[Analysis of success predictive factors in the treatment of urinary lithiasis by extracorporeal shock wave lithotripsy. patient optimization: ESWL score.]
Extracorporeal shock wave lithotripsy (ESWL) represents one of the most frequently used methods to treat urinary tract calculi. However, sometimes we do not obtain the fragmentation expected. The aim of this study is to evaluate the parameters that may influence ESWL final results, developing a classification for better patient's selection and outcome optimization. 270 patients with renal or ureteral stones were retrospectively reviewed after ESWL treatment, recording both clinical parameters (age, sex, location, laterality, body mass index [BMI]), and CT-Scan parameters (stone size and volume, skin-to-stone distance (SSD), mean and maximal stone density). Cutoff values were determined for each parameter based upon ROC curves, and final score (ESWL score) was calculated based on the number of parameters lower than the cutoff values. Of the 270 patients treated, 186 (68.8%) were considered as ESWL success, without significant differences between success and failure group. Parameters that showed significant difference after multivariate analysis were: size (cut off: 9.3 mm), volume (237.2 mm3), mean density (951 UH), SSD (133 mm) and BMI (26.9 kg/m2). AUC of ROC curve including all of these parameters, was 0.807. Stone free status was 17.6% for score 0, 25% (score 1), 48.8% (score 2), 74.1% (score 3), 86.3% (score 4) and 92.2% for score 5. Patient classification before ESWL treatment seems to allow us better selection, improving treatment success.


BM stem cells and cardiac repair: where do we stand in 2004?
Adult BM stem cells are being investigated for their potential to regenerate injured tissues by a process referred to as plasticity or transdifferentiation. Although data supporting stem cell plasticity is extensive, a controversy has emerged based on findings that propose cell-cell fusion as a more appropriate interpretation for this phenomenon. A major focus of this controversy is the claim that acutely infarcted myocardium in adult hearts can be regenerated by BM stem cells. Many researchers consider the adult heart to be a post-mitotic organ, whereas others believe that a low level of cardiomyocyte renewal occurs throughout life. If renewal occurs, it may be in response to cardiac stem cell activity or to stem cells that migrate from distant tissues. Post-mortem microscopic analysis of experimentally induced myocardial infarctions in several rodent models suggests that cardiomyocyte renewal is achieved by stem cells that infiltrate the damaged tissue. For a better understanding of the possible involvement of stem cells in myocardial regeneration, it is important to develop appropriate technologies to monitor myocardial repair over time with an emphasis on large animal models. Studies on non-human primate, swine and canine models of acute myocardial infarctions would enable investigators to utilize clinical quality cell-delivery devices, track labeled donor cells after precision transplantation and utilize non-invasive imaging for functional assays over time with clinical accuracy. In addition, if stem cell plasticity is to reach the next level of acceptance, it is important to identify the environmental cues needed for stem cell trafficking and to define the genetic and cellular mechanisms that initiate transdifferentiation. Only then will it be possible to determine if, and to what extent, BM stem cells are involved in myocardial regeneration and to begin to regulate precisely tissue repair.


Adjuvant potential of aggregate-forming polyglutamine domains.
Aggregation may significantly affect the fate of a polypeptide, including its susceptibility to proteasome-dependent or autophagic degradation, its interaction with chaperones, etc. Since all these factors may affect the antigenicity of a polypeptide, we hypothesized that stimulating aggregation of an antigenic protein by its fusion to polyQ domain may enhance its antigenic potential. This hypothesis was tested with the weakly immunogenic model antigen GFP, which was fused to either long polyQ domain that triggers protein aggregation (103Q), or short polyQ domain that does not promote aggregation (25Q). Plasmids encoding control pGFP or soluble 25Q-GFP generated a very weak antibody response, while a significant increase in anti-GFP antibody titer was seen in groups immunized with DNA encoding aggregating 103Q-GFP. Similarly, fusion with 103Q strongly enhanced anti-GFP CTL activity, compared to fusion with 25Q. No apparent toxicity was observed after immunization with polyQ-GFP fusions. These data suggest that fusion of an antigen with expanded polyQ domains could have a significant adjuvant potential.


Comparison of Open Reduction and Internal Fixation Versus Closed Reduction and Percutaneous Fixation for Medial Malleolus Fractures.
Surgical treatment of medial malleolus (MM) fractures can be performed through open or percutaneous approaches, although comparisons between these two approaches have not been undertaken. In this study, we compared patients with MM fractures treated with closed reduction and percutaneous fixation (CRPF) with patients treated with traditional open reduction and internal fixation (ORIF). A group of 165 consecutive patients underwent surgical fixation of a closed MM fracture from 2011 to 2015 at a single institution. Thirty-one underwent CRPF and 134 underwent ORIF. Patient demographics, injury characteristics, treatment methods, and outcome variables were recorded through review of patient charts, radiographs, and surgical reports. The rate of MM fracture comminution was higher in the ORIF group compared with the CRPF group (9.7% vs 27.6%; P = 0.04). All other patient and injury variables were similar between the two groups. There was no statistically significant difference observed between the CRPF and ORIF groups regarding outcomes, including nonunion, malunion, time to union, rate of hardware removal, and wound complications. Both CRPF and ORIF resulted in acceptable radiographic outcomes and low complication rates for the treatment of MM fractures.


D-cycloserine is not susceptible to self-administration using an intravenous self-administration model in male ketamine-habituated Sprague-Dawley rats.
N-methyl-d-aspartate receptor (NMDAR) antagonist antidepressants have known potential for abuse liability. The aim of this study was to evaluate the abuse liability of D-cycloserine (DCS), using a self-administration paradigm in which DCS was tested for its efficacy in substituting for ketamine in ketamine-dependent rats. A standard intravenous self-administration study was conducted in male adult Sprague-Dawley rats to study abuse liability. Potential for self-administration was assessed in ketamine-habituated subjects. Subjects were trained to press a lever to obtain food, prior to connection of the lever to the intravenous drug administration apparatus. DCS was provided for self-infusion by test subjects at doses of 1.5, 5.0, and 15 mg/kg per lever press. S-ketamine was seen to substitute for ketamine and to result in self-administration at the same frequency. DCS was not seen to result in self-administration at any of the test doses. The self-infusion behavior of DCS was similar to control (saline). D-cycloserine, a partial agonist of the NMDAR glycine site, which has been shown to have antidepressant and anti-suicidal properties in clinical studies, has no apparent potential for abuse liability in a standard rodent self-administration model.


Different signaling mechanisms regulating IL-6 expression by LPS between gingival fibroblasts and mononuclear cells: seeking the common target.
To reduce connective tissue IL-6 level stimulated by LPS, it is essential to control IL-6 expression in both mononuclear cells and fibroblasts. However, it is unclear whether the regulatory mechanisms for both cells are similar or not. In this study, we found that signaling pathways mediating LPS-stimulated IL-6 in mononuclear U937 cells and fibroblasts were different. Furthermore, our studies showed that while LPS activated AP-1 and NFκB in U937 cells, it only activated NFκB in fibroblasts. Analysis of nuclear AP-1 subunits showed that LPS stimulated c-Fos, Fra-1 and Jun D activities in U937 cells, but not fibroblasts. The lack of ERK involvement in LPS-stimulated IL-6 in fibroblasts was further supported by the observations that simvastatin, which is known to target ERK-AP-1, failed to inhibit LPS-stimulated IL-6 by fibroblasts. Finally, we showed that targeting NFκB pathway was highly effective in inhibition of LPS-stimulated IL-6 in coculture of U937 cells and fibroblasts.


Thermal comfort provided by different shading structures in free-range systems in Brazilian savanna.
This work aimed to evaluate the thermal comfort provided by shading structures in free-range systems under a tropical environment, based on microclimate variables of nets with different materials. During the experiment, the unshading area; the natural shading of a native tree species to the Brazilian Savanna; and the artificial 80% shadings nets: black polypropylene, heat-reflective aluminized, and association of both were evaluated. The shading structures were analyzed in paddocks at the Água Limpa Farm from the University of Brasília, where dry-bulb, wet-bulb, black globe temperatures, and wind speed were collected for the micrometeorological characterization from 8:00 am to 4:00 pm. From the temperatures, the vapor pressures and the humidities were calculated. The shortwave radiation was calculated through the sum of direct, diffuse, and reflected radiations. The mean radiant temperature, radiant heat load, and black globe temperature and humidity index were calculated. The internal and external surface temperatures of the nets and the soil temperature were measured every 30 min. The data were analyzed with aid of the statistical analysis system. The air temperature varied according to the shortwave radiation, from 25.6 °C at 8:00 am to 29.6 °C at 1:00 pm, with a decrease over the hours. Despite the air temperature of the trees showed the lowest average, the nets association structure was the most reduced all the thermal comfort indexes. The heat-reflective net presented the lowest soil temperature at all hours (under 26.1 °C). In general, the shadings proved to be efficient in promoting thermal comfort in free-range systems.


Ganglioside biosynthesis in rat liver: different distribution of ganglioside synthases in hepatocytes, Kupffer cells, and sinusoidal endothelial cells.
The activities of five glycolipid-glycosyltransferases, GL2, GM3, GM2, GM1, and GD1a synthase, were determined in a cell-free system with homogenate protein of total rat liver, isolated hepatocytes, Kupffer cells, and sinusoidal endothelial cells. In rat liver parenchymal and nonparenchymal cells ganglioside synthases were distributed differently. Compared to hepatocytes, Kupffer cells expressed a nearly sevenfold greater activity of GM3 synthase, but only 14% of GM2, 19% of GM1, and 67% of GD1a synthase activity. Sinusoidal endothelial cells expressed a pattern of enzyme activities quite similar to that of Kupffer cells with the exception of higher GM2 synthase activity. Activity of GL2 synthase was distributed unifromly in parenchymal and nonparenchymal cells of rat liver, but differed by sex. It was 1 to 2 orders of magnitude below that of all the other ganglioside synthases investigated. The results indicate GL2 synthase regulates the total hepatic ganglioside content, and hepatocytes but not nonparenchymal liver cells have high enzymatic capacities to form a-series gangliosides more complex than GM3.


