Knowledge, attitude, practice towards breast self-examination and associated factors among women in Gondar town, Northwest Ethiopia, 2021: a community-based study.
Breast cancer is the most common type of cancer among women, particularly in low and middle-income countries. Breast self-examination is one of the non-invasive methods of screening in which a woman looks at her breast for any abnormal findings like lumps, distortions, or swellings. Despite, realized effects of breast self-examination in detecting breast cancer earlier, the vast majority of the cases still present with an advanced stage. This study aimed to assess knowledge, attitude, and practices toward breast self-examination and associated factors among women in Gondar Town, Northwest Ethiopia, 2021. A community-based cross-sectional study was conducted on women living in Gondar town. A simple random sampling method was used to select 571 participants. Interviewer administered questionnaires were used for data collection. Data was entered into Epi-data version 4.6 and exported to Statistical Package for Social Science (SPSS) version 25 for analysis. Multivariate logistic regression was used where a p-value < 0.05 was used to identify variables significantly associated with the outcome variable. From the total of 571 women, about 541 participants were involved in the study with a response rate of 94.7%. Of these, 56%, 46% and 45.8% of women had adequate knowledge, favourable attitudes, and performed breast self-examination (BSE) respectively. Women College and above AOR: 3.8 (95% CI: 1.43-10.14) and spouses College and above AOR: 3.03 (95% CI: 1.04-8.84), Women College and above AOR: 4.18 (95% CI: 1.59-10.92) and history of breast cancer AOR: 6.06 (95% CI: 2.19-16.74) and knowledge level AOR: 2.67 (95% CI: 1.18-6.04) were significantly associated with knowledge, attitudes, and practices towards breast self-examination respectively. The findings of this study were considerable for inadequate knowledge, unfavourable attitude and poor practice towards BSE among women. Emphasis should be made on boosting the knowledge, attitude, and practice of the women toward breast self-examination and strengthening the implementation of comprehensive, systematic, and continuous BSE educational programs that were recommended along with a breast cancer awareness campaign.


Defining the molecular response to trastuzumab, pertuzumab and combination therapy in ovarian cancer.
Trastuzumab and pertuzumab target the Human Epidermal growth factor Receptor 2 (HER2). Combination therapy has been shown to provide enhanced antitumour activity; however, the downstream signalling to explain how these drugs mediate their response is not clearly understood. Transcriptome profiling was performed after 4 days of trastuzumab, pertuzumab and combination treatment in human ovarian cancer in vivo. Signalling pathways identified were validated and investigated in primary ovarian xenografts at the protein level and across a timeseries. A greater number and variety of genes were differentially expressed by the combination of antibody therapies compared with either treatment alone. Protein levels of cyclin-dependent kinase inhibitors p21 and p27 were increased in response to both agents and further by the combination; pERK signalling was inhibited by all treatments; but only pertuzumab inhibited pAkt signalling. The expression of proliferation, apoptosis, cell division and cell-cycle markers was distinct in a panel of primary ovarian cancer xenografts, suggesting the heterogeneity of response in ovarian cancer and a need to establish predictive biomarkers. This first comprehensive study of the molecular response to trastuzumab, pertuzumab and combined therapy in vivo highlights both common and distinct downstream effects to agents used alone or in combination, suggesting that complementary pathways may be involved.


Positive findings on MRI in patients with asymmetrical SNHL.
This is a retrospective study of 100 consecutive patients who attended our ENT outpatient clinic in 6 month-period from April to September 2006. All of them presented with Asymmetrical SNHL. They were all investigated with MRI scan of the IAM and CPA. We did not employ any guidelines or protocols as to when to request MRI in patients with Asymmetrical SNHL. The mean age for the studied group was 52.97. Gender distribution in the studied group was 53% for males and 47% for females. The pickup rate was 1% for CPA lesion which was vestibular schwannoma. However, incidentally, there were 15% of cases with vascular loop at the CPA.


Mass spectrometry vs immunofixation for treatment monitoring in multiple myeloma.
Monitoring of the monoclonal protein (M-protein) by electrophoresis and/or immunofixation (IFE) has long been used to assess treatment response in multiple myeloma (MM). However, with the use of highly effective therapies, the M-protein becomes frequently undetectable, and more sensitive methods had to be explored. We applied IFE and mass spectrometry (EXENT&FLC-MS) in serum samples from newly diagnosed MM patients enrolled in the PETHEMA/GEM2012MENOS65 obtained at baseline (n = 223), and after induction (n = 183), autologous stem cell transplantation (n = 173), and consolidation (n = 173). At baseline, the isotypes identified with both methods fully matched in 82.1% of samples; in the rest but 2 cases, EXENT&FLC-MS provided additional information to IFE with regards to the M-protein(s). Overall, the results of EXENT&FLC-MS and IFE were concordant in >80% of cases, being most discordances due to EXENT&FLC-MS+ but IFE- cases. After consolidation, IFE was not able to discriminate 2 cohorts with different median progression-free survival (PFS), but EXENT&FLC-MS did so; furthermore, among IFE- patients, EXENT&FLC-MS identified 2 groups with significantly different median PFS (P = .0008). In conclusion, compared with IFE, EXENT&FLC-MS is more sensitive to detect the M-protein of patients with MM, both at baseline and during treatment, and provides a more accurate prediction of patients' outcome. This trial was registered at www.clinicaltrials.gov as #NCT01916252.


The in vitro growth response of primary human colorectal and gastric cancer cells to gastrin.
A series of 31 colorectal and 13 gastric primary human tumours were screened for their growth response to human gastrin-17 in vitro, as assessed by 75Se-seleno-methionine incorporation. Fifty-five percent of colorectal and 69% of gastric tumours showed a significant trophic response to the hormone. The responses were achieved at physiological gastrin concentrations (post-prandial circulating gastrin levels) in 35% of colorectal and 55% of gastric tumours. Lymphocytes from tumour-associated lymph nodes showed no response to the hormone and "normal" mucosal cells (obtained from the resection margin of the surgical specimen) showed lower mean levels of 75Se-seleno-methionine uptake (colorectal: 110%; gastric: 119%, expressed as a percentage of the control) when compared to tumours (colorectal: 151%; gastric: 147%). The small number of well differentiated and/or Dukes' stage A colorectal tumours examined were gastrin-responsive, but all the responsive gastric tumours were poorly differentiated. With respect to ploidy, 89% of diploid and 67% of aneuploid colorectal tumours responded trophically to gastrin. Patients with colorectal or gastric tumours may benefit from treatment with gastrin antagonists.


Lateral flow immunoassay based on gold nanoparticles for rapid and sensitive detection of zoxamide in grape, tomato and cucumber samples.
In the study, we discovered zoxamide hapten (ZOX-hapten) by introducing a carboxyl extension chain, combined it with protein to make a complete antigen to immunize mice, and generated a monoclonal antibody (mAb) against ZOX. To identify ZOX residues in grape, tomato, and cucumber samples, we used our anti-ZOX mAb to develop a lateral flow immunoassay (LFIA) strip. In grape, tomato, and cucumber samples, the calculated detection limit of the LFIA strip in grape, tomato and cucumber samples was 3.44, 4.78 and 3.53 ng/g, respectively. Using the LFIA strip, the recovery rate from grape samples was 96.4-106.8%, and that from tomato samples was 98.4-107.5%, while the recovery from cucumber samples was 99.4-111.3%. These results showed that our LFIA strip could be expected to achieve rapid screening of ZOX residues in fruits and vegetables.


Emergence of gender differences in depression during adolescence: national panel results from three countries.
Although the gender gap in depression among adults is well established, the age at which this phenomenon appears during adolescence is less clear. To address this, the authors present a cross-national examination of the emergence of the gender gap in depression during adolescence using national longitudinal panel data from Canada, Great Britain, and the United States. The two-wave, 1994-1996 Canadian National Population Health Survey uses a diagnostic measure across a 24-month interval, providing 12-month prevalence rates of major depressive disorder. The British Youth Panel measures depressive symptomatology across five annual waves beginning in 1995. The two-wave, 1995-1996 National Longitudinal Study of Adolescent Health uses a measure of depressive symptomatology across a 12-month interval. Females have significantly higher rates of depression for each sample overall. When samples are decomposed by age, the gender gap in depression consistently emerges by age 14 across all three national samples, irrespective of the measure used or whether categorical cutoffs or untransformed scale scores are used to assess depressive symptomatology. There is a consistent pattern in the onset of the gender gap in depression at age 14 across all three countries and measures. This consistency provides important etiologic clues concerning underlying causes of depression and identifies at what age diagnosis, treatment, and intervention strategies should be directed.


Evaluation of the new Mycotube test-kit for yeast identification.
The performance of a modified Mycotube test for the identification of yeasts was evaluated using standard biochemical tests as reference. One hundred and eighty strains belonging to 12 medically important species (15 strains each) were tested. The overall rate of identification was 72%, and rose to 87.8% when macroscopic and microscopic morphologic features were also considered; a 100% rate was obtained with Candida albicans, Candida krusei, Candida parapsilosis, Candida pseudotropicalis, Candida tropicalis, Saccharomyces cerevisiae and Torulopsis glabrata. For the species Candida guilliermondii, Cryptococcus neoformans, Geotrichum candidum, Rhodotorula and Trichosporon cutaneum we propose a new evaluation chart and additional code numbers. Mycotube facilitates the routine identification of yeasts but recourse to macroscopic and microscopic examination may also be necessary.


Guidelines to assist hospitals in the use of ethylene oxide.
A survey undertaken by the American Society of Hospital Central Service Personnel and a study by the National Institute of Occupational Safety and Health formed the background for issuance of these guidelines. A listing of the guidelines is presented herein, including explanatory material.


Indazole as a Privileged Scaffold: The Derivatives and their Therapeutic Applications.
Heterocyclic compounds, also called heterocycles, are a major class of organic chemical compound that plays a vital role in the metabolism of all living cells. The heterocyclic compound, indazole, has attracted more attention in recent years and is widely present in numerous commercially available drugs. Indazole-containing derivatives, representing one of the most important heterocycles in drug molecules, are endowed with a broad range of biological properties. A literature search was conducted in PubMed, Google Scholar and Web of Science regarding articles related to indazole and its therapeutic application. The mechanism and structure-activity relationship of indazole and its derivatives were described. Based on their versatile biological activities, the compounds were divided into six groups: anti-inflammatory, antibacterial, anti-HIV, antiarrhythmic, antifungal and antitumour. At least 43 indazole-based therapeutic agents were found to be used in clinical application or clinical trials. This review is a guide for pharmacologists who are in search of valid preclinical/clinical drug compounds where the progress of approved marketed drugs containing indazole scaffold is examined from 1966 to the present day. Future direction involves more diverse bioactive moieties with indazole scaffold and greater insights into its mechanism.


