Comparison of assay systems for detecting antibodies to nuclear ribonucleoproteins.
The specificity and sensitivity of two commercial enzyme linked immunosorbent assays (ELISAs), Diamedix (Miami, Florida) and Lipogen (Noxville, Tennessee), were assessed and compared with haemagglutination and immunodiffusion assays. Sera from 53 patients with various connective tissue disorders were examined for the presence of antibodies to nuclear antigens (ANA), double stranded DNA (dsDNA), Sm, RNP, SSA/Ro, and SSB/La. Of the 53 patients, 42 were ANA positive, 11 were ANA negative, and 22 had antibodies to dsDNA. Seven patients had antibodies to Sm by haemagglutination assay; these were also positive in both ELISA systems (only five of the seven patients were assayed by the Lipogen ELISA system). Two additional Sm positive values were obtained in each of the ELISA systems but only one of these was positive in both. Ten positive RNP results were obtained by haemagglutination and nine of these were also positive by the Diamedix ELISA. Only eight samples were tested by the Lipogen assay and seven of these were positive. Three additional RNP positive values were obtained by the Diamedix and six by the Lipogen ELISA assays. Of these, only two were positive in both. Antibodies to SSA/Ro were obtained in 11 patients by immunodiffusion and lines of partial identity were observed in nine. SSB/La antibodies were positive in six patients and two had lines of partial identity. All the SSA/Ro and SSB/La positive sera were also positive in both ELISA systems. Moreover, eight additional SSA/Ro positive values were obtained in each of the ELISAs, four of which had partial identity lines in the immunodiffusion assay. Furthermore, three additional SSB/La positive values were obtained by the Diamedix and four by the Lipogen assays. Of these, only two were positive in both ELISAs. This study shows that the above ELISAs are comparable in specificity and sensitivity with haemagglutination assay for detection of antibodies to Sm and RNP antigens and are more sensitive than immunodiffusion for the detection of SSA/Ro and SSB/La antigens.


Technologies for interprofessional education: the interprofessional education-distributed "e-Classroom-of-the-Future".
Communications strategies are central to the planning and execution of interprofessional education (IPE) programs. The diversity of telecommunications-based tools and platforms available for IPE is rapidly expanding. Each tool and platform has a potentially important role to play. The selection, testing, and embedding of tools, such as social networking platforms, within education programs can be very challenging. The goal was to create, in Phoenix, a "command-and-control" video conferencing center (the T-Health Amphitheater or Telehealth Amphitheater) in which tele-consultation patients, located physically at one of the affiliated tele-clinics around the state, could be presented electronically to interprofessional teams of faculty members from the University of Arizona Colleges of Medicine, Nursing, Pharmacy, and Public Health, as well as those from the allied health colleges of other universities in Arizona, for interprofessional team training in a virtual classroom setting. The T-Health video conferencing facility was designed and built. Early assessments show that its novel learning environment is student- and faculty-friendly. T-Health Amphitheater's pair of innovative visible social networking platforms (eStacks™ and eSwaps™) may help break down some of the traditional communications barriers encountered in healthcare IPE and medical practices.


[Laparoscopy for the diagnostic and treatment of the acute appendicitis].
Results of diagnostics and treatment of patients with acute appendicitis, operated on laparoscopically during 2007-2009, were analyzed. Indications and contraindications for the use of laparoscopic method, as well as indications to conversion to traditional open access, were defined. Operative technique for different forms of appendicitis and clinical situations was described. Postoperative complications were analyzed with the use of clinical cases. Ways of decreasing its rate were suggested.


Flavodoxin with an air-stable flavin semiquinone in a green sulfur bacterium.
Flavodoxins are small proteins with a non-covalently bound FMN that can accept two electrons and accordingly adopt three redox states: oxidized (quinone), one-electron reduced (semiquinone), and two-electron reduced (quinol). In iron-deficient cyanobacteria and algae, flavodoxin can substitute for ferredoxin as the electron carrier in the photosynthetic electron transport chain. Here, we demonstrate a similar function for flavodoxin from the green sulfur bacterium Chlorobium phaeovibrioides (cp-Fld). The expression of the cp-Fld gene, found in a close proximity with the genes for other proteins associated with iron transport and storage, increased in a low-iron medium. cp-Fld produced in Escherichia coli exhibited the optical, ERP, and electron-nuclear double resonance spectra that were similar to those of known flavodoxins. However, unlike all other flavodoxins, cp-Fld exhibited unprecedented stability of FMN semiquinone to oxidation by air and difference in midpoint redox potentials for the quinone-semiquinone and semiquinone-quinol couples (- 110 and - 530 mV, respectively). cp-Fld could be reduced by pyruvate:ferredoxin oxidoreductase found in the membrane-free extract of Chl. phaeovibrioides cells and photo-reduced by the photosynthetic reaction center found in membrane vesicles from these cells. The green sulfur bacterium Chl. phaeovibrioides appears thus to be a new type of the photosynthetic organisms that can use flavodoxin as an alternative electron carrier to cope with iron deficiency.


Immediate Effects of two Isometric Calf Muscle Exercises on Mid-portion Achilles Tendon Pain.
The objectives of this randomized, cross-over pilot study were to determine whether isometric plantarflexion exercises resulted in an immediate change in Achilles tendon pain during a loading task, and whether this differed in knee extension or flexion. Eleven participants with mid-portion Achilles tendinopathy were recruited from NHS community physiotherapy services and local running clubs. Participants were then randomized to complete an isometric calf muscle exercise with the knee fully extended or flexed to 80°. Participants switched to the alternate exercise after a minimum seven-day period. Achilles tendon pain during a specific, functional load test was measured on a 11-point numeric pain rating scale (NPRS) pre- and post-intervention. There was a small, immediate, mean reduction in pain following isometric plantar flexion performed in both knee extension (1.6, 95%CI 0.83 to 2.45, p=0.001) and knee flexion (1.3, 95%CI 0.31 to 2.19, p=0.015). There were no significant differences between the two positions. A non-significant, potentially clinically relevant finding was a 20% larger reduction in symptoms in knee extension versus flexion (p=0.110). In conclusion, isometric plantarflexion holds gave an approximately 50% immediate reduction in Achilles tendon pain with a functional load test. There were no significant differences between the two positions and both were well tolerated.


Microneedle-mediated gene delivery for the treatment of ischemic myocardial disease.
Cardiovascular disorders are still the primary cause of mortality worldwide. Although intramyocardial injection can effectively deliver agents to the myocardium, this approach is limited because of its restriction to needle-mediated injection and the minor retention of agents in the myocardium. Here, we engineered phase-transition microneedles (MNs) coated with adeno-associated virus (AAV) and achieved homogeneous distribution of AAV delivery. Bioluminescence imaging revealed the successful delivery and transfection of AAV-luciferase. AAV-green fluorescent protein-transfected cardiomyocytes were homogeneously distributed on postoperative day 28. AAV-vascular endothelial growth factor (VEGF)-loaded MNs improved heart function by enhancing VEGF expression, promoting functional angiogenesis, and activating the Akt signaling pathway. The results indicated the superiority of MNs over direct muscle injection. Consequently, MNs might emerge as a promising tool with great versatility for delivering various agents to treat ischemic myocardial disease.


Pharmacological manipulation of cyclic GMP levels in brain restores learning ability in animal models of hepatic encephalopathy: therapeutic implications.
Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome present in patients with liver disease that includes impaired intellectual function. To develop therapeutic treatments to restore cognitive function, it is important to understand the molecular mechanisms that impair cognitive function in HE. This review summarizes data showing that: (a) cognitive function and learning are impaired in patients with liver disease and in animal models of chronic liver failure or hyperammonemia; (b) the glutamate-NO-cGMP pathway modulates some forms of learning; and (c) the function of this pathway is impaired in brain in vivo in rats with chronic hyperammonemia or liver failure and from patients who died from HE. Learning ability of hyperammonemic rats was restored by increasing cGMP by: (1) continuous intracerebral administration of zaprinast, an inhibitor of the cGMP-degrading phosphodiesterase; (2) chronic oral administration of sildenafil, an inhibitor of the phosphodiesterase that crosses the blood-brain barrier; and (3) continuous intracerebral administration of cGMP. The data summarized indicate that impairment of learning ability in rats with chronic liver failure or hyperammonemia is due to impairment of the glutamate-NO-cGMP pathway. Moreover, increasing extracellular cGMP by pharmacological means may be a new therapeutic approach to improve cognitive function in patients with HE.


[Eosinophilic granuloma of the cervical spine: case report].
Eosinophilic granuloma (EG) is a benign condition of histocytes proliferation localized or multifocal. It is presents in the cervical spine in 1.5%-20% of the cases of EG. We report the case of a seven-year-old girl that presented with a one month history of cervical pain, persistent wryneck and vicious posture of the neck. A computerized tomography was performed and confirmed the presence of spreading lesion, ostheodestructive to the level of the left laminae of C2, with invasion of the spine and the muscular tissue. A laminectomy was underwent for removal of the lesion. The patient had a good post-operative recovery with improvement of the symptoms. Chemotherapy with prednisone, vinblastine and ethoposide was administred. After six months, this protocol was repeated associaded to methotrexate. The patient improved and had no new symptoms in a follow-up of 36 months.


Ocular toxicity in children exposed in utero to antimalarial drugs: review of the literature.
The antimalarial drugs chloroquine (CQ) and hydroxychloroquine (HCQ) have been used for decades to treat rheumatic diseases. CQ is still beneficial for the management of malaria during pregnancy. A growing body of research suggests that antimalarials are safe during pregnancy. There have been concerns about adverse longterm effects, mainly retinal toxicity, in offspring of women exposed to antimalarials during pregnancy. Our objective was to review the published evidence on safety of antimalarials during pregnancy, focusing on ocular toxicity in the offspring. Ovid Medline, Embase, and Cochrane Library databases were searched for the period from their inception to May 2010 inclusive with no restrictions on language or year of publication. Randomized controlled trials (RCT) and observational studies examining the safety of CQ or HCQ during pregnancy and reporting on visual function or ocular toxicity in the offspring of exposed women at any point of the followup were eligible for inclusion. The quality of evidence was assessed according to established criteria (the GRADE approach). Twelve studies with a total of 588 offspring born to mothers treated with CQ or HCQ during pregnancy met the inclusion criteria. Five studies with a total of 251 exposed children reported no clinical visual abnormalities in any case. In an RCT on malaria prophylaxis, visual acuity in 251 infants exposed to CQ in utero did not differ from the placebo group. Detailed ophthalmological examination was performed in 4 studies and normal results were reported in all children (n = 59). Electro-physiological testing using electroretinogram was performed in 3 small cohorts and results were normal in all but 6 infants aged 3-7 months. All 6 children had normal fundoscopy before 4 years of age. Heterogeneity in comparison groups and in outcome measures precluded formal metaanalysis. Current evidence suggests no fetal ocular toxicity of antimalarial medications during pregnancy. The clinical significance of early electroretinogram anomalies reported in a small subset of infants remains to be established. Larger followup studies are warranted to confirm low risk of ocular toxicity in children following antenatal exposure to antimalarial medications.