In situ modification of the d-band in the core-shell structure for efficient hydrogen storage via electrocatalytic N2 fixation.
The electrochemical N2 reduction reaction (NRR) into NH3, especially powered by clean and renewable electricity, is a promising alternative to the capital- and energy-intensive Haber-Bosch process. However, the inert N[triple bond, length as m-dash]N bond and the frantic competition of the hydrogen evolution reaction lead to a poor NH3 yield rate and faradaic efficiency (FE). Here, we in situ construct a series of two-dimension core/shell V2O3/VN nanomeshes with a gradient nitride-layer thickness. Among them, V2O3/VN-2 exhibits the highest FE of 34.9%, an excellent NH3 yield rate of 59.7 μg h-1 mgcat. -1, and outstanding cycle stability, exceeding those of most of the NRR electrocatalysts reported to date. First-principles calculations reveal that the d-band center of VN shifts up in a nearly linear manner with the decrease of nitride-layer thickness, and V2O3/VN-2 with a d-band center closer to the Fermi level can strengthen the d-2π* coupling between the catalyst and N2 molecule, notably facilitating the N2-into-NH3 conversion.


Reduced binding of immunoglobulin A (IgA) from patients with primary IgA nephropathy to the myeloid IgA Fc-receptor, CD89.
Primary IgA nephropathy (IgAN) is associated with elevated levels of circulating IgA and is characterized by deposition of primarily IgA1 in the renal mesangium. It has not yet been clarified which mechanisms govern the deposition of IgA1 in the mesangium. One of the factors which may play a role in trapping of IgA in the mesangial area is the interaction of IgA with specific IgA receptors (Fc alphaR, CD89) on the mesangial cells. In the present study IgA derived from patients with IgAN and controls was investigated for its interaction with human CD89, expressed on the surface of the murine B cell line IIA1.6. IgA binding to CD89 expressing cells was specific, concentration dependent and binding of dIgA and pIgA occurred in a more efficient fashion than that of mIgA. IgA binding to CD89 directly from serum of patients compared to controls showed no significant difference. However these experiments are affected by differences in IgA concentration and combinations of different sizes of IgA. Using purified fractions of mIgA, dIgA, and pIgA isolated from serum, a significantly reduced binding of mIgA to CD89 from patients compared to controls was observed. Finally, the binding of aIgA2 to CD89 was less inhibited using mIgA from patients with IgAN compared to controls. The reduced binding of mIgA to CD89 seems to contradict a direct role for CD89 in deposition of IgA. However reduced binding of mIgA to CD89 may affect IgA clearance, leading to higher serum IgA. Furthermore, since it has been demonstrated that mIgA can interfere with binding of di- and pIgA, CD89 could still contribute to pIgA deposition in the mesangial area.


Molecular complexes of calf thymus DNA with various bioactive compounds: Formation and characterization.
The interaction between biomacromolecules and ligands has attracted great interest because of their biological properties. Calf thymus DNA (ctDNA) can interact with bioactive compounds to form complexes. Here, ctDNA-ligand complexes were studied using fluorescence, absorption, and infrared spectroscopy, circular dichroism, ABTS assay and competitive displacement. The binding constants of bioactive compounds at the intercalative site of ctDNA ranked in order kaempferol > apigenin > quercetin > curcumin > riboflavin, while the binding constants at minor groove sites ranked quercetin > kaempferol > naringenin ~ apigenin > hesperetin > curcumin ~ resveratrol ~ riboflavin > caffeic acid. CtDNA maintained stable B-form with an enhancement of base stacking and a decrease of right-handed helicity in the presence of these bioactive compounds, except for hesperetin and caffeic acid. Bioactive compounds preferentially bound to guanine bases and tended to transfer into a more hydrophobic environment upon complexation with ctDNA. The DNA complexation did not affect the ABTS·+ scavenging capacity of quercetin, kaempferol, resveratrol and apigenin but increased the ones of naringenin, caffeic acid, curcumin, hesperetin and riboflavin. The data gathered here should be useful to understand the binding modes of DNA with ligands for their potential application in pharmaceutical and food industries.


Effects of drugs on the accumulation and spontaneous release of noradrenaline in the rat anococcygeus muscle.
1 The ability of drugs to inhibit noradrenaline accumulation and to release noradrenaline was studied in the isolated anococcygeus muscle of the rat. 2 Noradrenaline, tyramine, 2-amino,6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (ADTN), 2-amino,6,7-dimethoxy-1,2,3,4-tetrahydronaphthalene (dimethyl ADTN), and 5-hydroxytryptamine were all potent inhibitors of noradrenaline accumulation and potent releasers of noradrenaline. ADTN was accumulated by the rat isolated anococcygeus muscle. 3 Amphetamine and desipramine were potent inhibitors of noradrenaline accumulation but poor releasers of noradrenaline. 4 Methoxamine, oxymetazoline, acetylcholine, and angiotensin were poor inhibitors of noradrenaline accumulation and did not release noradrenaline. 5 The mechanism of action of these drugs is discussed.


An observational study of once-daily modified-release methylphenidate in ADHD: effectiveness on symptoms and impairment, and safety.
ADHD affects over 5% of children worldwide. It is typically treated with stimulant medications, and methylphenidate (MPH) is the most commonly prescribed. This study investigated the effectiveness, on symptoms and impairment, and safety of Equasym XL(®), a combination of 30% immediate-release and 70% modified-release MPH, in the treatment of ADHD in daily clinical practice. This open-label, observational, post-marketing surveillance study was conducted in 169 centres in Germany. Eligible patients, aged 6-17 years, were diagnosed with ADHD and about to begin treatment with Equasym XL(®). Effectiveness was assessed by physicians using the clinical global impression (CGI) severity and improvement scales; teachers and parents completed questionnaires evaluating ADHD symptoms and behavioural problems (DAYAS, FBB-ADHD and SDQ-P). Assessments were carried out at baseline, after 1-3 and 6-12 weeks of treatment. Of 852 enrolled patients, 822 were evaluable; 25.30% were treatment naïve, 69.84% had previously received different MPH formulations, and 4.87% had received other medications. ADHD symptoms improved from baseline to last visit for the majority of patients for all outcome measures. According to physician ratings of core ADHD symptoms, 75.73% of patients showed improvements on the CGI-Improvement scale, 17.77% had no change, and 6.50% worsened. In teacher and parent ratings, the effectiveness of Equasym XL(®) was rated better than prior therapy at all measured time points across the day, particularly late morning (teachers) and early afternoon (parents). Equasym XL(®) was generally well tolerated; only 3.16% of patients permanently discontinued treatment due to adverse events. Equasym XL(®) is effective and well tolerated in daily clinical practice.


Fabrication of a novel sensor based on Cu quantum dot and SH-SiO2 nanoparticles supported on copper-based metal organic framework (Cu QD-SH-SiO2@Cu-MOF) and its application for the simultaneous determination of norepinephrine, piroxicam and epinephrine.
In this research, a novel electrochemical sensor with excellent sensitivity was fabricated based on Cu quantum dot (Cu QD) and SH-SiO2 nanoparticles immobilized on copper-metal-organic frameworks (Cu-MOFs) for determining piroxicam and simultaneous determination of norepinephrine, piroxicam and epinephrine. The nanoparticles were synthesized and characterized using FT-IR, EDX, FESEM, TEM and BET, and were subsequently used to modify carbon paste electrode. Cu QD-SH-SiO2@Cu-MOF for electrode modification possesses a distinctive structure and a high conductivity that raises the electron transfer rate and enhances the performance of electrochemical sensors. Square wave voltammetry was applied to investigate the redox properties of Cu QD-SH-SiO2@Cu-MOF/CPE, voltammograms showed three distinct anodic peaks at 0.41, 0.62 and 1.06 V in the presence of norepinephrine, piroxicam, and epinephrine. Various experimental parameters including the type and pH of electrolyte and scan rate were investigated. The calibration graph was obtained over the range 0.2-34285.0 μM including three linear segments. Also, the limit of detection was calculated as 0.05 μM of piroxicam. The introduced sensor was satisfactorily utilized for electrochemical determination of norepinephrine, piroxicam, and epinephrine in real samples. The obtained results using the introduced sensor were validated by high-performance liquid chromatography and the statistical tests confirmed the good agreement of them.


Efficient cell mediated lysis of human erythrocyte target cells is mediated by a human glycophorine A specific murine monoclonal antibody.
A human glycophorine A specific murine monoclonal antibody mediates the antibody dependent killing of antibody sensitized human erythrocytes by human K cells (monocyte-free mononuclear cells). The overall level of killing is lower than that mediated by conventional, human anti-D antibodies but it is significant on each target cell.


Multicenter trial of carperitide in patients with renal dysfunction undergoing cardiovascular surgery.
The aim of this study was to evaluate the efficacy of carperitide in maintaining renal function during intraoperative and postoperative management of patients with renal dysfunction undergoing elective cardiovascular surgery. The subjects were 88 patients with a preoperative serum creatinine level ≥1.2 mg/dl who underwent elective cardiovascular surgery using cardiopulmonary bypass. They were prospectively divided into a group that received carperitide from the start of surgery (carperitide group, n = 44) and a group that was not given carperitide (control group, n = 44). Carperitide infusion was initiated at the beginning of surgery and was continued for ≥5 days, with the central dose being 0.02 g/kg/min. The primary endpoint was the serum creatinine level on postoperative day (POD) 3. The serum creatinine levels on PODs 3, 4, and 7 were significantly lower, and creatinine clearance on PODs 2 and 3 was significantly higher in the carperitide group than in the controls. One patient in the control group and no patient in the carperitide group required continuous hemodiafiltration, but the difference was not statistically significant. Continuous low-dose infusion of carperitide from the start of cardiovascular surgery maintained renal function in patients with preoperative renal dysfunction.


A microcytotoxicity assay for thyroid-specific cytotoxic antibody, antibody-dependent cell-mediated cytotoxicity and direct lymphocyte cytotoxicity using human thyroid cells.
A microcytotoxicity assay for detection of thyroid-specific complement-dependent cytotoxic antibody (cytotoxic antibody), antibody-dependent cell-mediated cytotoxicity (ADCC) and direct lymphocyte cytotoxicity was developed using human, thyroid epithelial cells as targets. Thyroid tissue was obtained from patient with Graves' disease and was treated with collagenase and then trypsin. The red blood cells, interfollicular fibroblasts and infiltrating lymphoid cells in thyroid tissue from patients with Graves' disease could be removed by this procedure. To obtain entirely single cells as target cells, the suspension of dispersed thyroid epithelial cells was allowed to stand for 1 h at 4 degree C in culture medium to allow cell clumps to settle. For assay of cytotoxic antibody, a mixture of the single target cells, patient's serum and human complement was incubated in microwells for 18 h. After removing the detached cells, remaining target cells in the wells were fixed, stained and counted to assess cytotoxicity. For assay of ADCC and of direct lymphocyte cytotoxicity, target thyroid cells were precultured in the microwells for 18 h. Then effector cells with or without patient's serum were added and cultured further for 24-72 h. Cytotoxicity was assessed as described above. Adherence of effector cells to target thyroid cells sometimes disturbed the enumeration of target cells when the effector/target cell ratio was high. With this microassay system 3 different cytotoxic immune reactions against human thyroid cells could be measured quantitatively at the same time on 2-3 ml blood samples.


