KOunt: a reproducible KEGG orthologue abundance workflow.
Accurate gene prediction is essential for successful metagenome analysis. We present KOunt, a Snakemake pipeline, that precisely quantifies KEGG orthologue abundance. KOunt is available on GitHub: https://github.com/WatsonLab/KOunt. The KOunt reference database is available on figshare: https://doi.org/10.6084/m9.figshare.21269715. Test data are available at https://doi.org/10.6084/m9.figshare.22250152 and version 1.2.0 of KOunt at https://doi.org/10.6084/m9.figshare.23607834.


Pregnant woman and road safety: experimental crash test with post mortem human subject.
Trauma affect between 3 and 7% of all pregnancies in industrialized countries, and the leading cause of these traumas is car crashes. The difficulty to appreciate physiologic and anatomic changes occurring during pregnancy explain that majority of studies were not based on anatomical data. We present a protocol to create a realistic anatomical model of pregnant woman using a post mortem human subject (PMHS). We inserted a physical model of the gravid uterus into the pelvis of a PMHS. 3D acceleration sensors were placed on the subject to measure the acceleration on different body segments. We simulated three frontal impact situations at 20 km/h between two average European cars. Two main kinematics events were identified as possible causes of injuries: lap belt loading and backrest impact. Cadaver experiments provide one interesting complementary approach to study injury mechanisms related to road accidents involving pregnant women. This anatomical accuracy makes it possible to progress in the field of safety devices.


Ovarian serous borderline epithelial tumors with multiple retroperitoneal nodal involvement: metastasis or malignant transformation of epithelial glandular inclusions?
One of four patients who underwent lymph node excision at exploration for ovarian serous borderline epithelial tumor (OSBT) at Baystate Medical Center was found to have FIGO Stage III C lesion associated with extensive ovarian external (surface) papillary growth, peritoneal implants in the omentum and cul-de-sac, and involvement of multiple pelvic and periaortic lymph nodes by the tumor. Histologically, the lymph nodes showed an admixture of endosalpingeal glandular inclusions with neoplastic tissue identical to the ovarian tumor. The exact histogenesis and the prognostic significance of the nodal involvement by OSBT are still not fully understood. Although there is a small number of reported cases of lymph node involvement associated with OSBT, they are described as examples of nodal metastases or independent primary foci of malignant transformation. This paper presents an interesting association of OSBT with extensive pelvic and periaortic nodal involvement and reviews the relevant literature.


Chemical complementarity between tumor resident, T-cell receptor CDR3s and MAGEA3/6 correlates with increased melanoma survival: Potential relevance to MAGE vaccine auto-reactivity.
Cancer testis antigens have been of interest as possible targets for cancer immunotherapies. To better understand the opportunities for the use of such immunotherapy targets, we used a chemical complementarity scoring algorithm and an original web tool to establish aspects of electrostatic complementarity of the CTAs, MAGEA3 and MAGEA6, with melanoma specimen resident, T-cell receptor (TCR) complementarity determining region 3 (CDR3) amino acid sequences. Greater electrostatic complementarity between T-cell receptor CDR3 and tumor CTAs MAGEA3/6 was associated with a greater probability of overall survival, for both the cancer genome atlas and Moffitt Cancer Center samples; and was associated with high levels of T-cell cytotoxicity-related gene expression. Most importantly, this approach allowed for the highly efficient screening of specific segments of the MAGEA3/6 antigens which indicated that certain MAGE segments would have either more or less risk of auto-reactivity. In sum, the chemical complementarity algorithm, and its efficient application via the web tool, adaptivematch.com, offers a convenient opportunity to identify likely parameters important for immunotherapy considerations and melanoma patient risk stratifications.


Modeling homeostasis mechanisms that set the target cell size.
How organisms maintain cell size homeostasis is a long-standing problem that remains unresolved, especially in multicellular organisms. Recent experiments in diverse animal cell types demonstrate that within a cell population, cellular proliferation is low for small and large cells, but high at intermediate sizes. Here we use mathematical models to explore size-control strategies that drive such a non-monotonic profile resulting in the proliferation capacity being maximized at a target cell size. Our analysis reveals that most models of size control yield proliferation capacities that vary monotonically with cell size, and non-monotonicity requires two key mechanisms: (1) the growth rate decreases with increasing size for excessively large cells; and (2) cell division occurs as per the Adder model (division is triggered upon adding a fixed size from birth), or a Sizer-Adder combination. Consistent with theory, Jurkat T cell growth rates increase with size for small cells, but decrease with size for large cells. In summary, our models show that regulation of both growth and cell-division timing is necessary for size control in animal cells, and this joint mechanism leads to a target cell size where cellular proliferation capacity is maximized.


Crystal structures and vibrational and solution and solid-state (CPMAS) NMR spectroscopic studies in triphenyl phosphine, arsine, and stibine silver(I) bromate systems, (R3E)xAgBrO3 (E = P, As, Sb; x = 1-4).
Adducts of triphenyl phosphine, triphenyl arsine, and triphenyl stibine with silver(I) bromate have been synthesized and characterized both in solution ((1)H and ESI MS spectroscopy) and in the solid state (IR, single-crystal X-ray structure analysis). The triphenyl phosphine complexes have been also investigated by (31)P[(1)H] solution and (31)P cross-polarization magic-angle-spinning (CPMAS) NMR spectroscopy. The topology of the structures in the solid state was found to depend on the nature of EPh(3) and on the stoichiometric ratio AgBrO(3)/EPh(3). In AgBrO(3)/PPh(3) (1:1)(4) (1) and AgBrO(3)/PPh(3) (1:2) (2), the bromate is in the unfamiliar and hitherto structurally uncharacterized role of coordinating ligand, the complex having a mononuclear form in 2 and a less familiar tetrameric form in 1. In AgBrO(3)/AsPh(3) (1:4).CH(3)OH (7) and AgBrO(3)/SbPh(3) (1:4).C(2)H(5)OH (11), the cations are the familiar homoleptic [Ag(EPh(3))(4)](+) array with the bromate role simply that of counterion. The AgBrO(3)/AsPh(3) (1:2)(2).0.7"H(2)O" derivative (6) is binuclear L(2)Ag(mu-BrO(3))(2)AgL(2) with a four-membered ring core (L = AsPh(3)).


Photodynamic induced uptake of liposomal doxorubicin to rat lung tumors parallels tumor vascular density.
Visudyne®-mediated photodynamic therapy (PDT) at low drug/light conditions has shown to selectively enhance the uptake of liposomal doxorubicin in subpleural localized sarcoma tumors grown on rodent lungs without causing morphological alterations of the lung. The present experiments explore the impact of low-dose PDT on liposomal doxorubicin (Liporubicin™) uptake to different tumor types grown on rodent lungs. Three groups of Fischer rats underwent subpleural generation of sarcoma, mesothelioma, or adenocarcinoma tumors on the left lung. At least five animals of each group (sarcoma, n = 5; mesothelioma, n = 7; adenocarcinoma, n = 5) underwent intraoperative low-dose (10 J/cm(2) at 35 mW/cm(2) ) PDT with 0.0625 mg/kg Visudyne® of the tumor and the lower lobe. This was followed by intravenous (IV) administration of 400 µg Liporubicin™. After a circulation time of 60 min, the tumor-bearing lung was processed for HPLC analyses. At least five animals per group underwent the same procedure but without PDT (sarcoma, n = 5; mesothelioma, n = 5; adenocarcinoma, n = 6). Five untreated animals per group underwent CD31 immunostaining of their tumors with histomorphometrical assessment of the tumor vascularization. Low-dose PDT significantly enhanced Liporubicin™ uptake to all tumor types (sarcoma, P = 0.0007; mesothelioma, P = 0.001; adenocarcinoma, P = 0.02) but not to normal lung tissue compared to IV drug administration alone. PDT led to a significantly increased ratio of tumor to lung tissue drug uptake for all three tumor types (P < 0.05). However, the tumor drug uptake varied between tumor types and paralleled tumor vascular density. The vascular density was significantly higher in sarcoma than in adenocarcinoma (P < 0.001) and mesothelioma (P < 0.001), whereas there was no significant difference between adenocarcinoma and mesothelioma. Low-dose Visudyne®-mediated PDT selectively enhances the uptake of systemically administered liposomal doxorubicin in tumors without affecting the drug uptake to normal lung. However, drug uptake varied significantly between tumor types and paralleled tumor vascular density.


Investigations on the action of cefazedone and gentamicin, alone and combined, on renal enzyme excretion in rats.
Administration of (6R, 7 R)-7-(2-[3,5-dichloro-4-oxo-1(4 H)-pyridyl]-acetamido)-3-([(5-methyl-1,3,4-thiadiazol-2-yl)-thio]methyl)-8-oxo-5-thia-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid (cefazedone, Refosporen) in a dose of 1000 mg/kg led to a statistically significant rise of the alkaline phosphatase activity in rat urine. The excretion of leucinaminopeptidase activity was not significantly affected. The enzyme activity in the animals' urine was raised by the administration of 100 mg/kg of gentamicin. Combined administration of the two antibiotics in the doses mentioned did not lead to any additive action. The established increases in activity were in the same range as after the administration of only one of the antibiotics.


The effect of hydroxyethylrutosides on capillary filtration rate in the lower limb of man.
The rate of capillary filtration in the lower limbs after hydroxyethylrutosides administered in various doses and by different routes was studied in patients with chronic venous insufficiency. Capillary filtration rate decreased immediately after intravenous and from 55 to 85 minutes after oral administration, depending on the dose. The slow-release tablets produced a definite falt in capillary filtration 240 minutes after administration.


TMEM70 mutations cause isolated ATP synthase deficiency and neonatal mitochondrial encephalocardiomyopathy.
We carried out whole-genome homozygosity mapping, gene expression analysis and DNA sequencing in individuals with isolated mitochondrial ATP synthase deficiency and identified disease-causing mutations in TMEM70. Complementation of the cell lines of these individuals with wild-type TMEM70 restored biogenesis and metabolic function of the enzyme complex. Our results show that TMEM70 is involved in mitochondrial ATP synthase biogenesis in higher eukaryotes.


Deep Learning-Based Precision Analysis for Acrosome Reaction by Modification of Plasma Membrane in Boar Sperm.
The analysis of AR is widely used to detect loss of acrosome in sperm, but the subjective decisions of experts affect the accuracy of the examination. Therefore, we develop an ARCS for objectivity and consistency of analysis using convolutional neural networks (CNNs) trained with various magnification images. Our models were trained on 215 microscopic images at 400× and 438 images at 1000× magnification using the ResNet 50 and Inception-ResNet v2 architectures. These models distinctly recognized micro-changes in the PM of AR sperms. Moreover, the Inception-ResNet v2-based ARCS achieved a mean average precision of over 97%. Our system's calculation of the AR ratio on the test dataset produced results similar to the work of the three experts and could do so more quickly. Our model streamlines sperm detection and AR status determination using a CNN-based approach, replacing laborious tasks and expert assessments. The ARCS offers consistent AR sperm detection, reduced human error, and decreased working time. In conclusion, our study suggests the feasibility and benefits of using a sperm diagnosis artificial intelligence assistance system in routine practice scenarios.