Thermal behavior and coloration study of silica-coated alpha-Fe2O3 and beta-FeOOH nanocapsules.
This manuscript reports characterization of the colorations and thermal behaviors of the silica-coated alpha-Fe2O3 and beta-FeOOH nanocapsules. Prepared beta-FeOOH and alpha-Fe2O3 nanoparticles were coated with silica using tetraethylorthosilicate (TEOS) and cetyltrimethyl-ammonium bromide (CTAB) as a surface modifier for the comparison of physical properties of both samples. XRD patterns of the silica-coated beta-FeOOH and alpha-Fe2O3 nanoparticles were heated to 1000 degrees C, show a hematite (alpha-Fe2O3) structure. The silica-coated beta-FeOOH nanoparticles became almost entirely hollow at 1000 degrees C due to their volume reduction. In addition, the coloration values of the transformation nano capsule alpha-Fe2O3 are lower than those of the silica-coated alpha-Fe2O3 nanostructures. On the other hand, the silica-coated alpha-Fe2O3 nanoparticles retained their colorations and shapes after being heated to 1000 degrees C. The morphologies, crystal structures and colorations of the as prepared samples were analyzed by scanning electron microscope (SEM), transmission electron microscope (TEM), X-ray diffraction and CIE colorimeter.


The chicken transforming growth factor-beta 3 gene: genomic structure, transcriptional analysis, and chromosomal location.
In this paper, we report the isolation, characterization, and mapping of the chicken transforming growth factor-beta 3 (TGF-beta 3) gene. The gene contains seven exons and six introns spanning 16-kb of the chicken genome. A comparison of the 5'-flanking regions of human and chicken TGF-beta 3 genes reveals two regions of sequence conservation. The first contains ATF/CRE and TBP/TATA sequence motifs within an 87-bp region. The second is a 162-bp region with no known sequence motifs. Identification of transcription start sites using chicken RNA isolated from various embryonic and adult tissues reveals two sites of initiation, P1 and P2, which map to these two conserved regions. Comparison of 3'-flanking regions of chicken and mammalian TGF-beta 3 genes also revealed conserved sequences. The most significant homologies were found in the 3'-most end of the transcribed region. DNA sequence analysis of chicken TGF-beta 3 cDNAs isolated by 3'-RACE revealed multiple polyadenylation sites unusually distant from a poly(A) signal motif. A Msc I restriction fragment length polymorphism (RFLP) marker was used to map the TGFB3 locus to linkage group E7 on the East Lansing reference backcross. Linkage to the TH locus showed that the TGFB3 locus was physically located on chicken chromosome 5.


A pilot study of intensive cyclophosphamide, epirubicin and fluorouracil in patients with axillary node positive or locally advanced breast cancer.
A multicentre pilot study has been conducted to determine an intensive regimen of cyclophosphamide, epirubicin, and fluorouracil which was tolerable and acceptable to patients with node positive breast cancer. Consecutive patients with operable axillary node positive breast cancer (T1-3, N1-2, M0), 266 patients, or locally advanced breast cancer (T4), 22 patients, were treated with cyclophosphamide post-operatively for 14 days and epirubicin and fluorouracil, both intravenously on days 1 and 8. Each cycle was repeated monthly for 6 months. Dosages were increased according to predetermined guidelines. Outcome measures were admission to hospital for febrile neutropenia and change in cardiac function as assessed by radionuclide angiography. The first 46 patients were treated at the doses of cyclophosphamide = 75 mg/m2, epirubicin = 50 mg/m2, fluorouracil = 375 mg/m2 (level 1), then 42 patients at cyclophosphamide = 75 mg/m2, epirubicin = 50 mg/m2 and fluorouracil = 500 mg/m2 (level 2), 69 patients at cyclophosphamide = 75 mg/m2, epirubicin = 60 mg/m2, and fluorouracil = 500 mg/m2 (level 3), and 42 patients at cyclophosphamide = 75 mg/m2, epirubicin = 70 mg/m2, and fluorouracil = 500 mg/m2 with concurrent antibiotics (level 4). The rates of febrile neutropenia were 8.7% (level 1), 7.1% (level 2), 18.8% (level 3), and 31% (level 4), respectively, P = 0.002. Accrual to level 4 was discontinued according to study guidelines and a further 89 patients were recruited at level 3 dosages with antibiotic prophylaxis (level 3a), resulting in a 5.6% rate of febrile neutropenia. The difference in febrile neutropenia rates between levels 3 and 3a was statistically significant. There were no toxic deaths and 2 cases of heart failure. In conclusion, through a careful dose-finding study in patients with operable or locally advanced breast cancer, an intensive epirubicin-containing adjuvant regimen has been established which is presently being compared with standard CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy in a randomised trial. In addition, this study suggests that antibiotic prophylaxis reduces the risk of febrile neutropenia in breast cancer patients receiving intensive chemotherapy.


Hedgehog Signaling Pathway Proteins in Prognosis of Pancreatic Ductal Adenocarcinoma and Its Differentiation From Chronic Pancreatitis.
The Hedgehog signaling pathway (Hh) probably plays a role in development and progression of pancreatic ductal adenocarcinoma (PDAC). In our study, 114 patients (83 with PDAC and 31 with chronic pancreatitis [CP]) after pancreatic surgery were enrolled. The immunoexpression of Sonic hedgehog (Shh), Smoothened (Smo), and Glioblastoma transcription factor 1 (Gli1) and Ki-67 were detected in tissue specimens. Mean (standard deviation) immunoexpression of all Hh pathway molecules was significantly higher in PDAC than in CP patients: Shh, 2.24 (0.57) versus 1.17 (0.25) (P < 0.01); Smo, 2.62 (0.34) versus 1.21 (0.23) (P < 0.01); and Gli1, 1.74 (0.74) versus 1.15 (0.72) (P < 0.01). Patients with a lower expression level (z score <0) of Shh and Ki-67 have longer overall survival when compared with z score >0 (15.97 vs 8.53 months [P = 0.0087] and 15.20 vs 5.53 months [P = 0.0004], respectively). In addition, Shh sensitivity in PDAC detection was 84.3%; specificity, 93.5%; positive predictive value, 97.2%; and negative predictive value, 69%. Our results suggest the prognostic role of the Hh pathway in PDAC and a role in the differential diagnosis with CP.


Colonic spirochetosis is associated with colonic eosinophilia and irritable bowel syndrome in a general population in Sweden.
Irritable bowel syndrome (IBS) is a functional disorder defined by symptoms in the absence of overt pathology. Colonic spirochetosis (CS), defined by histologic observation of spirochetal strains of Brachyspira in colonic biopsies, is uncommon and considered of doubtful significance. We aimed to determine the prevalence of CS in the general population, identify subtle colon pathologies, and evaluate a link with symptoms of IBS. Colonoscopy was performed in 745 subjects (aged 19-70 years, mean age 51 years, 43% male) with biopsies (ileum and 4 colonic sites) from a random population sample, Stockholm, Sweden, who completed a validated questionnaire of gastrointestinal symptoms; IBS was identified by Rome III criteria. CS was identified by histology and immunohistochemistry. In a general population, 17 individuals (2.28%; 95% confidence interval, 1.2%-3.5%) were diagnosed as having CS by histology; 6 (35%) had IBS. CS was always present in the sigmoid colon, but only 14 rectal biopsies. Eosinophils were increased in colon biopsies in CS cases versus controls, in the transverse (P = .02), sigmoid colon (P = .001), and rectum (P = .0005) with subepithelial eosinophil clusters (P = .053). Lymphoid follicles (at any site) were present in 13 CS (P = .0003). There was a 3-fold increased risk of IBS in CS (odds ratio, 3.59; 95% confidence interval, 1.27-10.11; P = .015). Polyps and diverticular disease were similar in CS cases and controls. The prevalence of CS in a general population is 2% and associated with nonconstipating IBS. Colonic eosinophilia with lymphoid follicles may signify the presence of CS.


Effect of task-related extracerebral circulation on diffuse optical tomography: experimental data and simulations on the forehead.
The effect of task-related extracerebral circulatory changes on diffuse optical tomography (DOT) of brain activation was evaluated using experimental data from 14 healthy human subjects and computer simulations. Total hemoglobin responses to weekday-recitation, verbal-fluency, and hand-motor tasks were measured with a high-density optode grid placed on the forehead. The tasks caused varying levels of mental and physical stress, eliciting extracerebral circulatory changes that the reconstruction algorithm was unable to fully distinguish from cerebral hemodynamic changes, resulting in artifacts in the brain activation images. Crosstalk between intra- and extracranial layers was confirmed by the simulations. The extracerebral effects were attenuated by superficial signal regression and depended to some extent on the heart rate, thus allowing identification of hemodynamic changes related to brain activation during the verbal-fluency task. During the hand-motor task, the extracerebral component was stronger, making the separation less clear. DOT provides a tool for distinguishing extracerebral components from signals of cerebral origin. Especially in the case of strong task-related extracerebral circulatory changes, however, sophisticated reconstruction methods are needed to eliminate crosstalk artifacts.


