Distinct role of calmodulin and calmodulin-dependent protein kinase-II in lipopolysaccharide and tumor necrosis factor-alpha-mediated suppression of apoptosis and antiapoptotic c-IAP2 gene expression in human monocytic cells.
Exposure of phagocytic cells to bacterial endotoxin (lipopolysaccharide; LPS) or inflammatory cytokines confers antiapoptotic survival signals; however, in the absence of the appropriate stimulus, monocytes are programmed to undergo apoptosis. Macrophage survival may thus influence inflammatory and immune responses and susceptibility to microbial pathogens. Herein, we demonstrate that LPS and the proinflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), enhance monocytic cell survival through the induction of the antiapoptotic c-IAP2 gene in a human promonocytic THP-1 cell line. We also investigated the role of upstream signaling molecules including the mitogen-activated protein kinases, phosphatidylinositol 3-kinase, and the calcium signaling pathways in the regulation of c-IAP2 expression and eventual survival of monocytic cells. Our results suggest that LPS and TNF-alpha-induced c-IAP2 expression was regulated by calmodulin (CaM) through the activation of calmodulin-dependent protein kinase-II (CaMKII). In addition, CaM and CaMKII regulated c-IAP2 expression in LPSand TNF-alpha-stimulated cells through NF-kappaB activation. Moreover, the CaM/CaMKII pathway also regulated LPS- and TNF-alpha-mediated inhibition of apoptosis in these cells. Taken together, these results suggest that LPS- and TNF-alpha-induced c-IAP2 expression and its associated antiapoptotic survival signals in THP-1 cells are regulated selectively by CaM/CaMKII through NF-kappaB activation.


Dynamic correlation between CTL response and viral load in primary human immunodeficiency virus-1 infected Koreans.
HIV-1 specific cytotoxic T lymphocytes (CTLs) have an important role as antiviral effector cells for controlling HIV-1 infection. To investigate CTL response during the early stage of HIV infection, we measured immunity-related factors including CD4+ T cell counts, CD8+ T cell counts, HIV-1 RNA viral loads and IFN-γ secretion according to CTL response in 78 selected primary HIV-1-infected Koreans. The CTL response was strongly induced by HIV-1 specific Gag and Nef peptides (p = 0.016) compared with induction by Tat or Env peptides. These results suggest that the major antiviral factors inducing strong HIV-specific CTL responses are associated with the Gag and Nef viral regions in primary HIV-1 infected Koreans. The relationship between viral load and CTL response showed varying correlations with time following HIV infection. CTL response was inversely correlated with viral loads at preseroconversion stage I (r = -0.224 to -0.33) and changed to a positive correlation at the preseroconversion stage II (r = 0.132 to 0.854). Finally, it changed to an inverse correlation again after seroconversion until a viral set point was established on serological profiling (r = -0.195 to -0.407). These findings demonstrate a dynamic correlation between viral load and subsequent CTL responses during early HIV infection.


Metabolic modes of action of the statins in the hyperlipoproteinemias.
Conflicting results have been published during the past few years regarding the physiologic modes of action of the hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors, generally referred to as statins, using standard doses. Three mechanisms have been described: increased LDL catabolic rate, increased removal of LDL precursors resulting in decreased LDL production and decreased VLDL production. The physiologic effects of statins seem to depend on the underlying pathology of the disorders under therapy. More recent data using either the more potent atorvastatin or larger doses of previously available statins (e.g. simvastatin 80-160 mg/day), suggest that both the potency of the statins and the underlying pathopHysiology are important in determining the predominant physiologic responses of patients. To understand physiologic responses more completely, drug-dose-physiologic response curves of apo B kinetics in various groups of patients are needed. Simultaneous studies of apo B, triglycerides and cholesterol metabolism are also needed and are currently feasible.


Solitary neurofibroma of the spermatic cord.
We report a case of solitary neurofibroma of the spermatic cord. Such benign tumors arise from perineural and Schwann cells and may be located in various parts of the body, but are rarely observed in the spermatic cord. No clinical or laboratorial manifestations of von Recklinghausen disease (Neurofibromatosis) were identified. Distinct criteria have been established for a diagnosis of von Recklinghausen disease, so that a solitary neurofibroma may not represent this complex. Only a little number of solitary neurofibromas of the spermatic cord are reported in the literature.


Dynamic causal modeling of eye gaze processing in schizophrenia.
Abnormal eye gaze perception is related to symptoms and social functioning in schizophrenia. However, little is known about the brain network mechanisms underlying these abnormalities. Here, we employed dynamic causal modeling (DCM) of fMRI data to discover aberrant effective connectivity within networks associated with eye gaze processing in schizophrenia. Twenty-seven patients (schizophrenia/schizoaffective disorder, SZ) and 22 healthy controls (HC) completed an eye gaze processing task during fMRI. Participants viewed faces with different gaze angles and performed explicit gaze discrimination (Gaze: "Looking at you?" yes/no) or implicit gaze processing (Gender: "male or female?"). Four brain regions, the secondary visual cortex (Vis), posterior superior temporal sulcus (pSTS), inferior parietal lobule (IPL), and posterior medial frontal cortex (pMFC) were identified as nodes for subsequent DCM analysis. SZ and HC showed similar generative model structure, but SZ showed altered connectivity for specific self-connections, inter-regional connections during all gaze processing (reduced excitatory bottom-up and enhanced inhibitory top-down connections), and modulation by explicit gaze discrimination (increased frontal inhibition of visual cortex). Altered effective connectivity was significantly associated with poorer social cognition and functioning. General gaze processing in SZ is associated with distributed cortical dysfunctions and bidirectional connectivity between regions, while explicit gaze discrimination involves predominantly top-down abnormalities in the visual system. These results suggest plausible neural mechanisms underpinning gaze processing deficits and may serve as bio-markers for intervention.


Seasonal variation in onset of pulmonary embolism is independent of patients' underlying risk comorbid conditions.
As for many cardiovascular events, pulmonary embolism (PE) is not randomly distributed over time, but shows rhythmic patterns. The purpose of this study was to investigate whether such temporal pattern of occurrence varied in subgroups of patients according to different risk comorbid conditions. All cases of PE observed at the Hospital of Ferrara, Italy, from 1998 to 2001, were considered. After determination of the day of onset, the population was grouped by gender and the most common underlying risk comorbid conditions, e.g., deep vein thrombosis (DVT), neoplasms, cardiomyopathies, traumas/surgical operations, diabetes mellitus, pulmonary diseases, hypertension, cerebrovascular diseases, heart failure, hematologic diseases. For statistical analysis, chi-square test for goodness of fit and partial Fourier series were used. A total of 784 cases (mean age 71 +/- 14 years) were included. Frequency of onset was higher in winter for total population (p = 0.002), men (p = 0.004), DVT (p = 0.001), pulmonary disease (p = 0.008), cardiomyopathies (p = 0.011), and major traumas/surgical operations (p = 0.049). Chronobiologic analysis identified a winter peak for total population (p = 0.008), men (p < 0.001), DVT (p = 0.006), pulmonary diseases (p = 0.017), and hypertension (p = 0.026). This study confirms the winter peak of PE and provides evidence that it is not influenced by the underlying clinical conditions, but probably by endogenous variations.


Modification of the clonogenic assay for the detection of lymphokine activated killer cell activity.
The soft agar clonogenic assay using [3H]thymidine uptake as an endpoint was adapted for the detection of human LAK activity against the Daudi lymphoma cell line and human tumor cells obtained by biopsy. Using Daudi cells as the target population the modified agar assay was more sensitive than the conventional 4 h 51Cr release assay. Use of a single layer agar assay allowed the assessment of LAK cytotoxic/cytostatic activity against Daudi lymphoma cells after cell to cell contact, while a two layer system permitted evaluation of the role of soluble mediators in LAK/target cell interactions. This study shows that LAK cells can either kill or inhibit the proliferation of Daudi cells by two mechanisms: one which requires cell-to-cell contact, and a second via soluble mediators. As determined by the use of neutralizing antisera, the soluble factor(s) are not tumor necrosis factor and interferon-gamma. Of the nine individual human tumor samples obtained by biopsy. 89% were sensitive to allogeneic LAK cells when the two populations were admixed. Of these nine tumors 44% were inhibited by LAK-derived soluble factors. The soft agar assay system should serve as a useful tool for determining the sensitivity of human tumors to LAK cells and for studying the mechanisms of LAK anti-tumor activity.


Neuroendocrine control of T cell development in mammals: role of growth hormone in modulating thymocyte migration.
The thymus gland is a primary lymphoid organ, in which bone-marrow-derived T cell precursors undergo differentiation, eventually leading to migration of positively selected cells to the peripheral lymphoid organs. This differentiation occurs along with cell migration in the context of the thymic microenvironment, a three-dimensional network formed by epithelial cells, macrophages, dendritic cells, fibroblasts and extracellular matrix components. A series of data clearly shows that growth hormone (GH) pleiotropically modulates thymic functions. For example, GH upregulates proliferation of thymocytes and thymic epithelial cells. Accordingly, GH-transgenic mice, as well as animals and humans treated with exogenous GH, exhibit an enhanced cellularity in the organ. Growth hormone stimulates the secretion of thymic hormones, cytokines and chemokines by the thymic microenvironment, as well as the production of extracellular matrix proteins, leading to an increase in thymocyte migratory responses and intrathymic traffic of developing T cells. In addition, GH stimulates the in vivo export of thymocytes from the organ, as ascertained by studies with intrathymic injection of GH in normal mice and with GH-transgenic mice. Moreover, since GH is produced by thymocytes and thymic epithelial cells, which express GH receptors, we should consider that, in addition to the classic endocrine pathway, the GH control of the thymus may include an autocrine/paracrine pathway. Finally, since GH promotes a replenishment of the thymus and an increase of thymocyte export, it could be envisioned as a potential adjuvant therapeutic agent in the treatment of immunodeficiencies associated with thymic atrophy.


Ocular surface manifestation of COVID-19 and tear film analysis.
To evaluate the ocular manifestation in patients hospitalized with coronavirus disease 2019 (COVID-19) and to search for the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in tears. This study was conducted in 29 hospitalized patients who were admitted to the COVID center at the Policlinic Hospital of the University of Messina, Italy. All patients underwent an ophthalmologic assessment comprising a Standardized Patient Evaluation of Eye Dryness (SPEED) questionnaire, anterior segment, and the ocular surface examination of both eyes using a portable slit lamp. The Schirmer I test was performed, and the filter paper strip was used to search for the presence of SARS-CoV-2 on the ocular surface by real-time quantitative polymerase chain reaction (RT-qPCR). A total of 10 patients reported ocular symptoms; in particular, four reported eye burning, three reported foreign body sensation, and three reported tearing. Moreover, seven patients presented conjunctival hyperemia and/or chemosis, eleven patients presented blepharitis signs such as lid margin hyperemia and/or telangiectasia, crusted eyelashes, and meibomian orifices alterations. Tear analysis did not reveal the presence of SARS-CoV-2. Ocular symptoms are common in patients with COVID-19; although, tear analysis did not reveal the presence of SARS-CoV-2.