Preoperative use of sotalol versus atenolol for atrial fibrillation after cardiac surgery.
Atrial fibrillation is one of the most common complications of cardiac surgery. Beta blockers have been demonstrated to decrease the incidence of postoperative atrial fibrillation. Preliminary investigations reporting sotalol and atenolol to be effective in preventing postoperative atrial fibrillation are encouraging, but no studies have been conducted comparing both drugs. A total of 253 consecutive eligible patients (66 +/- 8 years; mean +/- standard deviation) scheduled to undergo cardiac surgery were enrolled in this study. Patients were randomized in a prospective open manner 1.5:1 to atenolol group (50 mg/daily; 153 patients) or sotalol group (80 mg twice daily; 100 patients). Atrial fibrillation occurred in 44/253 patients (17.45%). A significant difference was found in the occurrence of atrial fibrillation in the atenolol group (34 patients, 22%) compared with those receiving sotalol (10 patients, 10%; p = 0.013). Therapeutic efficiency and efficacy was 12% and 54%, respectively. Stepwise logistic regression analysis revealed that age more than 68 years old (odds ratio = 2.72; 95% confidence interval [CI] = 1.37-5.41; p = 0.004), the use of beta-adrenergic agents (odds ratio = 2.74; 95% CI = 1.5-5; p = 0.001), and sotalol (odds ratio = 0.46; 95% CI = 0.23-0.95; p = 0.035) were independently associated with development of atrial fibrillation. Oral low-dose sotalol provides a considerable reduction in the occurrence of atrial fibrillation. A selective approach based on clinical risk prediction should decrease the occurrence of atrial fibrillation after cardiac surgery.


[Electron microscopic investigations of the phagocytosis and digestion of foreign erythrocytes by peritoneal macrophages (author's transl)].
The erythrophagocytosis begins after 30 up to 60 min. The hemolysis is detectable 30 min later. After that myelin figures are formed which are digested up to 36 h. After 24 h the digestive vacuoles and the cytoplasm show ferritin molecules. After 14 d the digestion is finished.


Overview of Research Development on the Role of NF-κB Signaling in Mastitis.
Mastitis is the inflammation of the mammary gland. Escherichia coli and Staphylococcus aureus are the most common bacteria responsible for mastitis. When mammary epithelial cells are infected by microorganisms, this activates an inflammatory response. The bacterial infection is recognized by innate pattern recognition receptors (PRRs) in the mammary epithelial cells, with the help of Toll-like receptors (TLRs). Upon activation by lipopolysaccharides, a virulent agent of bacteria, the TLRs further trigger nuclear factor-κB (NF-κB) signaling to accelerate its pathogenesis. The NF-κB has an essential role in many biological processes, such as cell survival, immune response, inflammation and development. Therefore, the NF-κB signaling triggered by the TLRs then regulates the transcriptional expression of specific inflammatory mediators to initiate inflammation of the mammary epithelial cells. Thus, any aberrant regulation of NF-κB signaling may lead to many inflammatory diseases, including mastitis. Hence, the inhibiting of NF-κB signaling has potential therapeutic applications in mastitis control strategies. In this review, we highlighted the regulation and function of NF-κB signaling in mastitis. Furthermore, the role of NF-κB signaling for therapeutic purposes in mastitis control has been explored in the current review.


Completion thyroidectomy: effect of timing on clinical complications and oncologic outcome in patients with differentiated thyroid cancer.
Despite improved preoperative diagnostics, incidental postoperative detection of differentiated thyroid cancer in the final histology is still common. In most of these cases, completion thyroidectomy is recommended by national and international guidelines, although secondary surgery is associated with an increased operative risk. The optimal timing of completion thyroidectomy is still controversial. Between January 1993 and December 2009, a total of 128 patients underwent completion thyroidectomy for differentiated thyroid carcinoma: papillary (n = 87) and follicular (n = 41). These patients were divided into five groups according to the time of the completion thyroidectomy after primary surgery (groups A, 1-3 days; B, 4-7 days; C, 1-7 weeks; D, 7-12 weeks; E, >3 months). Clinical complications and oncologic outcomes were analyzed. The mean follow-up was 82.5 ± 17 months. The overall rates of transient and persistent postoperative hypocalcemia were 7.0 and 3.1%, respectively. The rates of persistent hypocalcemia were significantly increased in groups B, C, and D in comparison to those in groups A and E (p < 0.003). The hypocalcemia rates were 7.1, 4.5, and 3.8% versus 0%, respectively. Transient or persistent vocal cord paresis was observed in eight (6.2%) and four patients (3.1%), respectively. The incidence of persistent vocal cord paresis (VCP) was significantly higher in groups B, C, and D than in groups A and E (p < 0.003). The VCP rates were 7.1, 4.5, and 3.8% versus 0%, respectively. There was no significant difference regarding survival or recurrence among the five groups. Considering perioperative morbidity and oncologic outcomes, completion thyroidectomy should be performed either within 3 days or beyond 3 months after primary surgery.


1O2 determined from the measured PDT dose and 3O2 predicts long-term response to Photofrin-mediated PDT.
Photodynamic therapy (PDT) that employs the photochemical interaction of light, photosensitizer and oxygen is an established modality for the treatment of cancer. However, dosimetry for PDT is becoming increasingly complex due to the heterogeneous photosensitizer uptake by the tumor, and complicated relationship between the tissue oxygenation ([3O2]), interstitial light distribution, photosensitizer photobleaching and PDT effect. As a result, experts argue that the failure to realize PDT's true potential is, at least partly due to the complexity of the dosimetry problem. In this study, we examine the efficacy of singlet oxygen explicit dosimetry (SOED) based on the measurements of the interstitial light fluence rate distribution, changes of [3O2] and photosensitizer concentration during Photofrin-mediated PDT to predict long-term control rates of radiation-induced fibrosarcoma tumors. We further show how variation in tissue [3O2] between animals induces variation in the treatment response for the same PDT protocol. PDT was performed with 5 mg kg-1 Photofrin (a drug-light interval of 24 h), in-air fluence rates (ϕ air) of 50 and 75 mW cm-2 and in-air fluences from 225 to 540 J cm-2. The tumor regrowth was tracked for 90 d after the treatment and Kaplan-Meier analyses for local control rate were performed based on a tumor volume ⩽100 mm3 for the two dosimetry quantities of PDT dose and SOED. Based on the results, SOED allowed for reduced subject variation and improved treatment evaluation as compared to the PDT dose.


Computer analysis of transrectal ultrasound images of the prostate for the detection of carcinoma: a prospective study in radical prostatectomy specimens.
The reliability and objectivity of computer assisted transrectal ultrasound are examined. Pathological examination of radical prostatectomy specimens was compared prospectively to automated cancer detection in corresponding transrectal ultrasound images. For automated cancer detection, a sensitivity of 0.75 and a specificity of 0.78 were obtained. Moreover, 74% of human interpretation of the percentage of malignancy in the analyzed images was equal to the actual calculated percentage (Pearson's product moment correlation coefficient 0.85). Comparing these results to those obtained with normal transrectal ultrasound, automated analysis provides additional information in the interpretation of transrectal ultrasound images by color coding them in an objective manner according to the probability of malignancy.


Genetic Interaction Scoring Procedure for Bacterial Species.
A genetic interaction occurs when the phenotype of an organism carrying two mutant genes differs from what should have been observed given their independent influence. Such unexpected outcome indicates a mechanistic connection between the perturbed genes, providing a key source of functional information about the cell. Large-scale screening for genetic interactions involves measuring phenotypes of single and double mutants, which for microorganisms is usually done by automated analysis of images of ordered colonies. Obtaining accurate colony sizes, and using them to identify genetic interactions from such screens remains a challenging and time-consuming task. Here, we outline steps to compute genetic interaction scores in E. coli by measuring colony sizes from plate images, performing normalisation, and quantifying the strength of the effect.


β-Catenin and Rho GTPases as downstream targets of TGF-β1 during pulp repair.
TGF-β1 (transforming growth factor-β1) plays a central role in regulating proliferation, migration and differentiation of dental pulp cells during the repair process after tooth injury. Our previous study showed that p38 mitogen-activated protein kinase may act downstream of TGF-β1 signalling to effect the differentiation of dental pulp cells. However, the molecular mechanisms that trigger and regulate the process remain to be elucidated. TGF-β1 interacts with signalling pathways such as Wnt/β-catenin and Rho to induce diverse biological effects. TGF-β1 activates β-catenin signalling, increases β-catenin nuclear translocation and interacts with LEF/TCF to regulate gene expression. Morphologic changes in response to TGF-β1 are associated with activation of Rho GTPases, but are abrogated by inhibitors of Rho-associated kinase, a major downstream target of Rho. These results suggest that the Wnt/β-catenin and Rho pathways may mediate the downstream events of TGF-β1 signalling.


Modeling of floating marine litter originated from the Eastern Ionian Sea: Transport, residence time and connectivity.
A Lagrangian particle tracking model coupled to a circulation was used to explore the transport, residence time and connectivity of floating litter that originated from the Εastern Ionian Sea during 2011-2014. At the end of simulations, on average 26% of litter was retained within the coastal waters of the Eastern Ionian Sea, whereas 58% was washed into offshore waters without formulating permanent accumulation areas, as the basin-wide surface circulation was characterized by considerable interannual variability. The inflow of litter into the Adriatic and Eastern Mediterranean Seas was moderate, ranging between 9% and 20%, and the beached litter was on average 9.2%, mostly located in the northern subregions. The average residence time of litter particles ranged between 20 and 80 days, implying their temporary retention before drifting offshore. Connectivity patterns depicted an exchange of litter mainly between adjacent subareas and with a northward direction.


Vancomycin.
Vancomycin is a narrow-spectrum bactericidal antibiotic used primarily for treatment of serious staphylococcal infections. It is the alternative therapy of choice when the penicillins and cephalosporins cannot be used. Vancomycin is also used in (1) methicillin-resistant Staphylococcus aureus infections; (2) streptococcal endocarditis in conjunction with an aminoglycoside in patients intolerant of penicillin or ampicillin; (3) infections, including those involving prosthetic devices, caused by gram-positive organisms with multiple antibiotic resistance; (4) antibiotic-induced enterocolitis caused by Clostridium difficile; and (5) prophylaxis for endocarditis in patients who are at risk and cannot tolerate a penicillin, cephalosporin, or erythromycin. The major toxic effect associated with the use of vancomycin is ototoxicity, which may develop when serum levels exceed 30 micrograms/ml.