Identification of a novel fungus, Leptosphaerulina chartarum SJTU59 and characterization of its xylanolytic enzymes.
Xylanolytic enzymes are widely used in processing industries, e.g., pulp and paper, food, livestock feeds, and textile. Furthermore, certain xylanotic enzymes have demonstrated the capability to improve the resistance and immunity of plants. Screening of high-yield microbial xylanolytic enzyme producers is significant for improving large-scale cost-effective xylanolytic enzyme production. This study provided new evidence of high-level xylanolytic enzyme production by a novel fungus, designated Leptosphaerulina chartarum SJTU59. Under laboratory conditions, L. chartarum SJTU59 produced xylanolytic enzymes of up to 17.566 U/mL (i.e., 878.307 U/g substrate). The enzyme solution was relatively stable over a wide range of pH (pH 3.0 to pH 9.0) and temperature (40°C to 65°C) while showing high resistance to the majority of metal ions tested. Composition analysis of the hydrolytic products of xylan showed sufficient degradation by xylanolytic enzymes from L. chartarum SJTU59, mainly the monosaccharide xylose, and a small amount of xylobiose were enzymatically produced; whereas in the presence of sufficient xylan substrates, mainly xylooligosaccharides, an emerging prebiotic used in food industry, were produced. In addition, the xylanolytic enzyme preparation from L. chartarum SJTU59 could initiate tissue necrosis and oxidative burst in tobacco leaves, which may be related to enhanced plant defense to adversity and disease. L. chartarum SJTU59 possessed a complex xylanolytic enzyme system, from which two novel endo-β-1,4-xylanases of the glycoside hydrolase (GH) family 10, one novel endo-β-1,4-xylanase of the GH family 11, and one novel β-xylosidase of the GH family 43 were obtained via rapid amplification of complementary DNA ends. Given the high yield and stable properties of xylanolytic enzymes produced by L. chartarum SJTU59, future studies will be conducted to characterize the properties of individual xylanolytic enzymes from L. chartarum SJTU59. xylanolytic enzymes-encoding gene(s) of potential use for industrial and agricultural applications will be screened to construct genetically engineered strains.


Self-reported medication nonadherence predicts cholesterol levels over time.
Self-report measures of medication nonadherence are frequently adapted to new clinical populations without evidence of validity. We evaluated the predictive validity of a medication nonadherence measure previously validated in patients with hypertension among patients taking cholesterol-reducing medications. This secondary analysis involves data from a randomized trial (VA HSR&D IIR 08-297) conducted at the Durham Veterans Affairs Medical Center. At baseline, 6-months, and 12-months, serum cholesterol was obtained and participants (n = 236) completed a 3-item measure of extent of nonadherence to cholesterol-reducing medications. Two cross-lagged panel models with covariates, in addition to growth curve analysis, were used to examine the predictive utility of self-reported nonadherence on concurrent and future cholesterol levels, while accounting for potential reverse-causation. Extent of nonadherence items produced reliable scores across time and fit a single-factor model (CFI = 0.99). Nonadherence, and changes in nonadherence, moderately predicted future cholesterol values, and changes in cholesterol values (7 of 9 longitudinal associations were significant at p < .05; B's ranged from 0.16 to 0.35). Evidence for reverse associations was weaker (3 of 9 longitudinal associations were significant at p < .05; B's ranged from 0.16 to 0.36). Analyses support the predictive validity of this medication nonadherence measure over the competing reverse-causation hypothesis.


Cytidine monophosphate N-acetylneuraminic acid synthetase enhances invasion of human triple-negative breast cancer cells.
Cancer cells have altered bioenergetics, which contributes to their ability to proliferate, survive in unusual microenvironments, and invade other tissues. Changes in glucose metabolism can have pleomorphic effects on tumor cells. To investigate potential mechanisms responsible for the increased malignancy associated with altered glucose metabolism, we used an unbiased nuclear magnetic resonance spectroscopy screening method to identify glucose metabolites differentially produced in a highly malignant human triple-negative breast cancer (TNBC) cell line (BPLER) and a less malignant isogenic TNBC cell line (HMLER). N-acetylneuraminic acid (Neu5Ac), the predominant sialic acid derivative in mammalian cells, which forms the terminal sugar on mucinous cell surface glycoproteins, was the major glucose metabolite that differed. Neu5Ac was ~7-fold more abundant in BPLER than HMLER. Loss of Neu5Ac by enzymatic removal or siRNA knockdown of cytidine monophosphate N-acetylneuraminic acid synthetase (CMAS), which activates cellular sialic acids for glycoprotein conjugation, had no significant effect on cell proliferation, but decreased the ability of BPLER to invade through a basement membrane. Conversely, overexpressing CMAS in HMLER increased invasivity. TNBCs in The Cancer Genome Atlas also had significantly more CMAS copy number variations and higher mRNA expression than non-TNBC, which have a better prognosis. CMAS knockdown in BPLER ex vivo blocked xenograft formation in mice. Neu5Ac is selectively highly enriched in aggressive TNBC, and CMAS, the enzyme required for sialylation, may play an important role in TNBC tumor formation and invasivity.


An Unusual Cervical Mass in the Hyoid Bone: Intermediate-Grade Chondrosarcoma.
We describe a case of a 31-year-old woman with a chondrosarcoma of the hyoid bone. The patient presented with a mass in the left submandibular region. Fine-needle aspiration cytology suggested chondroma, but further imaging investigation with CT revealed an exophytic tumor originating from the body of the hyoid bone. Histopathology of the surgical specimen confirmed the diagnosis of a intermediate-grade chondrosarcoma. Chondrosarcomas account for 11% of all bone cancers. Primary sites of the head and the neck include the nasal cavity, the skull base, the maxilla, the mandible. Chondrosarcomas of the hyoid bone are very rare, with only 23 cases previously reported in the literature.


Axial elongation of caudalized human organoids mimics aspects of neural tube development.
Axial elongation of the neural tube is crucial during mammalian embryogenesis for anterior-posterior body axis establishment and subsequent spinal cord development, but these processes cannot be interrogated directly in humans as they occur post-implantation. Here, we report an organoid model of neural tube extension derived from human pluripotent stem cell (hPSC) aggregates that have been caudalized with Wnt agonism, enabling them to recapitulate aspects of the morphological and temporal gene expression patterns of neural tube development. Elongating organoids consist largely of neuroepithelial compartments and contain TBXT+SOX2+ neuro-mesodermal progenitors in addition to PAX6+NES+ neural progenitors. A critical threshold of Wnt agonism stimulated singular axial extensions while maintaining multiple cell lineages, such that organoids displayed regionalized anterior-to-posterior HOX gene expression with hindbrain (HOXB1) regions spatially distinct from brachial (HOXC6) and thoracic (HOXB9) regions. CRISPR interference-mediated silencing of TBXT, a Wnt pathway target, increased neuroepithelial compartmentalization, abrogated HOX expression and disrupted uniaxial elongation. Together, these results demonstrate the potent capacity of caudalized hPSC organoids to undergo axial elongation in a manner that can be used to dissect the cellular organization and patterning decisions that dictate early human nervous system development.


How COVID-19 exposed pre-existing roadblocks for cancer control in Africa: strategies, lessons and recommendations from the 2019-2020 Africa Cancer Research and Control ECHO.
The COVID-19 related mitigation measures adversely affected various cancer control activities in Africa, with cancer prevention and screening activities amongst the most significantly impacted. When the COVID-19 pandemic struck, the Africa Cancer Research and Control ECHO utilised their virtual platform to share experiences and knowledge of how to continue cancer service delivery during the pandemic. This analysis describes the evolved strategies, dilemmas, and recommendations to strengthen the health systems for cancer control in Africa. Eleven 1-hour-long sessions about the then newly emerging coronavirus infection and its impact on cancer control in Africa were held from April 2020 to August 2020, using Zoom®. An average of 39 participants attended the sessions including scientists, clinicians, policymakers and global partners. Sessions were analysed thematically. Most strategies to maintain cancer services during the COVID-19 pandemic centred around cancer treatment, with few strategies on maintaining cancer prevention services, early detection, palliative care and research services. The most mentioned challenge during the pandemic was fear of exposure to COVID-19 infection at the health facility during diagnosis, treatment or follow-up for cancer care. Other challenges were disruptions to service delivery, inaccessibility of cancer treatment, disruption of research activities and a lack of psychosocial support for COVID-19 related fear/anxiety. Significantly, this analysis shows that the COVID-19 related mitigation measures exacerbated existing predicaments in Africa, such as inadequate attention to cancer prevention strategies, psychosocial and palliative services and cancer research. The Africa Cancer ECHO recommends African countries to leverage the infrastructure developed in response to COVID-19 pandemic to strengthen the health system along the entire cancer control continuum. This calls for urgent action to develop and implement evidence-based frameworks and comprehensive National Cancer Control Plans that will withstand any future disruptions.


Correlations between clinical severity, genotype and muscle pathology in limb girdle muscular dystrophy type 2A.
Limb girdle muscular dystrophy type 2A (LGMD2A) is characterised by wide variability in clinical features and rate of progression. Patients with two null mutations usually have a rapid course, but in the remaining cases (two missense mutations or compound heterozygote mutations) prognosis is uncertain. We conducted what is to our knowledge the first systematic histopathological, biochemical and molecular investigation of 24 LGMD2A patients, subdivided according to rapid or slow disease progression, to determine if some parameters could correlate with disease progression. We found that muscle histopathology score and the extent of regenerating and degenerating fibres could be correlated with the rate of disease course when the biochemical and molecular data do not offer sufficient information. Comparison of clinical and muscle histopathological data between LGMD2A and four other types of LGMD (LGMD2B-E) also gave another important and novel result. We found that LGMD2A has significantly lower levels of dystrophic features (ie degenerating and regenerating fibres) and higher levels of chronic changes (ie lobulated fibres) compared with other LGMDs, particularly LGMD2B. These results might explain the observation that atrophic muscle involvement seems to be a clinical feature peculiar to LGMD2A patients. Distinguishing patterns of muscle histopathological changes in LGMD2A might reflect the effects of a disease-specific pathogenetic mechanism and provide clues complementary to genetic data.


Ex-vivo sensitivity profiling to guide clinical decision making in acute myeloid leukemia: A pilot study.
A precision medicine approach is appealing for use in AML due to ease of access to tumor samples and the significant variability in the patients' response to treatment. Attempts to establish a precision medicine platform for AML, however, have been unsuccessful, at least in part due to the use of small compound panels and having relatively slow turn over rates, which restricts the scope of treatment and delays its onset. For this pilot study, we evaluated a cohort of 12 patients with refractory AML using an ex vivo drug sensitivity testing (DST) platform. Purified AML blasts were screened with a panel of 215 FDA-approved compounds and treatment response was evaluated after 72h of exposure. Drug sensitivity scoring was reported to the treating physician, and patients were then treated with either DST- or non-DST guided therapy. We observed survival benefit of DST-guided therapy as compared to the survival of patients treated according to physician recommendation. Three out of four DST-treated patients displayed treatment response, while all of the non-DST-guided patients progressed during treatment. DST rapidly and effectively provides personalized treatment recommendations for patients with refractory AML.


