Scalability and severity of keratoconus in children.
To assess the severity of keratoconus at diagnosis and its scalability over a period of 2 years in children compared to adults. A retrospective monocentric study was conducted in the National Reference Center for Keratoconus, Bordeaux (France), between October 1997 and November 2010. In total, 216 patients were studied, comprising 49 patients (22.7%) aged ≤ 15 and 167 patients (77.3%) aged ≥ 27 years at diagnosis, who were seen within 2 years of diagnosis. Severity at diagnosis was assessed using Krumeich's classification, and the scalability criteria of the US Food and Drug Administration (2010) were used. Student t tests and χ(2) tests were performed to compare the 2 groups. Keratoconus in children was significantly more severe at diagnosis, with 27.8% being stage 4 vs 7.8% of adults (P < .0001). In addition, ophthalmoscopic signs were more frequent in children (42.9% vs 29.5%, P = .05), while mean values of maximum, average, and minimum keratometry as well as simulated keratometric astigmatism were higher (P < .0001, P = .0002, P = .0005, and P = .001, respectively). After diagnosis, keratoconus did not evolve more frequently in children. However, in the case of progression, keratoconus evolved faster in children, with significant differences in the spherical equivalent and maximum and minimum keratometry (P = .03, P = .02, P = .04, respectively). At diagnosis, keratoconus is often more advanced in children than in adults, with faster disease progression. Early detection and close monitoring are therefore crucial in young patients.


Activation of ubiquitin-dependent DNA damage bypass is mediated by replication protein a.
Replicative DNA damage bypass, mediated by the ubiquitylation of the sliding clamp protein PCNA, facilitates the survival of a cell in the presence of genotoxic agents, but it can also promote genomic instability by damage-induced mutagenesis. We show here that PCNA ubiquitylation in budding yeast is activated independently of the replication-dependent S phase checkpoint but by similar conditions involving the accumulation of single-stranded DNA at stalled replication intermediates. The ssDNA-binding replication protein A (RPA), an essential complex involved in most DNA transactions, is required for damage-induced PCNA ubiquitylation. We found that RPA directly interacts with the ubiquitin ligase responsible for the modification of PCNA, Rad18, both in yeast and in mammalian cells. Association of the ligase with chromatin is detected where RPA is most abundant, and purified RPA can recruit Rad18 to ssDNA in vitro. Our results therefore implicate the RPA complex in the activation of DNA damage tolerance.


Deciphering the export pathway of malaria surface proteins.
The intra-erythrocytic stages of Plasmodium falciparum assemble a unique protein trafficking system that targets parasite proteins to the red cell cytoplasm and cell surface. It is through this trafficking pathway that the primary virulence determinants of P. falciparum infections are targeted to the erythrocyte surface to mediate adhesion to host endothelial cells. A recent study has shown that SBP-1, a parasite protein associated with Maurer's clefts in the infected red cell cytosol, is essential for transport of the virulence factor PfEMP-1. This discovery sheds new light on the little-understood mechanisms that regulate protein trafficking in infected cells.


Bisphosphonate osteonecrosis of the jaw: a historical and contemporary review.
The use of bisphosphonate drugs has been popularised in the late 20th century for the management of many conditions associated with abnormalities of bone turnover, particularly metastatic and haematogenous malignancy and osteopenia. The increase in indications for the use of bisphosphonates was supported by what was thought to be a very good safety profile. However in 2003 cases of osteonecrosis related to the use of bisphosphonates were first described. The pathogenesis, and with this the explanation of why it only appears to affect the maxillofacial skeleton, and the best way of managing this problem remains unknown. In this review we examine the process of identification of this pathology and the development of guidelines from medical societies and professional bodies on the management of patients before commencing bisphosphonate therapy, requiring dental treatment whilst on therapy, or with a diagnosis of bisphosphonate associated osteonecrosis of the jaws.


Organ-specific, carcinogenic dibenzo[c,g]carbazole derivatives: discriminative response in S. typhimurium TA100 mutagenesis modulated by subcellular fractions of mouse liver.
7H-Dibenzo[c,g]carbazole (DBC) has carcinogenic effects on mouse subcutaneous fibroblasts and liver; the N-methyl derivative (N-MeDBC) induces only sarcomas; 3-methyl- and 5,9-dimethyldibenzo[c,g]carbazole (3-MeDBC and 5,9-DMeDBC) are specific, potent hepatocarcinogens in mice. The mutagenicity in S. typhimurium TA100 of these 4 compounds was evaluated in relation to the concentration of mouse liver 9000 X g supernatant (S9) and to the proportions of microsomes and cytosol in the medium. Optimal mutagenicity of N-MeDBC was seen with a low concentration of S9 or microsomes; a 5-10 times higher concentration of the subcellular fraction was necessary to induce optimal mutagenicity of the hepatocarcinogens 3-MeDBC and 5,9-DMeDBC. Intermediate quantities were needed in the case of DBC, which is carcinogenic in both cell types. Whereas the presence of cytosol had an inhibitory effect on the mutagenicity of the sarcomagenic N-MeDBC, the cytosolic fraction was essential for optimal mutagenic expression by the 2 hepatocarcinogenic derivatives. The activating cytosolic fraction is not inducible. These experiments show that programmed modulation of the metabolic activation system in the Ames test can be used to study organ-specific chemical carcinogenesis. The results suggest that differences in the enzymatic composition of target tissues are a determining factor in the organ specificity of carcinogens such as DBC.


[Application of internal standardization to rapid coprecipitation technique using APDC-Cu(II) for FAAS determination of lead in salt].
A method was proposed for the determination of trace lead in salt with flame atomic absorption spectrometry after preconcentration of lead by rapid coprecipitation technique with APDC-Cu(II) using nickel as an internal standard at pH 2.5. The standard addition recovery of lead is between 92%-101%. The detection limit is 3.27 x 10(-3) microg x mL(-1) when the sample volume is 100 mL. The effect of matrix can be overcome by the method, and the results are satisfying. The method proposed here is rapid and has good reproducibility.


On-chip generation and dynamic piezo-optomechanical rotation of single photons.
Integrated photonic circuits are key components for photonic quantum technologies and for the implementation of chip-based quantum devices. Future applications demand flexible architectures to overcome common limitations of many current devices, for instance the lack of tuneabilty or built-in quantum light sources. Here, we report on a dynamically reconfigurable integrated photonic circuit comprising integrated quantum dots (QDs), a Mach-Zehnder interferometer (MZI) and surface acoustic wave (SAW) transducers directly fabricated on a monolithic semiconductor platform. We demonstrate on-chip single photon generation by the QD and its sub-nanosecond dynamic on-chip control. Two independently applied SAWs piezo-optomechanically rotate the single photon in the MZI or spectrally modulate the QD emission wavelength. In the MZI, SAWs imprint a time-dependent optical phase and modulate the qubit rotation to the output superposition state. This enables dynamic single photon routing with frequencies exceeding one gigahertz. Finally, the combination of the dynamic single photon control and spectral tuning of the QD realizes wavelength multiplexing of the input photon state and demultiplexing it at the output. Our approach is scalable to multi-component integrated quantum photonic circuits and is compatible with hybrid photonic architectures and other key components for instance photonic resonators or on-chip detectors.


Identification of White Wines by using Two Oppositely Charged Poly(p-phenyleneethynylene)s Individually and in Complex.
We present a simple array composed of an anionic and a cationic poly(para-phenyleneethynylene) (PPE), together with an electrostatic complex between the two of them. The individual PPEs and the PPE complex were employed in the sensing of white wines at pH 13; the complex was also successfully employed as a sensor element at pH 3. The sensing mechanism is fluorescence quenching. Thirteen different wines were differentiated by this chemical tongue, which consists of four elements. The fluorescence quenching is not induced by the major components of the wines. Compounds such as acids, sugars, and alcohols alone do not quench the fluorescence, but rather the colored tannins and other polyphenols contained in wine are the main quenchers. However, the major constituents of wine significantly modulate the quenching of the PPEs by the tannins.


Prevalence of celiac disease in adult patients with iron-deficiency anemia of obscure origin in Kashmir (India).
The purpose of this study was to evaluate the prevalence of celiac disease in adult patients with iron-deficiency anemia of obscure origin. One hundred and sixty-one consecutive patients with iron-deficiency anemia of obscure origin were evaluated. Tissue transglutaminase antibodies levels were done and duodenal biopsies were scored according to Marsh classification. Diagnosis was based on positive IgA anti-tissue transglutaminase antibodies and abnormal histopathology. Gluten-free diet (GFD) was adviced for celiac disease patients. One hundred and sixty healthy blood donors were tested for IgA anti-tissue transglutaminase antibodies, and positive controls were subjected to endoscopic duodenal biopsy. Tissue transglutaminase antibodies were positive in 13 (8 %) patients with iron-deficiency anemia of obscure origin and 4 (2.5 %) in control group (p = 0.026) (odds ratio 3.42; 95 % confidence interval [CI]: 1.092-10.743). All 13 patients (8 %) and 2 out of 4 positive controls (1.25 %) had histopathology findings of celiac disease (p = 0.004). Duodenal biopsy showed Marsh grade 1 in 4, grade 2 in 4 (30.77 %), 3a in 1 (7.70 %), 3b in 2 (15.38 %), and 3c in 2 (15.38 %) patients. A statistically significant correlation was found between lower hemoglobin concentration and higher Marsh grading (Spearman's rho = -0.946, p = 0.001). Celiac disease patients adhered to GFD and after 6 months mean (SD) hemoglobin levels increased from 7.42 ± 0.96 to 10.47 ± 0.80 g/dL (p- < 0.001). Patients with iron-deficiency anemia of obscure origin had increased prevalence of celiac disease. Gluten-free diet improved anemia in celiac disease patients irrespective of grade of duodenal involvement.


Evaluating the ability of some natural phenolic acids to target the main protease and AAK1 in SARS COV-2.
Researchers are constantly searching for drugs to combat the coronavirus pandemic caused by SARS-CoV-2, which has lasted for over two years. Natural compounds such as phenolic acids are being tested against Mpro and AAK1, which are key players in the SARS-CoV-2 life cycle. This research work aims to study the ability of a panel of natural phenolic acids to inhibit the virus's multiplication directly through Mpro and indirectly by affecting the adaptor-associated protein kinase-1 (AAK1). Pharmacophore mapping, molecular docking, and dynamic studies were conducted over 50 ns and 100 ns on a panel of 39 natural phenolic acids. Rosmarinic acid (16) on the Mpro receptor (- 16.33 kcal/mol) and tannic acid (17) on the AAK1 receptor (- 17.15 kcal/mol) exhibited the best docking energy against both receptors. These favourable docking score values were found to be superior to those of the co-crystallized ligands. Preclinical and clinical research is required before using them simultaneously to halt the COVID-19 life cycle in a synergistic manner.


