Status of c-erbB-2 in gastric adenocarcinoma: a comparative study of immunohistochemistry, fluorescence in situ hybridization and enzyme-linked immuno-sorbent assay.
c-erb-2 amplification and overexpression are currently attracting a great deal of attention because a new adjuvant therapy using an antibody against the c-erbB-2 gene product, trastuzumab (Herceptin; Genentech, Inc., South San Francisco, CA), has proved effective in treating breast cancer with amplification and/or overexpression of c-erbB-2. Aberrations of c-erbB-2 have also been detected in ovarian, endometrial and gastric carcinomas at varied frequencies. Amplification of the c-erbB-2 locus (17q12-q21.32), overexpression of c-erbB-2 protein (p185) and serum levels of soluble c-erbB-2 protein fragments (p105) were examined in gastric cancer patients using fluorescence in situ hybridization (FISH), immunohistochemistry and enzyme-linked immunosorbent assay (ELISA), respectively. Overexpression of c-erbB-2 protein was found in 29 (8.2%) of the 352 gastric carcinomas analyzed. In FISH analysis, all tumors with 3+ immunostaining and 1 of 5 tumors with 2+ staining showed high-level amplification of c-erbB-2. Pre-operative serum p105 was quantified in serum specimens from 129 patients with gastric cancer and 28 patients with benign diseases. There were no significant differences in the serum p105 levels among 11 patients with c-erbB-2-overexpressing carcinomas, 118 patients with c-erbB-2 non-overexpressing carcinomas and 28 controls, although a single case of gastric carcinoma overexpressing c-erbB-2 with extensive liver metastasis had a higher level than the cut-off value. The mechanisms of overexpression of p185 and high-level amplification of c-erbB-2 in gastric adenocarcinomas seem similar to those well-established in breast cancers. Patients having gastric adenocarcinoma with c-erbB-2 amplification are potential candidates for a new adjuvant therapy using humanized monoclonal antibody.


Clinical indicators associated with unintentional weight loss and pressure ulcers in elderly residents of nursing facilities.
To monitor adults older than 65 years living in nursing facilities and who experience unintentional weight loss of more than 10% of actual body weight in 6 months or more than 5% in 1 month or who have stage II, III, or IV pressure ulcers. We reviewed 290 medical records for unintentional weight loss and 265 for pressure ulcers. Two data-collecting instruments were used: one for pressure ulcers and one for unintentional weight loss. Indicators for each instrument were selected to monitor clinical conditions that tend to be problem-prone areas for these two populations. Descriptive statistics were used to calculate the frequency of each indicator for each population. Of the 24 indicators for unintentional weight loss, the 6 indicators present most often, in descending order, were reduced functional ability, intake of 50% or less of food served for the past 3 consecutive days, chewing problems, serum albumin level less than 35 g/l with normal hydration status, cholesterol level less than 4.1 mmol/L, and refusal of 50% or more of food replacement for the past 7 days. For the residents with pressure ulcers, the indicator present most often was serum albumin level less than 35 g/L with normal hydration status. The three highest intervention indicators were receives 1.2 g protein per kilogram of actual body weight, receives 120 mg or more of vitamin C daily, and receives 1 1/2 times the energy required based on goal body weight. When serum albumin level was documented in the medical record, it was a valid indicator for both diagnoses. Inappropriate dietary intake, disease, and disability place residents in nursing facilities at risk for malnutrition. Thus, it is important to obtain laboratory values when assessing elderly residents and determining their nutritional status.


Determination of Gliotoxin in samples associated with cases of intoxication in camels.
Suspected cases of mycotoxicoses, characterized by clinical symptoms such as diarrhoea, haemorrhaging and death have been observed in breeding camels in U.A.E.Hay samples, body fluids and intestinal contents were investigated for the presence of mycotoxins using a cell culture bioassay (MTT-test) and/or physicochemical methods such as high performance liquid chromatography (HPLC) and mass spectrometry (MS).Extracts of the hay samples proved to be highly cytotoxic towards the swine kidney monolayers used as target cells in the bioassay. Subsequent analyses of the extracts showed the presence of the epidithiodioxopiperazine mycotoxin gliotoxin up to 0.49 mg/kg in the hay, which is the first proven case on the natural occurrence of this mycotoxin in feed. Trace amounts of ochratoxin A were also detected, while other mycotoxins known to occur naturally (i.e. aflatoxins or trichothecenes) could not be found. Gliotoxin positive HPLC-peaks were also found in some specimens (contents of rumen and intestine, allantois fluid) from camels.Gliotoxin is characterized by a variety of biological activities including antibiotic, antifungal, antiviral, cytotoxic and immunotoxic effects. Based on the results obtained, the involvement of gliotoxin as one causative agent of the intoxications is supposed.


Biofunctionalisation of electrically conducting polymers.
During a single decade of research, evidence has emerged that glial scar formation around the electro-tissue interface drives neural loss and increases the signal impedance of the electrodes, compromising the efficiency of the stimulating systems. Studies with conducting polymers (CPs) as electrode coatings have shown enhanced tissue integration and electrode performance in situ through biochemical and physicomechanical functionalisation. In this review, recent findings on CP modifications are provided in the context of neurospecific biomaterials, shedding light on the valuable impact of multifunctionalised strategies for biomedical applications.


Whole genome sequence analysis and in-vitro probiotic characterization of Bacillus velezensis FCW2 MCC4686 from spontaneously fermented coconut water.
In this study, the probiotic potential of B. velezensis FCW2, isolated from naturally fermented coconut water, was investigated by in vitro and genomic characterization. Our findings highlight key features of the bacterium which includes, antibacterial activity, high adhesive potential, aggregation capacity, production of nutrient secondary metabolites. In vivo safety assessment revealed no adverse effects on zebrafish. WGS data of B. velezensis FCW2 revealed a complete circular genome of 4,147,426 nucleotides and a GC content of 45.87%. We have identified 4059 coding sequence (CDS) genes that encode proteins involved in stress resistance, adhesion and micronutrient production. The genes responsible for producing secondary metabolites, exopolysaccharides, and other beneficial nutrients were identified. The KEGG and COG databases revealed that genes mainly involved amino acid metabolism, carbohydrate utilization, vitamin and cofactor metabolism, and biological adhesion. These findings suggest that B. velezensis FCW2 could be a putative probiotic in the development of fermented foods.


Spontaneous streptococcus pneumonia peritonitis in a patient with metastatic gastric cancer: a case report and etiologic consideration.
Spontaneous peritonitis in adults has not been previously reported to occur in association with ascites of neoplastic origin. We report a patient with metastatic gastric adenocarcinoma in whom spontaneous streptococcus pneumonia peritonitis occurred as a terminal event. Massive metastases may have resulted in significant loss of the hepatic reticuloendothelial system and impaired the capability of the liver to function as an effective bacterial filter, predisposing the patient to bacterial peritonitis.


ABA-induced 'lipid melting' and its reversal by umbelliferone in the plasmalemma of guard cell protoplasts: a breakthrough in plant hormone-receptor binding and hormone action.
The dynamics of stomatal opening and closure had to date been ascribed largely to the K(+)-fluxes and cell wall elasticity. Using protoplasts of guard cells of Vicia faba as model system, we document convincing first hand evidence a that lipid phase alterations could regulate ABA-induced closure of stomates and its reversal by umbelliferone. Backed up by the presence of plasmalemma-located ABA-receptor in guard cells, a novel theory could be put forth explaining guard cell opening and closure mediated by hormone induced reconfiguration via a probable lipid-protein lattice modification. The phase reversal of the plasmalemma by umbelliferone is postulated to be through modified hormone receptor complex structure, which is yet to be substantiated.


Bacterially expressed F1-20/AP-3 assembles clathrin into cages with a narrow size distribution: implications for the regulation of quantal size during neurotransmission.
F1-20/AP-3 is a synapse-specific phosphoprotein. In this study we characterize the ability of bacterially expressed F1-20/AP-3 to bind and assemble clathrin cages. We find that both of two bacterially expressed alternatively spliced isoforms of F1-20/AP-3 can bind and assemble clathrin as efficiently as preparations of F1-20/AP-3 from bovine brain. This establishes that the clathrin assembly activity found in F1-20/AP-3 preparations from brain extracts is indeed encoded by the cloned gene for F1-20/AP-3. It also demonstrates that post-translation modification is not required for activation of the clathrin binding or assembly function of F1-20/AP-3. Ultrastructural analyses of the clathrin cages assembled by bacterially expressed F1-20/AP-3 reveals a strikingly narrow size distribution. This may be important for the regulation of quantal size during neurotransmission. We also express the 33 kD NH2-terminus of F1-20/AP-3 in E. coli, and measure its ability to bind to clathrin triskelia, to bind to clathrin cages, and to assemble clathrin triskelia into clathrin cages. It has been suggested that the 33 kD NH2-terminus of F1-20/AP-3 constitutes a clathrin binding domain. We find that the bacterially expressed 33 kD NH2-terminus of F1-20/AP-3 binds to clathrin triskelia, fails to bind to preassembled clathrin cages, and is not sufficient for clathrin assembly. The finding that the 33 kD NH2-terminus of F1-20/AP-3 binds to clathrin triskelia but fails to assemble clathrin triskelia into clathrin cages is consistent with the published proteolysis studies. The finding that the 33 kD NH2-terminus of F1-20/AP-3 fails to bind to clathrin cages is novel and potentially important. It is clear from these experiments that the 33 kD NH2-terminus of F1-20/AP-3 is sufficient to carry out some aspects of clathrin binding; however it appears that defining the regions of the protein involved in clathrin binding and assembly may be more complex than originally anticipated.


Structural modifications of diarylpyrimidines (DAPYs) as HIV-1 NNRTIs: Synthesis, anti-HIV activities and SAR.
30 new analogues of diarylpyrimidines were synthesized for further structural modifications, involving not only the linker but also the wing α of DAPYs. The anti-HIV-1 activities of all target molecules were evaluated, and most of them exhibited potent anti-HIV-1 (WT) activities and low cytotoxicities. Among which, compound 4g showed excellent activities against WT HIV-1 with an EC50 value of 5.8nM and SI of up to 26,034. Another compound 4ab bearing a novel pyridinyl Wing α also displayed attractive activities. The structure-activity relationship (SAR) study was also summarized.


Column-switching high-performance liquid chromatographic determination of a 2-pyridinone-based human immunodeficiency virus type 1 (HIV-1)-specific reverse transcriptase inhibitor in human plasma.
A method for the determination of a 2-pyridinone-based specific HIV-1 reverse transcriptase inhibitor in human plasma is described. Plasma samples are extracted using phenyl solid phase extraction columns. The extract is analyzed via HPLC using a column-switching system to remove interferences from late-eluting endogenous components. Detection is based on UV absorbance at 314 nm. The assay was linear in the concentration range of 10-500 ng/ml, when 1-ml aliquots of plasma were extracted. The mean precision of the assay, expressed as the coefficient of variation, was 3.8%. The assay has been validated and utilized to support human pharmacokinetic studies.


