Prospective phase II trial of neoadjuvant chemo-radiotherapy with Oxaliplatin and Capecitabine in locally advanced rectal cancer (XELOXART).
Neo-adjuvant chemo-radiotherapy (CT-RT) has been shown to decrease local recurrence rate in locally advanced rectal cancer. This multicenter phase II trial was conducted to evaluate the feasibility, safety and effectiveness of a combination of pre-operative radiotherapy and concurrent Capecitabine plus Oxaliplatin (XELOXART Trial). From October 2008 to May 2011, fifty consecutive patients affected with T3/T4 and/or N+ rectal cancer were enrolled. Treatment protocol consisted of 50.4 Gy in 28 fractions, Oxaliplatin 60 mg/m(2) once a week for 6 weeks and oral Capecitabine 825 mg/m(2) twice daily from day 1 to 14 and from day 22 to 35. Surgery was planned 6-8 weeks after. Main endpoints were pathological complete response rate (pCR) and the type of surgery performed compared to the planned one at diagnosis. 50 patients were included; pCR (ypT0N0M0) was achieved in 6 patients (12 %). Tumour downstaging was observed in 27 patients (54 %), and nodal downstaging in 32 patients (64 %). A total of 32 patients had lower rectal cancer, with 24 candidate for abdominal-perineal resection. At the end of CT-RT, a total of 12/24 (50 %) underwent conservative surgery. Grade 3 toxicity (fatigue and diarrhoea) occurred in 4 % of patients; grade 4 sensory neuropathy occurred in 2 % of patients. Perioperative complications of any grade occurred in 10 % of patients. Pre-operative CT-RT with Capecitabine-Oxaliplatin was well tolerated and resulted in an encouraging sphincter preservation and tumour downstaging rate. No improvements in terms of pathological complete response rate were shown.


The External Auditory Canal: Examination and Evaluation.
The external auditory canal is a highly specialized skin appendage whose primary purpose is to provide a pathway for the transmission of sound to the tympanic membrane and beyond. It is also a frequent source of symptoms for our patients. Sources of pain, hearing loss, tinnitus, itching, and other sensations can be inferred from an appropriate history. This should be followed by a thorough cleaning of the ear, so that a thorough examination can be performed.


How I do it: surgical management of gastrointestinal stromal tumors.
The surgical management of gastrointestinal stromal tumors (GISTs) has been impacted by the development of tyrosine kinase inhibitors (TKIs), advances in surgical technique, and a better understanding of the natural history of this unique disease. In this article, we review the technical aspects of the operations, the expanding role of laparoscopy, and the indications for neoadjuvant and neoadjuvant TKI therapy in primary GIST. Furthermore, we explore the rationale for and incorporation of surgery in the multidisciplinary management of advanced GIST.


Alveolar oxygen uptake kinetics with step, impulse and ramp exercise in humans.
The breath-by-breath VO2A of five male subjects (21.2 years +/-3.2; 78.8 kg +/-5.9; 179.6 cm +/-5.8) was measured during a cycling exercise. Starting from a 10 W baseline, the subjects performed (i) ON and OFF step transitions (ST-ON; ST-OFF) to 50, 90, and 130 W; (ii) a ramp (R) exercise with work rate gradually increasing by 20 W min(-1); (iii) impulse transitions (I) to 250 and 410 W lasting 10 and 5 s, respectively. The VO2A data was modelled using non-linear weighted least square regressions. The amplitudes of the VO2A response turned out to be proportional to the input work rate intensities in all the modalities of exercise. Time constants (tau) and time delays (t (d)) of ST-ON and R responses were not significantly different, whereas those of ST-OFF were characterised by longer tau values. tau and t (d) of I responses turned out to be identical to those of ST-ON when the VO2A responses were fitted using a five-component model. These results suggest that: (i) the system controlling alveolar gas exchange behaves linearly when it is forced by ST and R inputs (the ON and OFF phases being considered separate); (ii) the analysis of the I response depends strongly on the models selected to fit the VO2A data. The asymmetry between the ON and OFF responses mirrors that found between the splitting and resynthesis rates of phosphocreatine, and these results support the notion that phosphocreatine could be the main controller of the skeletal muscle respiratory turnover in humans.


[Influence of social learning on alcohol consumption].
The history of social learning in relation to the alcohol consumption of 50 heavy and 50 average drinkers, matched according to socio- demographic factors, was compared. The main differences concerned the situation at home and relations with young colleagues. Drinking on festive occasions, together with the parents, seems to favour normal consumption in later years, even if the drinking starts at a young age. If, however, the parents used alcohol as a means to relieve tensions, or if the subject was in near contact with heavy drinking young colleagues that rather despised people who did not drink much, an association with high consumption could be noted. No significant differences have appeared in the behavior of adult acquaintances.


Pseudouridine detection improvement by derivatization with methyl vinyl sulfone and capillary HPLC-mass spectrometry.
A method is presented for improved detection of pseudouridine in nucleoside mixtures based on the specific derivatization with methyl vinyl sulfone followed by analysis by capillary HPLC-mass spectrometry. Reaction conditions were optimized in order to obtain the best yield and specificity. The method was successfully applied to different nucleoside mixtures.


YTHDF2 reduction fuels inflammation and vascular abnormalization in hepatocellular carcinoma.
Dynamic N6-methyladenosine (m6A) modification was previously identified as a ubiquitous post-transcriptional regulation that affected mRNA homeostasis. However, the m6A-related epitranscriptomic alterations and functions remain elusive in human cancer. Here we aim to identify the profile and outcome of m6A-methylation in hepatocellular carcinoma (HCC). Using liquid chromatography-tandem mass spectrometry and m6A-immunoprecipitation in combination with high-throughput sequencing, we determined the m6A-mRNA levels in human HCC. Human HCC exhibited a characteristic gain of m6A modification in tandem with an increase of mRNA expression, owing to YTH domain family 2 (YTHDF2) reduction. The latter predicted poor classification and prognosis of HCC patients, and highly correlated with HCC m6A landscape. YTHDF2 silenced in human HCC cells or ablated in mouse hepatocytes provoked inflammation, vascular reconstruction and metastatic progression. Mechanistically, YTHDF2 processed the decay of m6A-containing interleukin 11 (IL11) and serpin family E member 2 (SERPINE2) mRNAs, which were responsible for the inflammation-mediated malignancy and disruption of vascular normalization. Reciprocally, YTHDF2 transcription succumbed to hypoxia-inducible factor-2α (HIF-2α). Administration of a HIF-2α antagonist (PT2385) restored YTHDF2-programed epigenetic machinery and repressed liver cancer. Our results have characterized the m6A-mRNA landscape in human HCC and revealed YTHDF2 as a molecular 'rheostat' in epitranscriptome and cancer progression.


An ultrathin sectioning alignment tool with application to cell monolayers.
Details are given concerning the construction and use of a simple tool to help align a specimen block face in the vertical axis for subsequent ultrathin sectioning. Further instructions are given for the preparation of cell monolayers for ultrathin sectioning. The advantage is simple, repetitive and quick alignment of the specimen block face for ultrathin sectioning.


Effects on hemodynamics and gas exchange of omega-3 fatty acid-enriched lipid emulsion in acute respiratory distress syndrome (ARDS): a prospective, randomized, double-blind, parallel group study.
We investigated the effects on hemodynamics and gas exchange of a lipid emulsion enriched with omega-3 fatty acids in patients with ARDS. The design was a prospective, randomized, double-blind, parallel group study in our Intensive Medicine Department of Vall d'Hebron University Hospital (Barcelona-Spain). We studied 16 consecutive patients with ARDS and intolerance to enteral nutrition (14 men and 2 women; mean age: 58 +/- 13 years; APACHE II score: 17.8 +/- 2.3; Lung Injury Score: 3.1 +/- 0.5; baseline PaO2/FiO2 ratio: 149 +/- 40). Patients were randomized into 2 groups: Group A (n = 8) received the study emulsion Lipoplus 20%, B.Braun Medical (50% MCT, 40% LCT, 10% omega-3); Group B (n = 8) received the control emulsion Intralipid Fresenius Kabi (100% LCT). Lipid emulsions were administered during 12 h at a dose of 0.12 g/kg/h. Measurements of the main hemodynamic and gas exchange parameters were made at baseline (immediately before administration of the lipid emulsions), every hour during the lipid infusion, at the end of administration, and six hours after the end of administration lipid infusion. No statistically significant changes were observed in the different hemodynamic values analyzed. Likewise, the gas exchange parameters did not show statistically significant differences during the study. No adverse effect attributable to the lipid emulsions was seen in the patients analyzed. The lipid emulsion enriched with omega-3 fatty acids was safe and well tolerated in short-term administration to patients with ARDS. It did not cause any significant changes in hemodynamic and gas exchange parameters. ISRCTN63673813.


Expression of multiple tfb genes in different Halobacterium salinarum strains and interaction of TFB with transcriptional activator GvpE.
Halobacterium salinarum NRC-1 contains multiple TBP and TFB proteins required for the recruitment of RNA polymerase for transcription initiation. The presence and the expression of genes encoding TFB were investigated in the two Hbt. salinarum strains NRC-1 and PHH1 and the mutant strain PHH4. The plasmid-encoded tfbC and tfbE genes of NRC-1 were lacking in PHH1 and PHH4. The 5'-end of the tfbF transcript was determined and contained a 5'-untranslated region of 39 nucleotides able to form a stem-loop structure. The expression of these tfb genes was studied in cultures growing at 15, 37°C and under heat shock conditions. Cold temperatures reduced growth and except for tfbF also the amounts of all tfb transcripts. However, the formation of gas vesicles increased in PHH1 and NRC-1. Heat shock reduced growth of PHH1 and NRC-1, but PHH4 was not affected. A 100-fold increase in tfbA and tfbB mRNA was observed in PHH1 and PHH4, whereas NRC-1 reduced the amounts of these transcripts and increased the expression of tfbG. All TFB proteins tested were able to interact with the transcription activator GvpE involved in gas vesicle formation that thus is able to recruit TFB to the gvp promoter.


[1,4]Ditellurino[2,3-b:5,6-b']di-pyrazine.
[1,4]Ditellurino[2,3-b:5,6-b']di-pyrazine represents the first reported [1,4]chalcogena[2,3-b:5,6-b']di-pyrazine containing a heavy chalcogens The asymmetric unit consists of three mol-ecules. In contrast to its sulfur analog, which is planar [Lynch et al. (1994 ▸) Cryst. Struct. Commun. 50,1470-1472], C8H4N4Te2 is folded along the Te⋯Te axis to accommodate the larger chalcogenide atoms. The dihedral angle between the two Te2C2 rings of the central ring is 57.9° (mean of three). C-Te bond lengths range from 2.1105 (16) Å to 2.1381 (17) Å, in good agreement with those predicted by their covalent radii. All Te atoms are involved in inter-molecular Te⋯N contacts, with distances in the range 2.894 (2) to 2.963 (2) Å. These result in a spiral supra-molecular assembly, forming helical columns.