Evaluation of different smoking habits during music festivals through wastewater analysis.
Wastewater analysis is a powerful method that can provide useful information about the abuse of legal and illicit drugs. The aim of our study was to determine nicotine consumption during four different music festivals and to find a connection between smoking and preferences for specific music styles using wastewater analysis. The amount of the nicotine metabolite cotinine was monitored in wastewater at the influent of three waste water treatment plants WWTPs in the Czech Republic and Slovakia, where the festivals took place. Urinary bio-markers of nicotine utilization were analyzed by LC-HRMS. More than 80,000 festival participants were monitored during our study from June to September 2014. A significant increase of nicotine consumption was observed in wastewaters during music festivals. The nicotine ingestion level was back-calculated and expressed as mass of pure drug consumed per day and per 1000 inhabitants for selected cities of both countries. The highest differences between typical levels of cotinine in wastewaters and the levels during music festivals were detected in Piešťany: 4 g/L/1000 inhabitants during non-festival days compared to 8 g/L/1000 inhabitants during the Topfest pop-rock festival and 6g/L/1000 inhabitants during the Grape dance festival. No significant increase of the amounts of cotinine in wastewater was recorded for the Country and Folk festivals.


Increased Surgical Complications but Improved Overall Survival with Adult Living Donor Compared to Deceased Donor Liver Transplantation: A Systematic Review and Meta-Analysis.
Living donor liver transplantation (LDLT) provides an alternative to deceased donor liver transplantation (DDLT) for patients with end-stage liver disease in the circumstance of scarcity of deceased grafts. However, the outcomes of LDLT remain controversial. A systematic review and meta-analysis were performed to compare the outcomes of LDLT with DDLT. Twelve outcomes were assessed. Thirty-nine studies involving 38563 patients were included. LDLT was comparable in red blood cell transfusion, perioperative mortality, length of hospital stay, retransplantation rate, hepatitis C virus recurrence rate, and hepatocellular carcinoma recurrence rate with DDLT. Cold ischemia time was shorter and duration of recipient operation was longer in LDLT. Postoperative intra-abdominal bleeding rate occurred less frequently in LDLT recipients (odds ratio (OR) = 0.64, 95%confidence interval (CI) = 0.46 - 0.88, P = 0.006), but this did not decrease the perioperative mortality. LDLT was associated with significantly higher biliary (OR = 2.23, 95%CI = 1.59 - 3.13, P < 0.00001) and vascular (OR = 2.00, 95%CI = 1.31 - 3.07, P = 0.001) complication rates and better overall survival (OS) (1 year: OR = 1.32, 95%CI = 1.01 - 1.72, P = 0.04; 3 years: OR = 1.39, 95%CI = 1.14 - 1.69, P = 0.0010; and 5 years: OR = 1.33, 95%CI = 1.04 - 1.70, P = 0.02). According to subgroup analysis, biliary complication rate and OS improved dramatically as experience increased, while vascular complication rate could not be improved because it was mainly caused by the difference of the donor type itself. LDLT remains a valuable option for patients in need of liver transplantation for it provides an excellent alternative to DDLT without compromising recipient outcomes. Further refinement in biliary and vascular reconstruction techniques and the accumulation of liver transplantation centers' experience are the key factors in expanding the application of LDLT.


Altered gut microbiota of obesity subjects promotes colorectal carcinogenesis in mice.
Obesity is a risk factor for colorectal cancer (CRC). The role of gut microbiota in mediating the cancer-promoting effect of obesity is unknown. Azoxymethane (AOM)-treated, ApcMin/+ and germ-free mice were gavaged with feces from obese individuals and control subjects respectively. The colonic tumor load and number were recorded at the endpoint in two carcinogenic models. The gut microbiota composition and colonic transcriptome were assessed by metagenomic sequencing and RNA sequencing, respectively. The anticancer effects of bacteria depleted in fecal samples of obese individuals were validated. Conventional AOM-treated and ApcMin/+ mice receiving feces from obese individuals showed significantly increased colon tumor formation compared with those receiving feces from control subjects. AOM-treated mice receiving feces from obese individuals showed impaired intestinal barrier function and significant upregulation of pro-inflammatory cytokines and activation of oncogenic Wnt signaling pathway. Consistently, transferring feces from obese individuals to germ-free mice led to increased colonic cell proliferation, intestinal barrier function impairment, and induction of oncogenic and proinflammatory gene expression. Moreover, germ-free mice transplanted with feces from obese human donors had increased abundance of potential pathobiont Alistipes finegoldii, and reduced abundance of commensals Bacteroides vulgatus and Akkermansia muciniphila compared with those receiving feces from human donors with normal body mass index (BMI). Validation experiments showed that B. vulgatus and A. muciniphila demonstrated anti-proliferative effects in CRC, while A. finegoldii promoted CRC tumor growth. Our results supported the role of obesity-associated microbiota in colorectal carcinogenesis and identified putative bacterial candidates that may mediate its mechanisms. Microbiota modulation in obese individuals may provide new approaches to prevent or treat obesity-related cancers including CRC. This work was funded by National Key Research and Development Program of China (2020YFA0509200/2020YFA0509203), National Natural Science Foundation of China (81922082), RGC Theme-based Research Scheme Hong Kong (T21-705/20-N), RGC Research Impact Fund Hong Kong (R4632-21F), RGC-CRF Hong Kong (C4039-19GF and C7065-18GF), RGC-GRF Hong Kong (14110819, 14111621), and NTU Start-Up Grant (021337-00001).


Intake and blood levels of some minerals in an elderly Chinese population.
Twenty-four hour intakes of potassium, calcium, and iron, and plasma concentration of potassium, copper and zinc were determined in a cluster sample of 400 apparently healthy subjects aged 60 years and over living in the community. Potassium and calcium intakes were lower in older men and lower in men compared to women. Both were much lower than intakes reported among Caucasian elderly, while iron intakes are comparable. Plasma potassium concentration was lower than values from studies of all ages and from studies of Caucasian elderly subjects. Copper and zinc concentrations were comparable to published values for adults of all ages. The significance of low potassium and calcium intake among elderly subjects in the population is discussed.


Integrating mental health into chronic care in South Africa: the development of a district mental healthcare plan.
In South Africa, the escalating prevalence of chronic illness and its high comorbidity with mental disorders bring to the fore the need for integrating mental health into chronic care at district level. To develop a district mental healthcare plan (MHCP) in South Africa that integrates mental healthcare for depression, alcohol use disorders and schizophrenia into chronic care. Mixed methods using a situation analysis, qualitative key informant interviews, theory of change workshops and piloting of the plan in one health facility informed the development of the MHCP. Collaborative care packages for the three conditions were developed to enable integration at the organisational, facility and community levels, supported by a human resource mix and implementation tools. Potential barriers to the feasibility of implementation at scale were identified. The plan leverages resources and systems availed by the emerging chronic care service delivery platform for the integration of mental health. This strengthens the potential for future scale up.


A novel splenic B1 regulatory cell subset suppresses allergic disease through phosphatidylinositol 3-kinase-Akt pathway activation.
IL-10-producing regulatory B (B10) cells potently suppress allergic diseases, such as contact hypersensitivity (CHS). Splenic B10 cells share overlapping phenotypic markers with CD5+ B1 B cells, CD1dhiCD21+CD23- marginal zone (MZ) B cells, and CD1dhiCD21+CD23+ T2-MZ precursor B cells but do not exclusively belong to either subset. In this study we investigated the signaling mechanisms and a novel phenotypic parameter of B10 cells. We performed microarray analysis comparing IL-10+ and IL-10- B cells. B cell-specific phosphatase and tensin homolog (PTEN)-deficient mice, which exhibit aberrant activation of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway in B cells, were examined. Microarray analysis revealed that the PI3K-Akt pathway is important for IL-10 production in B cells. PI3K-Akt pathway inhibitors reduced B10 cell numbers in vitro. B10 cell numbers were significantly increased in B cell-specific PTEN-deficient mice. The CHS response was significantly diminished in PTEN-deficient mice. Unexpectedly, splenic B10 cells in these mice were found within the B1 B-cell subset but not within the MZ B-cell subset. In wild-type mice not only MZ B10 cells but also B1-B10 cells were identified in the spleen. In addition, these 2 B10 cell subsets were predominantly found within the CD9+CD80+ B-cell fraction. A novel splenic B1 regulatory cell subset (B1-B10 cells) was identified. Our findings show that the PI3K-Akt pathway in B cells is critical for B10 cell development and CHS response and that CD9/CD80 coexpression is a novel phenotypic parameter for both MZ-B10 and B1-B10 cells.


Inhaled corticosteroids during pregnancy: a review of methodologic issues.
There is evidence in the literature that inhaled corticosteroids (ICSs) are safe for pregnant women with asthma and their infants. Although this is useful information about ICS use during pregnancy, some articles must be viewed cautiously because of lack of power and adjustment for potentially important confounding variables. To summarize evidence on the potential effects of ICSs to treat asthma in pregnant mothers and their children with particular focus on study power. Studies published before September 1, 2007, and focusing mainly on ICS use for asthma treatment during pregnancy were researched in Pubmed and the Cochrane Library. Post hoc power calculations were completed using data reported in the published articles. Twenty-three studies that evaluated the associations between ICS use during pregnancy and maternal and/or perinatal outcomes were retained. Only six studies on the association between ICS use and maternal outcomes reported significant results; five studies found significant associations between ICS use and perinatal outcomes. Regarding non-significant results, two studies on maternal outcomes and seven studies on perinatal outcomes had a power higher than 80% to detect a relative risk of 1.5 or a mean birth weight difference of 500 g. While there currently is some degree of evidence to support the safety of ICS use during pregnancy, this review highlights the limited statistical power of several studies published in this area.


Mouse and human strategies identify PTPN14 as a modifier of angiogenesis and hereditary haemorrhagic telangiectasia.
Hereditary haemorrhagic telangiectasia (HHT) [corrected] is a vascular dysplasia syndrome caused by mutations in transforming growth factor-β/bone morphogenetic protein pathway genes, ENG and ACVRL1. HHT [corrected] shows considerable variation in clinical manifestations, suggesting environmental and/or genetic modifier effects. Strain-specific penetrance of the vascular phenotypes of Eng(+/-) and Tgfb1(-/-) mice provides further support for genetic modification of transforming growth factor-β pathway deficits. We previously identified variant genomic loci, including Tgfbm2, which suppress prenatal vascular lethality of Tgfb1(-/-) mice. Here we show that human polymorphic variants of PTPN14 within the orthologous TGFBM2 locus influence clinical severity of HHT, [corrected] as assessed by development of pulmonary arteriovenous malformation. We also show that PTPN14, ACVRL1 and EFNB2, encoding EphrinB2, show interdependent expression in primary arterial endothelial cells in vitro. This suggests an involvement of PTPN14 in angiogenesis and/or arteriovenous fate, acting via EphrinB2 and ACVRL1/activin receptor-like kinase 1. These findings contribute to a deeper understanding of the molecular pathology of HHT [corrected] in particular and to angiogenesis in general.