Radiotherapy target volume definition in newly diagnosed high grade glioma using 18F-FET PET imaging and multiparametric perfusion MRI: A prospective study (IMAGG).
The aim of this study was to prospectively investigate tumor volume delineation by amino acid PET and multiparametric perfusion magnetic resonance imaging (MRI) in patients with newly diagnosed, untreated high grade glioma (HGG). Thirty patients with histologically confirmed HGG underwent O-(2-[18F]-fluoroethyl)-l-tyrosine (18F-FET) positron emission tomography (PET), conventional Magnetic Resonance Imaging (MRI) as contrast-enhanced (CE) and fluid-attenuated inversion recovery (FLAIR) and multiparametric MRI as relative cerebral blood volume (rCBV) and permeability estimation map (K2). Areas of MRI volumes were semi-automatically segmented. The percentage overlap volumes, Dice and Jaccard spatial similarity coefficients (OV, DSC, JSC) were calculated. The 18F-FET tumor volume was significantly larger than the CE volume (median 43.5 mL (2.5-124.9) vs. 23.8 mL (1.4-80.3), p = 0.005). The OV between 18F-FET uptake and CE volume was low (median OV 0.59 (0.10-1)), as well as spatial similarity (median DSC 0.52 (0.07-0.78); median JSC 0.35 (0.03-0.64)). Twenty-five patients demonstrated both rCBV and CE on MRI: The median rCBV tumor volume was significantly smaller than the median CE volume (p < 0.001). The OV was high (median 0.83 (0.54-1)), but the spatial similarity was low (median DSC 0.45 (0.04-0.83); median JSC 0.29 (0.07-0.71)). Twenty-eight patients demonstrated both K2 and CE on MRI. The median K2 tumor volume was not significantly larger than the median CE volume. The OV was high (median OV 0.90 (0.61-1)), and the spatial similarity was moderate (median DSC 0.75 (0.01-0.83); median JSC 0.60 (0.11-0.89)). We demonstrated that multiparametric perfusion MRI volumes (rCBV, K2) were highly correlated with CE T1 gadolinium volumes whereas 18F-FET PET provided complementary information, suggesting that the metabolically active tumor volume in patients with newly diagnosed untreated HGG is critically underestimated by contrast enhanced MRI. 18F-FET PET imaging may help to improve target volume delineation accuracy for radiotherapy planning.


Red cell aggregation during normal pregnancy.
Red cell aggregation (RCA) is responsible for the increase in whole blood viscosity at lower shear rates. RCA depends on the concentrations of red cells and plasma proteins with a high molecular weight and a large and asymmetrical spatial structure such as fibrinogen, immunoglobulin M and alpha 2-macroglobulin. During normal pregnancy, changes occur in all these concentrations. In a prospective study these changes and their influence on the resulting RCA were investigated in 24 healthy women with normal pregnancies. RCA was determined by light reflection measurement (syllectometry). RCA considerably increased during normal pregnancy in spite of the physiological haemodilution. The aggregation half time, used as a measure for RCA, decreased from an average non-pregnant value of 5.6 s to 3.3 s at 37 weeks. Multiple regression analysis showed that the increase in RCA could be mainly attributed to the raised fibrinogen concentration. However, at 37 weeks other factors, in addition to fibrinogen, contribute significantly to the increase in RCA.


Decreased births among black female adolescents following school desegregation.
Although the socioeconomic impact of school desegregation in the U.S. has been well documented, little is known about the health consequences of this policy. The purpose of this study was to quantify the associations between school desegregation and adolescent births among black and white females. We compared the change in prevalence of adolescent births in areas that implemented school desegregation plans in the 1970s with areas that implemented school desegregation plans in other decades, using difference-in-difference methods with 1970 and 1980 Census microdata. School desegregation policy in the U.S. in the 1970s was associated with a significant reduction of 3.2 percentage points in the prevalence of births among black female adolescents between 1970 and 1980. This association was specific to black female adolescents and was not observed among white adolescents.


High dose of formaldehyde exposure during pregnancy increases neutrophils lung influx evoked by ovalbumin in the offspring.
Considering that asthma might have their onset in the intrauterine life and the exposure to FA during pregnancy interferes in the immune system of offspring, here we hypothesized that high dose of FA exposure during pregnancy could to contribute for development and severity of asthma in the offspring. Pregnant Wistar rats were submitted to FA inhalation (6.13 mg/m(3), 1 h/day, 5 days/week, for 21 days) or vehicle (distillated water). After 30 days of birth, the offspring was sensitized with ovalbumin (OVA)-alum and challenged with aerosolized OVA (1%, 15 min, 3 days). After 24 h the OVA challenge, the analyses were performed. Non-manipulated rats were used as basal parameters. Our data show that the exposure to high dose of FA during pregnancy predisposes the development of neutrophilic lung inflammation in the offspring, as observed by the profile of cells and cytokines in the lung. This study contributes to the understanding of effects of pollution on the development of lung diseases.


Progression of a fracture site impaction as a prognostic indicator of impacted femoral neck fracture treated with multiple pinning.
We evaluated the clinical and radiologic results of impacted femoral neck fractures treated with multiple pinning and determined the influence of the progression of impaction at the fracture site on clinical outcome. There were 34 patients with a mean age of 65.5 years. The mean follow-up period was 3.4 years. Progression of fracture site impaction was measured using an articulo-trochanteric distance index and the percentage decrease in the articulo-trochanteric distance index between follow-up intervals. The failure of treatment was clarified as non-union and avascular necrosis. Other characteristics of the patients, including mean waiting time for surgery, preoperative Singh index score, and body mass index, were also measured to evaluate the influence on the clinical outcome of surgery. There were 6 fractures which were not treated successfully (3 non-union, 8.8% and 3 avascular necrosis, 8.8%). The mean percentage decrease of the articulo-trochanteric distance index within the first 6 weeks after surgery was 4.5% in the successful group and 25.1% in the failure group (p < 0.001). There was also a significant mean percentage decrease in the articulo-trochanteric distance index between 6 weeks and 3 months (p < 0.001). Primary stabilization with Knowles pins for impacted femoral neck fractures had a reasonable clinical outcome with low morbidity. Despite a significant difference of a mean percentage decrease in the articulo-trochanteric distance index between the successful group and the failure group, we could not verify it as a risk factor for failure of treatment because the odds ratio was not statistically significant.


Effects of 5-HT1C-receptor expression on cell proliferation control in hamster fibroblasts: serotonin fails to induce a transformed phenotype.
5-HT1c receptors have been shown to act as protooncogenes in NIH 3T3 cells, inducing ligand-dependent focus formation. In order to assess their mitogenic and oncogenic potential in a different cell system, we transfected these receptors into CCL39 hamster fibroblasts, a well-characterized growth factor-dependent cell line. Cell clones expressing functional receptors were isolated and tested for (a) growth factor dependence of proliferation measuring thymidine incorporation in response to varying doses of serum, (b) the response to serotonin alone or in combination with other growth factors, and (c) the capacity for anchorage-independent proliferation. In the absence or presence of serotonin, the large majority of the clones isolated showed normal morphology and normal growth factor dependence and was unable to grow in soft agar. None of the clones showed a significant response to serotonin alone in DNA synthesis reinitiation experiments, but synergy was observed between serotonin and the tyrosine kinase activating growth factors EGF and FGF. However, the major part of this effect could be abolished by an antagonist of 5-HT1b receptors, which are endogenous in CCL39 cells. The same receptor was found to mediate a significant mitogenic response to the neurotransmitter in Ha-ras-transfected cells. The fact that 5-HT1c receptors do not readily induce a transformed phenotype in CCL39 cells clearly distinguishes them from strong dominantly acting oncogene products like RAS, SRC, or FMS.


Different extraction methods bring about distinct physicochemical properties and antioxidant activities of Sargassum fusiforme fucoidans.
Fucoidan is a complex sulfated polysaccharide and an active component found in the cell wall of brown seaweeds. In the present study, fucoidans were obtained from Sargassum fusiforme using different extraction methods, including hot water (prepared fucoidan was named as WSFF), dilute hydrochloric acid (ASFF), and calcium chloride solution (CSFF). The assessments were performed on S. fusiforme fucoidans based on their chemical composition, molecular conformations, and in vitro antioxidant activities. ASFF showed the maximum extraction yield (11.24%), whereas CSFF exhibited the minimum yield (3.94%). The monosaccharide composition of WSFF, ASFF, and CSFF was similar, but the molar ratio of monosaccharide was quite different. Moreover, their molecular weight, Fourier transform infrared (FT-IR) spectrum, surface morphology, uronic acid content and degree of sulfation were distinct. The Congo red test and Circular dichroism spectroscopy analysis displayed some differences in solution conformation of these samples. Furthermore, WSFF, ASFF, and CSFF showed distinct in vitro antioxidant activities evaluated by DPPH and hydroxyl radical scavenging assays. The present study provides scientific evidence on the influences of extraction methods on the physicochemical characteristics, conformation behaviors and antioxidant activities of S. fusiforme fucoidans.


Lipoproteins may provide fatty acids necessary for human lymphocyte proliferation by both low density lipoprotein receptor-dependent and -independent mechanisms.
Human lymphocytes respond optimally to mitogenic stimulation when cultured in serum-free medium supplemented with transferrin if fatty acids necessary for maximal proliferation are provided. Either lipoproteins or exogenous fatty acids support optimal lymphocyte responses. The current studies examined the role of cell surface receptors for low density lipoprotein (LDL) in the enhancement of lymphocyte proliferation. Support of lymphocyte growth by limiting concentrations of LDL was found to involve interaction of the lipoprotein with LDL receptors. Thus, modification of LDL by reductive methylation so as to inhibit receptor-mediated interactions markedly decreased the capacity of LDL to enhance lymphocyte proliferation. Moreover, growth of lymphocytes obtained from patients with LDL receptor-negative homozygous familial hypercholesterolemia was minimal when cultures were supplemented with low concentrations of LDL (less than 10 micrograms cholesterol/ml). LDL also enhanced lymphocyte proliferation by a receptor-independent mechanism since high concentrations (greater than or equal to 50 micrograms cholesterol/ml) supported growth of both normal and familial hypercholesterolemia lymphocytes. In contrast, support of lymphocyte proliferation by high density lipoprotein (HDL) subclass 3 was completely independent of LDL receptors. Thus, HDL3 enhanced responses of both normal and familial hypercholesterolemia lymphocytes in an equivalent concentration-dependent manner; this effect was not altered by reductive methylation of HDL3. One function of lipoproteins in this system may be the provision of fatty acids since oleic and linoleic acids enhanced DNA synthesis by both normal and familial hypercholesterolemia lymphocytes in the absence of lipoproteins. These results indicate that lipoproteins may provide fatty acids necessary for optimal proliferation of human lymphocytes by both LDL receptor-mediated and LDL receptor-independent interactions.