Pathogens in early-onset and late-onset intensive care unit-acquired pneumonia.
To compare the type of pathogens isolated from patients with early-onset intensive care unit (ICU)-acquired pneumonia with those isolated from patients with late-onset ICU-acquired pneumonia and to study risk factors for the isolation of pathogens that are potentially resistant to multiple drugs. Prospective cohort study. Patients admitted to the ICU of a 677-bed, university-affiliated teaching hospital in Belgium during 1997-2002. ICU-acquired pneumonia was defined as a case of pneumonia that occurred 2 days or more after admission to the ICU in combination with a positive results of radiologic analysis, clinical signs and symptoms, and a positive culture result. All cases of pneumonia were categorized as either early onset (within 7 days after admission) and late onset (7 days or more after admission), with or without previous antibiotic treatment, and the corresponding pathogens were analyzed. Risk factors for the isolation of pathogens potentially resistant to multiple drugs (ie, Pseudomonas aeruginosa, Serratia marcescens, Enterobacter species, Morganella morganii, methicillin-resistant Staphylococcus aureus, Citrobacter species, Acinetobacter species, Burkholderia species, extended-spectrum beta -lactamase-producing pathogens, and Stenotrophomonas maltophilia) were analyzed using logistic regression analysis. A total of 4,200 patients stayed at the ICU for 2 or more days, 298 of whom developed ICU-acquired pneumonia, for an overall incidence of 13 cases (95% confidence interval [CI], 11-14 cases) per 1,000 ICU-days. Pathogens potentially resistant to multiple drugs were isolated from 52% of patients with early-onset pneumonia. Risk factors for the isolation of these pathogens were greater age and previous receipt of antibiotic prophylaxis (adjusted odds ratio [aOR], 4.6 [95% CI, 1.6-13.0]) or antibiotic therapy (aOR, 8.2 [95% CI, 2.8-23.8]). The length of ICU admission and hospital stay were weaker risk factors for the isolation of these pathogens. Pathogens potentially resistant to multiple drugs were isolated in 52% of cases of early-onset ICU-acquired pneumonia. Previous antibiotic use (both prophylactic and therapeutic) is the main risk factor for the isolation of these pathogens.


Diagnostic Potential of an IgE-ELISA in Detecting Strongyloidiasis.
Strongyloides stercoralis infection is prevalent worldwide and can cause lifelong infection in immunocompetent individuals, and potentially death in immunosuppressed patients. The diagnosis is hindered by the low sensitivity of microscopic examination, thus making serology an important complementary test to improve the detection rate. However, there were reports that some Strongyloides-infected individuals were negative with specific IgG and IgG4 assays, and other helminth infections were positive with commercial Strongyloides IgG-ELISAs. Thus, there is a need to develop better serodiagnostic methods for strongyloidiasis. We investigated the diagnostic potential of IgE-ELISAs using Strongyloides larval lysate. Sera from two groups infected with Strongyloides served as the positive reference, that is, 1) positive by commercial IgG-ELISAs and IgG4 rapid test, and stool samples positive by microscopy and/or PCR (group IA; n = 20); and 2) negative by IgG-ELISAs and IgG4 rapid test, but stool samples were PCR positive (group IB sera; n = 11). Sera from another two groups served as negative reference (controls), that is, 1) infected with other parasites (group II; n = 73) and 2) healthy donors (group III; n = 22). Results showed a 100% diagnostic sensitivity in detecting sera from groups IA and IB. The latter group of individuals probably had early infection because their IgG and IgG4 assays were negative. The optical density values of group IB sera were also significantly lower than those of group IA (P < 0.003). The IgE-ELISA was 100% specific when tested against sera from groups II and III. This study highlights the diagnostic potential of IgE-ELISA using larval lysate to detect strongyloidiasis, especially those with probable early infection.


Uncoupling of actomyosin adenosinetriphosphatase by heparin and its fragments.
Heparin and its enzymatic fragments, prepared by degradation of heparin with heparinase from Flavobacterium heparinum, were capable of inhibiting the actomyosin-ATPase activity obtained from striated and smooth vascular muscles. Heparin did not inhibit the myosin-ATPase activity in absence of actin. The results show that heparin changes the step of ATP hydrolysis of the complex actomyosin-ATPase by uncoupling the conformational transition on the myosin-head induced by actin upon the nucleotide-binding site. This mechanism is cooperative and dependent on conformational states of actomyosin complex which in turn is regulated by ATP and calcium levels. It was observed that in the presence of ATP, actin does not compete with heparin for binding to myosin showing that heparin and actin have different binding sites on myosin. The binding of heparin and ATP is cooperative suggesting that the nucleotide binding leads to an exposition of a second heparin-binding site. However, in the absence of ATP, actin competes with heparin for a binding site on the myosin. These results strongly suggest that in the weakly binding state of actin to myosin, the binding of heparin is powerful and in the rigor state its binding is decreased.


Medication Adherence Among Patients with Multimorbidity in the United Arab Emirates.
Multimorbidity, defined as having two or more chronic diseases, has a major impact on public health and Sustainable Development Goals (SDG). This study aims to assess the prevalence of medication adherence and associated factors among patients with multimorbidity. A questionnaire-based, cross-sectional survey was conducted by a trained interviewer across patients with multimorbidity attending outpatient clinics in two tertiary referral hospitals in the United Arab Emirates (UAE). Demographic and social variables and the outcome (self-reported adherence to long-term medication) were measured using the General Medication Adherence Scale (GMAS). Multiple logistic regression was used to assess medication adherence and associated factors. From a total of 630 participants included in this study, the estimated prevalence of high medication adherence is 78.57% (±1.63478) with a 95% confidence interval (CI) [75.19, 81.61]. The odds of high medication adherence increased with age. The odds of high medication adherence for patients aged 66 years and older than those aged 19-35 years is adjusted odds ratio (AOR) = 3.880, with a 95% CI [1.124, 13.390]. Patients with income more than 50,000 had the odds, AOR = 5.169 with a 95% CI [1.282, 20.843], compared to those earning less than 10,000 Dirhams (AED). Patients aged 36-65 with health insurance coverage had higher medication adherence than groups on the other end. The number of current medications is significantly (p-value = 0.027) associated with high medication adherence with the odds of high medication adherence, AOR = 4.529 with a 95% CI [1.184, 17.326], the highest for those currently taking four medications. This study highlights younger population having multimorbidity in the context of an increasing life expectancy and suboptimal therapeutic outcomes. Furthermore, the study highlights multimorbidity is associated with low medication adherence and out-of-pocket payment, and non-availability of insurance is a major hindrance to medication adherence.


Upper Airway Computed Tomography Measures and Receipt of Tracheotomy in Infants With Robin Sequence.
Airway management in infants with Robin sequence is challenging. Objective upper airway measures associated with severe airway compromise requiring tracheotomy are needed to guide decision making. To define objective upper airway measures in infants with Robin sequence from craniofacial computed tomography (CT) and to identify those measures in Robin sequence associated with tracheotomy. A cohort study (2003 to 2014, over 1-year follow-up) of 37 infants with Robin sequence evaluated for surgical management and 37 selected age- and sex-matched controls without a craniofacial condition conducted in a pediatric institution's craniofacial center. Define and compare CT-generated upper airway measures in these groups: infants with Robin sequence vs controls, and infants with Robin sequence with vs without tracheotomy. A negative difference signifies lower values for the Robin sequence and tracheotomy groups. Clinical data collected included age and height at time of CT scan, sex, tracheotomy presence, associated syndrome, and laboratory indicators of hypoventilation and hypoxemia. To evaluate interrater reliability, 2 raters performed each measurement in the Robin sequence group. In 74 infants, 17 of 28 measures were different between infants with Robin sequence and those in the control group. Tracheotomy was performed in 14 of 37 (38%) infants with Robin sequence. Infants with tracheotomy more commonly had associated syndromes (12 of 14 [86%] vs 11 of 23 [48%]) and a history of hypoventilation and hypoxemia (13 of 14 [93%] vs 15 of 23 [65%]). Five of the 11 measures associated with tracheotomy were reliable and simpler to measure with the following mean differences (95% CIs) between groups: tongue length, 0.87 (0.26 to 1.48); tongue position relative to palate, 0.83 (0.22 to 1.45); mandibular total length, -0.8 (-1.42 to -0.19); gonial angle, 0.71 (0.08 to 1.34); and inferior pogonial angle, 0.66 (0.02 to 1.29). Using a receiver operating characteristic analysis, a composite score of these 5 measures for predicting tracheotomy risk yielded an area under the curve of 0.83 and achieved 86% sensitivity and 74% specificity. Computed tomography measures quantifying tongue position and mandibular configuration can identify infants with Robin sequence, and importantly, differentiate those who have severe upper airway compromise requiring tracheotomy. Following validation, these measures can be used for objective upper airway assessment and for expediting clinical decision-making in these challenging cases for which no such tools currently exist.


Cost-effectiveness of a lifestyle intervention in high-risk individuals for diabetes in a low- and middle-income setting: Trial-based analysis of the Kerala Diabetes Prevention Program.
Data on the cost-effectiveness of lifestyle-based diabetes prevention programs are mostly from high-income countries, which cannot be extrapolated to low- and middle-income countries. We performed a trial-based cost-effectiveness analysis of a lifestyle intervention targeted at preventing diabetes in India. The Kerala Diabetes Prevention Program was a cluster-randomized controlled trial of 1007 individuals conducted in 60 polling areas (electoral divisions) in Kerala state. Participants (30-60 years) were those with a high diabetes risk score and without diabetes on an oral glucose tolerance test. The intervention group received a 12-month peer-support lifestyle intervention involving 15 group sessions delivered in community settings by trained lay peer leaders. There were also linked community activities to sustain behavior change. The control group received a booklet on lifestyle change. Costs were estimated from the health system and societal perspectives, with 2018 as the reference year. Effectiveness was measured in terms of the number of diabetes cases prevented and quality-adjusted life years (QALYs). Three times India's gross domestic product per capita (US$6108) was used as the cost-effectiveness threshold. The analyses were conducted with a 2-year time horizon. Costs and effects were discounted at 3% per annum. One-way and multi-way sensitivity analyses were performed. Baseline characteristics were similar in the two study groups. Over 2 years, the intervention resulted in an incremental health system cost of US$2.0 (intervention group: US$303.6; control group: US$301.6), incremental societal cost of US$6.2 (intervention group: US$367.8; control group: US$361.5), absolute risk reduction of 2.1%, and incremental QALYs of 0.04 per person. From a health system perspective, the cost per diabetes case prevented was US$95.2, and the cost per QALY gained was US$50.0. From a societal perspective, the corresponding figures were US$295.1 and US$155.0. For the number of diabetes cases prevented, the probability for the intervention to be cost-effective was 84.0% and 83.1% from the health system and societal perspectives, respectively. The corresponding figures for QALY gained were 99.1% and 97.8%. The results were robust to discounting and sensitivity analyses. A community-based peer-support lifestyle intervention was cost-effective in individuals at high risk of developing diabetes in India over 2 years. The trial was registered with Australia and New Zealand Clinical Trials Registry ( ACTRN12611000262909 ). Registered 10 March 2011.