Decolorization of the azo dye Acid Orange 51 by laccase produced in solid culture of a newly isolated Trametes trogii strain.
This study concerns the decolorization and detoxification of the azo dye Acid Orange 51 (AO51) by crude laccase from Trametes trogii produced in solid culture using sawdust as support media. A three-level Box-Behnken factorial design with four factors (enzyme concentration, 1-hydroxybenzotriazole (HBT) concentration, dye concentration and reaction time) combined with response surface methodology was applied to optimize AO51 decolorization. A mathematical model was developed showing the effect of each factor and their interactions on color removal. The model predicted that Acid Orange 51 decolorization above 87.87 ± 1.27 % could be obtained when enzyme concentration, HBT concentration, dye concentration and reaction time were set at 1 U/mL, 0.75 mM, 60 mg/L and 2 days, respectively. The experimental values were in good agreement with the predicted ones and the models were highly significant, the correlation coefficient (R2) being 0.9. Then the desirability function was employed to determine the optimal decolorization condition for each dye and minimize the process cost simultaneously. In addition, germination index assay showed that laccase-treated dye was detoxified; however in the presence of HBT, the phytotoxicity of the treated dye was increased. By using cheap agro-industrial wastes, such as sawdust, a potential laccase was obtained. The low cost of laccase production may further broaden its application in textile wastewater treatment.


Thermochromic Phantom and Measurement Protocol for Qualitative Analysis of Ultrasound Physiotherapy Systems.
Thermochromic test bodies are promising tools for qualitatively evaluating the acoustic output of ultrasound physiotherapy systems. Here, a novel phantom, made of silicone mixed with thermochromic powder material, was developed. Additionally, a procedure was developed to evaluate the stability and homogeneity of the phantom in a metrologic and statistical base. Twelve phantoms were divided into three groups. Each group was insonated by a different transducer. An effective intensity of 1.0 W/cm(2) was applied to each phantom; two operators performed the procedure three times in all phantoms. The heated area was measured after image processing. No statistical difference was observed in the heated areas for different samples or in the results for different operators. The heated areas obtained using each transducer were statistically different, indicating that the thermochromic phantom samples had sufficient sensitivity to represent the heated areas of different ultrasonic transducers. Combined with the evaluation procedure, the phantom provides an approach not previously described in the literature. The proposed approach can be used to quickly assess changes in ultrasonic beam cross-sectional shape during the lifetime of ultrasound physiotherapy systems.


Gamma-irradiation potentiates L-arginine-dependent nitric oxide formation in mice.
Gamma-irradiation of mongrel mice at a sublethal dose (700 Roentgen) enhanced the formation of nitric oxide (NO) in the liver, intestine, lung, kidney, brain, spleen or heart of the animals. NO formation was determined by the increase in intensity of the EPR signal due to trapping of NO into mononitrosyl iron complexes (MNIC) with exogenous diethyldithiocarbamate (DETC) injected intraperitoneally. The EPR signal of these MNIC-DETC complexes was characterized by g-factor values at g perpendicular values at g perpendicular = 2.035 and g parallel = 2.02 and a triplet hyperfine structure at g perpendicular. The NO synthase inhibitor, NG-nitro-L-arginine, prevented MNIC-DETC complex formation both in liver and intestine, demonstrating the involvement of endogenous NO formed. Thus, gamma-irradiation may enhance endogenous NO biosynthesis in these tissues, presumably by facilitating the entry of Ca2+ ions into the membrane as well as the cytosol of NO-producing cells through irradiation-induced membrane lesions.


Carbapenemase-Producing Gram-Negative Bacteria in Andalusia, Spain, 2014-2018.
The emergence and spread of carbapenemase-producing gram-negative bacteria is a major public health concern. We used data collected from microbiology laboratories as part of the PIRASOA program during 2014-2018 to study the epidemiology of carbapenemase-producing bacteria in Andalusia, Spain. Our findings highlight the importance of ongoing surveillance and epidemiologic studies for these bacteria.


A single cyclohexadienyl dehydrogenase specifies the prephenate dehydrogenase and arogenate dehydrogenase components of the dual pathways to L-tyrosine in Pseudomonas aeruginosa.
Dual biosynthetic pathways diverge from prephenate to L-tyrosine in Pseudomonas aeruginosa, with 4-hydroxyphenylpyruvate and L-arogenate being the unique intermediates of these pathways. Prephenate dehydrogenase and arogenate dehydrogenase activities could not be separated throughout fractionation steps yielding a purification of more than 200-fold, and the ratio of activities was constant throughout purification. Thus, the enzyme is a cyclohexadienyl dehydrogenase. The native enzyme has a molecular weight of 150,000 and is a hexamer made up of identical 25,500 subunits. The enzyme is specific for NAD+ as an electron acceptor, and identical Km values of 0.25 mM were obtained for NAD+, regardless of whether activity was assayed as prephenate dehydrogenase or as arogenate dehydrogenase. Km values of 0.07 mM and 0.17 mM were calculated for prephenate and L-arogenate, respectively. Inhibition by L-tyrosine was noncompetitive with respect to NAD+, but was strictly competitive with respect to either prephenate or L-arogenate. With cyclohexadiene as variable substrate, similar Ki values for L-tyrosine of 0.06 mM (prephenate) and 0.05 mM (L-arogenate) were obtained. With NAD+ as the variable substrate, similar Ki values for L-tyrosine of 0.26 mM (prephenate) and 0.28 mM (L-arogenate), respectively, were calculated. This is the first characterization of a purified, monofunctional cyclohexadienyl dehydrogenase.


Activation of basal forebrain cholinergic neurons improves colonic hyperpermeability through the vagus nerve and adenosine A2B receptors in rats.
Intestinal barrier dysfunction, a leaky gut, contributes to the pathophysiology of various diseases such as dementia and irritable bowel syndrome (IBS). We recently clarified that orexin, ghrelin, or adenosine A2B signaling in the brain improved leaky gut through the vagus nerve. The present study was performed to clarify whether basal forebrain cholinergic neurons (BFCNs) are implicated in the central regulation of intestinal barrier function. We activated BFCNs using benzyl quinolone carboxylic acid (BQCA), a positive muscarinic M1 allosteric modulator, and evaluated colonic permeability by quantifying the absorbed Evans blue in rat colonic tissue. Intracisternal (not intraperitoneal) injection of BQCA blocked the increased colonic permeability in response to lipopolysaccharide. Vagotomy blocked BQCA-induced improvement of colonic hyperpermeability. Intracisternally administered pirenzepine, a muscarinic M1 selective antagonist, prevented intestinal barrier function improvement by intravenously administered 2-deoxy-d-glucose, central vagal stimulant. Adenosine A2B receptor antagonist but not dopamine or opioid receptor antagonist prevented BQCA-induced blockade of colonic hyperpermeability. Additionally, intracisternal injection of pirenzepine blocked orexin- or butyrate-induced intestinal barrier function improvement. These results suggest that BFCNs improve leaky gut through adenosine A2B signaling and the vagal pathway. Furthermore, BFCNs mediate orexin- or butyrate-induced intestinal barrier function improvement. Since BFCNs play a role in cognitive function and a leaky gut is associated with dementia, the present finding may lead us to speculate that BFCNs are involved in the development of dementia by regulating intestinal barrier function.


Development of genome-specific SSR markers for the identification of introgressed segments of Sinapis alba in the Brassica juncea background.
Sinapis alba L. (white mustard) is recognized for carrying host resistance against several biotic stresses including, Alternaria brassicae, which is responsible for blight disease in cultivated Brassica. However, another cultivated Brassica has a dearth for genetic resistance for these stresses due to its narrow genetic base. Therefore, we performed introgression of the genomic regions of S. alba into backcross progenies of B. juncea + S. alba somatic hybrids. These advanced generations with S. alba chromosomal segments are named B. juncea-S. alba introgression lines (ILs). In the present study, we developed the S. alba genome-specific microsatellites from the draft genome to track the S. alba genome introgressions and responsible regions for resistance to A. brassicae. For developing these SSR markers, the unique contigs of S. alba draft genome were identified through BLASTN with B. juncea, B. rapa, B. nigra, and B. oleracea reference genome assemblies, including mitochondrial and chloroplast genomes, and further used for marker development. Out of 403,423 contigs, we have identified 65,343 non-hit contigs of S. alba that yielded a total of 1231 genome-specific microsatellites, out of which 1107 were expected to produce a single allele upon amplification. Out of the total SSRs, 234 primer pairs were randomly picked from whole-genome and validated between B. juncea and S. alba genomes for their specificity. In the validation experiment, these markers gave a single amplicon into S. alba, while they did not amplify in B. juncea genome. Of these, 59 microsatellites were used to track S. alba introgressions in 80 BC2F3 lines. To the best of our knowledge, this is the first time that these two genetic resources are developed in the form of B. juncea-S. alba ILs and S. alba-specific markers. Therefore, both the resources unlock a new avenue of Brassica breeding for biotic and abiotic stresses along with quality traits. The online version contains supplementary material available at 10.1007/s13205-022-03402-0.


Nonagricultural emissions enhance dimethylamine and modulate urban atmospheric nucleation.
Gas-phase dimethylamine (DMA) has recently been identified as one of the most important vapors to initiate new particle formation (NPF), even in China's polluted atmosphere. Nevertheless, there remains a fundamental need for understanding the atmospheric life cycle of DMA, particularly in urban areas. Here we pioneered large-scale mobile observations of the DMA concentrations within cities and across two pan-region transects of north-to-south (∼700 km) and west-to-east (∼2000 km) in China. Unexpectedly, DMA concentrations (mean ± 1σ) in South China with scattered croplands (0.018 ± 0.010 ppbv, 1 ppbv=10-9 L/L) were over three times higher than those in the north with contiguous croplands (0.005 ± 0.001 ppbv), suggesting that nonagricultural activities may be an important source of DMA. Particularly in non-rural regions, incidental pulsed industrial emissions led to some of the highest DMA concentration levels in the world (>2.3 ppbv). Besides, in highly urbanized areas of Shanghai, supported by direct source-emission measurements, the spatial pattern of DMA was generally correlated with population (R2 = 0.31) due to associated residential emissions rather than vehicular emissions. Chemical transport simulations further show that in the most populated regions of Shanghai, residential DMA emissions can contribute for up to 78% of particle number concentrations. Shanghai is a case study for populous megacities, and the impacts of nonagricultural emissions on local DMA concentration and nucleation are likely similar for other major urban regions globally.