Apparent reversion of stable in vitro genetic markers detected in tumour cells from spontaneous metastases.
The evolution towards more aggressive and autonomous behaviour of many cancerous tumours, often referred to as tumour progression, is thought to stem from the development of heterogeneity within the tumour cell population, combined with the continuous selection of progressively more malignant cellular phenotypes. During the course of the disease, the tumour cells show multiple phenotypic changes in a stepwise, but apparently random fashion, becoming more anaplastic, increasingly independent of growth controls and more metastatic. Several laboratories, including our own, have analysed aspects of tumour heterogeneity and cancer metastasis by selecting and studying the properties of lectin-resistant (LecR) membrane mutant tumour sublines; in a few cases, such variants have been claimed to be less tumorigenic or metastatic than the parental cells from which they were derived. We have attempted to study the factors involved in the reestablishment of tumour heterogeneity by monitoring the stability in vivo of LecR phenotypes of metastatic tumour cells after injection of cloned LecR tumour cells. We now report that spontaneous metastases arising after a subcutaneous (s.c.) injection of cells from variant tumour lines selected from a highly metastatic DBA/2 mouse tumour known as MDAY-D2, and which are stably resistant in tissue culture to wheat germ agglutinin (WGA), no longer carry the WGA-resistant (WGAR) phenotype. The results demonstrate that WGAR tumour cells do not metastasize, but rather, 'revertants' for the WGAR phenotype, which presumably were generated in vivo after injection, were the cells actually capable of metastatic growth.


Unravelling the pathogenesis of foramen magnum stenosis in patients with severe achondroplasia: a CT-based comparison with age-matched controls and FGFR3 craniosynostosis syndromes.
Foramen magnum(FM) stenosis can be responsible for acute and chronic damage to the cervicomedullary junction in children with achondroplasia. The bony anatomy and patterns of suture fusion of the FM in this context are incompletely understood, yet becoming increasingly important in the light of novel medical therapies for achondroplasia. The objective of this study was to describe and quantify bony anatomy and fusion patterns of FM stenosis in patients with achondroplasia using CT scans, comparing them to age-matched controls and other FGFR3 craniosynostosis patients. Patients with achondroplasia and severe FM stenosis, classified as achondroplasia foramen magnum score(AFMS) grades 3 and 4, were identified from a departmental operative database. All had pre-operative CT scans of the craniocervical junction. Measurements obtained comprised sagittal diameter (SD), transverse diameter (TD), foramen magnum area, and opisthion thickness. Anterior and posterior interoccipital synchondroses (AIOS and PIOS) were graded by the extent of fusion. These measurements were then compared with CT scans from 3 age-matched groups: the normal control group, children with Muenke syndrome, and children with Crouzon syndrome with acanthosis nigricans (CSAN). CT scans were reviewed in 23 cases of patients with achondroplasia, 23 normal controls, 20 Muenke, and 15 CSAN. Children with achondroplasia had significantly smaller sagittal diameter (mean 16.2 ± 2.4 mm) compared to other groups (control 31.7 ± 2.4 mm, p < 0.0001; Muenke 31.7 ± 3.5 mm, p < 0.0001; and CSAN 23.1 ± 3.4 mm, p < 0.0001) and transverse diameters (mean 14.3 ± 1.8 mm) compared with other groups (control 26.5 ± 3.2 mm, p < 0.0001; Muenke 24.1 ± 2.6 mm, p < 0.0001; CSAN 19.1 ± 2.6 mm, p < 0.0001). This translated into a surface area which was 3.4 times smaller in the achondroplasia group compared with the control group. The median grade of the AIOS fusion achondroplasia group was 3.0 (IQR 3.0-5.0), which was significantly higher compared with the control group (1.0, IQR 1.0-1.0, p < 0.0001), Muenke group (1.0, IQR 1.0-1.0, p < 0.0001), and CSAN (2.0, IQR 1.0-2.0, p < 0.0002). Median PIOS fusion grade was also highest in the achondroplasia group (5.0, IQR 4.0-5.0) compared with control (1.0, IQR 1.0-1.0, p < 0.0001), Muenke (2.5, IQR 1.3-3.0, p < 0.0001), and CSAN (4.0, IQR 4.0-4.0, p = 0.2). Distinct bony opisthion spurs projecting into the foramen magnum were seen in achondroplasia patients but not others, resulting in characteristic crescent and cloverleaf shapes. Patients with AFMS stages 3 and 4 have significantly reduced FM diameters, with surface area 3.4 times smaller than age-matched controls. This is associated with premature fusion of the AIOS and PIOS in comparison with controls and other FGFR3-related conditions. The presence of thickened opisthion bony spurs contributes to stenosis in achondroplasia. Understanding and quantifying bony changes at the FM of patients with achondroplasia will be important in the future quantitative evaluation of emerging medical therapies.


Well-differentiated lipomatous neoplasms with p53 alterations: a clinicopathological and molecular study of eight cases with features of atypical pleomorphic lipomatous tumour.
Well-differentiated lipomatous neoplasms encompass a broad spectrum of benign and malignant tumours, many of which are characterised by recurrent genetic abnormalities. Although a key regulator of p53 signalling, MDM2, is characteristically amplified in well-differentiated liposarcoma, recurrent abnormalities of p53 itself have not been reported in well-differentiated adipocytic neoplasms. Here, we present a series of well-differentiated lipomatous tumours characterised by p53 alterations and histological features in keeping with atypical pleomorphic lipomatous tumour (APLT). We reviewed the morphological, immunohistochemical and molecular genetic features of eight lipomatous tumours with p53 alterations. Four tumours arose in the thigh, and one case each arose in the shoulder, calf, upper back, and subclavicular regions; six tumours were deep/subfascial and two were subcutaneous. Relevant clinical history included two patients with Li-Fraumeni syndrome. Morphologically, all cases showed well-differentiated adipocytes with prominent nuclear pleomorphism, limited mitotic activity, and no tumour cell necrosis. All cases were negative for MDM2 overexpression and amplification as determined with immunohistochemistry and fluorescence in-situ hybridisation, respectively. Immunohistochemically, p16 was diffusely overexpressed in all cases; seven tumours (88%) showed abnormal loss of Rb and p53. TP53 mutation or deletion was identified in four of six tumours evaluated with exon-targeted hybrid capture-based massively parallel sequencing; RB1 mutation or deletion was present in five of six cases. We present a series of eight well-differentiated lipomatous neoplasms characterised by p53 alterations in addition to Rb loss and histological features of APLT. These findings suggest that impaired p53 signalling may contribute to the pathogenesis of APLT in a subset of cases.


Azido-iodo-phenyl-analogs of 2',5'-dideoxy-adenosine as photoaffinity ligands for adenylyl cyclase.
Azidoiodophenyl-analogs of 2',5'-dideoxyadenosine were synthesized and tested as potential 'P'-site selective affinity probes for adenylyl cyclases. The 3'-substituted analogs included: 1: 3'-[(4-nitrophenyl)-acetyl]-2',5'-dideoxy-adenosine 2: 3'-[(4-nitrophenyl)-butyryl]-2',5'-dideoxyadenosine 3: 3'-[(4-azido-3-iodophenyl)-acetyl]-2',5'-dideoxyadenosine and 4: 3'-[(4-azido-3-iodophenyl)-butyryl]-2',5'-dideoxyadenosine. The azidoiodo-phenyl-analogs inactivated adenylyl cyclase irreversibly and in a light-dependent manner. This was observed with detergent-dispersed enzyme from rat brain, purified native enzyme from bovine brain, and recombinant Type I bovine adenylyl cyclase expressed in membranes from fall army worm ovarian (Sf9) cells. Inactivation of the recombinant enzyme was inversely dependent on ATP concentration and was not completely prevented by 2',5'-dideoxyadenosine. Inhibition kinetics with the recombinant enzyme in the absence of light suggested two sites of inhibition, whereas with the native Type I enzyme inhibition kinetics exhibited a straightforward noncompetitive mechanism. Occupation of either or both sites by ligand protected the enzyme against denaturation by UV-irradiation per se. The data are consistent with inactivation of the recombinant enzyme occurring both through the 'P'-site and the catalytic active site, but suggest that this is a characteristic of the recombinant enzyme and is not dependent on the probes per se. The data suggest the potential for independent interactions of such ligands with different sites on a given enzyme and also with other enzymes containing adenosine or adenine nucleotide binding domains.


Lopinavir + ritonavir tablets: new formulation. More convenient, but minimal evaluation.
Kaletra tablets have the advantage of being stored at room temperature, but potential interactions are poorly documented.


Mucocutaneous lymph node syndrome: report of two cases complicated by gallbladder hydrops and diagnosed by ultrasound.
Two patients with mucocutaneous lymph node syndrome are presented. During the course of their illnesses, they developed acute abdominal pain secondary to hydrops of the gallbladder. The diagnosis and management of each case was facilitated by ultrasonography.


Decoding individual identity from brain activity elicited in imagining common experiences.
Everyone experiences common events differently. This leads to personal memories that presumably provide neural signatures of individual identity when events are reimagined. We present initial evidence that these signatures can be read from brain activity. To do this, we progress beyond previous work that has deployed generic group-level computational semantic models to distinguish between neural representations of different events, but not revealed interpersonal differences in event representations. We scanned 26 participants' brain activity using functional Magnetic Resonance Imaging as they vividly imagined themselves personally experiencing 20 common scenarios (e.g., dancing, shopping, wedding). Rather than adopting a one-size-fits-all approach to generically model scenarios, we constructed personal models from participants' verbal descriptions and self-ratings of sensory/motor/cognitive/spatiotemporal and emotional characteristics of the imagined experiences. We demonstrate that participants' neural representations are better predicted by their own models than other peoples'. This showcases how neuroimaging and personalized models can quantify individual-differences in imagined experiences.


Superficial lightning injuries--their "fractal" shape and origin.
The origin of superficial lightning burns was studied. A recently developed mathematical model was invoked to identify fern-shaped burns as 'so-called' fractals. On the basis of this model and discharge experiments, we conclude that 'fractal burns' are caused by surface discharges of a positive polarity. The recognition of such burns can help to elucidate the type and mechanism of the lightning strike.


Radiotherapy of anal canal cancer.
We present the update of the recommendations of the French society for radiation oncology on external radiotherapy and brachytherapy of anal canal carcinoma. The following guidelines are presented: indications, treatment procedure, as well as dose and dose-constraints objectives, immediate postoperative management, post-treatment evaluation, and long-term follow-up.


