 and P<0.0001, respectively). The FAME yield from algae grown under low nitrogen (3mM) and phosphate concentration (20 μM) increased throughout the experiment and the highest FAME yield (42.2 ± 2.5% of AFDW) as well as C16 and C18 content (95.8 ± 1.6% of AFDW) was achieved under these conditions. Algae grown under medium nitrogen concentration (10mM) and low phosphate concentration (20 μM) had the highest FAME productivity (426.0mg/L ± 135.0mg/L). Thus, the lower nitrogen concentration (3mM-10mM) and low phosphate concentration (20 μM) would be an optimal combination tested to produce the most FAME from S. rubescens-like algae.


Antimicrobial and anti-inflammatory effects of clarithromycin on Mycobacterium avium complex replication in cultured human bronchial epithelial cells.
The Mycobacterium avium complex (MAC) invades cultured human bronchial cells, can replicate intracellularly, and facilitates the release of inflammatory cytokines and chemokines from cells. The purpose of this study was to examine the effects of clarithromycin (CAM) on MAC invasion, replication, and the release of cytokines and chemokines. A human bronchial epithelial cell line (BEAS-2B) monolayer grown on a tissue culture plate was infected with MAC. After 24 h, the cells were washed with Hanks' buffered salt solution, and extracellular bacteria were killed. The monolayer was further cultured for 5 days in medium containing CAM and subjected to a replication assay. The supernatants were assessed using a microchemotaxis assay and enzyme-linked immunosorbent assay (ELISA). mRNA expression was evaluated using a DNA array. The amount of intracellular MAC on day 5 of culture was significantly lower in the presence of CAM at the levels of 1× and 4× MIC. CAM inhibited the release of chemotactic activity and the production of interleukin (IL)-8 and macrophage chemotactic protein (MCP)-1. DNA array analysis of mRNA expression in BEAS-2B cells showed that CAM inhibited the expression of inflammatory cytokines and chemokines, involving IL-6, MCP-1, and IL-8 mRNA. MAC invaded and replicated in BEAS-2B cells and induced the production of chemotactic factors. In contrast, CAM may have bactericidal and bacteriostatic effects leading to the inhibition of inflammatory events.


Sorsby's fundus dystrophy.
Ever since Sorsby described his pseudoinflammatory dystrophy in five families, its characteristics have been unclear. The findings in ten affected members of a seven-generation pedigree are discussed and the literature is reviewed. Patients with this dominantly inherited fundus dystrophy lose central vision between the second and fourth decade of life. Three variations in the fundus appearances were distinguished: in the first and most common, white to yellow fundus spots (which are not drusen) accompany a disciform macular degeneration; in the second, the fundus spots are absent; in the third, the yellow deposits are associated with atrophic macular degeneration. Atrophy of the retina, pigment epithelium, and choroid then slowly progresses toward the periphery. Treatment does not halt the progress of the disease. Although variations in this dystrophy may be examples of genetic heterogeneity, Sorbsy's fundus dystrophy is a distinct clinical disorder.


Hippocampal pattern separation of emotional information determining risk or resilience in individuals exposed to childhood trauma: Linking exposure to neurodevelopmental alterations and threat anticipation.
Childhood adversity increases the risk of developing psychiatric symptoms later in life. However, the neurobiological mechanisms underlying this association are unknown. This paper reviews the current literature regarding structural and functional alterations in the hippocampus and amygdala following childhood adversity, ultimately converging into a model that proposes impaired 'pattern separation' as an important underlying mechanism associated with risk or resilience for psychopathology through increased fear generalization. In the present model, decreased DG/CA3 activity and amygdala hyper-reactivity are considered to be a consequence of childhood adversity, which in turn may result in impaired pattern separation of emotional information. Impaired pattern separation is hypothesized to result in increased fear generalization, threat anticipation, and social threat interpretation, thus increasing risk for later affective, anxiety and psychotic symptoms. The proposed model provides testable hypotheses for future studies and stresses the need to stratify according to childhood adversity as an etiological factor.


Entry receptor LDLRAD3 is required for Venezuelan equine encephalitis virus peripheral infection and neurotropism leading to pathogenesis in mice.
Venezuelan equine encephalitis virus (VEEV) is an encephalitic alphavirus responsible for epidemics of neurological disease across the Americas. Low-density lipoprotein receptor class A domain-containing 3 (LDLRAD3) is a recently reported entry receptor for VEEV. Here, using wild-type and Ldlrad3-deficient mice, we define a critical role for LDLRAD3 in controlling steps in VEEV infection, pathogenesis, and neurotropism. Our analysis shows that LDLRAD3 is required for efficient VEEV infection and pathogenesis prior to and after central nervous system invasion. Ldlrad3-deficient mice survive intranasal and intracranial VEEV inoculation and show reduced infection of neurons in different brain regions. As LDLRAD3 is a determinant of pathogenesis and an entry receptor required for VEEV infection of neurons of the brain, receptor-targeted therapies may hold promise as countermeasures.