Assessing the detoxication efficiencies of wastewater treatment processes using a battery of bioassays/biomarkers.
A battery of in vitro bioassays, including a Neutral Red (NR) assay using MCF-7 cells for predicting cytotoxic chemicals, an ethoxy resorufin-O-deethylase (EROD) activity assay using H4IIE cells to check for dioxin-like chemicals, and a recombinant gene yeast assay for screening estrogenic chemicals, was conducted to assess the removal efficiencies of trace toxic chemicals by different treatment processes in the waste water treatment plant (WWTP). The effluents were extracted by solid phase extraction (SPE) and were fractionated into three fractions based on polarities. The battery of bioassays was performed for each fraction. In the battery, the toxicities of the effluents were described according to their modes of actions (MOA) or biomarkers and the properties of the toxic chemicals were categorized by their polarities and MOAs. The proposed procedure could be used as a tool to diagnose the toxic characteristics of the complicate mixture. The results showed that cytotoxic, dioxin-like and estrogenic chemicals could be detected in all samples. In the influent, cytotoxic and dioxin-like chemicals were mainly in polar fraction and estrogenic chemicals were in non-polar and moderate-polar fractions. The secondary treatment (active sludge) could remove a small amount of these toxicants. Among different types of advanced treatments, flocculation was good enough to remove most of the cytotoxic chemicals and a combination of flocculation, ozone oxidation, and post-biological treatment could eliminate most of the dioxin-like and estrogenic chemicals.


Pharmacological distinction between the excitatory junctional potential and the glutamate potential revealed by concanavalin A at the crayfish neuromuscular junction.
The effect of concanavalin A(Con A) on desensitization of the glutamate receptor was investigated in the crayfish opener muscle. The depolarization of the crayfish muscle fiber caused by bath-applied L-glutamate was greatly augmented by Con A. The time course of the appearance of the augmentation was slow. Con A completely prevented the development of desensitization of the glutamate receptor. When L-glutamate was applied iontophoretically with a constant current pulse, a decline of the depolarization was seen during the course of the drug application which was presumably due to desensitization of the glutamate receptor. The glutamate potential was slightly increased by Con A, though the increase was transient. On the other hand, the amplitude of excitatory junctional potentials (EJPs) was not increased but decreased by addition of Con A. In normal saline, the amplitudes of both glutamate potentials and EJPs remarkably decreased because of desensitization of the glutamate receptor, but the decrease in amplitude of the glutamate potential was completely prevented by previous application of Con A. On the other hand, Con A had no influence upon the decrease in amplitude of EJPs. These results show that there is a pharmacological difference between the glutamate potential and EJPs.


Is lymph node dissection mandatory among early stage endometrial cancer patients? A retrospective study.
Whether routine lymph node dissection for early endometrial cancer is beneficial to survival is still controversial. However, surgeons usually perform lymph node dissection on all patients with early endometrial cancer. This study aimed to prove that the risk of lymph node metastasis, as defined by our standard, is very low in such patients and may change the current surgical practice. 36 consecutive patients who had staged surgery for endometrial cancer were collected. All eligible patients meet the following very low risk criteria for lymph node metastasis, including: (1) preoperative diagnosis of endometrial cancer (preoperative pathological diagnosis), (2) tumors confined to the uterine cavity and not beyond the uterine body, (3) PET-MRI lymph node metastasis test is negative. PET-MRI and pathological examination were used to assess the extent and size of the tumor, the degree of muscular invasion, and lymph node metastasis. The median age at diagnosis was 52 years (range 35-72 years). The median tumor size on PET-MRI was 2.82 cm (range 0.66-6.37 cm). Six patients underwent robotic surgery, 20 underwent laparoscopic surgery, 8 underwent Laparoscopic-assisted vaginal hysterectomy, and 2 underwent vaginal hysterectomy. 23% (63.9%) patients had high-grade (i.e. 2 and 3) tumors. Among the 36 patients who underwent lymph node sampling, the median number of lymph nodes retrieved was 32 (range 9-57 nodules). No patient (0%) was diagnosed with lymph node metastasis. According to the policy of each institution, 8 patients (22.2%) received adjuvant therapy, and half of them also received chemotherapy (4 patients; 50%). None of the patients who met the criteria had a pathological assessment of lymph node metastasis. Omitting lymph node dissection may be reasonable for patients who meet our criteria.


Significance of urethral vascular pulsations in genuine stress urinary incontinence.
Urodynamic tracings of 100 women with genuine stress incontinence revealed urethra vascular pulsations in 15 patients, while 85 lacked vascular pulsations. The presence of vascular pulsations correlated with the maximal urethral closure pressure and identified a subgroup of genuine stress incontinence with normal sphincter strength and reflex activity. The only identifiable cause of stress incontinence for each patient in this group was a deficiency in the anatomic supports of the urethrovesical junction responsible for poor transmission of intra-abdominal pressure to the urethra during stress. Those patients lacking vascular pulsations demonstrated resting sphincter weakness as well as decompensation of the sphincteric mechanism with changes in bladder volume and posture. In most women with genuine stress incontinence, the etiology is a combination of urethral sphincter dysfunction and poor anatomic support of the urethrovesical junction.


Genome-wide identification of SF1 and SF2 helicases from archaea.
Archaea microorganisms have long been used as model organisms for the study of protein molecular machines. Archaeal proteins are particularly appealing to study since archaea, even though prokaryotic, possess eukaryotic-like cellular processes. Super Family I (SF1) and Super Family II (SF2) helicase families have been studied in many model organisms, little is known about their presence and distribution in archaea. We performed an exhaustive search of homologs of SF1 and SF2 helicase proteins in 95 complete archaeal genomes. In the present study, we identified the complete sets of SF1 and SF2 helicases in archaea. Comparative analysis between archaea, human and the bacteria E. coli SF1 and SF2 helicases, resulted in the identification of seven helicase families conserved among representatives of the domains of life. This analysis suggests that these helicase families are highly conserved throughout evolution. We highlight the conserved motifs of each family and characteristic domains of the detected families. Distribution of SF1/SF2 families show that Ski2-like, Lhr, Sfth and Rad3-like helicases are ubiquitous among archaeal genomes while the other families are specific to certain archaeal groups. We also report the presence of a novel SF2 helicase specific to archaea domain named Archaea Specific Helicase (ASH). Phylogenetic analysis indicated that ASH has evolved in Euryarchaeota and is evolutionary related to the Ski2-like family with specific characteristic domains. Our study provides the first exhaustive analysis of SF1 and SF2 helicases from archaea. It expands the variety of SF1 and SF2 archaeal helicases known to exist to date and provides a starting point for new biochemical and genetic studies needed to validate their biological functions.


Aromatase deficiency: a novel compound heterozygous mutation identified in a Chinese girl with severe phenotype and obvious maternal virilization.
Aromatase deficiency is a rare autosomal recessive disorder that is caused by an impairment of androgen conversion to estrogens. Affected 46, XX individuals generally present with virilization of external genitalia at birth and mutations in CYP19A1 gene. This study described the clinical features and molecular basis of a Chinese 46, XX girl born with ambiguous genitalia and investigated the functional alteration of two novel mutations of the CYP19A1 gene. Obvious prepartum virilization and remarkably elevated testosterone were observed in the mother, who was initially suspected to have a testosterone-producing ovarian tumor. Clinical phenotypes and hormone profiles of the patient and her mother were investigated. Genotyping analyses of the CYP19A1 gene were performed in the patient and her parents. Functional impairment of the mutations was explored using three-dimensional computer model and mutagenesises in vitro transfection assays. A compound heterozygous mutation of the CYP19A1 gene was revealed in the patient, with a G deletion in nucleotide 264 of exon 3 in one allele and a 23-bp insertion in exon 9 in another allele; both mutations resulted in reading frame-shifts that led to truncated proteins of 87 and 360 amino acids, respectively. Molecular modeling analysis suggested that the two renascent truncated proteins lacked crucial amino acids that were involved in substrate access and catalysis as well as heme-binding region. Functional studies in transfected HEK-293T cells exhibited a nearly complete abolishment of enzyme activity, which may underlie the phenotype and hormone profile. Two novel CYP19A1 mutations were identified in a Chinese girl born with ambiguous genitalia and severe maternal virilization during pregnancy. Maternal virilization should prompt consideration of aromatase deficiency, preventing unnecessary interventions in pregnancy. This study broadens the spectrum of phenotype and genetic mutations of this rare disorder.


Transmural metabolite distribution in regional myocardial ischemia as studied with 31P NMR.
Phosphorus-31 nuclear magnetic resonance (31P NMR) has been applied to study the canine heart prior to and during regional myocardial ischemia induced by partial flow reduction in the left anterior descending coronary artery (LAD). NMR data were acquired in a transmural fashion by restricting the signal to a column perpendicular to the heart wall using B0 gradients and obtaining spectroscopic spatial resolution along the third dimension using the B1 gradient and adiabatic excitation. With this approach, transmural spectra were accumulated in five separate voxels spanning the wall of the left ventricle from the epicardium to the endocardium. In the normal canine myocardium the levels of high-energy phosphates CP and ATP were relatively constant throughout the left ventricular wall, with only minor evidence of free inorganic phosphate in any of the transmural voxels. However, during sustained partial occlusion of the LAD, significant regional differences between the epi- and the endocardium were noted. The data demonstrate the importance of studying cardiac bioenergetics with transmural differentiation.


Induction of N-glycosylation activity in cultured embryonic rat brain cells.
Developmental changes in protein N-glycosylation activity have been studied using cultures of dissociated fetal rat brain cells as an in vitro model system. These cultures undergo an initial phase of neurite outgrowth and cell proliferation (4-6 days in culture), followed by a period of cellular differentiation. N-Glycosylation activity has been measured by assaying the incorporation of [2-3H]mannose into dolichol-linked oligosaccharides and glycoprotein over a period of 1-25 days in culture. This study revealed a marked induction of N-glycosylation activity beginning at approximately 1 week of culture. [2-3H]Mannose incorporation into the oligosaccharide-lipid intermediate fraction and glycoprotein reached maximal values between 12 and 16 days of culture and declined thereafter. The major dolichol-linked oligosaccharide labeled by the brain cell cultures was shown to be Glc3Man9GlcNAc2 by HPLC analysis. Parallel incorporation studies with [3H]leucine showed that the increase in protein N-glycosylation was relatively higher than a concurrent increase in cellular protein synthesis observed during the induction period. Maximal labeling of glycoprotein corresponded to the period of glial differentiation, as indicated by a sharp rise in the marker enzymes, 2',3'-cyclic nucleotide 3'-phosphohydrolase (an oligodendroglial marker) and glutamine synthetase (an astroglial marker). The results describe a developmental activation of the N-glycosylation pathway and suggest a possible relationship between N-linked glycoprotein assembly and the growth and differentiation of glial cells.