Corrigendum: Functioning of Long Noncoding RNAs Expressed in Macrophage in the Development of Atherosclerosis.
[This corrects the article DOI: 10.3389/fphar.2020.567582.].


A newly discovered role of metabolic enzyme PCK1 as a protein kinase to promote cancer lipogenesis.
Highly active lipogenesis is essential for rapid tumor growth. Sterol regulatory element-binding protein (SREBP) is a key transcriptional factor for lipogenesis and activated by reduced sterol and oxysterol levels. However, the mechanism by which cancer cells activate SREBP without altering these sterol/oxysterol levels remains elusive. In one of our recent studies published in Nature entitled "The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for lipogenesis", we demonstrated that activated AKT-mediated phosphoenolpyruvate carboxykinase 1 (PCK1) S90 phosphorylation reduces the gluconeogenic activity of PCK1 and triggers its translocation to the endoplasmic reticulum (ER), where PCK1 acts as a protein kinase and uses GTP, rather than ATP, as a phosphate donor to phosphorylate Insig1/2 thereby reducing oxysterol's binding to Insig1/2 and activating SREBP-mediated lipogenesis for tumor growth. These findings elucidate a coordinated regulation between gluconeogenesis and lipogenesis and uncover a critical role of the protein kinase activity of PCK1 in SREBP-dependent lipid synthesis.


What factors could influence physicians' management of women of childbearing age with chronic inflammatory disease? A systematic review of behavioural determinants of clinical inertia.
Pregnancy represents a complex challenge to clinicians treating women with chronic inflammatory disease. Many clinicians face a situation of heightened sensitivity to the potential risks and uncertainties associated with the effect of pharmacological treatment on pregnancy outcomes. This may create an environment vulnerable to clinical inertia, whereby behavioural factors such as cognitive heuristics and biases, and other factors such as attitudes to risk and emotion can contribute. This systematic review was undertaken to assess if clinical inertia has been investigated/identified in this setting and took a behavioural science approach to identify and understand the potential determinants of clinical inertia in this treatment setting. A systematic literature search was conducted to identify publications which investigated or described clinical inertia or its determinants (e.g. heuristics, biases etc.). Results were coded for thematic analysis using two inter-related behavioural models: the COM-B model and the Theoretical Domains Framework. Whilst studies investigating or describing clinical inertia in this treatment setting were not identified, the behavioural analysis revealed a number of barriers to the pharmacological management of women of fertile age affected by chronic inflammatory disease. Factors which may be influencing clinician's behaviour were identified in all domains of the COM-B model. The primary factors identified were a lack of knowledge of treatment guidelines and fears concerning the safety of medications for mother and fetus. Lack of experience of treating pregnant patients was also identified as a contributing factor to undertreatment. Using a behavioural approach, it was possible to identify potential factors which may be negatively influencing clinician's behaviour in this treatment setting, although specific research was limited.


Photosynthetic characteristics of Tamarix chinensis under different groundwater depths in freshwater habitats.
Groundwater is the major source of water for Tamarix chinensis growth in the Yellow River Delta (YRD) region, and the groundwater depth (GWD) dramatically influences the physiological activities of T. chinensis. The quantitative response of the photosynthetic physiological process of T. chinensis to the GWD in freshwater habitats remains unclear. In this study, the response characteristics of gas exchange parameters in the leaves of three-year-old T. chinensis seedlings were measured and analyzed at a graded series of seven GWDs (0 m, 0.3 m, 0.6 m, 0.9 m, 1.2 m, 1.5 m and 1.8 m). The GWD thresholds corresponding to drastic changes in the photosynthetic efficiency and the GWDs of several levels of photosynthetic productivity and efficiency were also determined. In the freshwater habitats of the YRD, variations in GWD significantly altered the relative soil water content (RSWC) and thus influenced the photosynthetic efficiency of T. chinensis. RSWC at 0 ≤ GWD ≤ 0.9 m and GWD at 1.2 m ≤ GWD ≤ 1.8 m directly influenced the photosynthetic physiology of T. chinensis. When the GWD was 1.2 m, net photosynthetic rate (Pn), apparent quantum efficiency and water use efficiency (WUE) values all peaked. Thus, T. chinensis exhibited a high light and water use efficiency, wide ecological amplitude in terms of light, and high photosynthetic capacity. The optimum GWD for photosynthetic carbon assimilation and WUE in T. chinensis was determined to be 1.2 m. At a deep (≥1.64 m) or shallow (≤0.53 m) GWD, both Pn and WUE in T. chinensis clearly decreased below the corresponding mean values. The main causes for the reduction in Pn in these two GWD ranges (≤0.53 m, ≥1.64 m) were stomatal and nonstomatal limitations, respectively. Additionally, a moderate GWD of 1.09-1.25 m corresponded to the "high-productivity and high-efficiency GWD" range, in which T. chinensis displayed a high photosynthetic yield and WUE. Overall, the photosynthetic capacity of T. chinensis shows characteristics of high tolerance to moderate GWDs from 1.09 m to 1.25 m but intolerance at both shallow (≤0.53 m) and deep (≥1.64 m) GWDs in freshwater habitats.


The role of the seven crude drug components in the sleep-promoting effect of Yokukansan.
Yokukansan is a traditional Japanese "Kampo" medicine derived from Yi-Gan San in traditional Chinese medicine. Many studies have been published on its effects and mechanisms. In this study, we focused on the sleep-promoting effects of Yokukansan. Yokukansan composes of seven crude drugs: Uncaria Hook, Bupleurm Root, Cnidium Rhizome, Japanese Angelica Root, Poria Sclerotium, Atractylodes Lancea Rhizome, and Glycyrrhiza. Although each has distinctive effects in isolation, they combine to work as a sleep aid in the Yokukansan formula. We examined the roles of the seven crude drug components in the sleep-promoting effect of Yokukansan. In this study, we used an easy in vivo assay method which we developed previously to screen sleeping substances using thermography. This assay method focuses on the decrease in skin temperature of mice during sleep inducement. By administering the crude drug components of Yokukansan one at a time, it was possible to separate them into two groups: those that caused a decrease in body temperature (Uncaria Hook, Bupleurm Root, Cnidium rhizome, and Japanese Angelica root) and those that did not (Poria Sclerotium, Atractylodes Lancea Rhizome, and Glycyrrhiza). Accordingly, it was thought that the crude drugs causing a drop in body temperature were responsible for promoting sleep, while those in the other group would have no such effect in isolation. To investigate whether the crude drugs that did not cause a decrease in body temperature might be unnecessary for the sleep-promoting effect of Yokukansan, a number of decoctions were prepared using only six of the seven crude drug components, excluding a different crude drug in each case. Results showed that when any of the three components (Poria Sclerotium, Atractylodes Lancea Rhizome, or Glycyrrhiza) of Yokukansan that had no effect on body temperature in isolation were removed from Yokukansan, the resulting extract no longer had any of Yokukansan's sleep-promoting effects. This result suggested that these three crude drug components were involved indirectly in the activity of Yokukansan, by supporting other crude drugs. The interactions of the three supporting crude drugs were then examined further. As a result, a combination of Poria Sclerotium, Atractylodes Lancea Rhizome, and Glycyrrhiza was found to cause a decrease in body temperature, even though none of the three crude drugs had this effect in isolation. When an extract prepared by infusing the three crude drugs together was tested alongside extracts made by infusing the three crude drugs separately, the latter showed no effect and there were differences between the two in constituent analysis by HPLC. These results indicate that some reactions may occur during extraction. Results of this study show that all crude drug components of Yokukansan contribute to its sleep-promoting effects. This is the first report to show the role of the seven clude drug components in the sleep-inducing effects of Yokukansan.


Graphitic‑carbon nitride based mixed-phase bismuth nanostructures: Tuned optical and structural properties with boosted photocatalytic performance for wastewater decontamination under visible-light irradiation.
To enhance the activities of advanced semiconductor photocatalysts, the charge carriers must be separated effectively. One strategy for achieving this is the use of heterogeneous structures, which can be prepared by hydrothermal synthesis and post-synthetic thermal and ultrasonic treatment. Herein, we report a mixed-phase composite of basic bismuth nitrate/pentabismuth heptaoxide nitrate (PC) prepared by hydrothermal synthesis under basic conditions and post-synthetic thermal treatment. In addition, sulfur-doped-graphitic carbon nitride (S-g-C3N4) was prepared and combined with PC in different ratios, denoted as PC-1, PC-2, and PC-3, using sonication-assisted treatment. The characterization of these catalysts confirmed the formation of mixed basic bismuth nitrate/pentabismuth heptaoxide nitrate phases and the composite nanostructure. The developed nanostructure showed interesting morphological features, for example, layered sheets of S-g-C3N4. The prepared PCs were tested for their visible light responsiveness for the photocatalytic degradation of a representative organic dye (Rhodamine B). We found that the modified photocatalysts showed superior activity to that of pristine PC. The optimal photocatalyst (PC-3) was also used to degrade methylene blue and Congo red, achieving 99% degradation. Thus, we present not only an efficient photocatalyst but also insights into the post-synthetic modification of basic bismuth nitrate/pentabismuth heptaoxide nitrate with stable carbon-based nanostructures.


The effect of ACTH on the arterial blood pressure, heart rate and blood histamine level in rabbits.
A rapid blood pressure fall, persisting for over one hour, was observed after ACTH injection. The heart rate was initially increased and returned to its basal level within one hour. On the other hand, the level of histamine was significantly increased only in the 60th minute of the experiment. The results obtained showed that a possibility of an indirect ACTH action through an effect of histamine metabolism cannot be excluded.