Decreased cardiac beta-adrenoceptors in hypertensive rats.
1. beta-Adrenoceptors have been investigated in cardiac and renal cell membranes from hypertensive and normal rats. 2. The 125I-labelled beta-adrenoceptor antagonist 1-(4-iodophenoxy)-3-isopropylaminopropan-2-ol was used to measure directly the number and affinity of receptors. 3. Cardiac membranes from hypertensive rats had a lower concentration of beta-adrenoceptors than membranes from control normotensive animals, but the affinities of the receptors remained unchanged. Receptor concentration decreased by half and was similar in each of the three models of experimental hypertension investigated. 4. In contrast, kidney membranes from hypertensive animals had the same beta-adrenoceptor concentration and affinity as membranes from normotensive rats. 5. The decrease in cardiac beta-adrenoceptor concentration may reflect an increase in cardiac sympathetic drive in these experimental hypertensive models.


Effects of an early-season folivorous moth on the success of a later-season species, mediated by a change in the quality of the shared host, Lupinus arboreus Sims.
Larvae of Platyprepia virginalis (Lep.: Arctiidae) and Orgyia vetusta (Lep.: Lymantriidae) feed on the foliage of bush lupine (Lupinus arboreus Sims) at Bodega Bay, California, USA, in February-April and May-July, respectively. Female O. vetusta attained lower pupal weights and produced fewer eggs on branches of L. arboreus which had experimentally received P. virginalis damage earlier in the same year, compared to those reared on control branches.Growth rates of first-instar O. vetusta were lower on undamaged leaves of previously damaged L. arboreus than on leaves of undamaged controls. This was true for lupine bushes damaged by P. virginalis in the field; and also for greenhouse-grown lupine plants damaged by Estigmene acrea (Lep.: Arctiidae) when excised foliage was used in the assay. However, fifth (last) instar female O. vetusta larvae showed no preference for damaged versus undamaged greenhouse-grown L. arboreus in their feeding or choice of a site for pupation.These experiments demonstrate the potential for competition-like interactions between herbivores mediated by changes in quality of the shared host.


Analysis of the calibration results obtained with Liulin-4J spectrometer-dosimeter on protons and heavy ions.
We are developing a portable dosimeter (Liulin-4J) based on a silicon semiconductor detector for use in measuring the absorbed dose from primary or secondary cosmic rays to astronauts and airplane crews. The dosimeter can measure not only the flux and dose rate, but also the deposited energy spectrum for silicon in per unit time. In order to calibrate the dosimeter, we have carried out exposures at the NIRS cyclotron and HIMAC heavy ion synchrotron facilities. We obtained a detector response function for using in measuring energy deposition and LET.


Synovial sarcoma of the neck associated with previous head and neck radiation therapy.
Synovial sarcoma is a rare neoplasm that uncommonly arises in the neck. Fourteen years after facial and neck radiation therapy for acne, synovial sarcoma of the neck developed in a young man. Possible radiation-induced benign and malignant neoplasms that arise in the head and neck region, either of thyroid or extrathyroid origin, remain a continuing medical problem.


Two new flavonol glycosides from Gymnema sylvestre and Euphorbia ebracteolata.
Two new flavonol glycosides, namely kaempferol 3-O-beta-D-glucopyranosyl-(1-->4)-alpha-L-rhamnopyranosyl-(1-->6)-beta-D-galactopyranoside (1) and quercetin 3-O-6"-(3-hydroxyl-3-methylglutaryl)-beta-D-glucopyranoside (2), have been isolated from the aerial parts of Gymnema sylvestre and Euphorbia ebracteolata, respectively. Their structures were determined on the basis of chemical and spectroscopic methods.


Neurotoxic damage to the nigrostriatal system in rats following intranigral administration of MPDP+ and MPP+.
Unilateral intranigral administration of the oxidative metabolites of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 1-methyl-4-phenyl-dihydropyridine (MPDP+) or 1-methyl-4-phenylpyridine (MPP+) produced dose-dependently a depletion of dopamine in the ipsilateral striatum of rats two weeks following treatment. d-Amphetamine and apomorphine induced circling toward the lesioned side in these unilaterally treated animals. No contralateral circling behavior was observed after challenging with apomorphine. This dopamine lesioning effect of MPP+ was not blocked by pretreatment of animals with a dopamine uptake blocker, GBR 12909. Furthermore, MPP+ increased the 45Ca accumulation into cells at the site of injection and produced "nonspecific" cell membrane and/or cytotoxic damage seen by histological procedures. These results indicate that MPDP+ and MPP+ produced localized cytotoxic damage to nigrostriatal neurons, caused a decrease in striatal dopamine, and disrupted the nigrostriatal system's functioning following intranigral administration to rats. It is postulated that the cationic surfactant properties of MPDP+ and MPP+ might contribute to its neurotoxic effects.