Proteomic Dynamics of Breast Cancer Cell Lines Identifies Potential Therapeutic Protein Targets.
Treatment and relevant targets for breast cancer (BC) remain limited, especially for triple-negative BC (TNBC). We identified 6091 proteins of 76 human BC cell lines using data-independent acquisition (DIA). Integrating our proteomic findings with prior multi-omics datasets, we found that including proteomics data improved drug sensitivity predictions and provided insights into the mechanisms of action. We subsequently profiled the proteomic changes in nine cell lines (five TNBC and four non-TNBC) treated with EGFR/AKT/mTOR inhibitors. In TNBC, metabolism pathways were dysregulated after EGFR/mTOR inhibitor treatment, while RNA modification and cell cycle pathways were affected by AKT inhibitor. This systematic multi-omics and in-depth analysis of the proteome of BC cells can help prioritize potential therapeutic targets and provide insights into adaptive resistance in TNBC.


EHR based Genetic Testing Knowledge Base (iGTKB) Development.
The gap between a large growing number of genetic tests and a suboptimal clinical workflow of incorporating these tests into regular clinical practice poses barriers to effective reliance on advanced genetic technologies to improve quality of healthcare. A promising solution to fill this gap is to develop an intelligent genetic test recommendation system that not only can provide a comprehensive view of genetic tests as education resources, but also can recommend the most appropriate genetic tests to patients based on clinical evidence. In this study, we developed an EHR based Genetic Testing Knowledge Base for Individualized Medicine (iGTKB). We extracted genetic testing information and patient medical records from EHR systems at Mayo Clinic. Clinical features have been semi-automatically annotated from the clinical notes by applying a Natural Language Processing (NLP) tool, MedTagger suite. To prioritize clinical features for each genetic test, we compared odds ratio across four population groups. Genetic tests, genetic disorders and clinical features with their odds ratios have been applied to establish iGTKB, which is to be integrated into the Genetic Testing Ontology (GTO). Overall, there are five genetic tests operated with sample size greater than 100 in 2013 at Mayo Clinic. A total of 1,450 patients who was tested by one of the five genetic tests have been selected. We assembled 243 clinical features from the Human Phenotype Ontology (HPO) for these five genetic tests. There are 60 clinical features with at least one mention in clinical notes of patients taking the test. Twenty-eight clinical features with high odds ratio (greater than 1) have been selected as dominant features and deposited into iGTKB with their associated information about genetic tests and genetic disorders. In this study, we developed an EHR based genetic testing knowledge base, iGTKB. iGTKB will be integrated into the GTO by providing relevant clinical evidence, and ultimately to support development of genetic testing recommendation system, iGenetics.


Attempts to localize the defect in dysgammaglobulinemia of UM-B19 chickens by studying the effect of immunomodulating substances on immunoglobulin and antibody production.
The extreme decreased levels of IgG in dysgammaglobulinemic UM-B19 chickens are linked with decreased antibody activity. Antibody activity to T-dependent (although diminished) and T-independent antigens is present but is restricted to IgM and IgA antibodies. Complete Freund's adjuvant enhances the existing isotype pattern of serum immunoglobulins and antibodies. The antibody response to a "T-independent" antigen (B. abortus) is greatly increased by CFA in dysgammaglobulinemic chickens. Beside the appearance of high levels of IgG in dysgammaglobulinemic chickens during the first weeks of life and in transitory dysgammaglobulinemia, remarkable IgG synthesis can be temporarily induced by the mitogenic activity of LPS and even more by the regulatory function of Levamisole. Furthermore, LPS and Levamisole induce IgG antibody synthesis to concomitantly administered antigen, the IgG antibodies appearing within the normal time. Contrary to a missing feedback inhibition from total IgG to IgM serum immunoglobulins, a feedback inhibition from IgG to IgM antibodies is found. No correlation can be found between Levamisole-induced IgG immunoglobulin concentrations, and IgG antibodies. Germfree rearing for one week or longer prevents the dysgammaglobulinemic defect. The following conclusions are drawn: Early antigenic stimulation seems to be the inducing factor for dysgammaglobulinemia in UM-B19 chickens. A BG cell pool is still present in adult dysgammaglobulinemic chickens. This BG cell pool is probably diminished to a varying extent. T cell helper functions seem to be present (albeit they may be disturbed) and can be stimulated. IgG specific T cell suppression is probable. From these conclusions the etiology of the dysgammaglobulinemia in UM-B19 chickens is hypothesized to be primarily due to delayed bursal development: Immature BG cells are eliminated by environmental antigens during the neonatal period in a process similar to tolerance induction. This event, in turn, induces suppressor mechanism(s) or disturbance in helper mechanism(s).


The gingival Stillman's clefts: histopathology and cellular characteristics.
Stillman's cleft is a mucogingival triangular-shaped defect on the buccal surface of a root with unknown etiology and pathogenesis. The aim of this study is to examine the Stillman's cleft obtained from excision during root coverage surgical procedures at an histopathological level. Harvesting of cleft was obtained from two periodontally healthy patients with a scalpel and a bevel incision and then placed in a test tube with buffered solution to be processed for light microscopy. Microscopic analysis has shown that Stillman's cleft presented a lichenoid hand-like inflammatory infiltration, while in the periodontal patient an inflammatory fibrous hyperplasia was identified. Stillman's cleft remains to be investigated as for the possible causes of such lesion of the gingival margin, although an inflammatory response seems to be evident and active from a strictly histopathological standpoint.


Adaptation of agriculture to extreme weather events: evidence from apple farmers' organic fertilizer use in China.
Overcoming the challenge of more frequent and extreme weather events holds importance in agricultural production. We take spring frost disasters as a representative extreme weather event to identify how perennial economic crop farmers adjust the quantity of organic fertilizer used in response to extreme weather events and their adjustment mechanism. In this study, we establish a conceptual framework for the adaptation mechanism of apple growers under extreme weather events. This article draws and verifies five hypotheses through on-site investigations of apple growers in Shaanxi Province, China. Empirical evidence shows that farmers increase the quantity of commercial organic fertilizer materials in the year and in the following year when spring frost occurs, indicating that their adaptative behavior can be subdivided into repair and prevention. Mechanism analysis shows that liquidity constraints impact farmers' adaptive behavior. Liquidity constraints limit the ability of farmers to increase the quantity of commercial organic fertilizer materials to adapt to a spring frost disaster. Furthermore, for farmers not constrained by liquidity constraints, household resource endowment conditions still affect their adaptive behavior. Significantly, the household labor force size mainly influences farmers to increase commercial organic fertilizer to adapt to a spring frost disaster. Our findings highlight the differences between the adaptive behavior mechanism of perennial crop farmers and food crop farmers. Moreover, we reconfirm the stimulating effect of organic fertilizer on crop production.


Comprehension of directly and indirectly stated main ideas and details in discourse by brain-damaged and non-brain-damaged listeners.
Aphasic, right-hemisphere-damaged, and non-brain-damaged subjects heard short narrative paragraphs. Each paragraph contained four main ideas and one or more details related to each main idea. After each paragraph was presented, subjects' comprehension and retention of main ideas and details from the paragraph were tested. Some of the test items directly restated information from paragraphs and others paraphrased information from paragraphs. All groups of subjects remembered main ideas better than they remembered details, and no group of subjects was significantly affected by whether test items directly or indirectly stated information from paragraphs. Disfluent aphasic and right-hemisphere-damaged subjects' overall paragraphs comprehension scores were not significantly poorer than those of non-brain-damaged subjects. Fluent and mixed aphasic subjects' overall paragraph comprehension scores were significantly worse than those of non-brain-damaged and right-hemisphere-damaged subjects. Token Test and Boston Diagnostic Aphasia Examination auditory comprehension scores did not predict aphasic subjects' paragraph comprehension scores. right-hemisphere-damaged subjects' overall paragraph comprehension scores were not significantly those of non-brain-damaged and right-hemisphere-damaged subjects. Token Test and Boston Diagnostic Aphasia Examination auditory comprehension scores did not predict aphasic subjects' paragraph comprehension scores.


Behaviour in a standardized assay, but not metabolic or growth rate, predicts behavioural variation in an adult aquatic top predator Esox lucius in the wild.
This study tested for links among behaviour, state and life-history variables as predicted by the pace-of-life hypothesis in adult pike Esox lucius. First, a standardized open-field behavioural assay was developed to assess individual behaviour of wild-captured adult E. lucius. Behaviour within the standardized assay predicted swimming behaviour in the lake, providing an ecological validation of the assay. There was no relationship between standardized behaviour and any of the life-history and state variables, including metabolism, body condition, juvenile growth rate and adult growth rate in contrast to predictions from the pace-of-life hypothesis. This study demonstrates that it is possible to assess ecologically relevant behavioural variation in a large-bodied top predator using a standard open-field assay, but it is noteworthy that this standardized behaviour is not systematically related to standard metabolism or growth.


Comparison of angiographic and CT findings between patients with multi-infarct dementia and those with dementia due to primary neuronal degeneration.
The CT and angiographic appearances in multi-infarct dementia have been compared with those of primary neuronal degeneration. It was possible to make a CT or angiographic diagnosis of multi-infarct dementia in about 40% of patients diagnosed by the ischaemic scoring method of Hachinski et al.


The problem of partial endoreduplication.
Partial endoreduplication (PE) as defined by Lejeune et al. (1966) has only been found in a few instances. Similar configurations, also called PEs, seem to originate from a different process. A series of 12 PEs is presented in this paper, discovered in metaphases from healthy individuals, and in patients with or without chromosome-breakage syndrome and after treatment with chromosome-breaking agents. Interpretations of the microscopic appearance of each configuration led to the conclusion that there are three different modes of origin for such rare events, one being true partial endoreduplication, the second a partial pseudoendoreduplication, and the third a homologous triradial chromatid translocation.