Impaired vascular reactivity in newborn infants of smoking mothers.
A transcutaneous PO2 technique was used to study the influence of cigarette smoking during pregnancy on postocclusive reactive hyperaemia of the skin of newborn infants and their mothers. Forty-seven mothers and their infants were studied on two occasions (24-48 and 96-144 h) after birth. Twenty of the mothers were habitual smokers, 27 were non-smokers. All mothers were healthy and their pregnancies and deliveries were normal. The infants were all healthy throughout their first week of life. The mothers had more marked reactive hyperaemia than their newborn infants (p less than 0.001). Infants of smoking mothers had a significantly weaker postischaemic hyperaemic response 24-48 h after birth than infants of nonsmoking mothers (p less than 0.01). This difference had disappeared 96-144 h after birth. Smoking mothers also showed a significantly weaker hyperaemic response to ischaemia than the control mothers at the first investigation (p less than 0.05). This difference was smaller and not statistically significant at the second recording. A decreased capacity for postocclusive reactive hyperaemia might be particularly harmful in asphyctic infants, but it may also be detrimental for a normal postnatal circulatory adaptation.


Comparison of phosphotungstate and dextran sulfate-Mg2+ precipitation procedures for determination of high density lipoprotein cholesterol.
Because of the controversy over the best method for assaying high density lipoprotein (HDL) cholesterol in the clinical laboratory, a commonly used phosphotungstate method for precipitating low density and very low density lipoproteins (LDL and VLDL) was compared with a recently recommended dextran sulfate precipitation method. The accuracy and precision of HDL cholesterol determinations were similar for both methods. Either of these procedures would appear to be equally satisfactory for the assay of HDL cholesterol in the clinical laboratory.


Metal enriched quasi-ultrafine particles from stainless steel gas metal arc welding induced genetic and epigenetic alterations in BEAS-2B cells.
Recent evidence has supported welding fume (WF)-derived ultrafine particles (UFP) could be the driving force of their adverse health effects. However, UFP have not yet been extensively studied and are currently not included in present air quality standards/guidelines. Here, attention was focused on the underlying genetic and epigenetic mechanisms by which the quasi-UFP (Q-UFP, i.e., ≤ 0.25 μm) of the WF emitted by gas metal arc welding-stainless steel (GMAW-SS) exert their toxicity in human bronchial epithelial BEAS-2B cells. The Q-UFP under study showed a monomodal size distribution in number centered on 104.4 ± 52.3 nm and a zeta potential of -13.8 ± 0.3 mV. They were enriched in Fe > Cr > Mn > Si, and displayed a relatively high intrinsic oxidative potential. Dose-dependent activation of nuclear factor erythroid 2-related factor 2 and nuclear factor-kappa B signaling pathway, glutathione alteration, and DNA, protein and lipid oxidative damage were reported in BEAS-2B cells acutely (1.5 and 9 μg/cm2, 24 h) or repeatedly (0.25 and 1.5 μg/cm2, 3 × 24 h) exposed to Q-UFP (p < 0.05). Alterations of the Histone H3 acetylation were reported for any exposure (p < 0.05). Differentially regulated miRNA and mRNA indicated the activation of some critical cell signaling pathways related to oxidative stress, inflammation, and cell cycle deregulation towards apoptosis. Taken together, these results highlighted the urgent need to better evaluate the respective toxicity of the different metals and to include the Q-UFP fraction of WF in current air quality standards/guidelines relevant to the occupational settings.


Immunological effects of taxol and adryamicin in breast cancer patients.
Antineoplastic chemotherapy still consists in the major first-line therapeutics against cancer. Several reports have described the immunomodulatory effects of these drugs based on in vitro treatment, but no previous data are known about these effects in patients and its association with immunological-mediated toxicity. In this study, we first characterize the immunological profile of advanced breast cancer patients treated with doxorubicin and paclitaxel protocols, immediately after chemotherapy infusion. Our findings included an immediate plasmatic reduction in IL-1, IL-10, and TNF-α levels in doxorubicin-treated patients, as well as high levels of IL-10 in paclitaxel patients. Further, it was demonstrated that both drugs led to leukocytes oxidative burst impairment. In vitro analysis was performed exposing healthy blood to both chemotherapics in the same concentration and time of exposition of patients, resulting in low IL-10 and high IL-1β in doxorubicin exposition, as low TNF-α and high IL-1 in paclitaxel treatment. Nitric oxide levels were not altered in both in vivo and in vitro treatments. In conclusion, our data revealed for the first time that the immediate effects of chemotherapy could be mediated by cytokines signaling in patients and that the results observed in patients could be a resultant of host immune cells activation.


Molecular and clinical characterization of two unrelated families with factor V deficiency, including a novel nonsense variant (p.Gln1532*).
Factor V (FV) is an essential cofactor in the coagulation cascade. The characterization of novel mutations is advantageous for the clinical management of FV-deficient patients. Coagulation screening and thrombin generation assay were performed with the plate-poor plasma. All 25 exons of the F5 gene were amplified and sequenced. The ClustalX-2.1 software was applied to the multiple sequence alignment. The possible adverse effects of mutations were investigated with online bioinformatics software and protein modeling. Two unrelated families with FV deficiency were under investigation. Proband A was an 18-year-old youth with recurrent epistaxis. Proband B was a 29-year-old woman who did not present with any bleeding symptoms. Three heterozygous mutations (p.Gln1532*, p.Phe218Ser, and p.Asp2222Gly) were detected. Interestingly, they were compound heterozygotes and both contained the p.Asp2222Gly, a polymorphism. The thrombin generation assay showed that both patients had impaired ability of thrombin generation, and in particular, proband A was more severe. Conservation, pathogenicity and protein modeling studies all indicated that these three mutations could cause deleterious effects on the function and structure of FV. These three mutations are responsible for the FV-deficient in two pedigrees. Moreover, the nonsense variant p.Gln1532* is first reported in the world.


Hypothalamic stimulation counteracts sympathetically mediated gastrointestinal inhibition in chloralose-anaesthetised cats.
The inhibitory motor effect of the sympathetic gastrointestino-gastrointestinal (GI-GI) reflex was studied in cats with isolated innervated ileal (Thiry-Vella) loops. They were subjected to acute experiments under chloralose-gallamine anaesthesia where gastric volume, arterial blood pressure and heart rate were continuously monitored. The cervical vagi were sectioned and used for efferent stimulation. The hypothalamus was systematically explored by means of stereotaxically guided electrodes. When the abdomen was undisturbed, gastric contractile responses to central stimulation were virtually absent, regardless of whether a vagally induced tone was present or not. Distension of the isolated intestinal loop induced marked inhibition of vagally induced gastric tone, indicating activation of the GI-GI reflex. Under these conditions, about 17% of the hypothalamic points induced gastric excitation, due to withdrawal of sympathetic tone. The GI-GI reflex can thus be inhibited from diencephalic levels. This inhibition is not linked to any distinct cardiovascular 'pattern'.


The Impact of Heating, Ventilation, and Air-Conditioning Design Features on the Transmission of Viruses, Including SARS-CoV-2: Overview of Reviews.
The COVID-19 or SARS-CoV-2 outbreak was declared a pandemic by the World Health Organization in March 2020. Almost 2 years later (early February 2022), the World Health Organization reported over 383 million cases of the disease caused by the virus, with over 5.6 million deaths worldwide. Debate regarding the routes of transmission was substantial early in the pandemic; however, airborne transmission emerged as an important consideration. Infectious airborne agents can spread within the built environment through heating, ventilation, and air-conditioning (HVAC) systems. Multiple features of HVAC systems can influence transmission (eg, ventilation, filtration, UV radiation, and humidity). Understanding how HVAC features influence airborne transmission is critical to mitigate the spread of infectious agents. Given the airborne transmission of SARS-CoV-2, an overview of reviews was conducted to understand what is already known from the scientific literature about how virus transmission may be affected by HVAC design features in the built environment. Ovid MEDLINE and Compendex were searched from inception to January 2021. Two reviewers independently screened the titles, abstracts, and full text of potentially relevant reviews, using a priori inclusion criteria: systematic reviews examining the effects of HVAC design features on virus transmission. Two reviewers independently assessed the methodological quality using AMSTAR2. Searching identified 361 citations, of which 45 (12.5%) were potentially relevant and 7 (2%) were included. Reviews were published between 2007 and 2021 and included 47 virus studies. Two earlier reviews (2007 and 2016) of 21 studies found sufficient evidence that mechanical ventilation (airflow patterns and ventilation rates) plays a role in airborne transmission; however, both found insufficient evidence to quantify the minimum mechanical ventilation requirements. One review (2017) of 9 studies examining humidity and indoor air quality found that influenza virus survival was lowest between 40% and 80% relative humidity; the authors noted that ventilation rates were a confounding variable. Two reviews (2021) examined mitigation strategies for coronavirus transmission, finding that transmission decreased with increasing temperature and relative humidity. One review (2020) identified 14 studies examining coronavirus transmission in air-conditioning systems, finding that HVAC systems played a role in virus spread during previous coronavirus outbreaks. One review (2020) examined virus transmission interventions in public ground transportation, finding ventilation and filtration to be effective. Seven reviews synthesizing 47 studies demonstrated a role for HVAC in mitigating airborne virus transmission. Ventilation, humidity, temperature, and filtration can play a role in the viability and transmission of viruses, including coronaviruses. Recommendations for minimum standards were not possible owing to few studies investigating a given HVAC parameter. This overview examining HVAC design features and their effects on the airborne transmission of viruses serves as a starting point for future systematic reviews and identifying priorities for primary research.


Colpocephalum holzenthali n. sp. (Mallophaga: Menoponidae) from the barred forest-falcon Micrastur ruficollis (Falconidae) in Peru.
Colpocephalum holzenthali, a new species of chewing louse, is described from a series of lice collected in Peru from Micrastur ruficollis zonothorax, the barred forest-falcon. Colpocephalum holzenthali is most similar to members of the Colpocephalum polybori species group.


Portal gas in a patient with acute obstructive cholangitis: report of a case with emphasis on US findings.
Portal gas is relatively rare, and its relationship to ischemic bowel diseases has been emphasized. We report the case of a 70-year-old woman with acute obstructive cholangitis in whom portal gas was detected by ultrasonography (US) but not by computed tomography (CT). The former showed multiple echo spots moving in the portal vein. Doppler signals confirmed them to be bidirectional and spiky, which immediately led to the diagnosis of portal gas. Immediate appropriate antibiotic treatment and biliary drainage yielded the disappearance of the portal gas. We stress the usefulness of US and Doppler US for detecting and diagnosing portal gas. Our observation suggests that when portal gas is detected by US, the possibility of cholangitis should be included in the differential diagnosis.