Ratings of cancer chemotherapy toxicity by oncologists, nurses, and pharmacists.
In order to examine the perceived toxicity of commonly used drug regimens for cancer chemotherapy, eight oncologists, twelve nurses, and five pharmacists rated the toxicity of 30 different drug combinations. Although the correlations revealed a high degree of agreement, the oncologists' ratings and the nurses' ratings differed systematically at the lower- and the higher-toxicity levels. This was most readily described by a "regression effect," wherein oncologists' ratings appear to regress toward the mean relative to the nurses' ratings. The perception of both toxicity and the importance of side effects such as nausea and vomiting may be substantially different between physicians and nurses, and hence, has important implications for how patients communicate these to the various health care professionals.


Raman spectroscopy of cytoplasmic muscle fiber proteins. Orientational order.
The polarized Raman spectra of glycerinated and intact single muscle fibers of the giant barnacle were obtained. These spectra show that the conformation-sensitive amide I, amide III, and C-C stretching vibrations give Raman bands that are stronger when the electric field of both the incident and scattered radiation is parallel to the fiber axis (Izz). The detailed analysis of the amide I band by curve fitting shows that approximately 50% of the alpha-helical segments of the contractile proteins are oriented along the fiber axis, which is in good agreement with the conformation and composition of muscle fiber proteins. Difference Raman spectroscopy was also used to highlight the Raman bands attributed to the oriented segments of the alpha-helical proteins. The difference spectrum, which is very similar to the spectrum of tropomyosin, displays amide I and amide III bands at 1,645 and 1,310 cm-1, respectively, the bandwidth of the amide I line being characteristic of a highly alpha-helical biopolymer with a small dispersion of dihedral angles. A small dichroic effect was also observed for the band due to the CH2 bending mode at 1,450 cm-1 and on the 1,340 cm-1 band. In the C-C stretching mode region, two bands were detected at 902 and 938 cm-1 and are both assigned to the alpha-helical conformation.


Stochastic resonance and coherence resonance in groundwater-dependent plant ecosystems.
Several studies have shown that non-linear deterministic dynamical systems forced by external random components can give rise to unexpectedly regular temporal behaviors. Stochastic resonance and coherence resonance, the two best known processes of this type, have been studied in a number of physical and chemical systems. Here, we explore their possible occurrence in the dynamics of groundwater-dependent plant ecosystems. To this end, we develop two eco-hydrological models, which allow us to demonstrate that stochastic and coherence resonance may emerge in the dynamics of phreatophyte vegetation, depending on their deterministic properties and the intensity of external stochastic drivers.


Separation of phosphatidylinositols and other phospholipids by two-step one-dimensional thin-layer chromatography.
A quick and efficient thin-layer chromatographic procedure is described for the separation of phosphatidylinositol-4,5-bisphosphate, phosphatidylinositol-4-monophosphate, phosphatidylinositol, phosphatidylcholine, phosphatidic acid, and phosphatidylethanolamine. The method involves development of the phospholipids successively in two different solvent systems but in the same direction. The method is simple, reproducible, and gives good resolution of the six different phospholipids tested. About 8-10 32P-labeled phospholipids isolated from rat hepatocytes were separated by this method; the six mentioned above were identified. Thus, the technique has potential application for both qualitative and quantitative analysis of phospholipid mixtures, such as the phosphoinositides, in cell or tissue extracts.


Chromosome abnormalities in 10 lung cancer cell lines of the NCI-H series analyzed with spectral karyotyping.
The karyotypes of 10 lung cancer cell lines of the NCI-H series were analyzed with spectral karyotyping (SKY): 7 non-small lung cancer (NSCLC) lines and 3 small cell lung cancer (SCLC) lines. Modal chromosome number ranged from 42 (NCI-H2171) to 72 (NCI-H2126). All lines showed at least six structural abnormalities, and most had amplifications visible as double minutes or homogeneously staining regions (HSRs). Four reciprocal translocations were found: t(1;17)(p10;p10) in NCI-H82, t(3;6)(q24;q21) and t(12;17)(p10;p10) in NCI-H2009, and a complex t(2;6) in NCI-H1437. NCI-H1770 had a striking HSR containing many copies of the NMYC region. Karyotypes showed a wide range of relationship between numerical and structural change. Two of the lines showed little numerical change but many structural rearrangements (NCI-H209 with mode 46, but 12 rearrangements, and NCI-H2009 with mode 48 but 27 rearrangements). A second group had karyotypes that appeared to have evolved by unbalanced translocation leading to proportionate loss of chromosomes, with or without endoreduplication. In other lines, notably NCI-H2122, the structurally abnormal chromosomes appeared to have been added to a near-diploid karyotype. The karyotypes contribute to a full genomic characterization of these lines, almost all of which have matching normal lymphoblastoid cell lines.


Assessment of microbiome variation during the perioperative period in liver transplant patients: a retrospective analysis.
Understanding the composition of the microbial populations in the intestines of liver transplant patients is important to preventing postoperative infection. We investigated the relationship between the risk of postoperative infection and variation in the predominant fecal microbial composition during the perioperative period. We prospectively analyzed the predominant intestinal microbiome of five asymptomatic adult carriers of hepatitis B virus (as controls without any antibiotics) at four weekly follow-up visits and 12 patients before operation and at three weekly postoperative follow-up visits within the first month. Analysis was by denaturing gradient gel electrophoresis (DGGE) and sequencing with digital processing of DGGE profiles using BioNumerics software. Our results showed that the predominant intestinal microbial diversity decreased substantially in eight patients during the perioperative period. Among these, five patients experienced infection with a postoperative hospital stay of more than 30 days. The rest of the four patients who experienced shorter postoperative hospital stays showed only slight variation in predominant intestinal bacterial composition and temporal stability similar to asymptomatic controls. Postoperative fecal DGGE profiles showed mostly bands assigned to Bacteroides and Firmicutes. We conclude that an empiric prophylaxis strategy that destructs gut microecological balance will not be effective in reducing the risk of postoperative infection. Instead, the destruction of intestinal microbiota might result in the appearance of opportunistic pathogens such as Bifidobacterium dentium which rarely appears in the intestinal DGGE profiles of normal humans. Cognizance of the variation of intestinal microbial profiles during the perioperative period is a critical aspect of caring for liver transplant recipients.


Recent advances in bacterial cellulose-based antibacterial composites for infected wound therapy.
Wound infection arising from pathogenic bacteria brought serious trouble to the patient and medical system. Among various wound dressings that are effective in killing pathogenic bacteria, antimicrobial composites based on bacterial cellulose (BC) are becoming the most popular materials due to their success in eliminating pathogenic bacteria, preventing wound infection, and promoting wound healing. However, as an extracellular natural polymer, BC is not inherently antimicrobial, which means that it must be combined with other antimicrobials to be effective against pathogens. BC has many advantages over other polymers, including nano-structure, significant moisture retention, non-adhesion to the wound surface, which has made it superior to other biopolymers. This review introduces the recent advances in BC-based composites for the treatment of wound infection, including the classification and preparation methods of composites, the mechanism of wound treatment, and commercial application. Moreover, their wound therapy applications include hydrogel dressing, surgical sutures, wound healing bandages, and patches are summarized in detail. Finally, the challenges and future prospects of BC-based antibacterial composites for the treatment of infected wounds are discussed.


Senile ptosis II--posterior approach and complications.
A posterior approach repair of aponeurotic defects is described and the results in 55 cases reviewed. The complications of surgery for senile (involutional) ptosis are discussed.


Cu(I)-catalyzed tandem benzyldiazoester coupling with terminal alkyne-allene formation-Michael reaction: application to the syntheses of oxa and azacycles.
A simple and practical procedure for the synthesis of aza- and oxacycles, which possess an array of stereogenic functionalities, is described. This protocol relies on tandem Cu-catalyzed coupling of suitably functionalized terminal alkyne with diazoester followed by isomerization and subsequent aza or oxa-Michael reaction, thus generating the required scaffold with high diastereoselectivity.


Synaptotagmin-11 mediates a vesicle trafficking pathway that is essential for development and synaptic plasticity.
Synaptotagmin-11 (Syt11) is a Synaptotagmin isoform that lacks an apparent ability to bind calcium, phospholipids, or SNARE proteins. While human genetic studies have linked mutations in the Syt11 gene to schizophrenia and Parkinson's disease, the localization or physiological role of Syt11 remain unclear. We found that in neurons, Syt11 resides on abundant vesicles that differ from synaptic vesicles and resemble trafficking endosomes. These vesicles recycle via the plasma membrane in an activity-dependent manner, but their exocytosis is slow and desynchronized. Constitutive knockout mice lacking Syt11 died shortly after birth, suggesting Syt11-mediated membrane transport is required for survival. In contrast, selective ablation of Syt11 in excitatory forebrain neurons using a conditional knockout did not affect life span but impaired synaptic plasticity and memory. Syt11-deficient neurons displayed normal secretion of fast neurotransmitters and peptides but exhibited a reduction of long-term synaptic potentiation. Hence, Syt11 is an essential component of a neuronal vesicular trafficking pathway that differs from the well-characterized synaptic vesicle trafficking pathway but is also essential for life.


Pharmacokinetics of temafloxacin after multiple oral administration.
Four multiple dose studies involving 102 healthy volunteers were reviewed to determine the sources of intersubject variability in the pharmacokinetics of temafloxacin. As a result of the preferential distribution of temafloxacin into muscle, liver and kidney compared with adipose tissue, the best anthropometric explanatory variable was found to be lean body mass, rather than total body mass or body surface area. Single dose studies have confirmed that the distribution volume of temafloxacin is smaller in subjects in whom the lean body mass:total body mass ratio is low, notably in females, the elderly, and those with hepatic impairment. Average creatinine clearance for the volunteers included in this analysis was normal (109 +/- 29 ml/min), and renal function was only a marginally significant covariate; however, renal clearance accounts for 60 to 70% of total clearance (CLT) and has been shown to be a major factor in the elderly, as well as in patients with renal or hepatic impairment. Since temafloxacin is partially reabsorbed renally, urine flow rate was found to be a potentially important secondary factor. Overall, the pharmacokinetics of temafloxacin are essentially linear, with steady-state plasma concentrations at trough (Cssmin) and 2h postdose (Css2h) averaging slightly more than 0.5 and 1.0 mg/L per 100mg administered every (q) 12h. For example, mean Cssmin and peak steady-state plasma concentration (Cssmax) values after administration of temafloxacin 600mg q12h were 3.3 +/- 1.1 and 6.2 +/- 1.8 mg/L, respectively. Total apparent clearance (CLT/F) and the terminal elimination half-life (t1/2) averaged 11 L/h (184 ml/min) per 55kg lean body mass and 8.4h, respectively. Considering that the data reviewed came from 4 studies with doses ranging from 100 to 800mg q12h, the intersubject coefficients of variation were low for an orally administered drug, ranging from 15.4% for t1/2, 20.6% for Css2h, 21.2% for CLT/F and 25% for Cssmin.