Induced sample via transient isotachophoresis mediated with sweeping in micellar electrokinetic chromatography for the dual-stacking strategy of non-steroidal anti-inflammatory drugs in environmental water samples.
Realising the need to devise a simple, sensitive, and reliable detection method, this study investigated the development of a dual-stacking transient isotachophoresis (t-ITP) and sweeping in micellar electrokinetic chromatography with diode array detector (t-ITP/sweeping-MEKC-DAD) for the determination of selected non-steroidal anti-inflammatory drugs (NSAIDs); ketoprofen, diclofenac and naproxen from aqueous matrices. Prior to the system setup, various parameters were optimised to assess the potential use of the t-ITP paired with the sweeping stacking technique in micellar background electrolyte for dual preconcentration and separation of trace amounts of NSAIDs. Once the optimum conditions have been established, the method performance was validated and applied to 17 environmental water samples. Based on the results, the combined t-ITP and sweeping approach significantly improved the stacking and separation sensitivity. A large volume of samples could also be introduced and subsequently separated by MEKC with greater focusing effects due to the sweeping. Under optimised conditions, the developed method exhibited excellent linearity at a high range (0.1-500 ng/mL, r2 ≥ 0.998), low limits of detection (LODs) of 0.01-0.07 ng/mL, and a remarkable relative recovery (RR) of 99.6-101.9% with a relative standard deviation (RSD) of 1.4-8.6% (n = 9). Ultimately, the sensitivity enhancement factors improved up to 666-fold using the optimised method. Therefore, the proposed method presents a simplified yet effective and suitable for the determination of NSAIDs from aqueous matrices.


Quantifying the impact of unmeasured confounding in observational studies with the E value.
The E value method deals with unmeasured confounding, a key source of bias in observational studies. The E value method is described and its use is shown in a worked example of a meta-analysis examining the association between the use of antidepressants in pregnancy and the risk of miscarriage.


Cytrellis: A Novel Microcoring Technology for Scarless Skin Removal: Summary of Three Prospective Clinical Trials.
We introduce an innovative and novel technology that achieves scarless skin removal without the use of thermal energy. Microcoring technology (MCT) uses a modified, hollow hypodermic needle to remove skin safely and without a scar. This method is advantageous compared to other fractional devices, given that it has the same benefits as energy-based devices (removal of skin cores without a scar), with the added value of immediate closure along the relaxed skin tension lines, with significantly less thermal energy. Three prospective clinical safety trials analyzing MCT treatment on abdominal and facial skin (short- and long-term) are described. MCT treatment of human skin resulted in scarless skin removal that was well tolerated by patients. Healing occurred rapidly, with limited side effects. Skin area reduction (skin tightening) and increase in skin thickness were observed long term. MCT treatment of human skin is safe and well tolerated. Although further studies on efficacy are required to evaluate the full potential of MCT in skin rejuvenation, early findings such as skin tightening and increase in skin thickness are encouraging.


Leading and Inspiring by Example.
Joan Steitz radiates a passion for science. Whether she's teaching an undergraduate course, mentoring a grad student or post-doc, or speaking at a scientific conference, her enthusiasm and curiosity for all things RNA is infectious. Joan, the recipient of the 2018 Lasker-Koshland Special Achievement Award in Medical Science, spoke with Cell editor (and her former post-doc) Lara Szewczak about how she came to be an advocate for women in science and shared advice for young scientists entering the research community today. Annotated excerpts from this conversation are presented below, and the full conversation is available with the article online.


Glucose-binding membrane proteins.
To identify glucose-binding proteins amongst the polypeptides of the mouse duodenal brush border membrane, three types of experiments are reported. The first involved the introduction of labelled glucose and its analogue phlorizin into the lumen of separate groups of ligatured duodenal segments. Several proteins were shown to have bound both labelled species in situ by liquid scintillation counting of slices from polyacrylamide gels on which solubilised membrane protein had been electrophoretically separated. The second type of experiment was designed to determine the competitive nature of the binding of both labelled and cold phlorizin to proteins which had already bound glucose. Only three bands could competitively bind phlorizin. Finally, gels on which solubilised protein from in situ glucose-binding experiments had been run were placed in solutions containing labelled phlorizin. The binding of phlorizin to proteins in the same three bands as above suggested a confirmation of the conclusion that there were three membrane protein types which appeared to be involved in phlorizin-sensitive glucose-binding.


Sequence microheterogeneity of parvalbumin pI 5.0 of pike: a mass spectrometric study.
Parvalbumin (PA) is a muscle and neuronal calcium-binding protein, the major fish and frog allergen. Its characteristic feature is the presence of multiple isoforms with significantly different amino acid sequences. Here we show that the major isoform of northern pike muscle PA (pI 5.0, alpha-PA) exhibits microheterogeneity of amino acid sequence. ESI Q-TOF mass-spectrometry (MS) analysis of alpha-PA sample showed the presence of two components with mass difference of 71 Da. Analysis of tryptic and endoproteinase Asp-N digests of alpha-PA by MALDI-TOF MS revealed peptides, corresponding to two different amino acid sequences. The sequence differences between variant proteins are limited to AB-domain and include substitutions K27A and L31K, and an extra Leu residue between K11 and K12. Since the affected residues comprise a cluster on the surface of PA, an involvement of the identified region into target recognition is suggested. The substitutions at positions 27 and 31 are located in the region of previously identified epitopes of parvalbumin relevant for PA-specific IgE and IgG binding, which suggests different immunoactivities of the variants. The found microheterogeneity of PA is suggested to be of importance for physiological adaptation of the propulsive musculature to developmental and/or environmental requirements and may contribute to PA allergenicity.


Post-bariatric surgery satisfaction and body-contouring consideration after massive weight loss.
Following a bariatric surgery and massive weight-loss, the outcome is usually sullied by consequences on the body's contour and redundant skin. We aimed to record the frequency of contour irregularities and quantify patients' satisfaction with appearance and anticipations from body contouring surgery. The ethical committee at King Abdulaziz University Hospital approved the study, and patients were consented. A cross-sectional study targeting the post-bariatric patients from May 2011 to April 2012 was conducted at our hospital. We used post-massive weight loss Satisfaction Questionnaire. The total numbers of patients were 64 (51 women and 13 men), of which 57 patients (89.2%) developed sagging skin. Most patients were dissatisfied with their appearance after weight loss. The most common zones were the upper arms (50%) and abdomen (45%). Considerably more women (36.2%) than men (24%) were dissatisfied with certain body areas. The most noticeable expectation of patients from body contouring surgery was improved cosmetic appearance (65.6%) and self-confidence (64.1%). More women (70.58%) than men (46.15%) expected a better cosmetic appearance after body contouring (P = 0.003). After bariatric surgery, sagging excess skin is an unsatisfactory problem. Therefore, body contouring surgery must be included in morbid obesity management.


Notable efficacy of Shugan Jieyu capsule in treating adult with post-stroke depression: A PRISMA-compliant meta-analysis of randomized controlled trials.
Post stroke depression (PSD), which happens in 40%-60% stroke patients, is one of the most common complications after cerebrovascular accident. Shugan Jieyu Capsule (SGJYC), a traditional Chinese medicine, has been widely prescribed for PSD in China. This study designed and conducted a PRISMA compliant meta-analysis to evaluate the efficacy of SGJYC in treating adults with PSD of randomized controlled trials (RCTs) under the condition that none PRISMA-compliant systematic evaluation or meta-analysis was conducted to fully evaluate the efficacy of SGJYC. The study protocol has been registered in PROSPERO with registration number CRD42021250162. PubMed, ScienceDirect, CNKI, and Wanfang Databases were systematically searched to include eligible RCTs which used SGJYC and other antidepressants or placebo for the treatment of PSD adults with the Hamilton Depression Scale (HAMD). The Cochrane Risk of Bias 2 (RoB2) tool was used to evaluate the quality of included RCTs. Outcome measures including HAMD continuous data, efficacy data, and remission data were extracted for meta-analysis on a random-effects model. Adequate essential analyses including subgroup analysis, sensitivity analysis, and meta-regression analysis were performed according to the characteristics of RCTs to test the reliability and robustness of the overall effect sizes. Publication bias was detected with funnel plot, Egger's test, and Begg's test. The evidence strength of this meta-analysis was assessed with the GRADE method. A total of 63 eligible RCTs and 6036 participants were included. The RoB2 found that the overall risk of included RCTs was high. The MD of continuous data was 3.59 (95% CI: [2.63, 4.55]) with statistical significance (P < 0.00001) and significant heterogeneity (Chi2 = 2083.77, I2 = 97%, p < 0.00001). The OR of efficacy data was 2.12 (95% CI: [1.82, 2.47]) with statistical significance (P < 0.00001) and insignificant heterogeneity (Chi2 = 60.52, I2 = 22%, P = 0.09). The OR of remission data was 1.66 (95% CI: [1.45, 1.91]) with statistical significance (P < 0.00001) and insignificant heterogeneity (Chi2 = 26.45, I2 = 0%, P = 0.96). Adequate essential analyses found consistent results of overall effect sizes and most publication bias analyses found insignificant results. The overall evidence strength was assessed as moderate. The moderate evidence strength from this PRISMA-compliant meta-analysis found that SGJYC has notable efficacy in treating adults with PSD, although the quality of included RCT was low. The high-quality RCTs with large-sample, multi-centers, and long follow-up periods are still warranted to improve the evidence quality of SGJYC for PSD in further study.


Performance evaluation of UF-4000 body fluid mode for automated body fluid cell counting.
Cytological analysis of body fluids (BF) provides important information for diagnosis in various medical conditions. We evaluated the analytical performance of the UF-4000 BF mode for ascitic, cerebrospinal, pleural, synovial and continuous ambulatory peritoneal dialysis fluids compared to light microscopy counting (LM). 223 consecutive BF were analyzed by UF-4000 and results were compared using Pearson's correlation, Bland-Altman analysis, and contingence tests at relevant cut-off values. This study also included the evaluation of precision, linearity, and carryover. For white and red blood cells (WBC, RBC) counts in all BF, correlation was excellent with Pearson's coefficients R2 > 0,98. Bland-Altman analysis didn't reveal significant differences with limited bias for WBC ranging from -10 to -1 WBC/µL and bias ranging from -43 to -6/µL for RBC. At specific cut-off values for WBC, Se and Spe were 100% except for ascites (Spe = 98%) due to two false positive. Precision evaluated at three concentration levels was good for each parameter (WBC < 10%). Linearity was excellent for WBC (R2 > 0,99) and carryover negligible (<0,004%). UF-4000 BF mode is a good alternative to manual LM for BF cell counting. This automated method gives rapid and accurate results which is important for therapeutic decisions.