The ghosts in the machine: DNA methylation and the mystery of differentiation.
Methylation regulates DNA by altering chromatin and limiting accessibility of transcription factors and RNA polymerase. In this way, DNA methylation controls gene expression and plays a role in ES cell regulation, tissue differentiation and the development of the organism. In abnormal circumstances methylation can also induce diseases and promote cancer progression. Chromatin remodeling proteins such as the SNF2 family member Lsh regulates genome-wide cytosine methylation patterns during mammalian development. Lsh promotes methylation by targeting and repressing repeat sequences that are imbedded in heterochromatin. Lsh also regulates cytosine methylation at unique loci. Alterations in histone modifications (such as H3K4me3, histone acetylation, H3K27me3 and H2Aub) can be associated with DNA methylation changes making Lsh-mediated cytosine methylation part of a larger epigenetic network defining gene expression and cellular differentiation during development. This article is part of a Special Issue entitled: Chromatin in time and space.


Clinical evaluation of contrast-enhanced digital mammography and contrast enhanced tomosynthesis--Comparison to contrast-enhanced breast MRI.
To compare the diagnostic accuracy of contrast-enhanced digital mammography (CEDM) and contrast-enhanced tomosynthesis (CET) to dynamic contrast enhanced breast MRI (DCE-MRI) using a multireader-multicase study. Institutional review board approval and informed consents were obtained. Total 185 patients (mean age 51.3) with BI-RADS 4 or 5 lesions were evaluated before biopsy with mammography, tomosynthesis, CEDM, CET and DCE-MRI. Mediolateral-oblique and cranio-caudal views of the target breast CEDM and CET were acquired at 2 and 4 min after contrast agent injection. A mediolateral-oblique view of the non-target breast was taken at 6 min. Each lesion was scored with forced BI-RADS categories by three readers. Each reader interpreted lesions in the following order: mammography, tomosynthesis, CEDM, CET, and DCE-MRI during a single reading session. Histology showed 81 cancers and 144 benign lesions in the study. Of the 81 malignant lesions, 44% (36/81) were invasive and 56% (45/81) were non-invasive. Areas under the ROC curve, averaged for the 3 readers, were as follows: 0.897 for DCE-MRI, 0.892 for CET, 0.878 for CEDM, 0.784 for tomosynthesis and 0.740 for mammography. Significant differences in AUC were found between the group of contrast enhanced modalities (CEDM, CET, DCE-MRI) and the unenhanced modalities (all p<0.05). No significant differences were found in AUC between DCE-MRI, CET and CEDM (all p>0.05). CET and CEDM may be considered as an alternative modality to MRI for following up women with abnormal mammography. All three contrast modalities were superior in accuracy to conventional digital mammography with or without tomosynthesis.


Timing of antiretroviral therapy initiation after diagnosis of recent human immunodeficiency virus infection and CD4(+) T-cell recovery.
We retrospectively examined the timing of antiretroviral therapy (ART) initiation and CD4(+) T-cell recovery over 36 months among recent human immunodeficiency virus (HIV) infections using BED (HIV-1 subtypes B, E and D) immunoglobulin G capture enzyme immunoassay (BED-CEIA). Regardless of baseline CD4(+) counts, individuals (n = 393) who initiated ART >2 months after diagnosis had significantly decreased probability and rate of achieving CD4(+) counts ≥900 cells/μL or ≥600 cells/μL than those individuals (n = 135) who started ART earlier (≤2 months). But the mean CD4(+) counts in two groups converged after 30 months of treatment. Early ART initiation leads to accelerated CD4(+) recovery, but does not offer a long-term advantage in CD4(+) counts.


L-glutamine for sickle cell disease: more than reducing redox.
Oxidative stress is a major contributor to the pathophysiology of sickle cell disease (SCD) including hemolysis and vaso-occlusive crisis (VOC). L-glutamine is a conditionally essential amino acid with important roles, including the synthesis of antioxidants, such as reduced glutathione and the cofactors NAD(H) and NADP(H), as well as nitric oxide. Given the increased levels of oxidative stress and lower (NADH):(NAD + + NADH) ratio in sickle erythrocytes that adversely affects the blood rheology compared to normal red blood cells, L-glutamine was investigated for its therapeutic potential to reduce VOC. While L-glutamine was approved by the United States (US) Food and Drug Administration to treat SCD, its impact on the redox environment in sickle erythrocytes is not fully understood. The mechanism through which L-glutamine reduces VOC in SCD is also not clear. In this paper, we will summarize the results of the Phase 3 study that led to the approval of L-glutamine for treating SCD and discuss its assumed mechanisms of action. We will examine the role of L-glutamine in health and propose how the extra-erythrocytic functions of L-glutamine might contribute to its beneficial effects in SCD. Further research into the role of L-glutamine on extra-erythrocyte functions might help the development of an improved formulation with more efficacy.


Adjuvant interferon therapy for patients at high risk for recurrent melanoma: an updated systematic review and practice guideline.
After complete resection of melanoma, some patients remain at high risk for recurrence. The efficacy of adjuvant systemic therapy has been inconsistent in randomised trials and remains controversial. An updated systematic review was conducted to identify new evidence on the role of adjuvant interferon therapy in patients with high-risk resected primary melanoma. Outcomes of interest included overall survival, disease-free survival (DFS), adverse effects and quality of life. MEDLINE, EMBASE, Cochrane Library and the proceedings of the American Society of Clinical Oncology were systematically searched to identify new randomised controlled trials, systematic reviews or meta-analyses. An updated meta-analysis of trials comparing high-dose interferon alpha with observation alone was conducted. The new data are presented in this review. Seven randomised controlled trials met the inclusion criteria: six trials of interferon alone and two trials of interferon plus chemotherapy. Two meta-analyses of adjuvant interferon alpha were also identified. Overall survival was not significantly different between adjuvant high-dose interferon and observation alone (hazard ratio 0.93; 95% confidence interval 0.78-1.12; P = 0.45). A meta-analysis of DFS showed a significant benefit for high-dose interferon over control (hazard ratio 0.77; 95% confidence interval 0.65-0.92; P = 0.004). One trial reported a significant DFS benefit for pegylated interferon over observation alone. Our updated literature review indicates that adjuvant interferon therapy does not confer a significant long-term overall survival benefit in patients with high-risk resected primary melanoma; however, a significant DFS benefit for high-dose interferon or pegylated interferon treatment has been shown. An revised practice guideline was developed based on the systematic review.


Acetylcholinesterase in intestinal cell differentiation involves G2/M cell cycle arrest.
Here we examine differentiation of the intestinal cell line Caco-2 following exposure to sodium butyrate (NaBT), using alkaline phosphatase (ALP) activity and carcinoembryonic antigen (CEA) levels as markers of differentiation. We show that acetylcholinesterase (AChE) activity and RNA levels increase during differentiation. Treatment with AChE inhibitors or knockdown of AChE levels by shRNA markedly decrease ALP and CEA levels in a concentration- and time-dependent manner. Finally, our observations suggest that NaBT-induced differentiation of intestinal cells involves AChE-induced cell cycle arrest.


Bioactive natural products from the genus Salinospora: a review.
Actinomycetes are an important source for bioactive secondary metabolites. Among them, the genus Salinispora is one of the first salt obligatory marine species worldwide and is typically found in various types of substrates in tropical and subtropical marine environments including sediments and marine organisms. This genus produces a wide range of chemical scaffolds and bioactive compounds such as lomaiviticins, cyclomarins, rifamycins, salinaphthoquinones, and salinosporamides. This review arranged Salinispora derived secondary metabolites according to the three species that comprise the genus. Moreover, muta- and semi-synthesis analogs derived from salinosporamide were also described in this review.


The nutrient composition of three cuts obtained from P-class South African pork carcasses.
The shoulder, loin and leg from P-class pork carcasses were used to determine the nutrient composition of both raw and cooked cuts. Significantly lower fat content were observed in the current study for the leg (5.21g/100g) and loin (6.99g/100g) compared to the shoulder cut (10.32g/100g). The overall percentage fat for all three cuts was less than 10% which is recommended by the South African Heart Mark. The cooked loin cut contained the most protein (27.50g/100g) of the three cooked cuts. When compared to other meat products (beef, mutton and chicken) it is clear that pork is a good source of B vitamins, especially vitamin B3. The cooked loin cut contained the least vitamin B1 (0.22mg/100g), B2 (0.02mg/100g) but the most vitamin B3 (7.09mg/100g), of the three cooked cuts. The 100g cooked shoulder, loin and leg cuts provide on average 40.11% protein, 5.19% magnesium, 3.37% calcium, 24.29% phosphorus, 18.22% zinc, 22.33% iron and 22.50% vitamin B1, 2.57% vitamin B2 and 42.6% vitamin B3 of Recommended Daily Allowances for males, age 25-50. Energy from a 100g portion provides 5.81% of the Recommended Daily Allowances. To conclude, the pork cuts are undoubtedly a good source of nutrients that is required for good health because it is high in protein, have a low fat content and are a nutrient-packed choice for the family and compares favourably with the fat, energy, and cholesterol content of many other meats and poultry.


Platelet glycoprotein Ibα provides radiation protection.
Platelet membrane glycoprotein Ibα (GPIbα), the major ligand-binding subunit of the GPIb-IX-V complex, binds to a number of ligands contributing to hemostasis, thrombosis, and inflammation. Binding to von Willebrand factor (VWF) initiates the process of hemostasis/thrombosis, while binding to the leukocyte receptor Macrophage-1 antigen (Mac-1) has been implicated in modulating the inflammatory response. Thus as GPIbα resides at the nexus of thrombosis and inflammation, we investigated the impact of GPIbα on radiation injury outcomes as this injury triggers both the thrombotic and inflammatory pathways. We used wild-type (WT) C57BL/6J mice and a dysfunctional GPIbα mouse model, in which endogenous GPIbα is replaced with a non-functional α-subunit (hIL-4R/Ibα), to determine whether the impairment of platelet GPIbα alters radiation response. Following exposure to 8.5 Gy total body irradiation (TBI), a series of parameters including radiation lethality, platelet-neutrophil/monocyte interactions, neutrophil/monocyte activation, serum cytokine levels and intestinal injury, were compared between the strains. The lack of functional GPIbα resulted in higher radiation lethality, greater monocyte activation, increased levels of serum pro-inflammatory cytokines, heightened intestinal damage, and a reduction of intestinal neutrophil recovery. These data suggest that loss of platelet GPIbα enhances radiation toxicity and that GPIbα-mediated interactions may play a crucial role in limiting radiation damage. Thus, a mechanistic understanding of the biological impact of GPIbα following TBI could provide crucial insights for improving the safety of radiotherapy and minimizing the deleterious effects of accidental or occupational exposure to high-dose radiation.