Phage display of environmental protein toxins and virulence factors reveals the prevalence, persistence, and genetics of antibody responses.
Microbial exposures are crucial environmental factors that impact healthspan by sculpting the immune system and microbiota. Antibody profiling via Phage ImmunoPrecipitation Sequencing (PhIP-Seq) provides a high-throughput, cost-effective approach for detecting exposure and response to microbial protein products. We designed and constructed a library of 95,601 56-amino acid peptide tiles spanning 14,430 proteins with "toxin" or "virulence factor" keyword annotations. We used PhIP-Seq to profile the antibodies of ∼1,000 individuals against this "ToxScan" library. In addition to enumerating immunodominant antibody epitopes, we studied the age-dependent stability of the ToxScan profile and used a genome-wide association study to find that the MHC-II locus modulates bacterial epitope selection. We detected previously described anti-flagellin antibody responses in a Crohn's disease cohort and identified an association between anti-flagellin antibodies and juvenile dermatomyositis. PhIP-Seq with the ToxScan library is thus an effective tool for studying the environmental determinants of health and disease at cohort scale.


Mutagenicity testing of a rodenticide, zinctox (zinc phosphide) in a mouse in vivo system.
The genotoxic potential of zinctox (zinc phosphide) was evaluated in mice in vivo employing different bioassays: bone marrow chromosome aberration, micronucleus and sperm shape abnormality. A significant increase of chromosome aberrations was induced by three doses. Interestingly, the highest percentage was induced by the middle dose. In a route-responsive study the highest percentage of chromosome aberration was induced by the oral route. A dose-dependent increase in the incidence of micronuclei was noticed in the bone marrow cells. In the sperm shape abnormality test a high percentage of abnormal sperm was induced by all three dose levels. The results revealed the genotoxic potential of zinctox in the tested mouse in vivo system.


Structure-based design of stabilized recombinant influenza neuraminidase tetramers.
Influenza virus neuraminidase (NA) is a major antiviral drug target and has recently reemerged as a key target of antibody-mediated protective immunity. Here we show that recombinant NAs across non-bat subtypes adopt various tetrameric conformations, including an "open" state that may help explain poorly understood variations in NA stability across viral strains and subtypes. We use homology-directed protein design to uncover the structural principles underlying these distinct tetrameric conformations and stabilize multiple recombinant NAs in the "closed" state, yielding two near-atomic resolution structures of NA by cryo-EM. In addition to enhancing thermal stability, conformational stabilization improves affinity to protective antibodies elicited by viral infection, including antibodies targeting a quaternary epitope and the broadly conserved catalytic site. Stabilized NAs can also be integrated into viruses without affecting fitness. Our findings provide a deeper understanding of NA structure, stability, and antigenicity, and establish design strategies for reinforcing the conformational integrity of recombinant NA proteins.


The contraceptive use of Depo-Provera in U.S. adolescents.
Little is known about the use of depot medroxyprogesterone acetate (Depo-Provera, DMPA) in U.S. adolescents before the FDA approved its usage for contraception in 1992. To determine the experience with DMPA use in adolescents for contraception in the United States. A questionnaire survey was sent to U.S. physicians identified as adolescent health care providers. DMPA had been prescribed by 41% of surveyed physicians who prescribe contraception for adolescents. Eighty-five percent of patients continued use beyond nine months and 40% continued beyond 21 months. Sixty-seven percent of physician/respondents reported using DMPA in mentally retarded patients. Many providers used DMPA for contraception in adolescents prior to its FDA approval for contraception. DMPA has a high rate of continuation of use as a contraception in adolescents.


Acute toxicity of aristolochic acid in rodents.
The acute toxic effects of aristolochic acid (AA) were tested in rats and mice of both sexes. Oral or intravenous administration in high doses was followed by death from acute renal failure within 15 days. Histologically, the predominant features were severe necrosis affecting the renal tubules, atrophy of the lymphatic organs and large areas of superficial ulceration in the forestomach, followed by hyperplasia and hyperkeratosis of the squamous epithelium. The LD50 ranged from 56 to 203 mg/kg orally or 38 to 83 mg/kg intravenously, depending on species and sex.


A novel pit pattern identifies the precursor of colorectal cancer derived from sessile serrated adenoma.
Sessile serrated adenomas (SSAs) are known to be precursors of sporadic colorectal cancers (CRCs) with microsatellite instability (MSI), and to be tightly associated with BRAF mutation and the CpG island methylator phenotype (CIMP). Consequently, colonoscopic identification of SSAs has important implications for preventing CRCs, but accurate endoscopic diagnosis is often difficult. Our aim was to clarify which endoscopic findings are specific to SSAs. The morphological, histological and molecular features of 261 specimens from 226 colorectal tumors were analyzed. Surface microstructures were analyzed using magnifying endoscopy. Mutation in BRAF and KRAS was examined by pyrosequencing. Methylation of p16, IGFBP7, MLH1 and MINT1, -2, -12 and -31 was analyzed using bisulfite pyrosequencing. Through retrospective analysis of a training set (n=145), we identified a novel surface microstructure, the Type II open-shape pit pattern (Type II-O), which was specific to SSAs with BRAF mutation and CIMP. Subsequent prospective analysis of an independent validation set (n=116) confirmed that the Type II-O pattern is highly predictive of SSAs (sensitivity, 65.5%; specificity, 97.3%). BRAF mutation and CIMP occurred with significant frequency in Type II-O-positive serrated lesions. Progression of SSAs to more advanced lesions was associated with further accumulation of aberrant DNA methylation and additional morphological changes, including the Type III, IV and V pit patterns. Our results suggest the Type II-O pit pattern is a useful hallmark of the premalignant stage of CRCs with MSI and CIMP, which could serve to improve the efficacy of colonoscopic surveillance.


[Risk score and postoperative complications in pediatric surgery].
We have developed a risk score meeting the special demands of pediatric surgery. It conveys an objective impression of the patients' preoperative condition and enables us to predict their individual intra- and postoperative behavior. This study compiles the course of 1425 operations carried out between 1986 and 1990. They were divided into low, intermediate and high risk. In addition, the patients were classified into six different age groups. We demonstrate that the number of points assigned by our risk score is highly correlated with the rate of complications that occurred, that accompanying malformations and diseases are correctly picked up and weighed by the score as far as their importance for the postoperative course is concerned, that the score is suitable for ascertaining which patients have a high probability of developing complications: the specificity is close to 100% for more than 12 points on the score, and the proportion of correctly predicted lethal courses (sensitivity) is also close to 100%. The significance of the risk score lies first in the possibility of giving patients exact data on the intra- and postoperative risk, and secondly in the provision of an objective measure of quality control--which is legally prescribed in Germany--and comparison with other hospitals. Third, the risk score gives clear starting points for research aiming at improvement in the field of surgery in sick children, and lastly it forms the basis for reliable preoperative recognition of high-risk as needed patients for modern payment methodology of the per-cose costs and thus makes it possible to charge accordingly.


Eureka! A surprising appearance after aspiration of a haemopneumothorax: treat the patient not the radiograph.
We describe the aspiration of a traumatic haemopneumothorax and an unexpected anteroposterior chest radiograph finding after the procedure. Chest aspiration is now routine emergency management for spontaneous pneumothorax. There have been no previous documented reports of this clinical scenario of radiological deterioration with clinical improvement after aspiration of a haemopneumothorax.


How GVC division affects embodied carbon emissions in China's exports?
With the rapid growth of China's foreign trade scale, the embodied carbon emissions in China's exports show a significant upward trend, which has been experiencing a considerable increase of researchers' attention. This study attempts to measure the embodied carbon emissions in China's exports from 1995 to 2011 based on the MRIO model and WIOD data. Compared with previous studies, this paper introduces the gross trade accounting method and constructs the GVC impact index and EC position index to comprehensively explore the impact of the GVC division on embodied carbon emissions in China's export trade. The main conclusions are as follows: (1) The fast-growing embodied carbon emissions in China's export trade were mainly caused by intermediate products trade. And the impact of the GVC division on embodied carbon emissions increased with the deepening of the participation in GVC division. (2) Although China played a role of the "pollution haven" in GVCs, China's EC position index ascended with the deepening of the participation in GVCs. (3) In the context of GVCs, consumer responsibility principle is more equitable and rational, which be widely suggested in the calculation of national carbon emissions responsibility.


Mucinous cystadenoma of the pancreas with predominant stroma creating a solid tumor.
Mucinous cystic neoplasm (MCN) of the pancreas is basically cystic epithelial neoplasm, unilocular or multilocular, occurring almost exclusively in women. A 51-year-old female presented with a pancreatic mass incidentally found on the abdominal computed tomography. She underwent distal pancreatectomy. The sectioned surface of the pancreas revealed a circumscribed, whitish gray ovoid firm mass with some cystic spaces. Microscopically, glandular or small cystic structures were scattered in the predominant stroma creating a solid appearance. The subepithelial stromal component was composed of cytologically bland looking spindle cells, which resembled ovarian stroma. The stromal cells were reactive to CD 34, vimentin, progesterone receptor and calretinin. The microscopy was consistent with mucinous cystadenoma of the pancreas. This case of mucinous cystadenoma of the pancreas showed very interesting pathology: It was solid rather than cystic, and accompanied by abundant benign transitional epithelia, which was a very unusual and novel finding in the mucinous cystic neoplasm of the pancreas.


Derivatization of agelastatin A leading to bioactive analogs and a trifunctional probe.
(-)-Agelastatin A (AglA, 1), a member of the pyrrole-aminoimidazole marine alkaloid (PAI) family, possesses a unique tetracyclic structure and is one of the most potent anticancer PAIs isolated to date. In efforts to expand the SAR of these agents and delineate sites that tolerate modification while retaining activity, we synthesized several derivatives and tested their anticancer activity. The cytotoxic effects of these derivatives were measured against several cancer cell lines including cervical cancer (HeLa), epidermoid carcinoma (A431), ovarian (Igrov and Ovcar3), osteosarcoma (SJSA1), acute T cell leukemia (A3), epidermoid carcinoma (A431) in addition to primary human chronic lymphocytic leukemia (CLL) cells. New positions for modification of AglA and new substitutions were explored leading to novel derivatives, 14-chloro AglA (3) and 14-methyl AglA (12), that retained activity toward various cancer cell lines with decreased toxicity toward B- and T-cells. The SAR data informed the synthesis of a trifunctional probe bearing an alkyne and a diazirine potentially useful for cellular target identification.