Y-V plasty of the foreskin as an alternative to circumcision for surgical treatment of phimosis during childhood.
To evaluate the result of Y-V preputioplasty and to compare this with an earlier technique of prepuce-sparing phimosis treatment. A total of 65 boys were treated surgically for phimosis without removing the foreskin. Indications were the failure of conservative ointment treatment, congenital uropathies (to prevent infections and to make proper cleaning of the glans and the inner preputium possible to ensure clean urine sampling), recurrent balanitis or painful ballooning of the prepuce, and/or the need for urethral instrumentation. Forty-seven patients were treated with one or two Y-V plasties to widen the narrow preputial ring; 18 were treated using transverse closure of longitudinal incisions of the narrow preputial ring. Of the 47 Y-V plasties, two patients had recurring complaints and needed further treatment (4.3%), and of the 18 patients treated by transversely closed longitudinal incisions, two patients had recurring complaints (11%). Recurrences occurred regardless of age and premedication with topical therapy. Cosmesis was considered to be excellent in all cases of Y-V plasty. Few patients complained about skin tags after longitudinal incisions. Y-V plasty of the preputial skin as an alternative to circumcision in the treatment of phimosis has good functional and cosmetic results. It is a minor operation with less impact on the penis than partial or total circumcision. The cosmetic results are superior to those after transversely closed longitudinal incisions.


Suppression of NLRP3 inflammasome by ivermectin ameliorates bleomycin-induced pulmonary fibrosis.
Ivermectin is a US Food and Drug Administration (FDA)-approved antiparasitic agent with antiviral and anti-inflammatory properties. Although recent studies reported the possible anti-inflammatory activity of ivermectin in respiratory injuries, its potential therapeutic effect on pulmonary fibrosis (PF) has not been investigated. This study aimed to explore the ability of ivermectin (0.6 mg/kg) to alleviate bleomycin-induced biochemical derangements and histological changes in an experimental PF rat model. This can provide the means to validate the clinical utility of ivermectin as a treatment option for idiopathic PF. The results showed that ivermectin mitigated the bleomycin-evoked pulmonary injury, as manifested by the reduced infiltration of inflammatory cells, as well as decreased the inflammation and fibrosis scores. Intriguingly, ivermectin decreased collagen fiber deposition and suppressed transforming growth factor-β1 (TGF-β1) and fibronectin protein expression, highlighting its anti-fibrotic activity. This study revealed for the first time that ivermectin can suppress the nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome, as manifested by the reduced gene expression of NLRP3 and the apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), with a subsequent decline in the interleukin-1β (IL-1β) level. In addition, ivermectin inhibited the expression of intracellular nuclear factor-κB (NF-κB) and hypoxia‑inducible factor‑1α (HIF-1α) proteins along with lowering the oxidative stress and apoptotic markers. Altogether, this study revealed that ivermectin could ameliorate pulmonary inflammation and fibrosis induced by bleomycin. These beneficial effects were mediated, at least partly, via the downregulation of TGF-β1 and fibronectin, as well as the suppression of NLRP3 inflammasome through modulating the expression of HIF‑1α and NF-κB.


Opsonization and phagocytosis of bacteria during various middle ear infections.
Samples of middle ear effusions (MEE) obtained from 50 children suffering from acute purulent otitis media (AOM; 23 ears), otitis media with effusion (OME; 15 ears) or chronic suppurative otitis media (COM; 23 ears) were subjected to cytological (cellular differentiation, degree of phagocytosis) and bacteriological (species quantification and identification, degree of opsonization) analyses. Methods used were direct microscopy of acridine orange stained material, immunofluorescence assay using fluorescein-labelled antibodies to immunoglobulin G (IgG) and complement cleavage product C3b, and standard bacterial culturing on agar plates. The most intense opsonization and phagocytosis was evident in COM effusions culture-positive for Staphylococcus aureus. AOM and OME effusions showed rather poor opsonization and roughly 1% of the phagocytes harboured intracellular bacteria. COM effusions, culture-positive for Pseudomonas aeruginosa, showed no bacterial opsonization or phagocytosis whatsoever. Opsonization and phagocytosis of bacteria in the middle ear cleft is highly species-specific.


Management of upper airway obstruction in the Pierre Robin syndrome.
Eight patients with Pierre Robin syndrome (PRS), were treated according to our management protocol. All our patients initially were given a trial of conservative, positional treatment, with high caloric gavage feeding. In five patients this therapeutic approach resulted in a good weight gain, with no significant respiratory distress. The remaining three patients showed no improvement, failed to thrive and therefore underwent the tongue to lip adhesion (TLA) procedure. Two patients then improved dramatically; whereas one continued with respiratory distress and failure to thrive and required tracheostomy. We conclude that when symptoms of respiratory distress and failure to thrive coexist in patients with PRS despite conservative management, surgical intervention to the airway is mandatory. TLA should be the first surgical procedure considered and if the ultimate goals of weight gain and respiratory comfort are still not achieved then tracheostomy seems inevitable.


The role of the 14-3-3 protein family in health, disease, and drug development.
14-3-3 proteins regulate intracellular signaling pathways, such as signal transduction, protein trafficking, cell cycle, and apoptosis. In addition to the ubiquitous roles of 14-3-3 isoforms, unique tissue-specific functions are also described for each isoform. Owing to their role in regulating cell cycle, protein trafficking, and steroidogenesis, 14-3-3 proteins are prevalent in human diseases, such as cancer, neurodegeneration, and reproductive disorders, and, therefore, serve as valuable drug targets. In this review, we summarize the role of 14-3-3 proteins in normal and disease states, with a focus on 14-3-3γ and ɛ. We also discuss drug compounds targeting 14-3-3 proteins and their potential therapeutic uses.


Conversion disorder: "an adverse reaction" to watch out for.
A subject was enrolled in a multicenter, double-blinded clinical trial of ofloxacin-containing multidrug therapy for leprosy by the World Health Organization in 1992 and she developed multiple physical symptoms a few hours after taking the regimen. Physical examination and laboratory work-ups could not support a medical diagnosis and she was eventually dropped from the study. Decoding revealed that she belonged in the control group given the World Health Organization/multiple drug therapy-multibacillary regimen. In the course of treatment, she was diagnosed with conversion disorder and was subsequently treated with an antipsychotic.


As simple as possible, but not simpler: Revisiting the International Trauma Questionnaire (ITQ) complex PTSD items omitted in the shortened version.
The risks of oversimplification of the symptomatology of Complex PTSD (CPTSD) have been highlighted in the literature. To re-examine 10 items representing disturbances in self-organization (DSO) that were deleted from the original 28-item version of the International Trauma Questionnaire (ITQ) when creating the current 12-item version. An online convenience sample of 1235 MTurk users. Online survey comprising the fuller 28-item previous version of the ITQ, Adverse Childhood Experiences (ACEs) questionnaire, and PTSD Checklist for DSM-5 (PCL-5). First, averaged endorsement of the 10 omitted items was lower than the 6 retained DSO items (d' = 0.34). Second, the 10 omitted DSO items accounted for incremental variance over and correlated equivalently to the 6 retained items with the PCL-5. Third, only the 10 omitted DSO items (r-part = 0.12) while not the 6 retained DSO items (r-part = -0.01) independently predicted ACE scores and, eight of these ten omitted DSO items differentiated higher ACE scores even among the subset of 266 participants who endorsed all 6 of the retained DSO items, most with medium effect sizes. Fourth, exploratory principal axis factor analysis differentiated two latent variables within the fuller set of 16 DSO symptoms, with the strongest indicators of the second factor, namely uncontrollable anger, recklessness, derealization, and depersonalization, being unmeasured within the 6 retained DSO items. Moreover, scores on both factors independently predicted both PCL-5 and ACE scores. There are conceptual and pragmatic advantages to revisiting a more content-valid and comprehensive conceptualization of CPTSD and DSO, partially as may be measured by the recently deleted items from the original and fuller length ITQ.


Green fluorescent protein (GFP) transgenic fish and their applications.
The coupling of the GFP reporter system with the optical clarity of embryogenesis in model fish such as zebrafish and medaka is beginning to change the picture of transgenic fish study. Since the advent of first GFP transgenic fish in 1995, GFP transgenic fish technology have been quickly employed in many areas such as analyses of gene expression patterns and tissue/organ development, dissection of promoters/enhancers, cell lineage and axonal pathfinding, cellular localization of protein products, chimeric embryo and nuclear transplantation, cell sorting, etc. The GFP transgenic fish also have the potentials in analysis of upstream regulatory factors, mutagenesis screening and characterization, and promoter/enhancer trap. Our own studies indicate that GFP transgenic fish may become a new source of novel variety of ornamental fish. Efforts are also being made in our laboratory to turn GFP transgenic fish into biomonitoring organisms for surveillance of environmental pollution.


The intriguing role of rhamnolipids on plasma membrane remodelling: From lipid rafts to membrane budding.
Rhamnolipids (RLs) comprise a class of glycolipids produced by Pseudomonas aeruginosa under appropriate culture medium. They act as biosurfactants being composed by a hydrophilic head of either one (mono-RL) or two (di-RL) rhamnose moieties coupled to hydroxyaliphatic chains. It is well accepted that RLs present low biolitic activity as compared to other synthetic surfactants. However, their mechanisms of action in biological systems are not well defined yet. The interaction of RLs with lipid bilayers are here investigated to address how they impact on plasma membrane at molecular level. Our experimental approach was based on a deep analysis of optical microscopy data from giant unilamellar vesicles (GUVs) dispersed in aqueous solutions containing up to 0.5 mM of commercially available RLs (a mixture of mono-RL, 33-37 mol%, and di-RL, 63-67 mol%, cmc of 0.068±0.005 mM). GUVs were made up of a single lipid POPC and a ternary system containing DOPC, sphingomyelin and cholesterol, which mimic lipid raft platforms. Our results demonstrate that RLs have a low partition in the lipid bilayer in respect to the total molecules in solution. We suppose that RLs insert in the outer leaflet with low propensity to flip-flop. In the case of POPC GUVs, the insertion of RL molecules in the outer leaflet impairs changes in spontaneous membrane curvature with incubation time. Then, small buds are formed that remain linked to the original membrane. No changes in membrane permeability have been detected. A remarkable result refers to the insertion of RLs in membranes containing liquid ordered (Lo) - liquid disordered (Ld) phase coexistence. The rate of interaction has been observed to be higher for Ld phase than for Lo phase (0.12·10-6 s-1 and 0.023·10-6 s-1 for Ld and Lo, respectively, at RL concentration of 0.5 mM). As a consequence, the preferential RL insertion in Ld phase may also alter the membrane spontaneous curvature which, coupled to the change in the line tension associated to the domains boundary, conducted to Lo domain protrusion. Even if it has been observed on a model system, such membrane remodelling might correlate to endocytic processes activated in cell membranes, regardless of the participation of specific proteins. Further, changes imposed by RLs in lipid rafts may affect the association of key proteins enrolled in cell signaling, which may perturb cell homeostasis.