Fetal growth of the anal sinus and sphincters, especially in relation to anal anomalies.
The anal sinuses, small furrows above the pectinate line, sometimes form perianal abscesses in adults. We examined the pattern of fetal growth of the anal sinus and sphincters using 22 mid-term (8-18 weeks) and 6 late-stage (30-38 weeks) fetuses. In mid-term fetuses, the external and internal sphincters gradually increased in thickness, depending on specimen size (from 0.2 to 1.5 mm), whereas the anteroposterior diameter of the anal canal at the epithelial junction was relatively stable (0.5-1.0 mm) irrespective of specimen size. Anal canal diameter increased less than twofold between mid-term and late-stage fetuses, from 0.5-1.0 to almost 2 mm, whereas sphincter thickness increased over tenfold, from 0.2-1.5 to almost 3.5 mm. The anal sinus often showed balloon-like enlargement when the sphincter muscle bundles were tightly packed in mid-term, but not in late-stage fetuses. Large concentric mechanical stress from the sphincters in late-stage fetuses apparently prevented the anal sinus from expanding in a balloon-like manner. Conversely, to avoid anal stenosis, the growing sinuses maintained a luminal space of the anal canal in response to stress from rapidly growing sphincters. The inferiorly extending sinus usually provided temporal double canals separated by a thick column. In the presence of double lumens, anal canal duplication is likely to develop without any abnormalities of the anal epithelium and sphincters.


A pilot study of intraarterial chemotherapy with cisplatin in locally advanced head and neck cancers.
A prospective pilot study involving preoperative intraarterial chemotherapy with cisplatin in locally advanced oral and oropharyngeal carcinomas was initiated in March 1982. Twenty patients with TNM Stages III and IV disease underwent continuous intraarterial chemotherapy with cisplatin (90 mg/m2, at 1 mg/hour) and intravenous chemotherapy with methotrexate (50 mg/m2 X 1 dose). Arterial access was obtained by retrograde cannulation of the superficial temporal artery. One patient died of sepsis from leukopenia (mortality 5%). Catheter-related complications, most of them avoidable, totalled 30%. The total tumor response rate was 94%. With a median duration of follow-up of 14 months, the median survival of the group was not yet reached at 39 months. Eleven patients subsequently underwent definitive surgery and radiation with curative intent. When compared with matched historical controls, survival benefit was demonstrated: 60% versus 28% alive at 39 months (P = 0.015). Regional chemotherapy of cancers of the head and neck region is a feasible procedure with acceptable and avoidable morbidity. It should continue to be investigated in experimental protocols to improve patient survival.


Contrast column interruption artefact in computed tomography pulmonary angiography.
Interruption of the contrast column during inspiration can lead to non-diagnostic CT pulmonary angiograms. The importance of this artefact will increase with more CT studies being performed for pulmonary embolism on multidetector row CT. We describe here an instance of such an artefact and discuss its aetiology.


Idiopathic chronic pancreatitis treated with ivacaftor in a CFTR carrier with methylmalonic acidemia.
CFTR mutation carriers, numbering 1 in 25 among Caucasians, have an increased risk of developing chronic pancreatitis due to the underlying dysfunction of ion channels created by the mutant allele. Carriers do not frequently manifest disease due to the remaining wild-type CFTR protein sufficiently maintaining normal pancreatic homeostasis. However, additional risk factors for pancreatitis, such as organic acidemias (as seen in our patient) that further impact function of pancreatic acinar cells can result in the precipitation of CFTR related pancreatitis. Here we report a CFTR carrier with methylmalonic acidemia who was treated with ivacaftor and subsequently experienced resolution of her chronic pancreatitis. Our report suggests that ivacaftor may rescue the function of mutant CFTR in carriers and treat pancreatitis caused by CFTR dysfunction in situations where there are additional precipitating factors.


Effect of glucan on neutrophil dynamics and immune function in Escherichia coli peritonitis.
Previous studies from our laboratory have demonstrated that glucan, a nonspecific immunomodulator, modifies the course of murine Escherichia coli peritonitis. The protective effect of glucan was mediated, in part, by macrophages. In the present study, leukocyte dynamics in the peritoneal cavity and peripheral blood of glucan-treated mice following E. coli challenge was examined. Additional studies examined in vitro bone marrow proliferation, as well as phagocytosis and intracellular killing of E. coli by neutrophils following glucan administration. ICR/HSD mice were injected ip with glucan (150 mg/kg) or dextrose (5% w/v) on Days 5 and 3 prior to ip challenge with 1 X 10(8) E. coli. Glucan increased (P less than 0.05) total peritoneal neutrophil numbers prior to and following septic challenge. Examination of peripheral blood revealed that ip glucan treatment in E. coli peritonitis significantly (P less than 0.001) increased the number of circulating neutrophils. Additionally, neutrophils from glucan-treated mice showed increased phagocytosis of E. coli in vitro. Glucan therapy also increased bone marrow proliferation. We conclude that (1) glucan enhances peritoneal neutrophil levels, (2) peripheral blood neutrophils are increased following glucan and E. coli, (3) ip glucan increases bone marrow proliferation, and (4) neutrophils from glucan-treated mice showed enhanced phagocytosis of E. coli in vitro. Thus, the beneficial effect of glucan is mediated not only by activated macrophages, but also by the neutrophilic leukocyte.


Influence of the molecular structure of surface-attached poly(N-alkyl acrylamide) coatings on the interaction of surfaces with proteins, cells and blood platelets.
Blood protein adsorption and blood platelet adhesion onto surface-attached poly(alkylacrylamide) networks that exhibit small and systematic variations in chemical composition are investigated. The polymer coatings are generated by depositing a thin layer of benzophenone-group-containing copolymer onto a solid substrate, followed by photo crosslinking and simultaneous surface-attachment. The correlation of the swelling of the obtained surface-attached networks with the adsorption of blood proteins and cellular adhesion is studied. The swollen surface-attached layers are inert to blood proteins and platelet cells. These results suggest that the hydrogel-coated materials are promising candidates for the generation of hemocompatible surfaces.


The release of petroleum hydrocarbons from a saline-sodic soil by the new biosurfactant-producing strain of Bacillus sp.
Adsorption of old-aged petroleum hydrocarbons to the soil solid phase, which causes biosurfactant loss of performance, is among the limiting factors for the remediation of the saline-sodic soils contaminated with petroleum. Therefore, to find a functional biosurfactant in oil-contaminated saline-sodic soils, the efficiency of 39 bacteria isolated from petroleum-contaminated soils was evaluated. The strains were cultured in the Bushnell-Haas medium, and the produced biosurfactants and bioemulsifiers in this medium were extracted using chloroform/methanol and ethyl acetate extraction methods, respectively. Their partial purification was performed by column chromatography, and eventually, their performance in releasing TPH from the contaminated soil was evaluated. The soil test results revealed that the highest TPH releases due to the effects of the biosurfactants and bioemulsifier produced from SHA302, SH21, and SH72 isolates were 42.4% ± 0.2, 21.6% ± 0.15 and 24.3% ± 0.91, respectively. Based on the 16S rRNA gene sequence, the SHA302 strain showed 93.98% phylogenetic similarity with Bacillus pumilus strain ATCC 7061. The Fourier transform infrared spectroscopy and thin-layer chromatography results proved that the biosurfactants produced by isolates SHA302, SH21 and SH72 showed lipopeptide, glycolipoprotein and glycoprotein natures, respectively. The performance of the biosurfactant produced by SHA302 isolate indicated that it could be used as a good candidate for releasing TPH from saline-sodic soils with old contamination and facilitating the degradation of hydrocarbons.


Defects dynamics during ageing cycles of InGaN blue light-emitting diodes revealed by evolution of external quantum efficiency--current dependence.
We report in detail the defect dynamics in the active region by monitoring the external quantum efficiency (EQE) - injection current curves, I-V curves, and electroluminescence spectra during the ageing test, under a forward current of 850 mA (85 A/cm2), room temperature. We apply a two-level model to analyze the EQE curves and the electroluminescence spectra. The results suggest that high injection density during the ageing may reduce the density of the Shockley-Reed-Hall nonradiative recombination centers and enhance the carrier mobility and diffusion length. The former effect would directly lead to initial surge of EQE, whereas the latter would enhance the effect of extended defects which leads to reduction in peak EQE and increase in EQE droop rate.


Cyclic Heterometallic Interactions formed from a Flexible Tripeptide Complex Showing Effective Antiferromagnetic Spin Coupling.
Developing tunable motifs for heterometallic interactions should be beneficial for fabricating functional materials based on cooperative electronic communications between metal centers. Reported here is the efficient formation of cyclic heterometallic interactions from a complex containing an artificial tripeptide with metal binding sites on its main chain and side chains. X-ray structural analysis and X-ray absorption spectroscopy revealed that the cyclic metal-metal arrangements arise from the amide groups connecting four square-planar CuII centers and four octahedral NiII centers in a cyclic manner. UV/Vis spectral studies suggested that this efficient formation was achieved by the selective formation of the square-planar CuII centers and a crystallization process. Magnetic measurements using SQUID clarified that the cyclic complex represented the S=2 spin state at low temperatures due to effective antiferromagnetic interactions between the NiII and CuII centers.


Phylogenetic species recognition and hybridisation in Lasiodiplodia: A case study on species from baobabs.
Lasiodiplodia species (Botryosphaeriaceae, Ascomycota) infect a wide range of typically woody plants on which they are associated with many different disease symptoms. In this study, we determined the identity of Lasiodiplodia isolates obtained from baobab (Adansonia species) trees in Africa and reviewed the molecular markers used to describe Lasiodiplodia species. Publicly available and newly produced sequence data for some of the type strains of Lasiodiplodia species showed incongruence amongst phylogenies of five nuclear loci. We conclude that several of the previously described Lasiodiplodia species are hybrids of other species. Isolates from baobab trees in Africa included nine species of Lasiodiplodia and two hybrid species. Inoculation trials with the most common Lasiodiplodia species collected from these trees produced significant lesions on young baobab trees. There was also variation in aggressiveness amongst isolates from the same species. The apparently widespread tendency of Lasiodiplodia species to hybridise demands that phylogenies from multiple loci (more than two and preferably four or more) are compared for congruence prior to new species being described. This will avoid hybrids being incorrectly described as new taxa, as has clearly occurred in the past.


Design of SPECT for BNCT to measure local boron dose with GAGG scintillator.
Boron Neutron Capture Therapy (BNCT) is a promising cancer therapy, which has recently been in practical use in Japan especially using an accelerator. In BNCT real-time measurement of local boron dose is required. In the present study, a novel design of a SPECT system for BNCT (BNCT-SPECT) has been carried out to realize estimation of the local boron dose, i.e., treatment effect of BNCT. Necessary performance which BNCT community requires includes accuracy of 5% and spatial resolution of 5 mm, which are regarded to be difficult to realize. A possible design was investigated to meet the requirements. The design results we achieved are as follows: As for the elemental detection device, GAGG (3.5 × 3.5 × 30 mm3) was selected, and for the collimator, the collimator hole diameter was 3.5 mm, the collimator hole pitch was 4 mm and the collimator length was 26 cm. For the obtained performance with the design, the accuracy was 4.4% and the spatial resolution was 5.1 mm. Currently prior to production of the real system, a prototype of BNCT-SPECT is being developed to acquire real projection data to confirm the performance and examine our own image reconstruction method with the obtained projection data.