Reversible binding of glycolytic enzymes and size change in the actin-containing filaments of the frog skeletal muscle.
Electron microscopy was used in order to study the change of the actin-containing filaments when the bound glycolytic enzymes were removed by a high ionic strength solution. The effectiveness of the extraction medium was checked by estimating the aldolase activity released. Evidence was provided that the larger diameter of the actin filaments in the I-bands in comparison with the A-bands can be accounted for by the bound glycolytic enzymes.


Phylogenetic analysis of invertebrate lysozymes and the evolution of lysozyme function.
We isolated and sequenced the cDNAs coding for lysozymes of six bivalve species. Alignment and phylogenetic analysis showed that, together with recently described bivalve lysozymes, the leech destabilase, and a number of putative proteins from extensive genomic and cDNA analyses, they belong to the invertebrate type of lysozymes (i type), first described by Jollès and Jollès (1975). We determined the genomic structure of the gene encoding the lysozyme of Mytilus edulis, the common mussel. We provide evidence that the central exon of this gene is homologous to the second exon of the chicken lysozyme gene, belonging to the c type. We propose that the origin of this domain can be traced back in evolution to the origin of bilaterian animals. Phylogenetic analysis suggests that i-type proteins form a monophyletic family.


A 1980-2018 global fire danger re-analysis dataset for the Canadian Fire Weather Indices.
This data descriptor documents a dataset containing over 38 years of global reanalysis of wildfire danger. It consists of seven fields to assess fuel moisture as well as fire behavior. The methodology employed to generate these data is based on the Canadian Forest Fire Weather Danger Rating and utilizes weather forcing from ERA-Interim, a global reanalysis dataset produced by the European Centre for Medium-range Weather Forecasts. Global fire danger reanalysis data are used to quantify the climatological expectation of fire danger at a certain time of the year and for any location on the globe. It can be regarded as a complementary product to the fire danger forecasts issued daily by the Global Wildfire Information System (GWIS) under the umbrella of the European Copernicus program.


Colour Doppler imaging before and after retrobulbar anaesthesia in patients undergoing cataract surgery.
To investigate the effect of retrobulbar anaesthesia on retrobulbar haemodynamics, colour Doppler imaging was performed. Furthermore, the additive effect of epinephrine was examined. Forty-one patients (age 72.7+/-8.9; 22 f, 19 m) undergoing planned cataract surgery were included in a prospective study. Colour Doppler imaging was performed before and directly after retrobulbar anaesthesia and after cataract surgery to measure the peak systolic velocity (PSV) and end-diastolic velocity (EDV) in the ophthalmic artery, central retinal artery and central retinal vein. In 18 patients lidocaine 2% without additives (2 ml, retrobulbar transconjunctival injection) and in 23 patients lidocaine 2% with epinephrine 1:200,000 was used. After retrobulbar anaesthesia both groups had a significant reduction of the PSV and of the EDV. After surgery flow velocities increased again. The addition of epinephrine resulted in a significantly greater reduction and slower recovery of flow velocities. Retrobulbar anaesthesia induces a marked reduction of velocity in the retrobulbar vessels. The supplement epinephrine increases this effect, and recovery is much slower. Thus, particularly in patients with already disturbed ocular haemodynamics epinephrine should not be used in order to avoid irreversible functional damage.


Endothelial targeting of a recombinant construct fusing a PECAM-1 single-chain variable antibody fragment (scFv) with prourokinase facilitates prophylactic thrombolysis in the pulmonary vasculature.
Means to prevent thrombus extension and local recurrence remain suboptimal, in part because of the limited effectiveness of existing thrombolytics. In theory, plasminogen activators could be used for this purpose if they could be anchored to the vascular lumen by targeting stably expressed, noninternalized determinants such as platelet-endothelial-cell adhesion molecule 1 (PECAM-1). We designed a recombinant molecule fusing low-molecular-weight single-chain prourokinase plasminogen activator (lmw-scuPA) with a single-chain variable fragment (scFv) of a PECAM-1 antibody to generate the prodrug scFv/lmw-scuPA. Cleavage by plasmin generated fibrinolytically active 2-chain lmw-uPA. This fusion protein (1) bound specifically to PECAM-1-expressing cells; (2) was rapidly cleared from blood after intravenous injection; (3) accumulated in the lungs of wild-type C57BL6/J, but not PECAM-1 null mice; and (4) lysed pulmonary emboli formed subsequently more effectively than lmw-scuPA, thereby providing support for the concept of thromboprophylaxis using recombinant scFv-fibrinolytic fusion proteins that target endothelium.


Genetically-encoded biosensors for analyzing and controlling cellular process in yeast.
Yeast has been a robust platform to manufacture a broad range of biofuels, commodity chemicals, natural products and pharmaceuticals. The membrane-bound organelles in yeast provide us the means to access the specialized metabolism for various biosynthetic applications. The separation and compartmentalization of genetic and metabolic events presents us the opportunity to precisely control and program gene expression for higher order biological functions. To further advance yeast synthetic biology platform, genetically encoded biosensors and actuators haven been engineered for in vivo monitoring and controlling cellular processes with spatiotemporal resolutions. The dynamic response, sensitivity and operational range of these genetically encoded sensors are determined by the regulatory architecture, dynamic assemly and interactions of the related proteins and genetic elements. This review provides an update of the basic design principles underlying the allosteric transcription factors, GPCR and optogenetics-based sensors, aiming to precisely analyze and control yeast cellular processes for various biotechnological applications.


Repair of osteochondral defect using icariin-conditioned serum combined with chitosan in rabbit knees.
Osteochondral defects caused by an acute traumatic injury or articular degeneration remains difficult to be manipulated. Repair of articular defects is still a great challenge for both tissue engineers and orthopedic surgeons. Therefore, combination of biomaterials with cartilage promotive drugs is well worth being developed to support the regeneration of both cartilage and subchondral bone. Rabbits undergoing osteochondral defect surgery were intrarticularly injected with icariin-conditioned serum (ICS), chitosan (CSSH) and combination of ICS with CSSH, respectively. Gait analysis was performed using VICON motion capture system. ICRS score and immunohistochemical (IHC) analysis including H&E, Safranin O, toluidine blue and collagen II staining was employed to evaluate macroscopic cartilage regeneration and determine the morphologic repair of cartilage. Rabbits with the treatment of ICS or CSSH alone showed mild improvement in hopping time and range of joint angles while ICS-CSSH group exhibited longer jumping time and larger range of joint angles. In addition, femoral condyle in ICS-CSSH rabbits could be seen with more native cartilage and subchondral bone regeneration in both macroscopic observation and IHC analysis. ICS combined with CSSH could promote the repair of osteochondral defect in rabbit knees. Combination of biomaterials with cartilage promotive drugs may ultimately have profound implications in the management of cartilage defect.


Wilms' tumor gene 1 regulates p63 and promotes cell proliferation in squamous cell carcinoma of the head and neck.
Wilms' tumor gene 1 (WT1) can act as a suppressor or activator of tumourigenesis in different types of human malignancies. The role of WT1 in squamous cell carcinoma of the head and neck (SCCHN) is not clear. Overexpression of WT1 has been reported in SCCHN, suggesting a possible oncogenic role for WT1. In the present study we aimed at investigating the function of WT1 and its previously identified protein partners p63 and p53 in the SCCHN cell line FaDu. Silencing RNA (siRNA) technology was applied to knockdown of WT1, p63 and p53 in FaDu cells. Cell proliferation was detected using MTT assay. Chromatin immunoprecipitation (ChIP)/PCR analysis was performed to confirm the effect of WT1 on the p63 promoter. Protein co-immunoprecipitation (co-IP) was used to find protein interaction between WT1 and p53/p63. Microarray analysis was used to identify changes of gene expression in response to knockdown of either WT1 or p63. WT1 RNA level was detected using real-time quantitative PCR (RT-qPCR) in patients with SCCHN. We found that WT1 and p63 promoted cell proliferation, while mutant p53 (R248L) possessed the ability to suppress cell proliferation. We reported a novel positive correlation between WT1 and p63 expression. Subsequently, p63 was identified as a WT1 target gene. Furthermore, expression of 18 genes involved in cell proliferation, cell cycle regulation and DNA replication was significantly altered by downregulation of WT1 and p63 expression. Several known WT1 and p63 target genes were affected by WT1 knockdown. Protein interaction was demonstrated between WT1 and p53 but not between WT1 and p63. Additionally, high WT1 mRNA levels were detected in SCCHN patient samples. Our findings suggest that WT1 and p63 act as oncogenes in SCCHN, affecting multiple genes involved in cancer cell growth.


MHC recognition by clones of Mls specific T-lymphocytes.
To test whether Mls determinants like other non-MHC or nominal antigens, are recognized by T-cells in association with H-2 determinants, the in vitro proliferative responses of T-cell lines and clones were studied. Lines and clones were prepared by soft agar cloning (B10.BR X BALB/c)F1 (H-2k/H-2d Mlsb/Mlsb) t-cells responding in a primary MLR to AKD2F1 (H-2k/H-2d, Mlsa/Mlsa) stimulator cells. All the T-cell clones obtained could respond equally well in a proliferative assay to the Mlsa determinant in association with the H-2 haplotype of either parent, i.e., DBA/2 (H-2d, Mls), and AKR (H-2K, Mlsa) both stimulated equally well. When the T-cell lines and clones were screened against stimulators from recombinant inbred (RI) strains, it became apparent that strains exhibiting the H-2b, Mlsa genotype stimulated poorly or not at all. This shows that the T-cell response to Mlsa involves MHC recognition, and raises the possibility that the response to Mlsa can involve recognition of H-2 specificities shared between the H-2k and H-2d haplotypes.


Inhibition of lipid peroxidation in spinal cord homogenates by various drugs.
The extent and kinetic profiles of lipid peroxidation induced with Fe2+-ascorbic acid in a homogenate of spinal cord from greyhound dogs were ascertained by measurement of the formation of malondialdehyde (MDA) and chemiluminescence in the presence of four drugs. Changes in MDA and chemiluminescence were correlated as a function of the activator or inhibitors. The kinetic profiles of chemiluminescence which were observed for 25 min after addition of the activator and individual inhibitors were similar regardless of the type of inhibitor studied. The most effective inhibition was by disulfiram which was approximately 11 and 33 times more effective than two other inhibitors, propyl gallate and promethazine, respectively, and 11,000 times more effective than D-alpha-tocopherol.