Effects of 12-week oral supplementation of Ecklonia cava polyphenols on anthropometric and blood lipid parameters in overweight Korean individuals: a double-blind randomized clinical trial.
The effects of 12-week supplementation with a polyphenol extract from Ecklonia cava (ECP) on anthropometry, serum biochemistry and hematology have been investigated. Ninety-seven overweight male and female adults (average age 40.5 ± 9.2 yr and body mass index (BMI) of 26.5 ± 1.6 kg/m²) were enrolled in a randomized, double-blind, placebo-controlled trial with parallel-group design. Subjects were randomly allocated into three groups designated as PC (placebo), LD (low-dose, 72 mg-ECP/day) and HD (high-dose, 144 mg-ECP/day). Both LD and HD groups showed significant decreases in BMI, body fat ratio, waist circumference, waist/hip ratio, total cholesterol, low-density lipoprotein (LDL) cholesterol, total cholesterol/high-density lipoprotein (HDL) cholesterol and atherogenic index (AI) after 12 weeks, as compared with the placebo group. The HD group also showed a significant increase in serum HDL cholesterol as compared with the placebo group. Only the HD group showed significant decreases in serum glucose and systolic blood pressure after 12 weeks. There was no significant adverse event related with ingestion of ECP, and serum biochemical and hematological parameters were maintained within normal range during the intervention period. In conclusion, these results demonstrated that ECP supplementation significantly contributed to lowering body fat and serum lipid parameters such as total and LDL cholesterols with dose dependence. Further studies using different populations, dosages or biological markers are highly recommended to better understand the physiological features of this polyphenol.


Exploiting the Dynamics of Soft Materials for Machine Learning.
Soft materials are increasingly utilized for various purposes in many engineering applications. These materials have been shown to perform a number of functions that were previously difficult to implement using rigid materials. Here, we argue that the diverse dynamics generated by actuating soft materials can be effectively used for machine learning purposes. This is demonstrated using a soft silicone arm through a technique of multiplexing, which enables the rich transient dynamics of the soft materials to be fully exploited as a computational resource. The computational performance of the soft silicone arm is examined through two standard benchmark tasks. Results show that the soft arm compares well to or even outperforms conventional machine learning techniques under multiple conditions. We then demonstrate that this system can be used for the sensory time series prediction problem for the soft arm itself, which suggests its immediate applicability to a real-world machine learning problem. Our approach, on the one hand, represents a radical departure from traditional computational methods, whereas on the other hand, it fits nicely into a more general perspective of computation by way of exploiting the properties of physical materials in the real world.


Analysis of smiling photograph; Operation US-Bangla Air Crash.
Human identification may be difficult when there is no antemortem data available. A photograph of the deceased may be valuable in such cases. Digital advancement and inclusion in the lives of ordinary people makes it easier to retrieve clear, high-resolution photos from social media accounts and other places. This paper describes three cases of forensic dental identification from a US-Bangla plane crash in Nepal in which a charred body was positively identified from a smiling photograph provided by the deceased's family. Each case is unique and their identification rests on the availability of pre- and post-mortem information. Thus, the number of concordant points may vary from single to multiple; there is no defined criteria for minimum number of concordance for a positive dental identification.


An Updated Review of Computer-Aided Drug Design and Its Application to COVID-19.
The recent outbreak of the deadly coronavirus disease 19 (COVID-19) pandemic poses serious health concerns around the world. The lack of approved drugs or vaccines continues to be a challenge and further necessitates the discovery of new therapeutic molecules. Computer-aided drug design has helped to expedite the drug discovery and development process by minimizing the cost and time. In this review article, we highlight two important categories of computer-aided drug design (CADD), viz., the ligand-based as well as structured-based drug discovery. Various molecular modeling techniques involved in structure-based drug design are molecular docking and molecular dynamic simulation, whereas ligand-based drug design includes pharmacophore modeling, quantitative structure-activity relationship (QSARs), and artificial intelligence (AI). We have briefly discussed the significance of computer-aided drug design in the context of COVID-19 and how the researchers continue to rely on these computational techniques in the rapid identification of promising drug candidate molecules against various drug targets implicated in the pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The structural elucidation of pharmacological drug targets and the discovery of preclinical drug candidate molecules have accelerated both structure-based as well as ligand-based drug design. This review article will help the clinicians and researchers to exploit the immense potential of computer-aided drug design in designing and identification of drug molecules and thereby helping in the management of fatal disease.


Early life nutritional programming of obesity: mother-child cohort studies.
The obesity epidemic has resulted in more overweight/obese women before and during pregnancy. Their offspring tend to have higher birth weights and more body fat, and carry an increased risk of obesity later in life. These effects may partly be related to the heightened risk of gestational diabetes, occurring in at least 16% of all pregnancies irrespective of current body weight. An ILSI Europe workshop reviewed the key contributors leading to adverse outcomes in pregnancy and childhood, including gestational weight gain and nutrition. New research opportunities from prospective mother-child cohort studies were explored. Simple measures of gestational weight gain provide insufficient detail of the underlying physiological and metabolic adaptations occurring in pregnancy, and should be complemented by measures of body composition, metabolic and endocrine responses. Recordings of maternal dietary intake and nutrient status are often limited and potential correlations with gestational weight gain have been poorly studied. Many pregnancies in overweight/obese women are uncomplicated and result in offspring of normal weight, leaving the main determinants of later adverse outcomes to be clarified. The workshop provided insights of primary measurements for the characterization of sustainable nutritional intervention strategies in the mother, infant and child for preventing obesity in later life.


An angiotensin II type 1 receptor activation switch patch revealed through evolutionary trace analysis.
Seven transmembrane (7TM) or G protein-coupled receptors constitute a large superfamily of cell surface receptors sharing a structural motif of seven transmembrane spanning alpha helices. Their activation mechanism most likely involves concerted movements of the transmembrane helices, but remains to be completely resolved. Evolutionary Trace (ET) analysis is a computational method, which identifies clusters of functionally important residues by integrating information on evolutionary important residue variations with receptor structure. Combined with known mutational data, ET predicted a patch of residues in the cytoplasmic parts of TM2, TM3, and TM6 to form an activation switch that is common to all family A 7TM receptors. We tested this hypothesis in the rat Angiotensin II (Ang II) type 1a (AT1a) receptor. The receptor has important roles in the cardiovascular system, but has also frequently been applied as a model for 7TM receptor activation and signaling. Six mutations: F66A, L67R, L70R, L119R, D125A, and I245F were targeted to the putative switch and assayed for changes in activation state by their ligand binding, signaling, and trafficking properties. All but one receptor mutant (that was not expressed well) displayed phenotypes associated with changed activation state, such as increased agonist affinity or basal activity, promiscuous activation, or constitutive internalization highlighting the importance of testing different signaling pathways. We conclude that this evolutionary important patch mediates interactions important for maintaining the inactive state. More broadly, these observations in the AT1 receptor are consistent with computational predictions of a generic role for this patch in 7TM receptor activation.


Protocol for the DisCoVeRy trial: multicentre, adaptive, randomised trial of the safety and efficacy of treatments for COVID-19 in hospitalised adults.
To find effective and safe treatments for COVID-19, the WHO recommended to systemically evaluate experimental therapeutics in collaborative randomised clinical trials. As COVID-19 was spreading in Europe, the French national institute for Health and Medical Research (Inserm) established a transdisciplinary team to develop a multi-arm randomised controlled trial named DisCoVeRy. The objective of the trial is to evaluate the clinical efficacy and safety of different investigational re-purposed therapeutics relative to Standard of Care (SoC) in patients hospitalised with COVID-19. DisCoVeRy is a phase III, open-label, adaptive, controlled, multicentre clinical trial in which hospitalised patients with COVID-19 in need of oxygen therapy are randomised between five arms: (1) a control group managed with SoC and four therapeutic arms with re-purposed antiviral agents: (2) remdesivir + SoC, (3) lopinavir/ritonavir + SoC, (4) lopinavir/ritonavir associated with interferon (IFN)-β-1a + SoC and (5) hydroxychloroquine + SoC. The primary endpoint is the clinical status at Day 15 on the 7-point ordinal scale of the WHO Master Protocol (V.3.0, 3 March 2020). This trial involves patients hospitalised in conventional departments or intensive care units both from academic or non-academic hospitals throughout Europe. A sample size of 3100 patients (620 patients per arm) is targeted. This trial has begun on 22 March 2020. Since 5 April 2020, DisCoVeRy has been an add-on trial of the Solidarity consortium of trials conducted by the WHO in Europe and worldwide. On 8 June 2020, 754 patients have been included. Inserm is the sponsor of DisCoVeRy. Ethical approval has been obtained from the institutional review board on 13 March 2020 (20.03.06.51744) and from the French National Agency for Medicines and Health Products (ANSM) on 9 March 2020. Results will be submitted for publication in peer-reviewed journals. NCT04315948 Eudra-CT 2020-000936-23.


Epigenetic regulation of miR-212 expression in lung cancer.
Many studies have shown that microRNA expression in cancer may be regulated by epigenetic events. Recently, we found that in lung cancer miR-212 was strongly down-regulated. However, mechanisms involved in the regulation of miR-212 expression are unknown. Therefore, we addressed this point by investigating the molecular mechanisms of miR-212 silencing in lung cancer. We identified histone modifications rather than DNA hypermethylation as epigenetic events that regulate miR-212 levels in NSCLC. Moreover, we found that miR-212 silencing in vivo is closely associated with the severity of the disease.