Comparison of thermal ablative methods and myomectomy for the treatment of fibroids: a systematic review and meta-analysis.
To examine the effectiveness and safety of thermal ablative methods and myomectomy for the treatment of uterine fibroids. We searched EMBASE, PubMed, the Cochrane Central Register of Controlled Trials, Scopus, CINAHL, ClinicalTrials.gov and Web of Science databases through April 2021. Clinical trials comparing the thermal ablative methods and myomectomy for the treatment of uterine fibroids were included. Thirteen studies including 4205 patients were eligible. The thermal ablative treatment group was associated with less major adverse events (only ultrasound guided high-intensity focused ultrasound) (RR, 0.111 [95% CI, 0.070-0.175], p=.0), shorter duration of hospital stays in observational studies (-0.1497 day, [95% CI, -1.593 to -0.321], p=.0) and in randomized controlled trials (RCTs) (-0.844 day, [95% CI, -0.1.142 to -0.546], p=.0), higher uterine fibroid symptom (UFS) score after operation (0.252 [95% CI, 0.165-0.339]; p=.0), transformed symptom severity (tSS) score after operation (0.515 [95% CI, 0.355-0.674]; p=.0) and quality of life (QoL) score after operation (0.188 [95% CI, 0.093-0.283]; p=.0) in comparison with myomectomy group. No statistically significant difference was found between the thermal ablative treatment group and myomectomy group with respect to reintervention rate and pregnancy rate. The current data available demonstrate that thermal ablative methods were not inferior to myomectomy in the treatment of uterine fibroids. The findings in this study need to be further confirmed by large RCTs.


SimpleSTORM: a fast, self-calibrating reconstruction algorithm for localization microscopy.
Although there are many reconstruction algorithms for localization microscopy, their use is hampered by the difficulty to adjust a possibly large number of parameters correctly. We propose SimpleSTORM, an algorithm that determines appropriate parameter settings directly from the data in an initial self-calibration phase. The algorithm is based on a carefully designed yet simple model of the image acquisition process which allows us to standardize each image such that the background has zero mean and unit variance. This standardization makes it possible to detect spots by a true statistical test (instead of hand-tuned thresholds) and to de-noise the images with an efficient matched filter. By reducing the strength of the matched filter, SimpleSTORM also performs reasonably on data with high-spot density, trading off localization accuracy for improved detection performance. Extensive validation experiments on the ISBI Localization Challenge Dataset, as well as real image reconstructions, demonstrate the good performance of our algorithm.


Oxytocin reduces adipose tissue inflammation in obese mice.
Obesity and adipose tissue expansion is characterized by a chronic state of systemic inflammation that contributes to disease. The neuropeptide, oxytocin, working through its receptor has been shown to attenuate inflammation in sepsis, wound healing, and cardiovascular disease. The current study examined the effects of chronic oxytocin infusions on adipose tissue inflammation in a murine model of obesity, the leptin receptor-deficient (db/db) mouse. The effect of obesity on oxytocin receptor protein and mRNA expression in adipose tissue was evaluated by Western blotting and real-time polymerase chain reaction. Mice were implanted with osmotic minipumps filled with oxytocin or vehicle for 8 weeks. At study endpoint adipose tissue inflammation was assessed by measurement of cytokine and adipokine mRNA tissue levels, adipocyte size and macrophage infiltration via histopathology, and plasma levels of adiponectin and serum amyloid A as markers of systemic inflammation. The expression of adipose tissue oxytocin receptor was increased in obese db/db mice compared to lean controls. In adipose tissue oxytocin infusion reduced adipocyte size, macrophage infiltration, IL-6 and TNFα mRNA expression, and increased the expression of the anti-inflammatory adipokine, adiponectin. In plasma, oxytocin infusion reduced the level of serum amyloid A, a marker of systemic inflammation, and increased circulating adiponectin. In an animal model of obesity and diabetes chronic oxytocin treatment led to a reduction in visceral adipose tissue inflammation and plasma markers of systemic inflammation, which may play a role in disease progression.


A method for the removal of tungsten carbide rings.
The removal of metal rings from fingers is a well-described process that often employs a toothed cutting wheel or bolt cutters to sever the ring and allow it to be pried open. However, tungsten carbide (TC) rings are impervious to these traditional ring-cutting devices. We sought to describe a method for removal of TC rings from cadaveric fingers and characterize potential complications of the technique. On cadaveric fingers, we placed TC rings and created a snug fit by injecting a fluorescein and saline solution. The rings were removed by a controlled crushing technique using a pair of locking pliers. Fingers were inspected under magnification and using an LED (light-emitting diode) black light, and X-ray studies of each finger were obtained. Injuries were characterized. Six rings were applied and successfully removed from six cadaveric fingers through controlled ring shatter. After ring removal, two fingers demonstrated superficial (<1 mm deep) lacerations, one of which had residual debris within the wound. No phalangeal fractures were identified. Removal of a TC ring can be performed through controlled crushing using locking pliers. Superficial lacerations and retained debris are potential complications.