Characterization of a somatomedin (insulin-like growth factor) synthesized by fetal rat liver organ cultures.
Explants of 19- to 20-day fetal rat liver synthesize polypeptides biochemically and immunologically related to the well characterized somatomedin (insulin-like growth factor) BRL-MSA, multiplication-stimulating activity. Fetal MSA was purified from media conditioned by fetal liver explants by chromatography on Sephadex G-75 under acid conditions. Partially purified fetal MSA: 1) inhibited the binding of BRL-MSA to the MSA receptor of rat liver plasma membranes, to somatomedin-binding proteins from rat serum, and to rabbit anti-BRL-MSA serum; 2) had a molecular weight of 4,500 to 12,500 determined by polyacrylamide gel electrophoresis in sodium dodecyl sulfate; 3) stimulated the incorporation of [3H]thymidine into the DNA of chick embryo fibroblasts and induced cell multiplication; 4) stimulated glucose oxidation in rat adipocytes and weakly inhibited the binding of insulin to the insulin receptors of IM-9 lymphocytes; and 5) stimulated sulfate uptake in costal cartilage from hypophysectomized rats. These activities were associated with the same molecular species in fetal MSA preparations following disc acrylamide electrophoresis and co-migrated with active BRL-MSA peptides.


A European multicentre study on the comparison of HCV viral loads between VERIS HCV assay and COBAS® TaqMan® HCV Test and RealTime HCV Assay.
Beckman Coulter has developed the VERIS HCV Assay for use on the new fully automated DxN VERIS Molecular Diagnostic System¥ for HCV viral load monitoring. Evaluate the clinical performance of the new quantitative VERIS HCV Assay. Comparison was performed on 279 plasma specimens from HCV infected patients tested with the VERIS HCV Assay and COBAS® Ampliprep/COBAS® Taqman® HCV Test and 369 specimens tested with the VERIS HCV Assay and RealTime HCV Assay. Patient monitoring sample results from four time points were also compared. The average bias between the VERIS HCV Assay and the COBAS® Ampliprep/COBAS® Taqman® HCV Test was 0.04 log10IU/mL, while between the VERIS HCV Assay and the RealTime HCV Assay average bias was 0.21 log10IU/mL. Bias, however, was not consistent across the measuring range. Analysis at the lower end of quantification levels 50, 100, and 1000IU/mL showed a predicted bias for VERIS HCV Assay versus COBAS® Ampliprep/COBAS® Taqman® HCV Test between -0.42 and -0.22 log10IU/mL and for VERIS HCV Assay versus RealTime HCV Assay between 0.00 and 0.13 log10IU/mL. Patient monitoring of HCV viral load over time demonstrated similar levels between VERIS HCV Assay results and COBAS® Ampliprep/COBAS® Taqman® HCV Test (52 samples from 13 patients) and RealTime HCV Assay (112 samples from 28 patients). VERIS HCV Assay for use on the DxN VERIS Molecular Diagnostic System represents a reliable new tool for easy sample to result HCV RNA viral load monitoring.


[The reduction of Cr(VI) by bacteria of the genus Pseudomonas].
Non-nitrate-reducing collection bacteria from the genus Pseudomonas were found to be able to use hexavalent chromium as a terminal electron acceptor. The reduction of Cr(VI) was accompanied by an increase in the cell biomass. At the Cr(VI) concentrations in the medium lower than 15 mg/l, the non-nitrate-reducing pseudomonads reduced Cr(VI) less efficiently than did denitrifying pseudomonads. In contrast, at the Cr(VI) concentrations higher than 30 mg/l, Cr(VI) was reduced more efficiently by the non-nitrate-reducing pseudomonads than by the denitrifying pseudomonads.


Medical students' decisions about authorship in disputable situations: intervention study.
In medicine, professional behavior and ethics are often rule-based. We assessed whether instruction on formal criteria of authorship affected the decision of students about authorship dilemmas and whether they perceive authorship as a conventional or moral concept. A prospective non-randomized intervention study involved 203s year medical students who did (n = 107) or did not (n = 96) received a lecture on International Committee of Medical Journal editors (ICMJE) authorship criteria. Both groups had to read 3 vignettes and answer 4 questions related to the distinction between conventional and moral domains. Written justification of student' choices whether the authorship in a vignette was right or wrong was rated by 4 independent raters as based on justice or a rule. Formal instruction had no effect on students' decisions on authorship in the vignettes (44, 34 and 39% ICMJE-consistent answers for 3 vignettes, respectively, by students receiving instruction vs. 38, 42 and 30% for those without instruction; P > 0.161 for all vignettes). For all dilemmas, more students decided contrary to ICMJE criteria and considered their decisions to be a matter of obligation and not a choice and to be general across situations and sciences. They were willing to change their decision if a rule was different only for peer situations but not for mentor-mentee situations. The number of students who used rule-based justification of their ICMJE criteria-consistent decisions was significantly higher in the instructed than in the uninstructed group. Instruction about formal authorship criteria had no effect on student's decisions about authorship dilemmas and their decisions were related to the moral rather than a conventional domain. Teaching about authorship and other professionalism and integrity issues may benefit from interventions that bring intuitive processes into awareness instead of those fostering rule-based reasoning.


What is appropriate health care for end-stage dementia?
This study sought to determine the kind of health care that professional and family caregivers viewed as appropriate for end-stage dementia patients. Survey. All 819 physician members and 1,000 randomly selected non-physician members of the Gerontological Society of America and 500 families of demented relatives from the Alzheimer's Association. Respondents chose the appropriate level of care from five choices on a continuum from highly aggressive to palliative. The majority of physicians who cared for elders (61%), gerontologists from other professions (55%), and families (71%) chose palliative care only. Increased age of the respondent and experience with terminal care choices were associated with the choice of palliative care. The majority favored hospice care for patients with end-stage dementia. Professional and family members of demented individuals, especially if they have experience in terminal care decisions, strongly favor palliative care for end-stage dementia. These findings may be helpful to professionals and families dealing with these choices.


Implementation of the Montreal heat response plan during the 2010 heat wave.
The objective of this paper is to describe Montreal's heat response plan and its application during the July 2010 heat wave. The Montreal heat response plan is designed to ensure the surveillance of weather and health indicators during the summer season and to coordinate actions to be undertaken during this period to reduce morbidity and mortality due to heat, particularly when weather thresholds are reached or an increase in health indicators is observed. It was developed to coordinate and apply intervention measures on the Island of Montreal and has been in effect since 2004. In the beginning of July 2010, Montreal experienced a heat wave that lasted 5 days. During this period, health indicators such as total mortality, prehospital emergency transports, calls to the health information line and hospital admissions were monitored by the Montreal public health surveillance system. The decision to implement emergency interventions and actions performed by regional and local public health and municipal partners (intervention level) was made following attainment of a predetermined weather threshold and increases in health indicators. The significant increase in daily observed mortality from all causes and in particular people dying at home or in the community prompted the Director of public health to conduct a chart review of all people deceased from July 5 to July 11, 2010 to determine cause of death and underlying health conditions. During the heat wave, there were 304 reported deaths from all causes in Montreal residents, of which 106 were probably or possibly heat-related. Major underlying health conditions in heat-related deaths included cardiovascular problems and mental health illness. Furthermore, in the case of people with mental illness who died during the heat wave, the chart review revealed that many were contacted 24 hours prior to their death by health care professionals, family members, neighbours or friends. Following the 2010 heat wave, the Montreal heat response plan and heat surveillance system were updated to include initiatives to better communicate preventive measures to the vulnerable populations and to intervene earlier during a heat wave.


Maximal mechanical power output and capacity of cyclists and young adults.
The maximal average power output (Wmax) has been examined in 10 male students, 22 pursuit and 12 sprint cyclists. In 24 of these subjects (8 students, 10 pursuit and 6 sprint cyclists), estimates of the maximal capacity (Wcap) of the short-term anaerobic energy yielding processes were made. The results show that the sprinters had a higher absolute Wmax (1241 +/- 266 W) and Wcap (16.7 +/- 4.9 kJ) than either the students (1019 +/- 183 W, 14.7 +/- 2.8 kJ) or the pursuit cyclists (962 +/- 206 W, 14.0 +/- 2.9 kJ). However, the differences were removed when the values were standardised for muscle size. In the sprinters the Wmax was attained at an optimal pedal frequency Vopt of 132 +/- 3 min-1 and the estimated maximal velocity of pedalling (V0) was 262 +/- 8 min-1. The comparable figures in the students and pursuit cyclists were 118 +/- 8 min-1, 235 +/- 17 min-1 and 122 +/- 6 min-1, 242 +/- 12 min-1 respectively. The coefficient of variation of duplicate measurements of Wcap was found to be +/- 9%. Using data of Wilkie (1968) for muscle phosphagen and glycolytic stores (27 mmol.kg-1), it was estimated that the probable efficiency of the anaerobic processes during maximal cycling was 0.22. It was concluded that Wmax and Wcap are largely determined by body size and muscularity. The efficiency of anaerobiosis appears to be of the same order of magnitude as found for oxidative work.


Measurement, Education and Tracking in Integrated Care (METRIC): use of a culturally adapted education tool versus standard education to increase engagement in depression treatment among Hispanic patients: study protocol for a randomized control trial.
Significant mental health disparities exist for Hispanic populations, especially with regard to depression treatment. Stigma and poor communication between patients and their providers result in low use of antidepressant medications and early treatment withdrawal. Cultural factors which influence treatment decisions among Hispanics include fears about the addictive and harmful properties of antidepressants, worries about taking too many pills, and the stigma attached to taking medications. Primary care settings often are the gateway to identifying undiagnosed or untreated mental health disorders, particularly for people with co-morbid physical health conditions. Hispanics, in particular, are more likely to receive mental healthcare in primary care settings. Recent recommendations from the U.S. Preventive Services Task Force are that primary care providers screen adult patients for depression only if systems are in place to ensure adequate treatment and follow-up. We are conducting a randomized controlled trial among 150 depressed adult Hispanics in a primary care safety net setting, testing the effectiveness of a culturally appropriate depression education intervention to reduce stigma and increase uptake in depression treatment among Hispanics, and implement a Measurement-Based Integrated Care (MBIC) model with collaborative, multidisciplinary treatment and culturally tailored care management strategies. This study protocol represents the first randomized control trial of the culturally adapted depression education fotonovela, Secret Feelings, among Hispanics in a primary care setting. The education intervention will be implemented after diagnosis using an innovative screening technology and enrolled in measurement-based integrated care for the treatment of depression, which will help build the evidence around cultural adaptations in treatment to reduce mental health disparities. ClinicalTrials.gov, NCT02702596. Registered on 20 March 2016.