Behavioral evidence of heterospecific bonding between the lamb and the human caregiver and mapping of associated brain network.
While behavioral mechanisms of bonding between young mammals and humans have been explored, brain structures involved in the establishment of such processes are still unknown. The aim of the study was to identify brain regions activated by the presence of the caregiver. Since human positive interaction plays an important role in the bonding process, activation of specific brain structures by stroking was also examined. Twenty-four female lambs reared in groups of three were fed and stroked daily by a female caregiver between birth and 5-7 weeks of age. At 4 weeks, an isolation-reunion-separation test and a choice test revealed that lambs developed a strong bond with their caregiver. At 5-7 weeks of age, lambs were socially isolated for 90min. They either remained isolated or met their caregiver who stroked them, or not, at regular intervals over a 90-min period. Neuronal activation was investigated at the end of the period for maximum c-Fos expression. Reunion with the caregiver appeased similarly the lambs whether stroking was provided or not. Stroking did not activate a specific brain network compared to no stroking. In both cases, brain regions associated with olfactory, visual and tactile cue processing were activated in the presence of the caregiver, suggesting a multisensory process involved. In addition, activation of the oxytocinergic system in the hypothalamic paraventricular nucleus induced by the presence of the caregiver suggests similar neuroendocrine mechanisms involved in inter-conspecific and animal-human bonding.


Increased Body Mass Index Associated with Increased Risky Sexual Behaviors.
The increasing prevalence of adolescent obesity has led to consideration of the potential effect of obesity on risky sexual behaviors. In the current study we examined whether body mass index (BMI) was related to age at sexual debut, type of sexual behavior, partner number, and condom use in a population of adolescent women at high risk for obesity and risky sexual behaviors. Cross-sectional examination of 860 sexually active, predominantly minority, adolescent women who received medical care at an urban health center from 2007 through 2013. Self-reported age at sexual debut, types of sexual intercourse, number of partners and condom use was compared with clinically assessed BMI. BMI was positively associated with number of sexual partners (P = .001) and history of attempted anal intercourse (P = .002). An inverse association was observed with age at first anal intercourse (P = .040). In this sample of adolescent women, increased BMI was associated with riskier sexual practices at a younger age. Results of this study suggest that overweight and obese adolescents are a vulnerable population who might need targeted sexual health counseling.


Zwitterionic chitin nanocrystals mediated composite and self-assembly with cellulose nanofibrils.
Zwitterionic dispersed chitin nanocrystals and TEMPO oxidized cellulose nanofibrils can be well mixed and self-assembled to be hydrogels/membranes. Active carboxyl groups ensure the well mixing of zwitterionic chitin nanocrystals and cellulose nanofibrils under neutral and alkaline condition. Electrostatic attraction between amino groups in chitin nanocrystals and carboxyl groups in chitin nanocrystals and cellulose nanofibrils further endows self-assemble property of composite suspensions. Simple standing for 12 h at room temperature is found enough for preparing self-assembled composite hydrogels. By 1-(3-dimethy-laminopropyl)-3-ethylcarbodiimide hydrochloride/N-hydroxy succinimide (EDC/NHS) mediated chemical crosslinking, the storage modulus of composite hydrogel can achieve almost 8 times higher than self-assembled hydrogel. Well dispersed composite suspensions also can be transformed to be membranes via filtration treatment. The strain increases almost 2.3 times higher with similar tensile strength for cellulose nanofibril rich samples, and chitin nanocrystals mainly contributes to the enhancement in strain of composite membranes.


Raised erythrocyte creatine in patients with pulmonary arterial hypertension--evidence for subclinical hemolysis.
Pulmonary arterial hypertension (PAH) has been associated with hemolytic conditions such as sickle cell disease but the possible role of hemolysis in the pathogenesis or pathophysiology of other forms of PAH has not been studied. Erythrocyte lifespan is the gold-standard test of hemolysis and may be measured by assaying erythrocyte creatine (EC) levels. EC decreases as the erythrocyte ages, so patients with hemolysis have high EC levels. We measured EC and other parameters of hemolysis in patients with idiopathic and connective tissue associated PAH and normal controls. In patients with PAH (n = 40), EC levels were higher than in controls n = 30 (patients EC 1.72 mcmol/g HgB 95%CI[1.51, 1.96], controls EC 1.05 mcmol/g HgB [0.93, 1.19], p < 0.0001). High levels of EC correlated with worse 6 min walk (r = -0.42, p < 0.0001) and worse functional class (p = 0.002). Other indirect indices of hemolysis (total lactate dehydrogenase, red cell distribution width) were also increased in patients with PAH relative to controls. There is evidence of subclinical hemolysis in patients with PAH, and higher levels of hemolysis are associated with poorer exercise capacity.


Resveratrol alleviates cardiac apoptosis following exposure to fenitrothion by modulating the sirtuin1/c-Jun N-terminal kinases/p53 pathway through pro-oxidant and inflammatory response improvements: In vivo and in silico studies.
Fenitrothion (FNT), a commonly used organophosphate, can cause oxidative damage and apoptosis on various organs. However, the underlying mechanisms for FNT-induced cardiotoxicity did not formally report. Here, we have evaluated the possible ameliorative roles of resveratrol (RSV) against FNT-induced cardiac apoptosis in male rats through the sirtuin1 (SIRT1)/c-Jun N-terminal kinase (c-JNK)/p53 pathway concerning pro-oxidant and inflammatory cytokines. Forty-eight male rats were equally grouped into control, RSV (20 mg/kg), 5-FNT (5 mg/kg), 10-FNT (10 mg/kg), 20-FNT (20 mg/kg), 5-FNT-RSV, 10-FNT-RSV, and 20-FNT-RSV where all doses administrated by gavage for four weeks. The present findings demonstrated that RSV markedly diminished the level of hyperlipidemia and elevation in lactate dehydrogenase (LDH), total creatine kinase (CK-T), and troponin T (TnT) levels following FNT intoxication. Furthermore, RSV significantly reduced FNT-induced cardiac oxidative injury by reducing malondialdehyde (MDA) level and improving the levels of glutathione (GSH), glutathione reductase (GR), superoxide dismutase (SOD), catalase (CAT), and acetylcholinesterase (AchE). Also, the levels of interleukin-1β (IL1β,), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) were significantly attenuated in the co-treated groups. Moreover, RSV alleviated the histopathological changes promoted by FNT and repaired the transcript levels of SIRT1, c-JNK, and caspase-9/3 along with p53 immunoreactivity. In silico study revealed that the free binding energies of RSV complexes with protein and DNA sequences of SIRT1 were lower than docked complexes of FNT. Therefore, RSV reserved myocardial injury-induced apoptosis following exposure to FNT by modulating the SIRT1/c-JNK/p53 pathway through cellular redox status and inflammatory response improvements.


The History of Cortisone Discovery and Development.
Philip Hench, Edward Kendall, and Tadeus Reichstein received the Nobel Prize in medicine and physiology in 1950 for their "investigations of the hormones of the adrenal cortex." Hench and Kendall took compound E from the laboratory to the clinic to the Nobel Prize in a span of 2 years. This article examines the paths that led to the day when the first rheumatoid arthritis patient received cortisone, and from there to the 1950 Nobel Prize ceremony. The aftermath of this achievement is also discussed. Although there have been significant advances in corticosteroid preparations and use since 1950, the side effects remain daunting.


High-field atherosclerotic plaque magnetic resonance imaging.
Manifestations of atherosclerotic plaque in different arterial beds range from perfusion deficits to overt ischemia such as stroke and myocardial infarction. Atherosclerotic plaque composition is associated with its propensity to rupture and cause vascular events. Magnetic resonance (MR) imaging of atherosclerotic plaque using clinical 1.5 T scanners can detect plaque composition. Plaque MR imaging at higher field strengths offers both opportunities and challenges to improving the high spatial resolution and contrast required for this type of imaging. This article summarizes the technological requirements required for high-field plaque MR imaging and its application in detecting plaque components.


Application of a microbial siderophore desferrioxamine B in sunlight/Fe3+/persulfate system: from the radical formation to the degradation of atenolol at neutral pH.
The present work reported a modified persulfate activation process with a microbial siderophore named desferrioxamine B (DFOB). DFOB was a natural complexing agent and could complex with Fe3+ strongly. The photochemical reactivity of Fe(III)-DFOB was studied. Fe2+ and HO• were produced from Fe(III)-DFOB photolysis. Furthermore, the degradation of atenolol (ATL) was followed in light/persulfate (PS)/Fe(III)-DFOB system. The main oxidative radicals were SO4•- in this system. The results of pH effect showed that there was no obviously fluctuation on ATL degradation efficiency with the pH increased from 2.5 to 8.4. Moreover, kSO4•-,DFOB was determined by laser flash photolysis (LFP) experiments. DFOB had positive effect on Fe2+ formation but negative effect on ATL degradation due to the high react rate constant between DFOB and SO4•-. The effects of chloride and carbonate ion were also investigated. The results in this study proposed the reaction mechanism of the modified persulfate activation process, and it could be applied in neutral and weak-alkaline pH range.


Analbuminemia in a Slovak Romany (gypsy) family: case report and mutational analysis.
Analbuminemia is a rare autosomal recessive disorder manifested by the absence, or severe reduction, of circulating serum albumin. Here we report three new cases of hereditary analbuminemia, fortuitously detected in three Slovak Romany children, members of the same family, and define the molecular defect that causes the analbuminemic trait. Total DNA, extracted from peripheral blood samples from six members of the family, was PCR-amplified using oligonucleotide primers designed to amplify the 14 exons of the human albumin gene and the flanking intron regions. The products were screened for mutations by single-strand conformation polymorphism (SSCP) and heteroduplex analyses (HA). HA allowed the identification of the abnormal fragment, which was then sequenced. In the 3 patients the analbuminemic trait was caused by the same mutation, an AT deletion at nucleotides 2430-31, the 91 th and 92 th bases of exon 3. This defect, previously identified as Kayseri mutation, produces a frameshift leading to a premature stop, two codons downstream. The predicted translation product would consist of 54 amino acid residues. The parents were found to be heterozygous for the mutation. Our results confirm that the combination of SSCP and HA represents a powerful tool to study the molecular defects causing analbuminemia in humans.