Effect of forage species and season on nutrient digestion and supply in grazing cattle.
1. A total of twenty Friesian steers were grazed on pure swards of either perennial ryegrass (Lolium perenne cv. Melle) or white clover (Trifolium repens cv. Blanca) from May to late August to examine the effect of forage species and season on nutrient digestion and supply. Within each forage species, two daily allowances of forage (i.e. 30 and 60 g dry matter (DM)/kg live weight) were given, and nutrient flow into the small intestine was measured on thirteen separate occasions (viz. seven grasses and six clovers). 2. Total nitrogen content of the grasses varied between 28 (early season), 19 (mid-) and 33 (late) g/kg DM, whilst the clovers showed a much narrower range and all values were higher (39-45 g/kg DM). In vitro organic matter (OM) digestibilities of plucked samples ranged from 742 to 809 g/kg OM (grass) and 712 to 790 g/kg OM (clover), the lowest values being noted in late June (grass) and mid-July (clover). 3. OM intakes calculated from estimated faecal OM output (using unlabelled ruthenium) and predicted OM digestibility of the consumed forage indicated mean values of 20.9 (grass) and 26.0 (clover) g/kg live weight (P less than 0.001), whilst the higher forage allowances increased OM intake by approximately 8% on both grass and clover (P less than 0.01) compared with the low allowance. OM intake was significantly (P less than 0.01) lower on the two primary growths of grass examined in May (mean 16.8 g/kg live weight) than the other five grass diets. 4. Rumen molar propionate levels declined with season but were at all times higher on the grass than on the clover diets, whilst acetate levels were unaffected by forage species. Apart from the late-season grass, mean rumen ammonia concentration was less than 100 mg NH3-N/l on all grass diets, whilst values on the clover diets ranged from 200-350 mg/l. 5. Daily duodenal OM flows in relation to animal live weight were approximately 20% higher on the clover than on the grass diets (grass 9.2, clover 11.2 g/kg live weight, P less than 0.001), but estimates of the proportion of digestible OM apparently digested in the rumen were not significantly influenced by forage species (grass 0.69, clover 0.71).(ABSTRACT TRUNCATED AT 250 WORDS)


Pharmacokinetics and safety of golimumab in healthy Chinese subjects following a single subcutaneous administration in a randomized phase I trial.
Golimumab is an anti-tumor necrosis factor-α human immunoglobulin G1κ monoclonal antibody that is efficacious for the treatment of moderate to severe rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis in adults. The objective of this study was to assess the pharmacokinetic characteristics of golimumab in healthy male Chinese subjects following a single subcutaneous (SC) administration of golimumab 50 or 100 mg. The safety, tolerability, and immunogenicity of a single SC administration of golimumab in Chinese subjects were also evaluated. This was a phase I, randomized, open-label, single-dose, single-period, single-center study. Twenty-four healthy male Chinese subjects were randomized (1:1) to receive a single SC administration of golimumab 50 or 100 mg. Serial blood samples for the measurement of serum golimumab concentrations were collected and analyzed using a validated electrochemiluminescent immunoassay method. The pharmacokinetic parameters [maximum observed serum concentration (C(max)), time to reach C(max) (t(max)), area under the serum concentration-time curve from time zero to infinity (AUC∞), and terminal half-life (t(½))] of golimumab were derived using a noncompartmental analysis. Following a single SC administration of golimumab 50 or 100 mg in Chinese male subjects (age 19-41 years, body weight 60-76 kg), mean ± standard deviation C(max) (3.6 ± 1.6 and 7.5 ± 1.4 μg/mL, respectively) and AUC∞ (59.8 ± 19.8 and 132.8 ± 27.0 μg·day/mL, respectively) increased in a dose-proportional manner. The median t(max) was in the range of 4.5-5.0 days, and the mean t(½) was in the range of 10.8-11.9 days. Among 24 subjects, 23 had appropriate samples for evaluation of antibodies to golimumab, and one subject (1/23, 4.3%) in the 100-mg group tested positive. Three mild adverse events were reported (infected sebaceous cyst, upper respiratory tract infection, and headache), all in the 50-mg group; none were considered to be related to the study agent. Golimumab exhibited linear pharmacokinetics at dose levels of 50 and 100 mg following a single SC administration in healthy Chinese subjects. Single SC administrations of golimumab 50 or 100 mg were considered to be generally well tolerated. The results from this study indicate that there are no apparent ethnic differences in the pharmacokinetics of golimumab between Chinese and Caucasian subjects.


Bacteriologic culture results obtained before and after elective midtrimester urea abortion.
Twenty patients undergoing elective midtrimester abortion by urea amnioinfusion had bacteriologic culture data obtained before and after the procedure. Despite the presence of pathogens in the vagina and cervix prior to the procedure, only 20% of patients exhibited endometrial growth following abortion. Factors that seem to favor such endometrial growth include increased injection-abortion intervals and the requirement for curettage to manage incomplete abortion.


Development of corticogeniculate synapses in the cat.
The development of corticogeniculate synapses was studied in 16 cats ranging in age from newborn to adult. Tritiated proline was injected into areas 17 and 18 of the visual cortex in order to label corticogeniculate terminals in lamina A of the dorsal lateral geniculate nucleus. The labeled terminals were then characterized ultrastructurally using electron microscopic autoradiography. Labeled synaptic profiles were found in newborn kittens, indicating that corticogeniculate connections are present in the cat at birth. Morphologically, however, many corticogeniculate endings in newborn and 1-week-old kittens are different from those in older animals in that they do not form well-defined terminal boutons, and their synaptic vesicles are often loosely packed. In kittens 2 weeks of age and older, corticogeniculate axons end as RSD terminals exclusively; i.e., they are relatively small in size and contain round, densely packed synaptic vesicles, and occasionally an electron-dense mitochondrion (Guillery: Z. Zellforsch. 99: 1-38, '69). However, not all RSD terminals in the LGN represent input from visual cortex. Injections of 3H-proline into the mesencephalic reticular formation also label RSD terminals selectively in the lateral geniculate nucleus. At all ages corticogeniculate axons make synaptic contacts with dendrites exclusively, and they are always presynaptic. This suggests that the essential pattern of corticogeniculate synapses is formed early and is not altered during subsequent development. Quantitatively, there is no significant change in the size of corticogeniculate terminals or their synaptic vesicles in kittens 2 weeks of age (the youngest measured) and older. In contrast, the synaptic contact lengths of these terminals decreases about 28% between 2 and 12 weeks. During this same period there is approximately a twofold increase in the density of corticogeniculate terminals in the neuropil of lamina A. Since the volume of neuropil in lamina A increases almost fourfold between 2 and 12 weeks, the doubling of corticogeniculate terminal density represents about an eightfold increase in terminal number. After 12 weeks there is little change in the length, density, or number of corticogeniculate synaptic contacts, which suggests that the morphological development of the corticogeniculate pathway is essentially complete by this age.


Effects of curcumin and Ginkgo biloba on matrix metalloproteinases gene expression and other biomarkers of inflammatory bowel disease.
Treatment of inflammatory bowel disease (IBD) by synthetic active ingredients leads to many side effects. The objective of this study was to manage IBD using natural products as curcumin and Ginkgo biloba. Rats were divided into four groups (control, IBD, curcumin treated, and ginkgo treated). Inflammation was assessed by determination of myeloperoxidase, matrix metalloproteinases, metalloproteinase-1 inhibitor, nitric oxide, hydroxyproline, tumor necrosis factor-alpha, ceruloplasmin, and histopathological scoring. IBD induction significantly increased all measured parameters. Treated groups had significantly lower levels when compared with the IBD group. In conclusion, curcumin and ginkgo were effective in prevention and treatment of IBD.


Eggshell composition of squamate reptiles: relationship between eggshell permeability and amino acid distribution.
Most snakes and lizards produce eggs with flexible shells that interact with the environment to maintain water balance. Geckos produce rigid eggshells that are independent of an external source of water and can be oviposited in more open, dryer locations. In this study, we analyzed and compared the amino acid composition of 24 lizard species, six snake species, and four outgroups (including avian and reptilian elastin and chicken eggshell). Rigid Gecko eggshells had significantly lower levels of seven of the 17 amino acids evaluated. Multivariate analysis showed that proline was the most important amino acid in distinguishing between these two groups of eggshells, occurring at significantly higher levels in flexible eggshells. High levels of proline have also been observed in the eggshells of other species. Proline and other amino acids are associated with the alleviation of water and salt stress in plants.


Treatment of High Flow Arteriovenous Fistulas after Successful Renal Transplant Using a Simple Precision Banding Technique.
Observation versus ligation of a functional arteriovenous fistula (AVF) after successful renal transplantation (SRT) has been a controversial topic of debate. Congestive heart failure and pulmonary hypertension are common in dialysis patients, and more frequent when vascular access flow is excessive. Renal transplant failure may occur in up to 34% of patients after 5 years, therefore maintaining a moderate flow AVF appears warranted. We review SRT patients with high flow-AVFs (HF-AVF) and clinical signs of heart failure where a modified precision banding procedure was used for access flow reduction. Patients referred for HF-AVF evaluation after SRT were identified and records reviewed retrospectively. In addition to recording clinical signs of heart failure, each patient had ultrasound AVF flow measurement before and after temporary AVF occlusion of the access by digital compression. Pulse rate and the presence or absence of a cardiac murmur was noted before and after AVF compression. Adequacy of access flow restriction was evaluated intraoperatively using ultrasound flow measurements, adjusting the banding diameter in 0.5 mm increments to achieve the targeted AVF flow. Twelve patients were evaluated over a 19-month period. Eight (66%) were male and one (8%) obese. Ages were 15-73 years (mean = 42). The AVFs were established 24-86 months previously. The mean pulse rate declined after AVF compression from 90/min to 72/min (range 110-78). Six patients had a precompression cardiac flow murmur that disappeared with temporary AVF compression. One patient with poor cardiac function underwent immediate AVF ligation with dramatic improvement in cardiac status. All other patients underwent a precision banding procedure with real-time flow monitoring. Mean access flow was 2,280 mL/min (1,148-3,320 mL/min) before access banding and was 598 mL/min (481-876) after flow reduction. The clinical signs of heart failure disappeared in all patients. All AVFs remained patent although one individual later requested ligation for cosmesis. Two patients had renal transplant failure and later successfully used the AVF. Follow-up postbanding was 1-18 months (mean = 12). Patients with successful renal transplants and HF-AVFs had resolution of heart failure findings and maintenance of access patency using a modified precision banding procedure. Flow reduction in symptomatic renal transplant patients with elevated access flow is recommended. Further study is warranted to substantiate these recommendations and clarify the appropriate thresholds for such interventions.