Developmental fate of skeletal muscle satellite cells.
Radioisotopically labeled satellite cells from clonal cultures were implanted into normal muscle of the original donor. Implanted cells invariably retained their myogenic potential by participating in the regeneration of damaged myofibers or in the development of existing fibers.


Exploring the Use of Monoclonal Antibodies and Antiviral Therapies for Early Treatment of COVID-19 Outpatients in a Real-World Setting: A Nationwide Study from England and Italy.
Real-world data on early treatment of coronavirus disease 2019 (COVID-19) outpatients with newly approved therapies are sparse. To explore the pattern of use of monoclonal antibodies (mAbs)/antiviral therapies approved for early COVID-19 treatment in non-hospitalized patients from England and Italy from December 2021 to October 2022. Public national dashboards on weekly mAb/antiviral use and/or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection diagnoses from the Italian Medicines Agency, the Italian National Institute of Health, National Health Service in England and the UK Government were explored. Prevalence of antiviral use in outpatients during the entire study period and every two weeks was calculated, as a whole and by class and compounds. An interrupted time-series (ITS) analysis was carried out to assess the impact of predominant SARS-CoV-2 variants over time on the prevalence of use of mAbs/antivirals in England and Italy. Overall, 77,469 and 195,604 doses of mAbs/antivirals were respectively administered to a total of 10,630,903 (7.3 per 1000) and 18,168,365 (10.8 per 1000) patients diagnosed with SARS-CoV-2 infection in England and Italy. Prevalence of use every two weeks increased from 0.07% to 3.1% in England and 0.9% to 2.3% in Italy during the study period. Regarding individual compounds, sotrovimab (prevalence of use, 1.6%) and nirmatrelvir/ritonavir (1.6%) in England, and nirmatrelvir/ritonavir (1.7%) and molnupiravir (0.5%) in Italy, reported the highest prevalence during a 2-week period. In the ITS analysis, the transition from Delta to Omicron variant predominance was associated with a significant increase in the use of sotrovimab, molnupiravir, remdesivir and nirmatrelvir/ritonavir in both England and Italy, with a reduction of other marketed mAbs. The extent of the increase was higher in England than in Italy for all these drugs except for nirmatrelvir/ritonavir. In this dual nationwide study, the prevalence of use of mAbs/antivirals against SARS-CoV-2 for early outpatients' treatment increased slowly up to 2.0-3.0% of all patients diagnosed with SARS-CoV-2 infection in both England and Italy from December 2021 to October 2022. The trend of individual drug use varied in relation to predominant SARS-CoV-2 variants with some differences across countries. In line with scientific societies' guidelines, nirmatrelvir/ritonavir was the most frequently prescribed antiviral in both countries in the most recent period.


Superior Vena Cava Syndrome.
Superior vena cava (SVC) syndrome comprises a constellation of clinical signs and symptoms caused by obstruction of blood flow through the SVC. The management of patients with life-threatening SVC syndrome is evolving from radiation therapy to endovascular therapy as the first-line treatment. There is a paucity of data and societal guidelines with regard to the management of SVC syndrome. This paper aims to update the practicing interventionalists with the contemporary and the evolving therapeutic approach to SVC syndrome. In addition, the review will focus on endovascular techniques, including catheter-directed thrombolysis, angioplasty, and stenting, and their associated complications.


Erythropoietin and granulocyte-macrophage colony-stimulating factor allow acceleration and dose escalation of cyclophosphamide/epidoxorubicin/5-fluorouracil chemotherapy: a dose-finding study in patients with advanced breast cancer.
To verify whether the association of granulocyte-macrophage colony-stimulating factor (GM-CSF) and erythropoietin (EPO) would allow both the acceleration and the dose escalation of the cyclophosphamide/epidoxorubicin/5-fluorouracil (CEF) regimen as first-line therapy in advanced breast cancer patients, we conducted a dose-finding study. Cohorts of three consecutive patients received cyclophosphamide (Ctx, dose range 800-1400 mg/m2), epidoxorubicin (Epidx, dose range 70-100 mg/m2), and 5-fluorouracil (5-Fu, 600 mg/m2, fixed dose) given as an intravenous bolus on day 1 every 14 days; GM-CSF at 5 micrograms/kg given as a subcutaneous injection from day 4 to day 11; and EPO at 150 IU/kg given as a subcutaneous injection three times a week. In no single patient was any dose escalation allowed. A total of 14 patients entered the study. At the 4th dose level (Ctx 1400 mg/m2, Epidx 100 mg/m2, 5-Fu 600 mg/m2), two patients had dose-limiting mucositis and one patient developed dose-limiting neutropenia. Therefore, the 3rd cohort received the maximum tolerated dose, i.e. Ctx at 1200 mg/m2, Epidx at 90 mg/m2, and 5-Fu at 600 mg/m2, given every 18.5 (+/-2.5) days. Toxicity was moderate and manageable in an outpatient setting. Only 1 admission at the 4th dose level was required. Throughout the 4 dose levels there was no toxicity-related death; grade IV leukopenia ranged from 24% to 75% of cycles and grade IV thrombocytopenia ranged from 6% to 8%. No grade IV anemia was recorded. Increasing the doses of Ctx and Epidx while maintaining a fixed dose of 5-Fu with the support of both EPO and GM-CSF allows safe acceleration and dose escalation of CEF chemotherapy. Further controlled studies will evaluate the activity and efficacy of this strategy.


Phenotypes and genotypes underlying paradoxical pupillary reaction in children.
Paradoxical pupillary reaction (initial pupillary constriction to darkness) has been most associated with the inherited retinal disorders congenital stationary night blindness and achromatopsia. However, underlying genotypes and associations with other pediatric retinal phenotypes are not well documented. A retrospective review for paradoxical pupillary reaction was performed at the Ocular Genetics Clinic of Cleveland Clinic Abu Dhabi (2016-2020). Four children from 4 different families were identified, all of whom had had genetic confirmation of the clinical diagnosis. Associated pathogenic variants were in TRPM1 (biallelic; two boys; congenital stationary night blindness), CABP4 (biallelic; one boy, congenital cone-rod synaptic disorder) and PAX2 (monoallelic; one girl, papillorenal syndrome). Genetically confirmed affected relatives of the 2 probands with TRPM1-related congenital stationary night blindness did not show the phenomenon. This study documents novel genotypes and phenotypes that can be associated with paradoxical pupillary reaction in children and confirms potential intrafamilial variable expressivity for the phenomenon.


Periodic episodes of aphasia as an unusual manifestation of partial status epilepticus.
Recurrent episodes of aphasia due to partial status epilepticus is an uncommon clinical entity. We report here a 78-year-old-woman with episodic aphasia which occurred periodically. During the ictal period, she was conscious, but had difficulty in speech and could not comprehend verbal commands. The ictal EEG showed continuous spike and sharp waves over the left frontotemporal area. After the administration of antiepileptic drugs, her language activity returned to near the baseline level and the epileptic discharges were significantly reduced. Nonconvulsive partial status epilepticus should be considered in the differential diagnosis of recurrent aphasia, even if the symptoms occur periodically.


Substrate recognition by norovirus polymerase: microsecond molecular dynamics study.
Molecular dynamics simulations of complexes between Norwalk virus RNA dependent RNA polymerase and its natural CTP and 2dCTP (both containing the O5'-C5'-C4'-O4' sequence of atoms bridging the triphosphate and sugar moiety) or modified coCTP (C5'-O5'-C4'-O4'), cocCTP (C5'-O5'-C4'-C4'') substrates were produced by means of CUDA programmable graphical processing units and the ACEMD software package. It enabled us to gain microsecond MD trajectories clearly showing that similar nucleoside triphosphates can bind surprisingly differently into the active site of the Norwalk virus RNA dependent RNA polymerase. It corresponds to their different modes of action (CTP-substrate, 2dCTP-poor substrate, coCTP-chain terminator, cocCTP-inhibitor). Moreover, extremely rare events-as repetitive pervasion of Arg182 into a potentially reaction promoting arrangement-were captured.


Modulation of p,p'-DDT-induced tremor by catecholaminergic agents.
p,p'-DDT (1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane; 75 mg/kg) or corn oil was administered po to male Fischer 344N rats. Tremor was quantified 8 hr later by spectral analysis of whole body movements. The effect of sc injection of pharmacological challenges on the spectral profile of body movements was determined. The alpha antagonist phenoxybenzamine decreased the intensity of movements over most of the power spectra in animals exposed to DDT, but decreased spectral power only at lower frequencies in control subjects. The alpha-1 antagonist prazosin had similar effects in animals given DDT. The alpha-2 antagonist yohimbine and the beta antagonist propranolol produced lethality and increased the intensity of movements in animals administered DDT, without significantly affecting control animals. The alpha-2 agonist clonidine decreased the spectral profile over a wide range of frequencies in animals exposed to DDT, while depressing the spectral power of control animals only at higher frequencies. The dopamine antagonist haloperidol increased the intensity of movements in DDT-treated animals, without altering the spectral profile of controls. The dopamine agonist apomorphine induced stereotypy in control animals, but failed to significantly alter the power spectra in subjects given DDT. These data suggest a facilitatory and inhibitory role, respectively, for alpha-1 and alpha-2 receptors in the modulation of DDT-induced tremor. Dopamine and beta receptors may be involved in the tonic inhibition of tremor produced by DDT.


De novo genetic codes and pure translation display.
It is appealing to envision engineering translation for the genetically encoded synthesis of new classes of molecules. The complete reassignment of codons to unnatural amino acids at one or two non-adjacent sites per protein has already found wide utility (see other papers in this volume). This has been achieved by suppression at stop codons or rarely used sense codons in crude systems and in vivo. However, competing aminoacyl-tRNAs, aminoacyl-tRNA synthetases, and release factors limit efficiencies and generalization. We maximize flexibility by omitting the competing components and by reconstituting translation from His-tagged initiation and elongation factors. This approach opens up all 64 codons to amino acid reassignment and has allowed incorporation of several adjacent unnatural amino acids for the study of translation mechanism. One potential application is "peptidomimetic evolution" for ligand discovery. Toward this goal, we have demonstrated the display of polypeptides on their mRNAs in a purified translation system, termed "pure translation display."