Fine-mapping of a major QTL (Fwr1) for fusarium wilt resistance in radish.
A major radish QTL (Fwr1) for fusarium wilt resistance was fine-mapped. Sequence and expression analyses suggest that a gene encoding a serine/arginine-rich protein kinase is a candidate gene for Fwr1. Fusarium wilt resistance locus 1 (Fwr1) is a major quantitative trait locus (QTL) mediating the resistance of radish inbred line 'B2' to Fusarium oxysporum, which is responsible for fusarium wilt. We previously detected Fwr1 on radish linkage group 3 (i.e., chromosome 5). In this study, a high-resolution genetic map of the Fwr1 locus was constructed by analyzing 354 recombinant F2 plants derived from a cross between 'B2' and '835', the latter of which is susceptible to fusarium wilt. The Fwr1 QTL was fine-mapped to a 139.8-kb region between markers FM82 and FM87 in the middle part of chromosome 5. Fifteen candidate genes were predicted in this region based on a sequence comparison with the 'WK10039' radish reference genome. Additionally, we examined the time-course expression patterns of these predicted genes following an infection by the fusarium wilt pathogen. The ORF4 expression level was significantly higher in the resistant 'B2' plants than in the susceptible '835' plants. The ORF4 sequence was predicted to encode a serine/arginine-rich protein kinase and includes SNPs that result in nonsynonymous mutations, which may have important functional consequences. This study reveals a novel gene responsible for fusarium wilt resistance in radish. Further analyses of this gene may elucidate the molecular mechanisms underlying the fusarium wilt resistance of plants.


[Castration-resistant prostate cancer: surgical and radio-oncological therapeutic options].
Treatment of patients suffering from castration-resistant prostate cancer is a challenge for the attending physician. Due to the polysymptomatic nature of this disease, multidisciplinary cooperation (urology, radiation oncology, medical oncology, palliative care, orthopaedics, neurosurgery) is the centre of attention. Different surgical and radio-oncological therapeutic options are available based on different stages of this disease. Optimizing quality of life should always be the focus of attention in these patients.


Clinical spectrum, treatment and outcome of myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease in children: a tertiary care experience.
Anti-myelin oligodendrocyte glycoprotein antibodies have been associated with a wide range of clinical presentations including monophasic and relapsing disease courses. Lack of a definitive marker for predicting further relapses and the final diagnoses complicates the clinical follow-up and treatment decisions for patients with the first episode. This study retrospectively analyzed the clinical spectrum, treatment protocols and outcome of nine children with MOG antibody-associated demyelinating disease. Diagnoses at first presentation were acute disseminated encephalomyelitis (ADEM) in six cases (67%), optic neuritis in two cases (22%), and clinically isolated syndrome in one case (11%). The disease remained monophasic in five (56%) cases. All cases with a monophasic disease course were negative for anti-MOG antibody titers in the third month. The initial diagnosis of all relapsing cases was ADEM. Three of the four cases with a relapsing disease course were available for anti-MOG antibody testing at the third month and all were positive, however, antibody titers at the sixth month were inconsistent. Cases with a relapsing disease course had no further attacks after monthly intravenous immunoglobulin treatment. Relapsing disease course is not rare in childhood MOG-antibody associated demyelinating disease. Monthly IVIG treatment may be a good alternative for the long-term treatment of relapsing cases with a low side effect profile. Anti-MOG antibody serostatus at remission periods should be interpreted cautiously. Further studies are needed to better understand and predict the clinical course of pediatric patients with MOG-antibody associated diseases.


Low expression of long noncoding RNA CTC-297N7.9 predicts poor prognosis in patients with hepatocellular carcinoma.
Long noncoding RNAs (lncRNAs) are reported to play important roles in tumorigenesis of various malignant tumors. However, the clinical significance of aberrant lncRNA expression in hepatocellular carcinoma (HCC) is still elusive. Firstly, a differentially expressed lncRNA CTC-297N7.9 in HCC was detected by analyzing the data from The Cancer Genome Atlas (TCGA). Secondly, the expression level of CTC-297N7.9 was examined in four HCC cell lines and 60 pairs of HCC tissues by polymerase chain reaction (PCR) assay at our center. Thirdly, receiver operating characteristic (ROC) analysis was performed to evaluate the diagnostic value of CTC-297N7.9 for HCC. Correlation and survival analysis of HCC patients from the TCGA and our center were also carried out to assess the predictive value of CTC-297N7.9. Finally, survival prognostic models were established combining lncRNA expression and other clinical parameters. The expression of CTC-297N7.9 was downregulated in HCC cell lines and HCC tissues. ROC curve revealed its significant diagnostic value in HCC. CTC-297N7.9 expression correlated with serum alpha-fetal protein (AFP), tumor stage, and tumor differentiation. Survival analysis indicated that overall survival (OS) and disease-free survival (DFS) are all positively associated with CTC-297N7.9 expression, especially in patients without viral hepatitis or cirrhosis. Cox regression analysis showed that CTC-297N7.9 expression level is an independent prognostic factor for both OS and DFS in HCC patients. Based on the model, CTC-297N7.9 was observed to be negatively correlated to risk score, indicating its role as a protective factor for HCC. Our study demonstrated that the low expression of CTC-297N7.9 is associated with poor prognosis in HCC patients, suggesting its possible role as a potential prognostic marker for HCC.


Identification of human calphoglin-induced phosphoglucomutase phosphorylation in Escherichia coli.
Orthologous proteomes, universal protein networks conserved from bacteria to mammals, dictate the core functions of cells. To isolate mammalian protein sequences that interact with bacterial signaling proteins, a BLASTP genome search was performed using catalytic domains of bacterial phosphoryl-transfer enzymes as probes. A [32P]phosphoryl-transfer assay of these mammalian cDNA-expressing Escherichia coli cells was used to screen proteins retrieved from the database. Here we report that the expression of a human protein, named calphoglin, resulted in a significant increase in the phosphorylation of a 55-kDa protein in E. coli. The phosphorylation of the 55-kDa protein was acid-stable and its isoelectric point was determined to be 5.4. The 55-kDa protein was sequentially purified from an E. coli extract using three chromatography and two-dimensional polyacrylamide gel electrophoresis. Finally, the 55-kDa protein was purified 830-fold to homogeneity and the N-terminal amino acid sequence was analyzed. The sequence obtained, AIHNRAGQPAQQ, was identical to the N-terminal amino acids of E. coli phosphoglucomutase (PGM). This method may be applicable to the detection and analysis of other orthologous proteomes.


Microbial changes in clover rhizosphere after foliar and soil application of cobalt.
Application of cobalt(II) nitrate to the leaves of red clover (Trifolium pratense L.) resulted in a pronounced increase of dry weight and the number of root nodules. Counts of bacteria in the rhizosphere, content of ammonia and production of carbon dioxide in rhizosphere soil were also higher, whereas the content of nitrates decreased. Differences in the counts of bacteria, actinomycetes, Azotobacter, anaerobic bacteria and cellulose decomposing bacteria in the rhizosphere of control and treated plants were not directly related to the way of application of cobalt. Genera Penicillium, Fusarium and Trichoderma predominated among fungi. The relative occurrence of penicillia was higher after the application of cobalt, the incidence of fusaria was lower. The effects of foliar and soil application of cobalt on rhizosphere microflora were not identical.


Effects of oral administration of benzylamine on glucose tolerance and lipid metabolism in rats.
Repeated administration of benzylamine plus vanadate have been reported to exhibit anti-hyperglycemic effects in different models of diabetic rats. Likewise oral treatment with Moringa oleifera extracts which contain the alkaloïd moringine, identical to benzylamine, has also been shown to prevent hyperglycemia in alloxan-induced diabetic rats. With these observations we tested whether prolonged oral administration of benzylamine could interact with glucose and/or lipid metabolism. Seven week old male Wistar rats were treated for seven weeks with benzylamine 2.9 g/l in drinking water and were submitted to glucose tolerance tests. A slight decrease in water consumption was observed in benzylamine-treated animals while there was no change in body and adipose tissue weights at the end of treatment. Blood glucose and plasma insulin, triacylglycerol or cholesterol levels were not modified. However, benzylamine treatment resulted in a decrease in plasma free fatty acids in both fed and fasted conditions. Benzylamine treatment improved glucose tolerance as shown by the reduction of hyperglycemic response to intra-peritoneal glucose load. Oral benzylamine treatment did not alter the response of adipocytes to insulin nor to insulin-like actions of benzylamine plus vanadate, via in vitro activation of glucose transport or inhibition of lipolysis. This work demonstrates for the first time that oral administration of benzylamine alone influences glucose and lipid metabolism. However, these results obtained in normoglycemic rats require to be confirmed in diabetic models.


The mechanism of sevoflurane-induced cardioprotection is independent of the applied ischaemic stimulus in rat trabeculae.
Sevoflurane protects the myocardium against ischaemic injury through protein kinase C (PKC) activation, mitochondrial K+ATP-channel (mitoK+ATP) opening and production of reactive oxygen species (ROS). However, it is unclear whether the type of ischaemia determines the involvement of these signalling molecules. We therefore investigated whether hypoxia (HYP) or metabolic inhibition (MI), which differentially inhibit the mitochondrial electron transport chain (ETC), are comparable concerning the relative contribution of PKC, mitoK+ATP and ROS in sevoflurane-induced cardioprotection. Rat right ventricular trabeculae were isolated and isometric contractile force (Fdev) was measured. Trabeculae were subjected to HYP (hypoxic glucose-free buffer; 40 min) or MI (glucose-free buffer, 2 mM cyanide; 30 min), followed by 60 min recovery (60 min). Contractile recovery (Fdev,rec) was determined at the end of the recovery period and expressed as a percentage of Fdev before hypoxia or MI, respectively. Chelerythrine (CHEL; 6 microM), 5-hydroxydecanoic acid sodium (100 microM) and n-(2-mercaptopropionyl)-glycine (MGP; 300 microM) were used to inhibit PKC, mitoK+ATP and ROS, respectively. Fdev,rec after HYP was reduced to 47 (3)% (P<0.001 vs control; n=5) whereas MI reduced Fdev,rec to 28 (5)% (P<0.001 vs control; n=5). A 15 min period of preconditioning with sevoflurane (3.8%) equally increased contractile recovery after HYP [76 (9)%; P<0.05 vs HYP] and MI [67 (8)%; P<0.01 vs MI]. Chelerythrine, 5-hydroxydecanoate and n-(2-mercaptopropionyl)-glycine abolished the protective effect of sevoflurane in both ischaemic models. Trabeculae subjected to HYP or MI did not demonstrate any increased apoptotic or necrotic markers. PKC, mitoK+ATP and ROS are involved in sevoflurane-induced cardioprotection after HYP or MI, suggesting that the means of mitochondrial ETC inhibition does not determine the signal transduction pathway for cardioprotection by anaesthetics.


A 50-cm fillet flap for preservation of maximal lower extremity residual limb length.
A 50-cm fillet flap permitted above-knee amputation in lieu of hip disarticulation in a 20-year-old woman who had sustained severe injuries in a motorcycle accident. Although the flap was unusually long, the principles followed were the same as those for posterior flaps used in below-knee amputations and fillet flaps of the digits. The flap allowed preservation of maximal length in the residual limb and fully sensible skin coverage, both of which facilitated prosthetic usage.