Post-transplant gastric antral vascular ectasia after intra-venous busulfan regimen.
Gastric antral vascular ectasia (GAVE) is an angiodysplastic disorder that causes gastric bleeding. GAVE can develop as a complication of hematopoietic stem cell transplantation (HSCT-GAVE), and it has been suggested that it may be associated with oral administration of busulfan. We report two cases of HSCT-GAVE after a conditioning regimen containing intra-venous busulfan (ivBu), not oral busulfan. The first case, a 42-year-old woman with blastic plasmacytoid dendritic cell neoplasm, underwent second allogeneic HSCT with conditioning regimen consisting of cyclophosphamide (120 mg/kg) and ivBu (12.8 mg/kg). HSCT-GAVE developed on day 84 post-transplant, and argon plasma coagulation (APC) was performed successfully. The second case, a 60-year-old woman with acute myelogenous leukemia, underwent allogeneic HSCT with the conditioning regimen consisting of ivBu (12.8 mg/kg) and fludarabine (150 mg/kg). She developed melena and was diagnosed with GAVE by endoscopy on day 145 post-transplant. Although complete hemostasis was not achieved despite four administrations of APCs, the melena spontaneously terminated on day 235 post-transplant. To our knowledge, this is the first report describing HSCT-GAVE after ivBU-based HSCT. Although there is no established therapy for HSCT-GAVE, APC may be an option for HSCT-GAVE.


The neurotoxicology of lead.
In the past six years, our research group has investigated the relationship between lead exposure and mental and behavioural development. This has been carried out through studies in children and animals. Earlier studies in children have shown that associations might be expected between environmental exposure to lead and various aspects of cognitive and behavioural development. Our study has examined and continues to examine, a cohort of children sub-divided into three groups according to the level of lead exposure during early 'in utero' development. Data amassed to date includes measurement of psychometric function and post natal development, together with biochemical measures of lead exposure. Assessment will continue through to early scholastic performance and will include measurement of deciduous tooth lead concentration as an integrated measure of long term exposure. In addition to these studies in children, a series of neurochemical studies have been carried out using a rat model of lead exposure. Data obtained from both our own neurochemical experiments and those of other groups indicate an extremely complex plethora of neurotoxic actions of lead.


Selection bias in follow-up interviews with individuals attending the emergency department for occupational injuries.
To examine whether supplementary interview participation was comparable for occupationally injured patients attending two hospital emergency departments and to investigate the magnitude of selection bias in relation to sex, age, severity, job tasks and industry risk level. Workers aged 18-70 years who contacted the two emergency departments for an acute occupational injury in 2013 were eligible and given a short questionnaire. Following written consent, a semi-structured interview concerning health and transient risk factors was conducted by telephone. The two departments were compared for study recruitment by age and sex. Respondents and non-respondents to the interview were compared for age, sex, injury severity, job tasks and industry risk level. Of 4002 patients attending the two hospitals, 1693 (42%) participated in the interview. One hospital had a markedly higher response rate to the questionnaire, but the proportions of participation in the interview were similar in the two hospitals. Patients aged <30 years were over-represented among non-respondents whereas sex, injury severity, job task and industry risk level were not significantly different between respondents and non-respondents. Despite a relatively low interview participation rate among injured individuals attending the emergency department, selection bias was limited. This indicates that results regarding injury risk patterns may be more widely generalisable when examining the causality of occupational injuries. However, the study also showed that young injured workers were less likely to participate in follow-up interviews, which is an important factor when interpreting age-related risk of injury.


Human teratocarcinomas cultured in vitro produce unique retrovirus-like viruses.
We have previously reported that among a series of human tumours investigated, only human teratocarcinoma cell lines derived from testicular tumours or pulmonary metastases of patients in Germany and the U.S.A. produced retrovirus-like particles spontaneously, albeit in low amounts. In a recent publication electron microscopical data suggested that the human teratocarcinoma-derived ( HTD ) particles were morphologically closely related, but not identical, to the type C retroviruses of animals. In this communication, the explantation of three human teratocarcinoma cell lines is briefly described. Evidence is presented that HTD particles (i) are synthesized only in a fraction of the epithelioid and differentiating cells; (ii) can be induced biochemically in a manner characteristic of retroviruses; (iii) either are not infectious or possess a peculiar host range; (iv) are immunologically unrelated to animal retrovirus strains; (v) possess an endogenous RNA-dependent DNA polymerase activity that can be banded at 1.16 g/ml in linear sucrose gradients. These results may be taken as suggestive evidence that HTD particles represent a novel group of unique retroviruses.


Classification of human breathing sounds by the common vampire bat, Desmodus rotundus.
The common vampire bat Desmodus rotundus is one of three bat species that feed exclusively on the blood of mammals often more than 1000 times its size. Vampire bats even feed on human blood. Moreover, they tend to feed on the same individual over consecutive nights. Using psychoacoustical methods, we show that vampire bats can recognize individual humans by their breathing sounds. Accompanying psychoacoustical experiments using the same stimuli and procedure but with human listeners show that even these trained and instructed listeners were unable to achieve the vampire bats' performance under the most difficult conditions, where the breathing sounds had been recorded under physical strain. It is suggested that vampire bats can make use of an individual acoustic signature imposed on breathing sounds in a way similar to that in which we identify humans by their vocalizations.


Enhanced visualization during dental practice using magnification systems.
The practice of dentistry involves viewing and evaluating small details of teeth, soft tissues, restorations, casts, and instruments. Although normal vision often is adequate to view details to make treatment decisions, the use of magnification loupes provides the clinician with an increased image size for improved visual acuity and improved posture while practicing. There are many choices when selecting a magnifying system. This article recommends the use of a binocular surgical telescope, either a flip-up type or a fixed-lens system, because it affords the clinician more choices in power of magnification, working distance, field of view, depth of field, and working angulation for improved posture.


Prenatal effects of 2,4,5-T, 2,4,5-trichlorophenol, and phenoxyacetic acid in mice.
The herbicide 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) and two structurally related compounds, phenoxyacetic acid and 2,4,5-trichlorophenol, were suspended in a 1:1 solution of honey:water and administered by gavage to pregnant mice on one of gestation days 8-15 (copulation plug day = day 1) or on three consecutive days (7-9, 10-12, or 13-15). Doses were 800-900 mg/kg for single and 250-300 mg/kg/day for multiple treatments. With the exception of 2,4,5-trichlorophenol treatment on day 14, only 2,4,5-T treatment significantly increased prenatal mortality, and only 2,4,5-T was associated with decreased fetal weight when comparisons were made with the solvent controls. Although low incidences were seen in all treatment groups, only 2,4,5-T significantly increased cleft palate or other gross malformations. Significant skeletal, visceral or histopathological defects were not observed. These results indicate that both the carboxyl group and chlorination of the aromatic ring are essential for an unambiguous teratogenic response.


Age and paracetamol self-poisoning.
Whereas paracetamol poisoning is predominantly seen in adolescents and young adults, the majority of paracetamol associated deaths occur in an older population. The aim of the present study was to evaluate age as a risk factor for fulminant hepatic failure (FHF) and death in a large population of patients with paracetamol poisoning. A total of 746 patients transferred to a specialised unit with severe paracetamol poisoning and 273 unselected patients admitted from the local region over a 10 year period. A partly retrospective study based on hospital charts. The risk associated with age was evaluated by multivariate analysis. Paracetamol poisoning most frequently occurred in the age group 15-24 years. Transferred patients were significantly older than local patients (median age 37 years v 29 years; p = 0.0006). In contrast, FHF and death from paracetamol poisoning most frequently occurred in patients aged 40 years or above. In a logistic regression analysis, "age >/=40 years" was associated with an excess risk of FHF (odds ratio (OR) 2.33 (95% confidence interval (CI) 1.50-3.64)) and death or liver transplantation (OR 4.18 (95% CI 2.17-8.05)). In addition, older age was associated with other risk factors for paracetamol hepatotoxicity such as regular alcohol abuse and late presentation. Age 40 years or above was identified as a significant independent risk factor for FHF and mortality following paracetamol overdose. Patients aged 40 years or above should be considered as high risk patients, in particular when older age appears in combination with regular alcohol abuse or late presentation.


Association of guideline publication and delays to treatment in pediatric status epilepticus.
To determine whether publication of evidence on delays in time to treatment shortens time to treatment in pediatric refractory convulsive status epilepticus (rSE), we compared time to treatment before (2011-2014) and after (2015-2019) publication of evidence of delays in treatment of rSE in the Pediatric Status Epilepticus Research Group (pSERG) as assessed by patient interviews and record review. We performed a retrospective analysis of a prospectively collected dataset from June 2011 to September 2019 on pediatric patients (1 month-21 years of age) with rSE. We studied 328 patients (56% male) with median (25th-75th percentile [p25-p75]) age of 3.8 (1.3-9.4) years. There were no differences in the median (p25-p75) time to first benzodiazepine (BZD) (20 [5-52.5] vs 15 [5-38] minutes, p = 0.3919), time to first non-BZD antiseizure medication (68 [34.5-163.5] vs 65 [33-142] minutes, p = 0.7328), and time to first continuous infusion (186 [124.2-571] vs 160 [89.5-495] minutes, p = 0.2236). Among 157 patients with out-of-hospital onset whose time to hospital arrival was available, the proportion who received at least 1 BZD before hospital arrival increased after publication of evidence of delays (41 of 81 [50.6%] vs 57 of 76 [75%], p = 0.0018), and the odds ratio (OR) was also increased in multivariable logistic regression (OR 4.35 [95% confidence interval 1.96-10.3], p = 0.0005). Publication of evidence on delays in time to treatment was not associated with improvements in time to treatment of rSE, although it was associated with an increase in the proportion of patients who received at least 1 BZD before hospital arrival.


Multiple meningiomas of the central nervous system without the stigmata of neurofibromatosis. Clinical and therapeutic study.
Multiple meningiomas are relatively rare tumors without known neurofibromatosis. In this paper, such eight cases of multiple meningiomas as described by CUSHING and EISENHARDT are presented. Certain aspects of diagnosis and surgical management of this rare condition are discussed with particular emphasis on the importance of the distinction among multiple meningioma, meningiomatosis, or recurrences of these tumors. Fortunately, many of these patients tolerate multiple surgical interventions well, although the removal of these tumors in critical areas is a difficult problem. Thus, we think that it is important to examine and supervise all patients who have had a meningioma for a possible occurrence of a second meningioma.