The influence of psychological factors on low back pain-related disability in community dwelling older persons.
To assess the influence of fear avoidance beliefs (FAB) and catastrophizing on low back pain (LBP)-related disability in Spanish community dwelling retirees. Correlation between variables measured with previously validated instruments. Majorca, Spain. 1,044 community dwelling subjects attending conferences for retired persons. Visual analog scales for LBP and pain referred to the leg (LP), Roland Morris Questionnaire (RMQ) for disability, FAB-Phys questionnaire (FABQ) for FAB, and the Coping Strategies Questionnaire (CSQ) for catastrophizing. In subjects without clinically relevant LBP, FAB correlated moderately with catastrophizing (r = 0.535) and disability (r = 0.390), and weakly with LP (r = 0.119) and LBP (r = 0.197). In subjects with LBP, FAB correlated moderately with catastrophizing (r = 0.418) and disability (r = 0.408), and weakly with LP (0.152), but not with LBP. Correlations among CSQ, FABQ, and RMQ were similar in subjects with and without current LBP. In regression models, the coefficient for effect of FAB on disability was 0.14 for participants with no LBP, and 0.28 for those with pain. Corresponding values for catastrophizing were 0.17 and 0.19. In Spanish community dwelling retirees, the influence of FAB and catastrophizing on LBP-related disability is clinically small.


[Immunoenzyme demonstration of isoantigens A, B and H in kidney tissue changed by putrefaction].
In contrast to blood serology, which usually fails in specimens more than a few days old, immunohistochemistry (PAP technique) provided reliable information on the blood group (ABO) and, in most cases, also the secretor character of 23 kidney specimens stored for months at room temperature. Better results were obtained with monoclonal antibodies than with human sera. In the late stages of decomposition, blood group diagnosis is based on the more decomposition-resistant antigens of the collecting tubular epithelium (in secretors) and the endothelia of the arteriolae medullares rectae and not on the identification of erythrocytic antigens. In addition, a decomposition-resistant epithelial antigen in the distal convoluted tubules (Tc II) is unmasked by autolysis or heterolysis. "Blood group" antigens were frequently detected in bacteria and fungi. These antigens, however, were clearly distinguishable from blood group characters of the tissue. A transient, weak, false-positive reaction with monoclonal anti-B appeared in decomposed Tc II epithelia.


Validation of a Spanish version of the Leicester Cough Questionnaire in cystic fibrosis.
Cough is a main symptom in cystic fibrosis (CF). We aim to validate a Spanish version of the Leicester Cough Questionnaire (LCQ-Sp) to measure the impact of cough in CF bronchiectasis. A prospective longitudinal multicentre study was performed. Internal consistency and score changes over a 15-day period in stable state were assessed to analyse reliability. Concurrent validity was analysed by correlation with Saint George's Respiratory Questionnaire (SGRQ) and convergent validity by assessing the association with clinical variables. Changes in scores between stable state and the first exacerbation were assessed to analyse responsiveness. 132 patients (29.73 ± 10.52 years) were enrolled in four hospitals. Internal consistency was high for the total score and good for the three domains (Cronbach's α 0.81-0.93). The test-retest reliability showed an intraclass correlation coefficient of 0.86 for the total score. The correlation between LCQ-Sp and SGRQ scores was -0.74. The LCQ-Sp score negatively correlated with sputum volume, and the mean score decreased at the beginning of exacerbations (16.04±3.81 vs 13.91±4.29) with a large effect size. The LCQ-Sp is a reliable, repeatable and responsive instrument to assess the impact of cough in CF bronchiectasis and is responsive to change in the event of exacerbations.


Research on the emissions from industrial products exported from Guangdong Province-an input-output model analysis.
This study uses an input-output model to analyze the wastewater, waste gas, and solid waste emissions in Guangdong's industrial exports from 2004 to 2015; the Logarithmic Mean Divisia Index (LMDI) is used to analyze the factors influencing such pollution. The results reveal that embodied emissions of waste gas and solid waste in Guangdong's export trade are increasing, while the increase in wastewater emissions is not apparent. The Logarithmic Mean Divisia Index (LMDI) is used to analyze the influencing factors of pollution, specifically, the structural, scale, and technical effects. We discovered that emissions of the top five industries account for about 80% of total emissions and the wastewater emissions' technical effect has more impact; however, it is difficult for this technical effect in terms of embodied waste gas and solid waste to offset the scale and structural effects' impacts. Moreover, the trends and factors influencing various industries' pollution emissions differ. This study proposes that when the government carries out environmental pollution control measures, they should consider the embodied pollution caused by products from foreign trade and focus on treating industries with severe pollution. Simultaneously, the pollution controlling measures of different industries should also vary.


Simultaneous fabrication of carbon nanodots and hydroxyapatite nanoparticles from fish scale for biomedical applications.
Fish industries and markets produce large quantities of fish scales, skins, shells, and bone wastes post processing that contaminate the environment and cause health risks in humans. In this context, we have developed a novel and simple integrated process to valorize the Lethrinus lentjan fish scales by fabricate carbon nanodots (CDs) and hydroxyapatite nanoparticles (HA NPs) simultaneously. The fish scale treatment was carried out by hydrothermal method at 280 °C that produced CDs and HA NPs simultaneously. Under hydrothermal treatment, organic and inorganic substances of fish scale is transformed to CDs and HA NPs respectively. As TEM images confirmed that fish scale derived CDs were spherically shaped and ~3 to 15 nm in size. The CDs exhibited excitation-dependent emission in photoluminescence. The HA NPs were ~8 to 12 nm in diameter and ~50 to 100 nm in length with rod shape. Also, HA NPs possess spherical shape nanostructures with 15-50 nm in diameter. Furthermore, we assessed the cytotoxic behavior of synthesized nanostructures using the MTT assay and acridine orange/ethidium bromide (AO/EB) staining. These results showed that synthesized CDs and HA NPs did not cause significant changes in cell viability and morphology, indicating biocompatibility. Additionally, the synthesized CDs and HA NPs were exploited as fluorescent probes for cellular imaging and osteogenic differentiation of stem cells respectively. Overall, the study results indicate that low-cost fish waste was valorized by producing CDs and HA NPs concurrently. The synthesized nanostructures can be applicable for bio-imaging and bone tissue engineering applications.


Major determinants and possible mechanism of dobutamine-induced left ventricular outflow tract obstruction in patients with a sigmoid ventricular septum.
A sigmoid ventricular septum (SVS) may be related to normal aging, but some people with an SVS develop a left ventricular outflow tract (LVOT) obstruction (defined as a gradient of >30 mmHg). Therefore, we investigated the association of LVOT obstructions with an SVS by dobutamine stress echocardiography (DSE) and assessed the possible mechanism of the latent LVOT obstruction. DSE was performed in 64 subjects with SVS (mean age: 73.3±7.7 years; 36 women) without an LVOT obstruction. In 40 of the 64 subjects, an LVOT obstruction occurred during the DSE (defined as latent obstruction). At rest, the subjects with a latent obstruction had a shorter end-systolic mitral leaflet tethering distance ("α" distance, i.e. the distance between the tip of the posterior papillary muscle and the contralateral anterior mitral annulus) than those without one (29.9±4.2 mm versus 35.2±4.6 mm), as well as a smaller end-systolic LVOT diameter (13.4±2.7 mm versus 16.1±3.4 mm) and larger ejection fraction (72.0±5.0% versus 67.8±5.9%) (all p<0.05). They also had a higher LV outflow velocity at rest (1.23±0.24 m/s versus 1.03±0.24 m/s) and during the Valsalva maneuver (1.31±0.27 m/s versus 1.03±0.27 m/s) (both p<0.05). After adjusting for these parameters, the resting end-systolic "α" distance and LV outflow velocity at rest remained independent predictors of a latent obstruction. A short leaflet tethering distance ("α") was the major determinant of a latent obstruction, suggesting that a mitral leaflet displacement/redundancy caused by a short "α" distance contributes to the LVOT obstruction.


Effects of a pedometer-based walking intervention on young adults' sleep quality, stress and life satisfaction: Randomized controlled trial.
The purpose of this study was to evaluate the effect of daily walking exercise on sleep quality, perceived stress and life satisfaction. It aimed to investigate the interaction between daily walking exercise and sleep components (sleep quality, sleep latency, sleep duration, sleep disturbance, sleep medication use, and daytime functioning). A four-week randomized control trial (RCT) was conducted by assigning 54 research volunteers into two groups randomly. The participants in the intervention group (IG) were asked to carry out a daily aerobic walking exercise (DAWE), and participants in the control group (CG) were requested to maintain a sedentary life style. Sleep quality, perceived stress and life satisfaction were assessed at the baseline and at the end of the intervention. All participants were equipped with Omron HJ-112 pedometer to record their daily exercise and to fulfil a daily diary sheet. By the end of the intervention, 26 out of 54 participants (Mage = 24.96; SD = 5.13) completed the task. There was no statistical significance between the two groups when comparing global sleep quality, stress and life satisfaction. The within group comparison showed positive effect of DAWE on subjective sleep quality (p = 0.05), less sleep medication use (p < 0.05), positive effect on daytime function (p < 0.01) and improved life satisfaction (p = 0.05) after four weeks of intervention. Findings suggested that incorporating daily aerobic walking exercise might be beneficial to sleep health. Further studies are suggested to ascertain the pedometer-based daily walking exercise's long-term effects and to unfold the biological mechanisms leading to its sleep quality improvement effect.


Role of non-coding RNAs in modulating the response of cancer cells to paclitaxel treatment.
Paclitaxel is a chemotherapeutic substance that is administered for treatment of an extensive spectrum of human malignancies. In spite of its potent short-term effects against tumor cells, resistance to paclitaxel occurs in a number of patients precluding its long-term application in these patients. Non-coding RNAs have been shown to influence response of cancer cells to this chemotherapeutic agent via different mechanisms. Mechanistically, these transcripts regulate expression of several genes particularly those being involved in the apoptotic processes. Lots of in vivo and in vitro assays have demonstrated the efficacy of oligonucleotide-mediated microRNAs (miRNA)/ long non-coding RNAs (lncRNA) silencing in enhancement of response of cancer cells to paclitaxel. Therefore, targeted therapies against non-coding RNAs have been suggested as applicable modalities for combatting resistance to this agent. In the present review, we provide a summary of studies which assessed the role of miRNAs and lncRNAs in conferring resistance to paclitaxel.


Detection and characterization of Streptococcus downei, a rare bacterial species of mutans streptococci from caries-active patients.
The oral bacteria, mutans streptococci (MS), are an etiological agent of dental caries. Of MS, Streptococcus downei are rarely isolated bacteria. The aim of this study was to isolate and characterize S. downei from caries-active subjects. In all, 65 dental plaque samples were collected from dental caries-active subjects. All the isolates were further identified and characterized using 16S rDNA sequencing, biochemical tests, antibiogram, and minimum inhibitory concentration (MIC). Five isolates have been identified as S. downei using 16S rDNA sequencing. Phylogenetic analysis showed that S. downei was closely related to S. sobrinus. The biotype traits of these five isolates were IV (n = 3), V (n = 1), and variants (n = 2). The study proposed one new biotype, classified as biotype VIII for the variant strain. The antibiogram tests revealed that all the strains of S. downei were susceptible to all the antibiotics used in the study with higher sensitivity to penicillin and ampicillin. The MIC of ampicillin and erythromycin against S. downei was 0.047 and 0.39 μg/mL, respectively. The study reports the prevalence of S. downei in caries-active subjects and recommends further investigations to determine its role in the disease.