[Characterization of hepatitis B virus strains from the Central African Republic: preliminary results].
Genotyping of Hepatitis B virus (HBV) strains from patients in Central African Republic and comparison with results obtained in other African countries. Sera were collected from patients admitted with symptoms of acute or chronic hepatitis to the "Hôpital de l'Amitié de Bangui", Central African Republic (CAR). The complete sequence of preS2/S gene has been defined for determining genotypes. Hundred and ninety-six sera were collected from 112 men and 84 women. Ninety-two percent of patients had contact with HBV (anti-HBc postitive) and the HBsAg prevalence was about 62%. HBV DNA was detected in 66% of HBsAg positive sera. No HBV-DNA was evidenced among patients with negative HBsAg. Ninety-three percent of the HBV strains belonged to genotype E; one (3.4%) belonged to genotype A1, and one (3.4%) belonged to genotype D. The high prevalence of HBV infection in the studied population is due to their recruitment. The genotype E is predominant in CAR and the intragroup variability of HBV genotype E reached only 1.8%. Genotypes A and D were less common in CAR their presence may be explained by importation.


Detection of Host Response to Viral Respiratory Infection by Measurement of Messenger RNA for MxA, TRIM21, and Viperin in Nasal Swabs.
Respiratory viruses frequently cause symptomatic infections in children but are often detected also in healthy children. We investigated myxovirus resistance protein A (MxA), viperin, and tripartite-motif 21 (TRIM21) messenger RNA indexes in nasal swabs as potential biomarkers of viral respiratory infection in children. Respiratory viruses were detected by polymerase chain reaction in the same swabs. Nasal MxA and viperin indexes were increased in symptomatic virus-positive children. Nasal viperin index was found to be a robust marker of viral respiratory tract infection with a sensitivity of 80% and specificity of 94% in distinguishing children with symptomatic virus infections from asymptomatic virus-negative children.


How effector-specific is the effect of sequence learning by motor execution and motor imagery?
The aim of the present study was twofold. First, we wanted to examine how effector specific the effect of sequence learning by motor execution is, and second, we wanted to compare this effect with learning by motor imagery. We employed a Go/NoGo discrete sequence production task in which in each trial a spatial sequence of five stimuli was presented. After a Go signal the corresponding spatial response sequence had to be executed, while after a NoGo signal, the response sequence had to be mentally imagined. For the training phase, participants were divided into two groups. In the index finger group, participants had to respond (physically or mentally) with the left or right index finger, while in the hand group they had to respond with four fingers of the left or right hand. In a final test phase both execution modes were compared and all trials had to be executed. Response times and the percentage of correct responses were determined to establish learning effects. Results showed that sequence learning effects as assessed in the test phase were independent of the effector used during the training phase. Results revealed the presence of aspecific learning effects in the case of learning a required motor task with an index finger, but sequence-specific learning effects, both due to motor execution and to motor imagery, were not effector specific.


Illness Experiences of Adults with Spina Bifida: Protecting the Whole Self.
To understand and describe the illness experiences of adults with spina bifida (SB) which is an incurable birth defect and chronic condition that must be managed throughout life. A qualitative study using grounded theory was adopted. Data were collected through individual interviews with 16 adults with SB between 2016 and 2017 in South Korea. All interviews were audiotaped, and the transcribed data were analyzed using constant comparative analysis. The basic socio-psychological process that underlies the illness experiences of adults with SB was identified as protecting the whole self. This consists of three stages: strict self-concealment, attempting self-disclosure, and balancing between self-concealment and self-disclosure. These stages reveal a process of establishing a firm sense of self by freeing oneself from the shame and stigma of society. Three different patterns of living emerged as a result: living as a non-disabled person, living as a marginal person between non-disabled and disabled, and living as a disabled person. Adults with SB struggle to protect their whole self while managing their chronic conditions by having to constantly balance between self-concealment and self-disclosure. Intervention for adults with SB needs to be based on the stage of sociopsychological maturation. In the early stage, intervention needs to be focused on self-concealment to help establish a firm sense of self. On the other hand, in the later stage when psychological maturity occurs, an intervention that focuses on self-disclosure would be helpful so as not to be isolated from society.


Steroidogenic changes and steady state amount of messenger RNA encoding steroidogenic enzymes, gonadotropin receptors and cell-death signalling in the dominant ovarian follicle during estradiol-induced atresia in cattle.
Changes in steroidogenic function and associated gene expression were characterized in dominant ovarian follicles (DF) of cattle where follicles were induced to become atretic by systemic administration of estradiol benzoate (EB). In experiment 1, follicular fluid (FF) steroid concentrations in the DF were measured at 12-hourly time points for 48 h in heifers treated with 1 mg EB i.m./500 kg body weight (EB; n=20) as compared with untreated controls (C; n=19). Treatment with EB promoted a transient reduction in circulating FSH, a rapid (12 h) and sustained reduction in FF estradiol, a rapid (12 h) but transient reduction in FF progesterone and a delayed (36 h) increase in FF testosterone concentrations. In experiment 2, whole follicular wall tissue was collected from DF of mature non-lactating cows allocated to a 0 h control group (0 HC: n=7), a 24h control group (24 HC; n=7) or an EB-treated group where tissue was collected 24 h after administration of 1 mg EB i.m./500 kg body weight (EB; n=8). As for experiment 1, EB promoted a transient reduction in circulating FSH, a pronounced reduction in FF estradiol and a smaller but significant reduction in FF progesterone concentrations. Semi-quantitative RT-PCR on follicular wall tissue revealed that the loss in estrogen activity at 24 h after EB was associated with two-fold reduction in aromatase mRNA, with an apparent acceleration in loss of 17alpha-hydroxylase mRNA. Expression of genes for gonadotropin receptors (LHR and FSHR) and a cell-death signalling pathway (Fas antigen and Fas ligand) were unchanged during the initial 24h of EB-induced atresia. These results suggest that EB initiates atresia in dominant ovarian follicles through a rapid suppression of follicular estradiol synthesis, an effect associated with down-regulation of the aromatase gene. A transient suppression in circulating FSH following administration of EB appears to have initiated these events, and it is suggested that subsequent processes involved in atresia follow this loss in estrogenic function.


Soluble interleukin-2 receptor and cellular profiles in bronchoalveolar lavage fluid from patients with bronchial asthma.
To elucidate the role of T-cell activation in the physiologic changes and cellular infiltrations in the bronchial tree of patients with symptomatic bronchial asthma, we measured the concentration of soluble interleukin-2 receptor (sIL-2R), cellular compositions and IL-2R expression on cells in bronchoalveolar lavage (BAL) fluid. We also measured physiologic parameters, including a provocation concentration of histamine required to reduce the forced expiratory volume in 1 second by 20% of the prechallenge baseline (PC20). The concentration of sIL-2R and the ratio of IL-2R expression on CD3 positive lymphocytes were significantly higher in BAL fluid from 20 patients with symptomatic bronchial asthma than concentrations in fluid from nine healthy controls (p < 0.01) and six asymptomatic patients with bronchial asthma (p < 0.05). The concentration of sIL-2R correlated with the percentage of IL-2R expression on CD3 positive lymphocytes (rs = 0.709, p < 0.01). There was no difference in sIL-2R concentration of BAL fluid between the healthy control and the patient with asymptomatic bronchial asthma. Among the inflammatory cells recovered in BAL fluid, the percentages of eosinophils showed significant positive correlation with the concentration of sIL-2R in BAL fluid in the patients with bronchial asthma. The concentration of sIL-2R significantly correlated with forced expiratory volume one second, peak expiratory flow rate, and PC20 when observed in all study subjects, but not in the patients with bronchial asthma. We conclude that T-cell activation within the bronchial tree appears to have a role in the infiltration of eosinophils into the bronchial tree, which may lead to enhanced bronchial hyperreactivity in patients with bronchial asthma.


Biocompatibility of N-(2-hydroxypropyl) methacrylamide copolymers containing adriamycin. Immunogenicity, and effect on haematopoietic stem cells in bone marrow in vivo and mouse splenocytes and human peripheral blood lymphocytes in vitro.
N-(2-hydroxypropyl)methacrylamide polymeric prodrugs containing adriamycin bound to polymers via glycylphenylalanylleucylglycine side chains and, in one case, galactosamine bound via the same sequence, were tested for immunogenicity after intravenous, subcutaneous and oral application in two inbred strains of mice. The serum antibody level was determined by enzyme-linked immunoassay on the 3rd and 6th day after the last treatment. It was found that antibodies were only produced in very small amounts. In some experimental groups, the antibody titres measured following administration of copolymer conjugate were comparable with those present in non-treated controls. Attachment of adriamycin to N-(2-hydroxypropyl)methacrylamide copolymer considerably decreased its toxicity against haematopoietic precursors in bone marrow as measured by the in vivo colony-forming unit-spleen assay and its ability to inhibit [3H] thymidine incorporation by mouse splenocytes and human peripheral blood lymphocytes measured in vitro.


Quantitative 1H NMR with global spectral deconvolution approach for quality assessment of natural and cultured Cordyceps sinensis.
Cordyceps sinensis is a precious medicinal food which has been successfully cultivated indoors. It remains to be investigated for a simultaneous comparison on aqueous components of natural and cultivated samples. Herein, an approach of quantitative nuclear magnetic resonance (qNMR) analysis combined with global spectral deconvolution (GSD) was established for simultaneous quantification of 26 aqueous components in C. sinensis. Processed by GSD, the distorted baselines of 1H NMR spectra were greatly improved, and overlapped signals were also well separated so as to achieve accurate identification and quantitation of components in C. sinensis. Method validation by UHPLC-QTOF-MS and TOF-SIMS analysis revealed that qNMR combined with GSD is a reliable approach for simultaneous quantification of multiple components including characteristic markers of glutamine, GABA and trehalose in authentic and fake C. sinensis. The well-established qNMR approach can be used for quality assessment of natural and cultivated C. sinensis as well as differentiation from fake ones.


Improved liver function and decreased hepatitis C viral load after tacrolimus was replaced by cyclosporine.
Potential antiviral properties of cyclosporine against hepatitis C virus have been highlighted in several publications. Therefore, we investigated the effect of a switch from tacrolimus to cyclosporine in a liver transplant recipient with recurrent hepatitis C who did not respond to antiviral therapy. The patient received a liver transplant for hepatitis C cirrhosis. Initial immunosuppressive treatment was based on tacrolimus. Because of viral activity, a combined therapy was initiated 20 months later including interferon and ribavirine. Then, due to a lack of virological and biochemical response, tacrolimus was replaced by cyclosporine (Neoral), while maintaining the same antiviral therapy. Decreases in the viral load and transaminases levels were observed.