Regulation of B-type natriuretic peptide synthesis by insulin in obesity in male mice.
Human studies suggest that insulin resistance and obesity are associated with a decrease in B-type natriuretic peptide (BNP) plasma concentrations. The objective of the study was to gain insights into the mechanisms involved in the association between insulin resistance and decreased BNP plasma concentrations. Mice fed a high-fat, high-fructose (HFHF) diet for 4 weeks developed mild obesity and systemic insulin resistance. Elevated plasma concentrations of insulin, glucose and triglycerides were noted. The HFHF diet was also associated with myocardial insulin resistance, characterized by an impaired response of the phosphoinositide 3-kinase-AKT (PI3K-AKT) pathway to insulin in the left ventricle. Myocardial BNP expression and protein were decreased in HFHF-fed mice compared with control animals. Exposure of cardiomyocytes to 100 nm insulin activated PI3K-AKT signalling (15 min) and induced a 1.9 ± 0.3-fold increase in BNP gene expression (6 h). Prolonged exposure of cardiomyocytes to a high insulin concentration (100 nm) for 48 h induced insulin resistance, characterized by an impaired response of the PI3K-AKT signalling pathway and a decreased response of the BNP gene expression to insulin. The decreased response in BNP gene expression was reproduced by treating cardiomyocytes for 7 h with a PI3-kinase inhibitor (wortmannin). In conclusion, HFHF diet in vivo, prolonged exposure to an elevated concentration of insulin or inhibition of the PI3K-AKT pathway in vitro all decrease BNP mRNA levels; this decrease may in turn contribute to the decreased BNP peptide concentrations in plasma observed in insulin-resistant individuals.


Heterogeneity of metabotropic glutamate receptors in the striatum: electrophysiological evidence.
In order to investigate the functional role of metabotropic glutamate receptors (mGluRs) in the striatum we performed extracellular and intracellular recordings from a corticostriatal brain slice preparation. The effects of L-2-amino-3-phosphopropionic acid (L-AP3), an antagonist of mGluRs, were studied both on long-term synaptic depression (LTD) and on presynaptic inhibition of excitatory postsynaptic potentials (EPSPs) induced by different agonists of mGluRs. L-AP3 produced a dose-dependent (3-30 microM) reduction of the LTD evoked in the striatum by the tetanic stimulation of the corticostriatal pathway. In contrast to this action, L-AP3 (10-100 microM) did not significantly affect the presynaptic inhibitory effect of 1-amino-cyclopentyl-trans-dicarboxylic acid (t-ACPD), an agonist of mGluRs, on corticostriatal transmission. Higher concentrations of L-AP3 (0.3-1 mM) reduced by themselves the EPSP amplitude. The inhibitory effect of t-ACPD on the cortically evoked EPSPs was mimicked either by the active stereoisomer 1S,3R-ACPD or by amino-4-phosphonobutyric acid (L-AP4), a glutamate autoreceptor agonist. In some neurons, these inhibitory actions were coupled with membrane depolarizations. The depression of synaptic transmission caused by t-ACPD, 1S,3R-ACPD and L-AP4 was not altered following the induction of LTD. Chronic lithium treatment of the animals (60-120 mg/kg i.p. for 10 days) blocked striatal LTD but not presynaptic inhibition mediated by mGluR agonists. The present findings show that the mechanisms underlying LTD and the presynaptic inhibition induced by different agonists of mGluRs exhibit functional and pharmacological differences. These data suggest heterogeneity of mGluRs in the striatum.


Embedding Patient-Centricity by Collaborating with Patients to Transform the Rare Disease Ecosystem.
What is patient-centricity? In some contexts, it has been associated with targeting therapies based on biomarkers or enabling healthcare access. There has been a surge in patient-centricity publications, and in many cases for the biopharmaceutical industry, patient engagement is used to endorse pre-held assumptions at a specific moment in time. Rarely is patient engagement used to drive business decisions. Here we describe an innovative partnership between Alexion, AstraZeneca Rare Disease and patients that allowed a deeper understanding of the biopharmaceutical stakeholder ecosystem and an empathic understanding of each patient's and caregiver's lived experience. Alexion's decision to build patient-centricity frameworks resulted in the formation of two unique organisation design platforms: STAR (Solutions To Accelerate Results for patients) and LEAP (Learn, Evolve, Activate and deliver for Patients) Immersive Simulations. These interconnected programmes required cultural, global, and organisational shifts. STAR generates global patient insights that are embedded in drug candidate and product strategies while helping to establish enterprise foundational alignment and external stakeholder engagement plans. LEAP Immersive Simulations produce detailed country-level patient and stakeholder insights that contribute to an empathetic understanding of each patient's lived experience, support country medicine launches and provide ideas to have a positive impact along the patient journey. Combined, they deliver integrated, cross-functional insights, patient-centric decision making, an aligned patient journey, and 360° stakeholder activation. Throughout these processes, the patient is empowered to dictate their needs and validate the proposed solutions. This is not a patient engagement survey. This is a partnership where the patient co-authors strategies and solutions.


Igneous processes in the small bodies of the Solar System I. Asteroids and comets.
Igneous processes were quite widespread in the small bodies of the Solar System (SBSS) and were initially fueled by short-lived radioisotopes, the proto-Sun, impact heating, and differentiation heating. Once they finished, long-lived radioisotopes continued to warm the active bodies of the Earth, (possibly) Venus, and the cryovolcanism of Enceladus. The widespread presence of olivine and pyroxenes in planets and also in SBSS suggests that they were not necessarily the product of igneous processes and they might have been recycled from previous nebular processes or entrained in comets from interstellar space. The difference in temperature between the inner and the outer Solar System has clearly favored thermal annealing of the olivine close to the proto-Sun. Transport of olivine within the Solar System probably occurred also due to protostellar jets and winds but the entrainment in SBSS from interstellar space would overcome the requirement of initial turbulent regime in the protoplanetary nebula.


Effects of transcutaneous electrical nerve stimulation via peroneal nerve or soleus muscle on venous flow: A randomized cross-over study in healthy subjects.
Transcutaneous electrical nerve stimulation (TENS) is used to prevent venous stasis and thromboembolism. However, best electrostimulation parameters have yet to be established. The aim of the study was to compare the hemodynamic effects and the participants' relative discomfort of 3 TENS sequences at the maximum tolerated intensity stimulus. Twenty-four healthy university students (50% male) participated in a cross-over, randomized study. Each participant received 2 TENS sequences on peroneal nerve at 1 and 5 Hz, and the third one on soleus muscle at 5 Hz. Popliteal flow volume (FV) and peak velocity (PV) were measured using Doppler ultrasound and the relative change from basal values was recorded. Discomfort questionnaires -visual analogue scale (VAS) and verbal rating scale (VRS)- were also administered to compare sensations among the three applications. All interventions produced significant hemodynamic responses compared to baseline. Both 5 Hz applications obtained higher FV increments than 1 Hz TENS (P < .001). The muscle application resulted in the lowest PV increment (P < .001). TENS at 5 Hz on nerve location was the worst tolerated, with higher values in VRS (P = .056) and VAS (P = .11), although not significant. TENS at 5 Hz on soleus site may be the most appropriate protocol for enhancing venous return.


Two-dimensional spreads of synaptonemal complexes from solanaceous plants. I. The technique.
Using beta-glucuronidase the cell walls of tomato and potato primary microsporocytes can be digested. When the resulting protoplasts are exposed to distilled water, they burst, and complete sets of synaptonemal complexes are released to settle on plastic coated slides. After drying and formalin fixation, the synaptonemal complexes can be stained with silver or phosphotungstic acid and observed in the light and/or electron microscope. Silver staining gives better contrast for both light and electron microscopy but stains only lateral elements and kinetochores. Phosphotungstic acid staining gives little or no contrast for light microscopy, but stains both the lateral and central elements of the synaptonemal complex, kinetochores, and structures that are probably recombination nodules for electron microscopy. This technique offers a powerful tool for genome analysis by allowing (1) the determination of relative and absolute lengths of synaptonemal complexes and chromosome arm ratios at pachytene, (2) the analysis of complex patterns of synapsis, and (3) the location of what are probably recombination nodules along the length of synaptonemal complexes.


Quality of life assessment in a living donor kidney transplantation program: evaluation of recipients and donors.
Quality of life (QOL) in donors before and after living kidney donor transplantation (LKDT) has been an important concern. Investigation of these issues in related recipients is not as common. Since 2002, a protocol of psychosocial evaluation for donors and recipients was included in the living kidney donation program. We sought to evaluate QOL in donors and recipients, before and after transplantation, and to compare the 2 groups. Before and after transplantation, 35 recipients and 45 donors completed a Sociodemographic Questionnaire and Short-Form 36 Health Survey Questionnaire (SF-36). The Wilcoxon test, Mann-Whitney test, and logistic regression were applied. Before transplantation, recipients had lower QOL values than donors for all dimensions (P < .05), with the exception of Mental Health. After transplantation, they had higher values (P < .05) for every dimension on the SF-36. Among donors, there were no significant changes. Physical function and social function were considered poorer by donors versus recipients (P < .05). In this LKDT program, more females were donors and fewer were recipients. Most of donors were siblings. All donors were related (the Portuguese law pertaining to unrelated donation was enacted in 2007). QOL was significantly poorer among recipients before surgery. After surgery, QOL significantly improved in recipients and was not poorer in donors. LKDT improved recipients' lives and did not affect donors' negatively.


Local and systemic effects of tetrodotoxin on the formation and elimination of synapses in reinnervated adult rat muscle.
1. Polyneuronal innervation of normal and reinnervated fourth deep lumbrical muscle fibres was studied with tension measurements and intracellular recordings. From the tenth day after a complete crush of the muscle nerve, some of the reinnervated muscles were completely paralysed for up to 15 days by local application of tetrodotoxin (TTX) to the sciatic nerve. Other animals received only systemic infusion of TTX during the muscle reinnervation.2. Measurements of tetanic-tension overlap suggested that about 6% of the muscle fibres in the normal lumbrical muscle were polyneuronally innervated, while intracellular recordings suggested that the percentage was as high as 25%. This discrepancy was mainly due to the presence of one small, sub-threshold end-plate potential (e.p.p.) and one large, suprathreshold e.p.p. in almost all polyneuronally innervated muscle fibres.3. Intracellular recordings during muscle reinnervation showed that the extent of polyneuronal innervation reached a maximum of 50% 10-15 days after denervation and that by 16-20 days this had decreased to a level similar to that found in normal muscle.4. After a week of total muscle paralysis the extent of polyneuronal innervation had increased to about 80%, estimated by both tension measurements and intracellular recordings. Subsequently, there was no sign of any net elimination of the polyneuronal innervation, even in muscles paralysed for up to two weeks. Many of the polyneuronally innervated fibres were innervated by at least two motor axons. each producing suprathreshold e.p.p.s.5. In muscles contralateral to the paralysed muscles, the extent of polyneuronal innervation reached a maximum of 50% 10-15 days after denervation as in reinnervated muscles not exposed to TTX. But in contrast to the subsequent decrease in the extent of polyneuronal innervation in animals which received no TTX, this level of polyneuronal innervation persisted in muscles contralateral to the paralysed muscles. The same was true for reinnervated muscles in animals which only received TTX systemically.6. The increased level of polyneuronal innervation after TTX application was not caused by differences in the number of motor units or in number of muscle fibres.7. Paralysed muscles relaxed much more slowly than non-paralysed muscles at the end of a fused tetanic contraction. The tetanus/twitch ratio of these muscles was also smaller than in contralateral control muscles and the rise time of the twitch was greater.8. It is concluded that a substantial fraction of the fibres in the normal lumbrical muscle of young rats is polyneuronally innervated. After reinnervation, the normal innervation pattern is re-established, but no net elimination of the polyneuronal innervation occurs unless either nerve or muscle or both are active. A net elimination of synapses is also prevented when TTX is present systemically in low concentrations.