Protocol for treatment of constipation with polyethylene glycol 3350 plus electrolytes in critically ill children.
No studies have analysed the effectiveness of treatment for constipation in critically ill children. The aim of this study was to assess the implementation, efficacy and safety of a treatment protocol using polyethylene glycol 3350 with electrolytes (PEG 3350 + E) for constipation in critically ill children. We conducted a single-centre prospective study in children admitted to the paediatric intensive care unit for a minimum of 72 h and who developed constipation. Children with previous gastrointestinal disorders or diseases were excluded. The patients were treated with rectal enemas or with the oral PEG 3350 + E protocol at the discretion of the treating physician. We compared clinical and demographic variables as well as adverse events (diarrhoea, abdominal distension and electrolyte imbalances). The sample included 56 patients with a mean age of 48.2 ± 11.9 months, of who 55.4% were male. Forty-four patients (78.6%) were treated with PEG 3350 + E and 12 (21.4%) with rectal enemas. The proportion of patients that responded well to treatment was greater in the PEG 3350 + E group (79.5%) compared to the enema group (58.3%), but the difference was not statistically significant (P = .151). There were no significant differences between the groups in any of the adverse effects. Treatment with PEG 3350 + E was more effective in children aged less than 2 years (100%) compared to older children (100% vs 65.4%; P < .01), with no significant differences in the development of adverse events. The PEG 3350 + E treatment protocol for constipation in critically ill children was effective and associated with few adverse events, even in children aged less than 2 years.


Construction of a spheroid array culture system on a suspended permeable hydrogel membrane scaffold for improving the expression of a liver-specific drug-metabolizing enzyme of HepG2 cells.
Herein, we constructed a spheroid array culture system on a flexible hydrogel membrane suspended in the culture medium. When we applied this culture system to HepG2 cells, the results suggested that an aerobic culture environment was implemented, and the gene expression of a liver-specific drug-metabolizing enzyme was improved in comparison with that of the conventional immobilized monolayer culture.


Iliac artery stenosis in a child with cutis marmorata telangiectatica congenita.
Cutis marmorata telangiectatica congenita (CMTC) is a rare congenital disorder. We describe an 8-year-old boy with CMTC who presented with symptomatic claudication and diminished distal pulses. Imaging showed severe stenosis of the right common iliac artery, and the child underwent uncomplicated ilio-iliac bypass using prosthetic graft. This is the first report of a patient with CMTC and major vessel stenosis, successfully treated with a prosthetic graft bypass.


Citrullination, a possible functional link between susceptibility genes and rheumatoid arthritis.
Antibodies directed to citrullinated proteins (anti-cyclic citrullinated peptide) are highly specific for rheumatoid arthritis (RA). Recent data suggest that the antibodies may be involved in the disease process of RA and that several RA-associated genetic factors might be functionally linked to RA via modulation of the production of anti-cyclic citrullinated peptide antibodies or citrullinated antigens.


Molecular cloning and expression in vitro of a carboxylesterase gene from the Glanville fritillary butterfly (Melitaea cinxia).
Carboxylesterase (EC 126.96.36.199) is a member of the carboxyl/cholinesterase (CCE) superfamily, which is widely distributed in animals, plants and microorganisms. This enzyme has been known to be associated with insecticide resistance and detoxification. Although CCEs have been extensively studied in insects, including lepidopterans, the research on butterflies, a major subgroup in Lepidoptera, is still poor. In the present study, we cloned a CCE gene (McCCE1) from the Glanville fritillary butterfly (Melitaea cinxia, Lepidoptera: Nymphalidae). The full-length cDNA encoding McCCE1 was 1786 bp, containing a 1641 bp open reading frame encoding 546 amino acids, a 38 bp 5'-untranslated region (5'-UTR), and a 107 bp 3'-UTR with a poly(A) tail. The functionally conserved amino acids in McCCE1 shared the 55% identity with the cytoplasmic esterase CCE017a in Helicoverpa armigera (Lepidoptera: Noctuidae), which has been associated with detoxification. Assays in vitro showed that the recombinant McCCE1 could hydrolyze α- and β-naphthyl acetate. Thus, the present study adds to the body of knowledge concerning the detoxification of pesticides by lepidopterans.


The effects of hypoxia on sediment nitrogen cycling in the Baltic Sea.
Primary production in the eutrophic Baltic Sea is limited by nitrogen availability; hence denitrification (natural transformation of nitrate to gaseous N(2)) in the sediments is crucial in mitigating the effects of eutrophication. This study shows that dissimilatory nitrate reduction to ammonium (DNRA) process, where nitrogen is not removed but instead recycled in the system, dominates nitrate reduction in low oxygen conditions (O(2) <110 μM), which have been persistent in the central Gulf of Finland during the past decade. The nitrogen removal rates measured in this study show that nitrogen removal has decreased in the Gulf of Finland compared to rates measured in mid-1990s and the decrease is most likely caused by the increased bottom water hypoxia.


Autologous conditioned serum (ACS) for intra-articular treatment in Osteoarthritis: Retrospective report of 28 cases.
Autologous conditioned serum (ACS) is a novel blood product developed for intra-articular injection as a novel therapy for Osteoarthritis (OA). This study is a retrospective evaluation of 28 cases (25 Knee-OA and 3 hip-OA) treated with ACS between November 2013 and February 2016. ACS was prepared according to standards in an accredited Cell Manipulation Lab, and applied by an expert clinician (2 ml injection once weekly over 4 weeks). At any injection visit (Timepoints 1-4), and after a follow-up of 1 (Timepoint 5) and 6 months (Timepoint 6), patients were asked to describe the intensity of their pain with the VAS (visual analog scale) psychometric scale, and the objective parameter ROM (Range Of Motion) was recorded in case of injection in the knee. Pain (VAS) reduced in all cases since the first injection up to Timepoint 5. A significant improvement was observed in VAS between Timepoint 1 and 6 (primary objective), with a median VAS decrease of 60 mm (range 20-100, p < 0.01). A significant difference was also recorded in ROM between Timepoint 1 and 6 (secondary objective), with a median increase of 25° (range 5-40, p < 0.01). Ten out of 14 patients (71%) who were undergoing a chronic therapy to relieve pain were able to interrupt it. No serious adverse events were recorded. Treatment with ACS produced a rapid decline in pain, accompanied by a large improvement in ROM. These results suggest that ACS is a valid option for the treatment of OA.


Strong exciton-photon coupling in microcavities containing new fluorophenethylamine based perovskite compounds.
We synthetize some new perovskite thin layers: p-fluorophenethylamine tetraiodoplumbate pFC(6)H(4)C(2)H(4)NH(3))(2)PbI(4) perovskite molecules, included in a PMMA matrix. We report on the optical properties of the perovskite doped PMMA thin layers and we show that these layers are much more stable under laser illumination and present a smaller roughness than the spin-coated (C(6)H(5)C(2)H(4)NH(3))(2)PbI(4) layers. These new layers are used as the active material in vertical microcavities and the strong-coupling regime is evidenced by a clear anti-crossing appearing in the angular-resolved reflectivity experiments at room temperature.


Criteria for intraventricular conduction disturbances and pre-excitation. World Health Organizational/International Society and Federation for Cardiology Task Force Ad Hoc.
In an effort to standardize terminology and criteria for clinical electrocardiography, and as a follow-up of its work on definitions of terms related to cardiac rhythm, an Ad Hoc Working Group established by the World Health Organization and the International Society and Federation of Cardiology reviewed criteria for the diagnosis of conduction disturbances and pre-excitation. Recommendations resulting from these discussions are summarized for the diagnosis of complete and incomplete right and left bundle branch block, left anterior and left posterior fascicular block, nonspecific intraventricular block, Wolff-Parkinson-White syndrome and related pre-excitation patterns. Criteria for intraatrial conduction disturbances are also briefly reviewed. The criteria are described in clinical terms. A concise description of the criteria using formal Boolean logic is given in the Appendix. For the incorporation into computer electrocardiographic analysis programs, the limits of some interval measurements may need to be adjusted.


Outcome from treatment for spinal arteriovenous malformation.
Our knowledge of the outcome from treatment for spinal arteriovenous malformations (AVMs) is limited to a few small, anecdotal series and is thus far from complete. Furthermore, with the recent rapid evolution of our knowledge of AVM pathology, many reported cases are difficult to place in the current classification system. In general, outcome for the four classifications of AVMs are as follows: type I respond well to surgical disconnection of the arteriovenous fistula if treatment is early; type II AVMs are currently best treated by surgery but risks of a poor outcome need to be carefully considered; type III are only rarely treatable; type IVa and IVb are likely to respond well to surgery but our knowledge is limited; and type IVc are likely to fare poorly from surgery but should have a better outcome from endovascular therapy.


Asymmetric construction of allylicstereogenic carbon center featuring atrifluoromethyl group via enantioselective reductive fluoroalkylation.
Emerging as a powerful tool for lead optimization in pharmaceutical research and development, to develop the facile, general protocols that allows the incorporation of fluorine-containing motif in drug candidates has accumulated enormous research interest in recent years. Among these important motifs, the incorporation of strategic motif CF3 on aliphatic chain especially with the concomitant construction of trifluoromethylated alkanes bearing a CF3-substituted stereogenic carbon, is of paramount importance. Herein, we disclose an asymmetric nickel-catalyzed reductive trifluoroalkylation of alkenyl halides for enantioselective syntheses of diverse α-trifluoromethylated allylic alkanes, offering a general protocol to access the trifluoromethyl analogue to chiral α-methylated allylic alkanes, one of the most prevalent key components among natural products and pharmaceuticals. Utilities of the method including the application of the asymmetric trifluoroalkylation on multiple biologically active complex molecules, derivatization of transformable alkenyl functionality were demonstrated, providing a facile method in the diversity-oriented syntheses of CF3-containing chiral drugs and bioactive-molecules.