Atmospheric particle-bound polycyclic aromatic hydrocarbons, n-alkanes, hopanes, steranes and trace metals: PM2.5 source identification, individual and cumulative multi-pathway lifetime cancer risk assessment in the urban environment.
The occurrence of atmospheric fine particles (PM2.5)-associated polycyclic aromatic hydrocarbons (PAHs), trace metals and organic molecular markers was investigated by conducting an intensive sampling campaign at the Eastern Mediterranean urban area of Nicosia (Cyprus). Sixty-two 24-hr PM2.5 samples were collected and analyzed for fifty parent and alkylated PAHs, twenty-five long chain n-alkanes, seventeen hopanes and twelve steranes used for source apportionment. The same number and kind of samples were analyzed to determine twenty-eight trace metals. Emphasis was given to investigate the air levels of the scarcely monitored although highly carcinogenic PAHs such as dibenzopyrenes, dibenzoanthracenes, 7H-benzo[c]fluorene and 5-methyl-chrysene, not included in the USEPA's sixteen PAH priority list (USEPA-16). UNMIX receptor model was applied to apportion the sources of atmospheric emissions of the determined organic compounds and trace metals and evaluate their daily contributions to the corresponding PM2.5 associated concentrations. For comparison purposes, principal component analysis with multiple linear regression (PCA/MLR) was also applied and its results are reported. The UNMIX receptor model, compared to PCA/MLR, offered a more precise source profile and more reliable daily mass source distributions by eliminating negative contributions. The individual and cumulative multi-pathway lifetime cancer risk (posed via inhalation, ingestion and dermal contact) by exposure to PM2.5-associated USEPA-16 listed and non-listed PAHs and selected airborne trace metals (As, Cd, Co, Ni, and Pb) were assessed. To estimate the contribution of each emission source to the total cancer risk, multiple linear regression analysis was performed, using as independent variables the daily source mass contributions and as dependent variables the respective cancer risk units. The estimated total cumulative cancer risk comprising all toxic PAHs, besides those included in the priority list, and metals was higher than the USEPA's threshold by a factor of eight, denoting a potential risk for long-term exposure of a population in the urban environment.


Evaluation of the respiratory muscle strength of cirrhotic patients: relationship with Child-Turcotte-Pugh scoring system.
Pulmonary abnormalities are observed in chronic hepatopathy. The measurement of the maximum inspiratory and expiratory pressure may evaluate lung function and the risks associated with hepatic transplantation. Thus, the present work sought to evaluate the respiratory muscle strength of 29 patients between 17 and 63 years old who were enrolled for liver transplantation. The patients were classified according to Child-Turcotte-Pugh score as A, B, or C, and also according to a physiotherapeutic evaluation, which included measurement of respiratory muscle strength by means of a digital manovacuometer, which determines the maximum inspiratory pressure (MaxIP) and the maximum expiratory pressure (MaxEP). The tests were performed with seated individuals having their nostrils obstructed by a nasal clip. The MaxIP was measured during the effort initiated in the residual volume, whereas the MaxEP was measured during the effort initiated in the total pulmonary capacity, keeping pressures stable for at least 1 second. The statistical analysis was performed through using the Mann-Whitney test with a 5% level of significance. The MaxIP values of Child A 95.5 +/- 40.507 cm H(2)O (average +/- DP) and Child B 87.2 +/- 35.02 patients were higher than those for Child C patients (34.83 +/- 3.68; P < .05). Similar results were observed for the MaxEP of Child A and B groups (116.25 +/- 31.98 and 97.28 +/- 31.08, respectively; P < .05), versus the Child C group (48.16 +/- 22.60). Between groups A and B, the MaxEP were similar (P > .05). We concluded that Child C patients display muscle weakness significantly greater than that of subjects classified as Child A or B.


Blockade of leucocyte function-associated antigen-1 (LFA-1) decreases lymphocyte trapping in the normal pulmonary vasculature: studies in the isolated buffer-perfused rat lung.
Adhesion molecules regulate the migration of lymphocytes in lymphoid and non-lymphoid organs. In the lung, little is known about lymphocyte sticking and migration through the pulmonary vascular endothelium in physiological or pathological situations. Therefore the isolated buffer-perfused rat lung was used to investigate the mobilization of lymphocytes out of the normal lung into the venous effluent and to the bronchoalveolar space. The lymphocyte subset composition was characterized in the venous effluent, the lung tissue and the bronchoalveolar lavage (BAL) using immunocytology. Lymphocytes continuously left the normal lung at a total of 5.0 +/- 0.7 x 106 cells within the first hour of perfusion. The injection of 200 x 106 lymphocytes via the pulmonary trunk increased the venous release of lymphocytes by 170%. To investigate the effect of LFA-1 and CD44 on the adhesion of lymphocytes to the pulmonary endothelium, lymphocytes preincubated with an anti-LFA-1 MoAb, which blocks the interaction of LFA-1 and intercellular adhesion molecule-1 (ICAM-1), or lymphocytes preincubated with an anti-CD44 MoAb, were injected. The injection of LFA-1-blocked lymphocytes led to an increase by 70% of injected cells recovered in the perfusate within the first hour, whereas anti-CD44 treatment of injected lymphocytes had no effect. The LFA-1-blocked lymphocytes showed higher numbers of T and B cells in the effluent. Thus, the present experiments demonstrate that LFA-1 influences the trapping of lymphocytes in the vasculature of the healthy rat lung.


Observational data from the adalimumab post-marketing PYRAMID registry of patients with Crohn's disease who became pregnant: A post hoc analysis.
PYRAMID was an international post-marketing registry that aimed to collect data on the long-term safety and effectiveness of adalimumab treatment per local standard of care in patients with moderately to severely active Crohn's disease (CD). Here, we present post hoc analyses of observational data from patients who became pregnant while participating in this registry and receiving adalimumab. From the subpopulation of patients receiving adalimumab who became pregnant while taking part in PYRAMID, data on patient characteristics, pregnancy outcomes, and complications of pregnancy were analysed retrospectively. Across the PYRAMID registry, 293 pregnancies occurred in patients who had gestational adalimumab exposure (average disease duration at last menstrual period: 8.6 years), resulting in 300 pregnancy outcomes. A total of 197 pregnancies (67.2%) were exposed to adalimumab in all trimesters per physician's decision. Of the known reported outcomes (96.3%), 81.7% (236/289) were live births, 10.4% (30/289) were spontaneous abortions, 4.8% (14/289) elective terminations, 2.8% (8/289) ectopic pregnancies, and 0.3% (1/289) was a stillbirth. Congenital malformations (pulmonary valve stenosis and tricuspid valve incompetence) were reported in one infant. In addition to the pregnancy outcomes described above, 23 complications of pregnancy were reported in 20 patients. This analysis showed that adalimumab treatment in patients with CD, who became pregnant whilst participating in the PYRAMID registry, contributed no additional adverse effects during the pregnancy course or on pregnancy outcomes.


Development of an automatic Doppler flow signal detection system: variability of pulmonary and aortic peak flow velocity.
Automatic Doppler flow signal detection systems can provide beat-to-beat information for large blood vessels. We have developed new equipment for automatic measurement of Doppler flow signals. The reliability of the system was examined, and the variability of aortic and pulmonary peak flow velocity was determined. We measured peak flow velocity using a newly developed system in healthy volunteers and patients with atrial fibrillation. Analysis of variability of peak flow velocity was performed with maximal entropy methods. In Bland-Altman plots, the mean and standard deviation (SD) of differences in aortic peak flow velocities between the automatic and manual measurements were 0.22 ± 0.75 cm/s and 0.85 ± 0.38 cm/s, respectively, in five normal volunteers. Moreover, less than 5% of the plotted points were beyond ± 2 SD of the differences. Furthermore, good reproducibility was demonstrated using Bland-Altman plots and Pearson's correlation analysis. Identical reliability was obtained in patients with atrial fibrillation. The same results were obtained for pulmonary peak flow velocity. In five healthy subjects, aortic and pulmonary peak flow showed standard deviations of 7.2 ± 2.4 and 3.8 ± 0.6 cm/s, respectively, and coefficients of variation of 6.1% ± 1.0% and 5.1% ± 1.1%, respectively, in time-domain variability. Similarly, frequency-domain variability was obtained for both peak flow velocities. The present study demonstrated the reliability of a newly developed automatic Doppler flow signal detection system. Using this system, the present study demonstrated for the first time aortic and pulmonary peak flow velocity variability. The present analytical methods may have considerable potential for studying aortic and/or pulmonary flow variability in connection with cardiac performance and prognosis of cardiac disease.


Nitrogen-containing bisphosphonate-loaded micro-arc oxidation coating for biodegradable magnesium alloy pellets inhibits osteosarcoma through targeting of the mevalonate pathway.
Osteosarcoma (OS) remains one of the most threatening primary malignant human tumors of the bone, especially in the first or second decade of life. Unfortunately, the clinical therapeutic efficacy has not substantially improved over the past four decades. Therefore, to achieve efficient tumor eradication, a new approach to prevent tumor recurrence is urgently needed. Here, we develop a new bisphosphonate (BP)-loaded microarc oxidation (MAO) coated magnesium-strontium (Mg-Sr) alloy pellet that can inhibit OS, and we illuminate the cellular and molecular mechanisms of the inhibiting effect. To generate such pellets, nitrogen-containing BP is chemically conjugated with a MAO coating on hollow Mg-Sr alloys. We demonstrate that BP coated Mg pellet has multiple desired features for OS therapy through in vitro and in vivo studies. At the cellular level, BP coated Mg pellets not only induce apoptosis and necrosis, as well as antitumor invasion of OS cells in the two-dimensional (2D) cell culture environment, but also damage the formation of multicellular tumor spheroids by OS cell lines in the three-dimensional (3D) cell culture environment. At the in vivo level, BP coated Mg pellets can destroy tumors and prevent neoplasm recurrence via synergistic Mg degradation and drug release. It is further suggested that the superior inhibitory effect on OS of our pellet is achieved by inhibiting the mevalonate pathway at the molecular level. Hence, these results collectively show that the BP coated Mg pellet is a promising candidate for future applications in repairing defects after tumor removal in OS therapy.