[Pain management in 2023].
Pain is a frequent symptom for healthcare professionals in the community and in hospital. Appropriate management of pain begins with a precise and comprehensive assessment, whether acute or chronic. The available therapies are summarized below, so that they can be used as closely as possible to the pathophysiology of pain. Available drug analgesics are reinforced by non-drug interventions, which are increasingly present in the algology care offering. In 2023, the authorities have announced a new ten-year national plan for pain and palliative care. Proof that this public health issue, at the heart of caregivers' concerns, is also a priority for political leaders.


Coherently averaged dual-comb spectroscopy with a low-noise and high-power free-running gigahertz dual-comb laser: erratum.
This erratum corrects a typographical error in equation (8) of our published paper [Opt. Express31, 7103 (2023)10.1364/OE.479356]. All the calculations used the correct equation, so all the results and conclusions remain unchanged.


Immune thrombocytopenic purpura due to mixed viral infections.
An 11-year-old boy presented with epistaxis, petechial hemorrhages, easy bruising, and purpuric rash. He was diagnosed to have immune thrombocytopenic purpura and evidence of concomitant parvovirus B19 and dengue viral infection.


Mycobacterium smegmatis fatty acid synthetase. A mechanism based on steady state rates and product distributions.
The initial steady state rate and product distribution of fatty acid synthesis catalyzed by Mycobacterium smegmatis fatty acid synthetase has been investigated as a function of various concentrations of acetyl-CoA, malonyl-CoA, mycobacterial polysaccharide, and bovine serum albumin. Polysaccharide has a large effect on both rate and chain length. The steady state rate stimulation by polysaccharide is not duplicated by other acyl-CoA-binding molecules such as bovine serum albumin. It is concluded that relief of product inhibition does not adequately explain the specific effects of the mycobacterial polysaccharide. A general mechanism is presented which accounts for variations in reaction rate and produce pattern over a wide range of experimental conditions. We propose that the diffusion of long chain acyl-CoA (C14 to C24) from the enzyme is the rate-limiting step in fatty acid synthesis catalyzed by the M. smegmatis synthetase. Polysaccharide facilitates this rate-limiting step by forming a ternary complex with enzyme-bound acyl-CoA causing rapid release of product.


Circulating endothelial cells: a novel marker of endothelial damage.
Circulating endothelial cells (CECs) were first described over 30 years ago in smears of peripheral blood. Since then, more sophisticated techniques for CEC isolation have become available. In particular, immunomagnetic isolation and fluorescence-activated cell sorting (FACS) have been employed with success. We provide a short historical perspective and a comprehensive review on the subject. We review isolation and enumeration of CECs with an emphasis on CD146-driven immunomagnetic isolation and FACS. We describe, in great detail, advantages and pitfalls of both approaches and compare their specificity. Moreover, we provide a comprehensive list of clinical studies in this field and describe the possible clinical use of CECs. We also describe the phenotype of these cells and list typical surface markers. In addition, we review the phenotype of CECs and discuss mechanisms of detachment. We speculate about potential interactions between CECs and other cell subsets. We also describe other serum markers of endothelial damage and compare CECs with these markers. Finally, we highlight differences between circulating endothelial cells and endothelial progenitor cells. In summary, CECs must now be regarded as a sensitive and specific marker of endothelial damage. We emphasize that use of CECs in a clinical setting is on the horizon and pathogenetic clues may also be obtained.


Effect of antenatal corticosteroid administration on Doppler flow velocity parameters in pregnancies with absent or reverse end-diastolic flow in the umbilical artery.
Evaluation of alterations of Doppler flow velocity waveforms after antenatal corticosteroid therapy. Pulsatility index of the umbilical artery, middle cerebral artery and ductus venosus waveforms was measured in high-risk pregnancies complicated by umbilical AREDV directly prior to and within 24 or 48 hours after application of the first dose of a steroid treatment course. Return of a positive end-diastolic flow after umbilical AREDV or conversion of REDV into zero-flow was detected in 9 of 20 (45%) pregnancies after steroid application. Neither in the group which showed altered umbilical end-diastolic flow nor in the total of patients investigated was there any significant change in the PI of the umbilical artery or the ductus venosus waveforms. In contrast, there was an overall drop of pulsatility in the middle cerebral artery. Antenatal corticosteroid administration could increase cerebral perfusion but has no influence on umbilical and venous blood flow.


Memantine increases brain production of kynurenic acid via protein kinase A-dependent mechanism.
We describe a novel aspect of action of memantine ex vivo, in the brain cortical slices and in vitro, in mixed glial cultures. The drug potently increased the production of kynurenic acid, an endogenous tryptophan metabolite blocking N-methyl-D-aspartate (NMDA) and nicotinic alpha7 receptors. In cortical slices memantine, an open-channel NMDA blocker (100-150 microM), but not the competitive NMDA receptor antagonist, LY235959 increased the production of kynurenic acid. Neither SCH23390, D1 receptor antagonist (50 microM) nor raclopride, D2 receptor antagonist (10 microM) changed the memantine-induced effects. Propranolol (100 microM) has partially reduced its action. Selective cAMP-dependent protein kinase (PKA) inhibitor, KT5720 (1 microM), but not selective protein kinase C (PKC) inhibitor, NPC15437 (30 microM) totally reversed the action of memantine. In mixed glial cultures, 2-24 h incubation with memantine (2-50 microM) enhanced the production of kynurenic acid. Memantine (up to 0.5 mM) has not affected the activity of kynurenic acid biosynthetic enzymes. The obtained data suggest that memantine enhances the production of kynurenic acid in PKA-mediated way. This effect may partially contribute to the therapeutic actions of memantine and be of a potential clinical importance.


The electrodiagnostic approach to carpal tunnel syndrome.
CTS is a clinically defined syndrome; however, there is value added by an evidence-based electrodiagnostic approach to (1) efficiently confirm the diagnosis (particularly before invasive interventions), (2) to identify neurogenic mimickers or superimposed processes that may influence the response to treatment, and (3) to stratify the degree of neurogenic injury to help the clinician make management decisions in conjunction with the severity of the clinical symptoms. The literature on the electrodiagnostic diagnosis of CTS is reviewed and an evidence based diagnostic algorithm is proposed. Confounders to CTS electrodiagnostic diagnosis are discussed (crossovers, peripheral neuropathy, and recurrent symptoms after surgical release).


[A experimental study on arthroscopic subchondral drilling for repair of osteochondral defect of temporomandibular joint (TMJ)].
To investigate the resurfacing ability of TMJ cartilage of rhesus monkeys with osteochondral defect. 3-millimeter-diameter, 5-millimeter-depth, cylindrical full-thickness drilled osteochondral defect of articular cartilage on the functional slope of TMJ were made on 12 rhesus monkeys(24 joints) by arthroscope. Every 3 monkeys were sacrificed at 4, 8, 12 and 24 weeks postoperatively and the repaired tissue were studied by gross observation, histology and immunohistochemical staining (IHC). The repaired tissues after subchondral drilling were dominated with fibrous tissues and IHC showed that Type II collagen stain was negative and Type I collagen stain was positive. The osteochondral defect in TMJ can be repaired by arthroscopic subchondral drilling. The nature of repaired tissue is fibrous connective tissue, something different from normal cartilage. Subchondral drilling can be regarded as one of the treatments for articular cartilage defect.


The effects of L-659,066, a peripheral alpha2-adrenoceptor antagonist, on dexmedetomidine-induced sedation and bradycardia in dogs.
To investigate the influence of L-659,066, a peripheral alpha2-adrenoceptor antagonist, on dexmedetomidine-induced sedation and reduction in pulse rate (PR) in dogs. Randomized, cross-over. Animals Six healthy laboratory Beagles. All animals received dexmedetomidine (5 microg kg(-1) IV, DEX) alone or in combination with L-659,066 (250 microg kg(-1) IV, DEX + L) with a 7-day rest period between treatments. Sedation was assessed using a composite sedation score and PRs were recorded. Atipamezole (50 microg kg(-1) IM, ATI) was administered to reverse the sedation. Overnight Holter-monitoring was carried out to obtain a minimum heart rate (MHR) at rest. Bioequivalence was shown for clinical sedation between DEX and DEX + L. Heart rate was significantly higher with DEX + L during the period of sedation. Bioequivalence was demonstrated between MHR and PR in the DEX + L group during the period of sedation. Recoveries after ATI were uneventful. L-659,066 did not affect the quality of dexmedetomidine-induced sedation whilst it attenuated the reduction in PR. Thus, L-659,066 could prove a useful adjunct to reduce the peripheral cardiovascular effects attributed to dexmedetomidine in dogs. The clinical safety of alpha2-adrenoceptor agonists could be markedly improved with less peripheral cardiovascular effects.


Unravelling the Mechanism of Intermediate-Temperature CO2 Interaction with Molten-NaNO3 -Salt-Promoted MgO.
The optimization of MgO-based adsorbents as advanced CO2 -capture materials is predominantly focused on their molten-salt modification, for which theoretical and experimental contributions provide great insights for their high CO2 -capture performance. The underlying mechanism of the promotion effect of the molten salt on CO2 capture, however, is a topic of controversy. Herein, advanced experimental characterization techniques, including in situ environmental transmission electron microscopy (eTEM) and CO2 chemisorption by diffuse-reflectance infrared Fourier transform spectroscopy (DRIFTS), transient 18 O-isotopic exchange, and density functional theory (DFT), are employed to elucidate the mechanism of the CO2 interaction with molten-salt-modified MgO in the 250-400 °C range. Herein, eTEM studies using low (2-3 mbar) and high (700 mbar) CO2 pressures illustrate the dynamic evolution of the molten NaNO3 salt promoted and unpromoted MgO carbonation with high magnification (<50 nm). The formation of 18 O-NaNO3 (use of 18 O2 ) and C16 O18 O following CO2 interaction, verifies the proposed reaction path: conversion of NO3 - (NO3 - → NO2 + + O2- ), adsorption of NO2 + on MgO with significant weakening of CO2 adsorption strength, and formation of [Mg2+ … O2- ] ion pairs preventing the development of an impermeable MgCO3 shell, which largely increases the rate of bulk MgO carbonation.