Mercury, APOE, and children's neurodevelopment.
The benefit of the nutritious elements in fish is insufficient for explaining the controversial finding regarding prenatal mercury (Hg) exposure and neurodevelopment; the varying frequency of susceptible genes among these populations may shed light on these observations. However, limited studies have been reported on the association between genetic susceptibility of prenatal Hg exposure and child development. Apolipoprotein E (APOE, protein; Apoe, gene) is a major protein transporter expressed in the brain. The Apoe epsilon 4 (ε4) allele is associated with poor neural repair function and is a risk factor associated with Alzheimer disease. We conducted a prospective cohort study in 2004 and 2005. In this study, 168 subjects were recruited at delivery and followed up at two years of age, and genetic polymorphisms of Apoe were included to assess genetic susceptibility and to determine the relationship between Hg concentrations in cord blood and neurodevelopment. The results showed that adverse effects on neurodevelopment were consistently associated with prenatal Hg exposure in all subtests of Comprehensive Developmental Inventory for Infants and Toddlers (CDIIT) among ε4 carriers as assessed by both simple linear and multiple linear regression models. After controlling for confounding factors, statistical significance was found in the subtests of cognition tests (β=-8.47, 95% confidence interval (CI)=-16.10 to -0.84), social tests (β=-11.02, 95% CI=-20.85 to -1.19) and the whole test of CDIIT (β=-10.45, 95% CI=-17.36 to -3.54) in a multiple linear regression model. Additionally, the interaction effect between gene polymorphisms of Apoe and Hg levels was significant in the whole test CDIIT and subtests of cognition, language and fine motor tests. In conclusion, Apoe modifies the adverse effects of cord blood Hg on neurodevelopment at the age of two years.


Systematic review and meta-analysis of risk factors for Mesh infection following Abdominal Wall Hernia Repair Surgery.
Surgical Mesh Infection (SMI) after Abdominal Wall Hernia Repair (AWHR) represents a catastrophic complication. We performed a systematic review and meta-analysis to analyze the risk factors for SMI in the context of AWHR. PubMed, Embase, Scielo, and LILACS were searched without language or time restrictions from inception until June 2021. Articles evaluating the association between demographic, clinical, laboratory and surgical characteristics with SMI in AWHR were included. 23 studies were evaluated, comprising a total of 118,790 patients (98% males; mean age 56.5 years) with a mesh infection pooled prevalence of 4%. Significant risk factors for SMI were type 2 diabetes mellitus, obesity, smoking history, steroids use, ASA III/IV, laparotomy vs laparoscopy, emergency surgery, duration of surgery and onlay mesh position vs sublay. The quality of evidence was regarded as very low-moderate. Several factors, highlighting sociodemographic characteristics, comorbidities, and the clinical scenario, may increase the risk of developing mesh infections in AWHR. The recognition and mitigation of these may significantly reduce mesh infection rates in this context.


The vasodilator-stimulated phosphoprotein (VASP) is involved in cGMP- and cAMP-mediated inhibition of agonist-induced platelet aggregation, but is dispensable for smooth muscle function.
The vasodilator-stimulated phosphoprotein (VASP) is associated with actin filaments and focal adhesions, which form the interface between the cytoskeleton and the extracellular matrix. VASP is phosphorylated by both the cAMP- and cGMP-dependent protein kinases in a variety of cells, including platelets and smooth muscle cells. Since both the cAMP and cGMP signalling cascades relax smooth muscle and inhibit platelet activation, it was speculated that VASP mediates these effects by modulating actin filament dynamics and integrin activation. To study the physiological relevance of VASP in these processes, we inactivated the VASP gene in mice. Adult VASP-deficient mice had normal agonist-induced contraction, and normal cAMP- and cGMP-dependent relaxation of intestinal and vascular smooth muscle. In contrast, cAMP- and cGMP-mediated inhibition of platelet aggregation was significantly reduced in the absence of VASP. Other cAMP- and cGMP-dependent effects in platelets, such as inhibition of agonist-induced increases in cytosolic calcium concentrations and granule secretion, were not dependent on the presence of VASP. Our data show that two different cyclic, nucleotide-dependent mechanisms are operating during platelet activation: a VASP-independent mechanism for inhibition of calcium mobilization and granule release and a VASP-dependent mechanism for inhibition of platelet aggregation which may involve regulation of integrin function.


Bioprospecting for new exopolysaccharide-producing microalgae of marine origin.
Microalgae are photosynthetic organisms that can produce biomolecules with industrial interest, including exopolysaccharides (EPS). Due to their structural and compositional diversity, microalgae EPS present interesting properties that can be considered in cosmetic and/or therapeutic areas. Seven microalgae strains from three different lineages, namely Dinophyceae (phylum Miozoa), Haptophyta, and Chlorophyta, were investigated as EPS producers. All strains were found to be EPS producers, though the highest EPS yield was obtained for Tisochrysis lutea, followed by Heterocapsa sp. (126.8 and 75.8 mg L-1, respectively). Upon assessment of the polymers' chemical composition, significant contents of unusual sugars, including fucose, rhamnose, and ribose, were found. Heterocapsa sp. EPS stood out due to its high content of fucose (40.9 mol%), a sugar known to confer biological properties to polysaccharides. The presence of sulfate groups (10.6-33.5 wt%) was also noticed in the EPS produced by all microalgae strains, thus contributing to the possibility that these EPS might have biological activities worth exploring.


Activity of tricyclic nucleoside 5'-phosphate in model systems of human ovarian cancer.
Tricyclic nucleoside 5'-phosphate (TCN-P) was evaluated in two models of human ovarian cancer. TCN-P reduced both colony number and volume in clonogenic assays employing human ovarian cancer cell lines. TCN-P cytotoxicity depended on the concentration, exposure duration and cell line studied, but not on cell line plating efficiency or growth rate in soft agarose. Comparison of experimental IC50 concentrations for 1 hour or continuous TCN-P exposure with reported clinically relevant concentrations suggests that therapeutic TCN-P levels are more likely to be achieved by continuous infusions. Cell lines and sublines with resistance to several standard chemotherapeutic agents acquired both in vivo and in vitro were at most 2.6-fold cross-resistant to TCN-P with 1 hour drug exposure. Cross-resistance was not evident with continuous TCN-P exposure. Intermittent bolus TCN-P (100 mg/kg/d X 5) was ineffective in an in vivo xenograft model of human ovarian cancer. These data suggest that TCN-P is most likely to be clinically effective against ovarian cancer, and may be non-cross-resistant with several standard agents, if administered by continuous infusion. Preclinical evaluation of new agents, such as TCN-P, in these experimental models may provide information useful in subsequent clinical trials.


Vascularity of human atrioventricular valves: a myth or fact?
Knowledge of heart valve vascularity is an important factor for understanding the valvular pathology and to develop tissue-engineered valves for repair procedures. Some investigators believe that blood vessels may exist in normal human heart valves whereas some recent publications have proposed that the presence of blood vessels in the valves is secondary to inflammation. Tissues from 60 normal formalin-fixed human hearts were examined microscopically for type, location, and number of vessels in atrioventricular valves. The age of the patient ranged from 10 to 70 years, and an attempt was made to study the age-related morphologic changes in atrioventricular valves. Of the 60 tricuspid and 60 mitral valves examined, 12 tricuspid (20%) and 14 mitral (23.33%) valves were found to have vessels without the presence of an inflammatory process. In tricuspid valves the vessels were observed mainly in the fibrosa layer with a range of 1 to 4 vessels, whereas in mitral valves the vessels were situated mainly in the spongiosa layer with a range of 1 to 2 vessels. The maximum vascularity was seen in the fourth decade of life, in which the vessels were found in 40% of both tricuspid and mitral valves. The mean transverse diameter of these vessels was 0.23 ± 0.18 mm, with a range of 0.06 to 0.79 mm in tricuspid valves, whereas it was 0.15 ± 0.08 mm, with a range of 0.04 to 0.4 mm in mitral valves. The capillaries (3-11 capillaries) were found scattered in the fibrosa and spongiosa with an average lumen area of 0.39 ± 0.18 mm(2). The blood vessels in atrioventricular valves also can be seen in the absence of inflammation and are likely to be a necessary component of valve leaflets. Thus, when performing procedures involving in situ tissue engineering and valve repair the physician needs to be aware of the presence of these vessels in human heart valves.


Genetic variation at the catalytic subunit of glutamate cysteine ligase contributes to the susceptibility to sporadic colorectal cancer: a pilot study.
Glutathione is a tripeptide detoxifying a variety of exogenous and endogenous free radicals and carcinogens, and a deficiency of glutathione is associated with an increased host susceptibility to oxidative stress, a pathological condition implicated in the development and progression of cancer. The catalytic subunit of glutamate-cysteine ligase (GCLC) is an enzyme responsible for the initial and rate-limiting step of glutathione biosynthesis. The aim of this pilot study was to investigate whether genetic variation at the GCLC gene contributes to the risk of colorectal cancer (CRC). DNA samples from 681 unrelated Russian individuals (283 patients with CRC and 398 age- and sex-matched healthy controls) were genotyped for six common functional SNPs of the GCLC gene (SNPs) such as rs12524494, rs17883901, rs606548, rs636933, rs648595 and rs761142 of the GCLC gene using the MassARRAY-4 system. We found that genotype rs606548-C/T is significantly associated with increased risk of CRC regardless of sex and age (OR 2.24; 95% CI 1.24-4.03; P = 0.007, FDR = 0.04). Moreover, ten GCLC genotype combinations showed association with the risk of CRC (P < 0.05). Functional SNP annotation enabled establishing the CRC-associated polymorphisms are associated with a decreased GCLC expression that may be attributed to epigenetic effects of histone modifications operating in a colon-specific manner. The present study was the first to show that genetic variation at the catalytic subunit of glutamate-cysteine ligase may contribute to the risk of colorectal cancer risk. However, further genetic association studies with a larger sample size are required to substantiate the role of GCLC gene polymorphisms in the development of sporadic colorectal cancer.