Effect of rutin on anxiety-like behavior and activity of acetylcholinesterase isoforms in specific brain regions of pentylenetetrazol-treated mice.
The aim of the present study was to investigate the effect of rutin administration (100 mg/kg/day) to pentylenetetrazol (PTZ)-treated Balb-c mice (60 mg/kg/day), with respect to anxiety-like behavior using both open-field and elevated plus-maze (EPM) tests, and acetylcholinesterase (AChE) activity in salt-soluble (SS) fraction and detergent-soluble (DS) fraction of the cerebral cortex, hippocampus, striatum, midbrain, and diencephalon. Our results demonstrated that the administration of PTZ in 3 doses and the induction of seizures increased significantly anxiety behavior of mice and reduced significantly DS-AChE activity in all brain regions examined, while the reduction in the SS fraction was brain region-specific. Rutin administration to normal mice did not affect their behavior, while it induced a brain region-specific reduction in SS-AChE and a significant decrease in DS-AChE in all brain regions. We demonstrated for the first time that pretreatment of PTZ-mice with rutin (PTZ + Rutin group) prevented the manifestation of anxiety and induced interestingly a further significant reduction on the SS- and DS-AChE activities only in the cerebral cortex and striatum, in comparison with PTZ group. Our results show that rutin exhibits an important anxiolytic effect and an anticholinesterase activity in specific brain areas in the seizure model of PTZ.


Integrating public engagement to intensify pollination services through ecological restoration.
Globally, human activities impose threats to nature and the provision of ecosystem services, such as pollination. In this context, ecological restoration provides opportunities to create managed landscapes that maximize biodiversity conservation and sustainable agriculture, e.g., via provision of pollination services. Managing pollination services and restoration opportunities requires the engagement of distinct stakeholders embedded in diverse social institutions. Nevertheless, frameworks toward sustainable agriculture often overlook how stakeholders interact and access power in social arenas. We present a perspective integrating pollination services, ecological restoration, and public engagement for biodiversity conservation and agricultural production. We highlight the importance of a comprehensive assessment of pollination services, restoration opportunities identification, and a public engagement strategy anchored in institutional analysis of the social arenas involved in restoration efforts. Our perspective can therefore guide the implementation of practices from local to country scales to enhance biodiversity conservation and sustainable agriculture.


Characteristics of Z-DNA helices formed by imperfect (purine-pyrimidine) sequences in plasmids.
The capacities of three synthetic sequences to adopt left-handed helices were evaluated in recombinant plasmids. The sequences consisted of very short runs of (CG)n (n = 2-4) interspersed with runs of alternating A.T base pairs and/or with regions of non-alternating base pairs. The plasmids were studied by two-dimensional gel electrophoresis to determine the natures of the conformational transitions and their free energies of formation. These results coupled with analyses with chemical (diethyl pyrocarbonate, osmium tetroxide, and bromoacetaldehyde) and enzymatic (S1 nuclease, T7 gene 3 product, and MHhaI) probes indicated that the entire sequence was adopting a left-handed helix in each case. In one of these sequences, Z-DNA formation necessitated the retention of the anti conformation of one of the guanines in a region of non-alternation. In a sequence which contains out-of-phase regions of alternation, our results indicate the formation of a separate left-handed helix in the central (CG)2 region, thus forming two Z-Z junctions. In summary, we conclude that only very short regions of alternating CG are necessary to effect the B to Z transition and that this conformational change can be transmitted through non-alternating regions. A set of empirical rules governing the characteristics of the B to Z transition and the types of left-handed helices in supercoiled plasmids was derived from studies on a systematic series of 17 plasmids.


[Factors Associated With Coronary Heart Disease Among Adult Residents in Jinjiang District,Chengdu City].
Objective To analyze the prevalence of coronary heart disease among community residents over 18 years old in Jinjiang district of Chengdu city,Sichuan province,and explore its associated factors,so as to provide a reference for the prevention and control of coronary heart disease in communities.Methods From October 15 to November 10 in 2021,a total of 5220 adult residents from 33 communities in Jinjiang were selected by multi-stage stratified random sampling for face-to-face questionnaire survey,physical examination,and laboratory blood test.Binary Logistic regression was employed to predict the factors associated with coronary heart disease among adult residents in Jinjiang.Results The crude and standard prevalence rates of coronary heart disease among 5220 adult residents were 3.39% and 2.11%,respectively.Logistic regression analysis showed that age (OR=1.068,95%CI=1.051-1.086,P<0.001),depressive symptoms (OR=1.639,95%CI=1.037-2.591,P=0.034),regular exercise (OR=0.584,95%CI=0.378-0.902,P=0.015),elevated blood pressure (OR=3.529,95%CI=2.344-5.312,P<0.001),dyslipidemia (OR=2.152,95%CI=1.291-3.587,P=0.003),and core knowledge score of chronic diseases (OR=1.144,95%CI=1.066-1.228,P<0.001) were associated with coronary heart disease among adult residents in Jinjiang.Conclusions The prevalence of coronary heart disease is high among adult residents in Jinjiang district of Chengdu.The urban residents who are older,have depressive symptoms,lack of exercise,elevated blood pressure,dyslipidemia,and score higher on core knowledge of chronic diseases are prone to coronary heart disease.


Intrapartum sacral stress fracture due to pregnancy-related osteoporosis: a case report.
Low back pain (LBP) and hip pain frequently occur during pregnancy and postpartum period. Although pelvic and mechanic lesions of the soft tissues are most responsible for the etiology, sacral fracture is also one of the rare causes. A 32-year-old primigravid patient presented with LBP and right hip pain which started 3 days after vaginal delivery. Although direct radiographic examination was normal, magnetic resonance imaging of the sacrum revealed sacral stress fracture. Lumbar spine and femoral bone mineral density showed osteoporosis as a risk factor. There were no other risk factors such as trauma, excessive weight gain, and strenuous physical activity. It is considered that the patient had sacral fatigue and insufficiency fracture in intrapartum period. The patient's symptoms subsided in 3 months after physical therapy and rest. In conclusion, sacral fractures during pregnancy and postpartum period, especially resulting from childbirth, are very rare. To date, there are two cases in the literature. In cases who even do not have risk factors related to vaginal delivery such as high birth weight infant and the use of forceps, exc., sacral fracture should be considered in the differential diagnosis of LBP and hip pain started soon after child birth. Pregnancy-related osteoporosis may lead to fracture during vaginal delivery.


Quality Measurements in Radiology: A Systematic Review of the Literature and Survey of Radiology Benefit Management Groups.
As the US health care system transitions toward value-based reimbursement, there is an increasing need for metrics to quantify health care quality. Within radiology, many quality metrics are in use, and still more have been proposed, but there have been limited attempts to systematically inventory these measures and classify them using a standard framework. The purpose of this study was to develop an exhaustive inventory of public and private sector imaging quality metrics classified according to the classic Donabedian framework (structure, process, and outcome). A systematic review was performed in which eligibility criteria included published articles (from 2000 onward) from multiple databases. Studies were double-read, with discrepancies resolved by consensus. For the radiology benefit management group (RBM) survey, the six known companies nationally were surveyed. Outcome measures were organized on the basis of standard categories (structure, process, and outcome) and reported using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The search strategy yielded 1,816 citations; review yielded 110 reports (29 included for final analysis). Three of six RBMs (50%) responded to the survey; the websites of the other RBMs were searched for additional metrics. Seventy-five unique metrics were reported: 35 structure (46%), 20 outcome (27%), and 20 process (27%) metrics. For RBMs, 35 metrics were reported: 27 structure (77%), 4 process (11%), and 4 outcome (11%) metrics. The most commonly cited structure, process, and outcome metrics included ACR accreditation (37%), ACR Appropriateness Criteria (85%), and peer review (95%), respectively. Imaging quality metrics are more likely to be structural (46%) than process (27%) or outcome (27%) based (P < .05). As national value-based reimbursement programs increasingly emphasize outcome-based metrics, radiologists must keep pace by developing the data infrastructure required to collect outcome-based quality metrics.


Total synthesis and development of bioactive natural products.
The first total synthesis and development of a variety of bioactive natural products have been accomplished by using carbohydrates as a chiral source. In addition, practically useful intermediates have been created, analogs of natural products have been prepared, their structure-activity relationships studied, and the large-scale preparations of medicinally useful compounds established. The key target molecules have been the "Big Four" antibiotics (macrolides, aminoglycosides, beta-lactams and tetracyclines), pyranonaphthoquinone antibiotics, glycosidase inhibitors, and a side-chain of cephem antibiotics.


An awareness-dependent mapping of saliency in the human visual system.
The allocation of exogenously cued spatial attention is governed by a saliency map. Yet, how salience is mapped when multiple salient stimuli are present simultaneously, and how this mapping interacts with awareness remains unclear. These questions were addressed here using either visible or invisible displays presenting two foreground stimuli (whose bars were oriented differently from the bars in the otherwise uniform background): a high salience target and a distractor of varied, lesser salience. Interference, or not, by the distractor with the effective salience of the target served to index a graded or non-graded nature of salience mapping, respectively. The invisible and visible displays were empirically validated by a two-alternative forced choice test (detecting the quadrant of the target) demonstrating subjects' performance at or above chance level, respectively. By combining psychophysics, fMRI, and effective connectivity analysis, we found a graded distribution of salience with awareness, changing to a non-graded distribution without awareness. Crucially, we further revealed that the graded distribution was contingent upon feedback from the posterior intraparietal sulcus (pIPS, especially from the right pIPS), whereas the non-graded distribution was innate to V1. Together, this awareness-dependent mapping of saliency reconciles several previous, seemingly contradictory findings regarding the nature of the saliency map.


Recombinant human milk fat globule-EGF factor VIII (rhMFG-E8) as a therapy for sepsis after acute exposure to alcohol.
Alcohol intake predisposes to infections and sepsis. Alcohol and sepsis inhibit the expression of milk fat globule epidermal growth factor-factor VIII (MFG-E8), a glycoprotein essential for optimal efferocytosis, resulting in the release of proinflammatory molecules and increased sepsis severity. We previously reported that recombinant mouse (rm) MFG-E8 attenuates sepsis-induced organ injury in rats with acute alcohol intoxication. In order to develop a therapy that can be safely used in humans, we have produced recombinant human (rh) MFG-E8 and evaluated its efficacy to ameliorate sepsis after acute exposure to alcohol. We induced acute alcohol intoxication with a bolus injection of alcohol (1.75 g/kg BW) followed by an intravenous infusion of 300 mg/kg/h alcohol for 10 h. Sepsis was then induced by cecal ligation and puncture (CLP). At -10, 0, and 10 h relative to CLP, rats received MFG-E8 or vehicle (albumin) intravenously. Animals were euthanized at 20 h after CLP for blood and tissue collection. Additional groups of animals were used for a survival study. Compared to vehicle, rhMFG-E8 treatment ameliorated blood levels of proinflammatory cytokines (% improvement: TNF-α 49.8%, IL-6 34.7%) and endotoxin (61.7%), as well as of transaminases (AST 36.2%, ALT 40.1%) and lactate (18.4%). Rats treated with rhMFG-E8 also had a significant histological attenuation of the acute lung injury, as well as a reduction in the number of apoptotic cells in the thymus (43.4%) and cleaved caspase 3 (38.7%) in the spleen. In addition, rhMFG-E8 improved the 10-day sepsis survival rate from 45 to 80% CONCLUSION: rhMFG-E8 significantly ameliorated sepsis in rats with acute alcohol exposure, demonstrating rhMFG-E8's potential to be developed as an effective therapy for sepsis in alcohol abusers.