Phenotypic variation of native chicken populations in northwest Ethiopia.
Seven indigenous chicken populations were identified and characterized from four administrative zones in northwest Ethiopia. A total of three hundred chickens were characterized under field conditions for qualitative and quantitative traits following standard chicken descriptors. Large phenotypic variability among chicken populations was observed for plumage color. About 25.49, 22.3, and 16.4 % of the chickens have white, grayish and red plumage colors, respectively. The rest showed a considerable heterogeneity like black, multicolor, black with white tips, red brownish and white with red striped plumage colors. The following characteristics were also displayed: plain head shape (51.18%), yellow shank color (64.42%) and pea comb (50.72%). About 97.52% of the chickens did not have feathers on their legs. Variations were also observed on quantitative characters such as shank length, egg size and body weight and other reproductive traits characterized on intensive management system.


Paxillin enables attachment-independent tyrosine phosphorylation of focal adhesion kinase and transformation by RAS.
Paxillin and HIC5 are closely related adapter proteins that regulate cell migration and are tyrosine-phosphorylated by focal adhesion kinase (FAK). Paxillin, HIC5, and FAK tyrosine phosphorylation increase upon cell attachment and decrease upon detachment from extracellular matrix. Unexpectedly, we found that although FAK tyrosine phosphorylation in attached cells did not require paxillin, in detached fibroblasts there was remaining FAK tyrosine phosphorylation that required expression of paxillin and was not supported by HIC5. The support of attachment-independent FAK tyrosine phosphorylation required the paxillin LIM domains and suggested that paxillin might facilitate oncogenic transformation. Paxillin but not HIC5 augmented anchorage-independent cell proliferation induced by RAS. Both anchorage-independent FAK tyrosine phosphorylation and RAS-induced colony formation required multiple docking sites on paxillin, including LD4 (docking sites for FAK-Src and GIT1/2-PIX-NCK-PAK complex), LD5, and all four carboxyl-terminal LIM domains (that bind tubulin and PTP-PEST). Analysis using paxillin mutants dissociated domains of paxillin that are required for regulation of cell migration from domains that are required for anchorage-independent cell proliferation and demonstrated essential functions of the paxillin LIM domains that are not found in HIC5 LIM domains. These results highlight the role of paxillin in facilitating attachment-independent signal transduction implicated in cancer.


Evolutionary trends of the COVID-19 epidemic and effectiveness of government interventions in Nigeria: A data-driven analysis.
Nigeria became the first sub Saharan African country to record a case of COVID-19 after an imported case from Italy was confirmed on February 27, 2020. Moving averages and the Epidemic Evaluation Indices (EEI) are two important but complementary methods useful in monitoring epidemic trends, they can also serve as a useful guide for policy makers and inform the timing of decisions on preventive measures. The objectives of this paper are to graphically depict the trends of new COVID-19 cases nationally and in two key States (Lagos and Kano) and the Federal Capital Territory (FCT) using the moving averages and the EEI. In addition, we examined the effects of government's public health interventions on the spread of COVID-19 and appraise the progress made so far in addressing the challenges of COVID-19 in Nigeria. We used data on new cases of COVID-19 from public sources released by the Nigeria Center for Disease Control (NCDC) from the 27th February 2020, when the first case was recorded, to 11th May, 2020, one week after the lockdowns in Lagos and the FCT were lifted. We computed moving averages of various orders, the log transformations of the moving averages and then the EEIs of new COVID-19 cases for Nigeria as a whole, and then for two of the most affected states i.e. Lagos and Kano, as well as the Federal Capital Territory (FCT). Then, we plotted graphs to depict these indices and show the epidemic trends for COVID-19 in each scenario. Nationally, the number of new cases of COVID-19 showed an initial gradual rise from the first reported case on the 27th February 2020. However, by the second week in April, these numbers began to show a relatively sharper increase and this trend has continued till date. Similar trends were observed in Lagos state and the FCT. The rate of growth of the logarithm-transformed moving average in the period leading to, and including the lockdowns reduced by a factor of 0.65. This suggests that the policies put in place by the government including the lockdown measures in Lagos and the FCT may have had a positive effect on the development of new cases of COVID-19 in Nigeria. Nationally and in Lagos, the EEIs of the COVID-19 cases started off on very high notes, however, the effects of the lockdown gradually became evident by the end of April and early May 2020, as the EEIs headed closer to 1.0. In all case scenarios, the EEIs are still above 1.0. The number of new cases of COVID-19 has been on a steady rise since the first reported case. In Nigeria especially across the two states and the FCT, public health interventions including the lockdown measures appear to have played a role in reducing the rate of increase of new infections. The EEIs are still above 1.0, suggesting that despite the progress that appears to have been made, the epidemic is still evolving and Nigeria has not yet reached her peak for COVID-19 cases. We recommend that aggressive public health interventions and restrictions against mass gatherings should be sustained.


Serious systemic toxicity resulting from use of tetracaine for pharyngeal anesthesia in upper endoscopic procedures.
Three cases of serious systemic toxicity from tetracaine pharyngeal anesthesia for upper endoscopic procedures are described. The pathophysiologic basis for systemic toxicity is discussed and a recommendation for preendoscopic anesthesia is provided.


Utility of a Single Itch-Related Question and the Skindex-10 Questionnaire for Assessing Pruritus and Predicting Health-Related Quality of Life in Patients Receiving Hemodialysis.
Chronic kidney disease-associated pruritus has been linked with poorer mental and physical health-related quality of life (HR-QOL) in patients receiving hemodialysis. We used the Skindex-10 questionnaire and a single itch-related question to evaluate their prediction of HR-QOL. Prospective, international cohort. We analyzed data from 4,940 patients receiving hemodialysis from 17 countries enrolled in phase 5 (2013) of the Dialysis Outcomes and Practice Patterns Study. The responses to the 10 questions of Skindex-10 (0-6 scale) pertaining to itchiness in the past week were summed to create a summary score (range, 0-60). Concurrently, a single question from the Kidney Disease Quality of Life 36-item survey asked "during the past 4 weeks, to what extent were you bothered by itchy skin?" with 5 responses, ranging from "not at all" to "extremely" bothered. Physical component summary (PCS) and mental component summary (MCS) scores of HR-QOL. We used separate linear regression models to evaluate the predictive power, based on R2 values, for 3 models: 1 for each predictor and 1 with both predictors. The correlation between the single itch-related question and the Skindex-10 score was 0.72. A 10-point higher Skindex-10 score was associated with a 1.2-point lower PCS score (95% CI, -1.4 to -0.9) and a 1.5-point lower MCS score (95% CI, -1.7 to -1.3) . The R2 value for PCS was 0.065 when the single question was used and only 0.033 when Skindex-10 was used as the predictor; the R2 value for MCS was 0.056 for the single question versus 0.052 for Skindex-10. Measurement bias and translation issues in the questionnaires. The single question about the extent to which the patients were bothered by itchy skin was highly correlated with the Skindex-10 score and at least as predictive of key HR-QOL measures. In daily clinical practice, using 1 simple question about the extent to which patients are bothered by itchy skin can be a feasible and efficient method for the routine assessment of pruritus.


Kinetic characterization of oxyresveratrol as a tyrosinase substrate.
Oxyresveratrol is a stilbenoid described as a powerful inhibitor of tyrosinase and proposed as skin-whitening and anti-browning agent. However, the enzyme is capable of acting on it, considering it as a substrate, as it has been proved in the case of its analogous resveratrol. Tyrosinase hydroxylates the oxyresveratrol to an o-diphenol and oxidizes the latter to an o-quinone, which finally isomerizes to p-quinone. For these reactions to take place the presence of the Eox (oxy-tyrosinase) form is necessary. The kinetic analysis of the proposed mechanism has allowed the kinetic characterization of this molecule as a substrate of tyrosinase, affording a catalytic constant of 5.39 ± 0.21 sec(-1) and a Michaelis constant of 8.65 ± 0.73 µM.


Bacterial mineralization of chromium-copper spinel with highly performance in electroplating effluent.
Cr (VI) contamination has posed severe challenges to water quality, food safety, and land resources. Microbial reduction of Cr(VI) to Cr(III) has drawn considerable attention due to its low cost and environmental friendliness. However, recent reports have shown that Cr(VI) generates highly migratable organo-Cr(III) rather than stable inorganic chromium minerals during the biological reduction process. In this work, it was reported for the first time that spinel structure CuCr2O4 was formed by Bacillus cereus in Cr biomineralization process. Different from known biomineralization models (biologically controlled mineralization and biologically induced mineralization), the chromium-copper minerals here appeared as specialized minerals with extracellular distribution. In view of this, a possible mechanism of biologically secretory mineralization was proposed. In addition, Bacillus cereus demonstrated a high conversion ability in the treatment of electroplating wastewater. The Cr(VI) removal percentage reached 99.7%, which satisfied the Chinese emission standard of pollutants for electroplating (GB 21,900-2008), indicating its application potential. Altogether, our work elucidated a bacterial chromium spinel mineralization pathway and evaluated the potential of this system for application in actual wastewater, opening a new avenue in the field of chromium pollution treatment and control.


Infusion-rate independent cellular adriamycin concentrations and cytotoxicity to human bone marrow clonogenic cells (CFU-GM).
The effect of adriamycin (ADM) infusion-rate on cellular ADM concentrations and on clonogenicity of human haematopoietic cells was studied in vivo and in vitro. In patients an ADM dose of 30 mg m-2 was administered as a bolus injection, or as a 4 h or a 24 h infusion. In vitro the effect of ADM on clonogenic cell growth was determined after exposure during 5 min, 2 h and 24 h of human bone marrow cells to increasing ADM concentrations. ADM showed rapid intracellular accumulation, to levels 100-fold the plasma concentration in vivo or the incubation medium concentration in the in vitro experiments. After a bolus injection or 5 min exposure only approximately 10% of the cellular peak ADM was retained after elimination of the drug from the plasma or the incubation medium. Ninety percent of the ADM was apparently 'loosely' bound. After 4 h and 24 h constant-rate infusions and also after 2 h and 24 h incubations in vitro, the cells accumulated ADM gradually, and the subsequent washing-out of the cellular ADM was substantially less, most of the ADM being 'tightly' bound. Despite these different patterns of uptake and retention after in vivo short- and long-lasting infusion of the same total dose, the 'tightly-bound' cellular ADM concentrations were the same. Moreover, comparable cellular ADM concentrations, retained after efflux of the 'loosely-bound' cellular ADM fraction were equally cytotoxic to normal human clonogenic cells. Short-lasting cellular peak ADM concentrations which occur after a bolus injection or after short exposure to high ADM concentrations are not essential for the cytotoxic effect, in contrast to the retained, 'tightly-bound' cellular ADM levels.