Ultrasound-guided Stellate Ganglion Block Improves Gastrointestinal Function After Thoracolumbar Spinal Surgery.
The purpose of this study was to investigate the effects of stellate ganglion block (SGB) on gastrointestinal function after thoracolumbar spinal surgery. Forty patients with thoracolumbar fracture scheduled for posterior spinal surgery were randomly assigned to 2 groups: ultrasound-guided SGB or sham (control group). After induction, ultrasound-guided SGB (n = 20) or a sham procedure (n = 20) was conducted with a 6-mL injection of 1% lidocaine or 0.9% saline, respectively. Primary outcomes were postoperative gastrointestinal function, including auscultation of bowel sounds, incidence and degree of abdominal bloating, flatus time, and paralytic ileus. Patients in the SGB group had better gastrointestinal function compared with those in the sham (control) group, as indicated by more regular bowel sounds at 24 and 36 hours postoperatively (80% vs 40%, P = 0.024, and 95% vs 60%, P = 0.023), lesser abdominal bloating (10% vs 45%, P = 0.034), and slightly shorter flatus time (mean [SD], 12.0 [4.4] vs 14.7 [4.6] hours, P = 0.068). Survival analysis based on regular bowel sounds found a significant difference between the 2 groups (P = 0.004). In addition, more patients had higher satisfaction after SGB (85% vs 45%, P = 0.020). No postoperative ileus or mortality occurred. In this preliminary study, ultrasound-guided SGB accelerated the return of gastrointestinal transit, alleviated bowel symptoms, and improved patient satisfaction after thoracolumbar spinal surgery. chictr.org.cn identifier: ChiCTR-TRC-14004289.


Drp1 and the cytoskeleton: mechanistic nexus in mitochondrial division.
Dynamin-related protein 1 (Drp1), the master regulator of mitochondrial division (MD), interacts with the cytoskeletal elements, namely filamentous actin (F-actin), microtubules (MT), and septins that coincidentally converge at MD sites. However, the mechanistic contributions of these critical elements to, and their cooperativity in, MD remain poorly characterized. Emergent data indicate that the cytoskeleton plays combinatorial modulator, mediator, and effector roles in MD by 'priming' and 'channeling' Drp1 for mechanoenzymatic membrane remodeling. In this brief review, we will outline our current understanding of Drp1-cytoskeleton interactions, focusing on recent progress in the field and a plausible 'diffusion barrier' role for the cytoskeleton in MD.


Docosahexaenoic Acid and Amino Acid Contents in Pasteurized Donor Milk are Low for Preterm Infants.
To evaluate whether pasteurized donor human milk meets the nutritional needs of preterm infants in terms of free fatty acid and amino acid contents. Milk samples were prospectively collected from 39 donors to the Mothers' Milk Bank of Ohio. The fatty acid and amino acid compositions in donor milk samples were measured before and after pasteurization, and values were compared with previously published findings and preterm infant nutrition guidelines. The nutritional adequacy of donor milk for preterm infants was based on estimated daily intake of 150 mL/kg. Statistical significance was adjusted to account for multiple comparisons. Pasteurization did not appreciably affect donor milk composition. Docosahexaenoic acid level (0.1 mol wt %), and concentrations of glycine, aspartate, valine, phenylalanine, proline, lysine, arginine, serine, and histidine in donor milk were all significantly lower than previously reported concentrations in milk. Donor milk is not substantially affected by pasteurization, but has low concentrations of docosahexaenoic acid and amino acids. Targeted nutritional supplementation of human donor milk for feeding preterm infants might be warranted.


Anorectal verrucose squamous carcinoma: report of two cases.
Two cases of anorectal verrucose squamous-cell carcinoma are presented. The clinical course and pathology of these tumors are reviewed. Surgical treatment based on the depth of histologic invasion is recommended.


Influence of hepatic load from far-off dry period to early postpartum period on the first postpartum ovulation and accompanying subsequent fertility in dairy cows.
The aim of the present study was to investigate nutritional and metabolic parameters during the dry and early postpartum periods of ovulatory and anovulatory cows, as well as their postpartum reproductive performance. Blood samples from 20 multiparous Holstein cows were collected once a week from the far-off dry period to 3 weeks postpartum. Early postpartum (0-3 weeks) ovulation was confirmed using plasma progesterone concentration profiles, and cows were considered ovulatory if they had resumed luteal activity by this point (n = 9), whereas cows that had not were considered anovulatory (n = 11). Data from the ovulatory and anovulatory cows were analyzed separately for the far-off dry period (7-4 weeks prepartum), the close-up dry period (3-1 weeks prepartum), and the early postpartum period (0-3 weeks). Serum gamma-glutamyl transpeptidase activity (far-off, P = 0.065; close-up, P = 0.051; and early postpartum, P = 0.030) and aspartate aminotransferase (close-up, P = 0.050 and early postpartum, P = 0.087) activities were higher in anovulatory than in ovulatory cows. The days open period was longer (P = 0.019) in anovulatory than in ovulatory cows, and the number of artificial inseminations per conception (P = 0.025) was greater. In conclusion, we found that continuously high gamma-glutamyl transpeptidase activities in serum, which may be induced by liver disorders, prevent subsequent ovulation and affect subsequent fertility, even if cows obtain sufficient ovulation-related energy and β-carotene.


Adenomatoid hyperplasia of the minor salivary glands on the buccal mucosa: A rare case report.
Adenomatoid hyperplasia of the minor salivary glands is a hyperplastic oral lesion which may be seen on minor salivary gland bearing areas on all oral mucosa, especially on soft and hard palate. This study reports a rare case of buccal adenomatoid hyperplasia of the minor salivary glands and discusses the clinical significance. 48 year old male patient presented with a complaint of a swelling on his left cheek. Clinical examination revealed a bluish mass on the buccal mucosa. A provisional diagnosis of salivary gland neoplasm was made and the lesion was excised under local anesthesia. The histological diagnosis was adenomatoid hyperplasia of the minor salivary glands. Buccal localization of the adenomatoid hyperplasia of the minor salivary glands is quite uncommon in the literature. There are two cases in the English literature for our knowledge. In the clinical examination, the nodular and protuberated appearance of the lesion resembles buccal minor salivary gland tumors and vascular lesions. Histological analysis is fundamental to achieve correct diagnosis. The differential diagnosis of buccal nodular, exophytic and colored mucosal lesions should include adenomatoid hyperplasia of the minor salivary glands.


A functional polymorphism of the TNF-alpha gene that is associated with type 2 DM.
To examine the association of the tumor necrosis factor-alpha (TNF-alpha) gene region with type 2 diabetes (DM), 11 single-nucleotide polymorphisms (SNPs) of the region were analyzed. The initial study using a sample set (148 cases vs. 227 controls) showed a significant association of the SNP IVS1G+123A of the TNF-alpha gene with DM (p=0.0056). Multiple logistic regression analysis using an enlarged sample set (225 vs. 716) revealed the significant association of the SNP with DM independently of any clinical traits examined (OR: 1.49, p=0.014). The functional relevance of the SNP were examined by the electrophoretic mobility shift assays using nuclear extracts from the U937 and NIH3T3 cells and luciferase assays in these cells with Simian virus 40 promoter- and TNF-alpha promoter-reporter gene constructs. The functional analyses showed that YY1 transcription factor bound allele-specifically to the SNP region and, the IVS1+123A allele had an increase in luciferase expression compared with the G allele.


Evaluation of baseline optic disc pit and optic disc coloboma maculopathy features by spectral domain optical coherence tomography.
The aim of this study is to describe and compare the baseline demographic, ocular, and imaging characteristics of a cohort of patients with optic disc pit (ODP) or optic disc coloboma (ODC) maculopathy. This retrospective study included patients diagnosed with ODP or ODC on clinical examination between June 2017 and December 2022. These patients' baseline demographics, ocular characteristics, and optical coherence tomography (OCT) imaging characteristics were analyzed. Fundus examination revealed 11 eyes of 11 patients with ODP and 14 eyes of 9 patients with ODC, respectively. On OCT, maculopathy was observed more frequently in ODP (n = 10) than in ODC (n = 4) [p = 0.004] cases. Eyes with ODP were more likely to exhibit retinoschisis and/or serous macular detachment [SMD] (n = 7, 70%), communication of the retinoschisis with the optic disc (p = 0.015), whereas the SMD did not communicate with the optic disc (p = 0.005), and significant outer retinal layer thinning (p = 0.015). In contrast, eyes with ODC exhibited only SMD (p = 0.005) and no retinoschisis on the non-colobomatous retina. SMD in ODC communicated with the margin of the optic disc. In both clinical entities, hyperreflective foci were observed in the SMD. In summary, baseline maculopathy characteristics on OCT, including its type, location, and relationship to the optic disc, are among the most distinguishing characteristics between an ODP and an ODC. Not applicable.


Multicolor chromosome painting in diagnostic and research applications.
For many years whole chromosome painting probes have been the work-horses in a large variety of clinical and research molecular cytogenetic applications. In recent years painting probes have been complemented by an increasing number of further region-specific probes, which allow the specific staining of centromeres, subtelomeres or other regions within the genome. This development of new probe sets was greatly facilitated by the Human Genome Project from which well-characterized probes for any region within the genome have emerged. Furthermore, the evolution of different multicolor fluorescence in situ hybridization (FISH) technologies now allows the cohybridization of multiple DNA-probes of different colors. These developments have paved the way for FISH-based automated karyotyping or the simultaneous analysis of multiple defined regions within the genome. Using appropriate instrumentation and image processing, the analysis can be performed two-dimensionally on metaphase spreads or three-dimensionally in intact interphase nuclei. Here we summarize some of the most recent developments and discuss the application of painting probes in different scenarios.


Determination of fumonisins in corn: Evaluation of two purification procedures.
The performance of two solid phase extraction (SPE) purification procedures, used in the determination of fumonlsin B1 (FB1), B2 (FB2) and B3 (FB2) In corn, was evaluated using both thin-layer chromatography (TLC) and high performance liquid chromatography (HPLC). Fewer interferences were observed In extracts prepared using the strong anion exchange (SAX) media, in contrast to those purified on C18 media, where on occasions, visual discernment of the TLC bands was hampered by the presence of interfering compounds. Precipitate formation, resulting In the blocking of SPE cartridges was also encountered when using the C18 procedure. HPLC analyses of extracts prepared by both media indicated that they gave comparable fumonlsin recoveries from naturally contaminated corn samples. The results suggest that the C18 procedure, originally developed for the TLC analyses of FB1 in mixed feeds, may also be applied to the determination of FB2 and FB2. However, where TLC is used quantitatively for fumonlsin levels <1 μg/g, purification of sample extracts on SAX media is recommended.