Dual FITC lateral flow immunoassay for sensitive detection of Escherichia coli O157:H7 in food samples.
A pattern of signal amplification lateral flow immunoassay (LFIA) for pathogen detection, which used fluorescein isothiocyanate (FITC) labeled antigen and antibody for dual FITC-LFIA was developed. Escherichia coli O157:H7 (E.coli O157:H7) was selected as the model analyte. In the signal amplification LFIA method, FITC was mixed with sample culture medium, with the presence of E.coli O157:H7 in the samples, the bacteria could emit a yellow-green fluorescence after incubation, creating a fluorescent antigen probe. This antigen probe was added to LFIA, which already contained E.coli O157:H7 monoclonal antibodies-FITC (McAb-E.coli O157:H7-FITC) dispersed in the conjugate pad. Another E.coli O157:H7 McAb was the test line, and goat anti-mouse IgG antibody was the control line in nitrocellulose (NC) membrane. The visual limit of detection (LOD) of the strip for qualitative detection was 10(5) CFU/mL while the LOD for semi-quantitative detection could down to 10(4) CFU/mL by using scanning reader. Signal amplification LFIA was perfectly applied to the detection of food samples with E.coli O157:H7. The LOD was substantially improved to 1 CFU/mL of the original bacterial content after pre-incubation of the bread, milk and jelly samples in broth for 10, 8 and 8h respectively. The results of this method was more sensitive by 10-fold than the conventional colloidal gold (CG) based strips and comparable to the traditional ELISA. This simple, low-cost and easy to be popularized method served as a significant step towards the development of monitoring food-borne pathogens in food-safety testing.


Fine-tuned aminal cleavage: a concise route to differentially protected enantiopure syn-alpha,beta-diamino Esters.
A survey of routes for aminal cleavage of N-sulfinylimidazolidines has been carried out, and selective conditions to cleave the aminal moiety while preserving the sulfinamide group unaltered have been found. Thus, the treatment of enantiopure N-sulfinylimidazolidines with aqueous H(3)PO(4) in THF affords enantiopure N-sulfinyldiamino esters in excellent yields, while the presence of MeOH as cosolvent allows for the simultaneous removal of the sulfinamide group and aminal cleavage. The behavior of these substrates in a variety of chemical transformations has been explored.


Prosthetic replacement of congenitally missing teeth using single-tooth osseointegrated implants: a case report.
This article presents the use of single-tooth implants in the rehabilitation of a 17-year-old patient with congenitally missing teeth. Treatment options are discussed, and advantages of the use of osseointegrated fixtures in the rehabilitation of partial anodontia patients are presented. A dental team approach is advocated.


Design and synthesis of isoxazole and isoxazoline linkage for replacement of nucleotide phosphodiester.
Synthetic routes for oligonucleotides which have isoxazoline or isoxazole linkage have been developed, and di- and tri-nucleotides with thymine bases have been prepared.


[Femoral artery pseudoaneurysms encountered in orthopedics and traumatology].
Most published articles regarding orthopedic- and trauma-related femoral artery pseudoaneurysms (FAPs) are case reports in English. Reported cases are often associated with a literature review but actually provide little robust data. We wanted to summarize the current knowledge on diagnostic and therapeutic features of these FAPs. A new case of superficial FAP is described followed by a review of the literature. A bibliographic search was performed online (PubMed, ScinceDirect) from 1964 to 2015 using the descriptors "traumatic femoral pseudoaneurysm, orthopedic surgery, osteochondroma". A total of 64 cases of FAPs was analyzed. There were 50 men with an average age of 40.72±26.45 years old. The most common clinical presentation was painful swelling (34%). Arteriography was the commonest radiological investigation used (63%). The main etiologies were orthopedic injuries (47%), surgery of the upper thigh (30%) and femoral osteochondromas (23%). Arterial injuries included superficial femoral (47%) and profunda femoris artery (50%). The treatment was open surgery (56%) or endovascular repair (36%). Deep femoral artery and its branches were embolized (47%) or ligated (38%). Endovascular stenting was performed in 30% of posttraumatic FAPs. All FAPs relating to osteochondromas were repaired surgically. Postoperative courses were uneventful in 95% of patients. Endovascular embolization is preferred in management of postsurgical FAPs which have usually involved the deep femoral artery. Endovascular stenting graft may be proposed for posttraumatic FAPs, for which the superficial femoral trunk is the most often involved vessel. Surgical repair should be performed when endovascular stenting graft is not feasible. Surgical repair is mandatory for all FAPs secondary to traumatic exostoses.


Substrate selection by juvenile Atlantic cod (Gadus morhua): effects of predation risk.
Although predator avoidance has been proposed as one possible factor influencing the distribution of fish among substrate types, no study has addressed this question directly. Groups of juvenile Atlantic cod were offered a choice between pairs of the following three substrates: sand, gravel-pebble and cobble. Their distribution on these substrates was compared prior to, during and following exposure to a predator (i.e. a larger conspecific). With no apparent risk of predation, juvenile cod preferred sand or gravel-pebble. When cobble was present, juveniles hid in the interstitial spaces of this substrate in the presence of a predator. With no cobble present, juveniles showed no preference between sand and gravel-pebble, and did not seek refuge from predation in association with these substrates. Following exposure to a predator (i.e. 2.5 h later) larger juvenile cod again showed a preference for the finer-grained substrates, but smaller individuals continued to associated with the cobble. The presence of cobble resulted in fewer juveniles being captured and a significant increase in the latency until the first juvenile was captured by the predator. Results are discussed with respect to the effects of predation on the distribution and survival of fishes among substrate types.


Endothelial Gata6 deletion reduces monocyte recruitment and proinflammatory macrophage formation and attenuates atherosclerosis through Cmpk2-Nlrp3 pathways.
Endothelial dysfunction results in chronic vascular inflammation, which is critical for the development of atherosclerotic diseases. Transcription factor Gata6 has been reported to regulate vascular endothelial cell activation and inflammation in vitro. Here, we aimed to explore the roles and mechanisms of endothelial Gata6 in atherogenesis. Endothelial cell (EC) specific Gata6 deletion was generated in the ApoeKO hyperlipidemic atherosclerosis mouse model. Atherosclerotic lesion formation, endothelial inflammatory signaling, and endothelial-macrophage interaction were examined in vivo and in vitro by using cellular and molecular biological approaches. EC-GATA6 deletion mice exhibited a significant decrease in monocyte infiltration and atherosclerotic lesion compared to littermate control mice. Cytosine monophosphate kinase 2 (Cmpk2) was identified as a direct target gene of GATA6 and EC-GATA6 deletion decreased monocyte adherence, migration and pro-inflammatory macrophage foam cell formation through regulation of the CMPK2-Nlrp3 pathway. Endothelial target delivery of Cmpk2-shRNA by intercellular adhesion molecule 2 (Icam-2) promoter-driven AAV9 carrying the shRNA reversed the Gata6 upregulation mediated elevated Cmpk2 expression and further Nlrp3 activation and thus attenuated atherosclerosis. In addition, C-C motif chemokine ligand 5 (Ccl5) was also identified as a direct target gene of Gata6 to regulate monocyte adherence and migration influencing atherogenesis. This study provides direct in vivo evidence of EC-GATA6 involvement in the regulation of Cmpk2-Nlrp3, as well as Ccl5, on monocyte adherence and migration in atherosclerosis development and advances our understanding of the in vivo mechanisms of atherosclerotic lesion development, and meanwhile provides opportunities for future therapeutic interventions.


Isolation of epithelial cells in the developing primary lip and palate.
Failure of the primary lip and palate to fuse leads to clefts of the lip, a birth defect with an incidence of 1 for every 500 in some races. Epithelial cells lining the facial processes of the primary lip and palate, the lateral and medial nasal processes (LNP and MNP), must first make contact to go through a series of highly regulated and coordinated sequence of events to form the normal midface. As yet, many of the basic mechanisms underlying the fusion events of the epithelial-lined surfaces are not known. This is due in part to the difficulty associated with the isolation of the epithelial cells for further study and analysis. The objective of this study was to test the use of laser capture microdissection to collect clean populations of primary lip and palate epithelial cells destined to fuse. Fusing and nonfusing epithelial cell populations of the MNP and LNP were isolated by laser capture microdissection and assayed for gene expression of Bmp-4, Tgfβ-2, and their type 1 receptors, Alk-3 and Alk-5, respectively. Transcripts of Bmp-4/Alk-3 and Tgfβ-2/Alk-5 were restricted to the epithelial seam of the fusion site, and the epithelium of the prefusion site, in patterns previously reported. Data indicated our ability to isolate clean populations of epithelial and mesenchymal cells around the primary palate fusion site, allowing precise analysis of tissue and site-specific gene expression at high resolution. This study provides the basis of further analysis of the potential molecular players of MNP and LNP fusion and nonfusion of epithelial cells.


Biofilm bioactivity affects nitrogen metabolism in a push-flow microalgae-bacteria biofilm reactor during aeration-free greywater treatment.
Non-aeration microalgae-bacteria biofilm has attracted increasing interest for its application in low cost wastewater treatment. However, it is unclear the quantified biofilm characteristics dynamics and how biofilm bioactivity affects performance and nitrogen metabolisms during wastewater treatment. In this work, a push-flow microalgae-bacteria biofilm reactor (PF-MBBfR) was developed for aeration-free greywater treatment. Comparatively, organic loading at 1.27 ± 0.10 kg COD/(m3⋅d) gave the highest biofilm concentration, density, specific oxygen generation (SOGR) and consumption rates (SOCR), and pollutants removal rates. Contributed to low residual linear alkylbenzene sulfonates and bioactivity, reactor downstream showed low bacteria and protein concentrations and SOCR (12.8 mg O2/g TSS·h), but high microalgae, carbohydrate, biofilm density, SOGR (49.4 mg O2/g TSS·h) and pollutants removal rates. Dissolved organic nitrogen (DON) showed higher molecular weight, CHONS and fraction with 4 atoms of N in reactor upstream. Most of nitrogen was fixed to newly synthesized biomass during assimilation process by related functional enzymes, minor contributed to denitrification due to low N2 emission. High nitrogen assimilation by microalgae showed high SOGR, which favored efficient multiple pollutants removal and reduced DON emission. Our findings favor the practical application of PF-MBBfR based on biofilm bioactivity, enhancing efficiency and reducing DON emission for low- energy-input wastewater treatment.


Contact dermatitis in the construction industry: the role of filaggrin loss-of-function mutations.
A high prevalence of contact dermatitis (CD) and respiratory symptoms has been observed in the construction industry, probably due to widespread exposure to irritants and allergens. It is unknown whether carriers of loss-of-function mutations in the gene encoding filaggrin (FLG), a known risk gene for eczema and asthma, are at increased risk. To investigate associations of FLG mutations with CD and respiratory symptoms in Dutch construction workers. A questionnaire including items on dermal and respiratory symptoms such as wheeze, shortness of breath and asthma was administered to construction workers. Total and specific serum IgE was analysed by enzyme immunoassays. Four FLG loss-of-function mutations were genotyped. CD was diagnosed by a team of a dermatologist and a clinical occupational medicine specialist using photographs of the subjects' hands and self-reported questionnaire data. Of the 506 participating workers, 6·3% carried at least one FLG mutation. Mild CD was diagnosed by the specialists in 34·0%, and severe CD in an additional 24·3%. CD was considered work related in 282 of 295 subjects (95·6%). Carriers of FLG variants had an increased risk of CD compared with subjects carrying wild-type alleles [mild CD: odds ratio (OR) 5·71, 95% confidence interval (CI) 1·63-20·06; severe CD: OR 8·26, 95% CI 2·32-29·39]. FLG variants and the presence of CD were not associated with respiratory symptoms and atopy. Contact dermatitis prevalence in construction workers is high. FLG loss-of-function mutations increase the risk of CD even further. FLG mutations were not associated with respiratory symptoms or atopy.