Leukocytoclastic vasculitis (cutaneous small-vessel vasculitis) after COVID-19 vaccination.
Vaccinations may induce cutaneous adverse events, due to nonspecific inflammation or immuno-mediated reactions. Several types of vasculitis have been observed. We report on a 71-year-old woman who developed cutaneous small-vessel vasculitis after the second dose of Vaxzevria COVID-19 vaccination, showing leukocytoclastic vasculitis on histopathological examination of a skin biopsy. Cutaneous small-vessel vasculitis is a rare condition which can be idiopathic or secondary to underlying infections, connective tissue disorders, malignancy, and medications. The pathogenesis involves immune complex deposition in small blood vessels, leading to activation of the complement system and recruitment of leukocytes. Exacerbation of small-vessel vasculitis has been reported following the administration of various vaccines, particularly influenza vaccine. It is expected that SARS-CoV-2 vaccine results in the activation of B- and T-cells and antibody formation. We hypothesize that leukocytoclastic vasculitis caused by immune complex deposition within cutaneous small vessels could be a rare side effect of Vaxzevria COVID-19 vaccination.


Enantioselective Formal [4+1] Cycloaddition of Diazoarylacetates and the Danishefsky's Diene: Stereoselective Synthesis of (-)-1,13-Herbertenediol.
Rodium chiral diene complex-catalyzed enantioselective cycloaddition of aryl α-diazoarylacetates and electron-enriched Danishefsky-type dienes afforded highly functionalized and optically enriched cyclopentenones in excellent yields (up to 97% yield) and with good to excellent enantioselectivities (60-92% ee). (-)-1,13-Herbertenediol was successfully synthesized in an overall 25% yield employing the optically enriched cyclopentenone with an all-carbon quaternary center as the key intermediate.


Operational use of multispectral images for macro-litter mapping and categorization by Unmanned Aerial Vehicle.
The use of Unmanned Aerial Systems (UAS, aka drones) has shown to be feasible to perform marine litter surveys. We operationally tested the use of multispectral images (5 bands) to classify litter type and material on a beach-dune system. For litter categorization by their multispectral characteristics, the Spectral Angle Mapping (SAM) technique was adopted. The SAM-based categorization of litter agreed with the visual classification, thus multispectral images can be used to fasten and/or making more robust the manual RGB image screening. Fully automated detection returned an F-score of 0.64, and a reasonable categorization of litter. Overall, the image-based litter density maps were in line with the manual detection. Assessments were promising given the complexity of the study area, where different dunes plants and partially-buried items challenged the UAS-based litter detection. The method can be easily implemented for both floating and beached litter, to advance litter survey in the environment.


Stent implantation at the site of the myocardial bridge after myocardial infarction. Long-term results.
Although myocardial bridge is asymptomatic in most patients, it can lead to myocardial ischemia, myocardial infarction, cardiac arrhythmias, and sudden death. The authors report the case of a symptomatic myocardial bridge treated by classical stenting of the mid left anterior descending artery. The outcome was good. A control coronary angiography performed 36 months later showed no significant restenosis. No recurrence of angina during five years follow-up was observed.


Experimental investigation on the minimum ignition temperature of hybrid mixtures of dusts and gases or solvents.
Investigations on the minimum ignition temperatures (MIT) of hybrid mixtures of dusts with gases or solvents were performed in the modified Godbert-Greenwald (GG) furnace. Five combustible dusts and six flammable gases (three ideal and three real) were used. The test protocol was according to EN 50281-2-1 for dust-air mixtures whereas in the case of gases, solvents and hybrid mixtures this standard was used with slight modification. The experimental results demonstrated a significant decrease of the MIT of gas, solvent or dust and an increase in the likelihood of explosion when a small amount of dust, which was either below the minimum explosion concentration or not ignitable by itself, was mixed with gas and vice versa. For example, the MIT of toluene decreased from 540°C to 455°C when small amount of lycopodium was added. It was also confirmed that a hybrid mixture explosion is possible even when both dust and vapour or gas concentrations are respectively lower than their minimum explosion concentration (MEC) and lower explosion limit (LEL). Another example is CN4, the MEC of which of 304 g/m(3) decreased to 37 g/m(3) when propane was added, even though the concentrations of the gas was below its LEL.


Airborne fine particulate matter induces multiple cell death pathways in human lung epithelial cells.
Our group was the first one reporting that autophagy could be triggered by airborne fine particulate matter (PM) with a mean diameter of less than 2.5 μm (PM2.5) in human lung epithelial A549 cells, which could potentially lead to cell death. In the present study, we further explored the potential interactions between autophagy and apoptosis because it was well documented that PM2.5 could induce apoptosis in A549 cells. Much to our surprise, we found that PM2.5-exposure caused oxidative stress, resulting in activation of multiple cell death pathways in A549 cells, that is, the tumor necrosis factor-alpha (TNF-α)-induced pathway as evidenced by TNF-α secretion and activation of caspase-8 and -3, the intrinsic apoptosis pathway as evidenced by increased expression of pro-apoptotic protein Bax, decreased expression of anti-apoptotic protein Bcl-2, disruption of mitochondrial membrane potential, and activation of caspase-9 and -3, and autophagy as evidenced by an increased number of double-membrane vesicles, accompanied by increases of conversion and punctuation of microtubule-associated proteins light chain 3 (LC3) and expression of Beclin 1. It appears that reactive oxygen species (ROS) function as signaling molecules for all the three pathways because pretreatment with N-acetylcysteine, a scavenger of ROS, almost completely abolished TNF-α secretion and significantly reduced the number of apoptotic and autophagic cells. In another aspect, inhibiting autophagy with 3-methyladenine, a specific autophagy inhibitor, enhanced PM2.5-induced apoptosis and cytotoxicity. Intriguingly, neutralization of TNF-α with an anti-TNF-α special antibody not only abolished activation of caspase-8, but also drastically reduced LC3-II conversion. Thus, the present study has provided novel insights into the mechanism of cytotoxicity and even pathogenesis of diseases associated with PM2.5 exposure.


Arterial stiffness and progression of white matter hyperintensities of presumed vascular origin in community-dwelling older adults of Amerindian ancestry: The Atahualpa Project Cohort.
Arterial stiffness - as measured by the aortic pulse wave velocity (aPWV) - has been associated with biomarkers of cerebral small vessel disease (cSVD), in particular with white matter hyperintensities (WMH) of presumed vascular origin. Most studies have been conducted in White and Asian populations, and information on this relationship in other ethnic groups is limited. We designed a longitudinal prospective study to assess the impact of aPWV on WMH progression in individuals of Amerindian ancestry. Participants of the Atahualpa Project Cohort were assessed at baseline with aPWV determinations, clinical interviews and brain MRIs. At the end of the study, brain MRIs were repeated in order to ascertain WMH progression. Poisson regression models adjusted for demographics and cardiovascular risk factors were fitted to assess WMH progression incidence rate by baseline levels of aPWV. The study included 260 individuals aged ≥60 years (mean age: 65.6 ± 6.1 years; 57 % women). The mean aPWV was 9.9 ± 1.5 m/s. Follow-up MRIs revealed WMH progression in 102 (39 %) individuals after a mean follow-up of 6.5 ± 1.4 years. Unadjusted analysis showed a higher baseline aPWV among subjects that developed WMH progression compared with those who did not (p < 0.001). Multivariate Poisson regression models showed an increased WMH progression rate among individuals in the second (IRR: 2.06; 95 % C.I.: 1.09-3.88) and third (IRR: 2.75; 95 % C.I.: 1.29-5.87) tertiles of aPWV compared with those in the first tertile. aPWV is associated with WMH progression, suggesting a link between atherosclerosis and cSVD in the study population.


Tailoring neoadjuvant treatment of HR-positive/HER2-negative breast cancers: Which role for gene expression assays?
Neoadjuvant chemotherapy (NACT) for breast cancer (BC) increases surgical and conservative surgery chances. However, a significant proportion of patients will not be eligible for conservative surgery following NACT because of large tumor size and/or low chemosensitivity, especially for hormone receptor (HR)-positive/ human epidermal growth factor receptor 2 (HER2)-negative tumors, for which pathological complete response rates are lower than for other BC subtypes. On the other hand, for luminal BC neoadjuvant endocrine therapy could represent a valid alternative. Several gene expression assays have been introduced into clinical practice in last decades, in order to define prognosis more accurately than clinico-pathological features alone and to predict the benefit of adjuvant treatments. A series of studies have demonstrated the feasibility of using core needle biopsy for gene expression risk testing, finding a high concordance rate in the risk result between biopsy sample and surgical samples. Based on these premises, recent efforts have focused on the utility of gene expression signatures to guide therapeutic decisions even in the neoadjuvant setting. Several prospective and retrospective studies have investigated the correlation between gene expression risk score from core needle biopsy before neoadjuvant therapy and the likelihood of 1) clinical and pathological response to neoadjuvant chemotherapy and endocrine therapy, 2) conservative surgery after neoadjuvant chemotherapy and endocrine therapy, and 3) survival following neoadjuvant chemotherapy and endocrine therapy. The purpose of this review is to provide an overview of the potential clinical utility of the main commercially available gene expression panels (Oncotype DX, MammaPrint, EndoPredict, Prosigna/PAM50 and Breast Cancer Index) in the neoadjuvant setting, in order to better inform decision making for luminal BC beyond the exclusive contribution of clinico-pathological features.


High-grade serous ovarian carcinoma with a sertoliform pattern associated with BRCA mutation: a clinicopathological and molecular analysis.
Herein, we report a clinicopathological and molecular analysis of a case of tubo-ovarian high-grade serous carcinoma (HGSC) with a sertoliform pattern. A 45-year-old woman underwent surgery due to an advanced bilateral adnexal carcinoma with peritoneal and appendiceal metastases. Histological examination revealed an HGSC exhibiting a distinct sertoliform component. Such component showed diffuse PAX8, p53 (mutation-type), and p16 (block-type) expression, increased vimentin and decreased WT1 expression compared to the conventional HGSC component, membrane β-catenin positivity, heterogeneous estrogen, and progesterone positivity, and retained PTEN and mismatch repair expression and negativity for GATA3, TTF1, inhibin, calretinin, CD10, CDX2, chromogranin, and synaptophysin. Molecular analysis showed a germline BRCA2 mutation; no mutations were detected in POLE, POLD1, MLH1, MSH2, MSH6, PMS2, APC, CTNNB1, MUTYH, and EPCAM. In conclusion, a sertoliform pattern can be part of the morphological spectrum of BRCA-related HGSC.


A new technique for the evaluation of the adrenal gland with gray scale ultrasonography.
Recent improvements in ultrasound instrumentation have provided the potential resolution to visualize the normal adrenal gland. However, conventional scanning approaches lack precise anatomic alignment. A new technique for scanning the adrenal gland and the results of a prospective evaluation of normal adrenal glands are presented.