Fascin-1 expression as stratification marker in borderline epithelial tumours of the ovary.
To evaluate the actin-bundling protein fascin-1 (FSCN1) as marker for borderline ovarian tumours (BOTs). We analysed a retrospective cohort of 140 BOTs with validated diagnosis by an independent pathologist. Immunohistochemical detection of FSCN1 was quantified as combined immunoreactive score (CIS) blinded to clinical patient data. Analyses were first performed for FSCN1 positive versus negative, and then verified using three categories derived from the observed distribution (negative, weak, strong; CIS 0, 1-2, 3-9). We detected FSCN1 positivity in 51.4%, and strong expression (CIS 3-9) in 14.3% of the samples. FSCN1 positivity was associated with serous subtype (p<0.001) and micropapillary pattern (p<0.001). Correlation with micropapillary pattern remained significant within the serous BOT (SBOT) subgroup (p=0.022). Strong FSCN1 expression (CIS 3-9) was associated both with the presence of implants (p=0.022), and a higher International Federation of Gynecology and Obstetrics (FIGO) stage (p=0.020). Our analysis links FSCN1 with SBOT with micropapillary pattern. Strong expression is associated with higher FIGO stage and the presence of implants, both related to elevated risk of recurrence. Hence, FSCN1 is an interesting marker worth further analyses of its prognostic value in BOTs.


Hair mass index obtained by cross-section trichometry: an objective and clinically useful parameter to quantify hair in chemotherapy-induced alopecia.
In order to evaluate the efficacy of scalp cooling for the prevention of chemotherapy-induced alopecia (CIA), it is essential to precisely quantify the amount of hair mass that is present. We wanted to determine if the hair mass index (HMI), obtained by cross-section trichometry (CST), was a suitable parameter for hair mass measurement, and whether or not marking the measurement site on the scalp was necessary. Ten patients receiving chemotherapy were sequentially measured using CST during their treatment. At the same time, they were asked to report severity of hair loss via three subjective parameters: World Health Organization (WHO) grade, visual analog scale (VAS) score, and patients' need to wear wig or head cover. To investigate the need of marking of the measurement area, differences in HMI between a random 2 × 2-cm site (HMI-C) and four surrounding areas (HMI-S4) on the scalp of eight volunteers and eight chemotherapy patients were calculated and compared. Using CTS, hair loss due to CIA was quite measurable and ranged from 13 to 82 %. Reported VAS scores and WHO grades showed an increase in patients in time; 50 % of patients reported the need to wear a wig or head cover. The difference between HMI-S4 and the HMI-C values in all subjects of the marking group was homogeneously distributed between -11 and +10 and was not statistically different between the volunteer and the patient groups (p = 0.465). CST for HMI measurement is a useful mechanical modality for assessing hair loss in CIA patients. It is quantitatively more precise than existing non-mechanical measuring methods. It is recommended when detection of minor changes in hair quantity is required. Marking a fixed sampling area to ensure return to the exact same site is only required when a minor change in pre- and posttreatment HMI values is anticipated and the mid-line locating device is not/cannot be used.


The possible protective role of zinc oxide nanoparticles (ZnONPs) on testicular and epididymal structure and sperm parameters in nicotine-treated adult rats (a histological and biochemical study).
Exposure to nicotine in smoking contributes to most unexplained male infertility but the mechanisms remain to be fully elucidated. Zinc (Zn) is an essential trace element in normal growth, development and reproduction. Zinc oxide nanoparticles (ZnONPs) are well-known antioxidants. Therefore, this work was designed to investigate the potential ability of ZnONPs to protect testis and epididymis in nicotine-treated rats. Forty adult male Wistar albino rats were divided into control group and two experimental groups (treated and supplemented rats). In the treated group, rats received nicotine at a dose of 1 mg/kg/day orally for 30 days. Rats in the supplemented group received ZnONPs (10 mg/kg/day) with nicotine (1 mg/kg/day), orally for the same period. Testicular and epididymal sections were stained with H&E to assess the histological changes. Negrosin-eosin staining of epididymal sperms was performed to assess their viability and morphological changes. Serum testosterone, FSH and LH levels were assessed. Also, oxidative stress parameters and semiquantitative real-time PCR for steroidogenic enzymes were measured. Morphometric studies of both organs were statistically analyzed. Mild to severe testicular and epididymal structural changes together with sperm morphological abnormalities were detected in nicotine-treated rats. Biochemical results also showed a decrease in all measured parameters except for an increased malondialdehyde (MDA) level that meant deterioration of their reproductive function. On the other hand, ZnONP supplementation in the last group showed an obvious improvement in all investigated parameters.


Antidepressant effect of repeated ketamine administration on kynurenine pathway metabolites in patients with unipolar and bipolar depression.
Ketamine has rapid antidepressant effects on treatment-resistant depression, but the biological mechanism underpinning this effect is less clear. Our aims were to examine whether kynurenine pathway metabolites were altered by six infusions of ketamine and whether these biological factors could act as potential biomarkers to predict ketamine's antidepressant effects. Six intravenous infusions of ketamine (0.5 mg/kg) were administered to 84 patients with unipolar and bipolar depression over a 12-d period. Symptom severity and response were assessed using the Montgomery-Asberg Scale (MADRS), and blood samples were collected at baseline and 24 h following the first infusion and at 24 h and 14 d after the sixth infusion (24 h, 13 d and 26 d). Blood samples from sixty healthy controls were collected for comparison with samples from the patients. Serum concentrations of tryptophan (TRP), kynurenine (KYN) and kynurenic acid (KYNA) were measured by the liquid chromatography-tandem mass spectrometry method. At baseline, serum levels of TRP and KYNA and the KYNA/KYN ratio were lower and the KYN/TRP ratio was greater in depressed patients than in healthy controls. Overall, fifty (59.5%) patients responded to ketamine at 13 d. Ketamine responders had a greater KYNA level and KYNA/KYN ratio than nonresponders at 24 h and 13 d (all P < 0.05). Elevations in the KYNA levels and KYNA/KYN ratio at 24 h were significantly associated with reductions in MADRS scores at 24 h, 13 d and 26 d in the linear regression analysis (all P < 0.05). Our results showed a possible involvement of the kynurenine pathway in the rapid antidepressant effect of ketamine. Early changes in serum KYNA levels and the KYNA/KYN ratio could be potential predictors of antidepressanteffects of repeated ketamine administration.


Normal sister chromatid exchange in lymphocytes from patients with multiple epidermal cancer?
Exposure to toxins in the environment and due to personal habits, e.g., tobacco smoking, may increase the rate of spontaneous sister chromatid exchange (SCE). The SCE in lymphocytes from a group of 31 patients with multiple epidermal cancer, who in the past had been exposed to various skin carcinogens, as a whole exceeded that of a control group--matched by sex, age, and smoking habits--but the difference was not statistically significant (p = 0.08). The individual SCE in these patients was also statistically independent of the nature of the carcinogenic exposure. We were unable to detect correlations between the SCE and UVC-radiation induced DNA synthesis, UVC-radiation tolerance, or rate of X-ray damage repair. This suggests that the molecular mechanisms involved in SCE induction and in repair of radiation damage are basically independent.


Persistent breast pain 5 years after treatment of invasive breast cancer is largely unexplained by factors associated with treatment.
The aim of our study was to establish the prevalence of breast pain persisting 5 years after the initial treatment of breast cancer (BC) and the relationship between those persistent symptoms and general well-being. The study involved women from Victoria, Australia, who had survived at least 5 years from diagnosis, remained free from recurrence or new BC and completed the fifth annual follow-up questionnaire. Analysis involved both multivariable logistic and linear regression. Of 1,205 women, 45 % reported breast pain which persisted for at least 3 months following initial treatment, and of these, 80 % reported pain persisting for at least 5 years. The factor contributing most to the likelihood of persistent breast pain was current lymphedema; however, a full multivariable model explained <10 % of the likelihood of breast pain persisting for 5 years. The presence of breast pain at 5 years was associated with only a modest reduction in general well-being. Breast pain persisting for at least 5 years after treatment for BC is common. As the pain is largely unexplained by factors associated with the characteristics of the cancer or its treatment, the contribution of patient expectations to persistent breast pain may be considerable. Where persistent pain occurs, referral for the management of pain and, where appropriate, lymphedema is warranted.


Fringe differentially modulates Jagged1 and Delta1 signalling through Notch1 and Notch2.
Proteins encoded by the fringe family of genes are required to modulate Notch signalling in a wide range of developmental contexts. Using a cell co-culture assay, we find that mammalian Lunatic fringe (Lfng) inhibits Jagged1-mediated signalling and potentiates Delta1-mediated signalling through Notch1. Lfng localizes to the Golgi, and Lfng-dependent modulation of Notch signalling requires both expression of Lfng in the Notch-responsive cell and the Notch extracellular domain. Lfng does not prevent binding of soluble Jagged1 or Delta1 to Notch1-expressing cells. Lfng potentiates both Jagged1- and Delta1-mediated signalling via Notch2, in contrast to its actions with Notch1. Our data suggest that Fringe-dependent differential modulation of the interaction of Delta/Serrate/Lag2 (DSL) ligands with their Notch receptors is likely to have a significant role in the combinatorial repertoire of Notch signalling in mammals.


Bradykinin-induced vasodilation is changed to a vasoconstrictor response in vessels of aged normotensive and hypertensive rats.
The vascular response to bradykinin was investigated in mesenteric vascular bed preparations preconstricted with methoxamine, obtained from 2- and 18-month old normotensive (WKY) and spontaneously hypertensive (SHR) rats. In preparations from young normotensive rats bradykinin (1 nm-10 microM) produced an endothelium-dependent vasorelaxant effect which was greatly reduced by the B2 receptor antagonist Ac-D-Arg[Hyp3,D-Phe7,Leu8]-bradykinin (1 microM), and was unaffected by the B1 receptor antagonist des-Arg9,[Leu8]-bradykinin (1 microM). The degree of vasodilation was similar in preparations from age-matched SHR rats. In vessels obtained from old animals bradykinin induced an endothelium-independent vasoconstrictor response; this effect was more pronounced in preparations from SHR than in those from WKY rats. The vasoconstriction was unaffected by both B1 and B2 receptor antagonists, and was abolished by 3 microM indomethacin. We conclude that the vasorelaxant effect of bradykinin in vessels of young animals is due to stimulation of B2 receptors. This vasodilating response can be converted by aging to a vasoconstriction and is probably due to the release of a prostanoid product; moreover it is more pronounced in spontaneously hypertensive animals.