Physical associations of microglia and the vascular blood-brain barrier and their importance in development, health, and disease.
Brain endothelial cells (BEC) of the vascular blood-brain barrier (BBB) interact with many different cell types in the brain, including microglia, the brain's resident immune cells. Physical associations of microglia with the BBB and the importance of these interactions in health and disease are an emerging area of study and likely involved in neuroimmune communication. In this mini-review, we consider how microglia and the BBB are intrinsically linked in the developing brain, discuss possible mechanisms that attract microglia to the vasculature in healthy physiological conditions, and examine the known microglial-vascular associated changes in systemic infection and various disease states. Our findings shed light on the complexities of microglial-vascular interactions and highlight the contributions of microglia to the functions of the neurovascular unit.


Causes of revisional surgery, reoperations, and readmissions after bariatric surgery.
Bariatric surgery is the most effective treatment for weight loss, with comorbidity control. With low complication rates, the reasons for reoperation are major complications or weight loss failure/weight regain. Nonsurgical problems can also present, such as anemia, dehydration, chronic pain, and malnutrition, among others. Our aim was to analyze the main causes of revisional surgery, reoperation, and hospital readmission, at a specialized bariatric center. A retrospective study was conducted on patients that underwent bariatric surgery within the time frame of 2012 and 2019. The baseline analysis included demographic, anthropometric, and perioperative data, as well as a sub-analysis of the main readmission causes and complications. A total of 776 primary surgeries were performed (649 RYGBP, 127 SG, and 10 revisional surgeries), and 99 patients were identified for the study: 10 revisional surgeries, 44 reoperations, and 45 readmissions. The incidence of revisional surgery was 1.2%, reoperation was 5.6%, and readmission 5.8%. Fifty percent of the revisional surgeries were performed due to insufficient weight loss or weight regain; the most frequent causes of reoperation were cholecystitis (38.6%) and internal hernias (9.1%); and the most common causes of readmission were nonspecific abdominal pain (35.5%) and dehydration (24.4%). The most frequent causes of postoperative readmission were nonsurgical events, followed by non-bariatric reoperations, and finally revisional surgeries. There was a low incidence of early reoperations. Knowledge of the abovementioned data is important for identifying higher-risk patients, to prevent major complications.


Sensitivity of tryptophan, tyrosine and phenylalanine mutants of Saccharomyces cerevisiae to phenethyl alcohol.
Phenethyl alcohol inhibits the growth of many microorganisms. It is believed that the growth inhibition is mediated by its effect on the cell membrane. Differences between sensitive and resistant strains are suggested to be due to alterations in membrane structure. We report that, in some strains, an unexpected relationship exists between auxotrophy for tryptophan, tyrosine and phenylalanine and sensitivity to phenethyl alcohol.


Giant-cell arteritis causing severe aortic regurgitation secondary to aneurysm of the ascending aorta--a case report.
This report describes a case of aneurysm of the ascending aorta with secondary, severe, aortic valve incompetence following temporal arteritis in a sixty-five-year-old woman.


Proceptive presenting elicited by electrical stimulation of the female monkey hypothalamus.
Proceptive presenting by female macaque monkeys was evoked by electrical stimulation of the ventromedial hypothalamic nucleus and the medial preoptic area, under conditions of partial restraint while sitting in a primate chair. This behavior could be elicited only when a male monkey was in close proximity and not when he was removed or was replaced with a female monkey or the human experimenter. This seems to be the first report on the effects of electrical brain stimulation on proceptivity in the female monkey.


[Parasitologic collection technic and examination methods in equatorial West Africa].
The author has been a medical doctor and parasitologist over some years in different West-African countries. Based on his personal experience he underlines the special methodological conditions as well for the diagnoser as for the collector of parasitological documenting material. In this respect, the climatological factors have to be regarded as well as sociological and religious situations.


Treatment of neonates with meconium aspiration syndrome by proportional assist ventilation and synchronized intermittent mandatory ventilation: a comparison study.
This study aimed to compare the relevant clinical parameters of neonates with MAS who are supported by proportion assisted ventilation (PAV) and synchronized intermittent mandatory ventilation (SIMV). Forty neonates diagnosed as MAS who required mechanical ventilation were divided randomly into PAV group and SIMV group (N.=20). The respiratory rate (RR), heart rate (HR), peak inspiratory pressure (PIP), mean arterial blood pressure (MABP), arterial-to-alveolar oxygen tension ratio (a/APO2), fraction of inspiration oxygen (FiO2), mean airway pressure (MAP) and tidal volume (VT) were measured before the ventilation, 1,12, 24, 48 hours after the ventilation and before weaning. We observed no significant differences in the mechanical ventilation time, oxygen supply time, hospital stay between PAV and SIMV groups. In addition, we found no significant differences in HR, MABP, a/APO2 and FiO2 at every time point between two groups (P>0.05). However, we observed significant differences in RR, MAP, PIP and VT at every time point between two groups (P<0.05). PAV and SIMV might be a useful ventilator mode to support the neonates with MAS who require ventilation. To achieve the same effect, PAV adopts rapid shallow breathing pattern, with smaller tidal volume and lower MAP and PIP.


Characterization of mevalonate-activating enzymes in the neonatal chick liver.
1. The 5-phosphomevalonate (MVAP) and 5-pyrophosphomevalonate (MVAPP) formation by cell-free extracts from 7-10 days chick liver shows an absolute nucleotide requirement, ATP being the most effective phosphate donor, though ITP and UTP can be used less effectively. 2. Mn2+ is a better activator than Mg2+ at low concentrations (0.1-5.0 mM). At higher concentrations (10.0 mM) Mn2+ produces a clear decrease in the MVAP formation, whereas the maximum MVAPP formation occurs in the presence of 10.0 mM Mg2+. 3. Mevalonate-activating enzymes maintain their activities for 48 hr at 4 degrees C and 24 hr at 37 degrees C. No MVAP is formed when the extracts are heated to 65 degrees C for 10 min. 4. Unlike other vertebrate mevalonate and phosphomevalonate kinases, these enzymes from chick liver are not activated by -SH group protectors as dithiothreitol, reduced glutathione, cysteine or beta-mercaptoethanol. However, the enzymes are found to be sensitive to thiol binding reagents p-hydroxymercuribenzoate and 5,5'-dithiobis-(2-nitrobenzoic acid).


Neuronal ceroid-lipofuscinoses in childhood.
Neuronal Childhood types of ceroid-lipofuscinoses (NCL) are reviewed. All three main types, infantile, late infantile and juvenile, are progressive encephalopathies characterized by neural and extraneural accumulation of ceroid- and lipofuscin like storage cytosomes. The pathogenesis of NCL is unknown. A disturbance of the peroxidation of polyunsaturated fatty acids and a defect in the processing and turn-over of the glycoproteins in the lysosomal membrane are those hypotheses which have been most widely investigated. Reduced membrane lipids and reduced membrane fluidity have recently been detected. Prenatal diagnosis, based on the characteristic ultrastructural findings, is possible in all types.


Advanced technology in the management of fibrous dysplasia.
The aim of this paper is to describe the applications of advanced imaging technology in optimising the surgical management of complex craniofacial fibrous dysplasia (FD). Preoperative planning involved a number of advanced technologies. Haptic modelling was used to simulate tumour excision and the design of the osteotomies, on a virtual 3D computerised tomographic (CT) scan. Rapid prototyping was employed in fabricating a physical prototype of the skull, featuring the ideal, symmetrical reconstruction. Tumour extirpation was carried out with the aid of stereotactic navigation. Intraoperatively, resorbable mesh is moulded precisely to the shape of the skull prototype, thereby transferring the surgical simulation to the patient in the operating room. The resorbable mesh serves as a template which guides the shape and spatial orientation of an autologous bone graft reconstruction. Pre- and postoperative volumetric differences were assessed to determine the accuracy of the final results. Short and long term follow-up examinations show excellent cosmetic outcome, with significant restoration of volumetric symmetry. The added complexity of using the new technologies increases preoperative planning time, but we believe that this is offset by the improved safety during the resection of the tumours as well as the excellent aesthetic outcomes.


Ureteral stents: coil strength and durometer.
To evaluate the coil strength before and after urine exposure and the stiffness of commercially available double-J ureteral stents because both properties may affect stent performance and patient comfort. Twelve commercially available 6F ureteral stents were tested for coil strength before and after 30 days of urine exposure. The proximal end of each stent was inserted through a 2-mm hole in bologna, allowed to recoil, and then pulled using a handheld force gauge. Ten different commercially available ureteral stent models were tested for tensile strength using an MTS MicroBionix Testing System and Testworks II software and a 5 N load cell. The Cook Black Silicone and Cook C-Flex stents had the strongest coil strengths before urine exposure at 0.480 +/- 0.0 lb (P < or = 0.0006) and were also the stents that had the greatest decrease in coil strength after urine exposure. After urine exposure, the weakest stent was the Applied Vertex stent at 0.088 +/- 0.008 lb (P < or = 0.02) and the strongest was the Cook Endo-Sof AQ at 0.223 +/- 0.014 lb (P < or = 0.03). Calculating the Young's modulus, E, the Cook C-Flex stent was the stiffest (E = 1472 +/- 196 KPa) and the Cook Black Silicone was the least stiff (E = 122 +/- 18 KPa). The stent models that demonstrated consistent E values across different lot numbers were the Circon Double J stent and Bard InLay. Ureteral stents can be differentiated according to their coil strength and stiffness. The impact of these properties on stent performance and patient comfort deserve additional evaluation. The significant variability found in stent stiffness among stents from different lot numbers suggests poor quality assurance in biomaterials or stent processing and increases the complexity of cross-stent comparisons.