Composite faces are not processed holistically: evidence from the Garner and redundant target paradigms.
Composite faces fuse the top half of one face with the bottom half of another. These stimuli inflict a strong illusion of a novel face on their viewers, and are often considered to be processed holistically. The current study challenges this holistic view. Here I present provocative evidence from various classic attention paradigms such as the Garner (1974) and the redundant target (Miller, Cognitive Psychology, 14, 247-279, 1982; Townsend & Nozawa, Journal of Mathematical Psychology, 39, 321-359, 1995) tasks showing that face parts are perceived and processed in an analytic rather than holistic fashion. In Experiment 1, composite faces failed to exhibit Garner interference, indicating perfect selective attention to the constituent parts. In Experiments 2 and 3, composite faces failed to exhibit super-capacity with same-identity composites, demonstrating limited or unlimited capacity. This pattern is consistent with analytic perception. Taken together, the results cast serious doubts on the validity of the holistic processing approach. In many respects, the study proposes disillusionment from the composite face illusion. In addition, the study highlights the importance of converging operations, model testability, and individual differences in the study of faces.


Hypofractionated-intensity modulated radiotherapy (hypo-IMRT) and temozolomide (TMZ) with or without bevacizumab (BEV) for newly diagnosed glioblastoma multiforme (GBM): a comparison of two prospective phase II trials.
To compare progression-free (PFS) and overall survival (OS) in patients treated in two consecutive phase II trials of hypofractionated-intensity modulated radiotherapy (hypo-IMRT) and temozolomide (TMZ) with or without bevacizumab (BEV). Patients with newly diagnosed glioblastoma multiforme (GBM) after biopsy or resection were enrolled on a clinical trial with hypo-IMRT and TMZ (hypo-IMRT/TMZ alone) from 2008 to 2010, or in the second protocol with the same hypo-IMRT and TMZ plus BEV (hypo-IMRT/TMZ/BEV) from 2010 to 2013. All patients received postoperative hypo-IMRT to the surgical cavity and residual tumor plus margin to a total dose of 60 Gy and to the T2 abnormality with margin to 30 Gy, both in ten fractions. Concurrent TMZ (75 mg/m(2)/day) was given to all patients for 28 consecutive days followed by adjuvant TMZ (150-200 mg/m(2)/day). Patients enrolled on the hypo-IMRT/TMZ/BEV trial received concurrent and adjuvant BEV (10 mg/kg) on days 1 and 15 of each 28-day cycle. Hazard ratios of PFS and OS were compared between trials in a Cox proportional hazards model. Twenty-six patients were enrolled on the hypo-IMRT/TMZ alone trial and 30 patients on the hypo-IMRT/TMZ/BEV trial. Median follow-up was 13.9 and 14.7 months, respectively. Median PFS was 3.4 months longer with hypo-IMRT/TMZ/BEV but the difference was not statistically significant (12.8 vs. 9.4 months, p = 0.58). Median (OS) was 16.3 months for both trials. The addition of BEV to TMZ and hypo-IMRT did not improve OS for patients with GBM in two phase II trials with small patient numbers; PFS was longer with BEV, but the difference was not statistically significant.


In-silico driven design and development of spirobenzimidazo-quinazolines as potential DNA gyrase inhibitors.
DNA gyrase and Topoisomerase IV are promising antibacterial drug targets as they regulate bacterial DNA replication and topology. In a quest for novel DNA topoisomerase inhibitors, a multidisciplinary approach was adopted that involves computational prediction of binding sites and molecular modelling followed by green synthesis and biological evaluation of antibacterial activity of spirobenzimidazo quinazolines derivatives. Using basic quantum chemistry principles, we evaluated spirobenzimidazo quinazolines derivatives with their pharmacokinetic profiles. Based on the results of the aforesaid in-silico studies, we synthesized a series of titled compounds using green synthetic methodology that were validated as potential antimicrobial agents. Quantum chemoinformatics based predicted activity for the synthesized compounds 9b, 9c, and 9j was concomitant with biological evaluation of broadspectrum antibacterial activity. Biological evaluation revealed that inhibition of biofilm formation was due to their potential antibacterial activity. We believe that the novel spirobenzimidazo quinazolines have the potential to be alternatives to aminocoumarins and classical quinazolines upon detailed target specific biological studies.


Cardiovascular responses to human calf muscle stretch during varying levels of muscle metaboreflex activation.
The purpose of the present study was to investigate the cardiovascular responses to muscle metaboreflex- and concurrent muscle stretch-induced mechanoreflex activation. Eight subjects (7 males, 1 female) performed 90 s of isometric calf plantarflexion at 0, 30, 50 and 70% of maximum voluntary contraction. During exercise and for 3.5 min postexercise, circulatory occlusion (PECO) was ensured by inflation of a thigh cuff. After 90 s of PECO the calf muscle was stretched for 60 s (Stretch). Heart rate (HR; assessed from ECG), blood pressure (BP; Finapres) and phase of respiratory cycle were recorded. Exercise increased diastolic BP (DBP) from rest by 1+/-0.8, 14+/-2.5, 29+/-3.9 and 35+/-3.6 mmHg, during the 0, 30, 50 and 70% conditions, respectively (ANOVA rest versus exercise, P<0.05). During PECO DBP remained elevated, by 2+/-0.4, 8+/-0.3, 12+/-0.3 and 13+/-0.9 mmHg, respectively. Stretch produced a further increase in DBP that was not different between conditions (3+/-1.4, 2+/-0.8, 3+/-1.0 and 3+/-0.9 mmHg, for the 0, 30, 50 and 70%, respectively). HR increased during exercise but returned to baseline during PECO. HR increased at Stretch onset in all conditions. No EMG was detected from the gastrocnemius and soleus during Stretch. Our data show that the cardiovascular responses to human calf Stretch are independent of the level of concurrent muscle metaboreflex activation.


Radiation exposure before and after the introductionof a dedicated total-body CT protocolin multitrauma patients.
Total-body CT (TBCT) scanning in trauma patients is being increasingly used in trauma assessment. One of the major disadvantages of CT scanning is the amount of radiation exposure involved. The aim of this study was to assess the number of radiological investigations and their associated radiation exposure in multitrauma patients before and after the introduction of a total-body CT protocol as a primary diagnostic tool. The Trauma Registry was used to identify trauma patients admitted to our Level 1 trauma centre in 2008 (pre-TBCT protocol) and 2010 (post-TBCT protocol). Consecutive patients with an Injury Severity Score of ≥16 were included. Patients aged 16 or under, referrals from other hospitals and patients with specific low-energy injury mechanisms were excluded. Subsequent effective doses were estimated from literature and from dose calculations. Three hundred one patients were included, 150 patients pre- and 151 post-introduction of the TBCT protocol. Demographics were comparable. In 2008, 20 % of severely injured patients underwent total-body CT scan, compared with 46 % of the patients in 2010. Trauma room radiation doses for conventional radiographs were significantly higher in 2008, while doses for CT scans were significantly lower. The total effective dose of trauma room radiological investigations was 16 milliSieverts (mSv) in 2008 vs. 24 mSv in 2010 (P = 0.223). The overall effective dose during the total hospital admission was not significantly different between 2008 and 2010 (20 vs. 24 mSv, P = 0.509).In conlusion, after the introduction of a dedicated TBCT protocol, the TBCT rate was more than doubled. Although this increased the CT-induced trauma room radiation dose, the overall radiation dose throughout hospital admission was comparable between patients in 2008 and 2010.


Medical students proposing questions for their own written final examination: evaluation of an educational project.
In order to emphasise learning more than control, from autumn 2000 we have invited medical students to propose questions for their own written examination in family medicine. One out of three student's proposals was guaranteed to be a part of their coming written examination, possibly somewhat modified. To evaluate how sixth year medical students experienced the project, and to what extent their performance in the examination was influenced. Sixth year medical students. The project was evaluated using (i) marks in examination; (ii) scores on self-administered questionnaires; and (iii) students' free text evaluation. Fifty-seven of 64 (89%) students taking their examination in autumn 2000, and 56 of 59 (95%) students taking the exam in spring 2001, responded. In autumn 2000, 34 (60%) students reported that the project had changed their learning strategies. During spring 2001, 46 of 56 students participated in producing questions, using a mean of 2.6 hours on the work. Students got 5-7% higher marks on their own questions on a scale ranging from 1 to 12. The students' free text evaluation showed that they had prepared especially thoroughly for the topics proposed by the students. They found it comforting to know at least one of the questions in the examination, and the students' questions were found relevant for general practice. Encouraging students to write questions for their own examination makes them feel more confident during the examination period, and may increase their reflective learning, without seriously limiting topics studied or violating the control function of the examination.


Light regulation of potassium in plants.
Essential macronutrient potassium (K) and environmental signal light regulate a number of vital plant biological processes related to growth, development, and stress response. Recent research has shown connections between the perception of light and the regulation of K in plants. Photoreceptors-mediated wavelength-specific light perception activates signaling cascades which mediate stomatal movement by altering K+influx/efflux via K+ channels in the guard cells. The quality, intensity, and duration of light affect the regulation of K nutrition and crop quality. Blue/red illumination or red combined blue light treatment increases the expression levels of K transporter genes, K uptake and accumulation, leading to increased lycopene synthesis and improved fruit color in tomato. Despite the commonalities of light and K in multiple functions, our understanding of light regulation of K and associated physiological and molecular processes is fragmentary. In this review, we take a look at the light-controlled K uptake and utilization in plants and propose working models to show potential mechanisms. We discuss major light signaling components, their possible involvement in K nutrition, stomatal movement and crop quality by linking the perception of light signal and subsequent regulation of K. We also pose some outstanding questions to guide future research. Our analysis suggests that the enhancement of K utilization efficiency by manipulation of light quality and light signaling components can be a promising strategy for K management in crop production.


The TP53 p.R337H mutation is uncommon in a Brazilian cohort of pediatric patients diagnosed with ependymoma.
Ependymoma (EPN) is the third most common childhood cancer of the central nervous system. RELA fusion-positive EPN accounts for approximately 70% of all childhood supratentorial tumors and shows the worst prognosis among the supratentorial EPNs. TP53 mutation is infrequent in RELA fusions EPNs. In the population from the Southern region of Brazil, there is a high incidence of the germline TP53 p.R337H mutation that predisposes carriers to develop early-onset tumors. However, despite this high incidence, the frequency of this mutation among EPN patients remains to be determined. Here, we investigated the presence of the TP53 p.R337H mutation in a larger cohort of pediatric EPNs of three institutions located in the state of São Paulo, Brazil. The TP53 p.R337H mutation was screened by conventional RT-PCR and Sanger sequencing in 49 pediatric EPNs diagnosed during the period from 1995 to 2016. We described for the first time a case of a 5-year-old girl with RELA fusion EPN with a heterozygous TP53 p.R337H mutation. The present finding indicates that the TP53 p.R337H germline mutation is uncommon in patients with EPN in Brazil and screening of pediatric patients RELA fusion EPN may be informative to better understand the role of TP53 germline mutations in the development and prognosis of these tumors.