The use of visual feedback is independent of visual awareness: evidence from visual extinction.
Milner and Goodale (The visual brain in action, Oxford Press, 1995) made a distinction between vision for perception and vision for action. In contrast to perception, many action tasks have strict temporal constraints, which can only be met if the visual information is relayed directly to the motor system without first passing through a conscious decision making process. Milner and Goodale therefore predict that visual stimuli do not have to reach visual awareness in order to guide rapid motor responses. Online visual feedback provides a good example of visual information that is used under tight temporal constraints to guide rapid motor responses. Online visual feedback provides information about the position of the moving limb. This information can be used to improve the accuracy of our movements. If vision for action operates independently of visual awareness, visual feedback should be beneficial even if the subject is unaware of this information. We tested this prediction in a patient (V.E.) with left-sided visual extinction, a condition in which a visual stimulus typically fails to reach awareness if a second stimulus is presented simultaneously at a more rightward location. V.E. was asked to point towards a central target with his left hand. In some trials a light-emitting diode (LED) provided brief visual feedback from the moving hand. However, in the majority of trials, V.E. was unaware of this LED, due to his extinction. His performance was nevertheless significantly better when visual feedback was present, regardless of whether or not the information was available for verbal report. We conclude that visual awareness is not essential for the effective use of online visual feedback.


Concurrent radiotherapy and chemotherapy with erlotinib followed by maintenance erlotinib in patients with Epidermal Growth Factor Receptor mutation- positive adenocarcinoma lung.
To assess the efficacy and tolerability of erlotinib in combination with radiation therapy followed by maintenance therapy in Stage III and IV, epidermal growth factor receptor mutationpositive adenocarcinoma lung patients. The single-arm, quasi-experimental study was conducted at the Mayo Hospital, Lahore, Pakistan, from September 2013 to December 2014, and comprised patients with lung adenocarcinoma who were followed up till December 2017. The patients received concurrent radiation therapy (60- 70 Gy in 30-35 fractions) along with erlotinib 150mg/day, followed by erlotinib 150mg/day as maintenance therapy till disease progression. Primary endpoint was overall response rate according to Response Evaluation Criteria in Solid Tumours guideline version 1.0, while secondary endpoint was progression-free survival, overall survival and toxicity assessment with Common Terminology Criteria for Adverse Eventsversion 3.0. Before starting erlotinib, all patients received four cycles of standard chemotherapy with platinum doublets (Pemetrexed, Docetaxel, Paclitaxel, Gemcitabine). Data was analysed using SPSS 16.. of the 62 patients initially enrolled, 49(79%) completed the study. Of them, 37(75.5%) patients were smokers. Mean age of the patients was 57.0±8.51 years (range: 31-73 years) and 40 (81.6%) were male subjects. Objective response rate was 71.4% (n=35). Median progression-free survival for stage III disease was 7.4 months and for stage IV disease 2.8 months. Corresponding median overall survival rates were 12.9 months and 5.5 months. Common adverse events observed were rash n=30(61.2%), fatigue n=21(42.9%) and diarrhoea n=18(36.7%). Concurrent radiotherapy with erlotinib was effective and well-tolerated in patients with locally advanced adenocarcinoma lung harbouring epidermal growth factor receptor mutation.


Diphyllobothriasis latum: the first child case report in Taiwan.
Diphyllobothriasis latum is an intestinal parasitosis caused by the ingestion of mostly raw fresh-water fish containing plerocercoids of Diphyllobothrium latum. We report an 8-year-old boy who came to our hospital with the complaint of a tapeworm hanging from the anus after defecation. The other symptom was mild abdominal cramping for a period of 1 year. The laboratory examination did not reveal anemia or vitamin B12 deficiency. Examination of gravid proglottids with rosette-like central uterus and typically operculated eggs of D. latum confirmed the diagnosis. The morphologic characters of proglottids and eggs size are compatible with D. latum. The patient had a history of eating uncooked fish for 1 year. Salmonids may be the infection source. He was treated with two doses of praziquantel and passed about 183 cm in length of all proglottids. There is a high prevalence of diphyllobothriasis latum in the northern temperate areas, but it is very rare in children. This patient is the first child case reported in Taiwan.


The roles of grouper TAK1 in regulating the infection of Singapore grouper iridovirus.
Transforming growth factor-β activated kinase 1 (TAK1) is a member of the mitogen-activated protein kinase family. It is an upstream factor of the IκB kinase, which activates IKKα and IKKβ. TAK1 is a key factor in the induction of nuclear factor κB (NF-κB) and plays a crucial role in the activation of inflammatory responses. However, the roles of TAK1 during viral infection in teleost fish are largely unknown. In this study, we cloned a TAK1 homolog (HgTAK1) from the hybrid grouper (Epinephelus fuscoguttatus♂ × Epinephelus lanceolatus♀). The open reading frame of HgTAK1 consists of 1728 nucleotides encoding 575 amino acids, and the predicted molecular weight is 64.32 kDa HgTAK1 has an S_TKc domain, which consists of a serine/threonine protein kinase and a catalytic domain. Expression pattern analysis showed that HgTAK1 was distributed in all tested tissues, with abundant contents in the heart, head kidney, and blood. Additionally, HgTAK1 was distributed in the cytoplasm of grouper spleen (GS) cells. After Singapore grouper iridovirus (SGIV) infection, the expression of HgTAK1 increased in GS cells. Overexpression of HgTAK1 could promote the replication of SGIV in GS cells and inhibit the activation of NF-κB and IFN stimulated response elements (ISRE) in reporter assay. When co-expressed with IRF3 or HgIRF7 in GS cells, HgTAK1 obviously down-regulated IRF3- or IRF7-mediated the NF-κB and ISRE promoter induction. The interaction between HgTAK1 and IRF3 or IRF7 has been identified by co-immunoprecipitation assay. These findings provide a basis for understanding the innate immune mechanism of the grouper response to viral infection.


An assessment of the magnitude, parallelism, and asymmetry of micro-implant-assisted rapid maxillary expansion in non-growing patients.
Micro-implant-assisted expanders have shown significant effects on the mid-face, including a degree of asymmetry. The aim of this study is to quantify the magnitude, parallelism, and asymmetry of this type of expansion in non-growing patients. A retrospective study on a sample of 31 non-growing patients with an average age of 20.4 years old, with cone beam computed tomography images taken before and right after expansion using maxillary skeletal expander (MSE) were assessed for skeletal expansion at three landmarks bilaterally. Average magnitude of total expansion was 4.98 mm at the anterior nasal spine (ANS) and 4.77 mm at the posterior nasal spine (PNS) which showed statistical significance using a paired t test with p < 0.01. Average expansion at the PNS was 95% of that at the ANS. The sample was divided into symmetric (n = 15) and asymmetric (n = 16) based on the difference in expansion at the ANS, with 16 out of 31 patients exhibiting statistically significant asymmetry. MSE achieves distinctly parallel expansion in the sagittal plane but can exhibit asymmetrical expansion in the transverse plane.


Altered kinetics of an intravenous calcium load in idiopathic hypercalciuria.
Increased gut calcium absorption or reduced renal tubular calcium reabsorption have been alternatively reported in idiopathic hypercalciuria with kidney calculi. The present study aimed to investigate the handling of an exogenous calcium load in hypercalciuric stone formers to detect possible differences with regard to tissue calcium metabolism in vivo. A constant rate intravenous calcium infusion (0.2 mmol kg bodyweight per two hours) was carried out on six absorptives and six renals, defined according to the reported criteria, as well as on normal controls from clinical staff. Serum ionized calcium concentration were determined at regular intervals during the infusion and in the four hours after the end of calcium load. Over the same period, urinary calcium excretion was evaluated in timed urine collections. Absorptive and renal hypercalciurics had lower serum ionized calcium levels compared with normal controls at all experimental times, a finding that suggests a faster disappearance of calcium from the circulation. The total body calcium clearance calculated from the area under the curve of the serum calcium concentrations was enhanced in hypercalciuric patients (P less than .001). Although renal calcium excretion was higher in hypercalciurics, renal calcium clearance accounted for only a minor fraction of the total body clearance, suggesting that the reduced serum calcium levels found in the hypercalciurics could not be explained by the renal calcium leak. The enhanced total body calcium clearance found in hypercalciuric subjects is therefore due to an increased tissue calcium uptake. This finding provides indirect evidence of altered cell calcium handling in idiopathic hypercalciura with no difference between the so-called absorptives and renals in terms of the pathophysiologic mechanism.


Application of bimetallic iron (BioCAT slurry) for pentachlorophenol removal from sandy soil.
Bimetallic iron nanoparticles have mostly been applied to the degradation of chlorinated compounds in the aqueous phase. In this study, the degradation of pentachlorophenol (PCP) spiked into sandy soil is considered as a first exploratory step for remediating PCP in real contaminated soil using a commercial preparation of bimetallic iron (Trade name BioCAT). After 21 days of treatment a PCP removal efficiency of 90% was achieved, along with 70% dechlorination efficiency, for a dosage of 600 mg BioCAT slurry/kg soil. Degradation of PCP by BioCAT follows first order kinetics in PCP. Stepwise dechlorination is the main pathway of PCP elimination from soil slurries contacted with BioCAT. Such dechlorination is confirmed by the appearance of intermediate products, as well as by release of chlorides. Additionally, the increasing pH value and the rapid decrease of the oxidation/reduction potential (ORP) also attest to the reductive dechlorination of PCP. The reaction products comprehend lower chlorinated phenols, including three TeCP isomers, four TrCP isomers, four DCP isomers, two MCP isomers and phenol. These findings indicate that BioCAT could be applied for field treatment of PCP-contaminated soil under ambient conditions.