Molecular mechanisms of the 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced inverted U-shaped dose responsiveness in anchorage independent growth and cell proliferation of human breast epithelial cells with stem cell characteristics.
Although 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has a variety of carcinogenic and noncarcinogenic effects in experimental animals, its role in human carcinogenicity remain controversial. A simian virus 40-immortalized cell line from normal human breast epithelial cells with stem cells and luminal characteristics (M13SV1) was used to study whether TCDD can induce AIG positive colony formation and cause increased cell numbers in a inverted U-shaped dose-response manner. TCDD activated Akt, ERK2, and increased the expression of CYP1A1, PAI-2, IL-lb mRNA, and ERK2 protein levels. TCDD was able to increased phosphorylation and expression of ERK2 in same dose-response manner as AIG positive colony formation. Thus, TCDD induced tumorigenicity in M13SV1, possibly through the phosphorylation of ERK2 and/or Akt. Further, cDNA microarray with 7448 sequence-verified clones was used to profile various gene expression patterns after treatment of TCDD. Three clear patterns could be delineated: genes that were dose-dependently up-regulated, genes expressed in either U-shape and/or inverted U-shape. The fact that these genes are intrinsically related to breast epithelial cell proliferation and survival clearly suggests that they may be involved in the TCDD-induced breast tumorigenesis.


Clinical characteristics of supine hypertension in de novo Parkinson disease.
Supine hypertension is frequently associated with autonomic failure. However, its clinical characteristics in patients with Parkinson disease (PD) remain unclear. The present study aimed to clarify the characteristics of supine hypertension in patients with de novo PD. The subjects were 72 patients with de novo PD. We studied blood pressure and plasma norepinephrine levels after the patients rested for 20 min in the supine position. Changes in blood pressure were also examined on head-up tilt-table testing. The disease duration was 1.7 ± 1.6 years (average ± SD). Thirty-three (45.8 %) patients had supine hypertension (defined as a blood pressure of ≥140/90 mmHg). Supine blood pressure positively correlated with the degree of orthostatic hypotension. Age and the proportion of patients with akinetic-rigid motor subtype or preexisting hypertension were higher among patients with supine hypertension than among those without supine hypertension. The Mini-Mental State Examination score was lower in patients with supine hypertension than in those without supine hypertension. Sex, disease duration, disease severity, and peripheral sympathetic nervous activity as evaluated by the cardiac uptake of (123)I-metaiodobenzylguanidine and the plasma norepinephrine level did not differ between patients with and those without supine hypertension. Older age, akinetic-rigid motor subtype, and preexisting hypertension are independent risk factors for supine hypertension. Supine hypertension alone may be associated with milder peripheral sympathetic nervous denervation than orthostatic hypotension alone. As for global cognitive decline, supine hypertension is a far riskier comorbidity of early-stage PD than is orthostatic hypotension.


[Metoclopramide (Cerucal) side-effects in the form of extrapyramidal disorders in combination with an other antidepressive agent].
The authors, by reference to a patient showing acathisia and other dyskinetic disorders following the administration to him of small doses of metoclopramide (Cerucal) and clomipramine, which is a thymoleptic, discuss extrapyramidal disorders attendant upon the therapy of larvated depressions or depressions accompanied by gastrointestinal disorders.


Eukaryotic elongation factor 1A2 cooperates with phosphatidylinositol-4 kinase III beta to stimulate production of filopodia through increased phosphatidylinositol-4,5 bisphosphate generation.
Eukaryotic elongation factor 1 alpha 2 (eEF1A2) is a transforming gene product that is highly expressed in human tumors of the ovary, lung, and breast. eEF1A2 also stimulates actin remodeling, and the expression of this factor is sufficient to induce the formation of filopodia, long cellular processes composed of bundles of parallel actin filaments. Here, we find that eEF1A2 stimulates formation of filopodia by increasing the cellular abundance of cytosolic and plasma membrane-bound phosphatidylinositol-4,5 bisphosphate [PI(4,5)P(2)]. We have previously reported that the eEF1A2 protein binds and activates phosphatidylinositol-4 kinase III beta (PI4KIIIbeta), and we find that production of eEF1A2-dependent PI(4,5)P(2) and generation of filopodia require PI4KIIIbeta. Furthermore, PI4KIIIbeta is itself capable of activating both the production of PI(4,5)P(2) and the creation of filopodia. We propose a model for extrusion of filopodia in which eEF1A2 activates PI4KIIIbeta, and activated PI4KIIIbeta stimulates production of PI(4,5)P(2) and filopodia by increasing PI4P abundance. Our work suggests an important role for both eEF1A2 and PI4KIIIbeta in the control of PI(4,5)P(2) signaling and actin remodeling.


Involvement of extraocular muscle in mitochondrial encephalomyopathy.
We carried out a histological examination of the extraocular muscles (EOMs) in a case of myoclonus epilepsy associated with ragged-red fibers (MERRF) and two cases of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), which did not manifest external ophthalmoplegia clinically. By light microscopy, many granular and vesicular fibers were seen associated with endomysial fibrosis. Electron microscopy revealed that the fibers showed prominent accumulation of abnormal mitochondria, extensive loss of myofibrils, proliferation of free sarcoplasmic reticulum and an increased amount of lipid vacuoles. These changes were more pronounced in MELAS than in MERRF. Hirano bodies were often seen in the subsarcolemmal area of muscle fibers and also in the intramuscular myelinated nerve fibers and axon terminals. These findings suggest the presence of mitochondrial myopathy of the EOMs in cases of MELAS and MERRF.


Management of acute knee dislocation with vascular injury: the use of the external fixator. A systematic review.
Vascular injuries after traumatic knee dislocation pose a potential limb threat for the patient. The benefits of external fixation have been described by many authors. However, the usefulness of the external fixator during acute management of knee dislocations with vascular injuries is a controversial aspect that has no consensus in the literature. The purpose of the present study was to provide data from the current literature on the utility of the external fixator and to investigate the percentage of knee dislocations with vascular injuries treated with an external fixator, the timing between external fixator and vascular repair, and the total time of external fixator. The present systematic review was conducted according to the PRISMA checklist. MEDLINE (Pubmed), Web of Science, and SCOPUS databases were searched for articles from 1 January 2000 to 6 February 2019. Studies reporting outcomes of treatment of knee dislocations with vascular injuries were included. Exclusion criteria included studies investigating chronic knee dislocations, knee arthroplasties, editorials, case reports, and expert opinions. Two authors independently extracted data and appraised the quality of evidence and risk of bias using the Methodological quality and synthesis of case series and case reports. Descriptive statistics were used to report the outcome of our findings. Seven studies related to the usefulness of the external fixator during acute management of knee dislocations with vascular injuries were included. The external fixator had been used in the majority of knee dislocations with vascular lesions (72%). Timing between external fixator and vascular repair was reported on four studies (57%), two studies performed external fixation before vascular repair, and two studies performed external fixation after vascular repair. Total time of external fixator was only reported on three studies, ranging from 3 weeks to 3 months. These studies reported acute management, without referring to long-term results and without comparative groups. External fixator was used in the majority of knee dislocations with vascular injuries but the justification for its use remained unclear. Larger studies are needed to fully understand the merit of the external fixator in knee dislocations with vascular injuries. Joint protocols between vascular surgeons and trauma surgeons are necessary to agree on the aspects related to the management of knee dislocations with vascular injuries. IV.


Impact of inconsistent resolution on VBM studies.
This paper considers the effects of using magnetic resonance scans with different voxel dimensions in voxel-based morphometry studies. This is of potential relevance to many longitudinal studies or any ad-hoc study that relies on pre-existing databases of subjects. In order to study this effect, a group of controls were contrasted with a group of semantic dementia as well as with a group of Alzheimer's disease patients using a mixture of different voxel dimensions scans on each side of the statistical test. Scans were interpolated using a sinc function in order to obtain a different voxel depth. The effects were measured by comparing the output of each analysis to the benchmark in which all scans had the original depth (and highest resolution), both visually and through the computation of the root-mean-square error difference between the resulting t-maps. It was shown that the impact is highly dependent on the scan itself, with some images showing more robustness to the interpolation process, and hence yielding fewer differences. A measure of robustness is proposed, which may be used in order to understand the impact of mixing different dimensions or adjusting them for each scan. Indiscriminate use of voxel dimensions on both groups was found to produce more errors (false positives/false negatives) than does an approach involving the use of balanced groups and a voxel dimension nuisance covariate.


Detection of microcystin-metal complexes by using cryospray ionization-Fourier transform ion cyclotron resonance mass spectrometry.
Complexes of microcystins (MCs) and metal ions were detected with mass spectrometry. To observe the MCs-metals complexes, CryoSpray ionization ion source was developed and it was equipped on a commercial Fourier transform ion resonance mass spectrometer. Mixtures of two MCs and five metals were applied to Fourier transform ion cyclotron resonance mass spectrometry coupled with CryoSpray. The analyses showed complexes of MC-LR-Fe(II), -Zn, -Cu, -Mg, MC-RR-Fe(II), -Zn, -Cu, and -Mg but MC-LR-Fe(III) and MC-RR-Fe(III) were not observed. Present study suggested that MCs may play roles in metal ion uptake and/or accumulation in the algal cells.


Anti-inflammatory effects of maslinic acid, a natural triterpene, in cultured cortical astrocytes via suppression of nuclear factor-kappa B.
Maslinic acid (2-α, 3-β-dihydroxyolean-12-en-28-oic acid) is a natural triterpenoid compound from Olea europaea. This compound prevents oxidative stress and pro-inflammatory cytokine generation in vitro. This study was planned to investigate the anti-inflammatory effects of maslinic acid in central nervous system by using rat astrocyte cultures stimulated with lipopolysaccharide (LPS). We evaluated different proteins implicated in the nuclear factor kappa B (NF-κB) signal transducer pathway employing Western blot and quantitative real time PCR techniques. Results demonstrated that maslinic acid treatment exerted potent anti-inflammatory action by inhibiting the production of Nitric Oxide and tumor necrosis factor alpha (TNF-α). Western blot analysis showed that maslinic acid treatment attenuated LPS-induced translocation of NF-κB p65 subunit to the nucleus and prevented LPS-induced IκBα phosphorylation in a concentration-dependent manner, Moreover, maslinic acid significantly suppressed the expression of cyclooxygenase 2 (COX-2) and inducible nitric oxide synthase (iNOS) at protein and mRNA levels. These results suggest that maslinic acid can potentially reduce neuroinflammation by inhibiting NF-κB signal transducer pathway in cultured cortical astrocytes.


Metagenomic data on the composition of bacterial communities in lake environment sediments for fish farming by next generation Illumina sequencing.
This article contains data on the bacterial communities of lagoon sediments with fish potential in the Central Andes of Peru. The surface sediment samples were collected from four lagoons destined for continental water fish farming. DNA extraction was performed from 0.5 g of sample through the Presto™ Soil DNA Extraction Kit. Bacterial sequencing of the 16S rRNA amplicon was performed on the DNA extracted from the sediment. At least 36 Phyla bacteria were detected, the bacterial communities being dominated by Proteobacteria, Cyanobacteria, Actinobacteria, Firmicutes, Chloroflexi. These data can be used for predictive analysis to gain a better understanding of the dynamics of bacterial communities in environments under pressure from fish farming.