Limited wedge resection for T1 colon cancer (LIMERIC-II trial) - rationale and study protocol of a prospective multicenter clinical trial.
The sole presence of deep submucosal invasion is shown to be associated with a limited risk of lymph node metastasis. This justifies a local excision of suspected deep submucosal invasive colon carcinomas (T1 CCs) as a first step treatment strategy. Recently Colonoscopy-Assisted Laparoscopic Wedge Resection (CAL-WR) has been shown to be able to resect pT1 CRCs with a high R0 resection rate, but the long term outcomes are lacking. The aim of this study is to evaluate the safety, effectiveness and long-term oncological outcomes of CAL-WR as primary treatment for patients with suspected superficial and also deeply-invasive T1 CCs. In this prospective multicenter clinical trial, patients with a macroscopic and/or histologically suspected T1 CCs will receive CAL-WR as primary treatment in order to prevent unnecessary major surgery for low-risk T1 CCs. To make a CAL-WR technically feasible, the tumor may not include > 50% of the circumference and has to be localized at least 25 cm proximal from the anus. Also, there should be sufficient distance to the ileocecal valve to place a linear stapler. Before inclusion, all eligible patients will be assessed by an expert panel to confirm suspicion of T1 CC, estimate invasion depth and subsequent advise which local resection techniques are possible for removal of the lesion. The primary outcome of this study is the proportion of patients with pT1 CC that is curatively treated with CAL-WR only and in whom thus organ-preservation could be achieved. Secondary outcomes are 1) CAL-WR's technical success and R0 resection rate for T1 CC, 2) procedure-related morbidity and mortality, 3) 5-year overall and disease free survival, 4) 3-year metastasis free survival, 5) procedure-related costs and 6) impact on quality of life. A sample size of 143 patients was calculated. CAL-WR is a full-thickness local resection technique that could also be effective in removing pT1 colon cancer. With the lack of current endoscopic local resection techniques for > 15 mm pT1 CCs with deep submucosal invasion, CAL-WR could fill the gap between endoscopy and major oncologic surgery. The present study is the first to provide insight in the long-term oncological outcomes of CAL-WR. CCMO register (ToetsingOnline), NL81497.075.22, protocol version 2.3 (October 2022).


Data on isolating mesenchymal stromal cells from human adipose tissue using a collagenase-free method.
The present dataset describes a detailed protocol to isolate mesenchymal cells from human fat without the use of collagenase. Human fat specimen, surgically cleaned from non-fat tissues (e.g., blood vessels) and reduced into smaller fat pieces of around 1-3 mm size, is incubated in complete culture media for five to seven days. Then, cells started to spread out from the fat explants and to grow in cultures according to an exponential pattern. Our data showed that primary mesenchymal cells presenting heterogeneous morphology start to acquire more homogenous fibroblastic-like shape when cultured for longer duration or when subcultured into new flasks. Cell isolation efficiency as well as cell doubling time were also calculated throughout the culturing experimentations and illustrated in a separate figure thereafter. This paper contains data previously considered as an alternative protocol to isolate adipose-derived mesenchymal stem cell published in "Proliferation and differentiation of human adipose-derived mesenchymal stem cells (ASCs) into osteoblastic lineage are passage dependent" [1].


The roles of exosomal miRNAs and lncRNAs in lung diseases.
An increasing number of studies have reported that exosomes released from various cells can serve as mediators of information exchange between different cells. With further exploration of exosome content, a more accurate molecular mechanism involved in the process of cell-to-cell communication has been revealed; specifically, microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) are shuttled by exosomes. In addition, exosomal miRNAs and lncRNAs may play vital roles in the pathogenesis of several respiratory diseases, such as chronic obstructive pulmonary disease (COPD), lung cancer, and asthma. Consequently, exosomal miRNAs and lncRNAs show promise as diagnostic biomarkers and therapeutic targets in several lung diseases. This review will summarize recent knowledge about the roles of exosomal miRNAs and lncRNAs in lung diseases, which has shed light on the discovery of novel diagnostic methods and treatments for these disorders. Because there is almost no published literature about exosomal lncRNAs in COPD, asthma, interstitial lung disease, or tuberculosis, we summarize the roles of exosomal lncRNAs only in lung cancer in the second section. This may inspire some new ideas for researchers who are interested in whether lncRNAs shuttled by exosomes may play roles in other lung diseases.


Effect of disulfide bonding and multimerization on proteoglycan 4's cartilage boundary lubricating ability and adsorption.
The objectives of this study were to assess the cartilage boundary lubricating ability of (1) nonreduced (NR) disulfide-bonded proteoglycan 4 (PRG4) multimers versus PRG4 monomers and (2) NR versus reduced and alkylated (R/A) PRG4 monomers and to assess (3) the ability of NR PRG4 multimers versus monomers to adsorb to an articular cartilage surface. PRG4 was separated into two preparations, PRG4 multimer enriched (PRG4Multi+) and PRG4 multimer deficient (PRG4Multi-), using size exclusion chromatography (SEC) and characterized by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). The cartilage boundary lubricating ability of PRG4Multi+ and PRG4Multi- was compared at a physiological concentration (450 μg/mL) and assessed over a range of concentrations (45, 150, and 450 μg/mL). R/A and NR PRG4Multi- were evaluated at 450 μg/mL. Immunohistochemistry with anti-PRG4 antibody 4D6 was performed to visualize the adsorption of PRG4 preparations to the surface of articular cartilage explants. Separation into enriched populations of PRG4Multi+ and PRG4Multi- was achieved using SEC and was confirmed by SDS-PAGE. PRG4Multi+ and PRG4Multi- both functioned as effective friction-reducing cartilage boundary lubricants at 450 μg/mL, with PRG4Multi+ being more effective than PRG4Multi-. PRG4Multi+ lubricated in a dose-dependent manner, however, PRG4Multi- did not. R/A PRG4Multi- lubricated similar to NR PRG4Multi-. PRG4-containing solutions showed 4D6 immunoreactivity at the articular surface; the immunoreactive intensity of PRG4Multi+ appeared to be similar to SF, whereas PRG4Multi- appeared to have less intensity. These results demonstrate that the intermolecular disulfide-bonded multimeric structure of PRG4 is important for its ability to adsorb to a cartilage surface and function as a boundary lubricant. These findings contribute to a greater understanding of the molecular basis of cartilage boundary lubrication of PRG4. Elucidating the PRG4 structure-lubrication function relationship will further contribute to the understanding of PRG4's role in diarthrodial joint homeostasis and disease.


Exosomes contain ubiquitinated proteins.
Multivesicular bodies (MVB) are endosomal compartments that contain multiple vesicles, which derive from a delimiting membrane by inward budding. Incorporation of membrane proteins into the luminal vesicles requires, at least for some model proteins, monoubiquitination of their cytoplasmic domain. The ubiquitin tags are recognized by a sorting machinery, of which some components are also monoubiquitinated. The ubiquitin tags and the sorting machinery are both removed before the vesicles bud into the MVB lumen. MVB vesicles are therefore not expected to contain monoubiquitinated proteins. The MVB content is degraded upon fusion of MVB with lysosomes. In many cell types, however, MVB can also fuse with the plasma membrane, resulting in secretion of their luminal vesicles into the extracellular milieu. Such secreted vesicles are termed exosomes, and their protein composition should, due to their origin, be identical to that of MVB luminal vesicles. We here demonstrate that exosomes contain polyubiquitinated proteins, many of which are not integrated into the membrane and relatively enriched as compared to total cell lysates. These results suggest that a subset of polyubiquitinated cytoplasmic proteins is incorporated into the MVB pathway. The potential cell biological relevance of this observation is discussed. Furthermore, these data indicate that ubiquitinated proteins can serve as markers for exosomes.


Management of recurrent cervical cancer.
Treatment for cervical cancer is very successful, especially in early stages. However, most patients presenting in late stages of disease will experience recurrence. The prognosis of recurrent disease is very poor and treatment options are limited. The diagnosis of recurrence may be apparent or difficult, but determining the extent of disease is always complex. Routine follow-up of asymptomatic patients has other objectives and is not a reliable way to detect recurrences. Symptomatic patients require extensive investigation to detect the extent of the disease. For patients with central pelvic recurrences, exenteration offers the prospect of survival in more than one-third of cases. Newer developments include laterally extended endopelvic resection that may become an option for patients with more extensive pelvic recurrence. For patients with recurrences of cervical cancer, the roles of second-time radiotherapy or postradiation chemotherapy are very limited. Palliative treatment is important for all patients with untreatable disease. Pain relief forms a central part of palliative care. Caregivers also experience emotional feelings and probably function best in a system offering strong colleageal support.


Mycobacterium abscessus Complex Infections in Children: A Review.
Infections in children with Mycobacterium abscessus complex represent a particular challenge for clinicians. Increasing incidence of these infections worldwide has necessitated focused attention to improve both diagnostic as well as treatment modalities. Published medical literature was reviewed, with emphasis on material published in the past 5 years. Increasing availability of new diagnostic tools, such as matrix-assisted laser desorption ionization-time of flight mass spectrometry and custom PCRs, has provided unique insights into the subspecies within the complex and improved diagnostic certainty. Microbiological review of all recent isolates at the University of Minnesota Medical Center was also conducted, with description of the antimicrobial sensitivity patterns encountered in our center, and compared with those published from other centers in the recent literature. A discussion of conventional antimicrobial treatment regimens, alongside detailed description of the relevant antimicrobials, is derived from recent publications. Antimicrobial therapy, combined with surgical intervention in some cases, remains the mainstay of pediatric care. Ongoing questions remain regarding the transmission mechanics, immunologic vulnerabilities exploited by these organisms in the host, and the optimal antimicrobial regimens necessary to enable a reliable cure. Updated treatment guidelines based on focused clinical studies in children and accounting especially for the immunocompromised children at greatest risk are very much needed.