Prognostic significance of monitoring leukemia-associated immunophenotypes by eight-color flow cytometry in adult B-acute lymphoblastic leukemia.
Minimal residual disease (MRD) is of the most important factor for predicting prognosis and guiding treatment of acute lymphoblastic leukemia (ALL). In this study, we investigated the prognostic significance of leukemia-associated immunophenotypes (LAIPs) as assessment of index of MRD in 125 adult B-lineage ALL (B-ALL) patients by eight-color flow cytometry. The LAIPs could be identified in 96% and 81.6% of patients with the sensitivity of 10(-4) and 10(-5), respectively. MRD-negative status could clearly predict a favorable 2-year relapse-free survival (RFS) and overall survival (OS) at the end of induction of complete remission and one cycle of consolidation treatment. Moreover, we identified a group of cases with MRD of 0.001% to <0.01%, which showed significantly higher 2-year relapse rate than those with undetectable one. In multivariate analysis, MRD status was associated with RFS or OS independently. Furthermore, MRD assessed by LAIPs and RQ-PCR assay for patients with BCR-ABL fusion gene yielded concordant results in 89.7% of cases. In conclusion, MRD evaluated by eight-color flow cytometry could provide an important tool to assess treatment response and prognosis precisely in adult B-ALL.


Chlorophyll-carotenoid excitation energy transfer and charge transfer in Nannochloropsis oceanica for the regulation of photosynthesis.
Nonphotochemical quenching (NPQ) is a proxy for photoprotective thermal dissipation processes that regulate photosynthetic light harvesting. The identification of NPQ mechanisms and their molecular or physiological triggering factors under in vivo conditions is a matter of controversy. Here, to investigate chlorophyll (Chl)-zeaxanthin (Zea) excitation energy transfer (EET) and charge transfer (CT) as possible NPQ mechanisms, we performed transient absorption (TA) spectroscopy on live cells of the microalga Nannochloropsis oceanica We obtained evidence for the operation of both EET and CT quenching by observing spectral features associated with the Zea S1 and Zea●+ excited-state absorption (ESA) signals, respectively, after Chl excitation. Knockout mutants for genes encoding either violaxanthin de-epoxidase or LHCX1 proteins exhibited strongly inhibited NPQ capabilities and lacked detectable Zea S1 and Zea●+ ESA signals in vivo, which strongly suggests that the accumulation of Zea and active LHCX1 is essential for both EET and CT quenching in N. oceanica.


The role of maternal body mass index in outcomes of vaginal births after cesarean.
To evaluate the association between maternal body mass index and obstetrical outcome in patients with a prior cesarean undergoing a trial of labor versus elective repeat cesarean. A perinatal database between 1991 and 1997 was used to identify secundipara at term after a previous cesarean section. In different groups according to maternal body mass index, the rates of successful vaginal birth after caesarean, uterine scar separation, and other obstetrical outcomes were evaluated. Of 8580 patients with a prior cesarean, 1862 (21.7%) underwent an elective repeat cesarean and 6718 (78.3%) underwent a trial of labor. Maternal body mass index correlated inversely with the rate of successful vaginal birth after caesarean but not with the rate of uterine scar separation. After adjustment for confounding factors including maternal age, birth weight, induction of labor, and preeclampsia, maternal body mass index remained associated with a lower rate of successful vaginal birth after cesarean. Maternal body mass index is an independent factor associated with a lower rate of successful vaginal birth after cesarean.


Fascin in Cell Migration: More Than an Actin Bundling Protein.
Fascin, an actin-binding protein, regulates many developmental migrations and contributes to cancer metastasis. Specifically, Fascin promotes cell motility, invasion, and adhesion by forming filopodia and invadopodia through its canonical actin bundling function. In addition to bundling actin, Fascin has non-canonical roles in the cell that are thought to promote cell migration. These non-canonical functions include regulating the activity of other actin-binding proteins, binding to and regulating microtubules, mediating mechanotransduction to the nucleus via interaction with the Linker of the Nucleoskeleton and Cytoskeleton (LINC) Complex, and localizing to the nucleus to regulate nuclear actin, the nucleolus, and chromatin modifications. The many functions of Fascin must be coordinately regulated to control cell migration. While much remains to be learned about such mechanisms, Fascin is regulated by post-translational modifications, prostaglandin signaling, protein-protein interactions, and transcriptional means. Here, we review the structure of Fascin, the various functions of Fascin and how they contribute to cell migration, the mechanisms regulating Fascin, and how Fascin contributes to diseases, specifically cancer metastasis.


Sleep Duration, Sleep Quality and Physical Activity, but Not Sedentary Behaviour, Are Associated with Positive Mental Health in a Multi-Ethnic Asian Population: A Cross-Sectional Evaluation.
We assessed the associations of sleep, physical activity and sedentary behaviour with positive mental health (PMH) in the multi-ethnic population of Singapore. The Singapore Health 2 study is a nationally representative cross-sectional survey among residents aged 18-79 years. A PMH instrument was administered to 1925 participants to obtain total PMH and six sub-component scores. Self-rated sleep duration, sleep quality, sedentary behaviour and physical activity were assessed. Multivariable linear regression analyses were conducted. The mean age of the participants was 40.1 (SD 14.3) years. Sleep duration (≥8 h/night: β = 0.17,95% CI: 0.02-0.32; 7-< 8 h/night: β = 0.17,95% CI: 0.03-0.30 versus <6 h/night, p = 0.002), sleep quality (very good: β = 0.45,95% CI: 0.29-0.60; fairly good: β = 0.20,95% CI: 0.06-0.33 versus very/fairly bad; ptrend < 0.001) and physical activity (high: β = 0.19,95% CI: 0.05-0.32; moderate: β = 0.15, 95% CI: 0.03-0.27 versus low; ptrend < 0.001) were directly associated with total PMH. Sedentary behaviour was not significantly associated with PMH. Sleep duration, sleep quality and physical activity were directly associated with the PMH sub-components 'emotional support' and 'personal growth and autonomy'. Duration and quality of sleep and physical activity were directly associated with PMH in an urban Asian population. These findings support incorporating sleep and physical activity interventions to improve population mental health.


Comparable Esophagectomy Outcomes by Surgeon Specialty: A NSQIP Analysis.
A few observational studies have found that outcomes after esophagectomies by thoracic surgeons are better than those by general surgeons. Non-emergent esophagectomy cases were identified in the 2016-2017 American College of Surgeons NSQIP database. Associations between patient characteristics and outcomes by thoracic versus general surgeons were evaluated with univariate and multivariate logistic regression. Of 1,606 cases, 886 (55.2%) were performed by thoracic surgeons. Those patients differed from patients treated by general surgeons in race (other/unknown 19.3% vs 7.8%; P<.001) but not in other baseline characteristics (age, sex, BMI, and comorbidities). Thoracic surgeons performed an open approach more frequently (48.9% vs 30.8%, P<.001) and had operative times that were 30 minutes shorter (P<.001). General surgeons had lower rates of reoperation (11.8% vs 17.2%; P=.003) and were more likely to treat postoperative leak with interventional means (6.3% vs 3.4%, P=.01). Thoracic surgeons were more likely to treat postoperative leak with reoperation (5.9% vs 3.6%, P=.01). There were no other differences in univariate comparison of outcomes between the two groups, including leak, readmission, and death. General surgery specialty was associated with lower risk of reoperation. Our multivariable model also found no relationship between general surgeon and risk of any complication (odds ratio 1.10; 95% CI .86 to 1.42). In our large, national database study, we found that outcomes of esophagectomies by general surgeons were comparable with those by thoracic surgeons. General surgeons managed postoperative leaks differently than thoracic surgeons.


Fluoroquinolone-resistant Neisseria gonorrhoeae isolates from Russia: molecular mechanisms implicated.
During a longitudinal study of the prevalence of antimicrobial resistance in Neisseria gonorrhoeae, a number of high-level fluoroquinolone-resistant isolates were obtained from the sexually transmitted diseases clinic in the Moscow region in 2002. The aim of the present study was to determine the molecular mechanisms of resistance and to assess the clonal relationship of these strains For the 32 clinical strains of N. gonorrhoeae studied, the MIC values were determined for four fluoroquinolones. The gyrA, parC, por and mtrR genes were studied for the presence of mutations associated with fluoroquinolone resistance. We detected strains of N. gonorrhoeae showing high-level resistance to fluoroquinolones (21 strains, with MICs 1-32 mg/L). Mutations in gyrA and parC known to cause fluoroquinolone resistance were detected in a majority of strains. There were four strains (among 21) without known changes in gyrA and parC. However, amino acid changes in the Por protein and mutations in the promoter or encoding region of the mtrR gene were detected in three of them. One strain had no alteration in gyrA, parC, por or mtrR. The present study documents the first case of fluoroquinolone-resistant N. gonorrhoeae in Russia.


Evaluation of underground hydraulic fracturing using transient electromagnetic method.
The effective area of hydraulic fracturing is the core index to evaluate its effects. Through conducting transient electromagnetic tests, this paper deals with the influential range of the underground hydraulic fracturing as well as water-cut detection and gas extraction in the fracturing area. The resistivity response law of the coal seam in hydraulic fracturing process is explored, and the water-bearing area is determined. The obtained results from the tests show that the water-cut areas of the coal seam, measured by anti-interference transient electromagnetic instrument after fracturing, are commonly placed in the low-resistance area of the transient test. Further, the variations of amplitude of the low-resistance area in various directions of the test line are different. According to the variation law of the apparent resistivity of the coal seam before and after fracturing, the effective influential area of the hydraulic fracturing is defined, and the influence range is evaluated to be 35 m. The water cut and the gas extraction tests of the coal seam before and after fracturing are performed. The results reveal that the growth of water content in the coal seam is inversely proportional to the distance from the hydraulic fracturing borehole. The effective fracturing zone with the increment of the water content reaching 0.2% is the effective fracturing zone, and the effective fracturing zone of #9 and #10 is 38 m. After hydraulic fracturing, the gas extraction concentration would be in the range of 25.4-75.4%, with the average of 70.22%, which is 21.22% higher than that of the original coal body. The net amount of the gas extraction after fracturing is about eight times of that before fracturing. The effective fracturing range, which is determined by transient electromagnetic, is verified successfully. Exploring the effective fracturing regions of the hydraulic fracturing process would be very helpful in improving the evaluation system of the hydraulic fracturing effect.


A novel matrine derivative, WM130, inhibits activation and movement of human hepatic stellate LX-2 cells by targeting cofilin 1.
Matrine, one of the active ingredients of Sophora flavescens Ait., has a protective effect in animal models on acute liver injury and liver fibrosis. However, since the protective effects are short-lived, a structural modification of matrine is needed to improve its anti-fibrotic effects. In the previous study we obtained a stable, highly active new matrine derivative, WM130, and explored its anti-fibrotic effects on the human hepatic stellate cell line, LX-2. CCK-8, wound healing, and transwell assays were used to investigate cell proliferation and migration, while 3D mimic study was used to determine the target of WM130. Western blots investigated the levels of α-SMA, cofilin 1, p-cofilin 1, F-actin, PI3K, p-Akt, Akt, and PTEN in LX-2 cells treated with MW130. The results revealed that WM130 can significantly inhibit the proliferation of LX-2 cells at an IC50 of 60 μg/ml. At 30 µg/ml, matrine or WM130 significantly inhibited the migration of LX-2 cells. Moreover, WM130 significantly reduced the expression of α-SMA, cofilin 1, F-actin, PI3K, and p-Akt, and increased PTEN levels. In conclusion, WM130 inhibits the proliferation, activation, and migration of human hepatic stellate LX-2 cells by targeting cofilin 1. The online version contains supplementary material available at 10.1007/s10616-022-00548-w.