High fascioliasis infection in children linked to a man-made irrigation zone in Peru.
We detected 10 protozoan and nine helminth species in surveys of 338 5-15 year-old Quechua schoolchildren in three communities of the Asillo zone of the Puno region, located at a very high altitude of 3910 m in the Peruvian Altiplano. The area proved to be hyperendemic for human fascioliasis with a 24.3% overall mean prevalence of Fasciola hepatica, local prevalences ranging between 18.8 and 31.3%, and infection intensities of up to 2496 eggs per gram of faeces (epg), with 196-350 epg (mean: 279 epg) and 96-152 epg (123 epg) as arithmetic and geometric means, respectively. Prevalences did not significantly vary between schools and in relation to sex. No statistical differences were found in intensities between schools, nor according to sex or age groups between and within schools, although the highest overall egg counts were detected in girls and in the youngest age group. Asillo zone is a man-made irrigation area built only recently to which both liver fluke and lymnaeid snails have quickly adapted. The region appears to be isolated from the Northern Bolivian Altiplano natural endemic area. Such man-made water resources in high altitude areas of Andean countries pose a high fascioliasis risk. Significant positive association of F. hepatica with protozooses following a one host life cycle, such as Giardia intestinalis, suggests that human infection mainly occurs through drinking water. This is supported by additional evidence such as the absence of typical aquatic vegetation in the drainage channels inhabited by lymnaeid snails, the absence of aquatic vegetables in the traditional nutrition habits of the Quechua inhabitants, and the lack of potable water systems inside dwellings, which requires inhabitants to obtain water from irrigation canals and drainage channels.


Workplace learning from a socio-cultural perspective: creating developmental space during the general practice clerkship.
Workplace learning in undergraduate medical education has predominantly been studied from a cognitive perspective, despite its complex contextual characteristics, which influence medical students' learning experiences in such a way that explanation in terms of knowledge, skills, attitudes and single determinants of instructiveness is unlikely to suffice. There is also a paucity of research which, from a perspective other than the cognitive or descriptive one, investigates student learning in general practice settings, which are often characterised as powerful learning environments. In this study we took a socio-cultural perspective to clarify how students learn during a general practice clerkship and to construct a conceptual framework that captures this type of learning. Our analysis of group interviews with 44 fifth-year undergraduate medical students about their learning experiences in general practice showed that students needed developmental space to be able to learn and develop their professional identity. This space results from the intertwinement of workplace context, personal and professional interactions and emotions such as feeling respected and self-confident. These forces framed students' participation in patient consultations, conversations with supervisors about consultations and students' observation of supervisors, thereby determining the opportunities afforded to students to mind their learning. These findings resonate with other conceptual frameworks and learning theories. In order to refine our interpretation, we recommend that further research from a socio-cultural perspective should also explore other aspects of workplace learning in medical education.


A New Insight into an Alternative Therapeutic Approach to Restore Redox Homeostasis and Functional Mitochondria in Neurodegenerative Diseases.
Neurodegenerative diseases are accompanied by oxidative stress and mitochondrial dysfunction, leading to a progressive loss of neuronal cells, formation of protein aggregates, and a decrease in cognitive or motor functions. Mitochondrial dysfunction occurs at the early stage of neurodegenerative diseases. Protein aggregates containing oxidatively damaged biomolecules and other misfolded proteins and neuroinflammation have been identified in animal models and patients with neurodegenerative diseases. A variety of neurodegenerative diseases commonly exhibits decreased activity of antioxidant enzymes, lower amounts of antioxidants, and altered cellular signalling. Although several molecules have been approved clinically, there is no known cure for neurodegenerative diseases, though some drugs are focused on improving mitochondrial function. Mitochondrial dysfunction is caused by oxidative damage and impaired cellular signalling, including that of peroxisome proliferator-activated receptor gamma coactivator 1α. Mitochondrial function can also be modulated by mitochondrial biogenesis and the mitochondrial fusion/fission cycle. Mitochondrial biogenesis is regulated mainly by sirtuin 1, NAD+, AMP-activated protein kinase, mammalian target of rapamycin, and peroxisome proliferator-activated receptor γ. Altered mitochondrial dynamics, such as increased fission proteins and decreased fusion products, are shown in neurodegenerative diseases. Due to the restrictions of a target-based approach, a phenotype-based approach has been performed to find novel proteins or pathways. Alternatively, plasma membrane redox enzymes improve mitochondrial function without the further production of reactive oxygen species. In addition, inducers of antioxidant response elements can be useful to induce a series of detoxifying enzymes. Thus, redox homeostasis and metabolic regulation can be important therapeutic targets for delaying the progression of neurodegenerative diseases.


Effects of Whey Protein Injection as a Curing Solution on Chicken Breast Meat.
The quality characteristics and storage stability of chicken breast meat (CBM) was investigated following the injection of whey protein (WP) as a curing ingredient. The moisture content of CBM decreased with increasing concentration of WP. The highest concentration of WP (7%) resulted in the lowest moisture and fat content and the highest protein content of CBM. Injection of WP elevated the pH and water holding capacity (WHC) of CBM. The cooking loss of CBM was significantly decreased with WP injections of 3% and higher. All WP injections increased the L* of the CBM but decreased the a* and b*. WP injection increased the springiness, cohesiveness, and chewiness and decreased the hardness of the CBM. WP injection increased 2-thiobarbituric acid reactive substances (TBARS) after 3 and 7 days of storage. The volatile basic nitrogen (VBN) content of the CBM increased with increased concentrations of WP. The total microbial count (TMC) of CBM injected with WP was higher initially and after 3 days of storage. Our results showed WP injection improved the WHC of CBM but decreased the storage stability by increasing TBARS, VBN and TMC.


Adenoviral Expression of a Bispecific VHH-Based Neutralizing Agent That Targets Protective Antigen Provides Prophylactic Protection from Anthrax in Mice.
Bacillus anthracis, the causative agent of anthrax, secretes three polypeptides, which form the bipartite lethal and edema toxins (LT and ET, respectively). The common component in these toxins, protective antigen (PA), is responsible for binding to cellular receptors and translocating the lethal factor (LF) and edema factor (EF) enzymatic moieties to the cytosol. Antibodies against PA protect against anthrax. We previously isolated toxin-neutralizing variable domains of camelid heavy-chain-only antibodies (VHHs) and demonstrated their in vivo efficacy. In this work, gene therapy with an adenoviral (Ad) vector (Ad/VNA2-PA) (VNA, VHH-based neutralizing agents) promoting the expression of a bispecific VHH-based neutralizing agent (VNA2-PA), consisting of two linked VHHs targeting different PA-neutralizing epitopes, was tested in two inbred mouse strains, BALB/cJ and C57BL/6J, and found to protect mice against anthrax toxin challenge and anthrax spore infection. Two weeks after a single treatment with Ad/VNA2-PA, serum VNA2-PA levels remained above 1 μg/ml, with some as high as 10 mg/ml. The levels were 10- to 100-fold higher and persisted longer in C57BL/6J than in BALB/cJ mice. Mice were challenged with a lethal dose of LT or spores at various times after Ad/VNA2-PA administration. The majority of BALB/cJ mice having serum VNA2-PA levels of >0.1 μg/ml survived LT challenge, and 9 of 10 C57BL/6J mice with serum levels of >1 μg/ml survived spore challenge. Our findings demonstrate the potential for genetic delivery of VNAs as an effective method for providing prophylactic protection from anthrax. We also extend prior findings of mouse strain-based differences in transgene expression and persistence by adenoviral vectors.


Spectrophotometric determination of creatinine by monosegmented continuous-flow analysis.
A monosegmented continuous-flow system (MCFS) has been evaluated for determination of creatinine in urine using the Jaffé reaction. The analyser is compact and allows 130 determinations to be performed per hour, with a relative standard deviation of the peak height better than 1.5% (N =10). The results for real samples agree with those obtained by. the standard manual Jaffé procedure and with the kinetic automatic method.


Aum Shinrikyo's Chemical and Biological Weapons: More Than Sarin.
The radical religious group Aum Shinrikyo was founded in Japan in the 1980s and grew rapidly in the 1990s. Aum members perpetrated a mass murder in Matsumoto City in 1994, where they used sarin as a chemical weapon to poison approximately 500 civilians. On March 20, 1995, Aum deployed sarin in an even larger terrorist attack on the Tokyo Subway System, which poisoned some 6,000 people. After the Tokyo Subway attack, the Japanese Police arrested the sect's senior members. From 2005 through 2011, 13 of these senior members were sentenced to death. In this article, aspects of Aum's chemical and biological terrorism are reviewed. Sarin production efforts by the sect are described, including how the degradation product of sarin in soil, methylphosphonic acid, enabled the detection of sarin production sites. Also, Aum's chemical-warfare agents other than sarin are described, as are its biological weapons. The author was permitted by the Japanese government to interview Dr. Tomomasa Nakagawa, one of the senior members of Aum Shinrikyo. From Dr. Nakagawa the author obtained valuable inside information about Aum's chemical and biological weapons programs.


Plasma parathyroid hormone level and prevalent cardiovascular disease in CKD stages 3 and 4: an analysis from the Kidney Early Evaluation Program (KEEP).
Cardiovascular disease (CVD) is the most common cause of death in patients with chronic kidney disease (CKD). Secondary hyperparathyroidism is common in patients with CKD, and its relationship to CVD is not well defined. This analysis aims to assess whether serum intact parathyroid hormone (PTH) level is an independent risk factor for CVD in patients with CKD stages 3 and 4. In this cross-sectional study, medical history surveys, including CVD events, were collected from 4,472 patients with stages 3 and 4 CKD identified by the National Kidney Foundation Kidney Early Evaluation Program (KEEP), which included blood pressure measurement and laboratory testing. Age, hemoglobin level, estimated glomerular filtration rate, serum phosphorus level, and serum calcium level were evaluated as continuous variables, and plasma PTH levels, by tertile: less than 35, 35 to 70, and greater than 70 pg/mL. Multivariate logistic regression was used to estimate odds ratios (ORs) of CVD predictor variables. Mean age was 68.3 +/- 11.8 years. Of the study population, 68% were women, 69% were white, 6% were current smokers, 45% were obese, 46% had diabetes, and 83% had hypertension. A history of CVD was present for 1,972 (44.1%), and plasma PTH level greater than 70 pg/mL, for 2,239 (50.1%). Multivariate logistic regression showed ORs for CVD events increasing with age (OR, 1.03; P < 0.001), male sex (OR, 1.51; P < 0.001), diabetes (OR, 1.73; P < 0.001), hypertension (OR, 1.43; P < 0.001), and intact PTH level greater than 70 pg/mL (OR, 1.51; P < 0.001; reference, <35 pg/mL). PTH level greater than 70 pg/mL is independently associated with CVD events in patients with CKD stages 3 and 4. No association was observed between serum phosphorus or calcium level and CVD events. These findings provide support for intact PTH testing, along with testing for other indicators of CKD mineral and bone disorders, at earlier CKD stages.