On the importance of carrion to reproduction in an omnivorous estuarine neogastropod, Ilyanassa obsoleta (Say).
The hypothesis that carrion provides a source of nutrition important to reproduction in the omnivorous neogastropod, Ilyanassa obsoleta (Say), was tested by collecting snails during winter, prior to reproductive season, and allowing them to feed ad libitum on three replicated diets (with starvation control) in the laboratory: vegetable, meat, and a mixture of meat and vegetable.The results indicate that, while a mixed diet is necessary for growth, meat may be the most important dietary constituent in terms of sexual condition and reproductive output of I. obsoleta. It is suggested that the chemotactic response to meat may be strongest for both sexes during the reproductive season, and may be responsible for some of the marked spatial heterogeneity in natural populations.


Real-time polymerase chain reaction for diagnosing infectious mononucleosis in pediatric patients: A systematic review and meta-analysis.
In this meta-analysis, we evaluated the diagnostic role of Epstein-Barr virus deoxyribonucleic acid detection and quantitation in the serum of pediatric and young adult patients with infectious mononucleosis. The primary outcome of this meta-analysis was the sensitivity and specificity of Epstein-Barr virus (EBV) deoxyribonucleic acid (DNA) detection and quantitation using polymerase chain reaction (PCR). A systematic review and meta-analysis was performed by searching for articles that were published through September 24, 2014 in the following databases: Medline, Cochrane, EMBASE, and Google Scholar. The following keywords were used for the search: "Epstein-Barr virus," "infectious mononucleosis," "children/young adults/infant/pediatric," and "polymerase chain reaction or PCR." Three were included in this analysis. We found that for detection by PCR, the pooled sensitivity for detecting EBV DNA was 77% (95%CI, 66-86%) and the pooled specificity for was 98% (95%CI, 93-100%). Our findings indicate that this PCR-based assay has high specificity and good sensitivity for detecting of EBV DNA, indicating it may useful for identifying patients with infectious mononucleosis. This assay may also be helpful to identify young athletic patients or highly physically active pediatric patients who are at risk for a splenic rupture due to acute infectious mononucleosis.


Role of ABCA2 and its single nucleotide polymorphisms (4873T>A and 4879G>C) in the regulation of multi-drug resistance in oral squamous carcinoma cells.
Lysosomal exocytosis is an essential cellular event for remodeling the extracellular matrix through secreting lysosomal enzymes and developing drug resistance. However, the detailed mechanism underlying the lysosomal exocytosis-driven acquisition of drug resistance is not completely understood. Genetic variations in gefitinib-sensitive (HSC3) and -resistant (HSC3/GR) oral squamous carcinoma cell lines were identified using whole-exome sequencing (WES). The physiological role of the ATP-binding cassette subfamily A member 2 (ABCA2) in gefitinib-induced lysosomal trafficking was evaluated in vitro, through overexpressing ABCA2 and its single nucleotide polymorphisms (SNPs). WES analysis showed that the 554 SNPs harboring 244 genes appeared to be differentially generated depending on gefitinib resistance. Among these genes, ABCA2 was enriched in 24 of 39 gene ontology terms. Two missense SNPs of ABCA2, 4873T > A (rs1831123356) and 4873T > A, were generated only in gefitinib-sensitive cells. Furthermore, HEK293 cells expressing the wild-type ABCA2 (WT ABCA2) acquired tolerance for gefitinib-induced cytotoxicity by increasing gefitinib sequestration in lysosomes and lysosomal exocytosis. Conversely, cells expressing each ABCA2 SNP exhibited lower efficacy in developing tolerance to gefitinib-induced responses than those expressing WT ABCA2. Notably, HSC3/GR cells were also tolerant to erlotinib and sunitinib but not osimertinib. Furthermore, tolerance for multiple tyrosine kinase inhibitors was attenuated by the deletion of ABCA2. These findings demonstrate that ABCA2 and its SNPs should be considered prominent targets for overcoming multi-drug resistance and enhancing the efficacy of chemotherapeutics.


Novel implementation research designs for scaling up global mental health care: overcoming translational challenges to address the world's leading cause of disability.
Despite established knowledge that Low and Middle Income Countries (LMICs) bear the majority of the world's burden of mental disorders, and more than a decade of efficacy research showing that the most common disorders, such as depression and anxiety, can be treated using readily available local personnel in LMICs to apply evidence-based treatments, there remains a massive mental health treatment gap, such that 75 % of those in LMICs never receive care. Here, we discuss the use of a new type of implementation science study design, the effectiveness-implementation hybrids, to speed the translation and scale up of mental health care in LMICs. We use our current study of Interpersonal Psychotherapy (IPT) delivered by local personnel for depression and trauma-related disorders among HIV+ women in Kenya as an example of effectiveness-implementation hybrid design for mental health services research in LMICs.


Data in support of optimized production of angiotensin-I converting enzyme inhibitory peptides derived from proteolytic hydrolysate of bitter melon seed proteins.
VY-7 has been demonstrated as a potent ACE inhibitory peptide in the previous study [1]. In this article, we provide accompanying data about the identification of bitter melon seed proteins (BMSPs), and quantitative analysis and optimized production of VY-7 in BMSPs hydrolysate.


Phase I Study of Niraparib in Combination with Radium-223 for the Treatment of Metastatic Castrate-Resistant Prostate Cancer.
To identify the safety of niraparib, a PARP inhibitor, in combination with Radium-223 for the treatment of metastatic castrate-resistant prostate cancer (mCRPC) in men without known BRCA mutations. Men with progressive mCPRC following ≥1 line of androgen receptor (AR)-targeted therapy and bone metastases but no documented BRCA-1 or BRCA-2 alterations or bulky visceral disease were included. Niraparib dose was escalated in combination with standard dosing of Radium-223 using a time-to-event continual reassessment method. The highest dose level with a DLT probability <20% was defined as MTD. Secondary endpoints included PSA change and progression-free survival. Exploratory analyses included assessing DNA mutations found in ctDNA as well as gene expression changes assessed in whole blood samples. Thirty patients were treated with niraparib and radium-223: 13 patients received 100 mg, 12 received 200 mg, and 5 patients received 300 mg of niraparib. There were six DLT events: two (13%) for neutropenia, two (13%) for thrombocytopenia, whereas fatigue and nausea each occurred once (3%). Anemia (2/13%) and neutropenia (2/13%) were the most common grade 3 adverse events. For patients with prior chemotherapy exposure, the MTD was 100 mg, whereas the MTD for chemotherapy naïve patients was 200 mg. Whole blood gene expression of PAX5 and CD19 was higher in responders and ARG-1, IL2R, and FLT3 expression was higher in nonresponders. Combining niraparib with Radium-223 in patients with mCRPC was safe; however, further studies incorporating biomarkers will better elucidate the role of combinations of PARP inhibitors with DNA damaging and other agents.


Brachial artery aneurysm in an infant: case report and review of the literature.
A case is reported of a congenital aneurysm of the brachial artery in a 9-month-old boy. The lesion was excised and the artery reconstructed with an end-to-end anastomosis. Review of the English language literature showed that brachial artery aneurysms in children usually occur in association with arteritis, connective tissue disorder, or a syndrome of multiple aneurysms of unknown origin.


Langerhans' cell histiocytosis of the spine in children with soft tissue extension and chemotherapy.
The objectives of this paper were to look into the possible incidence of obvious soft tissue extension from Langerhans' cell histiocytosis (LCH) of the spine in children and to evaluate the effects of chemotherapy for those patients. Eighteen patients with histopathological diagnosis of LCH were reviewed and nine with obvious paravertebral soft tissue extension were included in this study. Soft tissue extension was involved in the spinal canal and/or around the vertebral body in eight cases and posterior involvement was prevalent in one case. Eight patients experienced neurological symptoms. All received chemotherapy and one had surgical treatment. The mean follow-up time was 30.3 months. Soft tissue extension disappeared completely in all patients. No clinical evidence of disease was observed at the most recent follow-up. The incidence of LCH of the spine in children with obvious soft tissue extension was up to 50%. Chemotherapy is safe and effective, and surgical decompression was probably not necessary for most patients.


Variations in lipids and proteins of lipoproteins by fenofibrate in some hyperlipoproteinaemic states.
A total of 28 hyperlipoproteinaemic patients (8 type IIA, 12 type IIB and 8 type IV) were studied. Each patient was put on a 'prudent' isocaloric diet (50% carbohydrate, 30% fat, 20% protein) following a 2-month period of wash-out. Fenofibrate (300 mg/day) was then given for 2 periods of 2 months, each separated by a 2-month period in which only the dietary treatment was continued. Fenofibrate induced a significantly beneficial effect on the abnormal plasma levels of lipids and apolipoproteins A-I and B in all three phenotypes. Total cholesterol significantly decreased in type IIA and IIB; total triglycerides decreased significantly in all three types. HDL-C increased in all the patients but significantly only in those presenting types IIB and IV. ApoB significantly decreased in the 3 groups while apoA-I increased. The ratio apoA/apoB increased significantly in the three groups. Enzymatic parameters did not vary during the drug treatment. However, 6 patients (16%) dropped out because of gastro-intestinal side effects.


Differential Congo red staining: the effects of pH, non-aqueous solvents and the substrate.
Congo red is an acid-base indicator dye. In free solution the colour and absorption characteristics of Congo red depend not only on the pH but are also governed by the nature of the solvent environment. In tissue sections stained by Congo red, alteration of the pH and the use of non-aqueous solvents can effect differential colouring of the tissue components. Stained sections of unmodified and chemically substituted celluloses show that differential red or blue coloration reflects the acidic or basic character of the substrate. In stained tissue sections, secondary protein structure and porosity of the substrate may also influence their colour. The effect of non-aqueous solvents is probably to modify the ionization state of the dye-substrate complex, thus altering the colour of the Congo red. Such solvents may also change the aggregation or solvation states of the dye, with consequent modification in the colour of tissue components.


Immunofluorescent evidence for a specific binding site for phenytoin in the cerebellum.
The regional distribution of phenytoin in the brains of experimental animals was studied using the indirect fluorescent antibody technique. Using antibodies directed against phenytoin, we observed a specific pattern of staining the Purkinje and granule cell layers of the cerebellum. An identical pattern of staining was seen in phenytoin-treated and untreated animals. Several control procedures and studies indicated that the observed pattern was not caused by nonspecific staining or autofluorescence. The distinctive staining pattern obtained using this technique can be attributed to the high molecular specificity of antigen-antibody reactions and a discrete binding site for phenytoin in the vicinity of cerebellar Purkinje and granule cells.