Serological Response to SARS-CoV-2 Messenger RNA Vaccine: Real-World Evidence from Italian Adult Population.
This study aims to investigate the extent of the BNT162b2 mRNA vaccine-induced antibodies against SARS-CoV-2 in a large cohort of Italian subjects belonging to the early vaccinated cohort in Italy. A prospective study was conducted between December 2020 and May 2021. Three blood samples were collected for each participant: one at the time of the first vaccine dose (T0), one at the time of the second vaccine dose, (T1) and the third 30 days after this last dose (T2). We enrolled 2591 fully vaccinated subjects; 16.5% were frail subjects, and 9.8% were over 80 years old. Overall, 98.1% of subjects were seropositive when tested at T2, and 76.3% developed an anti-S IgG titer ≥4160 AU/mL, which is adequate to develop viral neutralizing antibodies. Seronegative subjects at T1 were more likely to remain seronegative at T2 or to develop a low-intermediate anti-S IgG titer (51-4159 AU/mL). In summary, vaccination leads to detectable anti-S IgG titer in nearly all vaccine recipients. Stratification of the seroconversion level could be useful to promptly identify high-risk groups who may not develop a viral neutralizing response, even in the presence of seroconversion, and therefore may remain at higher risk of infection, despite vaccination.


Asymmetric Reduction of Acetophenone by Aspergillus Species and Their Possible Contribution to Katsuobushi Flavor.
Eight strains of Aspergillus species isolated from katsuobushi (dried bonito) were grown in a liquid medium containing acetophenone, to examine the possibility of asymmetric reduction of acetophenone during the molding process in katsuobushi production. Seven strains produced predominantly the R-stereoisomer of α-phenethylalcohol. However, one strain gave the S-isomer predominantly.


[Value of procalcitonin for infants with bronchiolitis in an emergency department].
Very few studies have evaluated the role of procalcitonin (PCT) in infants with bronchiolitis. To describe infants who had both a diagnosis of bronchiolitis at the emergency department and a blood test including PCT, and to compare the characteristics of children according to the PCT value. Infants admitted to the Pediatric Emergency Department between 1 January 2014 and 31 December 2014 who had a diagnosis of bronchiolitis and a blood test including PCT were included. The clinical, biological, and radiological characteristics of the infants with PCT <1 or ≥1g/L were compared. One hundred thirty six infants were included. Patients with high PCT (n=20) had a higher temperature (38.5°C, IQR=37.8-38.6 vs. 37.5°C, IQR=37.1-38.2; P<0.01), C-reactive protein (50mg/L, IQR=25-83 vs. 5mg/L, IQR=0-19; P<0.01), and neutrophils (7.8×109/L, IQR=6.0-8.5 vs 4.5×109/L, IQR=2.9-6.6; P<0.01) higher than patients with low PCT (n=116). Presence on the chest x-ray of alveolar condensation did not differ between the two PCT groups. Infants coming from the low-PCT group received fewer antibiotics (14.7% vs 65%; P<0.01). In a Pediatric Emergency Department, PCT with a value of 1 or more cannot predict the presence of alveolar condensation on the chest x-ray. It seems to be associated with the antibiotics prescription, even if this could not be proved because of the design of the study.


[Current cases of falsified medicinal products within the competence of the Federal Institute for Drugs and Medical Devices (BfArM) : Case studies and extent].
The nature of a falsification of a medicinal product can vary a lot. Therefore the means to detect them and the potential risk to patient safety can also be very different. The whole range of falsification will be described using observed cases from the Federal Institute for Drugs and Medical Devices (BfArM).Based on the relatively low number of detected cases of falsified medicines, the legal supply chain can still be regarded as safe. It has to be assumed that in the illegal supply chain, e. g. illegal internet trade, the majority of the offered medicinal products are not only falsifications due to illegal trade but because they are completely falsified. Therefore there is an especially high risk for the consumer to be harmed by medicinal products that do not fulfil the required specifications.The trend indicates that increased efforts will be necessary to keep the legal supply chain safe and to contain illegal trade with falsifications. The higher federal authorities BfArM, PEI and BVL are involved in this task by coordinating and ensuring the flow of information to the concerned authorities and stakeholders as well as informing the public. Increased efforts are also necessary due to the rising involvement of organised crime in the falsification of medicinal products. A package of measures was enacted with the Falsified Medicines Directive 2011/62/EU to protect the legal supply chain from falsified medicinal products.


Dental Items of Interest: The Case of Delphic Sibyl by Michelangelo: Solitary Median Maxillary Central Incisor or Mesiodens.
A case of an anomaly in the maxillary dental arch on "Delphic Sibyl," a fresco by Michelangelo is reported. An accurate analysis of this fresco shows a single incisor tooth is present precisely in the midline. We hypothesize that it may be a case of solitary median maxillary central incisor (SMMCI) and discuss the differential diagnosis with another similar anomaly--the mesiodens.


Therapeutic administration of nitric oxide synthase inhibitors reverses hyperalgesia but not inflammation in a rat model of polyarthritis.
Nitric oxide (NO) has been postulated to play a role in pain as well as in inflammation. In the present studies, the effects of NO synthase (NOS) inhibitors on both pain and inflammation were examined in a rat model of polyarthritis. Female Lewis rats were injected intraperitoneally (i.p.) with peptidoglycan/polysaccharide (PG/PS) or saline to induce arthritis. Hind paw volume, response latency to thermal nociceptive stimulus and mechanical threshold were measured daily for the next 35 days. Paw inflammation, thermal hyperalgesia and mechanical allodynia developed in all rats that received PG/PS compared to saline. On day 19 (chronic inflammation phase), rats were given either N(G)-nitro-L-arginine methyl ester (L-NAME, non-selective NOS inhibitor, 100 mg/l), L-N (6)-(1-iminoethyl) lysine (L-NIL, selective inducible NOS inhibitor, 10 mg/l) or no drug in drinking water. By day 21, L-NAME treatment reversed the thermal hyperalgesia completely and this effect remained until day 35. Similarly, L-NIL treatment reversed thermal hyperalgesia from days 24 to 34. Neither treatment affected mechanical allodynia. Paw volume was not different between PG/PS treated and PG/PS plus L-NAME treated rats. However, the PG/PS plus L-NIL treatment produced an increase in paw volume greater than did PG/PS alone. Other rats were treated with PG/PS plus the antiinflammatory agent indomethacin (days 19-35). Indomethacin treatment reversed all the measured parameters, although the reversal of mechanical allodynia was only partial. These results suggest that NO is involved in thermal, but not mechanical sensory pathways and that the selective inhibition of inducible NOS activity exacerbates established inflammation.


Co-transcriptional genome surveillance by HUSH is coupled to termination machinery.
The HUSH complex recognizes and silences foreign DNA such as viruses, transposons, and transgenes without prior exposure to its targets. Here, we show that endogenous targets of the HUSH complex fall into two distinct classes based on the presence or absence of H3K9me3. These classes are further distinguished by their transposon content and differential response to the loss of HUSH. A de novo genomic rearrangement at the Sox2 locus induces a switch from H3K9me3-independent to H3K9me3-associated HUSH targeting, resulting in silencing. We further demonstrate that HUSH interacts with the termination factor WDR82 and-via its component MPP8-with nascent RNA. HUSH accumulates at sites of high RNAPII occupancy including long exons and transcription termination sites in a manner dependent on WDR82 and CPSF. Together, our results uncover the functional diversity of HUSH targets and show that this vertebrate-specific complex exploits evolutionarily ancient transcription termination machinery for co-transcriptional chromatin targeting and genome surveillance.


Relationships between the lung-heart ratio assessed from post-exercise thallium-201 myocardial tomograms, myocardial ischemia and the extent of coronary artery disease.
Uptake of thallium (Tl)-201 in the lungs has been proposed as a measure of left ventricular dysfunction. In this study we were interested in pursuing two goals: 1) to assess possible relationships between the post-exercise Tl-201 lung-heart (LH)-ratio determined from the anterior view during SPECT-acquisition, myocardial ischemia and the extent of coronary artery disease; and 2) to explore the effects of coronary revascularisation procedures on the LH-ratio. The study group consisted of 145 patients with early and late postexercise Tl-201 tomograms, including 32 PTCA-patients with pre- and post-PTCA studies and 20 patients who underwent coronary artery bypass surgery (CABG) with corresponding pre- and post-CABG studies. Ischemia was defined as evoked angina during the exercise test in combination with greater than or equal to 1 mm horizontal or downsloping ST-depression on the ECG. The severity of coronary obstructions was assessed from coronary angiograms with a PC-based digital caliper technique; a stenosis was defined to be significant when its severity exceeded 50% diameter stenosis. The LH-ratio was defined by the ratio of the mean pulmonary counts and the mean myocardial counts assessed from corresponding regions of interest (ROI's) positioned over the left lung and the heart, respectively in the anterior view of a tomographic data acquisition procedure. Our results made clear that the LH-ratio was not significantly different between patients with and without ischemia during exercise, and between patients with single vs. multiple vessel disease.(ABSTRACT TRUNCATED AT 250 WORDS)


The somatotrophic system in patients with dilated cardiomyopathy: relation of insulin-like growth factor-1 and its alterations during growth hormone therapy to cardiac function.
Treatment with human recombinant growth hormone has yielded conflicting results in patients with congestive heart failure. In addition, growth hormone resistance has been reported in severe heart failure. Therefore, the purpose of this study was to evaluate the somatotrophic axis and effects of growth hormone on haemodynamics in patients with heart failure due to dilated cardiomyopathy. Randomized, double-blind, placebo-controlled trial. Fifty clinically-stable patients with moderate heart failure (mean left ventricular ejection fraction = 26 +/- 2%) due to dilated cardiomyopthy were examined. Patients were randomly assigned to treatment with placebo or 2 IU/d sc human recombinant growth hormone for a mean of 14 weeks. Cardiac size and function were evaluated by magnetic resonance imaging. Central haemodynamics were obtained by right heart catheterization. Measurements of plasma noradrenaline, serum insulin-like growth factor-1, and insulin-like growth factor binding protein-3 were performed by standard assays at baseline and at the end of the treatment period. The severity of heart failure as determined by stroke volume, left ventricular end diastolic diameter and plasma noradrenaline concentrations correlated significantly to baseline serum insulin-like growth factor-1 levels (each P < 0.05). The growth hormone-induced increase of insulin-like growth factor-1 predicted the changes in ejection fraction (P < 0.05). A significant increase in ejection fraction of 7% was observed in patients whose insulin-like growth factor-1 increased by more than the median increase in comparison to the patients with an increase below the median (+ 4.0 +/- 2.3% vs. - 3.0 +/- 1.8%; P = 0.03). Serum levels of insulin-like growth factor-1, reflecting growth hormone secretion, are diminished in relation to the severity of heart failure in patients with dilated cardiomyopathy. Growth hormone induced increases of insulin-like growth factor-1 of more than 77 ng/l caused significant improvement of ejection fraction.