Enhanced Ectasia Detection Using Corneal Tomography and Biomechanics.
To test the accuracy of the Tomographic and Biomechanical Index (TBI) for ectasia detection in an independent population from the original study. Retrospective case-control study. Subjects: Patients were grouped according to clinical diagnosis including corneal topography (front-surface curvature): Normal group, including 1 eye randomly selected from 312 patients with normal corneas; Keratoconus group, including 1 eye randomly selected from 118 patients with keratoconus; a nonoperated ectatic eye from 57 patients with very asymmetric ectasia (57 eyes, VAE-E group), and the nonoperated fellow eye with normal topography (57 eyes, VAE-NT group). The ability of TBI to distinguish normal and ectatic corneas; and comparison with other indexes, including the Belin/Ambrósio Deviation Index (BAD-DI) and the Corvis Biomechanical Index (CBI), considering the areas under receiver operating characteristic curves (AUCs). The AUC of the TBI was statistically higher than all other tested parameters (DeLong, P < .001). Considering all cases, the cut-off value of 0.335 for the TBI provided a sensitivity of 94.4% and a specificity of 94.9% (AUC = 0.988; 95% confidence interval [CI] 0.982-0.995). Considering the VAE-NT group, optimized TBI cut-off value of 0.295 provided a sensitivity of 89.5% and a specificity of 91.0% (AUC = 0.960; 95% CI 0.937-0.983). The TBI was more accurate than all parameters tested for differentiating normal from ectatic corneas. The TBI may epitomize ectasia susceptibility and distinguish cases with fruste disease from true unilateral cases among the eyes with normal-topography VAE.


Bioisosteric Development of Multitarget Nonsteroidal Anti-Inflammatory Drug-Carbonic Anhydrases Inhibitor Hybrids for the Management of Rheumatoid Arthritis.
Multitarget nonsteroidal anti-inflammatory drug (NSAID)-carbonic anhydrase inhibitor (CAI) agents for the management of rheumatoid arthritis are reported. The evidence of the plasma stability of the amide-linked hybrids previously reported prompted us to investigate their pain-relieving mechanism of action. A bioisosteric amide to ester substitution yielded a series of derivatives showing potent target CAs inhibition and to undergo cleavage in rat or human plasma depending on the NSAID portion. A selection of derivatives were assayed in vitro to indirectly evaluate their effect on COX-1 and COX-2. MD simulations demonstrated that the entire hybrids are also able to efficiently bind the COX active site. In a rat model of RA, the most promising derivative (5c) showed major antihyperalgesic action compared with the equimolar coadministration of the single agents. The gathered data provided new insights on the action mechanism of these multitarget compounds, which induce markedly improved pain relief compared with the parent NSAIDs.


The prevalence of teat canal infections in lactating dairy cows as determined from foremilk and teat canal swab samples.
The diagnostic reliability of techniques for determining the prevalence of teat canal infections varies: bacteriological results obtained by examination of teat canal swabs were 20% higher on average than those of foremilk samples (FMS) examined and classified according to the criteria of the International Dairy Federation (IDF). Since they are based exclusively on the bacterio-cytological results of the FMS, the IDF criteria for the classification of the various forms of subclinical udder conditions do not permit an accurate classification of the health status of the udder.


Adrenoceptor-activated nitric oxide synthesis in salivary acinar cells.
We investigated the cellular regulation of nitric oxide synthase (NOS) activity in isolated acinar cells from rat parotid and human labial salivary glands, using the newly developed fluorescent nitric oxide (NO) indicator, DAF-2. We found that sympathetic stimulation with norepinephrine (NE) caused a strong increase in NO synthesis that was not seen after parasympathetic stimulation with acetylcholine. In rat parotid acinar cells, we furthermore investigated to which extent the NOS activity was dependent on the intracellular free Ca2+ concentration ([Ca2+]i) by simultaneously measuring NO synthesis and [Ca2+]i. It was found that a simple correlation between the rise in [Ca2+]i and the rate of NO production following NE stimulation does not exist, and studies in which [Ca2+]i was elevated by means of the Ca2+ ionophore, ionomycin, further established that even a very large rise in [Ca2+]i did not cause significant NO synthesis. We furthermore found that activating adrenoceptors with NE causes synthesis of cGMP by activating a guanylyl cyclase, and that an enhanced [cGMP] evoked by use of caged cGMP causes Ca2+ release from internal stores. Thus, upon sympathetic stimulation, salivary gland acini synthesize NO that, in addition to playing a role in controlling intracellular [Ca2+]i, also might play a role in retrograde signaling processes to the surrounding tissue.


CD154 polymorphism in Spanish populations. Differences in the allelic distribution between Canary islanders and Peninsulars.
The CD154 gene contains a dinucleotide repeat (CA)n in the 3' untranslated region. Allelic distribution in Spanish populations from two areas with different genetic background, the Canary Islands and Peninsula, are described. Seven alleles with different allelic distribution between the two groups, were found. This represents a highly polymorphic marker, useful for genetic studies on a critical molecule in immunity.


Induction of FoxP3+CD4+CD25+ regulatory T cells by a bone marrow population distinct from plasmacytoid-DC.
Facilitating cells (FC) are bone marrow-derived cells that facilitate allogeneic hematopoietic stem cell (SC) engraftment and induce transplantation tolerance without causing graft vs. host disease. Although there is evidence for FC directing the development of FoxP3+CD4+CD25+ regulatory T cells, the specific FC subsets that control regulatory T cell development have not been defined. The current study investigates the role of FC-CD3epsilon+ and FC-CD3epsilon- subpopulations in the development of FoxP3+CD4+CD25+ regulatory T cells. Here, we demonstrate that the induction of FoxP3+CD4+CD25+ regulatory T cells in coculture is mediated by not only the FC-CD3epsilon- subset but also the FC-CD3epsilon+ subset, which is distinct from plasmacytoid precursor dendritic cells (p-preDC). The identification of cell populations distinct from p-preDC that efficiently induce the generation of FoxP3+CD4+CD25+ regulatory T cells may prove useful for future therapeutic applications for the induction of tolerance following allogeneic SC transplantation.


Generation and partial characterization of melanoma sublines resistant to lymphokine activated killer (LAK) cells. Relevance to doxorubicin resistance.
To see whether a tumor cell population may contain cells resistant to lymphokine-activated killer (LAK) lymphocytes, cells from a LAK-sensitive melanoma line (Me 665/2) were co-cultured with LAKs. Three sublines were obtained after 1, 2 or 3 immunoselection cycles. Immunoselected (IS) sublines show reduced proliferation, decreased reactivity to the monoclonal antibody (MAb) R24 and appeared morphologically more differentiated in comparison with the parental Me 665/2 line. A progressively reduced sensitivity to LAKs was observed in IS sublines with a more than 8-fold reduction in LAK susceptibility. A reduced complement (C)-mediated lysis was also observed in IS sublines. Since we have previously shown that LAK sensitivity of melanoma cells may be associated with Doxorubicin (Dx) resistance, the sensitivity to Dx was tested in these lines. An augmented sensitivity to Dx was noted in IS sublines as compared with Me 665/2. The differences in LAK susceptibility between the IS sublines and the parental Me 665/2 line remained stable for 2 weeks but declined and disappeared thereafter. These results indicate that (1) a LAK-sensitive tumor line may contain a subpopulation of cells which are significantly less lysed by LAKs; (2) a correlation between LAK sensitivity and susceptibility to C-mediated lysis is also present; and (3) increased sensitivity to Dx is evident in the IS sublines.


Discovery of novel human inosine 5'-monophosphate dehydrogenase 2 (hIMPDH2) inhibitors as potential anticancer agents.
The enzyme inosine 5'-monophosphate dehydrogenase (IMPDH) catalyzes an essential step in the de novo biosynthesis of guanine nucleotides, and thus regulates the guanine nucleotide pool required for cell proliferation. Of the two isoforms, human IMPDH type 2 (hIMPDH2) is a validated molecular target for potential immunosuppressive, antiviral and anticancer chemotherapy. In search of newer hIMPDH2 inhibitors as potential anticancer agents, three novel series (A: 5-aminoisobenzofuran-1(3H)-one, B: 3,4-dimethoxyaniline and C: benzo[d]-[1,3]dioxol-5-ylmethanamine) were synthesized and evaluated for in vitro and cell-based activities. A total of 37 molecules (29-65) were screened for their in vitro hIMPDH2 inhibition, with particular emphasis on establishing their structure-activity relationship (SAR) trends. Eight compounds (hits, 30, 31, 33-35, 37, 41 and 43) demonstrated significant enzyme inhibition (>70% @ 10 μM); especially the A series molecules were more potent than B series (<70% inhibition @ 10 μM), while C series members were found to be inactive. The hIMPDH2 IC50 values for the hits ranged from 0.36 to 7.38 μM. The hits displaying >80% hIMPDH2 inhibition (30, 33, 35, 41 and 43) were further assessed for their cytotoxic activity against cancer cell lines such as MDA-MB-231 (breast adenocarcinoma), DU145 (prostate carcinoma), U87 MG (glioblastoma astrocytoma) and a normal cell line, NIH-3T3 (mouse embryonic fibroblast) using MTT assay. Most of the compounds exhibited higher cellular potency against cancer cell lines and notably lower toxicity towards NIH-3T3 cells compared to mycophenolic acid (MPA), a prototypical hIMPDH2 inhibitor. Two of the series A hits (30 and 35) were evaluated in human peripheral blood mononuclear cells (hPBMC) assay and found to be better tolerated than MPA. The calculated/predicted molecular and physicochemical properties were satisfactory with reference to drug-likeness. The molecular docking studies clearly demonstrated crucial interactions of the hits with the cofactor-binding site of hIMPDH2, further providing critical information for refining the design strategy. The present study reports the design and discovery of structurally novel hIMPDH2 inhibitors as potential anticancer agents and provides a guide for further research on the development of safe and effective anticancer agents, especially against glioblastoma.


Alignment modification for pencil eye shields.
Accurate alignment of pencil beam eye shields to protect the lens of the eye may be made easier by means of a simple modification of existing apparatus. This involves drilling a small hole through the centre of the shield to isolate the rayline directed to the lens and fabricating a suitable plug for this hole.