Genome-wide linkage search for cancer susceptibility loci in a cohort of non BRCA1/2 families in Sri Lanka.
Although linkage studies have been utilized for the identification of variants associated with cancer in the world, little is known about their role in non BRCA1/2 individuals in the Sri Lankans. Hence we performed linkage analysis to identify susceptibility loci related to the inherited risk of cancer in a cohort of Sri Lankans affected with hereditary breast cancer. The Illumina global screening array having 654,027 single nucleotide polymorphism markers was performed in four families, in which at least three individuals within third degree relatives were affected by breast cancer. Two-point parametric linkage analysis was conducted assuming disease allele frequency of 1%. Penetrance was set at 90% for carriers with a 10% phenocopy rate. Thirty-one variants exhibited genome-wide suggestive HLODs. The top overall HLOD score was at rs1856277, an intronic variant in MYO16 on chromosome 13. The two most informative families also suggested several candidate linked loci in genes, including ERAP1, RPRM, WWOX, CDH1, EXOC1, HUS1B, STIM1 and TUSC1. This study provides the first step in identifying germline variants that may be involved in risk of cancer in cancer-aggregated non-BRCA1/2 families from the understudied Sri Lankan population. Several candidate linked regions showed suggestive evidence of linkage to cancer risk.


Explaining Postdischarge Care Needs of Cancer Patients: A Qualitative Study.
This study aimed to explain the postdischarge care needs of cancer patients. In this qualitative content analysis, nine cancer patients presenting to the department of chemotherapy or an oncologist's office, four of patients' accompaniments, four nurses, and two oncologists were selected purposefully until data saturation. They underwent deep individual interviews. Data were collected from October 2016 to June 2017. Data were analyzed using Zhang's method with an inductive approach to extract the themes. Data analysis led to the formation of two main categories of healing and relaxation needs (with subcategories of "respect and friendship," "trust and confidence," "relief," "patience and tolerance," "empowerment," and "protection from tension and excessive pressure") and monitoring and balancing conditions (with subcategories of "care monitoring" and "protection"). Postdischarge needs are a set of needs for primary exposure to diagnosis, outpatient attendance at the hospital and treatment centers, access to the treatment team, family readiness, and care systems and community needs for acceptance and care of these patients. The discharge plan should be designed in accordance with the needs set out above, so that the patients can meet the needs of the acute and disease encounter phase and also can manage the emerging postdischarge needs, such as empowerment.


Oscillocusis: an unusual auditory aura in migraine.
We report a 14-year-old girl with a migraine aura characterized by the sense that ambient sounds were fluctuating in intensity, as if emanating from a radio while the volume control was being altered. These auditory oscillations lasted 5 to 10 minutes and were followed by a typical migraine headache. By analogy with oscillopsia, we term this unique form of migraine aura "oscillocusis."


RPA, RFWD3 and BRCA2 at stalled forks: a balancing act.
We recently identified E3 ligase RFWD3 as a modulator of stalled fork stability in BRCA2-deficient cells. We also show that BRCA1 might function upstream of BRCA2 during fork repair and that blocking fork degradation by depleting MRE11 does not guarantee fork repair. These findings provide new insights into the workings of BRCA1 and BRCA2 in the stalled fork repair pathway.


Attention and hypnosis: neural substrates and genetic associations of two converging processes.
Although attention is a central theme in psychological science, hypnosis researchers rarely incorporate attentional findings into their work. As with other biological systems, attention has a distinct anatomy that carries out basic psychological functions. Specific brain injuries, states, and drugs can all influence attentional networks. Investigation into these networks using modern neuroimaging techniques has revealed important mechanisms involved in attention. In this age of genomics, genetic approaches can supplement these neuroimaging techniques. As genotyping becomes an affordable and technologically viable complement to phenotyping, exploratory genetic assays offer insights into the genetic bases of both attention and hypnotizability. This paper discusses relevant aspects of attentional mechanisms and their underlying neuroanatomy as they relate to hypnosis. Underlining data from attentional networks, neuroimaging, and genetics, these findings should help to explain individual differences in hypnotizability and the neural systems subserving hypnosis.


Nucleocytoplasmic transport of proteins and poly(A)+ RNA in reconstituted Tpr-less nuclei in living mammalian cells.
It is known that Tpr is a component of an intranuclear long filament which extends from the nuclear pore complex (NPC) into the nucleoplasm. Since the over-expression of the full-length of or some fragments of Tpr in living cells leads to the accumulation of poly(A)+ RNA within the nuclei, it is generally thought that a relationship exists between Tpr and the nuclear export of mRNA in mammalian cells. In contrast, the nuclear export of poly(A)+ RNA was not inhibited in a double deletion mutant of yeast Tpr homologues (Mlp1p and Mlp2p). Therefore, the precise function of Tpr remains unknown. By microinjecting two types of polyclonal antibodies which are specific to Tpr into the cytoplasm of living mammalian interphase cells, we succeeded in reconstituting the Tpr-less nuclei. In the Tpr-less nuclei, the localization of the major components of the NPC, the nuclear import of SV40 T-NLS substrates and the nuclear export of HIV Rev NES-substrates were not affected. However poly(A)+ RNA accumulated in the non-snRNP splicing factor SC35-positive clusters, which became larger in size and fewer in number, compared with normal nuclei. These results indicate that Tpr plays a critical role in the intranuclear dynamics of RNA pol II transcripts, including the processing, intranuclear transport and targeting, as well as their translocation through the NPC in mammalian cells.


Utility of Kolliphor RH 40 in micellar sensitized fluorescence of the novel tyrosine kinase inhibitor "Erdafitinib": Application to human plasma.
Erdafitinib is the first treatment targeting susceptible fibroblast growth factor receptor (FGFR) genetic alterations in patients with locally advanced or metastatic urothelial carcinoma. A simple and precise spectrofluorimetric method was developed for its determination depending on fluorescence enhancement using Kolliphor RH 40 micellar medium at pH 10. The fluorescence intensity was measured at 495 nm after excitation at 410 nm. Different experimental parameters affecting the fluorescence intensity, including type of organized medium, diluting solvent, buffer type and pH were studied during optimization phase. Validation according to ICH Q2(R1) guidance was fully fulfilled. The method was linear over the range of 50 - 800 ng/mL. The lower limit of detection (LOD) and lower limit of quantitation (LOQ) were 14.36 and 43.50 ng/mL, respectively. The relative standard deviation values of intraday and interday precisions were less than 1.93 %. The proposed method was successfully applied to laboratory-prepared tablets. Furthermore, the high sensitivity of the method allowed its application on spiked human plasma samples with a high percent of recovery. The greenness of the method was investigated as an Eco-friendly alternative for erdafitinib determination with minimal organic solvent consumption.


MiR-342-3p inhibition promotes cell proliferation and invasion by directly targeting ID4 in pre-eclampsia.
This study aimed to explore the miR-342-3p expression in pre-eclampsia (PE) placentas and confirm whether miR-342-3p exerts effects on proliferation and migration of HTR-8/SVneo trophoblastic cells. The PE placentas (n = 8) were taken from gravidas complicated by PE and delivered after 34 weeks. The chorionic plates and the basal plates were separately taken from the placenta disc near the position of umbilical cord insertion. RT-qPCR was used to measure the expression of miR-342-3p in the chorionic plates and the basal plates. Cell invasion assay and MMT assay were used to assess the effects of miR-342-3p on proliferation and migration of HTR-8/SVneo trophoblastic cells. Luciferase reporter assay and Western blotting were used to analyze the target of miR-342-3p and investigate the detailed mechanisms. The expression of miR-342-3p was upregulated in both basal plates and chorionic plates in patients with PE compared with healthy pregnant individuals. MiR-342-3p inhibitor suppressed the cell viability and invasion, and induced apoptosis in trophoblast cells. Furthermore, inhibitor of DNA binding (ID)-4 (ID4) was a direct target of miR-342-3p, and knockdown of ID4 abrogated the regulation effect of miR-342-3p on cell viability, apoptosis and invasion. Inhibition of miR-342-3p expression may suppress the occurrence of PE by targeting ID4 in vitro.


Genital footprints of extragenital tuberculosis in infertile women: Comparison of various diagnostic modalities.
Genital tuberculosis (TB) continues to remain an important cause of infertility in women, especially in developing countries. It is mostly consequent to a primary infection elsewhere in the body. The diagnosis is challenging, considering its paucibacillary nature. Although there are many studies on association of genital tuberculosis with infertility, there is paucity of literature on impact of extragenital tuberculosis on fertility of women through involvement of female reproductive organs. The various diagnostic modalities available have limitations and quest is ongoing for the best diagnostic test. This was a prospective observational study conducted at the infertility clinic of a tertiary care health facility where 60 infertile women with either tubal factor or unexplained infertility with or without past history of extragenital tuberculosis were enrolled as study subjects or controls respectively. Mantoux test was performed in all women and diagnostic laparo-hysteroscopy was performed in all women to look for any evidence of uterine and/or tubal damage. The peritoneal fluid was sent for GeneXpert and Liquid culture for mycobacterium tuberculosis. Results of Mantoux test, GeneXpert and liquid culture were compared with the laparohysteroscopic findings. Of the thirty infertile women in the study group, 27/30 (90%) had a history of pulmonary tuberculosis and 3/30 (10%) had history of tubercular cervical lymphadenopathy. It was observed that Mantoux test was positive (induration >10 mm) in 27/30 (90%) of women in the study group as compared to only 4/30 (13.3%) controls. Abnormal hysteroscopic findings were documented in 26.6% (8/30) study group women as compared to 6.6% (2/30) women in the control group. Similarly, 60% (18/30) of women in the study group had abnormal laparoscopic findings compared to 33% (10/30) in the control group. Seven out of thirty (23.3%) women were positive for GeneXpert in the study group compared to only 1/30 (3.3%) in the control group. Similarly, liquid culture was positive in 6/30 (20%) of women in the study group as compared to 1/30 (3.3%) in the control group. All the above differences were statistically significant. We observed that the sensitivity of Mantoux test (75.8%) stand alone was higher than the other tests combined (50%). However, specificity and positive predictive value (PPV) increases markedly (up to 100%) to when all the three tests are combined. The authors conclude that all women presenting with infertility should be screened for a past history of tuberculosis and actively worked up for genital tuberculosis in case the history is positive. The various available tests (Mantoux test, GeneXpert and liquid culture) have their limitations for the diagnosis of genital tuberculosis. Thus an approach of early resort to laparohysteroscopy in suspected patients is desirable so that definitive management may be instituted timely and promptly.