[Reporting of patient deaths and grave injury incidental to clinical practice].
The Japan Surgical Society has developed guidelines for the reporting of patient deaths and grave injury incidentally occurring in their clinical courses, following its declaration in March 2001 in reference to practitioners' duty to notify the police under Article 21 of the Medical Act. These guidelines can be summarized into three points. First, they are ethical guidelines for practitioners and are not concerned with the legal duty required under the Medical Act. Second, they require reporting of patient deaths even if the cause is still not confirmed as medical malpractice, and reporting of grave injury due to apparent medical malpractice, not mention deaths due to apparent medical malpractice. Third, it is emphasized that the guidelines be applicable for the time being until some generalized system is established, which is specialized to accept reports about patient deaths and grave injury incidentally occurring in their clinical course from every hospital nationwide and to collect data concerning small incidents and risks in medical practice. The Japan Surgical Society strongly requests that such a general system start to function as soon as possible. In advance, the current guidelines should be amended repeatedly in reference to problems occurring in actual cases.


Ammonia and carbon dioxide concentrations in disposable and reusable static mouse cages.
The value of a static mouse cage is partially determined by the cage's ability to dissipate carbon dioxide and ammonia. The authors compared the concentrations of ammonia and carbon dioxide produced by mice housed in two types of static isolator cages: a newly introduced disposable cage and a conventional reusable cage. Female mice were housed in three disposable and three reusable cages (n = 5 per cage). After 7 d, groups that were housed in disposable cages were rehoused in fresh reusable cages and vice versa. Intracage carbon dioxide, ammonia, temperature and relative humidity were measured daily. Overall, there were no significant differences in carbon dioxide or ammonia concentrations between the cage types. Within 30 min of placing mice in cages, carbon dioxide concentrations rose to more than 10,000 ppm in both cage types and rarely dropped below 8,000 ppm during both phases of the study. Ammonia concentrations rose slowly until day 4 and then began to rise rapidly. The maximum average ammonia concentration was 710 ppm. There was a highly significant relationship between increasing levels of humidity and ammonia production in the disposable cages (r = 0.88). For the reusable cages, the correlation was not as strong (r = 0.68). Both cage types were similar in their ability to dissipate carbon dioxide and ammonia. The suggested frequency of cage changing can only be estimated; on the basis of existing literature, it seems prudent to change cages when the ammonia concentration reaches 50 ppm.


Interventions and lower-limb macroscopic muscle morphology in children with spastic cerebral palsy: a scoping review.
To identify and map studies that have assessed the effect of interventions on lower-limb macroscopic muscle-tendon morphology in children with spastic cerebral palsy (CP). We conducted a literature search of studies that included pre- and post-treatment measurements of lower-limb macroscopic muscle-tendon morphology in children with spastic CP. Study quality was evaluated and significant intervention effects and effect sizes were extracted. Twenty-eight articles were identified. They covered seven different interventions including stretching, botulinum neurotoxin A (BoNT-A), strengthening, electrical stimulation, whole-body vibration, balance training, and orthopaedic surgery. Study quality ranged from poor (14 out of 28 studies) to good (2 out of 28). Study samples were small (n=4-32) and studies were variable regarding which muscles and macroscopic morphological parameters were assessed. Inconsistent effects after intervention (thickness and cross-sectional area for strengthening, volume for BoNT-A), no effect (belly length for stretching), and small effect sizes were reported. Intervention studies reporting macroscopic muscle-tendon remodelling after interventions are limited and heterogeneous, making it difficult to generalize results. Studies that include control groups and standardized assessment protocols are needed to improve study quality and data synthesis. Lack or inconclusive effects at the macroscopic level could indicate that the effects of interventions should also be evaluated at the microscopic level. Muscle-targeted interventions to remodel muscle morphology are not well understood. Studies reporting macroscopic muscle remodelling following interventions are limited and heterogeneous. Passive stretching may preserve but does not increase muscle length. The effects of isolated botulinum neurotoxin A injections on muscle volume are inconsistent. Isolated strengthening shows no consistent increase in muscle volume or thickness.


Coping with stress: parallelism between the effects of septal lesions on growth hormone and corticosterone levels.
In order to characterize the effects of a septal lesion on plasma growth hormone levels, blood samples were taken from normal and sham-operated rats and rats with a bilateral septal lesion under conditions of rest and following stressful stimulation. Nonlesioned control rats evidenced a significant base line diurnal rhythm in plasma growth hormone levels which was unaffected by a septal lesion. In response to stress, plasma growth hormone levels evidenced a significant drop. Minimum levels were reached 15 min after stimulation and remained depressed during 1 hr of observation after stimulation. Rats with a septal lesion evidenced the same pattern of growth hormone response to stressful stimulation as nonlesioned rats, however the magnitude of response was potentiated in septal rats. The present data were compared to the previously published corticosterone data from the same animals. A septal lesion has similar effects on boting 24-hour rhythm of either of these hormones but potentiated the response of both corticosterone and growth hormone to stress even though the direction of response is opposite. The results are interpreted as suggesting the septum is an element in some central coping mechanism which is involved when an organism reacts to environmental demands. Preliminary data further suggest that the same central coping mechanism is involved in both the behavioral and hormonal responses to stress.


Immunomodulatory effects of heated ovomucoid-depleted egg white in a BALB/c mouse model of egg allergy.
Oral immunotherapy (OIT) is a promising therapeutic approach for treating food allergy. The treatment with heated ovomucoid-depleted egg white (HOMEW) in egg-allergic patients is noteworthy; however, OIT protocols are still experimental, and a better knowledge of the underlying mechanism is required. The objective of this work was to investigate the immunomodulatory effects of HOMEW and characterize the underlying mechanism in a BALB/c mouse model of egg allergy. Mice were sensitized with EW and treated with HOMEW. Post treatment, mice were challenged with EW and euthanized for collecting blood and spleen. Markers of allergic clinical outcomes were measured as histamine concentration, serum antibody activity, and cytokine production from cultured splenocytes. Digestibility of HOMEW was assessed mimicking physiological conditions in vitro. The HOMEW demonstrated high digestibility. The treatment induced a marked increase of the Th1/Th2 ratio in the high-dose treatment group. Treated mice had significantly less histamine, EW-specific IgE, and IL-4 and more IFN-γ and IL-10. This study confirms the mechanisms involved in successful tolerance induction with OIT using HOMEW and allows understanding of the vital role of surrogate allergy markers involved in immune modulation.


A dual-function SNF2 protein drives chromatid resolution and nascent transcripts removal in mitosis.
Mitotic chromatin is largely assumed incompatible with transcription due to changes in the transcription machinery and chromosome architecture. However, the mechanisms of mitotic transcriptional inactivation and their interplay with chromosome assembly remain largely unknown. By monitoring ongoing transcription in Drosophila early embryos, we reveal that eviction of nascent mRNAs from mitotic chromatin occurs after substantial chromosome compaction and is not promoted by condensin I. Instead, we show that the timely removal of transcripts from mitotic chromatin is driven by the SNF2 helicase-like protein Lodestar (Lds), identified here as a modulator of sister chromatid cohesion defects. In addition to the eviction of nascent transcripts, we uncover that Lds cooperates with Topoisomerase 2 to ensure efficient sister chromatid resolution and mitotic fidelity. We conclude that the removal of nascent transcripts upon mitotic entry is not a passive consequence of cell cycle progression and/or chromosome compaction but occurs via dedicated mechanisms with functional parallelisms to sister chromatid resolution.


Comparison of Marginal Bone Loss Between Implants with Internal and External Connections: A Systematic Review.
The objective of this systematic review was to compare the loss of marginal bone between implants with internal and external connections by analyzing results reported in studies published after 2010. A literature search in MEDLINE with the keywords "dental implant connections, external internal implant connection, bone loss implant designs, internal and external connection implant studies in humans" was conducted. Clinical trials on human beings, comparing both connections and published in English, from 2010 to 2016 were selected. Their methodologic quality was assessed using the Jadad scale. From the initial search, 415 articles were obtained; 32 were chosen as potentially relevant based on their titles and abstracts. Among them, only 10 finally met the inclusion criteria. A total of 1,523 patients with 3,965 implants were analyzed. Six out of 10 studies observed that internal connections showed significantly less bone loss compared with external connections. The remaining four articles did not find statistically significant differences between the two connections. According to this systematic review and considering its limitation due to the degree of heterogeneity between the included studies, both internal and external connections present high survival rates. To assess whether marginal bone loss differs significantly between the two connections, more homogenous clinical studies are needed with identical implant characteristics, larger samples, and longer follow-up periods. Studies included in this review and characterized by long-term follow-ups showed that the external connection is a reliable connection on a long-term basis.


Development of a deletion and genetic linkage map for the 5A and 5B chromosomes of wheat (Triticum aestivum).
The aims of the present study were to provide deletion maps for wheat ( Triticum aestivum L.) chromosomes 5A and 5B and a detailed genetic map of chromosome 5A enriched with popular microsatellite markers, which could be compared with other existing maps and useful for mapping major genes and quantitative traits loci (QTL). Physical mapping of 165 gSSR and EST-SSR markers was conducted by amplifying each primer pair on Chinese Spring, aneuploid lines, and deletion lines for the homoeologous group 5 chromosomes. A recombinant inbred line (RIL) mapping population that is recombinant for only chromosome 5A was obtained by crossing the wheat cultivar Chinese Spring and the disomic substitution line Chinese Spring-5A dicoccoides and was used to develop a genetic linkage map of chromosome 5A. A total of 67 markers were found polymorphic between the parental lines and were mapped in the RIL population. Sixty-three loci and the Q gene were clustered in three linkage groups ordered at a minimum LOD score of 5, while four loci remained unlinked. The whole genetic 5A chromosome map covered 420.2 cM, distributed among three linkage groups of 189.3, 35.4, and 195.5 cM. The EST sequences located on chromosomes 5A and 5B were used for comparative analysis against Brachypodium distachyon (L.) P. Beauv. and rice ( Oryza sativa L.) genomes to resolve orthologous relationships among the genomes of wheat and the two model species.