Strategies to Overcome Late Complications from Radiotherapy for Childhood Head and Neck Cancers.
Most pediatric head and neck cancers are treated with radiotherapy, but the morbidity associated with radiotherapy has become a prominent issue. This article discusses the common long-term complications associated with head and neck radiotherapy for childhood cancers. It reviews approaches to minimize toxicity and details the toxicities that head and neck radiation inflicts on relevant functional measures. In addition, it discusses the risk of radiation-induced secondary cancers in childhood cancer survivors, as well as strategies to reduce them. Thus, this article addresses approaches to minimize long-term radiation toxicities in order to improve the quality of life for childhood cancer survivors.


Influence of different spectra of NOTCH3 variants on the clinical phenotype of CADASIL - experience from Slovakia.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary vascular disorder causing ischaemic attacks and strokes in middle-aged adults. Though the clinical spectrum includes some typical symptoms, recognition of the disease, especially at an earlier stage, is very difficult because of the highly variable manifestation and incomplete clinical picture. Characteristic brain MRI findings and the presence of pathogenic variants in the NOTCH3 gene are fundamental for CADASIL diagnosis. In this paper, we provide the first comprehensive report on CADASIL patients from Slovakia. Altogether, we identified 23 different pathogenic variants in 35 unrelated families. In our cohort of patients with clinical suspicion of CADASIL, we found a causal genetic defect and confirmed the diagnosis in 10.2% of cases. We present the case reports with up-to-date unpublished NOTCH3 variants and describe their phenotype-genotype correlation: p.(Cys65Phe), p.(Pro86Leu/Ser502Phe), p.(Arg156*), p.(Cys408Arg), p.(Tyr423Cys), p.(Asp1720His), and p.(Asp1893Thrfs*13). The most frequently described location for pathogenic variants was in exon 4, whereas the most common single variant was p.Arg1076Cys in exon 20. Based on the results of our study, we propose a re-evaluation of the criteria for the selection of patients suitable for NOTCH3 gene analysis. We hereby state that the currently used protocol of a high score requirement is not ideal for assessing molecular analysis, and it will be desirable to be less strict in criteria for genetic testing.


Human embryo associated immunosuppressor factor(s) from pre- and post-implantation stages share some similarities.
The present study demonstrates that embryo associated immunosuppressive factor(s) (EASF) secreted by the human embryo at pre- and post-implantation stages share some similarities. Human EASF was partially purified from embryo growth media of in vitro fertilized ova and from first trimester pregnancy sera. Non-pregnancy sera were fractionated in parallel. During each step of purification the fractions were tested for immunosuppressive properties using concanavalin A-stimulated lymphocyte proliferation assay. Analysis of EASF positive fractions on SDS-PAGE identified 14 kDa and 24 kDa molecules in embryo growth media and pregnancy sera. No such molecules were found in control sera, suggesting that these factors are embryo associated. The relationship of pre- and post-implantation EASF was also analyzed by EASF binding assay using murine anti-EASF antibody, which was raised against EASF isolated from embryo growth media. Results show that murine antibody bound to EASF purified from pregnancy sera, but not to identical fractions from control sera, indicating that these post-implantation EASF possess some similarity with pre-implantation EASF. Results also indicate that a species of suppressor factors present in embryo growth media and pregnancy sera were unique for their origin. Presence of these three EASFs at various stages of gestation may play a role in suppressing maternal cellular immune responses thereby preventing maternal rejection of the embryo.


Health education and formation: essential tools into the echinococcosis/hydatidosis prevention programs.
Health Education represents essential elements in the control and eradication campaigns of Echinococcosis/Hydatidosis. The basic elements and the applicatory principles and methodologies are examined. Moreover, the most appropriate intervention methodologies are defined through reference target. There is also a description of the experiences and the methodologies adopted in different Countries of the Mediterranean basin, where the disease is endemic.


Utility of histogram analysis of apparent diffusion coefficient maps obtained using 3.0T MRI for distinguishing uterine carcinosarcoma from endometrial carcinoma.
We explored the role of histogram analysis of apparent diffusion coefficient (ADC) maps for discriminating uterine carcinosarcoma and endometrial carcinoma. We retrospectively evaluated findings in 13 patients with uterine carcinosarcoma and 50 patients with endometrial carcinoma who underwent diffusion-weighted imaging (b = 0, 500, 1000 s/mm(2) ) at 3T with acquisition of corresponding ADC maps. We derived histogram data from regions of interest drawn on all slices of the ADC maps in which tumor was visualized, excluding areas of necrosis and hemorrhage in the tumor. We used the Mann-Whitney test to evaluate the capacity of histogram parameters (mean ADC value, 5th to 95th percentiles, skewness, kurtosis) to discriminate uterine carcinosarcoma and endometrial carcinoma and analyzed the receiver operating characteristic (ROC) curve to determine the optimum threshold value for each parameter and its corresponding sensitivity and specificity. Carcinosarcomas demonstrated significantly higher mean vales of ADC, 95th, 90th, 75th, 50th, 25th percentiles and kurtosis than endometrial carcinomas (P < 0.05). ROC curve analysis of the 75th percentile yielded the best area under the ROC curve (AUC; 0.904), sensitivity of 100%, and specificity of 78.0%, with a cutoff value of 1.034 × 10(-3) mm(2) /s. Histogram analysis of ADC maps might be helpful for discriminating uterine carcinosarcomas and endometrial carcinomas. J. Magn. Reson. Imaging 2016;43:1301-1307.


Hepatocyte-specific activity of TSC22D4 triggers progressive NAFLD by impairing mitochondrial function.
Fibrotic organ responses have recently been identified as long-term complications in diabetes. Indeed, insulin resistance and aberrant hepatic lipid accumulation represent driving features of progressive non-alcoholic fatty liver disease (NAFLD), ranging from simple steatosis and non-alcoholic steatohepatitis (NASH) to fibrosis. Effective pharmacological regimens to stop progressive liver disease are still lacking to-date. Based on our previous discovery of transforming growth factor beta-like stimulated clone (TSC)22D4 as a key driver of insulin resistance and glucose intolerance in obesity and type 2 diabetes, we generated a TSC22D4-hepatocyte specific knockout line (TSC22D4-HepaKO) and exposed mice to control or NASH diet models. Mechanistic insights were generated by metabolic phenotyping and single-nuclei RNA sequencing. Hepatic TSC22D4 expression was significantly correlated with markers of liver disease progression and fibrosis in both murine and human livers. Indeed, hepatic TSC22D4 levels were elevated in human NASH patients as well as in several murine NASH models. Specific genetic deletion of TSC22D4 in hepatocytes led to reduced liver lipid accumulation, improvements in steatosis and inflammation scores and decreased apoptosis in mice fed a lipogenic MCD diet. Single-nuclei RNA sequencing revealed a distinct TSC22D4-dependent gene signature identifying an upregulation of mitochondrial-related processes in hepatocytes upon loss of TSC22D4. An enrichment of genes involved in the TCA cycle, mitochondrial organization, and triglyceride metabolism underscored the hepatocyte-protective phenotype and overall decreased liver damage as seen in mouse models of hepatocyte-selective TSC22D4 loss-of-function. Together, our data uncover a new connection between targeted depletion of TSC22D4 and intrinsic metabolic processes in progressive liver disease. Hepatocyte-specific reduction of TSC22D4 improves hepatic steatosis and promotes hepatocyte survival via mitochondrial-related mechanisms thus paving the way for targeted therapies.


Design, Manufacture, and Acceptance Evaluation of APO: A Lip-syncing Social Robot Developed for Lip-reading Training Programs.
Lack of educational facilities for the burgeoning world population, financial barriers, and the growing tendency in favor of inclusive education have all helped channel a general inclination toward using various educational assistive technologies, e.g., socially assistive robots. Employing social robots in diverse educational scenarios could enhance learners' achievements by motivating them and sustaining their level of engagement. This study is devoted to manufacturing and investigating the acceptance of a novel social robot named APO, designed to improve hearing-impaired individuals' lip-reading skills through an educational game. To accomplish the robot's objective, we proposed and implemented a lip-syncing system on the APO social robot. The proposed robot's potential with regard to its primary goals, tutoring and practicing lip-reading, was examined through two main experiments. The first experiment was dedicated to evaluating the clarity of the utterances articulated by the robot. The evaluation was quantified by comparing the robot's articulation of words with a video of a human teacher lip-syncing the same words. In this inspection, due to the adults' advanced skill in lip-reading compared to children, twenty-one adult participants were asked to identify the words lip-synced in the two scenarios (the articulation of the robot and the video recorded from the human teacher). Subsequently, the number of words that participants correctly recognized from the robot and the human teacher articulations was considered a metric to evaluate the caliber of the designed lip-syncing system. The outcome of this experiment revealed that no significant differences were observed between the participants' recognition of the robot and the human tutor's articulation of multisyllabic words. Following the validation of the proposed articulatory system, the acceptance of the robot by a group of hearing-impaired participants, eighteen adults and sixteen children, was scrutinized in the second experiment. The adults and the children were asked to fill in two standard questionnaires, UTAUT and SAM, respectively. Our findings revealed that the robot acquired higher scores than the lip-syncing video in most of the questionnaires' items, which could be interpreted as a greater intention of utilizing the APO robot as an assistive technology for lip-reading instruction among adults and children.


Analysis, Recognition, and Classification of Biological Membrane Images.
Biological membrane images contain a variety of objects and patterns, which convey information about the underlying biological structures and mechanisms. The field of image analysis includes methods of computation which convert features and objects identified in images into quantitative information about biological structures represented in these images. Microscopy images are complex, noisy, and full of artifacts and consequently require multiple image processing steps for the extraction of meaningful quantitative information. This review is focused on methods of analysis of images of cells and biological membranes such as detection, segmentation, classification and machine learning, registration, tracking, and visualization. These methods could make possible, for example, to automatically identify defects in the cell membrane which affect physiological processes. Detailed analysis of membrane images could facilitate understanding of the underlying physiological structures or help in the interpretation of biological experiments.