Drug allergy in older adults: A study from the United States Drug Allergy Registry.
Older adults have an increased risk of adverse drug reactions and negative effects associated with alternative antibiotic use. Although the number of antibiotic allergies reported increases with age, the characteristics and outcomes of older adults receiving drug allergy assessment are unknown. To assess the characteristics and outcomes of drug allergy evaluations in older adults. We considered patients aged above or equal to 65 years enrolled in the United States Drug Allergy Registry (USDAR), a US multisite prospective cohort (January 16, 2019 to February 28, 2022). Data were summarized using descriptive statistics. Of 1678 USDAR participants from 5 sites, 406 older adults aged above or equal to 65 years (37% 65-69 years, 37% 70-74 years, 16% 75-79 years, and 10% ≥80 years) received 501 drug allergy assessments. USDAR older adults were primarily of female sex (69%), White (94%), and non-Hispanic (98%). Most USDAR older adults reported less than or equal to 1 infections per year (64%) and rated their general health as good, very good, or excellent (80%). Of 296 (59%) penicillin allergy assessments in USDAR older adults, 286 (97%) were disproved. Other drug allergy assessments included sulfonamide (n = 41, 88% disproved) and cephalosporin (n = 20, 95% disproved) antibiotics. All 41 drug allergy labels in USDAR participants aged above or equal to 80 years and all 80 penicillin allergy labels in USDAR men aged above or equal to 65 years were disproved. Older adults represented a quarter of USDAR participants but were neither racially nor ethnically diverse and were generally healthy without considerable antibiotic need. Most older adults presented for antibiotic allergy assessments, the vast majority of which were disproved. Drug allergy assessments may be underutilized in the older adults who are most vulnerable to the harms of unconfirmed antibiotic allergy labels.


Endoscopic clips for closing esophageal perforations: case report and pooled analysis.
Acute and chronic esophageal perforations have traditionally been treated with surgery or a conservative approach. Recently, endoscopic repair has been reported in some case reports. To describe a case of a chronic esophagoperitoneal fistula successfully closed by endoscopic clips after several failed reoperations and stent placement. To perform a pooled analysis of the reports describing such closures. Case report and pooled analysis. Tertiary-care hospitals. Our patient presented with mature perforation in the distal esophagus caused by laparoscopic band gastroplasty. Patients for pooled analysis identified by a MEDLINE search (1966 to January 2007) performed for all the English language articles that reported esophageal perforation/fistulae and endoscopic clips. Endoscopic clip application after ablation of epithelialized edges in our patient. Pooled analyses for demographic and perforation variables, along with predictors for closure time after clipping, were performed. Closure of esophageal perforations. The fistula in our patient closed in 3 weeks after endoscopic clipping. The literature review identified a total of 11 articles that describe 17 patients (acute 7, intermediate 4, and chronic 6). The most common cause was iatrogenic (65%), and the size of the perforation ranged from 3 to 25 mm. The median healing time after clipping was 18 days (interquartile range 6-26). Both univariable and multivariable analyses identified only the duration of perforation as a significant predictor of closure time, P values .003 and .02, respectively. Small sample size, nonrandomized sample. Endoclips may be effective for closing both acute and chronic esophageal perforations. The duration of the perforation is a significant factor for predicting closure time.


A high-fidelity residential building occupancy detection dataset.
This paper describes development of a data acquisition system used to capture a range of occupancy related modalities from single-family residences, along with the dataset that was generated. The publicly available dataset includes: grayscale images at 32-by-32 pixels, captured every second; audio files, which have undergone processing to remove personally identifiable information; indoor environmental readings, captured every ten seconds; and ground truth binary occupancy status. The data acquisition system, coined the mobile human presence detection (HPDmobile) system, was deployed in six homes for a minimum duration of one month each, and captured all modalities from at least four different locations concurrently inside each home. The environmental modalities are available as captured, but to preserve the privacy and identity of the occupants, images were downsized and audio files went through a series of processing steps, as described in this paper. This dataset adds to a very small body of existing data, with applications to energy efficiency and indoor environmental quality.


The developmental change in the G gamma and A gamma globin. Proportions in hemoglobin F.
The proportions of G gamma and A gamma globins in hemoglobin F were determined in fetuses around the 20th week of gestation, newborns, and children 3 weeks to 5 months of age. In the last group, the G gamma/G gamma + A gamma ratio decreased continously; there was a good correlation between the decline of G gamma with respect to total gamma and the decline of Hb F (r = 0.88). In contrast, there was virtually no difference in the gamma globin composition of Hb F between the fetuses and the newborns, i.e. in late pregnancy, the decrease in the synthesis of both gamma globins appears to be proportionate. The G gamma and A gamma globin genes may be inactivated in a sigmoidal fashion with time, thus producing a G gamma/G gamma + A gamma ratio which at first changes only slightly and then declines linearily.


Differential effects of wortmannin on the release of substance P and amino acids from the isolated spinal cord of the neonatal rat.
1. Effects of wortmannin, an inhibitor of myosin light chain kinase, on the release of substance P and amino acids, GABA and glutamate, were investigated in the isolated spinal cord preparation of the neonatal rat. 2. Wortmannin at 0.5 - 10 microM depressed the release of substance P evoked by high-K+ (90 mM) medium from the spinal cord (IC50 = 1.1 microM). Wortmannin also depressed the high-K+ (70 mM)-evoked release of substance P from cultured dorsal root ganglion neurons of neonatal rats. In contrast, the high-K+ (90 mM)-evoked release of GABA and glutamate from the spinal cord was not affected by wortmannin (0.1 - 10 microM). 3. Upon stimulation of a dorsal root, a monosynaptic reflex and a subsequent slow ventral root depolarization were evoked in the ipsilateral ventral root of the same segment in the isolated spinal cord preparation. The magnitude of the slow ventral root depolarization was depressed gradually to about 70% of the control during the course of 30 min under wortmannin (1 microM). In contrast, the monosynaptic reflex was unaffected by wortmannin. 4. Immunofluorescent staining revealed that immunoreactivities of substance P and myosin II were colocalized at presynaptic terminals in the dorsal horn of the neonatal rat spinal cord. 5. The present results suggest that myosin phosphorylation by myosin light chain kinase may play a crucial role in the release of substance P, but not in the release of GABA and glutamate in the neonatal rat spinal cord. This may reflect a difference in the exocytic mechanisms of substance P-containing large dense core vesicles and amino acid-containing small clear vesicles.


Restoration of periodontally compromised dentitions using cross-arch bridges. Principles of perio-prosthetic patient management.
Severe periodontal disease often leads to tooth loss, necessitating prosthetic rehabilitation to restore function and aesthetics. The concept of perio-prosthetic treatment using extensive bridges of cross-arch design was introduced approximately 30 years ago. Long term follow-up studies have shown that teeth with reduced periodontal support can be used as abutments for extensive fixed prostheses, provided periodontal disease has been treated successfully, and an effective recall programme has been instituted to prevent periodontal disease recurrence. Low complication rates have been reported with these extensive constructions.


The tensile properties of alginate hydrogels.
Alginate hydrogels are currently being employed and explored for a broad range of medical applications including cell encapsulation, drug delivery, and tissue engineering. In these capacities, knowledge of the mechanical and material properties of the hydrogels and the properties that govern and influence them is necessary to adequately design and effectively use these systems. Although much is known about the mechanical properties of alginate in compression and shear, little is known about the tensile characteristics. Thus, an extensive tensile assessment of alginate hydrogels was completed as a function of alginate type, formulation, gelling conditions, incubation, and strain rate. In general, the initial tensile behavior and properties of alginate hydrogels were highly dependent on the choice of the alginate polymer and how it was processed. Specifically, high guluronic acid containing alginate polymers yielded stronger, more ductile hydrogels than high mannuronic acid containing alginates. The ultimate stress, ultimate strain, and tensile modulus were decreased by increased phosphate concentrations, solution reconstitution with phosphate buffered saline instead of culture media, and peptide modification. Incubation of hydrogels for at least 7 days diminished many of the initial tensile property differences associated with formulation and gelling conditions. Overall, by controlling the specific alginate polymer and processing methods, a wide range of tensile properties are available from these hydrogels.


4-Methylthioamphetamine-induced hyperthermia in mice: influence of serotonergic and catecholaminergic pathways.
4-Methylthioamphetamine (4-MTA), also known as p-methylthioamphetamine, is a new amphetamine derivative which in humans has been increasingly associated with severe intoxications and several deaths. As hyperthermia is considered to be one of the most life-threatening acute physiological consequences of amphetamine-related intoxications, it was our aim to determine whether 4-MTA induces changes in body temperature in a mouse model. Accordingly, we measured the subcutaneous temperature after acute administration of 4-MTA in CD1 mice. Because hyperthermia seems to result from the central and peripheral actions of catecholamines and serotonin (5-hydroxytriptamine or 5-HT), we also investigated the possible interactions of some catecholaminergic and serotonergic receptor blockers and the inhibition of monoamine oxidase (MAO) with this effect. 4-MTA induced hyperthermia in CD1 mice. Blockade of the 5-HT receptors with methysergide and MAO inhibition with pargyline resulted in the potentiation of the 4-MTA-induced hyperthermic effect. Blockade of the alpha(1)-adrenergic receptors with prazosin completely reverted the 4-MTA-induced hyperthermia while with the beta-adrenergic receptor blocker dl-propranolol this reversal was not complete. Blockade of the alpha(2)-adrenergic receptors with yohimbine had no effect on the hyperthermia induced by 4-MTA. These results suggest that 4-MTA-induced hyperthermia is highly influenced by the catecholaminergic and serotonergic receptor activation and the MAO activity.


CD4 T cell knockout does not protect against kidney injury and worsens cancer.
Most previous studies of cisplatin-induced acute kidney injury (AKI) have been in models of acute, high-dose cisplatin administration that leads to mortality in non-tumor-bearing mice. The aim of the study was to determine whether CD4 T cell knockout protects against AKI and cancer in a clinically relevant model of low-dose cisplatin-induced AKI in mice with cancer. Kidney function, serum neutrophil gelatinase-associated lipocalin (NGAL), acute tubular necrosis (ATN), and tubular apoptosis score were the same in wild-type and CD4 -/- mice with AKI. The lack of protection against AKI in CD4 -/- mice was associated with an increase in extracellular signal-regulated kinase (ERK), p38, CXCL1, and TNF-α, mediators of AKI and fibrosis, in both cisplatin-treated CD4 -/- mice and wild-type mice. The lack of protection was independent of the presence of cancer or not. Tumor size was double, and cisplatin had an impaired therapeutic effect on the tumors in CD4 -/- vs. wild-type mice. Mice depleted of CD4 T cells using the GK1.5 antibody were not protected against AKI and had larger tumors and lesser response to cisplatin. In summary, in a clinically relevant model of cisplatin-induced AKI in mice with cancer, (1) CD4 -/- mice were not protected against AKI; (2) ERK, p38, CXCL1, and TNF-α, known mediators of AKI, and interstitial fibrosis were increased in CD4 -/- kidneys; and (3) CD4 -/- mice had faster tumor growth and an impaired therapeutic effect of cisplatin on the tumors. The data warns against the use of CD4 T cell inhibition to attenuate cisplatin-induced AKI in patients with cancer. A clinically relevant low-dose cisplatin model of AKI in mice with cancer was used. CD4 -/- mice were not functionally or histologically protected against AKI. CD4 -/- mice had faster tumor growth. CD4 -/- mice had an impaired therapeutic effect of cisplatin on the tumors. Mice depleted of CD4 T cells were not protected against AKI and had larger tumors.