An Internet administered treatment program for obsessive-compulsive disorder: a feasibility study.
The present study evaluates efficacy of a new Internet-administered cognitive behavioral therapy (CBT) protocol, The OCD Program, designed to treat obsessive-compulsive disorder (OCD) remotely. This protocol comprises 8 online lessons delivered over 8 weeks and incorporates cognitive and behavioral techniques. Twenty-two individuals with a principal diagnosis of OCD received CBT-based online lessons, homework assignments, twice weekly contact from a clinical psychologist, and automated emails. Eighty-one percent of participants completed the lessons within the 8-week program. Post-treatment and 3-month follow-up data were collected from 21/21 (100%) and 19/21 (91%) participants, respectively. Participants improved significantly on the primary outcome measures, the Yale-Brown Obsessive Compulsive Scale and Obsessive Compulsive Inventory-Revised, with within-groups effect sizes (Cohen's d) at follow-up of 1.28 and 0.60, respectively. Participants rated the procedure as highly acceptable despite receiving an average of only 86min (SD=54.4min) telephone contact with the therapist over the 8 weeks. These results provide preliminary support for efficacy of Internet-administered treatment for obsessive-compulsive disorder.


Posterior urethral valves as a cause of neonatal uriniferous perirenal pseudocyst (urinoma).
Two neonates with uriniferous perirenal pseudocysts (urinomas) secondary to posterior urethral valves are presented. Early diagnosis was achieved and both patients survived. The characteristic roentgenographic appearance of the pseudocyst is described. An investigation for lower urinary tract obstruction should always be undertaken when pseudocyst or ascites is seen in the neonate. Prompt diagnosis and treatment is essential to avoid irreversible renal damage, electrolyte or fluid imbalance, or respiratory compromise.


Enzymatic synthesis of chiral amino-alcohols by coupling transketolase and transaminase-catalyzed reactions in a cascading continuous-flow microreactor system.
Rapid biocatalytic process development and intensification continues to be challenging with currently available methods. Chiral amino-alcohols are of particular interest as they represent key industrial synthons for the production of complex molecules and optically pure pharmaceuticals. (2S,3R)-2-amino-1,3,4-butanetriol (ABT), a building block for the synthesis of protease inhibitors and detoxifying agents, can be synthesized from simple, non-chiral starting materials, by coupling a transketolase- and a transaminase-catalyzed reaction. However, until today, full conversion has not been shown and, typically, long reaction times are reported, making process modifications and improvement challenging. In this contribution, we present a novel microreactor-based approach based on free enzymes, and we report for the first time full conversion of ABT in a coupled enzyme cascade for both batch and continuous-flow systems. Using the compartmentalization of the reactions afforded by the microreactor cascade, we overcame inhibitory effects, increased the activity per unit volume, and optimized individual reaction conditions. The transketolase-catalyzed reaction was completed in under 10 min with a volumetric activity of 3.25 U ml-1 . Following optimization of the transaminase-catalyzed reaction, a volumetric activity of 10.8 U ml-1 was attained which led to full conversion of the coupled reaction in 2 hr. The presented approach illustrates how continuous-flow microreactors can be applied for the design and optimization of biocatalytic processes.


[Administrative delays of temporary recommendation for use: Impact on access to innovation in melanoma].
Melanoma has benefited in recent years from therapeutic innovations, which have improved overall survival of patients. France has developed a regulatory arsenal allowing faster access to innovative drugs before marketing authorization: temporary authorization for use (ATU) and temporary recommendation for use (RTU). We describe here the decision-making processes that led to the non-publication of the decree on the funding of three RTU in adjuvant melanoma therapy: nivolumab, pembrolizumab and the combination of dabrafenib and trametinib, and we analyse the fate of these drugs in order to quantify the potential loss of chance. On 03AUG2018, the French National Agency for Medicines and Health Product Safety (ANSM) published 3 RTU in order to give rapid access to major innovations in adjuvant melanoma therapy: nivolumab, pembrolizumab and the combination of dabrafenib and trametinib. These drugs have respectively demonstrated reductions in the risk of recurrence by 35 %, 43% and 55% for target populations of 2200, 1900 and 650 patients per year. Despite a favourable opinion on reimbursement from the French National Authority for Health (HAS), the decrees on reimbursement will never be published, prohibiting the use of these products before the marketing authorisation, and depriving many patients of a potential cure. Despite a favourable opinion from scientists and health agencies for the rapid availability of a drug, the French public health code does not systematically imply access to a therapeutic innovation. The reform of access to innovation implemented on 01JUL2021 may help tackle this issue.


Effect of local and general fatiguing exercises on disturbed and static postural control.
This study compared the effect of local and general fatiguing exercise on disturbed and static postural control performances. Surface electromyography and center of pressure signals were respectively recorded during self-initiated perturbation test and static postural stability test from 7 young male subjects. Local fatiguing exercise was performed using intermittent isometric knee extensions at the level of 40% of maximal voluntary torques. General fatiguing exercise was implemented with rowing ergometer at a speed of 200 ± 5 m/min. Results of disturbed postural tests showed no significant change of anticipatory postural adjustment (APAs) organizations in individual muscles following both fatiguing exercises, but observed larger APAs coactivations in trunk and dorsal muscle pairs following local than general fatiguing exercise, and larger compensatory postural adjustments (CPAs) coactivation in dorsal muscle pair after both fatiguing exercises. In addition, the results of static postural tests indicated efficient static postural stability accompanying the down-weighting of visual input and the up-weighting of vestibular/somatosensory component following both fatiguing exercises. These findings evidenced a general compensation in the central nervous system in response to the neuromuscular deficiencies induced by local fatiguing exercise and put forward the function of sensory recalibration in maintaining postural stability under fatigue conditions.


Callosal projection neurons in area 17 of the fetal rhesus monkey.
We have studied the distribution of callosal projection neurons in area 17 of a fetal rhesus monkey which received large injections of horseradish peroxidase into the contralateral occipital cortex. In comparison to other cortical areas, area 17 contains few callosal projection neurons. Most of these cells are confined to a region extending tangentially about 2.5 mm from the 17/18 border, although a few neurons were noted as much as 5 mm from the border. Comparing the distribution of callosal projection neurons in the fetal monkey with what has been described in newborn and adult macaques, it is apparent that although some degree of refinement in striate callosal connections may occur during in utero development, the prenatal development of callosal connections in the macaque is inherently adult-like.


Baclofen-mediated gastro-oesophageal acid reflux control in patients with established reflux disease.
To explore the effect of baclofen on oesophageal acid exposure in patients with gastro-oesophageal reflux disease. Twenty patients with established reflux disease were included in this double-blind, randomized, crossover study. Baclofen, 40 mg, or placebo was given as a single dose with a washout period of 4 weeks. Symptoms were assessed by a visual analogue scale. Oesophageal pH was registered for 12 h and analysed for the whole period and for the 0-4-h, 4-8-h, 8-12-h and 2-h post-prandial periods. Baclofen significantly reduced the number of reflux episodes during the 0-4-h (7.9 vs. 16.5, P < 0.0001; post-prandially: 6.0 vs. 11.2, P < 0.0001) and 0-12-h (46.5 vs. 73, P=0.0001; post-prandially: 18.8 vs. 29.3, P < 0.0001) periods. The fraction of time with pH < 4 was significantly lowered during the 0-4-h period (9.3 vs. 15.6, P=0.0019; post-prandially: 16.1 vs. 23.5, P=0.0083). Similar results were also obtained in patients with a hiatus hernia (n=13). Belching was significantly reduced (32 vs. 69 episodes, P < 0.01). A single oral dose of 40 mg baclofen significantly reduced both the number of reflux episodes and the fraction of time with pH < 4, an effect primarily found during the first 4 h after dosing.


A comparison of outcome in patients with preoperative atrial fibrillation and patients in sinus rhythm.
Approximately 10% to 15% of patients undergoing cardiac operations suffer from atrial fibrillation (AF) at the time of surgery. The current risk stratification methods do not include preoperative arrhythmias. The aim of this study was to assess the effect of preoperative AF on the immediate postoperative outcome of patients undergoing cardiac surgery as well as in the midterm and long-term outcomes. We reviewed patient data for our institution for a 10-year period; a total of 14,320 patients undergoing any cardiac operation were included; 12,395 (86.5%) had sinus rhythm preoperatively and 1,925 (13.5%) were in persistent AF. After propensity matching and adjusting for the preoperative and operative characteristics, 1,800 patients remained in each group and were compared. Before and after adjusting for the preoperative and operative characteristics, inotropic support, ventilation time, renal failure, stroke, and surgical wound infection rates were all significantly higher for the patients with AF (p < 0.001). Intensive care unit stay and hospital stay as well as in-hospital mortality were also significantly higher among the patients with AF compared with the sinus rhythm group (p < 0.001). At 30 days, 5-year and 10-year mortality rates in the AF group were significantly higher compared with those in sinus rhythm group (p < 0.001). Atrial fibrillation preoperatively is associated with a higher incidence of postoperative complications. This arrhythmia is an important variable that appears to have been excluded from the current risk stratification systems. Our experience suggests that AF should be considered in the development/update of risk-stratifying methodologies to improve the predictive accuracy.


eSPRESSO: topological clustering of single-cell transcriptomics data to reveal informative genes for spatio-temporal architectures of cells.
Bioinformatics capability to analyze spatio-temporal dynamics of gene expression is essential in understanding animal development. Animal cells are spatially organized as functional tissues where cellular gene expression data contain information that governs morphogenesis during the developmental process. Although several computational tissue reconstruction methods using transcriptomics data have been proposed, those methods have been ineffective in arranging cells in their correct positions in tissues or organs unless spatial information is explicitly provided. This study demonstrates stochastic self-organizing map clustering with Markov chain Monte Carlo calculations for optimizing informative genes effectively reconstruct any spatio-temporal topology of cells from their transcriptome profiles with only a coarse topological guideline. The method, eSPRESSO (enhanced SPatial REconstruction by Stochastic Self-Organizing Map), provides a powerful in silico spatio-temporal tissue reconstruction capability, as confirmed by using human embryonic heart and mouse embryo, brain, embryonic heart, and liver lobule with generally high reproducibility (average max. accuracy = 92.0%), while revealing topologically informative genes, or spatial discriminator genes. Furthermore, eSPRESSO was used for temporal analysis of human pancreatic organoids to infer rational developmental trajectories with several candidate 'temporal' discriminator genes responsible for various cell type differentiations. eSPRESSO provides a novel strategy for analyzing mechanisms underlying the spatio-temporal formation of cellular organizations.


Adaptive reaction of nigral neurons following lesion of their ventromedial-thalamic projection field.
The response of reticulata-nigral neurons to injury of their ventromedial-thalamic (VM) projection was studied in the rat, by the autoradiographic [14C]deoxyglucose method. Electrolytic lesion of the VM induced reversible: reticulata hypoexcitability; and hyporesponsiveness of areas receiving reticulata efferents, to nigral electrical stimulus. The results suggest that distal axonal injury (in the VM) induces reversible rearrangement of functional properties in the nigral parent cells and their uninjured collaterals, as a retrograde reaction.