Need for systematic screening for IGD in adolescent psychiatric inpatients.
Psychiatric comorbidities are frequent in adolescents with internet gaming disorder (IGD). In contrast, the proportion of IGD among adolescents hospitalized for a psychiatric disorder has not been documented yet. In addition, parental ratings of IGD could be useful for diagnosis, but very few data exist on this issue. The objectives of this study were to: (1) assess the prevalence of IGD among adolescent psychiatric inpatients, using the Ten-Item Internet Gaming Disorder Test (IGDT-10), and (2) assess the parental version developed for this study (IGDT-10-P). A total of 102 patients, aged from 12 to 17 years old, were included from four psychiatric units of the French region Auvergne-Rhône-Alpes, during a 6-month inclusion period. Adolescents completed the IGDT-10 while one of their parents completed the IGDT-10-P. The inclusion rate among the eligible population was 57.95%. The prevalence of IGD in the sample, based on the IGDT-10 and IGDT-10-P, was 6.00% and 12.79%, respectively. Psychometric features of the IGDT-10-P indicated excellent internal consistency, a good model fit to the one factor model in confirmatory factor analysis, a strong correlation with gaming time, and a moderate correlation with the IGDT-10. Our results support the need for a systematic screening of IGD among adolescents hospitalized for a psychiatric disorder. Future studies should aim to confirm and explain the prevalence gap between self- and parent-reported criteria.


Experience with adrenal cortical carcinoma.
Eight cases of histologically proved cortical carcinoma are reviewed and compared with several series from the literature. Emphasis is given to defining endocrinologic function in these tumors and to the role of nonoperative treatments. Whereas surgical therapy offered significant demonstrated in any of the patients.


Tobacco Smoking in Islands of the Pacific Region, 2001-2013.
We provide an overview of tobacco smoking patterns in Pacific island countries and territories to facilitate monitoring progress toward the goal of a Tobacco-Free Pacific by 2025. We examined data from 4 surveys conducted in the region between 2001 and 2013, including the STEPwise approach to surveillance for adults (25-64 years); the Global School-Based Student Health Survey and the Global Youth Tobacco Survey (students 13-15 years); and the Youth Risk Behavior Surveillance System (grade 9-12 students) in United States affiliated Pacific Islands (USAPIs). Adult smoking prevalence ranged from less than 5% of women in Vanuatu to almost 75% of men in Kiribati. Smoking prevalence among students (13-15 years) ranged between 5.6% and 52.1%. There were declines in smoking among youths in many USAPIs. To achieve the tobacco-free goal and reduce disease burden, accelerated action is needed to align national legislation with international agreements and build capacity for tobacco control at all levels.


Orbital metastases from breast cancer: A retrospective analysis of 28 cases.
Breast cancer account about half of the cases of orbital malignancies due to metastasis. The prognosis is adverse, with average survival from 2 to 34 months. To analyze the clinical and pathological characteristics and outcomes of patients with orbital metastasis from breast cancer. A retrospective, cross-sectional study of 28 patients seen in the Oncology Hospital of the National Medical Center XXI Century, from February 2003 to February 2019. Of the 28 patients, the median age was 50.8 years. The average time from the diagnosis of breast cancer to the development of orbital metastases was 64 months. 42.8% of the patients were stage IV of onset. The lobular vs ductal ratio was 5.2:1. 92.8% of the cases had luminal profile (one case with overexpression of HER-2), while only one case was triple negative. The most frequent symptoms were: decrease in visual acuity (64.2%), pain (57.1%), amaurosis (28.5%), alterations in mobility (28.5%) and edema (21.4%). Bilateral activity was presented in 25%. A third of the patients received local treatment (radiotherapy, surgery, anti-VEGFR). Overall survival was 67.5 months (1-184 months); however, the overall survival from the diagnosis of orbital metastasis was 26.4 months (1-98 months), with an average progression-free survival of 13.7 months (1-48 months). Ophthalmologic evaluation should be performed on all patients with breast cancer and ocular symptoms. Early local treatment should be offered in order to prevent severe complications and reduce the negative impact on quality of life.


A high-throughput microfluidic method for fabricating aligned collagen fibrils to study Keratocyte behavior.
In vivo, keratocytes are surrounded by aligned type I collagen fibrils that are organized into lamellae. A growing body of literature suggests that the unique topography of the corneal stroma is an important regulator of keratocyte behavior. In this study we describe a microfluidic method to deposit aligned fibrils of type I collagen onto glass coverslips. This high-throughput method allowed for the simultaneous coating of up to eight substrates with aligned collagen fibrils. When these substrates were integrated into a PDMS microwell culture system they provided a platform for high-resolution imaging of keratocyte behavior. Through the use of wide-field fluorescence and differential interference contrast microscopy, we observed that the density of collagen fibrils deposited was dependent upon both the perfusion shear rate of collagen and the time of perfusion. In contrast, a similar degree of fibril alignment was observed over a range of shear rates. When primary normal rabbit keratocytes (NRK) were seeded on substrates with a high density of aligned collagen fibrils and cultured in the presence of platelet derived growth factor (PDGF) the keratocytes displayed an elongated cell body that was co-aligned with the underlying collagen fibrils. In contrast, when NRK were cultured on substrates with a low density of aligned collagen fibrils, the cells showed no preferential orientation. These results suggest that this simple and inexpensive method can provide a general platform to study how simultaneous exposure to topographical and soluble cues influence cell behavior.


Number of oocytes and IVF outcomes: Real-world evidence.
Randomized controlled trials (RCTs) are gold standard to study the effect of an intervention and establish causation between the treatment and outcomes. However, RCTs have the disadvantage of being expensive, entailing high resource investments and involving only selected patient populations under experimental settings. Real-world evidence (RWE) from real-world data (RWD) involves a heterogenous patient population in real-world settings. RWE is less expensive and quicker than RCTs; it can provide complimentary evidence if methodological challenges, such as residual confounding and susceptibility to bias, are considered when interpreting the findings. This review examines RWE regarding the association between the number of oocytes following ovarian stimulation and IVF outcomes into shaping current IVF practices.


Frequency and distribution of TUNEL-positive neurons in brains of dementia with Lewy bodies: comparison with those in brains of Alzheimer's disease.
The present study investigated the frequency and distribution of TUNEL-positive neurons in brains of dementia with Lewy bodies (DLB) in comparison with those in brains of Alzheimer's disease (AD), Down syndrome (DS) and non-demented elderly persons. In DLB brains, TUNEL-positive neurons were increased in frequency compared with those in non-demented elderly brains, and showed a distribution similar to those in AD and DS brains. DLB cases with TUNEL-positive neurons showing severe Lewy pathology were all neocortical type, while DLB cases of the limbic type showing mild Lewy pathology did not demonstrate TUNEL-positive neurons. In addition, we investigated the relationships between TUNEL-positive neurons and pathological hallmarks of DLB or AD brains. TUNEL-positive neurons had no Lewy bodies or neurofibrillary tangles, and were not located within amyloid deposits. These findings suggest that neuronal damage showing DNA fragmentations occurs in DLB brains as well as in AD and DS brains, and that it is accelerated by progression of Lewy pathology as well as Alzheimer pathology, although it is not directly related to their pathological hallmarks.


A prenatally ascertained, maternally inherited 14.8 Mb duplication of chromosomal bands Xq13.2-q21.31 associated with multiple congenital abnormalities in a male fetus.
Duplications of the X chromosome are rare cytogenetic findings, and have been associated with an abnormal phenotype in the male offspring of apparently normal or near normal female carriers. We report on the prenatal diagnosis of a duplication on the long arm of chromosome X from chromosomal band Xq13.2 to q21.31 in a male fetus with increased nuchal translucency in the first trimester and polyhydramnios at 22 weeks of gestation. Amniocentesis was undertaken and cytogenetic analysis revealed additional chromosomal material in the long arm of chromosome X at position Xq13. Analysis with high resolution array CGH revealed the additional material is in fact a duplication of the region Xq13.2-q21.13. The duplication is 14.8 Mb in size and includes fourteen genes: SLC16A2, KIAA2022, ABCB7, ZDHHC15, ATRX, MAGT1, ATP7A, PGK1, TBX22, BRWD3, POU3F4, ZNF711, POF1B and CHM. Analysis of the parents revealed the mother to be a carrier of the same duplication. After elected termination of the pregnancy at 28 weeks a detailed autopsy of the fetus allowed for genotype-phenotype correlations.


Observations on the development of the anterior chamber angle with reference to the pathogenesis of congenital glaucomas.
Abnormalities in neural crest cell migration may have a role in the pathogenesis of the congenital glaucomas, with or without changes in the gonioscopic appearance of the anterior chamber angle. Neural crest cells also contribute to the bones of the face, dental papilla, cartilage, bone, and meninges; this may explain the association of craniofacial, dental, and upper spinal malformations with some of the congenital glaucomas.


An essential role for nuclear factor kappaB in promoting double positive thymocyte apoptosis.
To examine the role of nuclear factor (NF)-kappaB in T cell development and activation in vivo, we produced transgenic mice that express a superinhibitory mutant form of inhibitor kappaB-alpha (IkappaB-alphaA32/36) under the control of the T cell-specific CD2 promoter and enhancer (mutant [m]IkappaB-alpha mice). Thymocyte development proceeded normally in the mIkappaB-alpha mice. However, the numbers of peripheral CD8(+) T cells were significantly reduced in these animals. The mIkappaB-alpha thymocytes displayed a marked proliferative defect and significant reductions in interleukin (IL)-2, IL-3, and granulocyte/macrophage colony-stimulating factor production after cross-linking of the T cell antigen receptor. Perhaps more unexpectedly, double positive (CD4(+)CD8(+); DP) thymocytes from the mIkappaB-alpha mice were resistant to alpha-CD3-mediated apoptosis in vivo. In contrast, they remained sensitive to apoptosis induced by gamma-irradiation. Apoptosis of wild-type DP thymocytes after in vivo administration of alpha-CD3 mAb was preceded by a significant reduction in the level of expression of the antiapoptotic gene, bcl-xL. In contrast, the DP mIkappaB-alpha thymocytes maintained high level expression of bcl-xL after alpha-CD3 treatment. Taken together, these results demonstrated important roles for NF-kappaB in both inducible cytokine expression and T cell proliferation after TCR engagement. In addition, NF-kappaB is required for the alpha-CD3-mediated apoptosis of DP thymocytes through a pathway that involves the regulation of the antiapoptotic gene, bcl-xL.